Duke University and Duke University School of Medicine






Acknowledgments Introduction


Just Say Know (A College Student’s Perspective by Leigh Heather Wilson and Jeremy Foster)

Test Your Drug Knowledge



liquor, whiskey, booze, hooch, wine, beer, ale, porter


coffee, tea, soft drinks, energy drinks, over-the-counter pain relievers and stimulants, some prescription medications


MDMA (X, XTC, Adam), MDE (Eve), MDA (Love)


lysergic acid diethylamide (LSD—acid, blotter, California sunshine, microdot, trip, yellow sunshine, etc.), mescaline (peyote, buttons, mesc, mescal, topi), psilocybin mushrooms (boomers, magic mushrooms, shrooms), dimethyltryptamine (DMT— businessman’s special), ayahuasca (caapi, yage, vegetal), belladonna alkaloids (atropine, scopolamine, belladonna, deadly nightshade, Jimsonweed, stink weed, mandrake), phencyclidine (PCP, angel dust, T, PeaCe pill), ketamine (Special K, K), dextromethorphan (Dex, robo, red devils), Salvia divinorum (ska, Maria, la Maria, ska Pastora)

Herbal Drugs

Herbal X-tacy, smart drugs, ginseng, melatonin, etc.


nitrites (butyl or amyl—bolt, bullets, climax, locker room, rush, poppers, snappers, aimes); anesthetics (nitrous oxide—Whippets; gaseous anesthesia agents used for surgery—halothane, ether); solvents, paints, sprays, and fuels (toluene, gasoline, glues, canned spray paint, etc.)


marijuana (reefer, pot, herb, ganja, grass, old man, Blanche, weed, sinsemilla, bhang, dagga, smoke), hashish (hash, tar), hash oil (oil, charas)


tobacco, nicotine chewing gum, nicotine skin patch, chewing tobacco, snuff, cigarettes, cigars, pipe tobacco


opium (Chinese molasses, dreams, gong, O, skee, toys, zero), heroin (Big H, dreck, horse, mojo, smack, white lady, brown), heroin and cocaine (speedballs), morphine, codeine, hydromorphone (Dilaudid), oxycodone (Percodan, OxyContin), meperidine (Demerol), diphenoxylate (Lomotil), hydrocodone (Vicodin), fentanyl (Sublimaze), propoxyphene (Darvon)


barbiturates (phenobarbital, pentobarbital [Nembutal], secobarbital [Seconal], amobarbital [Amytal]), chloral hydrate (Notec, Somnos, Felsules), glutethimide (Doriden), Equanil, Miltown, Noludar, Placidyl, Valmid, methaqualone (Quaaludes, ludes), benzodiazepines (such as Rohypnol, Valium, Librium, Ativan, Xanax, Halcion, and many others), drugs designed specifically to induce sleep (zolpidem [Ambien], eszopiclone [Lunesta], and ramelteon [Rozerem]), gamma-hydroxybutyrate (GHB)


steroids, roids, juice


cocaine (coke, blow, candy, crack, jack, jimmy, rock, nose candy, whitecoat), amphetamine (crank, bennies, uppers), methamphetamine (meth, crystal, crystal meth, ice), ephedrine, methylphenidate (Ritalin), methcathinone (cat, crank, goob)


Brain Basics Drug Basics Addiction
Legal Issues Illustrations Insert Index



FOR ALL OF our history, we humans have believed that it is possible to reach beyond our simple consciousness. We hunger to expand ourselves into a universe that we feel but cannot touch. Chemicals that alter the way we perceive the world have played a large role in this search. In some instances, people have believed that the chemicals themselves had spiritual powers and mystical properties.

Others use chemicals to reduce a particularly painful state. They use drugs to reduce anxiety or suppress shyness, or they are prescribed drugs to treat serious illnesses like depression and schizophrenia. Some seek the stimulation and power they do not have in their social situations and choose drugs to help them attain this. Some use chemicals as part of their daily life to stimulate or calm themselves as the situation dictates. As science has progressed, the laboratory has replaced nature as a source of chemicals, and the number of chemical choices has grown. There is every reason to believe that this trend will continue almost without bounds. So whether a person is seeking a way to expand his understanding or only trying to make normal life less painful, that person will have many, many choices of chemicals to use.

As scientists, we have devoted years to the study of the effects of drugs on the brain and behavior. We have seen the stunning advances in understanding the actions of the chemicals that have been with us for thousands of years. Yet surprisingly, little of this information is effectively translated for the public. We have become convinced that contemporary efforts to educate people about the effects of alcohol and other drugs are inadequate and misdirected. There is a lot of important information in the scientific literature about addiction and the effects of drugs, but it is not reaching the people who need to know it. The actions of drugs on the brain are complicated and vary tremendously from drug to drug and person to person, making it impossible to make blanket statements like “drugs kill” and have them believed by anyone who has any drug experience.

Imagine two trains headed at high speed in different directions, one being the scientific understanding of drug actions and addictions, the other being the public understanding of drug problems. The gap between scientific information and public information is growing hour by hour. This is the image portrayed in a speech by Dr. Alan Leshner, then director of the National Institute on Drug Abuse. In his words, “There is a unique disconnect between the scientific facts and the public’s perception about drug abuse and addiction. If we are going to make any progress, we need to overcome the ‘great disconnect.’”

We agree that it is crucial to get these trains headed in the same direction. Each of us must understand what different drugs do to our brains and our consciousness, and what the physical consequences of their use might be. The number of consciousness-altering chemicals is increasing rapidly as medical scientists and pharmaceutical companies take advantage of new discoveries in neuroscience. Every time a new brain circuit or a new neurochemical is discovered, that discovery provides an opportunity to develop drugs that alter brain function in a new way. Some of these prove to be valuable treatments for mental illness, and many of the drugs that are currently abused (for example, amphetamines, barbiturates, and “roofies”) come directly from this same medical research.

Because of the incredible complexity of the brain, most drugs that affect it have actions in addition to those for which they were developed. Often dangerous drugs remain on the prescription market because they offer the only opportunity to treat a medical condition; their potential side effects seem worth the risk if they are used under medical supervision. Yet recreational use may not be worth the risk of the known and unknown effects on health. The fast-acting opioid fentanyl used in the operating room is a great example. This chemical is very safe and effective if there is a medical professional monitoring body functions such as heart rate, blood pressure, and the amount of oxygen getting to the brain. But with just a small error, it can turn dangerous and deadly. So imagine how risky using it could be in some alley or dorm room, where it might be sold as “Apache” or “Jackpot.”

It is easy to see how drug information can become subject to distortion. The public can be easily confused and manipulated. For example, some people (especially those in the drug culture) know individuals who have consumed various drugs in various combinations in various settings over

long periods of time and do not seem permanently impaired or addicted, or are not involved with the legal system. Yet they may not realize that many drug effects can be subtle enough to do a good deal of harm before the damage is recognized.

Conversely, others routinely carry out drug education by telling the worst horror stories they can recall, and often place any illegal substance in the category of “terribly dangerous.” Stories of celebrity deaths from basketball players to musicians are used to illustrate the dangers of drug use. However, most people who use addictive drugs like cocaine and heroin do not die as a result, and the users and their friends certainly know it. Therefore, when horror stories are used as the principal tools in drug education, people soon recognize that such stories do not represent the whole truth. The educator then loses credibility.

Good drug education requires a lot of effort. The scientific and medical literature is often difficult for most people to find and even more difficult to understand. Most interpretations of this literature to the general public are oversimplified, inaccurate, or disseminated by organizations that slant the research to further political and moral agendas.

The marijuana controversy is an excellent example. Some organizations have taken a hard line that this drug is devastating to anyone who uses it. Other organizations view it as harmless and support its legalization for totally unregulated consumption. In our opinion, the truth is somewhere in between. As you will read in the marijuana chapter, marijuana causes memory problems and interacts with the immune system in unknown ways. It has effects many hours after it enters the body, even if the user is unaware of those effects. So it is not harmless. But people do not die from marijuana overdoses (as they do from overdoses of alcohol). Any truthful discussion of marijuana must include a range of topics and a realistic representation of risk, which cannot be accomplished by exchanging slogans.

Drugs should be viewed individually on a continuum of risk. Those we review in this book vary remarkably in their chemical structures; in target systems in the brain; and in their pharmacological, behavioral, and psychological effects. Also, people vary markedly in their reactions to drugs. The rapidly expanding literature on genetic and hereditary predispositions toward addiction is just one example of our growing understanding of individual differences in drug reactivity.

The internet is also making it difficult to carry out good drug education. An immense amount of easy-to-read information about drugs is accessible there, but much of it is wrong. Anyone can create a website and say whatever he or she pleases; the astute reader must weed out fact from fiction. A naïve reader, on the other hand, may get into serious trouble by following website advice. The drug GHB, for instance, can be deadly at doses not far above those that produce a high. Yet some of the internet literature would lead us to believe that the drug is not only safe but will treat alcoholism, insomnia, narcolepsy, sexual problems, and depression. One website that we accessed provided directions for making GHB and stated that “GHB is the safest recreational drug ever used by humanity.” This information could not be further from the truth, and readers who believe it are at great risk.

The primary goal of this book is to provide an unbiased, readable, and detailed presentation of the scientific facts about the drugs most commonly abused. We expect that this book will have its largest impact on people who are not addicted to drugs but are in a position to use drugs socially. During adolescence and young adulthood, most people—newly independent from parental control—will find themselves in situations in which drugs are available. College dorm rooms are often active, misguided psychopharmacology labs. We do not expect that this book will end drug abuse, but we hope it will prevent some bad experiences and some real tragedies.

We also hope that this book will facilitate a dialogue between scientists and legislators. The use of illegal drugs in the United States is common, and the social and legal reactions to that use have placed enormous stress on the resources of this country. The debate about drug laws in the United States is raging and has been driven in part by this usage and the huge increase in the prison population. It is very costly to keep a person in prison, and the number of sentenced prisoners in state and federal institutions has skyrocketed from

about 300,000 in 1978 to more than 1.5 million in 2016.* About 46 percent

of the people in federal prisons are there for drugs,† and as bad as these numbers are, they are an improvement over those we found as we wrote the previous editions of this book. It appears there is a trend toward reducing prison populations.

The distinction between drugs that are considered legal or illegal in a given society is often based on much more than just scientific information.

Traditions, economics, religion, and the popular media all influence the stance that a community takes on drugs. The religious rituals of some Native American communities include the use of hallucinogens, while many of those in Jewish and Christian traditions include the use of alcohol. Other cultures take very hard-line stances against the use of any substance that is considered intoxicating. Even within a given culture, the legality of drugs can change over time. In the United States, the use of alcohol was legal for more than a century, was declared illegal during Prohibition, and is now legal again. Similarly, marijuana was legal until the 1930s, when its use was prohibited. Now nine states and the District of Columbia have legalized both medical and recreational marijuana, and nineteen additional states have legalized medical marijuana.

Again, in the words of Dr. Leshner, “Science must replace ideology as the foundation for drug abuse and addiction prevention, treatment, and policy strategies.” The legislative authorities of developed societies must understand that no matter what legal efforts are taken, their citizens will have access to increasing numbers of chemicals that can cause addiction and impair human function. Effective protection from the kind of societal disruption being experienced in the United States rests in good education that is accessible to everyone and good scientific research that addresses the problems that drugs cause.

We hope that this book will be part of that process. The first twelve chapters are devoted to particular drugs or classes of drugs. Each one starts with a quick-reference summary of the effects and dangers of the drug. Next we present a detailed picture of how the drug works. We describe how the drug gets into and out of the body, its effects on physical and psychological functions, and its long-term effects. We’ve organized the drugs by class— even though some drug classes, like the entactogens, are much less familiar to most readers than the specific drug names—because drugs in the same class generally have the same mechanisms of action, effects, and risks. However, the table of contents, the chapter contents, and the index make it easy to determine where to go for information on a specific drug. In the second part of the book, we’ve provided general chapters on the brain, how drugs work, addiction, and legal issues. We recommend that any reader using the book for a broad general understanding, rather than as a quick reference, read those chapters first, as they provide an important background for all of the scientific information relating to specific drugs.

We believe that when provided with an unbiased and authoritative source of information about drugs and drug interactions, individuals are empowered to make healthy decisions.

* Bureau of Justice Statistics (
† US Federal Bureau of Prisons (


(A College Student’s Perspective by Leigh Heather Wilson and Jeremy Foster)

This section was written by our college interns for the first edition of Buzzed. We feel the advice is still as good and relevant as it was then and so we include it in this edition.

“JUST SAY NO.” Well, no thanks. We would like a bit more information before making decisions about drug use. And when you say “Just say no,” does that mean you’re telling us alcohol is as dangerous as cocaine? Before you start lumping together everything from smoking cigarettes to shooting heroin, could we have a little bit more information? “Just say no” might not always be the right choice. Hasn’t research shown that a glass of wine can be healthy? It is only natural that phrases like “Just say no” are not sufficient to satisfy many young people. It is the very basis of our society to value proof, logic, and fact above all. Instead of asking us to respond blindly, convince us!

We have been friends all our lives. Because Heather’s dad is a neuropharmacologist, we knew about psychoactive drugs early on. Ever since we can remember, drugs and how they do this or that to the something- or-another region of the brain has been a familiar topic of conversation.

Like many kids, in high school we became bored with the same-old, same-old that radio and MTV offered and wanted to broaden our musical horizons. This sparked an interest in some of the bands popular in the sixties and seventies. Consequently, we developed a fascination with the

surrounding culture. It was clear that drugs, of one character or another, were cast in many roles during those times. The deaths of Janis Joplin, Jim Morrison, and Jimi Hendrix were all related to their drug use, and still, by way of their association with these and other musicians, drugs have an air of romance and intrigue.

Around the same time that we became aware of these issues, similar concerns about the nineties’ music culture became a trendy topic in the media. The flurry of publicity on the rising use of drugs again among young people, as well as the resurgence of heroin use, in particular, has led many to compare our times to the sixties and seventies. All the hype—not to mention the allure of the positive feelings people say they get from taking drugs— made us quite curious about the subject.

We were both way past believing the slogans and hyperbole on the subject of drugs. Heather began nagging her dad with question after question about drugs in a struggle to understand their effects, and the questions evolved into a series of great conversations with him and some of his colleagues. We were so interested because finally we were getting straight, unbiased information about the actions of drugs in our bodies.

We learned a lot about heroin, which had seemed so attractively mysterious. Its “rush” is commonly described as better than experiencing an orgasm. Its associated dangers, however, included several major risks: addiction, overdose, and contracting HIV from needles. The risk of overdose, we learned, is unpredictable because of individual responses to the drug and varying degrees of purity of the compound sold by dealers. The particular compounds used to cut it can also be dangerous. So it became clear to us that with heroin, as with many other drugs, the safety issues are very complicated and often the danger is not limited to the specific effects of the drug but can include many other peripheral issues. For heroin, some of these issues arise from economic considerations because its high street value and relative scarcity lead dealers to cut it in unpredictable ways.

After all these conversations with Heather’s dad and his colleagues, heroin seemed far less alluring and mysterious, and we avoided it. We felt lucky to have learned the truth, and with the new knowledge we felt armed. If someone offered heroin to one of us, we wouldn’t be “just saying no,” but defending an informed decision to stay away from the drug.

Through learning about heroin we realized that not all the threats have direct causes and that by giving people good information, some of the dangers can be lessened (some people will use drugs regardless). We know that a drug’s effects can change in a novel environment, that the risk of overdose increases when the drug purity is not consistent, and that some drugs taken together become lethal. Making people aware of these kinds of issues could decrease some risks of using drugs.

Overall we were struck by the lack of unbiased and complete information available to people like us, and the contrast between the formal education we had received and the scientific facts we had learned.

During high school, we had had experiences with alcohol, many of them positive. It wasn’t until Heather’s freshman year in college that she had her first really adverse experience with drugs. During Parents’ Weekend, she, her roommate, and their parents went to her best friend’s room and found her soaked in blood and tears on the floor. Heather’s friend had a history of depression, and the combination of this, a bottle of Jack Daniel’s Black Label, and too much cold medicine left her ravaged and suicidal. She didn’t know that alcohol and antihistamines have a synergistic, depressing effect and that at high levels the combination can even be lethal. They found her in time to save her, but she will always carry the scars where she cut her wrists.

Heather’s friend wasn’t the only girl left with scars. Everyone involved was affected. She and Heather were part of an unusually close-knit group of five. They had, unknowingly, become a family to each other. By doing almost everything together, they had become a source of strength and love for each other as they adjusted to college life. When Heather’s friend went home, she left a hole, a missing link in that safety net. An irresponsible act, taken without knowledge of drugs and their interactions, changed the lives of everyone who found her, all of her friends, and all of her family.

A second experience occurred on the same dormitory hall. Heather and her friends were invited to share some Ecstasy with boys from a nearby school. They were excited, having heard that Ecstasy was a lot of fun. But Heather remembered one of the strongest statements about drug use her dad had ever made. He had said, “Ecstasy permanently alters your brain, Heather. It is a bad drug, and frankly, this is one that I would like to ask you, as a personal favor because I’m your dad and I love you, not to try. There are some kids who have used it and suffered problems with sleep, anxiety, and

depression. These poor kids have changed their own brains, and they will never be the same.”

Cindy Kuhn had loaned Heather a neuropharmacology textbook the year before; the students used it to read about Ecstasy. With a clear view of what the drug could do to their brains, most of them chose not to try it, though others decided to take the risk.

With these experiences still vivid in our minds, the vast and cavernous difference between what we know from the most current research on drugs and what drug education and prevention programs teach was obvious. We realized that we are all being sold a bill of goods when it comes to recreational drugs. There are dangers involved in using drugs, but the issue is much more complicated than that. Each drug works differently in the brain, and there are very different issues to consider with each drug. Also, some drugs pose risks that are far greater than others. We do an injustice to ourselves when we try to make blanket statements like “Drugs Kill” or “Users Are Losers.”

We realized that not everybody has a scientist to talk to and that the world needed a book that would not use scare tactics but would have reliable, in- depth information—a book that would not insult our intelligence. This book is about making the most current research on the pharmacological and psychological effects of drugs available to you in a friendly and useful way. We hope you enjoy reading it, but most of all, we believe that with information that is both clearly presented and unbiased, you will be qualified to make better decisions for yourself about drugs.


1. The effects of smoking pot can last for two days. True or false?

2. Chocolate and marijuana stimulate the same receptors in the brain. How much chocolate would you have to eat to get the same effect as one joint?

3. Which cup of coffee has more caffeine—the one brewed in the office coffeemaker from grocery-bought beans or the expensive cup from the new gourmet coffee bar?

4. Ecstasy was first popularized by California psychotherapists who tried to use it for “empathy training” in marriage counseling. True or false?

5. What popular recreational drug was originally developed as a treatment for asthma?

6. What popular nightclub drug is actually an animal tranquilizer—and the difference between a recreational dosage of it and an overdose is dangerously small?

7. What are the most dangerous drugs and also the ones most often used by children under age fourteen?

8. Which drug prescribed each year to millions of Americans impairs memory?

9. Put these drugs in the order of addictiveness: marijuana, nicotine, heroin.

10. Tonight you are at a club sipping on a soft drink, or still on your first beer, when suddenly you begin to feel very drunk and uncoordinated. What might have happened?

11. What was the drug misinformation promulgated by the movie Pulp Fiction?

12. What was the drug effect correctly portrayed by the movie Trainspotting?

13. Which drug carries a greater danger of fatal overdose—alcohol or LSD?

14. Right or wrong: alcohol before bed makes you sleep better.

15. Are the herbal remedies sold in health-food stores actually drugs?

16. Why do people inject a drug instead of just taking a pill?

17. What is the most popular illegal drug in America now?

18. If a child or an animal eats a cigarette, will it cause harm?

19. Does marijuana kill brain cells?

20. Does alcohol kill brain cells?

21. Isn’t it safe to drink a glass or two of wine with your dinner when you’re pregnant?

22. Is caffeine addictive?

23. Are crack babies doomed to mental retardation and behavioral problems?

24. What drug, popular on the club scene and among high school students, causes definitive brain damage in rodents and monkeys?


1. True. THC, the active ingredient in marijuana, is extremely fat- soluble and can still enter the bloodstream from the fatty tissues and have effects on the brain for up to two days after being smoked. Its by-products can turn up in the blood many months after the last use if the smoker suddenly loses a lot of weight. (See chapter 7.)

2. About twenty-five pounds. (See chapter 2.)

3. The office cup. The African robusta beans found in grocery stores can contain up to twice as much caffeine as the more expensive arabica beans found in specialty coffee shops. Plus you can add as much coffee as you want. (See chapter 2.)

4. True! (See chapter 3.)

5. Amphetamine, which was originally synthesized as a derivative of ephedrine, the active ingredient of the Chinese herbal drug mahuang. (See chapter 12.)

6. Ketamine, otherwise known as Special K (not the cereal!). (See chapter 4.)

7. Chemical solvents such as toluene, benzene, propane, and those found in glue and paint. More than 12 percent of eighth graders have used such inhalants. (See chapter 6.)

8. Valium and other drugs of its class. (See chapter 10.)

9. Nicotine, heroin, marijuana (actually, there is little evidence that
marijuana is addictive). (See chapter 7.)

10. Someone probably slipped a sedative into your drink, like a roofie (Rohypnol) or GHB (gamma-hydroxybutyrate), also known as Easy Lay. These drugs can be fatal, so seeking medical attention is wise. (See chapter 10.)

11. The movie shows a heroin overdose being treated by an injection of adrenaline into the heart, which is useless and dangerous. The opioid-blocking drug naloxone reverses heroin overdose after injection by more conventional routes. (See chapter 9.)

12. The main character in the movie is overcome with diarrhea after coming down off heroin. Because heroin causes constipation, once it’s eliminated from the body just the opposite effect kicks in. (See chapter 9.)

13. Alcohol. Many deaths each year are caused by alcohol overdose. There is little danger of LSD overdose unless it is combined with or contaminated by other drugs. (See chapter 1.)

14. Wrong. Alcohol might make you sleepy at first, but its by-products can cause sleeplessness, so after a night of drinking you might fall asleep quickly but wake up in the middle of the night feeling agitated. (See chapter 1.)

15. Anything you take with the intention of changing how your body acts is a drug. Any drug that comes from a plant is herbal. This includes nicotine, ephedrine, and cocaine. “Herbal remedies” are completely

unregulated and the amount and purity of what you buy is unknown. (See chapter 5.)

16. For the speed with which the drug gets into the bloodstream and into the brain. The faster it gets to the brain, the better the “rush.” This faster delivery also means a greater chance of overdose because the amount of drug can reach fatal levels before the user can do anything about it. (See chapter 13.)

17. Marijuana is used by far more people than any other illegal drug: 77 percent of all illegal drug users use marijuana, and almost 5 percent of the population used marijuana in the last month. (See chapter 7.)

18. Yes. There is enough nicotine in a cigarette to make a small child or animal very sick, or even to kill one. (See chapter 8.)

19. Probably not, but it does interfere with learning and memory. (See chapter 7.)

20. It is unlikely that a single drink kills brain cells, but long-term chronic drinking can cause permanent memory loss and definite brain damage. (See chapter 1.)

21. No. Studies have shown that even very moderate drinking during pregnancy can permanently hinder a child’s ability to learn and to concentrate. (See chapter 1.)

22. Not really. People who stop drinking coffee may experience mild withdrawal that includes drowsiness, headaches, and lethargy, but people very rarely engage in the compulsive, repetitive pattern of drinking coffee that typifies use of addictive substances. Addiction is not defined simply by the presence of withdrawal. (See chapter 2.)

23. Not necessarily. In fact, the most common problems that crack babies experience are the same as those experienced by children of women who smoke cigarettes: low birth weight and the associated health risks, and subtle developmental delays in childhood. Cocaine can cause very severe problems, including premature separation of the placenta from the uterus, premature birth, and intrauterine stroke, but these are rare. (See chapter 12.)

24. Ecstasy (MDMA). Studies show dramatic damage to nerves containing the neurotransmitter serotonin that is irreversible at doses approximating those consumed by humans. (See chapter 3.)

Part I



Drug Class: Sedative hypnotic

Individual Drugs: beer (3 to 7 percent alcohol on average; can be as high as 20 percent); wine (8 to 14 percent alcohol); “fortified” wine (17 to 22 percent alcohol); spirits, liquor, whiskey (40 percent or more alcohol)

Common Terms: liquor, whiskey, booze, hooch, wine, beer, ale, porter

The Buzz: When people drink alcohol, they feel pleasure and relaxation during the first half hour or so, often becoming talkative and socially outgoing. But these feelings are usually replaced by sedation (drowsiness) as the alcohol is eliminated from the body, so drinkers may become quiet and withdrawn later. This pattern often motivates them to drink more to keep the initial pleasant buzz going.

Overdose and Other Bad Effects: Under most circumstances, the chances of life-threatening overdose are low. However, people get into trouble when they drink a lot of alcohol very quickly—such as in a drinking game, on a dare, when unaware of how much alcohol is in their drinks, or when they can’t taste the alcohol (as in punch or Jell-O shots). Drinking on an empty

stomach is particularly risky. If a person becomes unconscious, is impossible to arouse, or seems to have trouble breathing, it is a medical emergency and immediate attention is necessary. Some very drunk people vomit, block their airway, suffocate, and die. Call for emergency medical assistance.

When drunk people pass out, their bodies continue to absorb the alcohol they just drank. The amount of alcohol in their blood can then reach dangerous levels and they can die in their sleep. Keep checking someone who has gone to sleep drunk. Do not leave the person alone.

“Binge drinking” is particularly dangerous because it is during binges that most fatal overdoses occur.

Unique Risks for Adolescents: Young people may respond quite differently from adults to alcohol. Alcohol may impair learning more in adolescents but be less potent at making them sleepy. The newest studies indicate that adolescents are at greater risk than adults for long-lasting effects of alcohol on the brain—even down to the cellular and molecular levels.

Dangerous Combinations with Other Drugs: It is dangerous to combine alcohol with anything else that makes you sleepy. This includes other sedative drugs, such as opioids (for example, heroin, morphine, or ‐ oxycodone), barbiturates (for example, phenobarbital), Quaaludes (methaqualone), Valium-like drugs (benzodiazepines), sleep medications like Ambien, and even the antihistamines found in some cold medicines. In recent years, THC content in some marijuana and cannabis edible and vapor products has gotten quite high, thus increasing the chances that combining even low doses of alcohol with cannabis products could lead to a dangerous level of sedation or distraction.

All sedative drugs share at least some of alcohol’s effects and each increases the other’s effects. Drugs can become deadly when combined. Even doses of drugs that do not cause unconsciousness or breathing problems alone can powerfully impair physical activities such as sports, driving a car, and operating machinery when taken together.

Finally, non-narcotic pain relievers such as aspirin, acetaminophen (the pain reliever in Tylenol), and ibuprofen (the pain reliever in Motrin) can each have bad side effects if taken with alcohol. Aspirin and ibuprofen can both be highly irritating to the stomach when taken with alcohol, and under

some circumstances the combination of extremely high amounts of acetaminophen with alcohol can damage the liver.


Types of “Alcohols”
How Alcohol Moves through the Body

Getting In

Getting Out
Effects on the Brain and Behavior

Acute Exposure Chronic Exposure Prenatal Exposure

Risk Factors for Alcohol Addiction Genetic Factors

A Special Risk for Men

How to Spot a Problem Drinker Special Considerations for Women

Different Sensitivity
Health Effects
Social and Psychological Issues

Alcohol and Sex
Children and Adolescents
Dangerous Interactions with Other Drugs Health Benefits of Moderate Alcohol Use

Relaxation and Stress Reduction Protection against Heart Disease Diminished Risk of Death

The use of chemicals to alter thinking and feeling is as old as humanity itself, and alcohol was probably one of the first substances used. Even the earliest historical writings make note of alcohol drinking, and breweries can be traced back some 6,000 years to ancient Egypt and Babylonia. In the Middle Ages, Arab technology introduced distillation—a way to increase the alcohol content in beverages—to Europe. In those times alcohol was believed to remedy practically any disease. In fact, the Gaelic term whiskey is best translated as “water of life.”

These days, beverage alcohol is clearly the drug of choice for much of Western culture, and we need only to look closely at much of the advertising in this country to see that it is still sold as a magic elixir of sorts. We use alcohol to celebrate successes, to mourn failures and losses, and to celebrate holidays of cultural and religious significance. Implicit in these uses are the hope and promise that alcohol will amplify the good times and help us through the bad ones.

Nowhere is the alcohol advertising more targeted, or the peer pressure to drink more powerful, than on adolescents and young adults—particularly young men. And the advertising works. We know that people’s choices about the alcoholic beverages they drink are powerfully influenced by advertising. While young people do most of the drinking in American society, they are also the ones who need their brains to be functioning at their highest levels because of the intellectual demands of education and career preparation.

For most people alcohol is not a terribly dangerous drug—but it is a powerful drug and must be treated accordingly. No one would take a powerful antibiotic or heart medication without the advice of a physician. But alcohol is available to virtually anyone who wants to have it, without a prescription. The vast majority of people in the United States face the decision of whether to use alcohol, and how much to use, during their high school or college years. The responsibility for making these decisions falls on each individual. This chapter provides the latest information about alcohol and its effects.


The alcohol that is used in beverages is called ethanol. It is actually only one of many different types. The alcohol that is rubbed on the skin as a disinfectant before giving an injection or drawing a blood sample is not the same—it is isopropyl alcohol. The chemical structures of most alcohols make them quite toxic to the human body. Ethanol is the only one that should ever be consumed, but people regularly poison themselves with other alcohols. For example, methanol, produced in home-distilling operations, can cause blindness. A case of methanol poisoning requires immediate medical attention. Therefore, home-distilled liquor, or “moonshine,” should always be avoided.


The amount of alcohol a person consumes at any given time will influence how it moves through the body, but it’s important to standardize the amount that we’re talking about first, because beer, wine, and spirits contain significantly different concentrations of ethanol. A standard drink is often classified as the amount of alcohol consumed in one twelve-ounce beer, one four-ounce glass of wine, or a mixed drink containing one ounce of hard liquor. Although these comparisons used to be a good general guideline for estimating how many “drinks” a person has had, the concentration of alcohol in many beers has increased quite a bit in recent years—sometimes reaching or even exceeding the concentration in wine. So it’s no longer safe to assume that one beer equals one standard “drink.”


Ethanol is a relatively small molecule that is easily and quickly absorbed into the body. Once a drink is swallowed, it enters the stomach and small intestine, where a high concentration of small blood vessels gives the alcohol ready access to the blood. About 20 percent of a given dose of alcohol is absorbed through the stomach, and most of the remaining 80 percent is absorbed through the small intestine. Once they enter the bloodstream, the alcohol molecules are carried throughout the body and into direct contact with the cells of virtually all the organs.

Often a person who goes out for a drink in the early evening before dinner reports, “The alcohol went straight to my head.” Actually, the alcohol went very rapidly throughout the whole body, and shortly after it was absorbed it became fairly evenly distributed. This process is called equilibration. But because a substantial proportion of the blood that the heart pumps at any given time goes to the brain, and because the fatty material of the brain absorbs alcohol (which dissolves in both fat and water) very well, that is where the effects are first and predominantly felt. In fact, before equilibration, alcohol’s concentration in the brain is actually higher than its concentration in the blood. Since it is alcohol’s effects on the brain that lead to intoxication, soon after drinking a person may be more impaired than her blood alcohol level would indicate. So, there is some truth in the statement, “That drink went right to my head.”

Indeed, the presence or absence of food in the stomach is perhaps the most powerful influence on the absorption of alcohol. When someone drinks on an empty stomach, the blood absorbs the alcohol very rapidly, reaching a peak concentration in about one hour. By contrast, the same amount of alcohol consumed with a meal would not be completely absorbed for nearly two hours. The food dilutes the alcohol and slows the emptying of the stomach into the small intestine, where alcohol is very rapidly absorbed. Peak blood alcohol concentration could be as much as three times greater in someone with an empty stomach than in someone who has just eaten a large meal.

The concentration of alcohol in the beverage consumed also significantly influences its absorption—in general, the higher the concentration, the faster it will be absorbed. So, relatively diluted solutions of alcohol, such as traditional beers, enter the bloodstream more slowly than more highly concentrated solutions, such as mixed drinks or shots. More rapid absorption usually means higher peak blood alcohol concentrations, so a person who drinks shots might have a higher blood alcohol level than a person who drinks the same amount of alcohol in the form of beer or wine. While you can prove this principle in tightly controlled scientific studies using subjects who have completely empty stomachs when they ingest only the dose of alcohol they receive from the researcher, this effect is pretty minimal when people are drinking recreationally, perhaps two to three drinks an hour. Furthermore, people rarely drink under such carefully controlled conditions, and so the safest assumption is that the most important determinant of what your blood alcohol concentration is going to be is the amount of alcohol you consume in an hour and whether you have just eaten—not the type of alcohol you consume.

The rapid absorption of high concentrations of alcohol can suppress the centers of the brain that control breathing and cause a person to pass out or even die. People who get into this kind of extreme medical emergency sometimes do so by accepting a challenge to drink a certain amount of alcohol in a short period of time, by playing drinking games that result in the rapid consumption of multiple drinks, or by taking something like Jell-O shots, which get a lot of highly concentrated alcohol into the body in a short time. Often, young people who cannot legally buy alcohol drink rapidly before going out to a school dance or other public event. Some people do a lot of drinking before leaving for an event where alcohol is not permitted.

(College students, most of whom are underage and must therefore conceal their drinking, refer to this as “pre-gaming.”) Given the rapid accumulation of alcohol in the brain, under these circumstances the drinker may be very impaired in terms of the ability to drive or think clearly, though the person’s blood alcohol level may not initially suggest this degree of impairment.

An individual’s body type also determines alcohol distribution. A particularly muscular or obese person may seem to be “really holding their booze” because there is more fat and muscle to absorb the alcohol. A heavy person would register a lower alcohol level in the blood than a lean individual after an identical dose. However, the extra weight also slows the elimination of alcohol, so the person would retain it longer.

In pregnant women, alcohol is freely distributed to the fetus. In fact, because of the large blood supply to the uterus and developing fetus, some studies actually indicate that the tissues of the fetus may achieve a higher alcohol concentration than those of the mother. Later in this chapter, we discuss the effects of alcohol on the fetus, and the lasting effects that prenatal exposure has on the child later in life. For now, it is important to recognize that when alcohol is distributed in the body, it does not discriminate between the tissues of the mother and those of the fetus.


The roadside Breathalyzer test is actually an excellent way of estimating the amount of alcohol consumed, even though 95 percent of the alcohol a person drinks is metabolized before the body excretes it. Only about 5 percent of the absorbed alcohol is eliminated unchanged, in the urine or through the lungs, but it is enough to result in “alcohol breath”—and the proportion exhaled stays constant enough to give a very accurate estimate of how much alcohol is in the blood.

Most alcohol is metabolized by the liver, where an enzyme called alcohol dehydrogenase, or ADH, breaks ethanol down into acetaldehyde, which in turn is broken down by another enzyme called acetaldehyde dehydrogenase into acetate, which then becomes part of the energy cycle of the cell. The intermediate product, acetaldehyde, is a toxic chemical that can make a person feel sick. Although under normal conditions acetaldehyde is broken down quite rapidly, if it accumulates in the body, intense feelings of nausea and illness result. One early drug therapy for alcoholism was a drug

called disulfiram (or Antabuse), which allows the concentration of acetaldehyde to accumulate, making a person feel quite ill after drinking and less likely to drink again. While this strategy appeared promising initially, it has not resulted in consistent positive clinical outcomes with alcohol- dependent patients.

There are about a billion people in the world who have a genetic variation that makes them nearly incapable of breaking down acetaldehyde through the usual route. When people who carry a copy of that gene drink alcohol, they experience a buildup of acetaldehyde that triggers symptoms— including marked flushing—as if they were on disulfiram. In the subgroup of people who have two identical copies of that gene, the symptoms are even worse. This effect is called the “Asian alcohol-induced flushing syndrome” because about 40 percent of the East Asian population carries at least one copy of the gene. This is associated with lower rates of alcohol abuse and addiction in those populations, though it is not clear if it’s the altered alcohol metabolism that is the true cause of the difference in addiction liability; there are many social and cultural factors at work as well.

The rate at which alcohol is metabolized and eliminated from the body is critical for understanding how long a person can expect to be affected by drinking. The rate of alcohol metabolism is constant across time. In general, an adult metabolizes the alcohol from one ounce of whiskey (which is about 40 percent alcohol) in about one hour. The liver handles this rate of metabolism efficiently. If the drinker consumes more than this amount, the system becomes saturated and the additional alcohol simply accumulates in the blood and body tissues and waits its turn for metabolism. The results are higher blood alcohol concentrations and more intoxication.

In addition, continued drinking increases the enzymes that metabolize alcohol. The increased level of these enzymes promotes metabolism of some other drugs and medications, harming the drinker in a variety of ways. For example, some medications used to prevent blood clotting and to treat diabetes are metabolized more rapidly in chronic drinkers and are thus less effective. Similarly, these enzymes increase the breakdown of the painkiller acetaminophen (found in Tylenol) into substances that can be toxic to the liver. Finally, metabolic tolerance to alcohol results in similar tolerance to other sedative drugs, such as barbiturates, even if the individual has never

taken barbiturates. This is called cross tolerance and may place the drinker at greater risk for the use or abuse of such drugs.


Once alcohol has been absorbed and distributed, it has many different effects on the brain and behavior. To a large extent these effects vary with the pattern of drinking. Therefore, we discuss the effects of acute, chronic, and prenatal alcohol exposure separately.


Effects on Behavior and Physical State

Although the effects that a given dose of alcohol will have on an individual vary considerably, the following table shows the general effects of a range of alcohol doses:


Ethanol Dose





Blood Ethanol

(mg/100 ml)

up to 100



Function Impaired

judgment fine motor coordination

reaction time

motor coordination reflexes

voluntary responses to stimulation

Physical State

happy talkative boastful

staggering slurred speech nausea, vomiting

hypothermia hyperthermia anesthesia

sensation movement
16–24 400–600 self-protective comatose


24–30 600–900 breathing heart dead function

Still, there is often a substantial difference between being impaired and appearing impaired. In one study, trained observers were asked to rate whether a person was intoxicated after drinking. At low blood alcohol concentrations (about half the legal limit for intoxication), only about 10 percent of the drinkers appeared intoxicated, and at very high concentrations (greater than twice the legal limit), all of the drinkers appeared intoxicated. However, only 64 percent of people who had blood alcohol concentrations of 100–150 mg/100 ml (well above the legal limit of 80 mg/100 ml) were judged to be intoxicated. So, in casual social interactions, many people who are significantly impaired—and who would pose a real threat behind the wheel of a car—may not appear impaired even to trained observers.

Alcohol and Brain Cells

You’ve probably heard some variation of the following statement: “Every time you take a drink of alcohol you kill ten thousand brain cells.” Although it is highly unlikely that anyone would drink enough alcohol in a given sitting to kill brain cells directly, as with many such generalizations there is a grain of truth in the warning.

One way that researchers have tried to determine which brain regions control which behaviors in animals is by destroying, or lesioning, a specific brain region and then testing the animal on a particular behavioral task. Early in the use of this lesioning technique, some researchers found that if they injected a very high concentration of alcohol into the brain (far higher than would be achieved by a drinking person), the cells in that region would die. There is also another grain of truth in the warning about alcohol and brain cells: chronic, repeated drinking damages and sometimes kills the cells in


specific brain areas. And it turns out that it might not take a very long history of heavy drinking to do so. We will address this in the “Chronic Exposure” section of this chapter.

There are fundamentally only two types of actions that a chemical can have on nerve cells—excitatory or inhibitory. That is, a drug can either increase or decrease the probability that a given cell will become active and communicate with the other cells to which it is connected. Alcohol generally depresses this type of communication, or synaptic activity, and thus its actions are similar to those of other sedative drugs, like barbiturates (such as phenobarbital) and benzodiazepines (such as Valium). Despite this general suppression of neuronal activity, however, many people report that alcohol activates or stimulates them, particularly soon after drinking, when the concentration of alcohol in the blood is increasing. Although we don’t know exactly why alcohol produces feelings of stimulation, there are a couple of possibilities. First, there is the biphasic action of alcohol. This refers to the fact that at low concentrations, alcohol actually activates some nerve cells. As the alcohol concentration increases, however, these same cells decrease their firing rates and their activity becomes suppressed. Or it might be that some nerve cells send excitatory signals to the other cells with which they communicate, prompting them to send inhibitory messages, actually suppressing the activity of the next cell in the circuit. So, if alcohol suppresses the activity of one of these “inhibitory” cells, the net effect in the circuit would be one of activation. Whatever the exact mechanism, it appears that there are several ways in which alcohol can have activating as well as suppressing effects on neural circuits.

Effects on Specific Neurotransmitters

GABA and Glutamate

For many years it was generally thought that alcohol treated all nerve cells equally, simply inhibiting their activity by disturbing the structure of the membrane that surrounds each cell. In this sense the effects of alcohol on the brain were thought to be very nonspecific. However, it is now clear that alcohol has specific and powerful effects on the function of many different cell types in the brain. Two cell types that are particularly important for understanding how alcohol affects the brain are those that express either

GABA receptors or glutamate receptors. GABA and glutamate are chemical neurotransmitters that account for much of the inhibitory and excitatory activity in the brain. When the terminals of one cell release GABA onto GABA receptors on the next cell, that cell becomes less active. When glutamate lands on a glutamate receptor, that cell becomes more active. It is in this way that many circuits in the brain maintain the delicate balance between excitation and inhibition. Small shifts in this balance can change the activity of the circuits and, ultimately, the functioning of the brain.

Alcohol increases the inhibitory activity of GABA receptors and decreases the excitatory activity of glutamate receptors. These are the two primary ways alcohol suppresses brain activity. While the enhancement of GABA activity is probably responsible for many of the general sedating effects of alcohol, the suppression of glutamate activity may have a more specific effect: impairment in the ability to form new memories or think in complex ways while intoxicated. We know that the activity of a particular subtype of glutamate receptor, called the NMDA receptor, is very powerfully inhibited by alcohol—even in very low doses. The NMDA receptor is also known to be critical for the formation of new memory. Alcohol’s powerful suppression of activity at the NMDA receptor may therefore account for the memory deficits that people experience after drinking.


The neurotransmitter dopamine is known to underlie the rewarding effects of such highly addictive drugs as cocaine and amphetamine. In fact, dopamine is thought to be the main chemical messenger in the reward centers of the brain, which promote the experience of pleasure. Alcohol drinking increases the release of dopamine in these reward centers, probably through the action of GABA neurons, which connect to the dopamine neurons. Studies in animals show that the increase in dopamine activity occurs only while the concentration of alcohol in the blood is rising—not while it is falling. So, during the first minutes after drinking the pleasure circuits in the brain are activated, but this “dopamine rush” disappears after the alcohol level stops rising. This may motivate the drinker to consume more alcohol to start the pleasure sequence again—“chasing the high.” The problem is that although the dopamine rush is over, there is still plenty of alcohol in the body. Continued drinking in pursuit of the pleasure signals could push the blood alcohol concentration up to dangerous levels.

Not only does drinking alcohol cause an increase in dopamine activity in the brain, but simply anticipating a drink can as well. This anticipatory dopamine release can add to the motivation for having a drink, and may contribute to the motivation for continued drinking, both on a given day and across time. One recent study shows that people with a family history of alcohol-use disorders get a bigger dopamine rush when they anticipate a drink than do people without that family history. This could partly explain why people with family histories of alcohol abuse are at greater risk for alcohol-use disorders.

Effects on Memory

One of the most common experiences people report after drinking is a failure to remember accurately what happened “the night before.” In more extreme cases, after heavy drinking, people often report that whole chunks of time simply appear to be blank, with no memory at all having been recorded. This type of memory impairment is often called a “blackout.” (Less extreme versions of this type of memory loss have been called “brown outs” or “gray outs,” in which the person may have only very hazy or incomplete memory for the events that occurred during the period of intoxication. In these instances, and even in blackouts, the drinker may remember more about events when reminded of them.) In the past, blackouts were thought to be relatively rare and were viewed as a strong indicator of alcoholism by many clinicians. However, it turns out that blackouts are far more common than previously thought and don’t just occur in people with serious alcohol problems. In recent years, researchers have looked more closely at how and when blackouts occur, and there appear to be some disturbing trends. First of all, blackouts appear to be quite frequent among college students, with as many as 40 percent reporting them. But it’s not just the memory loss that’s disturbing—it’s what happens during the periods for which no new memories are made. In one survey, students reported that after a night of heavy drinking they later learned about sexual activity, fights with friends, and driving, for which they had no memory at all. So it seems that blackouts may well be a serious health risk over and above the direct effects that alcohol has on the brain.

And some people are more likely to suffer the negative effects of such heavy drinking than others. For example, a recent study of college students shows that those who identify as transgender are not only more likely to experience blackouts than their cisgender peers, but they are also more likely to suffer negative consequences from heavy drinking, like sexual assaults or getting into trouble with authorities. This doesn’t mean that transgender peoples’ brains react to alcohol differently—they probably blacked out more because they also drank more. Still, these findings are an example of how some groups of people are more vulnerable than others to the negative effects of blackout-level drinking.

Sadly, many people joke about blackouts as an embarrassingly funny result of heavy drinking. But they are no joke. Think about it this way: anything that impairs brain function enough to interrupt memory formation is very dangerous. If it were a blow to the head, exposure to a toxic chemical, or a buildup of pressure in the brain that caused the blackout, it would be taken very seriously. Alcohol-induced blackouts should be taken seriously as well. Short of blackouts, though, it is also clear that alcohol impairs the ability to form new memories even after relatively low doses. Therefore, having a couple of beers while studying for an exam or preparing for a presentation at work is probably not a good strategy. The alcohol may promote relaxation, but it will also compromise learning and memory.


One of the best-known symptoms of a hangover is a pounding headache. The cause is not exactly clear, but it is probably related to the effects of alcohol on blood vessels and fluid balances in the body. In any case, it is much easier to prevent the onset of pain than it is to relieve the pain once it has started. Therefore, the sooner a pain reliever is taken, the better. Some people take one before going to bed after a night of drinking. This way the chemicals in the pain reliever can prevent the pain signals in the brain from getting started as the alcohol is eliminated from the body. However, Tylenol (acetaminophen) should not be taken to treat a hangover because it can interact in a very dangerous way with alcohol and its by-products and damage the liver in some people. Aspirin or ibuprofen can be used instead,

but both of these drugs can irritate the stomach and small intestine and together with alcohol may cause gastric upset.

The upset stomach and nausea associated with a hangover are harder to deal with. These may be caused by the toxic by-products of alcohol elimination, irritation to the stomach, or both. No medicines treat these effects specifically. Rather, the best strategy is to eat foods that are gentle on the stomach and to drink plenty of fluids. Morning coffee may help to start the day after a night on the town, but its irritating effects on the stomach may make it an unpleasant waking. And because caffeine is a diuretic, it may also contribute to the dehydration that often accompanies alcohol drinking.


Everybody wants to know how much drinking is bad for them. Some want to know how much drinking they can get away with before they cause themselves health problems. This question always reminds us of a common response to the old warning that masturbation would cause blindness: some people just wanted to know how much they could do it before suffering blurred vision.

The long-term effects of drinking depend on how much alcohol is consumed. Although there appear to be some health benefits associated with very moderate drinking in adults (this is discussed later in the chapter), chronic heavy drinking creates very serious problems in a number of body systems, including the brain, liver, and digestive system. Between the extremes of heavy and light drinking lies a “gray area” that is not completely understood. Moreover, this gray area appears to be rather small. That is, while an average of one-half to one drink per day may be healthy for your heart, it is perfectly clear that an average of two drinks per day significantly increases your risk of dying from heart disease or cancer.

The Incredible Shrinking Brain

Brain imaging techniques create a window into the effects of alcohol on the brain. Using these techniques, researchers have observed shrinkage of brain tissue in people after long-term use of alcohol. But there is also recovery of brain tissue volume in people who stop drinking and remain abstinent, so this

“shrinking” effect appears not to be due exclusively to the loss of brain cells. Interestingly, some studies indicate that certain parts of the brain may be more vulnerable to damage by alcohol than others, such as the cortex—the folded, lumpy surface of the brain (it gets its name because of its resemblance to the bark of a tree), which endows us with consciousness and controls most of our mental functions. One region of the cortex that appears to be particularly vulnerable is the frontal lobe. The frontal lobes are unique in that they act like a kind of executive manager for the rest of the brain. They monitor and help to coordinate the actions of the other cortical lobes—much like an executive does in a corporation. The analogy is so apt that the functions of the frontal lobes are often called “executive functions.” They endow us with the ability to bring together our mental abilities to solve complex problems, to make and execute plans of action, and to use judgment in service of those plans. Even in people who have never been diagnosed with an alcohol-use disorder, chronic drinking can contribute to frontal lobe damage. Another vulnerable region is the mammillary bodies, which are very important for memory. (These small, round structures near the base of the brain got their name from the neuroanatomists who first noticed them and thought that they looked like breasts. Actually, their resemblance to breasts is quite remote, but neuroanatomists do have good imaginations!)

Although many of the studies of brain shrinkage have assessed people with long histories of heavy drinking, some of the more recent ones have included social drinkers and found similar, though less severe, effects. The shrinkage occurs while the person is still using alcohol. If the person stops drinking for a prolonged period, the brain will recover somewhat—not because new nerve cells grow, but because support cells, or parts of the remaining nerve cells, grow. Therefore, the partial recovery of brain size does not mean that the deficits in mental functioning that many long-term heavy drinkers experience will be erased simply by abstaining from alcohol.

It is not known if there is a safe level of chronic drinking. Clearly many people who drink do not appear to suffer any damage to their mental functioning. Still, as with acute intoxication, the lack of any obvious impairment does not mean that there is none. Studies using animals instead of humans can look more closely at nerve cell damage. Such studies have shown that more moderate alcohol exposure can damage and kill brain cells. A number of these studies have shown large areas of nerve cell loss in a region of the brain called the hippocampus, which is known to be critical for

the formation of new memories. This could be one reason why people who drink chronically can end up with relatively poor memory function, though of course this will vary with the person’s drinking history.

Another study in animals has shown that in the case of very heavy drinking, brain damage may occur much sooner than previously thought. Using a model in which animals are exposed to a heavy “binge” of alcohol around the clock for four days, it was discovered that cells in some of these same regions started to die off after the first two days of the binge. If this holds true for humans, it will show that even one very heavy episode of binging across a couple of days could damage the brain. These effects were particularly pronounced in adolescent animals, raising some concern that teenage drinking may have more serious long-term consequences than we once thought.

Effects on Mental Functioning

Five areas of mental ability are consistently compromised by chronic alcohol abuse: memory formation, abstract thinking, problem solving, attention and concentration, and perception of emotion. As many as 70 percent of people who seek treatment for alcohol-related problems suffer significant impairment of these abilities.

Memory Formation

By memory formation we mean the ability to form new memories, not the ability to recall information that was learned in the past. That is, individuals with chronic drinking habits might vividly and accurately recall things learned early in life but may have difficulty remembering what they ate for lunch four hours ago. And the richness and detail of their memories during the past few years of drinking might be significantly less than in those earlier memories. On some tests of mental ability that assess different kinds of brain functions, chronic drinkers often perform just fine on most of the categories but perform poorly on the memory sections. This selective memory deficit may be a result of damage to specific brain areas, such as the hippocampus, the mammillary bodies, or the frontal lobes.

Abstract Thinking

By abstract thinking we mean being able to think in ways that are not directly tied to concrete things. We think abstractly when we interpret the meaning of stories, work on word puzzles, or solve geometry or algebra problems. Chronic drinkers often find these abilities compromised. One way to measure abstract thinking is to show someone a group of objects and ask her to group the objects according to the characteristics they share. Chronic drinkers will consistently group things based on their concrete characteristics (such as size, shape, and color) rather than on the basis of their abstract characteristics (such as what they are used for, or what kinds of things they are). It is as if abstract thoughts do not come to mind as easily for the chronic drinker.

Problem Solving

We all have to solve problems each day. Some are simple ones, like determining whether to do the laundry or the grocery shopping first. Some are more complicated, like setting up a new smart phone or deciding on what inventory to order for the next month’s needs in a business. In either case, one of the required abilities is mental flexibility. We need to be able to switch strategies and approaches to problems (particularly the complicated ones) to solve them efficiently. People with a history of chronic drinking often have a lot of difficulty with this. Under testing conditions, it often appears that they get stuck in a particular mode of problem solving and take a lot longer to get to a solution than someone who is better able to switch strategies and try new approaches. This difficulty could relate to the effects of chronic drinking on the “executive functions” of the frontal lobes.

Attention and Concentration

Chronic drinkers also develop difficulty in focusing their attention and maintaining concentration. This appears to be particularly difficult when related to tasks that require visual attention and concentration. Again, the deficits may not appear until the person is challenged. In casual conversation, the sober chronic drinker may be able to concentrate perfectly well, but placed in a more challenging situation (like reading an instruction manual, driving a car, or operating a piece of equipment), the person may be quite impaired.

Perception of Emotion

One of the most important elements of our social behavior is the ability to recognize and interpret the emotions of other people. Alcoholics have a deficit in the ability to perceive emotion in people’s language. There is a specific brain function that normally gives us the ability to detect attitude and emotion in conversation. It turns out that chronic, heavy drinking markedly reduces this ability. It is important to realize that this deficit is one of perception and does not reflect the alcoholic’s own emotional state. It’s as if the subtle things like the tone and cadences of the other person’s language that convey attitude and emotion are simply not perceived by the alcoholic. This is particularly interesting because we know that chronic heavy drinkers often have difficulty in social relationships. Perhaps this perceptual deficit causes some of these problems.

Do These Deficits Go Away?

Chronic heavy drinkers who quit recover these functions partially during the first month or two after the last drink. However, once this time passes, they have gotten back all that they will recover. It is difficult to identify precisely how much recovery occurs, but clear deficits do appear to persist permanently in these individuals. In one study, people who had quit drinking completely after many years of alcohol abuse were examined for seven years. Even after this time they had significant memory deficits. This persistent pattern of memory deficits in previous alcoholics is common enough to have a specific diagnosis. It is generally called either alcohol amnesic disorder or, in extreme cases, dementia associated with alcoholism.

What about “Social Drinkers”?

It is important to define exactly what we mean when we say that someone is a social drinker. The most consistent definition, looking across the literature on alcohol use and treatment, would be this: someone who drinks regularly but does not get drunk when drinking or have any of the clinical signs of addiction to alcohol. People who fit this pattern of drinking generally do not have nearly as severe deficits in mental functioning as those who drink heavily.

Among social drinkers, the pattern of alcohol consumption plays a very important role in determining whether the person will develop deficits in mental functioning. The more alcohol drunk during each drinking session, the higher the likelihood that mental deficits will develop. Consider two people

who each drink five drinks per week, on average. The first person has one drink on each of the five days of the week, and the second person has four drinks on each Saturday night and one in the middle of each week. The second person will be more likely to develop the kinds of deficits in the aforementioned abilities for chronic alcoholics. This is a particularly important point for young people, because heavy drinking on weekends is a typical pattern for many high school and college students as well as for young people in the work world.

It is difficult to say what amount of drinking over time will result in deficits in mental function. There have been many studies addressing this issue in different groups of people, and it’s very hard to boil all of these down to a clear and concise statement of risk. However, when all the complexities of the research are taken into consideration, it is reasonable to estimate that people who drink three or more drinks per day on average are at substantial risk of developing permanent deficits in certain cognitive abilities. This is not to say that drinking less is perfectly safe—indeed, we know that there are health risks associated with drinking less—but in terms of causing irreversible cognitive deficits, three drinks per day appears to be something of a threshold.


Development across Several Drinking Sessions

Tolerance means that after continued drinking, consuming an identical amount of alcohol produces a lesser effect—in other words, more alcohol is necessary to produce the original effect. The development of tolerance indicates that alcohol exposure has changed the brain. In some ways it is less sensitive to the alcohol, but in other ways it may remain quite sensitive. The brain effects that produce the high may diminish, while the effects that are toxic to the brain cells themselves may remain the same. Another problem is that as tolerance develops, the drinker may drink more each time to get the high. As we just learned, such a drinking pattern is more likely to produce deficits in mental functioning over time. Also, because the brain is the organ of addiction, the tolerant person who increases their drinking runs a greater risk of addiction. Finally, although the brain may need more alcohol to

produce the high, the liver and other internal organs are dealing with more and more alcohol, and they are at risk for permanent damage.

Development within One Drinking Session

Although tolerance to most alcohol effects develops gradually and over several drinking sessions, it has also been observed even within a single drinking session. This is called acute tolerance and means that the intoxication is greatest soon after the beginning of drinking. Acute tolerance does not develop to all the effects of alcohol, but it does develop to the feeling of being high. So, the drinker may drink more to maintain the feeling of being high, while the other intoxicating effects of alcohol (those that interfere with driving, mental function, and judgment) continue to build, placing the drinker at greater and greater risk.


It is important to distinguish between alcohol dependence and alcohol abuse. Generally, alcohol abuse refers to patterns of drinking that give rise to health problems, social problems, or both. Alcohol dependence (often called alcoholism) refers to a disease that is characterized by abnormal seeking and consumption of alcohol that leads to a lack of control over drinking. Dependent individuals often appear to crave alcohol. They seem driven to drink even though they know that their drinking is causing problems for them. In someone who is physically dependent, signs of alcohol withdrawal begin within hours after an individual stops drinking. They include anxiety, tremors (shaking), sleep disturbances, and, in more extreme cases, hallucinations and seizures. Until a chronic drinker actually stops drinking, it is quite difficult to make a definitive assessment of alcohol dependence. But for most practical purposes, this formal diagnosis is unnecessary, because the social and medical problems that most alcoholics experience should be recognizable to health professionals. See the section “How to Spot a Problem Drinker” on page 56 for some general guidelines.


The dangers of prenatal alcohol exposure have been noted since the time of Aristotle in ancient Greece. However, it was not until 1968 that formal

reports began to emerge. The early studies of fetal alcohol syndrome (FAS) described gross physical deformities and profound mental retardation among children of heavy-drinking alcoholic mothers. Although this was a very important set of findings, at first there was no evidence that women who drank more moderately were placing their children at risk. In fact, for many years, pregnant women were often encouraged to have a glass of wine with dinner or take a drink now and then during pregnancy to help them fall asleep or just to relax.

It took a while for the effects of moderate prenatal drinking to be noticed, because the children have none of the very obvious defects associated with the full-blown fetal alcohol syndrome. However, it is now clear that there is a less severe, but very well documented, pattern of deficits associated with more moderate prenatal drinking—a pattern described as fetal alcohol effects (FAE). School-age children with FAS or FAE are frequently described as hyperactive, distractible, and impulsive, with short attention spans—behaviors similar to those observed in children with attention deficit disorder (ADD). However, the FAS and FAE children differ from ADD children in that they are more intellectually impaired. In recent years the term fetal alcohol spectrum disorders (FASD) has emerged as an umbrella term to include the full range of neurological, cognitive, behavioral, and learning disabilities associated with prenatal alcohol exposure.

The impairments of intelligence and behavior in people with FASD appear to persist into adulthood and are probably lifelong, resulting in IQ scores markedly below average, often well into the moderately retarded range. Those with FAS scored worse than those with FAE, but both were significantly below normal, hampered in reading and spelling and most profoundly deficient in mathematical skills. More important, the FAE patients did not perform any better than the FAS patients on academic achievement tests, though their IQs were somewhat higher. What all this means is that even moderate drinking during pregnancy can create permanent intellectual disabilities. Some studies using animal models of FAE even suggest that just one drink per day impairs the function of brain areas related to learning in the adult offspring.

The bottom line is that there is no identified safe level of drinking during pregnancy. The smart decision for a woman is simply not to drink if she is pregnant or thinks that she might be. This advice may be important for

protecting more than the offspring who get exposed to alcohol in utero. Recent studies in animal models have indicated that brain abnormalities are present not only in the first generation’s offspring, but also in the offspring of those offspring—even if the second generation never had any alcohol exposure. Such transgenerational effects of fetal alcohol exposure on brain structure suggest that the alterations in gene expression caused by alcohol can be passed down to successive generations. Although we need to be careful not to assign undue importance to the results of early animal studies of this type, other areas of research have also begun to suggest transgenerational effects of environmental factors on gene expression. So, even taken with a grain of salt, these findings suggest that drinking while pregnant should be avoided.


Anyone can become dependent on alcohol. Continued exposure to alcohol changes the brain in ways that produce dependence. Although there are large differences in individuals’ risk for dependency and addiction, any person who puts enough alcohol into his brain over a long enough time will become physically dependent on the drug. Putting aside for a moment the risk factors that have been identified for alcohol dependence, the numbers generally show that the chances of a man becoming addicted to alcohol increase markedly if he drinks more than about three to four drinks per day. For women, the number of drinks is about three. Another consistent finding is that people who become addicted to alcohol are often those who report that they drink to relieve their emotional or social difficulties. In other words, if someone drinks to self-medicate—to block out emotional or social problems —he is especially likely to become addicted. But self-medication simply cannot account for all of the alcohol addiction in the world, and the big question remains: Why do some people choose to drink enough to get addicted?


Much of the evidence that genetic factors may lead to alcohol dependence has come from studies on twins and children of alcoholics who were adopted at birth and raised by nonalcoholic adoptive parents. Studies like these allow

researchers to begin to tease apart the separate influences of nature and nurture in the development of alcohol addiction. At present it seems clear that the basis of alcoholism is partly genetic but that genetic factors alone cannot account for the development of the disease. The real value of the nature versus nurture studies so far is that they have identified certain traits, or markers, that run in families and predispose people to alcohol dependence. Thus, they help to identify individuals who may be at risk for developing alcohol problems. If people know that they are at more risk than normal for this disease, then they can make better decisions about drinking.

It is very clear that alcoholism, like diabetes, runs in families. With no family history of alcoholism, the risk of developing alcohol abuse problems is about 10 percent for men and 5 percent for women. However, the risk nearly doubles if there is a family history of alcohol problems. For example, for women who have a first-degree relative (child, sibling, or parent) who is an alcoholic, the chances rise from 5 percent to 10 percent. For men with a first-degree relative who is an alcoholic, the risk goes from 10 percent to 20 percent. So, for both men and women, the risk is doubled. The risk goes to 30 percent for men and 15 percent for women who have both a first-degree relative and a second- (for example, uncle, aunt, grandparent) or third-degree relative (for example, cousin, great-grandparent) who is an alcoholic. So, being the child of an alcoholic increases the risk of developing alcohol abuse problems, but boys are at considerably more risk than girls.

It is important to know that these family studies do not conclusively demonstrate a genetic basis for alcoholism. It is likely that factors other than biological ones, such as being raised by an alcoholic parent, also contribute to drinking behavior. A number of studies show that being raised in a family in which alcohol is abused increases a child’s chances of becoming alcohol dependent.


Although genetic influences significantly affect the risk of alcoholism in both men and women, these influences appear to be particularly powerful in men. A number of studies compare the sons of alcoholic fathers with sons of nonalcoholic fathers. In general, it appears that the sons of alcoholic fathers are less impaired by alcohol than those of nonalcoholic fathers. However, early in the drinking session (when the pleasurable effects of alcohol

prevail), the sons of alcoholics appear to be more affected by alcohol than others. This difference suggests that sons of alcoholic fathers may have a more powerful experience of the pleasurable effects of alcohol and a less powerful experience of the impairing effects of alcohol than other men, creating a setup for these men to continue drinking over time and making them more susceptible to addiction.

In addition, a specific type of alcoholism seems to occur mostly in men. This is called Type II alcoholism and is characterized by an onset of drinking problems in adolescence, aggressive behavior, trouble with the law, and the use of other drugs. Type II alcoholism is considered to be very strongly influenced by genetics. Type I alcoholism is more common and less severe than Type II alcoholism, occurs in both men and women, and begins in adulthood. Men with fathers or brothers who show signs of Type II alcoholism should be particularly careful about alcohol use.


Health-care practitioners use several simple screening tests to assess whether an individual may have an alcohol problem. Before describing them, though, we must make two cautionary notes. First, a diagnosis of alcohol abuse, alcohol dependency, or alcoholism can only truly be made by a health professional trained specifically in addiction. These are very complex medical and psychological states, and no simple screening tool is adequate to make a foolproof assessment. Second, it sometimes does considerably more harm than good to confront a friend or relative with the impression that the individual may have a drinking problem. Although a concerned person may have the best of intentions and may be acting out of true concern, the other person may simply feel accused and withdraw from the very help being offered. The screening tests we describe in what follows are often used in doctors’ offices and clinics as a first indication that there might be a problem.

The most widely used screening test is called the CAGE:

• Have you ever felt the need to Cut down on your drinking?

• Have you ever felt Annoyed by someone criticizing your drinking?

• Have you ever felt Guilty about your drinking?

• Have you ever felt the need for an Eye-opener (a drink at the beginning of the day)?

If the person gives two or more positive responses to these questions, there is a good chance that there is some degree of an alcohol problem. But remember that screening tests are, by their nature, imperfect. For example, it is easy to imagine that a person with a history of heavy drinking might answer yes to all of the questions, even without having had a drink for years.

Another screening test, which has proven particularly useful with women, is called the TWEAK:

• Tolerance: How many drinks does it take to make you high?

• Worried: Have close friends or relatives worried or complained
about your drinking?

• Eye-opener: Do you sometimes take a drink in the morning to wake up?

• Amnesia (memory loss): Has a friend or family member ever told you things you said or did while you were drinking that you could not remember?

• (K)Cut: Do you sometimes feel the need to cut down on your drinking?
This test is scored differently from the CAGE, but a positive score of three or more is considered to indicate that the person likely has a drinking problem.
One final word of caution regarding these screening techniques: they all rely on one critical component (which is not always so reliable)—the person’s own responses. There are any number of reasons why a person might not respond fully accurately. Therefore, while these screening tools may be useful as a first-pass indicator of a possible problem, they must not be used in isolation to form impressions about a person.

Alcohol does not treat all people equally, and there are some big differences between the effects of alcohol on women and on men. As women have taken a more visible role in our society, they have found more freedom (and perhaps more encouragement) to drink. Consequently, drinking is on the rise among women in general. The percentage of women who drink alcohol has increased continually over the past fifty years, and the rate of this increase has also accelerated. At present about 69 percent of women drink and 9 percent engage in high-risk drinking, defined as having four or more drinks in a day. These recent findings represent marked increases in drinking among women, and are driven by large increases in the past fifteen years. So the impact of alcohol drinking on women’s health is becoming a more and more prevalent public health concern.

Women’s bodies differ from men’s bodies in a number of ways that make them react differently to alcohol. For one, women are generally smaller than men, and their bodies have a larger percentage of fat, which causes them to develop higher blood alcohol concentrations than men after drinking similar amounts of alcohol. There is also a chemical called alcohol dehydrogenase (ADH) that breaks down some of the alcohol in the stomach before it gets absorbed into the blood. Women under forty years of age appear to have less of this in their stomachs, so, compared to men, more of the alcohol they drink gets absorbed into the blood. In fact, after a given dose of alcohol, a woman may achieve a blood alcohol level 25 to 30 percent higher than a man. Women should know that they will likely be considerably more impaired than their male companions if they drink comparable amounts of alcohol.


Women who drink are at significantly greater risk for liver damage than men even if they drink less alcohol or drink for a shorter period of time. This increased risk has been reported for women who drink from one and a half to three drinks of alcohol per day and may be due to the differences in the way a woman’s body eliminates alcohol.

The pancreas, too, is more likely to be damaged by alcohol in women. The cells of the pancreas make chemicals that are used for digestion. When alcohol damages the pancreas cells, the digestive chemicals begin to leak out and can actually begin to digest the pancreas itself. Although this happens in both women and men, women tend to develop the disease sooner.

Women are also more likely than men to develop high blood pressure due to drinking alcohol. High blood pressure is one of the major causes of heart attack and stroke. Women who have two to three alcoholic drinks per day have a 40 percent greater risk of developing high blood pressure. The good news is that this additional risk diminishes when the woman stops drinking. Still, for women who drink even moderate amounts of alcohol, the increased risk of high blood pressure is substantial.

The risk of breast cancer is also increased in women who drink. The minimum amount of drinking that it takes to increase breast cancer risk has not been established. However, there is solid evidence that even as few as one to two drinks per day can increase a woman’s risk of breast cancer. And it does not take much more drinking to push the risk up considerably higher. For example, one analysis indicated that women who had two to four drinks per day increased their breast cancer risk by 41 percent while another showed that women who drank three or more drinks per day on average suffered a 69 percent higher risk of getting breast cancer.

Finally, women appear to be more sensitive to the effects of chronic alcohol drinking on brain function and seem to be more likely to show deficits in cognitive function.


Despite the increased acceptance of drinking by women during the past several decades, a number of studies have shown that women who drink a lot meet with more disapproval of their drinking than do men. In addition, the divorce rate for alcoholic women is higher than for alcoholic men. This suggests that women are less likely to leave relationships with alcoholic men than the reverse.


Anyone who has ever watched a commercial for beer can tell you that your sex life will improve considerably with drinking. The truth of the matter is that most of the effects of alcohol on sexual functioning are bad. Of course, some people may feel more suave and sexy after drinking, and may more easily convince themselves that their sexual prowess is unparalleled. But all

too often the mind makes a promise that the body can’t keep after a night of heavy drinking. Men, in particular, should consider the meaning of the term “brewer’s droop.”

As many as 40 to 90 percent of chronic male drinkers (depending on the study) report reduced sex drive. Chronic drinkers show reduced capacity for penile erection, decreased semen production, and lower sperm counts. One recent study showed decreased sperm counts in men who drank as few as five drinks per week. In fact, in alcoholic men the testes may actually shrink (a fact generally not presented in beer commercials). In extreme cases of chronic heavy alcohol abuse among men, a feminization syndrome can develop, which involves a loss of body hair and the development of breast tissue. Although these effects are most often seen in men who drink heavily over a prolonged period, some sexual and reproductive functions are impaired even by lesser intake. For example, evidence is accumulating that consuming two to three drinks per day may decrease sperm counts.


By far, alcohol is the drug used most often by high school students. Although most seniors cannot buy alcohol legally, 80 percent of them have tried alcohol and about one in five report that they have drunk heavily (more than five drinks in a row) in the past two weeks. This is actually good news, because the number of teens drinking heavily has declined somewhat in recent years. But that’s not the end of the story. Recent studies show that among students who engaged in heavy drinking, half had consumed ten or more drinks in one episode and a quarter had consumed fifteen. These levels of drinking are not limited to self-described heavy drinkers. Among US high school seniors, 10.5 percent reported drinking ten or more drinks in at least one episode in the past two weeks, and 5.6 percent reported drinking fifteen or more drinks in at least one episode in the past two weeks. So, while heavy drinking at the “low” end of the scale (about five drinks in an episode) has declined somewhat recently, the rates of extreme heavy drinking have remained high.

The story among college students is not as simple as the media sometimes portray. Reports of “binge drinking” among college students can be misleading. First, the term binge drinking is a bad one. Many people think of

an alcohol binge as a period of several days during which a person stays drunk nearly all the time. This, of course, is a very dangerous pattern of drinking but is not what is meant by the media when they report on binge drinking among college students. In that context, binge drinking refers to a man having five or more drinks in one sitting or a woman having four or more—clearly enough to put a person at risk for trouble, but hardly a binge in the traditional sense. We prefer to think of the four- or five-drink level as “high-risk drinking”—a more descriptive term. About 40 percent of college students report this level of high-risk drinking in the past two weeks, but there are also a significant number of college students who don’t drink at all —about 20 to 25 percent depending upon the college. So it’s important for students to know that, while a lot of students drink, not everybody on campus gets drunk every weekend, and a solid number of students don’t drink at all. Still, there are often negative consequences for those who do. Nearly 600,000 college students suffer unintentional alcohol-related injuries each year, and more than 1,800 die from those injuries. In addition, 25 percent of college students report negative academic consequences related to their drinking each year, and more than 150,000 develop a health problem related to alcohol use. Clearly, college drinking remains highly prevalent and continues to take a toll on students’ lives. Although much attention has been paid to drinking among college students, it’s important to remember that young, college-aged people who are not in school also drink. For quite a while the rate of high-risk drinking among non-college young people was lower than the rate for those in college. But now they have caught up.

The problems associated with underage drinking are well known, and in recent years research has continued to show that alcohol affects the brain of younger people very differently from the way it affects that of adults. Part of this may be related to brain development. For example, we know that the brain does not finish developing until a person is in his midtwenties and that one of the last regions to mature is the frontal lobe area, which is intimately involved with the ability to plan and make complex judgments. Young brains also have rich resources for acquiring new memories and seem to be “built to learn.” It is no accident that people in our society are educated during their early years, when they have more capacity for memory and learning. However, with this greater memory capacity come additional risks associated with the use of alcohol. Studies using animals have shown that when the brain is young, it is more susceptible to some of the dangerous

effects of alcohol, especially on learning and memory function. And one study in humans showed that people in their early twenties were more vulnerable to the effects of alcohol on learning than were people just a few years older, in their late twenties. So it appears that children and adolescents who drink are powerfully impairing the brain functions on which they rely so heavily for learning. This is already indicated by very detailed cellular studies on learning-related brain regions. In these studies (which, of course, can only be done using brain tissue from animals), it is clear that alcohol decreases the ability of brain circuits to change in the ways they must for learning to occur, and this effect is much more pronounced in the adolescent brain than in the adult brain. Additional strong words of caution come from animal studies that show the strong effects of alcohol on the ability of the brain to make new neurons. Normally, new brain cells are born in the hippocampus on an ongoing basis. Alcohol slows this process down—which may be part of the reason why it is so hard on learning and memory—and this slowing effect appears to be more pronounced in the brains of adolescent animals than in those of adults.

Although these studies suggest that alcohol has a more powerful effect on learning and learning-related brain functions in adolescents than in adults, there is at least one way in which the adolescent brain appears to be far less sensitive to the effects of alcohol—brain functions that make us sleepy are less activated by alcohol in adolescents, compared to adults. Again, it is only possible to do these studies in animals, but the results are striking. It takes much more alcohol to put an adolescent animal to sleep than it does for an adult. And even at the level of single brain cells, the kinds of brain functions that promote sedation (sleepiness) are activated far less in the brains of adolescent animals than in adults. This could mean that an adolescent may be able to drink far more than an adult before feeling sleepy enough to stop and along the way be impairing cognitive functions more than an adult would be. It is also important to recognize that sleepiness is one of the effects of alcohol that many people find unpleasant, rather than reinforcing. Most people like the initial buzz that they get after their first drink or two, but they find the sedation that follows that third or fourth drink to be aversive, thus providing motivation to stop drinking. But if the sedative effect is less powerful in adolescents or it takes more alcohol to get them sleepy, then they will be less likely than adults to stop drinking as the dose increases.

As research accumulated, showing that acute doses of alcohol affect the adolescent brain differently from the adult brain, scientists began to ask whether this might also mean that the adolescent brain is more vulnerable to the negative long-term effects of repeated drinking. As usual, animal studies came first, and there have now been a lot of them! One early study showed that rats given alcohol during adolescence were more susceptible to having disrupted memory function in adulthood. Importantly, rats who got the same kind of repeated alcohol exposure first as adults did not show similar long- term vulnerability. This suggests not only that repeated alcohol exposure during adolescence has long-term effects on memory, but also that adolescence is a particularly vulnerable time for inducing such long-lasting effects. Some studies have looked at the long-term effects of adolescent alcohol exposure without comparing the effects of similar exposure in adulthood. Such studies are important for understanding the enduring effects of adolescent drinking, but don’t address the question of whether adolescents are more sensitive to those enduring effects than adults. For example, other animal studies have now shown long-lasting effects of adolescent alcohol exposure on social behavior (including risk-taking) and some other behaviors related to frontal lobe and “executive” functions. And the long- term effects of adolescent alcohol exposure in animals are not limited to behavior.

During the past ten years many studies have shown changes in brain structure and function after adolescent alcohol exposure. For example, a recent study showed that the number of tiny “spines” that sit on the surface of neurons and receive incoming information from other neurons is markedly decreased in adult animals that had received repeated alcohol doses as adolescents. That decrease seems to have been caused by an increase in the expression of a specific gene that is known to regulate spine development. So some clues are emerging that might tell us more about the causes of those alcohol-induced changes at the molecular level, and clues like that can hold great promise for understanding how to prevent or reverse such negative effects. But those studies are just beginning. Other studies show that when alcohol is given to animals, the functioning of brain cells can be altered at a very basic level, changing the ways in which they process and react to incoming information. And these effects are very long-lasting. What’s particularly interesting (and disturbing) is that some of these changes in basic cellular functioning occur far more strongly when the alcohol exposure

occurs during adolescence as compared to adulthood. In other words, it appears that adolescence is not only a time when single doses of alcohol affect the brain differently but also a time of enhanced vulnerability to the long-term effects of repeated alcohol exposure—even down to the level of individual brain cells.

As promising as those basic studies in animal models are, we are always cautious in our interpretations, and it’s important to look at what we know from studies of people as well. Some brain imaging studies suggest that drinking during the teen years might be particularly bad for the hippocampus (the brain region that is critical for learning new information). The data indicated that people in their twenties who had used alcohol heavily as teens had smaller hippocampal volumes than people in their twenties who had not used alcohol heavily during adolescence. It’s important not to overinterpret this kind of study—it could be that those people had smaller hippocampi to begin with—but the data should at least be seen as another word of caution about teen drinking. But other recent studies have taken steps to avoid this chicken-and-egg problem and are beginning to show long-lasting negative cognitive effects of adolescent drinking, largely in the domains of memory and frontal lobe (executive) function. For example, one study followed a cohort of adolescents across a ten-year period and found that heavy alcohol use was associated with poorer verbal memory scores over time. A similar study of college students across the transition from late teens to early twenties indicated deficits in memory and executive functions in those who consumed alcohol regularly at “binge drinking” levels, and another multiyear study across the teen years showed deficits in verbal memory and visual- spatial processing late in adolescence among those who drank at high levels. Those same researchers recently reported a six-year longitudinal study in which participants’ ages extended into the twenties, and found adolescent drinking was associated with lower verbal learning scores and deficits in the ability to recall previously learned information.

Studies of brain structures after adolescent drinking tell a similarly cautionary tale. One study looked at brain structures associated with learning and executive function and found that normal developmental patterns were altered across an eight-year period between adolescence and the midtwenties among individuals who engaged in heavy drinking during adolescence. At present, studies of this type have followed subjects as far as the mid- to late twenties, and future studies of data from those later time points will tell us a

lot about how long deficits persist after heavy adolescent drinking. From our standpoint, the convergence of basic scientific studies in animal models and newly emerging studies in human adolescents and young adults adds to a strong and growing scientific literature that tells us adolescents should hold off on drinking. The emerging bottom line seems to be that repeated alcohol exposure during adolescence has lots of negative effects on the developing brain, some of which appear to persist into adulthood.

Another very good reason for teens to hold off on drinking is that there is a very strong relationship between the age at which one starts to drink and the likelihood of developing dependence on alcohol. People who start drinking in their early to midteens are far more likely to develop alcohol dependency, and to experience recurring episodes of dependency, than are people who start drinking at age twenty-one or older. There are certainly a number of reasons for this increased risk, and not all of them are biological, but it is clear from animal studies that adolescents develop tolerance to some of alcohol’s effects more rapidly than adults. In humans this could lead to a greater motivation to drink repeatedly. So, although it has always been controversial, our current state laws requiring a person to be twenty-one to drink make good sense from this perspective.

Most parents tend to be clueless when it comes to their children’s drinking. For example, while about 40 percent of tenth graders report having drunk alcohol in the past year, only 10 percent of parents of tenth graders believe that their child has consumed alcohol in that period. Interestingly, parents report believing that about 60 percent of tenth graders have consumed alcohol within the past year. So parents actually tend to overestimate the proportion of kids who drink—they just don’t think it’s their kids who are drinking! There are similar gaps between older teens’ reported drinking and parents’ beliefs about their drinking. Parents of twelfth graders are starting to see the light, but they still underestimate their kids’ drinking significantly. The important message for parents is that alcohol is out there and its use is getting thrust at their children from many angles. Talk to your children about alcohol, how it works, and the ways in which they are likely to encounter it.



Clearly the most dangerous drugs to mix with alcohol are other sedatives, or “downers,” such as phenobarbital and pentobarbital. The depressing effects of alcohol on brain function combined with the effects of the barbiturates can cause extreme impairment, unconsciousness, or even death. One of the most famous cases in medical ethics was that of a young woman, Karen Ann Quinlan, who drank alcohol in combination with Quaaludes (methaqualone— a powerful sedative drug) and went into a coma from which she never recovered. This tragic case gained national attention because it raised the issue of whether a person should be removed from life-support machines after it becomes clear that he or she will never recover from a vegetative state.

Although few people take alcohol-sedative combinations severe enough to cause coma or death, the combination of even relatively low doses of alcohol and sedatives can be dangerous, powerfully impairing the ability to think clearly, make good decisions, or drive a car. A person who is normally able to perform these tasks perfectly well at the end of an evening after having had three or four beers over the course of several hours might be totally unable to perform them if even a small dose of sedatives is added to the mix. The effects of the alcohol may be totally unexpected in the presence of the other sedative drug.

Antianxiety Medications

Antianxiety medications, such as Valium, Librium, and so forth, fall into the general category called benzodiazepines and are used to treat anxiety, sleep disturbances, and seizures. They are also used to treat alcohol withdrawal symptoms in detoxification clinics. These drugs are sedating and may cause severe drowsiness in the presence of alcohol, increasing the risk of household and automobile accidents.


In combination with acute doses of alcohol, some antibiotics can cause nausea, vomiting, headache, or even convulsions (seizures). Among the potentially dangerous ones are Furoxone (furazolidone), Grisactin (griseofulvin), Flagyl (metronidazole), and Atabrine (quinacrine).

Anticoagulants (“Blood Thinners”)

Warfarin (Coumadin) is prescribed to decrease the blood’s ability to clot. Alcohol increases the availability of warfarin in the body and increases the risk of dangerous bleeding. But in chronic drinkers, warfarin’s action is decreased, lessening these patients’ protection from the consequences of blood-clotting disorders.


Many people who are depressed use alcohol, and many alcoholics are also depressed. So, it is quite common for people to use alcohol with antidepressant drugs. Alcohol increases the sedative effects of the tricyclic antidepressants such as Elavil (amitriptyline). This impairs both mental and physical skills such as those necessary for driving. Chronic drinking appears to increase the action of some tricyclic antidepressants and decrease the action of others. Anyone who is on antidepressants should consult closely with their doctor about how the medication reacts with alcohol.

Antidiabetic Medications

Orinase (tolbutamide) is given orally to help lower blood sugar in diabetic patients. Acute alcohol drinking prolongs the action of this drug, and chronic drinking decreases its availability in the body. Alcohol can also cause nausea and headache when taken with some drugs of this class.


Antihistamines such as Benadryl (diphenhydramine) are available without a prescription and are used to treat allergic symptoms and sometimes

insomnia. They have sedative effects that may be intensified by alcohol, increasing the probability of accidents. In older persons these drugs can cause excessive dizziness and sedation, and their combination with alcohol may be particularly dangerous.

Antipsychotic Medications

Drugs such as Thorazine (chlorpromazine) are used to treat psychotic symptoms such as delusions and hallucinations. Acute alcohol drinking can increase the sedative effects of these drugs, resulting in impaired coordination and potentially fatal suppression of breathing.

Antiseizure Medications

One of the most widely used drugs prescribed to treat epilepsy (seizures) is Dilantin (phenytoin). Acute alcohol drinking increases the availability of Dilantin in the body and increases the probability of side effects. Chronic drinking may decrease the availability of Dilantin, dangerously hampering its effectiveness and increasing the patient’s risk of seizures.

Heart Medications

There are many medications used to treat disease of the heart or circulatory system. Acute alcohol drinking can interact with some of these to cause dizziness or fainting upon standing up. These drugs include the angina medicine nitroglycerin and the blood pressure medication Apresoline. In addition, chronic alcohol drinking reduces the effectiveness of the blood pressure medication Inderal (propranolol).

Narcotic Pain Relievers

These drugs (for example, morphine, Darvon, codeine, Demerol) are prescribed for moderate to severe pain, such as after surgery or dental work. The combination of any of these drugs with alcohol magnifies the sedative

effects of both, increasing the risk of death from overdose. This is one of the most common drug combinations to cause accidental overdose deaths.

Non-narcotic Pain Relievers

Some nonprescription pain relievers such as aspirin, Advil, and Aleve can cause stomach bleeding and prevent the blood from clotting normally. Alcohol can worsen these side effects. In addition, aspirin may increase the availability of alcohol within the body, thereby increasing the intoxicating effect of a given drink. As we stated before, the combination of Tylenol (acetaminophen) and alcohol can result in the formation of chemicals that can cause liver damage. This can occur even when the pain reliever is used in recommended doses and even if it is taken after drinking as a treatment for hangover.


It is perfectly clear that heavy drinking, either in one session or across decades, carries with it significant risks to health and safety. However, alcohol is not all bad. Used in an informed and moderate way, alcohol can convey some health benefits. For example, the similarity of its actions to those of antianxiety medications such as Valium makes alcohol a potent antianxiety agent for some people. The feeling of relaxation that accompanies an occasional drink of alcohol can help to reduce stress, and stress reduction is healthy. But remember: people who use alcohol heavily or too regularly as a way of coping with the difficulties in their lives are at considerable risk for becoming addicted. Ultimately, the use of alcohol for relaxation and stress reduction is a personal choice that must be made in as informed a way as possible.


There is no doubt that chronic heavy drinking damages the heart. However, recent studies show that light (and perhaps moderate) drinkers have a reduced risk for coronary artery disease—a principal cause of heart attacks.

Remember, though, that this research is still developing, and it is not possible to arrive at an exact “prescription” of alcohol use for cardiovascular protection. Still, a growing number of studies suggest that an average of a half to one and a half drinks per day may significantly lower a person’s risk for coronary artery disease.

A study from Harvard Medical School further supports these early findings—at least in men. A group of more than 22,000 men who ranged in age from forty to eighty-four were studied over a ten-year period. Compared to men who drank less than one alcoholic beverage per week on average, those who drank two to four alcoholic beverages per week were significantly less likely to die of a heart or circulatory disorder. These light-drinking men also suffered fewer cancers over the ten-year period. However, among men who drank two or more drinks per day, the death rate was 51 percent higher. This means that there is a narrow window for the possible health benefits of alcohol for men. Two drinks per week seem to be good; two drinks per day seem to be bad.

For women, however, these findings present a double-edged sword. Moderate alcohol drinking appears to reduce the risk of cardiovascular disease in women. But studies have also shown that women who drink an average of three to nine drinks per week are significantly more likely to develop breast cancer than women who do not drink. Still, the causes of breast cancer are quite complex and much work remains to determine the exact relationship of alcohol drinking to breast cancer. Women who choose to drink moderately, for whatever reasons, should keep in close touch with the latest information related to breast cancer risks.


There have been several large-scale studies, in both Eastern and Western countries, indicating that light to moderate drinking may diminish the risk of death in middle-aged men. A study in China showed that men who drank one to two drinks per day over a six-and-a-half-year period reduced their risk of death by about 20 percent—a finding that is consistent with studies in European countries. The protective effect was not limited to death from heart disease—the drinkers were also less likely to die from cancer or other causes. Further, the particular type of alcoholic beverage consumed was inconsequential: Beer drinkers, wine drinkers, and drinkers of hard liquor

shared equally in the benefits, as long as their consumption was not more than an average of two drinks per day. Beyond that level the risk of death was increased by about 30 percent. Alcohol appears to have some similar protective effects in women. But, as just noted, women are also more vulnerable to some of the negative effects of alcohol, so most studies suggest no more than one drink per day for women. With respect to deaths from cardiovascular causes, a 2017 study of over 300,000 participants indicated that the risk of dying from cardiovascular disease is about 20 to 30 percent lower in light drinkers, and this benefit was experienced by both men and women.

The bottom line seems to be that if you want to get the medicinal effects of alcohol, you have to take it like medicine—a little at a time.

Drug Class: Stimulant



Individual Drugs: coffee (75–150 mg per 8 oz cup), tea (30–60 mg per 8 oz cup), soft drinks (20–50 mg per 12 oz serving), energy drinks (30–80 mg per 8.4 oz serving), other energy formulations (concentrations vary), over-the-counter pain relievers (30–70 mg), over-the-counter stimulants (100–200 mg), some prescription medications (concentrations vary)

The Buzz: At low to moderate doses, many people report increased alertness and ability to concentrate, and even euphoria. Higher doses can result in nervousness and agitation.

Overdose and Other Bad Effects: Fatal overdose with caffeine is extremely rare, but it is possible. Some symptoms of caffeine poisoning include tremors (involuntary shaking), nausea, vomiting, irregular or rapid heart rate, and confusion. In extreme cases, individuals may become delirious or have seizures (convulsions). In these cases, death may be caused by seizures that result in an inability to breathe. In less severe cases, high doses have been associated with panic attacks.

In small children, toxic effects may be observed with doses of around 35 milligrams per kilogram (about 800 milligrams in a fifty-pound child). This level could be achieved by taking four Vivarin tablets or drinking about seven cups of strong coffee.

Dangerous Combinations with Other Drugs: Caffeine can raise blood pressure, so some physicians caution hypertensive patients, or those who experience irregular heartbeats, to limit their use of caffeine. In addition, it should be used cautiously by people who are taking other drugs that can raise blood pressure. These drugs include antidepressants that are MAO inhibitors, such as Marplan, Nardil, and Parnate, as well as high doses of cold medicines that contain phenylpropanolamine. Because caffeine is a stimulant, it can add to the effects of stronger stimulants such as cocaine, amphetamine, or methamphetamine.


A Brief History
How Caffeine Moves through the Body How Caffeine Works
Effects on the Brain
Effects on Other Body Parts

The Heart
The Kidneys
The Digestive System
The Respiratory System
Pregnancy and the Reproductive System The Eyes

Caffeine and Stress
Caffeine and Panic Attacks Enhancement of Physical Performance Positive Health Effects
Caffeine and Calcium
Treatment of Headaches
How We Take Caffeine

“Energy” Drinks Over-the-Counter Drugs Chocolate

Toxicity of Caffeine


It is difficult to write a brief history of caffeine because the history of its use in human culture is very old and very detailed. Today, caffeine is found in a variety of sodas, “energy” drinks, pain relievers, and other medications, but historically, coffee, tea, and chocolate were the caffeine-containing products consumed by people. The origins of tea use can be traced back to China in the fourth century, when it was thought to have significant medicinal properties. In the 1500s, medical uses also fueled interest in tea in Europe, but soon its stimulant actions came to be appreciated as well. Some ancient legends suggest that the effects of coffee beans on their early users were so powerful that they were thought to have powers given by divine intervention. These legends also indicate that the stimulant properties of these beans were appreciated and sought after from the very beginning. One often- cited story describes how a goat herder began chewing coffee beans after he observed the stimulating effects of the beans on his herd. Soon he and others began chewing the beans regularly to maintain their stamina and concentration through long, isolated hours of work.

Coffee was first cultivated in Yemen in the sixth century. However, many religious leaders of the time thought poorly of coffee, contending that it gave rise to personal (and political) treachery. On the other hand, users enjoyed its ability to combat fatigue and enhance physical endurance. Among some it gained a reputation for stimulating thought and intellectual conversation.

By the 1600s, trade merchants had introduced coffee to Europe, and “coffeehouses” spread rapidly. One of the hallmarks of these establishments was intellectual conversation. Not all of this conversation was viewed as politically correct, however, and coffeehouses were outlawed in England. That ban was very brief, and the growth of coffeehouses and the use of coffee spread even more rapidly thereafter. In fact, coffeehouses came to be known as places where one could go to learn from notable academic and political figures of the day. The environment created in coffeehouses turned out to be one that gave rise to creative thinking in the entrepreneurial and business realms as well. As an example, the giant insurance firm Lloyd’s of London actually began as a coffeehouse in the early 1700s.

Coffee and the United States have a strong relationship. Although tea was the caffeinated drink of choice in the English colonies for quite a while, the British Stamp Act of 1765 and the Trade Revenue Act of 1767 levied high taxes on the importation of tea to the colonies. This, of course, gave rise to the tide of rebellion that was symbolized so powerfully at the Boston Tea Party, ushering in the Revolutionary War. In protest of the tea taxes, coffee became our caffeinated drink of choice. By the 1940s, coffee consumption in the United States reached a high of around twenty pounds per person per year. Though by the early 1990s that level had

dropped to ten pounds per person per year, this did not mean that Americans were cutting their caffeine consumption in half. While the consumption of coffee was falling off, the consumption of caffeinated soft drinks was growing rapidly. But coffee made a big comeback. Specialty coffee shops and cafés began to spring up on the West Coast in the 1980s, and they have spread across the nation. Americans are now consuming more varieties of coffee and more types of coffee drinks than ever before. It is estimated that more than 80 percent of American adults drink coffee every day—at an average of about three cups each.

Finally, we cannot leave the history of caffeine without mention of another caffeine-containing delight—chocolate. Chocolate was actually introduced to Europe before either coffee or tea, but it did not become popular as rapidly because it was presented mostly as a thick preparation made from processed and ground cacao kernels. In the 1800s, the Dutch developed a process that removed much of the fat from this crude preparation, and the result was a more refined chocolate powder. The fat that was removed was then combined with sugar and the chocolate powder, and the result was the birth of the chocolate bar in the 1840s. As the technology for producing chocolate became better known in Europe, its use spread rapidly. Dark chocolate contains about twenty milligrams of caffeine per ounce. That means that a four-ounce bar of chocolate would contain approximately eighty milligrams of caffeine—about the same as in a cup of percolator-brewed coffee.


Caffeine is almost always taken by mouth, and so it is absorbed into the blood primarily through the linings of the stomach, small intestine, and large intestine. It is only slowly absorbed through the stomach, and so most absorption occurs at the next step along the gastrointestinal tract, the small intestine. However, once it reaches the intestines, virtually all of the caffeine that was ingested is absorbed. A given oral dose of caffeine takes full effect within thirty to sixty minutes, depending upon how much food is in the stomach and intestines and how concentrated the caffeine is in the substance that contains it.

Caffeine is evenly distributed throughout the body, metabolized by the liver, and its breakdown products are excreted through the kidneys. The body eliminates it rather slowly, with the half-life of a given dose of caffeine being approximately three hours. Thus, some of the caffeine that one consumes in the morning is still around well into the afternoon. A person who drinks several cups of coffee or caffeinated sodas across a morning or afternoon is adding on to an existing load of caffeine with each subsequent drink and may end up feeling rather jittery by the end of the day.


Caffeine is the best known of a class of compounds called xanthines (pronounced “zan-theenez”). Theophylline, another xanthine found in tea, is prescribed for breathing problems because it relaxes and opens breathing passages. However, there is so little of it in brewed tea that it exerts no significant stimulant effects in that form. In addition to a small amount of caffeine, chocolate contains theobromine, another xanthine, but one with far less potency than caffeine.

All the xanthines, including caffeine, have multiple actions. The major action is to block the action of a neurotransmitter/neuromodulator called adenosine, which is in the brain (more on this in the following). There are also adenosine receptors throughout the body, including those in blood vessels, fat cells, the heart, the kidneys, and many types of smooth muscle. These multiple actions create a confusing picture because the direct effects of caffeine on a system can be enhanced or suppressed by indirect effects on other systems.


Adenosine receptors, the main site of caffeine action, cause sedation when adenosine binds to them. Adenosine, a by-product of cellular metabolism, leaks out of cells. So, as neurons become more active, they produce more adenosine, and this provides a “brake” on all the neural activity—an ingenious self-regulation by the brain. Caffeine thus produces activation of brain activity by reducing the ability of adenosine to do its job. This is a good example of how a drug can produce an effect (in this case, central nervous system [CNS] stimulation) by inhibiting the action of a neurotransmitter that produces an inhibiting effect (a positive coming from two negatives). At moderate doses of around 200 milligrams (about what you get from one to two cups of strong coffee), electroencephalograph (EEG) studies indicate that the brain is aroused. Higher doses, in the range of 500 milligrams, increase heart rate and breathing. Activation of these centers also causes a constriction, or narrowing, of blood vessels in the brain (though outside the brain caffeine has a direct effect on blood vessels that does just the opposite—dilating, or widening, them).

Caffeine also lowers the amount of blood flow within the brain. It seems strange at first that a drug with such strong stimulant effects in the brain would actually decrease blood flow within the brain. But studies have shown that a dose of 250 milligrams (about what you get from two to three cups of coffee) reduces blood flow by nearly one-fourth in the gray matter of the brain (made up mostly of nerve cells) and by about one-fifth in the white matter through which fibers connect groups

of nerve cells into functioning circuits. The fact that caffeine has such powerful stimulant effects despite its decrease of cerebral blood flow underscores how powerful its stimulant effects really are. Further, the effects of a single dose of caffeine on cerebral blood flow were the same in heavy caffeine users and in light users, indicating that the blood flow effect is not one to which people become tolerant.

People may develop a mild tolerance to some of the effects of caffeine, but most tolerant people can achieve an arousing effect by increasing the dose. The tolerance that develops to the brain-arousing effects of caffeine is less severe than the tolerance that develops to some of its effects on other parts of the body (see the following).

Dependence on caffeine can develop as well, as indicated by the occurrence of withdrawal symptoms when caffeine intake is abruptly stopped. Between twelve and twenty-four hours after the last dose of caffeine, users generally experience headaches and fatigue that may persist for several days to a week but that are usually strongest during the first two days after quitting. Nonprescription pain relievers such as acetaminophen (Tylenol) or ibuprofen relieve the headaches, and moderate doses can be taken throughout the withdrawal period—just be careful to avoid taking pain medications that include caffeine (see table, page 93).

Many people have found that they enjoy, and indeed rely on, the psychological effects of caffeine. While this wouldn’t meet our definition of addiction, most caffeine users find the effects pleasant enough to continue using this drug. Therefore, those who decide to quit should also be prepared to give up those caffeine-aided feelings of alertness and mild euphoria, which may have become a very regular and important part of each day. A related issue is that people who drink caffeinated beverages often do so at the same or similar times of day. In that way the drinking itself may become a part of important daily rituals. It is important to anticipate that changing those rituals may be difficult as well.


Caffeine affects the heart in two ways: it acts on brain centers that regulate the cardiovascular system, and it acts directly on the heart. In people who are not tolerant to caffeine, a high dose (generally above 500 milligrams—about four cups of strong coffee) can increase the heart rate by as much as ten to twenty beats per minute (from a baseline of eighty to ninety). In some, this dosage can result in brief

periods of irregular heartbeat. However, in general, the morning cup of coffee does not have much effect on heart function in a healthy person.

There is controversy over the issue of caffeine and the gradual development of heart disease. At present, the scientific literature is inconsistent in its findings on the question of whether continued caffeine use increases the risk of heart disease or heart attack. One very large study of men found no relationship between coffee drinking and heart disease, while others have found an increased risk of heart attacks in coffee drinkers. In 2017 a very large meta-analysis was published in the Annual Review of Nutrition. (A meta-analysis is like a study of studies, in which researchers look back over years, and sometimes decades, of research papers on a specific topic in an effort to draw broad conclusions.) The conclusion they drew was that caffeine use up to a few cups a day had a small (5 percent) but meaningful protective effect against cardiovascular disease. So it seems that moderate caffeine consumption (up to 500 milligrams per day) probably does not place the user at significant risk for heart problems. Above that level, however, the risk of heart attack may increase. This would be particularly true for individuals with other risk factors for heart attack, such as smoking, being overweight, or having a family history of heart disease.

Caffeine is also known to increase blood pressure, so people with high blood pressure should be careful about how much coffee they drink, and some cardiologists recommend that patients with high blood pressure or a history of irregular heartbeats reduce their caffeine intake or avoid caffeine altogether. In people with normal blood pressure it generally takes rather high doses to produce significant elevations of blood pressure.


An association between coffee drinking and cholesterol levels has been suspected for some time, yet it remains controversial. It is safe to say that the relationship has not been ruled out, but the picture remains unclear. One solid study has shown that five to six cups of coffee per day can increase LDL cholesterol levels (this is the “bad” type of cholesterol as far as risk of heart disease is concerned) by 10 percent or more. This is not the case, however, if the coffee is prepared using a paper filter. While it is not clear exactly why filtered coffee fails to raise cholesterol levels, it is likely that oils from the coffee beans and other substances that promote fat buildup in the blood are trapped by the paper filter as the water passes over the coffee grounds.


The well-known bathroom break that follows the morning coffee is probably caused both by a direct effect on the kidneys and by effects in the brain. There are adenosine receptors in the kidneys and caffeine acts on these, causing effects similar to those of diuretics, which increase urine production. Caffeine may also slow the release of an antidiuretic hormone from the brain that normally slows urine production.


In coffee drinkers, the acids, oils, and caffeine can all irritate the stomach lining and promote secretion of acid, leading to gastritis (inflammation of the stomach). However, caffeine may not be the major villain, as decaffeinated coffee has effects almost as great as caffeine-containing coffee. Although coffee was once blamed for ulcers, the primary cause of ulcers is now thought to be bacteria (Helicobacter pylori). Irritating agents like coffee and aspirin can contribute to the process by damaging the protective mucous lining of the stomach walls, but they probably don’t cause ulcers on their own. In some individuals, caffeine in coffee can promote the reflux of stomach acid into the throat, resulting in painful heartburn.


Caffeine and similar drugs have two quite separate effects on breathing. The first was already mentioned: they stimulate the rate of breathing. Theophylline is sometimes used in treating premature infants with breathing problems. Xanthines also relax the smooth muscle in the bronchioles that take air into the lungs. This is very helpful in treating asthma, a disease in which breathing difficulties arise because these tubes constrict. Theophylline was used widely in the past to treat asthma and is still sometimes used today. However, concerns about side effects (restlessness, stomach upset) and the development of more effective treatments have diminished its use.


A number of studies in animals over the years have indicated a link between caffeine consumption and birth defects, and some early studies in humans have suggested that babies born to women who used caffeine during pregnancy have lower birth weights. Those findings remained controversial for quite a few years, but now it seems clear that caffeine exposure during pregnancy can be harmful in humans. The meta-analysis described above found that caffeine use during pregnancy was associated with elevated risk for a number of adverse outcomes. These included low birth weight and loss of pregnancy. Because caffeine easily

reaches the fetus, and certain aspects of caffeine breakdown are reduced during pregnancy, the fetus may be exposed to caffeine for quite a long time with each dose, and that could impair fetal growth. There is also some evidence that caffeine consumption (equivalent to more than one cup of coffee per day) can significantly reduce the chances of a woman becoming pregnant. Finally, there have been contradictory findings about the association between caffeine use and fibrocystic breast disease and eventual development of breast cancer. But the most recent studies do not support an association with the development of breast cancer.


Caffeine causes the tiny blood vessels in the eyes to constrict (become narrower) and thus decreases the flow of nutrients to the cells within the eyes and the clearing of waste products.


Caffeine increases some of the normal stress responses because it increases the amount of adrenaline that is active in the body under stressful circumstances. Thus, it seems that caffeine users who find themselves under stress (or who use caffeine even more during stressful periods to work more effectively) may experience more of the effects that stress can produce. Adrenaline release increases blood pressure during stress, and the caffeine-induced rise adds to this. Thus, caffeine and stress together lead to greater bodily stress responses than either does alone.


In some people, caffeine can contribute to the experience of panic attacks, which generally come on suddenly and involve powerful feelings of threat and fear. The experience can be very debilitating for a brief period of time. It seems that caffeine is more likely to bring on panic attacks in people who have had them previously. However, relatively high doses of caffeine (greater than 700 milligrams) have been reported to lead to panic attacks in people who have never experienced them.


Caffeine can slightly enhance physical endurance and delay fatigue associated with vigorous exercise in some people. One way that caffeine might accomplish this is by releasing fats into the blood for use as energy, enabling the body to conserve its

other energy stores (in the form of stored sugars), thus allowing the athlete to sustain physical activity for a longer period of time. Caffeine may also help muscle performance during physical exercise, although the way this happens is not clear. What we do know is that caffeine dilates the bronchioles, making it easier for air to pass into the lungs. This would seem to have a beneficial effect on certain types of physical performance. In one recent study of highly trained competitive cyclists, chewing gum that contained caffeine improved the cyclists’ sprint performance power during the final third of a 30-kilometer time trial. This was true for both male and female cyclists. Although many physiological measures were taken in the study, it was not possible to determine what specific bodily functions were responsible for the improvement; however, the researchers were able to conclude that the

effects were most likely due to increases in brain activity rather than effects on muscle or respiratory function. Still, the breadth of research remains somewhat inconsistent. In some cases there appear to be performance-enhancing effects, and in others there are none. So the jury remains out.

Two words of caution, though, for those who use caffeine for this purpose. Because caffeine causes an increased loss of water through urine production, a person exercising on caffeine may become dehydrated more rapidly during long periods of exercise such as distance running or cycling. This caution is particularly important for hot-weather exercisers. The other concern is the effects of caffeine on heart rate and heart rhythms. Strenuous exercise obviously stresses the heart, so a person with cardiovascular disease could experience problems while using caffeine to promote physical performance.

People who worry about their weight might be interested in the issue of fat metabolism. Products based on the supposed ability of caffeine and theophylline to “burn fat” include a theophylline cream placed on the market several years ago that was supposed to melt fat away. Just rub it on the offending fat pad! Unfortunately, the effectiveness of this treatment hasn’t been established (one big problem is probably getting the theophylline through the skin and into the fat cells).

Likewise, there is tremendous interest in whether a combination of caffeine and exercise can help to promote the burning of fat as fuel for weight loss. Fat cells really do have adenosine receptors, and xanthines really can cause a small release of stored fat, so some foods that include caffeine have been sold as fat burners. However, the scholarly research on these products has demonstrated only small weight-loss effects. Coffee and its cousins may prove to be a useful part of weight- loss programs in the future, but at this point nothing “melts” fat except old-fashioned exercise and a healthy diet.


Although we always urge caution when interpreting correlational studies, a large study based at the National Cancer Institute collected health data from more than 400,000 individuals in their fifties and sixties starting in 1995 and following them for thirteen years. Across that time, men who drank two or three cups of coffee per day were 10 percent less likely to have died, and women were 13 percent less likely to have died. The study was not designed to answer the question of why coffee drinking was associated with better survival, but the findings are worth knowing about. More recent studies of the same type suggest that moderate caffeine use may help protect against a number of types of cancer, possibly due to caffeine’s ability to enhance the body’s natural mechanisms for DNA repair. Some recent studies have also indicated that coffee may have some positive health effects by altering the gut microbiome (the balance of different types of bacteria in our gastrointestinal tracts). For example, coffee is known to be anti-inflammatory, and reducing inflammation can have wide-ranging positive effects on health. There are now studies in both humans and animal models suggesting that the anti-inflammatory effects of coffee may be related to its effects on the gut microbiome. There are also some studies that suggest a protective effect of caffeine use against the development of some neurodegenerative diseases, specifically Parkinson’s disease and Alzheimer’s disease. Caffeine has been shown to help protect neurons by virtue of its inhibitory actions at adenosine receptors, so this type of protective action could reduce the chances of developing such diseases. But before you run out and start up a heavy caffeine habit in order to preserve your brain function late in life, it would probably be wise to wait for specifically designed randomized clinical trials to confirm the correlations. Still, with moderation in mind, it does seem that caffeine has some health benefits, so there’s little reason to stop using it (unless you are pregnant or planning to become pregnant).

With respect to Alzheimer’s disease, specifically, several studies have indicated that caffeine may have benefits for memory function when memory is challenged or in decline. In one study, individuals with “mild cognitive impairment”—a strong predictor of Alzheimer’s disease—had their memory function evaluated and caffeine levels measured at the beginning of the study and again several years later. Those who had caffeine levels consistent with drinking about three cups of coffee were significantly less likely to have developed Alzheimer’s disease than were those with no caffeine in their systems. This doesn’t mean that caffeine prevents Alzheimer’s disease. It could be that there was something else about the lifestyles of the people who had caffeine in their systems that helped forestall the onset of full Alzheimer’s symptoms. For example, because caffeine is a stimulant it could simply have made the subjects more alert, making them more likely to engage in social or intellectual activities, both of which have been shown to promote cognitive health in older people.

In a different study, laboratory animals had their memory function impaired when their brains were deprived of oxygen for a brief time. This condition, called “ischemia,” often happens when people suffer a stroke and is known to result in memory and other cognitive deficits. Animal models of ischemia have been used for many years to help scientists understand what happens when the brain is damaged. In this study, half of the animals received a dose of caffeine before the oxygen deprivation and the other half did not. Later, those that had received the caffeine regained their ability to form new memories 33 percent faster than the ones that had received no caffeine. It was as if the presence of caffeine at the time of the ischemia protected the animals’ brains from suffering the full effect of the loss of oxygen. This could have been due to the caffeine disrupting the actions of adenosine in the brain. We wrote about how this action is part of why caffeine creates alertness. But when brain cells are injured or under stress, adenosine can reach dangerously high levels and actually damage the cells. Having the caffeine on board when the animals’ brains were stressed may have reduced the potential toxic effect of adenosine. Of course, this does not mean that everybody should walk around buzzed on caffeine all the time just in case they suffer a stroke or brain injury. But if it happens to be there, it might be protective.


Calcium is an important part of nutritional health and is particularly important for the development and maintenance of strong and healthy bones. Caffeine increases the excretion of calcium, and thereby lowers calcium levels in the body, but the effect is small. For example, one well-designed study that followed women over an eleven-year period showed that those who drank four or more cups of coffee per day had 2 to 4 percent lower bone density than those who drank only one cup per day. Although this bone density loss is not trivial, it also did not seem to have dire consequences, because the women in the high-drinking group were not at greater risk for bone fractures. There have also been some studies suggesting that caffeine may reduce the absorption of calcium, and thus limit the beneficial effects of calcium that is consumed in the diet or in supplements. Although there are still some questions about this possible effect, some nutritionists recommend that people who take calcium supplements try to take them at times of the day when they are less likely to have caffeine on board, such as an hour or so before the first dose of caffeine or a couple of hours after the last of the day.


Caffeine causes constriction of blood vessels, and this is likely the reason that it can be an effective treatment for migraine headaches, especially if it is taken at the first sign of the headache. In general, it is easier to head off growing pain than to remove pain once it is strong, so a cup of strong coffee at the first sign of a migraine can help stop the problem before it really gets started. Caffeine also increases the effectiveness of medications used to treat migraines, if taken at the first sign of the headache. Caffeine has even been touted as an effective treatment for nonmigraine headaches in some individuals, so it is easy to see why some over-the-counter pain relievers (such as Anacin, Excedrin, and Goody’s Powders) contain caffeine. However, its effectiveness in this regard really hasn’t been proven.


The amount of caffeine in a cup of coffee varies tremendously and depends on several factors.

Types of Coffee Beans

Robusta beans are often grown in Africa and may have as much as twice the caffeine as arabica beans, which are grown in South America and the Middle East, among other places. Robusta coffees are generally cheaper and are often used in the mass-produced canned coffees sold in grocery stores, though the package label may not indicate what kind of bean it is. Arabica coffees are considered to be of higher grade and to yield a better-tasting cup. Although generally available, they are predominant at specialty coffee retailers and through mail-order coffee businesses. Arabicas are also much more often sold in whole-bean form than are robustas. For purposes of comparison, a typical cup of coffee brewed from arabica beans generally has 70 to 100 milligrams of caffeine, whereas the comparable amount of robusta coffee may have closer to 150 milligrams.

Method of Roasting

Dark-roasted coffee beans contain less caffeine and less acid than lighter-roasted ones. Many people think that dark-roasted coffees contain more caffeine because they often have a more powerful taste than the lighter roasts. In fact, the additional roasting associated with the darker product allows more time for caffeine to be broken down in the beans.

Fineness of Grind and Method of Brewing

The method of brewing and the size of the granules of ground coffee interact to have a significant influence on the amount of caffeine per ounce of coffee produced. The finer the grind, the more surface area of ground coffee comes into contact with the brewing water. This creates more opportunity for caffeine to be extracted from the ground beans. As for brewing method, a cup of coffee made using a drip-type coffeemaker generally has about 20 percent more caffeine than a cup made in a percolator. French presses, or “plunger pots,” can also extract maximal caffeine levels from ground coffee because the grounds are actually soaked in the brewing water for several minutes prior to the plunger being lowered to separate them from the water.


Espresso is really a different drink from brewed coffee. It is made by passing water rapidly through relatively tightly packed coffee grounds under high pressure. The result is that the oils and other products in the coffee are more fully extracted than under other coffee brewing conditions, and the taste is considerably richer than that of other coffee brews. A typical “cup” of espresso contains about one and a half to two fluid ounces—much less than a cup of coffee. But espresso contains more caffeine per fluid ounce than coffee does. Thus, the amounts of caffeine in a cup of coffee and a cup of espresso are about the same. While an average cup of coffee brewed from arabica beans contains seventy to one hundred milligrams of caffeine, the average cup of espresso usually contains about sixty to ninety milligrams.

Why do so many people believe that espresso creates more of a “caffeine buzz” than coffee does? Perhaps because of the higher concentration of caffeine in the espresso. When a drug is more concentrated in a certain solution, it tends to be absorbed more rapidly across the membranes of the stomach and small intestine. So, even though a single espresso (espresso solo) may have the same or less caffeine than a cup of coffee, its more rapid absorption can result in a more rapid onset of the caffeine effects and a greater feeling of “rush.” Of course, a double espresso (or espresso dóppio) contains twice as much caffeine.

Other coffee drinks, such as cappuccino, caffè latte, and café mocha, are each generally made by adding a single shot of espresso to other ingredients. So, the caffeine content of these drinks should be roughly equal to that of a single espresso, though less concentrated.

Based on this information, it is obviously impossible to present a simple table describing the amount of caffeine in coffee drinks. Remember that these are broad

averages based on a survey of the pharmacological and dietary literatures.




Dripped robusta coffee (8 oz) 150 Dripped arabica coffee (8 oz) 100 Percolated robusta coffee (8 oz) 110 Percolated arabica coffee (8 oz) 75 Instant coffee (8 oz) 65 Decaffeinated coffee (8 oz) 3 Espresso (and espresso-based drinks) made from arabica beans

(1.5–2 oz)



With the rise in popularity of specialty coffees and coffee drinks, there are lots of products to choose from. The following table shows the caffeine content of a number of these drinks in their usual serving sizes as of 2003. (The caffeine content may have changed since then, but the main point is that different brands of coffee

may contain very different amounts of caffeine.)*

Espresso coffees

Big Bean Espresso

1 shot 75.8

Coffee and Origin


Dose (mg)

2 short shots


2 tall shots

1 shot 2 shots

2 shots

16 oz 16 oz 16 oz 16 oz 16 oz 16 oz 16 oz 16 oz

16 oz

16 oz 16 oz 16 oz 16 oz

16 oz Data taken from the Journal of Analytical Toxicology by permission of Preston Publications.



58.1 133.5


164.7 147.6 186.0 179.8 157.1 171.8 245.1 204.9


172.7 259.3 225.7 143.4


Starbucks Espresso, regular, small Hampden Café Espresso

Einstein Bros.® Espresso, double

Brewed Specialty Coffees

Big Bean, regular

Big Bean Boat Builders Blend, regular

Big Bean Organic Peru Andes Gold, regular

Big Bean French Roast, regular

Big Bean Ethiopian Harrar, regular

Big Bean Italian Roast, regular (grown in Brazil)

Big Bean Costa Rican French Roast, regular

Big Bean Kenya AA, regular

Big Bean Sumatra Mandheling, regular (grown in Indonesia)

Hampden Café Guatemala Antigua Starbucks regular
Royal Farms regular
Dunkin’ Donuts regular

Einstein Bros.® regular

Tea leaves are harvested from bushes that are grown mostly in India, Indonesia, and Sri Lanka. Leaves are of differing qualities, depending upon how far out on the stalk of the bush they grow. Generally, the bud leaves, which are closest to the stalk, are considered to be of the highest quality. The leaves are dried and allowed to ferment, which turns them to an orange hue. These are used to make black teas. However, some tea leaves are not fermented in this way and remain green. Green teas are brewed from these and are found in most Chinese and Japanese restaurants in the United States.

In general, a cup of tea will contain less caffeine than a cup of coffee. Although there is more caffeine in a pound of fermented tea than in a pound of coffee, that pound of tea might be used to brew three to four times as many cups as a pound of coffee would. In addition, the amount of tea in a “cup” is often less than the amount of coffee, by tradition. As with coffees, the amount of caffeine in a given cup may vary considerably, depending on several factors. As a general guide, the following are caffeine ranges in teas as found in the food science literature:

Black tea Green tea Iced tea

8 oz 8 oz 8 oz

14–61 mg 24–40 mg 5–11 mg

There are well-documented positive effects of both green and black teas on health. Studies have shown that people who drink one or two cups of tea per day are more likely to survive a heart attack than those who do not drink tea. It is not clear why there is this protective effect; nor is it clear if it only applies to heart attack survival or to cardiac health in general. But some scientists think the protection comes from the antioxidants contained in tea leaves. These compounds may contribute to lowered cholesterol levels, for example, and thus help protect the heart. It’s important to know that these positive effects have not been observed for herbal teas. It seems that the tea leaves themselves may be the source of the protective chemicals. They may also be the source of naturally stress-reducing chemicals. One well-designed study found that people who drank a beverage that contained the components of black tea daily over a six-week period were more able to manage stress than those who drank a control beverage that was identical to the tea beverage (including the caffeine), except that it lacked the chemicals that are found in the black tea leaves. The researchers even took care to serve the beverages cold to avoid the possible stress-reducing effects of sipping a warm beverage. Importantly, the people who drank the active beverage also had lower levels of the stress hormone cortisol in their blood after stressful events, indicating that the

noncaffeine components of black tea leaves can help dampen the body’s physical stress reactivity.


The consumption of caffeinated sodas in the United States has been on the rise for a number of years. Some people are bothered by the gastric upset that is sometimes associated with the acids in coffees and prefer to drink caffeine-containing soft drinks. In general, the concentration of caffeine per ounce in sodas is considerably lower than in coffees, but the typical serving of soda is twelve ounces, compared to six to eight ounces for coffee. The general range of doses in soft drinks is about twenty to fifty milligrams. The diet drinks contain the same amount of caffeine (though sometimes more) as their nondiet equivalents.


The term energy drink is not exactly accurate. These caffeinated drinks don’t actually produce more energy, but they can generate a feeling of alertness, and even a solid buzz, because of their caffeine content. The concentration of caffeine in these products is often twice as high as in regular caffeinated sodas, though the serving sizes are smaller (about eight and a half ounces, compared to twelve ounces for a regular soda), and most come in smaller containers. Most of these drinks contain about 50 to 75 milligrams of caffeine. Interestingly, although these drinks have the reputation of providing a big caffeine blast, they actually contain about the same concentration of caffeine as coffee—maybe even a bit less. A notable exception is “5-hour Energy,” which contains about 200 milligrams in just a two-ounce serving. These drinks also often contain any of a number of additional compounds that fall generally into the category of “supplements,” like ginkgo biloba, taurine, ginseng, B vitamins, and sugar. We will not address these in this chapter, but some of them are discussed in other chapters, and the energy drinks are also discussed in the chapter on stimulants.

Energy drinks have been in the beverage market for quite a while (Red Bull was introduced into the United States in 1997), but their sales grew 60 percent from 2008 to 2012, and in 2018 their total sales were expected to be nearly $15 billion (up from $11 billion just three years earlier). They have been marketed aggressively to young people and have obviously been successful. What makes these products so attractive as to have such a big market presence? One element of their popularity may relate to how they are consumed. Unlike caffeinated beverages that are hot and are generally sipped slowly, energy drinks tend to be consumed quickly, thus leading to more rapid absorption of the caffeine (and other chemicals) and a more rapid buzz. It is also likely that some of the many other ingredients in these drinks

interact with the caffeine, possibly modulating its effects. This may be true for taurine in particular, though there have been very few definitive studies on the interaction between caffeine and taurine.

Combining energy drinks with alcohol has also become popular. Some people believe that the energy drink enhances the pleasant buzz of the alcohol and diminishes the depressant effects. This is almost certainly incorrect. As we pointed out in the Alcohol chapter, combining caffeine with alcohol does not make a person less impaired—it just decreases sleepiness. Although this may seem appealing to someone who wants to be drunk but not sleepy, there is a danger. A person who feels alert and unimpaired might feel that drinking more alcohol is safe when in fact it may not be. In general, it is always wise to be wary of combining drugs, particularly when there have been few studies of their interactions. Still, the idea of combining alcohol and caffeine into one drink led to the creation of several caffeinated alcoholic beverages. Perhaps the best known (or most notorious!) is Four Loko, which was sold in 23.5-ounce cans and contained 12 percent alcohol and a high dose of caffeine—quite a blast! In fact, it rapidly gained the nickname “Blackout in a Can” and became very popular on the college drinking scene. Obviously the use of these drinks had little to do with “energy” and everything to do with rapid and sustained alcohol intoxication. However, after multiple reports of alcohol-related illnesses after its use, Four Loko came under scrutiny by the Food and Drug Administration (FDA) and was banned on many college campuses. The current product contains no caffeine but retains the alcohol, available in a range of concentrations from 6 to 14 percent.

In addition to energy drinks, per se, there are many “energy formulations” on the market. It can be mind-boggling to sift through all of their claims about how they provide energy and good health, but the bottom line is that they rely mostly on caffeine for their effects. One example is guarana, which is sold in capsule form. One formulation on the market provides 250-milligram capsules, each of which contains about 90 milligrams of caffeine (about as much as a cup of coffee). Guarana comes from the seeds of a South American shrub and is often described as an “herbal” energy supplement or a weight loss aid. In Amazonian societies it was traditionally used during periods of fasting to help people tolerate restricted diets. Although there was a time when it was thought to increase alertness because of something specific to the plant, it is now clear that it’s just the caffeine.

Some people also think that it is a good idea to exercise after consuming energy drinks. Although the caffeine might make you feel alert and motivated to exercise, it will also promote dehydration that can decrease physical performance. It’s important not to confuse these products with sports drinks like Gatorade, which has no caffeine and is rich in electrolytes that the body needs while exercising and

afterward. The following table shows the caffeine content and usual serving size of a number of energy drinks and sodas as of 2006. Like the data in the table on specialty coffees, these numbers are dated, but they still illustrate that these drinks

may contain way more caffeine than you realize.†


Energy Drinks

Red Devil®

Sobe® Adrenaline Rush

Sobe® No Fear

Hair of the Dog® Red Celeste

E MaxxTM AmpTM Red Bull®

KMXTM 5-hour Energy Cran-Energy Full Throttle Monster Rockstar Vault

Serving Size (oz)




8.4 8.3 8.4

8.4 8.3 8.4

2 8 8 8 8 8



76.7 141.1

none detected 75.2 73.6










Carbonated Sodas

Coca-Cola® Classic Coca-Cola Zero

Diet Coke®
Diet Coke® with Lime Caffeine-Free Diet Coke® Vanilla Coke®
Diet Pepsi®
Mountain Dew®
Mountain Dew® Live WireTM Dr Pepper®
Diet Dr Pepper®
Sierra MistTM
CelesteTM Cola
Seagram’s® Ginger Ale Barq’s® Root Beer
Pibb® Xtra
A&W® Root Beer

12 29.5 12 35 12 38.2

12 39.6
12 none detected 12 29.5
12 31.7
12 27.4
12 45.4
12 48.2
12 36.0
12 33.8
12 none detected 12 19.4
12 none detected 12 none detected 12 18.0
12 34.6
12 none detected

7–Up® 12 none detected Data taken from the Journal of Analytical Toxicology by permission of Preston Publications.


There are quite a few medicinal preparations that contain caffeine, some in very high amounts. The following table lists some of these.



Brand Name

Coryban-D Dristan Triaminicin

Diure tics


Pain Relievers

Excedrin Goody’s Powders Midol


Caffedrine NoDoz

Milligrams per Dose

30 16 30


32 65 33 32 33

200 100

Cold Remedies

NoDoz Maximum Strength 200 Vivarin 200


Chocolate is made from the bean of the Theobroma cacao bush, which contains a unique xanthine called theobromine. An average cup of cocoa may contain as much as 200 milligrams of theobromine, but this compound is much less potent than caffeine as a stimulant. However, chocolate also contains caffeine. For example, a one-ounce bar of baker’s chocolate contains about 25 milligrams of caffeine, a five- ounce cup of cocoa may contain 15 to 20 milligrams, a cup of chocolate chips contains about 100 milligrams, and one Awake energy mint contains 50 milligrams. On the other hand, a typical eight-ounce glass of chocolate milk generally contains less than 10 milligrams of caffeine, and one Hershey’s Kiss contains only 1 milligram.

One final note about chocolate: caffeine and theobromine may not be the only psychoactive compounds in it. One study reported that one of the components of chocolate is very similar to the natural chemical in the brain that interacts with our cannabinoid receptors—the receptors to which the psychoactive compound in marijuana binds. Although the concentration of this compound is quite low in chocolate (it was estimated that a person would have to eat twenty-five pounds of chocolate to stimulate the receptors as much as a typical dose of marijuana), it is possible that its presence could supplement the natural THC-like compound in the brain enough to produce a subtle effect. These results have led to speculation that the vague sense of well-being and happiness some people report in response to chocolate may be related to the interaction of the subtle drug effects associated with low-dose caffeine with those associated with activating the natural cannabinoid receptors in the brain.


Overall, caffeine is fairly safe if a healthy person takes it in moderate amounts. The undesirable side effects that most people experience are gastric upset and nervousness or jitteriness. As people age, they tend to have more problems with sleeplessness and often will limit their caffeine consumption in the afternoon and evening. Pills containing fairly hefty amounts of caffeine, however, can result in severe side effects in people who load up on them to stave off sleep (procrastinating students and sleepy truck drivers, for example). It is also important


to note that while caffeine may allow you to keep sleep at bay, sleeping is a very important biological need that you should not ignore for long.

Children who take theophylline for treatment of asthma can also experience toxicity if their blood levels get too high. The major symptoms are severe gastrointestinal upset and vomiting, extreme nervousness, and nervous system excitability, which eventually leads to seizures if blood levels get high enough. Remember, too, that people who have other conditions that impair their cardiovascular system (obesity, hypertension, etc.) are more vulnerable to anything that affects heart function.

* We recognize that these data are several years old, but product studies of this type are not often published in the peer-reviewed scientific literature, and we prefer to report older data that have passed the muster of peer review rather than rely on non-reviewed data sources.

† Here, too, we prefer to report older data that have passed the muster of peer review rather than rely on non- reviewed data sources.



Drug Class: Entactogens. All of the drugs mentioned in this chapter are legally considered Schedule I drugs (classified by the Drug Enforcement Administration as having a high potential for abuse and no accepted medical uses).

Individual Drugs: methylenedioxymethamphetamine (MDMA), methylenedioxyamphetamine (MDA), methylenedioxyethylamphetamine (MDE), methylone (3,4-methylenedioxy-N-methylcathinone), mephedrone (4-methyl methcathinone, 4 MMC), Ethylone (3,4 methylenedioxy-N-ethyl cathinone, Butylone (β-keto-N-methylbenzodioxolylbutanimine), Plephedrone (4-fluorocathinone), Naphyrnone (naphthylpyrovalerone)

Common Terms: Ecstasy, Rolls, Beans, Molly, X, XTC, Adam (MDMA); Eve (MDE); Love (MDA); drone, meph, meow (mephedrone); M1 (methylone)

The Buzz: All of the drugs in this class increase heart rate, blood pressure, and body temperature and produce a sense of energy and alertness like that observed after amphetamine use (see Stimulants chapter). These drugs also

suppress appetite. However, the effects of these drugs on mood are quite different from those caused by amphetamine. Instead of an energizing euphoria, they cause a warm state of “empathy” and good feelings for all those around.

Overdose and Other Bad Effects: At high doses of MDMA, users often describe jitteriness and teeth clenching that are unpleasant. MDMA has caused a number of deaths when it was used at high doses in conjunction with high levels of physical activity in hot environments (at “rave” dance parties). Death is usually typical of stimulant overdose, with greatly increased body temperature, hypertension, and kidney failure. Long-term damage to serotonin neurons is suggested by human and animal studies. Toxicities of MDA, MDE, methylone, and mephedrone are not well described, but case reports of similar toxicities and deaths exist.

Dangerous Combinations with Other Drugs: These drugs can be dangerous if taken in conjunction with antidepressants or illegal drugs that are monoamine oxidase (MAO) inhibitors or serotonin-specific reuptake inhibitors (SSRIs). They can trigger “serotonin syndrome,” the symptoms of which include a dangerous or lethal increase in heart rate, blood pressure, and body temperature.


A Brief History
Is It Really Ecstasy?
How MDMA Moves through the Body What MDMA Does to the Brain and Body How MDMA Works in the Brain
MDMA Toxicity
Is MDMA Really Neurotoxic?

Can You Keep Yourself Safe? MDMA Substitutes


MDMA was first made in 1912 by Merck and was patented as an intermediate in a chemical synthesis (not, as often asserted, as an appetite suppressant). It was never used clinically and not tested in humans until the 1950s. The first scientific study was conducted in 1953 by the US Army, but the results of the study were not published until 1969. A related drug, MDA (methylenedioxyamphetamine), was popular with drug users in the sixties, but MDMA did not return to the scene until after it was synthesized and tested by Sasha Shulgin and Dave Nichols in 1978. A group of psychotherapists decided that the empathic state produced by Ecstasy could be useful in psychotherapy by producing a temporary state of openness that could help patients achieve insight and mutual understanding. The therapeutic benefits of MDMA were not realized at that time, but recreational use spread quickly during the 1980s. This led to concerns that, combined with reports of toxicity, led to its classification by the Drug Enforcement Administration (DEA) as a Schedule I drug (a drug with no valid clinical use). Ecstasy moved quickly into the underground drug scene and was popularized through its use at underground dance parties (“raves”) in the United Kingdom. From there, it migrated rapidly to the United States. The Monitoring the Future Study showed that the lifetime use of MDMA rose from 4.6 percent of high school seniors in 1996 to 11.7 percent of high school seniors in 2001. However, rising concerns about the potential risks of MDMA, active education campaigns, and decreased availability have led to an equally rapid fall in reported Ecstasy use, which was down to 4.9 percent of high school seniors in 2017.


Many other substances have been identified in pills sold as Ecstasy. In fact, a 2017 survey of results from the DanceSafe website (2010–2015) that tests Ecstasy pills showed that about 60 percent of the pills submitted to the site contained at least some MDMA. This survey probably contains more fake pills than average, because a certain number were submitted to the site because users suspected that they were not MDMA. However, the chances of getting something that is not MDMA are pretty good. Sometimes you get something that is less dangerous than MDMA, such as caffeine or dextromethorphan, but methamphetamine, MDA

(methylenedioxyamphetamine), and MDE (methylenedioxyethylamphetamine) are also common contaminants. A partial list of contaminants from this study includes methylone, methamphetamine, benzylpiperazine, dextromethorphan, mephedrone, cocaine, and ketamine.

Molly is supposedly a form of MDMA that is 100 percent pure MDMA. This is not true. The same survey reported analyses of samples that were submitted as Molly, and only about 60 percent had any MDMA at all, and 40 percent had none: exactly the same percentages as pills sold as “MDMA.” An additional reason to use caution when it comes to MDMA and Molly use is that the list of substitutes is always changing. An informal survey of test results from January 2018 to June 2018 of drugs submitted from the United States showed that 80 percent had at least some MDMA, but 30 percent also contained one or more other substances, including MDA, methylone, caffeine, methylsulfonylmethane, methamphetamine, and cocaine.

The following discussion, as well as the Stimulants and Hallucinogens chapters, will dispel the myth that MDMA is safe and that only its contaminants are dangerous.


MDMA and its relatives are usually taken orally in the form of pills or capsules, synthesized by bootleg labs that make the pills in many different colors (white, yellow, purple, and beige). MDMA (especially as Molly) is also sold as a white powder that users snort, put in their own capsule to swallow, or dissolve in water and then swallow. The actual composition of pills can vary from a few milligrams up to 200 milligrams. An average dose is 100 milligrams. MDMA is well absorbed from the gastrointestinal tract, and peak levels are reached in about an hour. The effects last for three to six hours. The levels of other variants may peak sooner or later, but in the same general time frame.


MDMA users provide very consistent reports of the feelings that result from taking it. Almost all users say that it causes a feeling of empathy, openness,

and caring. The enhancement of positive emotions has been described as a decrease in defensiveness, fear, the sense of separation from others, aggression, and obsessiveness.

One first-time user reported the effects in this way: “What happens is, the drug takes away all your neuroses. It takes away your fear response. You feel open, clear, loving. I can’t imagine anyone being angry under its influence, or feeling selfish, or mean, or even defensive. You have a lot of insights into yourself, real insights that stay with you after the experience is over. It doesn’t give you anything that isn’t already there. It’s not a trip. You don’t lose touch with the world. You could pick up the phone, call your mother, and

she’d never know.”*

In both animals and humans, MDMA causes a combination of amphetamine- and hallucinogen-like effects. MDMA does not typically cause overt hallucinations, but many people have reported enhanced perception of sensory stimuli and distorted time perception while under the influence of the drug. It causes an amphetamine-like hyperactivity in people and animals, as well as the classic signs of stimulation of the fight-or-flight response. For instance, heart rate and blood pressure increase, and the smooth muscles of the breathing tubes (bronchioles) dilate. The pupils dilate, and blood flow to the muscles increases.

One way to test the qualities of an unknown drug is to give it to an animal that is trained to recognize a certain class of drugs and see if it recognizes this one. This is called a drug discrimination test. When such tests are done with MDMA, some animals trained to recognize amphetamine also recognize MDMA, while other animals trained to recognize LSD or other hallucinogens also recognize MDMA. This confusion almost never happens with other drugs. Amphetamine-like drugs are almost never confused with hallucinogens. This finding points out the unique behavioral effects of MDMA.

People report that MDMA decreases feelings of aggression, and animal studies confirm this impression. MDMA has contradictory effects on sexual function: while some people report greater sensory pleasure with stimulation, studies in animals and human self-report show a delay or inability to achieve orgasm. MDMA shares this effect with other drugs like SSRIs that raise synaptic serotonin. There is mixed information about whether MDMA is pleasurable and addictive the way cocaine is. Primates

will take this drug voluntarily, and the general profile of the way the drug acts on the brain indicates that it has the potential to be addictive. However, the typical pattern of human use is quite different from that of cocaine and amphetamine. While people clearly use it repeatedly, it is used most frequently in a specific environment, like rave dance parties. Although compulsive daily use as seen with cocaine or heroin is not typical with MDMA, some people do experience tolerance to the effects of MDMA and increase the number of pills to compensate. A student in a focus group reported, “The more you do it the less good you feel while on it and the worse you feel coming down.”

Overall, MDMA creates a very unusual behavioral profile. The positive feelings that people report are most similar to the effects of very high doses of the antidepressants fluoxetine (Prozac) and venlafaxine (Effexor). This makes sense, as we will see in what follows, because these three drugs share some biochemical actions. Overall, MDMA doesn’t fit into any other drug category, and the term entactogen, meaning “to touch within,” has been coined to describe drugs such as this.

MDA is very closely related to MDMA in chemical structure, and though it shares the amphetamine-like effects, its effects on mood are different. MDA acts more like a typical hallucinogen. MDE effects more closely resemble those of MDMA, but it lacks the unusual empathic qualities of MDMA.


Much of what MDMA does is explained by its ability to increase the levels of the monoamine neurotransmitters dopamine and norepinephrine (see the Stimulants chapter) and serotonin (see the Hallucinogens chapter) in the synapse. Like amphetamine, MDMA actively “dumps” them into the synapse, and the amount of these neurotransmitters that is released is much larger than is usually seen with cocaine. Unlike amphetamine, MDMA does a very good job of increasing the levels of serotonin. While amphetamine is ten to one hundred times better at releasing dopamine and norepinephrine than serotonin, MDMA is the opposite: it releases serotonin more effectively than it does dopamine.

Most MDMA effects make sense, given its biochemical profile. The increase in body temperature, the relatively low addiction potential, and the decrease in aggressiveness are typical of drugs that produce a big increase in serotonin levels in the synapse. The SSRIs, such as fluoxetine (Prozac), do this in a different way that causes more limited effects. While MDMA actively dumps serotonin into the synapse and produces very large increases this way, Prozac and drugs like it prevent serotonin recapture but do not actively release it. This means that the neuron has to release serotonin first before antidepressants can do anything. MDMA can make much more serotonin available because it doesn’t have to wait for the neuron to fire.

We don’t know if its effects on serotonin alone are enough to explain the unique effects of MDMA on mood, or whether some undescribed effect is responsible for the sense of empathy and positive feelings. Recent research in humans suggests that serotonin release is necessary for most of its effects on mood, because people who receive serotonin receptor–blocking drugs before MDMA experience much less intense mood changes than people who receive MDMA alone. This could be mediated in part by serotonin-induced release of the hormone oxytocin, which plays a role in affiliative behaviors. However, fenfluramine, an amphetamine derivative that has a similar ability to dump serotonin, shares some of these actions (like its ability to decrease aggression) but has not been reported to cause the same emotional changes. The actions of MDMA are still a mystery, because no other drug produces an identical state and because the neurochemical effects we have observed so far don’t completely explain all of these effects.

Dopamine and norepinephrine also play a role in the effects of MDMA. MDMA is somewhat reinforcing and animals will self-administer it, although not as readily as they will take cocaine or amphetamine. Dopamine also contributes to the dangerous body temperature increases that can occur when MDMA is used in warm environments. Norepinephrine, as the primary neurotransmitter of the sympathetic nervous system, is responsible for the fight-or-flight responses of heart rate and blood pressure.


MDMA can be unpleasant and even dangerous when used in high doses (two to four times greater than a usual single dose of 80 to 120 milligrams). The

bad effects are typical of an overdose of drugs that release all three monoamine neurotransmitters. People report jitteriness and teeth clenching as the dose moves up, as well as all the classic signs of overstimulation of the sympathetic nervous system. Hunger is suppressed, and people typically experience dry mouth, muscle cramping, and sometimes nausea. At higher doses, MDMA can cause a large increase in body temperature—one reason for its toxicity: the high temperature may be responsible for the muscle breakdown and kidney failure that have been seen in lethal cases reported from raves. When people dance for long periods of time in close quarters, the physical activity and tendency for dehydration can synergize in an especially dangerous way with the effects of the drug. MDMA has also caused lethal cardiovascular effects in people with underlying heart disease. It has caused heart attacks and strokes in a few people. Unfortunately, it is hard to know what dose is actually toxic based on these reports. People have usually taken Ecstasy at a party, often with other drugs, and later had little recollection of how much drug they took. Like most amphetamine-like drugs, MDMA can cause seizures at extremely high doses. A related drug, paramethoxyamphetamine (PMA), is more toxic at recreational doses, and people taking this drug inadvertently are more likely to experience a dangerous elevation of body temperature and cardiovascular function. However, the common myth that MDMA itself is not toxic is wrong. It is possible to take a lethal dose of MDMA in a typical recreational setting, though overall, the number of deaths caused by recreational MDMA use is small. It has become popular to ingest MDMA/Molly as a powder, and case reports of deaths indicate that blood levels of those who die are greater than those that occur after a normal recreational dose, suggesting that inexperienced users are colliding with a dosage form in which it is difficult to control how much you take. One factor in such deaths could be changes in the rate of metabolism of MDMA when levels in the blood are very high. In that situation, the liver cannot handle all the MDMA coming through it, and metabolism slows.

Some deaths attributed to MDMA actually have resulted from attempts to prevent MDMA toxicities. Many people try to protect against MDMA- induced dehydration and hyperthermia (high body temperature) by drinking lots of water. Some people ingest so much water in a short time, however, that they dilute the concentration of sodium in their blood. This condition, called hyponatremia, can lead to headache, nausea, vomiting, seizures, and,

in extreme cases, brain swelling and death. MDMA or hyperthermia-induced changes in the level of antidiuretic hormone can contribute to the situation by concentrating the urine and leaving water in the circulation. However, the biggest reason is simple: people drink much more water than needed to replace lost fluid. This happens to participants in many sports, including marathon runners. In the 2002 Boston Marathon, a study showed that 22 percent of the women runners were hyponatremic by the end of the race. This gender balance is relevant to MDMA because recent research shows that women are also more sensitive to the hyponatremia that MDMA causes. How much is too much? It depends on how much you sweat, and there are no experiments with MDMA users. For marathon runners, slow runners who drank about a liter an hour (thirty-six ounces, or one quart) tended to get in trouble. Fortunately, people can usually recover from hyponatremia if they receive medical care.

MDMA use has been responsible for a number of psychiatric/psychological problems. The most common consequence is the “down” that happens a few days after MDMA use. This is almost always temporary, but the mood changes can be severe enough to measure in the range of mild clinical depression. Some people also feel more irritable or aggressive. This effect can persist in heavy users and may be more severe in women than in men. Some patients have complained of panic attacks after repeated use of MDMA. These usually resolve eventually but have continued for months in a few people. Similarly, hallucinations and amphetamine-like paranoid psychotic symptoms have occurred in chronic, high-dose users. Again, these symptoms waned when drug use stopped.

Are there long-term effects of MDMA use? Understanding the long-term psychological effects of MDMA is difficult because most heavy MDMA users also use other drugs, including marijuana, alcohol, stimulants, and opioids, that influence their health and brain function. Recent research has begun to tease out MDMA’s effects from those of other drugs, and to pay attention to dose relationships. Reports of persistent anxiety, involvement in risky behaviors, and other psychological problems, sleeping problems, and small but measurable deficits in executive function (planning of thought and action) correlate with heavy lifetime use of MDMA (hundreds of doses, for example). A number of research reports show that heavy use of MDMA can be associated with impaired ability to update and access memories, and that this is due specifically to the MDMA—not to the use of other drugs. We

don’t know yet if these changes are reversible: the scientific literature is still a little mixed on this topic, although in at least some studies, ex-Ecstasy users perform better than current users. Furthermore, we also don’t know if some of the reported changes (like increases in impulsivity) are simply characteristics that the users had before they ever starting using MDMA.


There is still controversy about whether MDMA causes long-term damage to serotonin neurons, a concern that arose from previous experience with similar amphetamine-like serotonin-releasing drugs. Other drugs that release both dopamine and serotonin (methamphetamine, for example) have been shown in laboratory studies to cause long-lasting changes in either (or both) dopamine or serotonin neurons in the brain. In animal studies, a pattern of multiple, closely spaced MDMA doses led to loss of all serotonergic molecules from the serotonin nerve ending: serotonin itself, the serotonin transporter, and other components of the terminal were decreased markedly. With almost all of these drugs, the amount of damage is dose- and time- related. Small doses produce little or no damage; moderate doses produce marked decreases in serotonin indices but leave the serotonin system still functional; and large doses can eliminate the ability of these neurons to release serotonin for months.

MDMA acts like other drugs in the same class. In experimental studies in rats and primates, MDMA produced temporary loss of serotonin, which doesn’t present any real long-term problem but may be responsible for the midweek blues. It also produces the same kind of long-term changes that the other amphetamine-like drugs produce. With some dose regimens, a limited amount of recovery occurred, while with higher dose regimens, no recovery occurred. One of the controversies about MDMA is whether the loss of these markers really means that the nerve endings are gone or just depleted of their contents. However, there is little question that at the very least, the serotonin itself, the transporter, and the main synthetic enzyme are reduced to very low levels for a long time after repeated, heavy exposure to MDMA. How much MDMA is necessary to produce significant long-term damage? The dose range that produced permanent damage in experiments with squirrel monkeys was about the equivalent of a 150-pound person taking 350 milligrams

spaced over four days. Earlier studies showed that this occurred when the drug was administered by injection in the monkeys, but more recent studies using oral administration, resembling the way that humans take the drug, report similar results. An average human dose of Ecstasy is about 100 milligrams.

Does the same type of damage happen in people who take high doses of MDMA for a long time? An increasing number of studies suggest that the answer is yes. A recent review of about twenty studies in humans showed that levels of major serotonin markers like the serotonin transporter or the main metabolite of serotonin in the nervous system were suppressed in Ecstasy users. We don’t know if these effects reverse if someone stops using MDMA, although some studies indicate that this might be so.

What are the long-term effects of this type of serotonin loss? Are some of the anxiety and learning disorders that we discussed caused by this type of damage? Residual anxiety and irritability/hostility have been reported in a number of heavy Ecstasy users. Because increased levels of serotonin have been associated with improved mood (see the Hallucinogens chapter), and its loss with depression in some cases, it is not unreasonable to speculate that mood disorders might be in the future for heavy Ecstasy users.


Advocates and critics disagree about whether people can protect themselves from MDMA-induced toxicities by taking measures to keep their body temperature down and keep hydrated. Savvy ravers have adopted several practices designed to try to protect themselves from MDMA’s dangers. They drink extra water, try to keep their body temperature down by using “mist tents” in which people spray each other with water, keep the room temperature low, and sometimes even take SSRIs like fluoxetine (Prozac) in an attempt to protect against neurotoxicity and the amino acid tryptophan when they are coming down to help restore serotonin levels. Do these practices work? Certainly, the organ damage caused by high body temperature can be avoided if you stay in a cold enough environment. Protecting yourself against neurotoxicity is more controversial. There is animal literature showing that changes in serotonin neurons don’t happen if animals are kept cold. However, we don’t know yet if these findings extend to people. The same story is true of taking SSRIs like Prozac. This approach

has worked in studies on animals but is untested in people. If you take SSRIs before taking MDMA, these drugs keep MDMA from getting into the terminal. This prevents the damage completely but also prevents MDMA’s effects. Unfortunately, some users take it when they are coming down, which could present problems. Theoretically, if you take an SSRI too early, while lots of serotonin is still floating around, you could trigger the “serotonin syndrome.” SSRIs keep the serotonin from being recaptured by the nerve terminal, just like MDMA does. In combination, you can get a dangerous elevation of serotonin that leads to the effects of an MDMA overdose. A mild case could cause nausea, diarrhea, increased muscle tone, and increased blood pressure; a severe case could cause greatly elevated body temperature and death. Cases of serotonin syndrome have been reported after MDMA alone, and theoretically the combination could increase the risk.

Research about potential clinical benefits of MDMA is gaining more and more public interest, as is also the case for psilocybin, as noted in the Hallucinogens chapter. The rationale for this use is that MDMA, especially in the context of supervised counseling sessions, could help in clinical conditions like PTSD, or in end-of-life counseling, where there are no ideal pharmacotherapies. This dearth of alternatives has fueled interest in the potential of MDMA. Small Phase 1 FDA-approved trials have shown that no dangerous adverse effects occur during such therapeutic use, and larger clinical trials to establish clinical efficacy are under way. MDMA does not cause dangerous effects at doses that would likely be used clinically. Certainly, there are many clinically approved drugs like morphine and amphetamine that are equally dangerous at high doses, so the dangerous side effects are hardly unique. Most practitioners involved in this research embrace the approach of using MDMA in the context of supervised counseling sessions, where the risk of misuse is extremely low. Offsetting these “positives” are open questions: Are there long-term consequences to low-level use that could be dangerous? Can scientists advocating clinical use show convincingly that MDMA offers unique advantages that outweigh the advantages of other medications? Would a completely safe entactogen be a valid clinical drug or a “tonic” for treating the ills of normal life? Can insights and positive feelings aroused during a drug-induced state carry over into normal life?


Since the DEA placed MDMA in Schedule I, a constantly evolving series of substitutes has appeared in an attempt to come up with a “legal” alternative. The best-characterized of these are mephedrone and methylone. Methylone and mephedrone are “bath salts” (see the Stimulants chapter) and derivatives of the psychomotor stimulant cathinone. However, their neurochemical effects resemble those of MDMA. Like MDMA, they release all three monoamines, and much higher quantities of serotonin than do classical psychomotor stimulants. Their behavioral effects and toxicity are similar to those of MDMA. These drugs also elicit the unique “entactogen” profile. The pattern of toxicity includes stimulation of the sympathetic nervous system due to norepinephrine, high body temperature, and the cascading organ failure associated with dopamine and serotonin release. Little is known yet about long-term effects, although some preliminary reports indicate that they do not cause long-term decreases in serotonin like those caused by MDMA. However, there are only a few research reports out, so it is early to conclude much about their long-term effects. Additional variants keep appearing that possess significant serotonin release along with other catecholamines, and so have an entactogen behavioral profile. Some of these include ethylone and butylone, which release serotonin at much higher rates than dopamine or norepinephrine, and others like flephedrone and naphyrone, which more closely resemble the neurochemical profile of MDMA. Neither the acute behavioral effects nor the potential long-term effects have been described for any of these variants. Early animal studies have shown that behavioral and physiologic effects are fairly predictable based on the ratios of norepinephrine (sympathetic nervous system stimulation), dopamine (abuse potential), and serotonin (entactogen properties) that are released, which are unique to each molecule.

The piperazine drugs (mCPP, TFMPP, BZP) are another group of drugs that appear in pills that are supposed to be MDMA. These aren’t exactly MDMA-like, although there is some overlap in what they do. Each is a little different. BZP is like a stimulant: it causes stimulant-like behaviors in rodents and increases the release of dopamine and to a lesser extent serotonin. It also has properties common among addictive drugs in animal tests. TFMPP and mCPP are more serotonin selective and have been used to assess serotonin function in research laboratories for many years. Both

release serotonin but have hallucinogen-like behavioral actions that probably reflect a stimulation of serotonin receptors. The combination of BZP and TFMPP most closely resembles the effects of MDMA. TFMPP or mCPP alone resemble hallucinogens more than MDMA and can cause severe anxiety, hallucinations, and sympathetic nervous system stimulation. It is important to understand that all of these entactogen variants are illegal, and are listed as Schedule I by the DEA through the 2012 Synthetic Drug Abuse Prevention Act and the Controlled Substances Analogue Act.

* From Nicholas Saunder Londson, Ecstasy and the Dance Culture, 1995 (self-published).



Drug Class: Hallucinogens. Almost all of the drugs mentioned in this chapter are legally considered Schedule I drugs (classified by the Drug Enforcement Administration as having a high potential for abuse and no accepted medical uses). The exceptions are atropine, scopolamine, and ketamine, which have valid medical uses for which the user must have a prescription, and dextromethorphan, which is available without a prescription but requires proof of age for purchase in most states.

Individual Drugs: Serotonin-like group: lysergic acid diethylamide (LSD), psilocybin, mescaline (peyote), N,N-dimethyltryptamine (DMT), 4-bromo- 2,5-dimethoxyphenethylamine (2C-B), ayahuasca; belladonna alkaloids: Jimsonweed; dissociative anesthetics: phencyclidine (PCP), ketamine; dextromethorphan; Salvia

Common Terms: acid, blotter, California sunshine, microdot, trip, yellow sunshine, and many others (LSD); boomers, magic mushrooms, shrooms (psilocybin); buttons, mesc, mescal, topi, peyote (mescaline); caapi, yage, vegetal (ayahuasca); businessman’s special (DMT—dimethyltryptamine); atropine, scopolamine, belladonna, deadly nightshade, Jimsonweed, stink

weed, mandrake (belladonna alkaloids); PCP, angel dust, T, PeaCe pill (phencyclidine); Special K, K (ketamine); CCC, robo, red devils, poor man’s PCP, DXM, Dex (dextromethorphan); ska, Maria, la Maria, ska Pastora (Salvia divinorum); Nexus, Bromo, Venus (2-CB)

The Buzz: Hallucinogen experiences vary incredibly. Even the same person can have dramatically different experiences with the same drug on different occasions. The experience is strongly shaped by the user’s previous drug experience, his or her expectations, and the setting in which the drug is taken.

Mild effects produced by low doses can include feelings of detachment from one’s surroundings, emotional swings, and an altered sense of space and time. Hallucinations, pseudohallucinations, and illusions can all occur. Hallucinations are sensory experiences that are unreal. Pseudohallucinations are sensory experiences that are unreal but understood to be unreal, and illusions are sensory distortions of normal reality. A hallmark of the hallucinogen experience is a sensation of separation from one’s body. Some users experience intense feelings of insight with mystical or religious significance. These effects can last for minutes (with DMT) or for hours (with LSD).

Physical effects vary from drug to drug, but with LSD and similar drugs, users report jitteriness, racing (or slowed) heartbeat, nausea, chills, numbness (especially of the face and lips), and sometimes changes in coordination.

Overdose and Other Bad Effects: Hallucinogens should be divided into two groups: the drugs that produce mainly psychological problems—the LSD-like drugs—and the much more physically dangerous belladonna and PCP-like compounds. The belladonna drugs, such as atropine and scopolamine, can be lethal in the usual amounts that people ingest for intoxication. These drugs can stimulate the heart and increase body temperature dangerously. The point at which a user experiences hallucinations from these drugs is at or very near the life-threatening level. PCP can also be lethal at high doses, causing seizures, coma, or a psychosis- like state that can last for days.

The most likely negative effect of taking hallucinogens like LSD is a bad trip. The most common of these is a frightening experience that leads to acute anxiety and its accompanying physical effects. Users can accidentally injure

or kill themselves because they are not thinking clearly about their environment. They may try to fly, for example, and jump from a high place. Actual psychotic reactions are much more unusual, happening in about 1 to 3 percent of cases, but they can require hospitalization. Another problem can be “flashbacks,” or hallucinogen persisting perception disorder (HPPD), which are visual disturbances or other recalled events of the drug experience that emerge long after the drug is out of the body. HPPD is more common in heavy hallucinogen users than occasional users; some surveys have shown that up to 30 to 60 percent of heavy users experience these in one form or another, while incidence across all users is much lower (probably percentages in the single digits).

Finally, as with any street drug, the drug might not be what the seller says it is. Most of these compounds are manufactured and packaged by illegal and uncontrolled laboratories and distributed in a completely unregulated fashion. The old phrase “let the buyer beware” could not be more appropriate.

Dangerous Combinations with Other Drugs: The dangers of these drugs vary by class. The most dangerous combination is that of PCP-like drugs with alcohol or other sedatives. This combination can kill you. Taking atropine-like drugs with anything that stimulates the cardiovascular system or raises body temperature (for example, Ecstasy) can lead to a dangerous disturbance of heart rhythms or increased body temperature. Hallucinogens with amphetamine-like actions (for example, mescaline) can be dangerous when taken in combination with stimulants. Any drug that increases blood pressure as it begins to take effect can be dangerous in people with heart disease if they combine it with other drugs that can raise blood pressure (for example, nasal decongestants). The physical risks of drug combinations with serotonin-like hallucinogens (for example, LSD) are much less, although an already unpredictable experience becomes even more unpredictable if combined with marijuana, a common practice.

Hallucinogen History



This class of psychoactive drugs boasts a longer history; a greater mystique; and more botanical, chemical, cultural, and historical diversity than almost any other. The use of hallucinogens is evident in plant remains from cultures on every continent. Each student of hallucinogens has his favorite “oldest story.” One of ours explains how Siberian hunters discovered the fly agaric mushroom (Amanita muscaria). Apparently, the hunters noticed the abnormal behavior of reindeer grazing on these mushrooms, and decided to experiment with them. They found not only that the mushrooms had a profound hallucinatory effect but also that they were so potent that the urine of those who had ingested the drug still contained active drug, so the drug could be recycled among tribe members. It has been suggested that the same mushroom

What Is a Hallucinogen?
How Hallucinogens Move through the Body
The Hallucinogenic Experience: What Hallucinogens Do to the Brain Individual Hallucinogens

Psilocybin Mushrooms
Other LSD-like Hallucinogens
Salvia Divinorum
Belladonna Alkaloids
Phencyclidine (PCP) and Ketamine (Special K): Hallucinogenic Anesthetics Dextromethorphan

How Hallucinogens Work
LSD, Psilocin, Mescaline, and DMT Belladonna Alkaloids
PCP, Ketamine, and Dextromethorphan Salvia

Enlightenment or Entertainment? Dangers and Myths

Research on Hallucinogens Identification
Physical and Psychological Problems Flashbacks
Chromosomal Damage
Interactions with Other Drugs

provides the drug Soma described in the Rig-Veda, the book of religious writings from India that has been dated to at least 3,500 years ago. Hallucinogens were used in early Greece, and the plant riches of the New World provided a wealth of hallucinogenic agents that were known to the earliest migrants into South America from Eurasia. Archeological evidence suggests that the use of the peyote cactus goes back thousands of years.

Who uses hallucinogens today and why do they use them? Even the most commonly used drug, LSD, is only used by a small percentage of the population. However, use has increased since 2012; as of 2016, 5 to 10 percent of Americans eighteen or older had tried LSD (National Household Survey of Drug Use and Health, 2016). We don’t really have accurate statistics about the use of other hallucinogens, but the primary age group (eighteen to twenty-five) is the same for most. Finally, Native Americans and others also use hallucinogens for religious purposes.


Hallucinogens are drugs that change a person’s thought processes, mood, and perceptions. The word itself is derived from the Latin word alucinare, which means “to wander in mind, talk idly, or prate.” At high doses, these drugs cause people to perceive an experience as actually happening when, in fact, it is not. At lower dose levels, they cause milder disturbances of perception, thought, and emotion, but not the complete fabrication of unreal events.

Hallucinogens have often been called psychotomimetics or psychedelics. All of these names suggest that these drugs induce or mimic mental illness, but they are wrong to varying degrees. Hallucinogens do not really mimic psychosis or mental illness. Although they can trigger a psychotic experience in a vulnerable person, the drug experience itself is probably quite different. For example, the hallucinations caused by most of these drugs are usually seen, whereas the hallucinations of schizophrenia are usually heard. However, there is some overlap in effects, and recent research with psilocybin has found similarities between hallucinogen effects and some aspects of psychosis, especially feelings of detachment from one’s surroundings and feelings of universal understanding. The term psychedelic developed in the late 1950s to describe drugs that were “mind-expanding,” a

vague term that was popular at the time but not very descriptive. A similar term used to describe these drugs is entheogenic, which conveys the idea of finding “the god within.” None of these terms is completely adequate. The diversity of terminology to describe these drugs almost certainly results from the tremendous variation in the experiences that people have had with them.

This chapter describes three broad categories of hallucinogens. The most familiar is the LSD- or serotonin-like group. The prototype of this group is lysergic acid diethylamide (LSD). Dealers package LSD as a liquid, by placing drops onto a piece of absorbent paper (blotter paper), or sell it as a piece of candy, or as pills or capsules. Psilocybin mushrooms and peyote cacti are also in this category. Psilocybin mushrooms contain the active compounds psilocin and psilocybin, which roughly resemble LSD in the effects they produce. The peyote cactus contains mescaline. Mushrooms containing psilocybin and cactus buttons containing mescaline are usually consumed as the dried plant and look like it. There are many other hallucinogens that resemble LSD in their actions, including dimethyltryptamine (DMT) and bufotenine. There is also a group of amphetamine derivatives—including DOM (2,5 dimethoxy-4- methylphenylisopropylamine), also known as STP; TMA (trimethoxyamphetamine); and DMA (dimethoxyamphetamine)—that resemble mescaline in their actions. Many variations exist, and new versions seem to rise and fall in popularity. Other members of this alphabet soup that appear in the illicit drug trade include 2C-B (4-bromo-2,5- dimethoxyphenethylamine) and its variants, including more recently 25I- NBOMe (4 iodo-2,5-dimethoxy-N-(2-methoxybenzyl) phenethylamine). Many of these hallucinogens appear in pill form, and the actual content of the pills often differs from what the dealer has described. An herbal tea called ayahuasca, containing a combination of DMT and harmala alkaloids, has migrated from South America to the United States, where it has gained popularity for spiritual use.

The second major group of hallucinogens we will discuss are the belladonna alkaloids. These have been used medically for thousands of years, and ritually for even longer. However, their recreational abuse is just now becoming popular. Belladonna alkaloids in the United States are most often obtained either through prescription medication that contains them or from tea prepared from the leaves of the wild-growing Jimsonweed (Datura stramonium).

The dissociative anesthetics, or “horse tranquilizers”—phencyclidine (PCP), ketamine, and dextromethorphan—are the last category. Ketamine is an anesthetic used primarily in children and in veterinary practices. It appears as a solution for injection (that has been diverted from medical use) or as a powder (made from dried-out solution). People usually inject or ingest the solution and snort the powder. PCP appears in several different forms: pills, a powder for snorting, or “rocks” that can be smoked or, more rarely, dissolved for injection. Sometimes tobacco, marijuana, or parsley leaves are coated with PCP solution. These produce a bizarre, dissociative state that comes the closest to resembling psychosis of all the hallucinations. Dextromethorphan, the main ingredient in many cough syrups and pills, causes a unique, dissociative state at doses higher than those used for cough suppression. Finally, Salvia divinorum is a plant hallucinogen that causes an intense, brief, and usually unpleasant hallucinatory experience when users smoke the leaves.


Ritual use of hallucinogens by indigenous peoples involves many routes of administration, ranging from herbal teas to application to the skin to hallucinogenic snuffs. However, the major hallucinogens used in the developed world are almost always taken by mouth. All of the drugs listed in the previous section can be absorbed easily from the stomach or intestines. PCP is an exception because users also smoke or inject it. Only LSD is potent enough to be effective in tiny doses absorbed on paper. Users most often simply chew and swallow the plant-derived hallucinogens such as cactus buttons or dried mushrooms. Most hallucinogens, and frequently LSD or various drugs that are supposed to be LSD, are ingested in pill form.

The lag time between taking the drug and beginning the drug experience, and the duration of the experience itself, depends upon the drug. A typical LSD experience begins between thirty and sixty minutes after a user takes the drug. LSD is absorbed efficiently from the stomach and intestines and enters the brain fairly quickly. LSD trips last the longest of typical hallucinogens: the drug effects typically last four to six—but occasionally up to twelve— hours for a single dose.

Recent research about how LSD interacts with the receptors it stimulates provides an explanation for the very long duration of an LSD trip: LSD gets “stuck” on the receptor, dissociating over hours, allowing continued stimulation. What about the rumors to explain LSD flashbacks that LSD is stored in the spinal fluid for months? They are not true. LSD flashbacks do not occur because hidden drug in the body suddenly reappears. We do not understand the neurobiology underlying flashbacks, but it would be reasonable to speculate that they represent a change in the brain that remains after the drug experience. As we will see later, in the Brain Basics chapter, the central nervous system has the capacity to recall all sorts of experiences, and flashbacks may be just that.

Peyote trips can last almost as long as LSD trips. In contrast, psilocybin experiences usually last two to four hours. Dimethyltryptamine (DMT) is the shortest-acting of the commonly used hallucinogens, producing noticeable effects within ten minutes, peaking at about thirty minutes, and ending within an hour. This drug is often described as a “businessman’s special” for that reason. The differences from drug to drug are caused by differences in two properties. First, the more fat-soluble a drug is, the more quickly it enters the brain (this explains the rapid onset of DMT action). Second, the more slowly the drug gets degraded, the longer the trip. Again, this varies according to the particular chemical structure of the drug. Some drugs, like LSD and mescaline, produce particularly long-lived effects because they are not quickly metabolized by the liver.

PCP deserves some special notice because of the problems its chemical characteristics often cause. PCP is well absorbed when taken by mouth, and peak blood levels are reached even faster (within fifteen to thirty minutes) if it is smoked. However, it is broken down quite slowly, so the effects last a long time. The main drug experience lasts four to six hours, but significant amounts of the drug are present for twenty-four to forty-eight hours. The body’s slow metabolism of PCP, along with some users’ tendency to use it repeatedly over a day’s time, leads to overdose and very persistent drug effects for days after ingestion.

Myths about how to stop a trip abound; drinking milk is the most unlikely we have heard. There is no simple way to speed up the removal of most hallucinogens from the body. Users must simply wait for the drug to dissociate from its receptor and then for the liver and kidneys to do their job.

PCP is the only exception. In critical situations, emergency room personnel can use a drug that makes the urine more acidic, speeding up the removal of PCP by the kidneys. Some drug treatments (see the following) can help with the symptoms of acute panic. There are research drugs that can compete at the receptor activated by LSD-type hallucinogens and knock the hallucinogen off the receptor, but these are not routinely used clinically. At the moment, there is no quick fix like there is for opioid overdose.

So, it’s important to remember that, once begun, the trip on some of these drugs can last for hours. If the trip is unpleasant, there is not much to do except receive support from unimpaired companions. If someone is going to experiment with any of these drugs, it is crucial that he or she do so in a safe and supportive environment. Doing even the least dangerous of these drugs alone invites trouble.


It is very difficult to describe what a person experiences under the influence of these drugs because each experience is so individualized. The identity and amount of the drug, how it is taken, the user’s expectations, and the user’s previous experience all play a role. There are some common effects, however. Often, a trip begins with nausea; a feeling of jitteriness; and mild increases in blood pressure, heart rate, and breathing. Then the user usually feels a slight distortion of sensory perception. Visual effects predominate, with wavering images and distortion of size (things may seem much larger or smaller than they are).

At high doses, users experience illusions, pseudohallucinations, or hallucinations that are highly individual and profoundly influenced by the setting. They can range from simple color patterns (spirals or grids are common) to complex scenes, often with drug takers feeling like they are watching their actions from outside their body. The confusion of senses, or synesthesia, such as seeing sounds and hearing colors, is typical. The sense of time is distorted, so that minutes can seem like hours. At the peak of the drug experience, users frequently describe a sense of profound understanding or enlightenment. Sometimes there is a sense of oneness with the world, which some users report to last long after the drug experience is over.

Profound euphoria or anxiety can occur. As the drug effect wanes, users usually feel a sort of otherworldly sense and fatigue.

Although eloquent, fantastic, and entertaining reports abound in the literature, one of the best descriptions of the hallucinogenic experience was written by Dr. Albert Hofmann, the chemist who first synthesized LSD. The report is especially believable because Dr. Hofmann wrote it at a time when the effects of the drug had never before been described, so he could not have been influenced by expectations.

This was in the era when scientific self-experimentation was more common than it is today, so after an accidental experience in the laboratory that alerted him to the profound effect of the drug, he took some of it intentionally and recorded what happened. He reports two experiences in his book LSD, My Problem Child that demonstrate the incredible range of experiences that can occur even within the same individual.

Last Friday, April 16, 1943, I was forced to interrupt my work in the laboratory in the middle of the afternoon and proceed home, being affected by a remarkable restlessness, combined with a slight dizziness. At home I lay down and sank into a not unpleasant intoxicated-like condition, characterized by an extremely stimulated imagination. In a dreamlike state, with eyes closed (I found the daylight to be unpleasantly glaring), I perceived an uninterrupted stream of fantastic pictures, extraordinary shapes with intense, kaleidoscopic play of colors. After some two hours this condition faded away. . . .

The dizziness and sensation of fainting became so strong at times that I could no longer hold myself erect, and had to lie down on a sofa. My surroundings had now transformed themselves in more terrifying ways. Everything in the room spun around, and the familiar objects and pieces of furniture assumed grotesque, threatening forms. They were in continuous motion, animated, as if driven by an inner restlessness. The lady next door, whom I scarcely recognized, brought me milk—in the course of the evening I drank more than two liters. She was no longer Mrs. R., but rather a malevolent, insidious witch with a colored mask.

Even worse than these demonic transformations of the outer world, were the alterations that I perceived in myself, in my inner being. Every exertion of my will, every attempt to put an end to the disintegration of the outer world and the dissolution of my ego, seemed to be wasted effort. A demon had invaded me, had taken possession of my body, mind, and soul. I jumped up and screamed, trying to free myself from him, but then sank down again and lay helpless on the sofa. The substance, with which I had wanted to experiment, had vanquished me. It was the demon that scornfully triumphed over my will. I was seized by the dreadful fear of going insane. I was taken to another world, another place, another time. My body seemed to be without sensation, lifeless, strange. Was I dying? Was this the transition? At times I believed myself to be outside my body, and then perceived clearly, as an outside observer, the complete

tragedy of my situation.* INDIVIDUAL HALLUCINOGENS


Lysergic acid diethylamide (LSD) is probably the best known and most commonly used hallucinogen in the United States. It is also the most potent of commonly used hallucinogens. The effects of LSD depend upon the dose. Typical doses today are between 50 and 150 micrograms (typical doses of the sixties were 100 to 200 micrograms). These levels are enough to produce full-blown hallucinations in nontolerant individuals, although some experienced users take multiple “hits.”

Because LSD is so potent and so easily dissolved, it is easy to disguise. It is often diluted and dissolved in liquid and then absorbed into a piece of blotter paper. No other drug is potent enough to be used in this form. However, enterprising drug dealers sometimes sell other compounds as LSD. Historically, most of the LSD sold in the United States was made in very small, clandestine labs in California. However, the Dark Web has become a common source of LSD as well as other illegal drugs.

Although LSD itself was originally synthesized in a laboratory in the 1940s, the hallucinogenic and toxic effects of lysergic acid derivatives (the

ergot alkaloids) have been recognized for thousands of years. Certain species of morning glory seeds that provided a drug called ololiuqui (the exact species are not clear but may include Turbina corymbosa) or tlitlitzin (Ipomoea violacea) in ancient Mexico contain a related chemical, lysergic acid amide. A tea made from the seeds, an alcoholic beverage made by extraction of the seeds with a favorite form of alcohol, and chemically extracted hallucinogens all cause an LSD-like hallucinatory experience. As with most plant hallucinogens, the seeds contain other chemicals, and the combination can cause nausea, vomiting, and other unpleasant side effects. Lysergic acid compounds were recognized in the Middle East several thousand years ago through the poisonings that resulted when a fungus (Claviceps purpurea) infected rye that was used to prepare bread. This fungus produced a number of LSD-related ergot alkaloids and amino acids that caused hallucinations and constriction of the blood vessels that could lead to gangrene, loss of limbs, spontaneous abortion, and sometimes death. The disease caused by eating ergot-infected rye became known as St. Anthony’s fire, after the patron saint of the order of monks founded to care for the victims of these poisonings and the burning sensation caused by the intense constriction of blood vessels. This plant product was well understood in medieval Europe, and midwives used its ability to cause uterine contractions to accelerate labor.

As the LSD experience begins, many people report unusual sensations, including numbness, muscle weakness, or trembling. A mild fight-or-flight response occurs: heart rate and blood pressure increase a little, and pupils dilate. Nausea is quite common. These changes are rarely large enough to be dangerous, although they can be in individuals with underlying heart disease. A Swiss research lab studying hallucinogen effects in humans has codified this experience using a scale called “Altered States of Consciousness,” which is divided into three sections: one that scores “blissful state” and “experience of unity,” another that captures distortions of visual experience, including synesthesia, and a third that refers to feelings of disembodiment and loss of control. All of these effects were maximal for one to four hours. Most users reported strong feelings of well-being. Some animal studies of LSD report a later phase of behavioral activation, which has been reported as feelings of agitation by some human users.


Time Clinical Effects

0–30 min.

30–60 Blurred vision, increased contrasts, visual patterns, feelings min. of unreality, lack of coordination, tremulous speech

1–4 Increased visual effects, wavelike motions, impaired hr. distance perception, euphoria, slow passage of time

4–7 hr.

7–12 hr.

Late effects

Adapted from R. M. Julien, A Primer of Drug Action, 11th ed. (New York: Worth, 2008).

Rapid tolerance develops to LSD. Probably this effect, as well as the lingering exhaustion from a drug experience that lasts so long, is the reason why most users take LSD at fairly widely spaced intervals (once a week to once a month). The tolerance diminishes quickly, so that a week’s abstinence is usually enough to restore sensitivity to the drug.


Hallucinogenic mushrooms are probably the second most frequently used hallucinogen in the United States. The popular cottage industry that has arisen promoting sales of home-growing kits has increased public awareness of

Dizziness, nausea, weakness, twitches, anxiety

Waning of above effects
Returning to normal
Headache, fatigue, contemplative state

these agents. However, there is probably almost as much misinformation about “shrooms” as there is about LSD.

The shrooms to which most users refer belong to several genera of mushroom (Psilocybe, Panaeolus, and Conocybe). The most commonly used species in the United States are Psilocybe mexicana and Psilocybe cyanescens. These mushrooms contain two related compounds: psilocin (4- hydroxy-N, N-dimethyltryptamine) and psilocybin (4-phosphoryloxy-N, N- dimethyltryptamine). Although many people think that psilocybin is the active agent, this is probably not the case. Only after the liver has removed the extra chemical group (a phosphate group) can the remainder of the molecule (psilocin) enter the brain. Although there are rumors that phosphorylated serotonin or phosphorylated DMT are alternative hallucinogens that provide a unique new high, these molecules have an additional piece that slows entry into the brain and actually prevents rather than promotes psychoactivity. Psilocybin is distributed both in the dried mushroom form and as a white powder of purified crystalline compound. A typical dose is four to ten milligrams (two to four mushrooms of the genus Psilocybe cyanescens).

Use of these mushrooms is ancient. Statues of mushrooms dating from 100 to 1400 CE appear throughout Mexico and Central America, and a group of statues from central Guatemala that are even older (about 500 BCE) are widely interpreted as mushroom stalks associated with mushroom worship. Use of teonanactl, or “flesh of the gods,” persisted in Mexico until the arrival of the Spanish, who attempted to extinguish its use. Ethnobotanists, including R. Gordon Wasson, Richard Schultes, and others, worked in central Mexico in the 1930s to identify almost twenty species of mushrooms belonging to the genera Psilocybe (the majority), Conocybe, Panaeolus, and Stropharia that were used for healing and religious purposes.

Psilocybin has come full circle in some ways, from careful ritualistic use by native peoples to college students’ recreational shroom use during spring break and at weekend parties to the object of current research and religious interest regarding its ability to cause persevering beneficial psychological effects. This experience is generally viewed as a milder and shorter LSD- like experience. At low doses, psilocybin causes simple feelings of relaxation, physical heaviness or lightness, and some perceptual distortions (especially visual). At higher doses, more physical sensations occur,

including light-headedness; numbness of the tongue, lips, or mouth; shivering or sweating; nausea; and anxiety.

The psychological effects mirror those of LSD. The same Swiss researchers who studied LSD had previously used the same behavioral scale to report the effects of psilocybin, which were very similar to, but milder than, those reported for LSD. The records of a group of scientists who gave LSD, psilocybin, and PCP to college students during the mid-1960s provide a good description of the effects in contemporary terms. They published the verbatim transcripts of the experiences of three students. The following is an excerpt from a transcript of a female college senior (who previously had never taken hallucinogens) that was recorded during a psilocybin experiment.

About an hour after the drug: “When I close my eyes, then I have all these funny sensations. Funny pictures, they’re all in beautiful colors. Greens and reds and browns and they all look like Picasso’s pictures. Doors opening up at triangular angles and there are all these

colors . . . an unreal world. It must be my subconscious or something. If I open my eyes, now the screen is, the dome gets darker. Looks like something is moving on the outside. Right along the edge. Some writhing. There’s a figure—isn’t exactly a figure, huge wings like a hawk, head of a hawk, but legs of a man beneath a bed. Now it’s gone.”

About two hours after the drug: “Ho, ho, I wonder if, I know I can sing as I sang before, but there’s some flower vines running up. They start at one point, like at the bulb, and then they go up over an archway or something. And they have flowers on them: the vines are green . . . I have the feeling that someone is sticking their high-heeled shoe into the cotton in my right hand. But I can’t feel it, it’s not there. When I move my hand, my hands are very wet. And the lower part of my body, body, well, my body’s bent. Freud. I think he went too far. Ohh. I’m moving. I look like I’m just moving. I just looked down at my body. I wish I had a mirror. I suppose that wouldn’t help my seeing. . . . Now I can see a fire. It looks like a key and there’s the crackling again. There’s a cage and someone is opening the door of the cage. And there’s a spider inside. But I’m not going in. I could stay here forever. It’s so pleasant. Move slowly up and down, up and

down, back and forth, ripple and wave. I keep my eyes closed now and I see a purple flower.Ӡ

Trips are not always as benign as this one, and in some cases they can be terribly frightening. The following is a description of a very unpleasant trip experienced by a friend of ours.

“It was late in the evening and I had been hanging out with two friends since the afternoon. We were all pretty tired, but decided to take some mushrooms. I remember as the trip began that every time I closed my eyes huge, vividly colored plants would seem to grow really rapidly in the darkness behind my eyelids. I found this pretty interesting and entertaining. It happened every time I closed my eyes—as though the process and the images were completely beyond my control.” Later that night, after a botched attempt to go to a party and a brief spell of unconsciousness, our friend “lay there looking up into the darkness and perceived the darkness to begin to move ever so slightly in a circular motion. It was not a dizzy feeling that happens sometimes to people who are really drunk and think that the room is moving. I had not been drinking heavily at all. In my mind it was the darkness that was moving. I already felt pretty unsettled because of having passed out, and the sense of moving darkness was quite frightening. As I stared into the darkness it began to swirl slightly faster, and I had the feeling that it was moving toward me—bearing down on me. Lightly at first, but the force seemed to increase as the swirling gained speed. Before long I was consciously fighting with that swirling dark force, having to push hard against it with my mind to keep it at bay. The process continued. The swirling got faster, and the darkness now seemed bent on overtaking me. I was overcome with the thought that if I let it get all the way to me I would be dead. So, I mustered all the concentration and focus I could to continue holding it off. I struggled for some time, but very slowly it seemed to wear me down.

“I remember thinking that it was going to win, and I was going to die. I held it off with all the will I could muster, and finally, feeling quite exhausted, gave up with the thought that fighting that force was useless and I should just let it take me. So I did. I relaxed and felt that at least I was facing my death calmly. The swirling malevolence seemed to enter my body in the middle of my belly. Then everything was calm and quiet again. I really thought I was dead. After a brief moment, I remember suddenly feeling that

an intense white light was bursting from within me, moving outward. It was as if single, white laser beams were shining out through each and every pore of my skin. Later I remember interpreting the experience in terms of my fear of, and struggle with, my image of my own death. But while it was going on, I was more afraid than I can ever remember having been.”

A Cautionary Note on Mushrooms: Psilocybin mushrooms are not the only ones that produce discernible mental effects. However, they are the only mushrooms in wide use in North America. The other well-described hallucinogenic mushrooms can be dangerous. Amanita muscaria, which we discussed at the beginning of this chapter, contains a number of compounds that produce hallucinations, including muscimol and ibotenic acid. These compounds can cause a marked intoxication in which speech is slurred, coordination is impaired, and users experience nausea and often vomit. After this phase, a dreamy/sleepy state ensues followed by an intense hallucinogenic experience. However, this mushroom also contains muscarine, which stimulates acetylcholine receptors in the body. This compound mimics stimulation of the parasympathetic nervous system, causing intense salivation, nausea, vomiting, spasm of the bronchioles (breathing tubes), slowed heart rate, and extremely low blood pressure. These last two effects can theoretically lead to shock and death, although muscarinic effects are usually mild. Recreational use of amanita is rare, because the experience is often unpleasant and the mushrooms are not widely available.

Scientific studies of the basis of the hallucinogenic properties of psilocybin and its therapeutic potential are experiencing a resurgence. Studies by Franz Vollenweider in Switzerland have provided a quantifiable rating scale for its behavioral effects, confirmed the role of 5-HT2 receptors in its actions (see the following), and produced brain scans conducted in people who were experiencing drug effects. Studies by Roland Griffiths in the United States have investigated its effects in certain clinical situations like end-of-life care, in PTSD, and in the treatment of migraines, and laboratory studies are under way. These studies have established dosage ranges that cause significant effects (twenty to thirty milligrams), and participants report persevering insight as a result of the experience. These studies, among the first in the United States in decades, used careful experimental controls, recruited both hallucinogen users and nonusers, and

were reported in the peer-reviewed scientific literature. These studies have largely reported persevering beneficial effects for PTSD patients and cancer patients with end-of-life concerns, with no major adverse effects. Most hallucinogen researchers include pre-drug counseling and supervision by trained psychologists during the drug session, a strategy they recommend for any future clinical use of hallucinogens. In contrast to depression and PTSD, for which LSD has shown promising results, migraines are not likely to be a future clinical target of LSD. Nonhallucinogenic variants of LSD may work just as well. However, this research may point to future therapeutic approaches to treating this disorder.


There are many other molecules with chemical structures that resemble serotonin (tryptamines) or amphetamine (phenethylamines) that scientists or bootleg drug preparers have made. 2C-B is one example, but there are many, and odd variants pop up all the time. Those that have been studied scientifically owe their hallucinogen properties to the same mechanism as LSD. However, each one has the potential to exert additional effects due to interactions with multiple receptor types, and so the effects can be individual and perhaps not what the user expects. A former synthetic chemist, Alexander Shulgin, and his wife published two books that describe the synthesis and use of these drugs, which some use as a guidebook. Those with amphetamine-like structures often have amphetamine-like activities along with their hallucinogenic properties, which can lead to dangerous levels of sympathetic nervous system stimulation and increased heart rate and blood pressure, for example. All such drugs are illegal in the United States (see the Legal Issues chapter).


Dimethyltryptamine (businessman’s special) is one of the other serotonin-like hallucinogens that appear on the drug scene in North America. The compound originally derives from the beans of the tree Anadenanthera peregrina (sometimes referred to as Piptadenia peregrina), which grows in northern and central South America, and related species in southern South America. It has been used by South American tribes as a hallucinogenic snuff called

yopo or cohoba. However, it is most often available today as the pure compound, which users prepare as a tea or smoke by itself or in conjunction with marijuana by first soaking the leaves in a solution of DMT and then drying and smoking them. The drug takes effect very rapidly: the entire experience develops and finishes within an hour. Probably because the onset of action is so fast, DMT causes anxiety attacks much more frequently than LSD, although the basic experience is similar.

Some serotonin-derived compounds, such as 5-methoxy dimethyltryptamine (5-MeO-DMT) or bufotenine, are found in the skins of some toads, including the Colorado River toad. Milking the glands on the back of the toad to obtain the hallucinogens, which are then smoked or ingested, was an old Native American trick that has been repopularized to the extent that the Wall Street Journal reported it. The high that is produced is extremely brief and accompanied by much worse side effects than most hallucinogens, including increased blood pressure and heart rate, blurred vision, cramped muscles, and temporary paralysis. These are due mainly to the bufotenine. The same compounds also appear in the seeds of a number of trees that grow in the Caribbean, Central America, and South America (Piptadenia peregrina). The powdered seeds provide the basis for hallucinogenic snuffs used by indigenous peoples and have been identified as a component of voodoo powders. DMT, 5-MeO-DMT, and some other variants including 4-Acetoxy-DMT and 5-MeO-DiPT (N,N-diisopropyl-5- methoxy-tryptamine) also show up in pill form. The basic effects of these drugs are similar, although the duration of action varies.

Peyote Cactus (Mescaline)

The peyote cactus has likely been used as a hallucinogen by native tribes in Mexico for thousands of years, and its use by North American tribes is an accepted part of their histories. The species that is typically the source of hallucinogens in the United States is a cactus that grows in northwest Mexico: Lophophora williamsii. It produces mescaline, the active hallucinogen, as well as many other compounds. The dried “button” of the cactus is the usual form in which the drug is used, although it also appears in other dried forms (powders, etc.), as well as in a tea. While it can be smoked, the button is usually swallowed without chewing, and the active

agent is absorbed from the stomach and intestine. There are other cacti that produce hallucinogens, including the San Pedro cactus (Trichocereus pachanoi), which grows in the Andes Mountains of South America.

Mescaline’s chemical structure does not resemble LSD or psilocybin and the other serotonin-like hallucinogens. Instead, the structure looks more like amphetamine. The physical effects also resemble those of amphetamine— dilated pupils, increased heart rate, and increased blood pressure. The mental effects as described by ritual and recreational users, however, are surprisingly similar to LSD. Nausea and vomiting are common, especially soon after ingestion of the cactus buttons. After ingesting a number of cactus buttons, users often feel an increase in sensitivity to sensory images and see flashes of color followed by geometric patterns and sometimes images of people and animals. Time and space perception are distorted, as with LSD, and people often feel that they are outside themselves. The effects of ingesting pure mescaline versus the cactus button are similar but not identical, because there are at least thirty other compounds in the cactus.

The ritual use of this cactus by the shamans of native tribes, such as the Huichol in Mexico, persisted into recent times, and North American tribes adopted it in the late nineteenth century. The ritual use by North American tribes was then integrated with a number of Christian practices in the form of the Native American Church. The use of peyote as a part of this church’s religious rituals has been protected by the First Amendment and then later by the Religious Freedom Restoration Act (1993). The act states that the government can limit a person’s exercise of religious freedom only if “it is in furtherance of a compelling government interest, and is the least restrictive means of furthering that compelling interest.” Although the 1993 law was declared unconstitutional by the US Supreme Court in 1997, some states have since enacted protective legislation for religious use to replace the protection no longer provided by federal law.

“Designer” Mescaline-like Drugs

A large number of variations on the structure of mescaline were first “designed” during the original chemical studies of mescaline. The names sound like an alphabet soup: DOM (2,5 dimethoxy-4- methylphenylisopropylamine, also known as STP), MDA

(methylenedioxyamphetamine), DMA (dimethoxyamphetamine), MDMA (methylenedioxymethamphetamine, or Ecstasy). All of these drugs are less specific than mescaline and produce strong amphetamine-like effects in addition to hallucinations. As a result, all are more toxic than mescaline and appear much more rarely on the street today. However, some, including 2CB and 25I NBOMe (4-iodo-2,5-dimethoxy-N-(2-methoxybenzyl) phenethylamine) are more widely available and have been associated with serious toxicities and even deaths, probably due to their stimulant properties. Ecstasy provides a unique profile of effects, discussed in the Ecstasy chapter.

The spices nutmeg and mace deserve a final note as we discuss the mescaline-like hallucinogens. Someone who takes several teaspoons of nutmeg (if able to figure out how to avoid the overwhelming taste) might experience a very mild hallucinogenic state that includes perceptual distortions, euphoria, and sometimes mild visual hallucinations and feelings of unreality. The active compounds in nutmeg and mace are myristicin and elemicin, compounds with structures somewhat like mescaline. These compounds are very weak hallucinogens, and the dose required to evoke changes in perception causes a number of unpleasant side effects, including vomiting, nausea, and tremors. Furthermore, an aftereffect of sleepiness or a feeling of unreality can persist into the next day.


Ayahuasca (caapi, yage, vegetal) is a plant-based hallucinogen that users ingest as a drink containing a combination of plant products. Although formulations vary, the two essential components are the bark of the vine Banisteriopsis caapi and the leaves of Psychotria viridis. The active ingredients provided by this combination are the beta carbolines harmine and harmaline, and DMT (see previous section). This combination produces a period of intense nausea and vomiting, a period of anxiety or fear, followed by an intense hallucinatory and dissociative experience. The hallucinations are predominantly visual, although users report increased sensitivity to sensory stimuli also. Users frequently experience the dissociation common to other hallucinogens and a profound sense of insight. The experience lasts a number of hours.

Ethnobotanists including Richard Schultes documented use of this drug by indigenous peoples of the Amazon that probably goes back centuries. The Beat writer William Burroughs recorded his experiences with this drug in The Yage Letters, and the sixties generation learned about it from The Teachings of Don Juan by Carlos Castaneda. Use of ayahuasca has migrated to the United States from South American religious groups like the União do Vegetal (UDV) and Santo Daime that have revitalized the once common use of this drug by native shamans for magico-religious purposes, such as healing and divination. Unlike many hallucinogens, ayahuasca is almost never used recreationally, but more typically as a pharmacologic aid to personal insight and enlightenment. Religious use has been legal in the United States since a 2006 legal decision. While DMT itself is a Schedule I drug according to the DEA, the legal status of plants containing this hallucinogen is more ambiguous.


Indians of Mexico use a plant called Salvia divinorum (a rare member of the mint family) for religious purposes, and it has generated some curiosity in the United States mainly because it is not yet illegal. Indians chew the leaves, but in the United States, people more typically smoke the leaves. Salvia causes an intense and sometimes unpleasant hallucinatory experience that lasts about an hour. Users report a unique experience that resembles neither LSD nor other hallucinogens. This drug is more likely than other hallucinogens to produce an unpleasant experience due to its novel mechanism of action, and so repeated use is somewhat unusual. The active agent is probably a compound called Salvinorin A, the second most potent hallucinogen known after LSD. A smoked dose of as little as 200 to 500 micrograms produces hallucinations.


Belladonna alkaloids are a group of plant-based compounds that affect the central nervous system. They are produced by the plant Datura stramonium, or Jimsonweed, and other closely related plants of the nightshade family. The name “Jimsonweed” comes from records of a famous poisoning that left the settlers of the Virginia colony of Jamestown deathly ill. Someone unfamiliar with the edible plants of the New World included the leaves of this plant in a

salad, resulting in severe intoxication in the diners. The plant became known as Jamestown weed, which later was corrupted to Jimsonweed. Teas prepared from any part of the plant, or the chewed seeds alone, produce a bizarre dream state at extremely high doses. Most users do not remember the experience because the drug causes amnesia. Ingesting doses large enough to produce this mental state causes dangerous effects on heart rate, breathing, and body temperature.

The active agents in Jimsonweed are the belladonna alkaloids atropine and scopolamine. Atropine is responsible for many of the effects outside the brain. At low doses, this compound or similar drugs are used to treat asthma and some stomach problems, and also to diagnose eye problems. However, at higher doses atropine can be lethal. The dramatic effects on thought and perception are caused by the scopolamine. Scopolamine, unlike atropine, enters the brain easily and is responsible for all of the behavioral effects of this plant.

The belladonna alkaloids mimic the complete shutdown of the parasympathetic nervous system—the mouth becomes dry, the pupils dilate, the heart speeds up, the bronchioles (breathing passages in the lungs) dilate, and digestion slows. These drugs also affect regions of the brain involved in the control of body temperature, which can rise to dangerous levels. Finally, they block one receptor for the neurotransmitter acetylcholine that is important for memory, so users often don’t remember the experience. These compounds and related ones also exist in other plants, including the deadly nightshade (Atropa belladonna) and the mandrake root (Mandragora officinarum). Used properly, they are important and effective medicines. They have also been used for divining and other religious purposes by many cultures. However, recreational use, mainly by teenagers who don’t understand the drug’s effects, has resulted in hospitalizations and occasional deaths. The mandrake root is showing up in herbal remedies and has caused ‐ accidental poisonings in this form.

Belladonna alkaloids have very different actions from the serotonin- related hallucinogens. They induce a bizarre delirium that users remember only as strange dreams. These dreams often include the sensation of flying.

These compounds have been used throughout history, as often for poisoning as for hallucinations. The term belladonna, or “beautiful woman,” comes from their use during the Middle Ages to dilate the pupils of the eyes

for the enhancement of beauty. These drugs also were supposedly used by practitioners of female-deity worship in Europe and Eurasia during the rise of Christianity, when those using these drugs were depicted as “witches” by the early Church. These compounds were used in medicine at the time, and it is possible that famous stories of witches flying on broomsticks may derive from vaginal application of these drugs to treat gynecological disorders. Recent news that criminals in Colombia and Thailand drug tourists with “burundunga,” a plant-based drink containing scopolamine that causes a dissociative state that the victims do not remember, proves that the historical uses of these plants are still with us. Fortunately, rumors of similar burundunga poisonings in the United States have not been confirmed by reliable sources.


Phencyclidine (PCP, angel dust, etc.) has a bad reputation—and deserves it. Both PCP and ketamine were initially marketed as general anesthetics under the names Sernyl and Ketalar. Doctors do not use it in humans unless they received a Valium-like drug to minimize the hallucinations. Currently, ketamine is used mainly as a veterinary anesthetic. Use as an anesthetic in humans is limited to situations in which it is essential to avoid depression of heart function with an anesthetic, or in children. PCP is sold in many different forms: as rocks that are smoked like crack, as PCP-impregnated marijuana joints, as white powder, or as pills. It is taken orally, snorted, or injected intravenously. The main effects of a single dose last four to six hours, although the effects can linger for up to two days. Ketamine is usually obtained by diversion from medical use. It is typically injected, or dried powder prepared from the solution is snorted.

PCP and ketamine are among the most complicated drugs we discuss in this book, because they have so many different effects on brain activity. PCP can produce a state similar to getting drunk, taking amphetamine, and taking a hallucinogen simultaneously. It is most frequently taken for the amphetamine- like euphoria and stimulation it produces. Many of PCP’s bad side effects also resemble those of amphetamine, such as increased blood pressure and body temperature. However, at the same time, it causes a “drunken” state characterized by poor coordination, slurred speech, and drowsiness. People under the influence of PCP may be less sensitive to pain. Finally, at higher

doses it causes a dissociative state in which people seem very out of touch with their environment. Observers frequently report that a PCP-intoxicated person has a blank stare and seems very detached from what is going on.

Not surprisingly, PCP-intoxicated people frequently find themselves in trouble with the law. Their driving skills are poor, their judgment worse, they are not attending to their environment, and they are insensitive to pain. This condition indeed can resemble the “drug-crazed,” sometimes violent state that many misinformed people attribute to any drug of abuse. In the case of PCP, the stereotype has some truth. Few drugs cause a person to be more difficult to treat in an emergency room situation because the user is so out of touch, belligerent, and agitated. At high doses, muscle rigidity and general anesthesia occur. Extremely high doses can result in coma, seizures, respiratory depression, dangerously high body temperature, and extremely high blood pressure.

Ketamine doesn’t have quite the bad reputation that PCP has, perhaps because its stimulatory effects are less pronounced. People who take low doses of ketamine achieve a drunken state—they are a little spacey and uncoordinated, but more sociable. At higher doses, the intoxicated, dissociated feeling and loss of coordination get more intense. People describe “going down into a K-hole” to describe the feeling of being cut off from reality. They describe out-of-body and near-death experiences. This dissociated state is probably pretty similar to the one induced by PCP. Both of these drugs can cause amnesia, and so users often don’t remember the drug experience well.

The startling discovery that a single dose of ketamine can rapidly alleviate serious depressive symptoms has revitalized interest in the clinical use of this drug. This improvement can last for days to weeks, but eventually requires repeat dosing. Treatment must take place in a hospital because the dose required for antidepressant action causes feelings of dissociation that can be quite unsettling. However, the discovery of ketamine’s antidepressant properties has generated a lot of excitement in the research community, and research for safer alternatives is very active.


Dextromethorphan is the main constituent of many over-the-counter cough remedies. At appropriate doses (a teaspoon or two), this drug decreases

coughing and doesn’t do much else. However, it is a cousin of the hallucinogenic anesthetics PCP and ketamine, and some resourceful drug users—usually teenagers—have discovered that if they take excessive doses (equivalent to drinking an entire bottle of cough syrup—about 300 milligrams —or taking anywhere from ten to sixty DXM-containing pills), they can experience a dissociative state that is dose-related. While the lower end of the abused range (ten pills) leads to a mild state, very high numbers of pills (sixty pills) can lead to an intense dissociated, hallucinatory state, and there are case reports of psychotic behavior in people taking extremely high doses. Recent research shows that it indeed acts much like ketamine. Dextromethorphan also shows up in the guise of fake Ecstasy pills—it is a common substitute for MDMA. Toxic doses cause confusion, disorientation, elevated body temperature, high blood pressure, and vomiting or nausea. Some users develop patterns of repeated chronic use, although there is not much in the scientific literature about dextromethorphan tolerance, dependence, or addiction. Although it can cause toxicities, the lethal dose is still considerably above (roughly double or more) the highest doses the recreational users typically employ. However, the other constituents in cough syrups can add to the toxicities. Cough syrups with decongestants in them can raise blood pressure markedly, and the combination of DXM and the antihistamine (chlorpheniramine maleate) in some preparations can cause a serotonin syndrome–like toxicity in rare cases. Ingestion of high doses (thirty to sixty pills) of formulations with acetaminophen can deliver enough of this analgesic drug to damage the liver. While DXM is not illegal, most states have laws that prevent sales to anyone under the age of eighteen. This increased regulation has led to a decline in poison center reports of toxicities following a peak in 2015.


Neuroscientists know less about hallucinogens than most other psychoactive drugs. In part, this is because hallucinations can be studied most accurately in humans. No one would volunteer for the careful brain-lesion studies that can determine where critical drug effects reside, but imaging studies in living humans have proven useful. In addition, we do have a lot of information about the neurotransmitter systems involved from studies in animals. Because

there are so many hallucinogenic drugs, it will come as no surprise that there are several different neurochemical routes to hallucinatory states and that each drug produces a somewhat distinct state caused by a distinct mechanism of action.


The suspicion that drugs like LSD have something to do with the neurotransmitter serotonin (5-HT) has been prevalent since scientists first described the similarity of the chemical structures of LSD and psilocin to serotonin in the 1940s. It has been a long and tortuous road from this initial suspicion to a molecular understanding of what these drugs do. Serotonin is an important neurotransmitter that helps regulate mood and sleep, modulate eating behavior, maintain a normal body temperature and hormonal state, and perhaps limit vulnerability to seizures. Drugs that enhance all of the actions of serotonin are useful for treating depression and suppressing overeating. How, then, can drugs that affect serotonin produce such bizarre effects on perception without disrupting many of these other actions of serotonin?

Part of the difficulty in understanding hallucinogens came from using LSD as a test hallucinogen. All of the early test systems involved organs other than the brain. For example, serotonin can make the heart of a clam beat faster, so these hearts were an early favorite test system. Scientists would hang the clam heart from a wire attached to a pen that would move if the heart muscle contracted. When serotonin was dripped on the heart, it contracted. LSD prevented the effects of serotonin on clam hearts and other test systems, and for years it was thought that hallucinogens acted by preventing the actions of serotonin. When more sophisticated tests of serotonin action in the brain became available, they seemed to support this idea. Scientists measuring the rate at which serotonin neurons were firing showed that LSD inhibited their firing. However, this didn’t make a lot of sense, because shutting down the serotonin neurons so dramatically should have affected all of the other processes that rely on serotonin, but LSD did not produce such effects. Furthermore, mescaline did not have the same effect as LSD in these types of experiments, but because the structure of mescaline, unlike the other drugs, did not resemble serotonin, scientists were willing to assume that mescaline was working in some different way.

The answer to the question of what hallucinogens have to do with serotonin had to wait for scientists to discover that the neurotransmitter serotonin acts on a number of different receptors. At least thirteen types of serotonin receptors are now recognized, and we know that some seem to have very specific effects on behavior. Only one of these can trigger hallucinations. The thirteen receptors can be grouped into big classes (1–7), which themselves are subdivided. Virtually all serotonin-like hallucinogens are agonists (they stimulate) at two subtypes of the 5-HT2 receptors (5-HT2a and 5-HT2c). Researchers think that the hallucinogenic activity results from the stimulation of 5-HT2a. So far, every experimental drug tested that stimulates the serotonin-2a receptors causes hallucinations. We don’t know how this happens, but we are pretty sure that stimulating these receptors can do it. Most of these receptors are in the cerebral cortex, where we think hallucinogens have their major action. The fact that the highest density of 5- HT2a receptors occurs in areas related to the processing of visual stimuli is consistent with its dramatic visual effects, and research on neural activities in this part of the brain is beginning to yield insight into the mechanisms of visual hallucinations.

One mystery that remains about serotonin drugs is why the antidepressant drugs that increase the amount of serotonin in the synapse (see the Brain Basics chapter) do not usually cause hallucinations. These drugs increase serotonin everywhere in the brain, including sites that have 5-HT2a receptors, but although a rare patient taking one of these drugs experiences hallucinations, when the 5-HT2a receptors are stimulated in balance with all of the other serotonin systems, there are generally no hallucinogenic effects.


The belladonna alkaloids work by a completely different mechanism, which explains the different state that they cause. They act by preventing the actions of the neurotransmitter acetylcholine at one of its receptors. Acetylcholine is the neurotransmitter that nerves use to stimulate muscle and allow movement, and it is also the neurotransmitter mimicked by nicotine. It has two types of receptors: one is stimulated by nicotine, and the other (called the muscarinic receptor, because researchers discovered that it was stimulated by the compound muscarine from the Amanita muscaria mushroom) slows the heart

and probably helps to form memories. We describe this in more detail in the chapter on nicotine.


All three drugs block the actions of the neurotransmitter glutamate at one of its receptors, although PCP and ketamine are much better at it than dextromethorphan. This blockade can, on its own, produce most of the effects of these drugs, including feeling disconnected from your body or environment after either recreational use or medical use in anesthesia. This feeling has made it impossible to use these drugs to treat stroke, a medical use for which there was great hope when the ability of these drugs to limit stroke-induced brain damage was discovered. However, in clinical trials of these drugs, patients hallucinated. As you can imagine, it was terrifying for patients to wake up in the hospital, seriously ill, afraid that the stroke rather than the treatment was causing hallucinations.

PCP and to a lesser extent ketamine act like amphetamine to release the neurotransmitter dopamine. This accounts for the locomotor activation that PCP-intoxicated people can experience. Scientists once thought that these drugs directly affected dopamine neurons, but now they think PCP effects are the result of glutamate receptor blockade. In any case, this causes some good feelings and is why both drugs are somewhat addicting.

These drugs also decrease sensations of pain to a varying extent. NMDA receptor blockade likely plays a major role in the effect, but it also may reflect some activity on a group of receptors called “sigma” receptors that when activated cause a spectrum of effects including hallucinations and a loss of pain sensations. These receptors were once classified as opioid receptors, but they are not anymore. We do not know what they do in regulating normal brain function. Interest in this system has risen in recent years because researchers found that drugs that specifically stimulated this receptor system produced hallucinations without affecting the other opioid systems. Dextromethorphan is also a very weak stimulant of this receptor, which might contribute to its effects.

The most useful drugs are those that are most selective. PCP, ketamine, and dextromethorphan suffer from being the opposite—they block the action of the major neurotransmitter in the brain that excites other neurons, and so they affect many important brain functions.


Salvia has its own unique mechanism of action. Research on Salvinorin A, the likely psychoactive agent in the plant, has shown that it acts most like an agonist for the kappa opioid receptor—the receptor that causes dysphoria rather than euphoria (see the chapter on opioids). This explains the general lack of euphoria and repeated use of this drug. It does open a new area of research into the role of these receptors in hallucinations, as none was suspected before characterization of Salvia biochemistry.


The use of hallucinogens by many indigenous peoples is tightly controlled by their cultures, which restrict such drugs to ritual use for purposes of healing, enlightenment, or prophecy. In many cases, only particular individuals in a society are permitted to use the drugs at all.

Has the use of hallucinogens evolved from this spiritual purpose to recreational use/abuse in contemporary society? If you talk to college student users, the reasons they give for using these drugs vary tremendously. Some clearly and simply aim for a novel and exciting experience. However, interviews with regular and heavy users reveal a substantial percentage who use the drug for the sense of enlightenment they feel they gain by separating from themselves.

The difference between the novelty seekers and those seeking enlightenment may simply be in how they frame the experience. For example, many users report a sense of “dissolving boundaries” while under the influence: A user might be sitting on the ground and feel that the boundary between the ground and his body no longer exists. This feeling could lead to the very exciting (or unsettling) feeling of being sucked into the earth, or it could lead to a calming sense of “oneness” with Mother Earth.

Dr. Timothy Leary (1920–1996) provides an example of varying perspectives on LSD. He started out as a professor at Harvard, pursuing a traditional academic study of the potential therapeutic utility of hallucinogens. The stories his subjects told him convinced him that LSD had tremendous spiritual value, and he became famous (and lost his job at Harvard) for his advocacy of the free use of LSD. Today he is better known

for coining the phrase “turn on, tune in, drop out” during the 1960s than he is for his academic research.

In today’s environment of increasing acceptance of psychoactive drug use for medicinal and “health-promoting” activities, consumer consideration of LSD for such purposes is increasing. No less a cultural icon than Steve Jobs has credited LSD use with increasing his creativity and insight at work. There is more conversation about using tiny “microdoses” of LSD to improve health, work productivity, and creativity. Experimental researchers are actively investigating the possibility that subhallucinogenic doses of some hallucinogens may have health benefits.

Unfortunately for LSD advocates, these attitudes still conflict directly with the illegal status of these drugs, and many Americans prefer for their use to remain regulated.


One myth we want to dispel is that there is no credible scientific research conducted on hallucinogens. Research on hallucinogens (including LSD) can be legally conducted in the United States and Europe. Admittedly, the research history of hallucinogens is colorful and not always credible, ranging from military experiments on unsuspecting subjects to the blithe self- experimentation of Dr. Timothy Leary in the sixties. However, in recent years, research by credible biomedical researchers has expanded, focusing on a variety of topics ranging from what hallucinogen experiences can tell us about psychosis to the specific mechanisms by which these drugs act to cause persevering effects on religious insight.


Users can never really be sure which hallucinogen they are taking. Blotter- paper-like preparations are most likely to be actual LSD because other hallucinogens are not potent enough for an effective dose to be delivered in this way. However, a pill/capsule/powder could be anything, or any combination of things. Laboratory analyses of blood from people admitted to emergency rooms for LSD toxicity indicate that in some urban settings, only

about 50 percent of the drug samples that were thought to be LSD by their possessors actually were LSD. Finally, any drug that has been synthesized in an underground laboratory can contain various by-products that arise from poor chemical synthesis.

Hallucinogenic mushrooms represent another identification problem. It takes an educated and practiced eye to identify any mushrooms in the field, and this is always a dangerous proposition. Many mushroom species, including the aforementioned Amanita muscaria, contain psychoactive compounds that are extremely dangerous or lethal. Other species (Amanita phalloides, for example) contain toxins that produce fatal damage to the liver and kidneys. While simple “home” tests are much touted (“if the stem turns blue, it is psilocybin”), none of these are foolproof. A number of mail-order operations exist that claim to send out psilocybin-containing mushrooms, but the identity of the spores for “grow your own” operations can be very difficult to establish.


LSD, psilocybin, and mescaline do not generally cause dangerous physical reactions; and blood pressure, body temperature, and other vital signs remain reasonably stable unless there are acute anxiety reactions. A user is in little danger of seizures or coma. Furthermore, there is little evidence that these drugs activate the pleasure centers, and addiction and physical dependence do not occur. In this sense, they are remarkably safe. However, the psychological consequences for some users can be extreme. The bad trip, in which the drug user feels acute anxiety and perhaps fears an inability to return, is the most common. Fortunately, this reaction ends as the drug is eliminated from the body. Acute anxiety can usually be treated with a dose of a benzodiazepine (a Valium-like drug—see the Sedatives chapter). “Talking down” can be helpful, but it is not always practical. While antipsychotic medications like Thorazine (chlorpromazine) were once popular, they are not always effective on bad trips and, in fact, can make things worse. Now that we understand that many hallucinogens act on serotonin-2 receptors, it’s possible that an antagonist (blocking) treatment will become available that would terminate the trip immediately. Research studies show that a 5-HT2 antagonist called ketanserin effectively blocks most psychoactive effects of psilocybin. Such drugs exist but have not yet been investigated or approved

for this purpose in the United States. Similarly, the narcotic antagonist naloxone should stop a Salvia trip, but this hasn’t been tested yet.

What about the myth that taking LSD will make you crazy? Hallucinogens can worsen the symptoms of people who are already psychotic, but we don’t know if they can cause psychosis. They certainly don’t very often. However, a number of studies have shown that hallucinogen users are disproportionately represented among psychiatric inpatients, and that one to five people out of one thousand who take hallucinogens experience an acute psychotic reaction.

There is a “chicken and egg” problem in understanding this statistic. Most people who are hospitalized for a psychotic reaction to hallucinogens have never before been seen by a psychiatrist. So, it is impossible to know whether they were completely healthy before the drug experience. We do know that a small number of people have very serious reactions to LSD and similar drugs, including prolonged psychotic states. Also, people with a family history of, or other predisposition toward, mental illness should be particularly careful. Sometimes a hallucinogenic experience can bring out symptoms in such individuals.


The issue of flashbacks, or posthallucinogen perception disorder (PHPD), is clearer. Flashbacks are the reemergence of some aspect of the hallucinogenic experience in the absence of the drug. They are most commonly reported in frequent LSD users, although isolated case reports exist about flashbacks in individuals after use of other serotonin-like hallucinogens. The most common form includes altered visual images, wavering, altered borders to visual images, or trails of light. While flashbacks can occur after a single use of the drug, they may become increasingly common as the number of hallucinogenic experiences increases. Use of other drugs, like marijuana and alcohol, and even extreme fatigue, can trigger this phenomenon. The overall incidence is hard to judge because use of other drugs or psychiatric conditions must be ruled out. By our best guess, incidence for the common user is low.

People’s reactions to flashbacks vary widely. Some users experience anxiety and depression while others view flashbacks as an acceptable side effect of an otherwise positive experience. In many cases, flashbacks

diminish with abstinence, although symptoms that persist for years have been reported.

Persistent symptoms might actually reflect long-term changes in how the brain processes sensory images. Studies of vision of habitual LSD users (when they are not under the influence of the drug) show that their brains may continue to respond to visual stimuli after the stimuli are removed. This response suggests that repeated LSD usage may cause some neuroplastic changes that persist. In the Brain Basics chapter, we discuss the brain’s capacity to remember all sorts of experiences, including repeated drug applications.


We have one final myth to discuss: the idea that LSD will break chromosomes. This concern, based on scanty research, was raised during the 1960s. While women who used LSD during pregnancy have given birth to children with birth defects, this rate is not higher than that of the general population. Furthermore, most of these women also used other drugs during pregnancy. Most animal research has not shown remarkable effects of LSD on the developing fetus. Some concern about the effects of LSD goes back historically to the widespread use of related ergot alkaloids to induce abortion. However, LSD itself does not have this effect. Nevertheless, women who are pregnant, or who might be, should avoid drugs in general.


Conventional LSD-like hallucinogens are fairly unlikely to produce serious physical effects. However, some newer and fortunately rare designer hallucinogens have blurred the lines between stimulants and hallucinogens. For example, one of these—25I-NBOMe, 4-lodo-2,5-dimethoxy-N-(2- methoxybenzyl) phenethylamine—has been reported to cause deaths. This drug and some like it sometimes are marketed as bath salts, and sometimes as LSD. The particular problem with this drug is its extraordinary potency: like LSD, it has big effects at very small doses. This drug and several close relatives may represent serious risks to human users, but almost nothing is known about them.

The belladonna alkaloids represent a particular danger. These drugs prevent the action of one of the major neurotransmitters in the body (acetylcholine) at many of its synapses. At doses that cause hallucinations, they increase heart rate and body temperature to dangerous levels: death can result. It is important to understand that there is not a dose that produces significant behavioral effects that is not toxic: the behavioral effects, like delirium, are signs of overdose. These effects are easily treated by medical personnel if they know what the intoxicating drug is. Therefore, it is extremely important to seek medical attention.

PCP also can cause dangerous side effects or death from overdose (two to five times a single recreational dose). As the user increases the dose, general anesthesia can result (remember, this was the reason the drug was invented). However, a number of dangerous effects occur after high doses, any one of which can be lethal. Body temperature can rise to 108 degrees Fahrenheit, blood pressure can rise so much that a stroke occurs, breathing can cease, or a prolonged period of seizure activity can result. PCP can also cause a prolonged state resembling paranoid schizophrenia. This most often happens in people who use PCP for a long time; however, an abnormal psychiatric state that persists for days can result from a single use. The acute delirium caused by PCP or ketamine can be alleviated with benzodiazepine drugs, such as Valium.


Many people who experiment with hallucinogens combine them with other drugs. For example, it is not uncommon for people to take LSD or mushrooms and smoke marijuana at the same time. The effect of these combinations is highly individual and depends on the previous drug experience of the user, the doses, and the particular drugs involved. For example, smoking marijuana often triggers PHPD (flashbacks) in heavy LSD users. Many of these combinations produce bizarre, anxiety-provoking—but not dangerous—states.

The most troublesome reactions are those that are caused by the user taking something without knowing it. PCP is a frequent culprit in this regard. Marijuana can be adulterated with PCP without the user’s knowledge and can induce a terrifying or dangerous state in the unsuspecting users.

What about interactions with prescription drugs? Not surprisingly, other drugs that influence serotonin systems have been involved in reported interactions. There are multiple reports of serotonin-specific reuptake inhibitors (SSRIs) like Prozac (fluoxetine) triggering flashbacks in heavy LSD users. The opposite interaction also can happen: some patients who are taking SSRIs to treat depression report that they do not experience the effects of LSD. A more dangerous interaction could theoretically happen if people combine SSRIs and ayahuasca. The MAO inhibitor in the ayahuasca can synergize with the increase in serotonin caused by the SSRI, leading to the dangerous “serotonin syndrome” that we discuss in the Ecstasy chapter.

* From Albert Hofmann, LSD, My Problem Child (New York: McGraw-Hill, 1980).

†From J. C. Pollard, Drugs and Phantasy: The Effects of LSD, Psilocybin and Sernyl on College Students (New York: Little, Brown and Co., 1965).



Drug Class: Herbal drugs. The drugs mentioned in this chapter are not scheduled by the Drug Enforcement Administration. However, there are legal restrictions on some. Ephedrine requires a prescription.

Individual Drugs (just a few examples): Herbal X-tacy, beta phenylethylamine (PEA), dimethylamylamine (DMAA), synephrine, smart drugs, ginseng, melatonin

The Buzz: Most of these drugs are either members of other classes we have discussed or don’t have a buzz because they are ineffective or because they are used to improve brain function—not to intoxicate.

Overdose and Other Bad Effects: The biggest danger of these drugs is that many are untested and unregulated. For some, there is research support for effectiveness and safety, or evidence of traditional use by other cultures for centuries. For most, claims of efficacy are based on sometimes-skimpy research that may or may not include credible clinical studies. Even for effective medicines, the actual contents of herbal preparations are unknown. Furthermore, the user cannot rely on the instructions to be a reliable guide for

effective or safe use. In the worst cases, instructions suggest use of dangerous amounts of the drug. In the best cases, the doses are estimations based on sparse research.

Dangerous Combinations with Other Drugs: Ephedrine and similar stimulants can be dangerous when taken in combination with monoamine oxidase inhibitors, which are used to treat depression. The combination of these two drugs can lead to fatal increases in blood pressure or heart rate. The combination of ephedrine-like stimulants with caffeine is much more likely to lead to symptoms of cardiovascular activation, jitteriness, anxiety, and arousal than either drug alone.


What Is an Herbal Drug?
Herbal Drugs Are Not Regulated Like Regular Drugs Ephedrine and Its Substitutes
St. John’s Wort and Other Herbal Products for Depression Melatonin

What Is Melatonin?
Melatonin and Sleep
Melatonin and Fertility
Melatonin and Aging
Melatonin and Other Health Benefits Is Melatonin Safe?

Herbal Drugs and Cognitive Function Ginseng
Herbal “Smart Drugs”

Hazards of Herbal Drugs


Herbal drugs are simply drugs from plant matter. Many of the drugs discussed in this book fall under that large umbrella. Many of the most common intoxicants are ultimately derived from plant products. Nicotine

comes from tobacco plants, and many forms of alcohol are prepared by the fermentation of yeast in the presence of grain products. Many hallucinogens, ranging from psilocybin mushrooms to belladonna alkaloids, could be described as herbal drugs, along with many natural stimulants, including caffeine, ephedrine, and cocaine. There are also herbal sedatives—hypnotics such as kava—that act very much like alcohol. The herbal drugs we discuss in this chapter are those sold mainly over-the-counter under the assumption that they are natural products that can treat conditions including obesity, memory, immune function, and the like.

Herbal drugs are touted as safe and effective because they are “natural,” or a “normal constituent of the body.” This drug classification is an effective marketing device: A 2012 study reported that the market in herbal drugs in this country in that year totaled $12.8 billion. Because most of these preparations are sold as nutritional supplements rather than as drugs, they are not subject to FDA requirements. Therefore, neither their safety nor their effectiveness has been established in controlled scientific studies. This doesn’t mean that none of the drugs are effective; some certainly are. Furthermore, we should never discount the placebo effect: The promise of a remedy can have a powerful healing effect. And remember—herbal drugs are still drugs, because if they are effective, they change how your body works. That means when you visit the doctor, you should be sure to mention any supplements you are using. As you will see in this chapter, they can interfere with the effects of medications you may be prescribed.

This chapter discusses a subset of these drugs that are widely used to change brain function—either to optimize function or treat mental illness. This subject could be the topic of an entire book, so we have focused on the most common ingredients in the many supplements that are out there. It is important to bear in mind that these drugs are most often components of complex mixtures, and it is very difficult to know how much (or whether) a particular component contributes to the desired effect. A quick survey of energy supplements available online showed ingredient numbers ranging from three to more than fifty!


Herbal drugs are not regulated the way normal prescription and nonprescription medications are controlled in the United States. In 1994, Congress passed the Dietary Supplement Health and Education Act, or DSHEA. This law says that the FDA will not regulate any natural product (which they define as any product intended for ingestion as a supplement to the diet, including vitamins and minerals; herbs, botanicals, and other plant- derived substances; amino acids and concentrates; metabolites; constituents; and extracts of any of these substances). Therefore, such drugs can be marketed without proof that they are safe or effective. The FDA can only remove them from the market if they can prove they are dangerous—a strict requirement, and one that shifts the burden of proof from those marketing the drug to the FDA. Not all herbal drugs are ineffective or dangerous, but the buyer should consider several issues. First, what is the source of claims for effectiveness? Some herbal drugs have been tested by credible, well- controlled scientific studies. Others have been used by other cultures for centuries in a carefully documented way. Unfortunately, there is little evidence to back up claims about many other drugs. Furthermore, there is a growing interest in Eastern medicine that can sometimes lead to uncritical acceptance of herbal healing techniques. While many effective medicines derive from herbal sources, many ineffective ones do as well.

The second consideration is the safety and reliability of formulation. A frightening example happened in the early 1990s in the marketing of the amino acid tryptophan. Tryptophan, a normal constituent of the body, is used by some as a so-called smart drug to improve mental functioning and facilitate sleep. It is a component of many foods and has no known hazards when taken as a nutritional supplement. However, a still unknown contaminant in a tryptophan preparation from one particular supplier caused a serious and fatal disease—eosinophilia-myalgia syndrome. In addition, with almost daily revelations about contaminated food products from both foreign and domestic sources, caution with “herbal” preparations is warranted. A recent survey of melatonin products showed that the melatonin content of some preparations was half or double the amount listed on the label. Finally, an increasing number of “herbal” compounds actually contain a synthetic drug that is far more efficacious—common problems in this regard are diet aids that contain the drug sibutramine, and “herbal” sexual enhancers that contain sildenafil (Viagra). A recent survey of herbal weight loss products revealed that 50 percent of them contained sibutramine, a

former prescription drug that lost its FDA approval due to cardiovascular problems experienced by users. On one hand, users of these preparations may be satisfied because they are taking an active agent. On the other hand, they may experience health risks that they would not expect from the advertised herbal ingredients. Such substitutions can lead to greater-than- expected results.

Most people who use herbal drugs must rely upon self-experimentation to establish effective doses that lack side effects. Unlike in Europe, where the use of herbal drugs and homemade formulations is broader and pharmacists are more informed, there are few professionals in the United States who are qualified to give knowledgeable advice about herbal drugs, so users must depend upon an informal (and often uninformed) network of advocates— usually those marketing the compounds.

In 1998, Congress established a new division of the National Institutes of Health (the National Center for Complementary and Alternative Medicine) to study alternative and complementary medicines, including herbal drugs, and research is extremely active right now. We know more about the safety and effectiveness of these drugs all the time.

In early 2019, the FDA indicated that it was going to take a look at dietary supplements making claims that they could cure diseases like Alzheimer’s, so perhaps the regulatory environment is evolving.


Ephedrine is a molecule found in many plants that was sold widely as a sports supplement to enhance workouts, cause weight loss, and best of all, burn fat. It also was sold as an herbal (and safer) substitute for Ecstasy (methylenedioxymethamphetamine, MDMA). Ephedrine has been banned since 2004 (a ban upheld in 2007), although it sometimes crops up on the internet in some forms including herbal teas, in Chinese herbal remedies, and in a chemically synthetic form as an asthma treatment. Ephedrine is an effective medicine for treating asthma and has been used medically as such in appropriate doses for thousands of years because it acts as a mild stimulant to the sympathetic nerve endings to dilate bronchioles, increase heart rate and blood pressure, and raise blood glucose. However, this drug does not enter the brain well and at best causes a jitteriness that most people find

discomfiting even when used in appropriate amounts for the treatment of asthma. At higher doses, ephedrine causes an arousal and anxiety state that most people find unpleasant, although some report positive feelings with the arousal. Relative to other stimulants, these effects are mild.

These characteristics explain why ephedrine, especially at excessive doses, can be mistaken for MDMA and was popular for improving athletic performance. Ephedrine increases heart rate and blood pressure and can give the feeling of greater physical activation, which can be mistaken for improving athletic performance. High enough doses cause some increase in arousal and anxiety, so the users can “feel” a drug effect. But in fact, ephedrine does nothing to improve muscle development.

There may be some truth to claims that ephedrine can help contribute to weight loss due mainly to its effects on the body to facilitate fat breakdown and increase energy production, but the effects are minor. Ephedrine and ephedrine/caffeine preparations have been tested on obese humans and have been found to have a modest benefit (studies report a five- to ten-pound weight loss).

The FDA banned ephedrine because of many (thousands) reports of adverse events including milder side effects like tremors, headache, insomnia, nausea, vomiting, fatigue, and dizziness as well as a number of deaths in young, healthy people who experienced heart attacks or strokes (especially when using this drug while exercising).

Numerous substitutes for ephedrine have entered the marketplace. Some of these are relatives of ephedrine (p-synephrine), and some are plant products whose active ingredients aren’t known or listed (Hoodia, Cha de Bugre). Three common ingredients are beta phenylethylamine (PEA), p- synephrine (the active ingredient in bitter orange), and dimethylamylamine.

Beta phenylethylamine is a drug that works like ephedrine and so has very similar effects: it raises blood pressure and heart rate due to the release of norepinephrine. In addition to its ability to mimic sympathetic stimulation, it also stimulates “trace amine receptor 1,” a minor receptor that exists throughout the body through which it constricts arteries and probably has other actions. Unlike ephedrine, PEA enters the brain, and at high doses it causes the release of dopamine and norepinephrine and causes stimulant-like behavioral effects. Normally, these effects are limited by the rapid metabolism of PEA by monoamine oxidase in the liver and in the brain. Little

is known about how high PEA levels get when humans ingest pharmacologic amounts as supplements: there has been almost no investigation of this.

PEA has another unique characteristic: it is a natural constituent of the brain (albeit a minor one), and over the years scientists have measured levels in the urine and blood of patients with a variety of disorders, including attention deficit/hyperactivity disorder (ADHD), schizophrenia, depression, and Parkinson’s disease, in the hopes of understanding whether there is a link there. These research findings are mixed between speculations that it is beneficial (lifting depression after exercise) or harmful (contributing to the acceleration of dopamine neuron death after monoamine oxidase therapy). So is PEA a natural therapy or dangerous sympathomimetic? We don’t know. It is certainly physiologically and behaviorally active, based on a few studies. However, the same caveat exists for this supplement as for many others: you are not guaranteed to get the dose that is advertised, and sometimes not even the molecule that is advertised.

p-Synephrine is a simpler story. This is a very close relative of the nasal decongestant m-synephrine, better known as phenylephrine. It was used as a drug in the 1920s but has not been marketed for many years. However, its source as a dietary supplement is usually from immature (green) Seville oranges (Citrus aurantium). It is used primarily for weight loss and as a component of sports supplements. It has been used in traditional Chinese medicines for digestive problems. Its main well-characterized effect from the old animal studies of the sympathetic nervous system is to raise blood pressure, probably by stimulating the alpha-adrenergic receptor for norepinephrine, and perhaps through the weak inhibition of norepinephrine uptake. This effect has been observed in humans in some but not all studies. Its effectiveness as a weight-loss agent is in the eye of the beholder: reviewers who acknowledged their association with its marketing have taken a more positive view of the “modest” weight loss and benign side-effect profile than reviewers without a conflict of interest. Most studies of both its effectiveness as a weight-loss agent and its cardiovascular effects have been conducted on supplement mixtures containing caffeine, so it is hard to know the efficacy of the p-synephrine mixtures that are widely marketed. It would be logical to assume that the benefit-risk profile is similar to that of ephedrine. Finally, “bitter orange” preparations are among those products that can contain pure p-synephrine, not the plant products, and so it is possible to experience greater-than-expected effects with their use.

DMAA is marketed as a constituent of rose geranium, although formulations may have geranium extract or synthetic DMAA. It is currently under investigation by the FDA, which has contested its existence as a natural product in geranium and, hence, questioned the freedom to market it under the protection of natural-product legislation. The purified molecule was used as a nasal decongestant for decades, ending in the 1970s. It constricts blood vessels and raises blood pressure. There is little scientific evidence that it lowers weight or improves muscle mass. Furthermore, the first few reports are starting to trickle in of healthy young people experiencing strokes when using DMAA/caffeine combinations during heavy workouts—exactly the scenario that resulted in ephedrine casualties.

These drugs are often sold in complicated mixtures containing caffeine. A recent example includes Garcinia cambogia, soy phospholipids, Rhodiola rosea, green, white, and oolong tea extracts, and caffeine. How should you evaluate these mixtures? Obviously the tea and caffeine combination suggests that a major active ingredient is caffeine, likely in higher levels than you might get from a cup of coffee. As discussed in the Caffeine chapter, this ingredient alone can have measurable effects on exercise performance. Understanding the effects of the other ingredients requires a deep dive into the biomedical research literature, which most people cannot access, and which requires careful interpretation. While animal research supports claims of decreased body weight associated with Garcinia cambogia, human studies have not panned out. Rhodiola is a plant used historically in northern European countries, and a small literature supports some antidepressant activity, but the active molecules have not been identified, and the literature is pretty thin.

Combinations of ingredients that can raise blood pressure are the biggest concern. These include caffeine, ephedrine, DMAA, and the others mentioned above. These effects can be exaggerated, leading to dangerous increases in blood pressure in patients taking monoamine oxidase inhibitors for the treatment of depression (Marplan, Nardil, Parnate). However, side effects unrelated to the primary actions of these herbal drugs can occur. Liver failure has been reported, though rarely, after use of chromium, Garcinia cambogia, Camelia sinensis (tea extract), and hoodia, popular ingredients in weight loss/sports supplements, and contamination of multiple products with heavy metals occurs in some products.

These are just three examples of the many products touting fat burning and augmented sports performance. We have included those for which at least a modest body of research exists. There are many others sold, including capsaicin (the active molecule in hot peppers), forskolin (a plant product that markedly stimulates cAMP production and is used widely as a research chemical), chlorogenic acid (a chemical in green coffee beans), and isoflavones from many botanical sources. Each of these is biologically active with a study or two to support its efficacy, but no studies of safety or clinical efficacy. Manufacturers are not required to prove efficacy or safety. If all that happens is that you waste your money on an ineffective product (which might have placebo value for you), then it isn’t a big problem. But with drugs that simulate the effects of norepinephrine on the heart and blood vessels like many of these supplements, the outcomes of taking excessive amounts can be dangerous.


St. John’s wort may be the most widely used herbal preparation currently on the market. It is an extract prepared from a plant of the same name (Hypericum perforatum) that achieved recognition as an antidepressant following reports from Europe of clinical trials showing that it improved mild depression. Many people take St. John’s wort to stave off depression or just to improve their state of mind. Most research shows that St. John’s wort may have effectiveness in mild depression but not as much as pharmaceutical antidepressants, especially in cases of severe depression. There is disagreement over which biologically active molecule may be responsible for its antidepressant properties.

So why not take a little St. John’s wort? By itself, it isn’t particularly dangerous. However, it has proved to have many negative interactions with other drugs, including some important medications. St. John’s wort can stimulate the production of enzymes in the liver that break down other drugs. This allows the liver to break down some drugs so fast that a normal dose doesn’t work. Birth control pills are affected in this way, and there are cases in which women taking St. John’s wort have become pregnant because their birth control pills were being degraded too quickly. Even more serious

consequences have occurred. There are more than ten case reports of transplant patients who experienced tissue rejection when levels of their immunosuppressant medication fell drastically after they started taking St. John’s wort.

Finally, St. John’s wort can interact dangerously with one class of antidepressant, the selective serotonin reuptake inhibitors (SSRIs). Taking both St. John’s wort and SSRIs can lead to “serotonin syndrome” because serotonin is inactivated more slowly than usual, resulting in higher-than- normal levels of serotonin in the synapses. At its mildest, people just feel flushed and jittery; at its worst, it leads to an increase in body temperature, heart rate, and blood pressure, and can be fatal.

Several other plant products, including saffron, turmeric, ginseng, lavender, and Rhodiola rosea, have been touted as herbal treatments for depression. While there are animal studies and some human studies for each of these, none has been subjected to the level of scrutiny required in Western medicine for safe and efficacious treatment of depression. As depression is a serious and sometimes fatal psychiatric disorder, these do not seem to be a wise choice for self-medication at this time.


Melatonin (N-acetyl 5-methoxytryptamine) is widely sold in capsule or tablet form in health-food stores as a treatment for jet lag and other sleep disorders, as well as a cure-all that can prevent aging and such diseases as cancer. It could be called the prototype herbal drug. Melatonin is the molecule released by the pineal gland, so it is a normal part of the human body. It has been the object of scientific study, and some of the claims of substantial effects have been borne out in these studies. In fact, two FDA- approved sleep aids, ramelteon (Rozerem) and tasimelteon (Hetlioz), mimic the effects of melatonin. Scientists have not established a clear-cut safe and effective dose, the safety of long-term use has never been established, and the content of preparations marketed as melatonin is unregulated and varies widely.


Melatonin is a neurotransmitter that is structurally related to serotonin. It is produced mainly by the pineal gland (a tiny gland that sits on top of the brain), by the retina, in the GI tract, and by some immune cells. Melatonin is released only at night. Visual signals travel from the eye to an area in the brain that sets the circadian rhythm, and then to the nerves that travel to the pineal gland and cause it to release melatonin into the bloodstream and cerebrospinal fluid, where it produces some of its actions. Melatonin is very fat soluble and easily enters the brain (whether from a pill or your own natural melatonin) and acts on receptors at certain places in the brain. Melatonin mainly acts on two receptors (MT1 and MT2) and also has actions mediated by nuclear hormone receptors and the direct interaction with cellular constituents.


The very marked day-night rhythm in melatonin release is one reason why melatonin is associated with sleep. Normally, when darkness falls, the nerves that stimulate melatonin release become active, which then acts on its receptors to trigger sleep.

A growing number of research studies show that if melatonin is taken at a time earlier than normal bedtime (such as in the early evening or late afternoon), it can help people fall asleep faster. Scientists have studied melatonin for jet lag, night-shift workers, some insomniacs—even astronauts in the space shuttle! Melatonin can help with jet lag if people take it at the time that they would go to bed in their destination. Melatonin is most effective for people with “delayed sleep phase disorder” (people who fall asleep very late and sleep late), but is much less effective for people who simply have trouble falling asleep (primary insomnia).


Melatonin may help create day-night rhythms in other aspects of body function. It may contribute to the fall in body temperature that occurs at night. In species other than humans, melatonin may be very important in allowing animals to breed at appropriate times of the year. The shorter days and longer nights of winter cause an increasing release of melatonin. For some species, like sheep, which breed during the short days of winter, this increasing

release of melatonin improves fertility, while it decreases fertility in animals like hamsters, which breed in the summer, when days are long. Melatonin has a much less certain role in human reproduction. Humans are not “seasonal breeders”: they maintain fertility throughout the year. This fits nicely with the fact that the nightly rises in melatonin are not as great in humans as they are in other animals. Can human reproduction be affected by causing a larger nighttime rise in melatonin? Some scientific studies suggest that melatonin can decrease fertility in humans, although there is little research in this area. Melatonin (in doses that exceed usual doses by tenfold) has even been tested as a contraceptive, but given the possible side effects on sleep, it has some real disadvantages in comparison to more completely tested medications.


Melatonin has a measurable antioxidant action in model systems, although we are less certain that it has this action in humans who take supplemental melatonin. Much of aging-related tissue damage and disease may result from by-products of oxygen metabolism (oxygen radicals) that damage tissue. Certain compounds, such as vitamin E, are known to “scavenge” and eliminate these products before they interact with proteins and DNA and thus produce tissue damage. The melatonin molecule can act directly as a radical scavenger, and giving melatonin to experimental animals can prevent the DNA damage caused by compounds known to produce such oxygen radicals. However, this research is in its early stages, and effectiveness in lower primates or humans has not been tested. Again, taking a psychoactive compound that might suppress fertility for years to delay aging seems like a strategy that offers more risks than rewards.


Melatonin is also claimed to improve immune function, lower blood pressure, prevent bone loss due to aging, influence GI motility, and even reverse the graying of hair! While there are isolated studies to support these claims, research in these areas is not abundant.


Melatonin may be effective in some situations, but is it safe? In animal studies designed to test toxicity, it proved to be pretty safe. However, we don’t really know what an effective dose is for a person. Doses in scientific studies range from 0.1 to 5 milligrams, but in most health-food stores, melatonin is sold in amounts ranging from 1 to 5 milligrams. Further, users can purchase and consume unlimited quantities. Excessive doses might affect reproduction or other aspects of body function. Finally, we do not know conclusively the long-term effects of this drug. It isn’t even known whether melatonin is effective if given for a long period of time. Most sleep medications lose their effectiveness with time, and it wouldn’t be surprising if melatonin did as well. If so, a dangerous situation could develop if a person started increasing their dose to compensate for the loss of effect.


With rising rates of Alzheimer’s disease and other dementias among aging baby boomers, interest in finding treatments for these disorders is high. The lack of diverse therapeutic options available have understandably stimulated interest in herbal agents that might help slow the progress of dementia. There is truly a desperate need for drugs to retard the memory loss caused by Alzheimer’s disease and some other forms of dementia. However, despite years of effort, only a few marginally effective drugs have been developed (this is discussed in the Nicotine chapter). There have been many studies of some favored options, including ginseng and gingko biloba. However, only a few of these trials meet modern criteria (placebo control, double-blind, random assignment to treatment conditions). In addition, at least one-third of such studies are funded by the companies producing these products (a ratio that is likely true of almost every study cited in this chapter). So the jury is still out on many of these, as we discuss below.


The ginseng root has been used in Chinese medicine for thousands of years for a variety of ailments ranging from fatigue and stress to high blood pressure and even cancer. Traditionally it is used as a daily tonic. It is available here in the United States in a wide variety of forms, from teas to

the root (which is chewed). Ginseng comes from several members of the plant family Araliaceae. American, Korean, and Japanese ginseng are members of the genus Panax, and Siberian ginseng is a member of the genus Eleutherococcus. It is being used widely in the United States for reasons that include improving athletic performance, decreasing anxiety, and as a tonic to increase resistance to stress.

Does ginseng have real biologic activity? If you listen to testimonials by happy users, then the answer is yes. The most biologically active ingredients in ginseng (the ginsenosides) have some activities in the brain. Animal studies have shown improved memory in rats that were impaired by a drug or brain injury, as have a few studies in animal models of Alzheimer’s disease. Despite rising numbers of studies, the effects on human memory remain unclear. Part of the challenge in evaluating ginseng studies arises from different approaches to testing ginseng and many other nutritional supplements: while some studies try to show effects of a single dose in a highly controlled laboratory setting, others have used population studies in people who are self-medicating with supplements. The latter studies may be the best test of the efficacy of available supplement preparation. Unfortunately, these have been less successful than the more controlled tests with well-defined doses. One problem that arises in understanding the results of such studies is that people who choose to self-medicate with herbal drugs may be, in general, more health conscious than those who don’t, and may do a lot of other things that improve their health and maintain good brain function. Ginseng has a variety of effects in experimental cell systems including effects on cell growth and immune function. Its ability to lower blood glucose in animal models of diabetes has attracted some notice, and studies are under way in humans.

The recommended doses on preparations sold in a local health-food store come in the same range as doses used in the experimental studies (about 700 milligrams for a normal adult male). However, the exact content of these formulations is unknown, so potency can vary widely. In addition, the effectiveness of a single dose is not clear. Some studies fail to show significant effects except with repeated dosing. Fortunately, no dangerous side effects of single, high doses are known. The safety of repeated doses is unknown. Some case reports of uterine bleeding in postmenopausal women indicate that ginseng has effects resembling those of estrogen. As with many ancient herbal cures, there is active research ongoing to test the safety and

efficacy of ginseng in treating disease. This is another drug that might have potential, but we just don’t have enough information yet to judge.


An extract of the leaves of the ginkgo biloba tree is a popular herbal cure that is supposed to improve circulation in small blood vessels in the brain, and so improve memory and alertness. Like ginseng, it has many advocates. Animal studies have shown that ginkgo extracts, much like FDA-approved medications, can delay the degradation of the neurotransmitter acetylcholine. Numerous studies of memory in healthy adults offer conflicting results— some show benefits, while others do not. Research in this area has been active, and a recent meta-analysis shows modest benefits in some populations. One potential problem with ginkgo is that it can slow blood clotting, which can lead to dangerous hemorrhages if it is used in combination with prescribed anticoagulant medication. It is often marketed in combination with ginseng for similar conditions, such as stress. Its effectiveness as a stress cure remains to be proved.


The so-called smart drugs may win the contest for ingenious marketing of marginally effective agents. The recent explosion of “energy” drinks shows little sign of abating, as discussed in the Caffeine chapter. Although taking a drug to improve mental quickness instead of getting bombed certainly seems innocent, nowhere is superstition more rampant than in the marketing claims for drugs that improve memory and general mental acuity in otherwise healthy individuals.

The herbal smart drugs are often a concoction of various amino acids and similar compounds. The most common supplements in energy drinks and herbal “smart” supplements are the sulfur-containing amino acid taurine, carnitine, and precursors to neurotransmitters including tyrosine, phenylalanine, and choline. Should you take “smart” nutrients? First, if you are eating a normal American diet with the typical excess of protein, there is more than enough of most of these micronutrients in your diet to maintain optimal levels in your blood and brain. Second, these compounds act over

hours to days. They don’t produce the advertised immediate “energy boost.” Finally, even if enough amino acid is provided to boost the production of a neurotransmitter, it doesn’t automatically mean the neuron is releasing more to have greater effect. A newly made neurotransmitter is simply stored, awaiting the arrival of a nerve impulse to release it. So simply making more adds to the store that is ready for release. Adding more is effective only if stores are truly depleted. This generally happens only after life-threatening stresses (not a bad day at work).

Let’s look at a couple of examples. Phenylalanine is reputed to have marvelous pleasurable qualities as the precursor to dopamine. There is some truth to this claim. Tyrosine and phenylalanine are both amino acids that are required for the synthesis of proteins. Tyrosine is the basic building block for the neurotransmitters dopamine and norepinephrine, and it is logical to think that increasing tyrosine might improve mood. However, the average American eats enough protein to provide adequate levels of these amino acids. Taking a pharmacologic (big) dose of tyrosine may be able to boost catecholamine production for a short time, but the benefits are transient, and scientists are just starting to study the behavioral outcomes (if any) of supplementing tyrosine.

There may be more truth to the claims that taking large doses of other neurotransmitter precursors can influence the production of the neurotransmitter. Choline supplements can indeed enhance the production of the neurotransmitter acetylcholine, which is important for many aspects of brain function, including memory. The death of acetylcholine neurons may contribute to the disabling memory loss of Alzheimer’s disease, and supplementing acetylcholine production can produce slight and temporary improvement in the memory of Alzheimer’s patients. The choline precursor citicoline actually may improve memory a bit in both healthy people and those who have experienced brain injury and Alzheimer’s disease, but whether the effect is large enough to overcome the disease process remains to be seen. Similarly, the tryptophan in high-protein foods like milk can enhance the production of serotonin in the brain. Because increases in serotonin are speculated to enhance sleep, there may be some truth to the old wives’ tale that warm milk enhances sleep. Another claim that might have some credibility is that ingesting extra tryptophan could help to prevent the loss of serotonin that occurs when a person takes Ecstasy. There is a rapid loss of serotonin in this case, which perhaps can be lessened by providing an

extra precursor. Unfortunately, this does not diminish the dangerous side effects of MDMA at all.

Taurine and carnitine are the most common additions to energy drinks. Taurine is a sulfur-containing amino acid and is very abundant in the body, including in the brain, and it seems important for maintaining many body functions including blood pressure and metabolism. It may function as an inhibitory neuromodulator, especially in situations like ischemia or stroke where it may counteract the release of excitatory neurotransmitters. Studies in animals seemed to indicate it was a panacea—it lowers blood pressure, improves glucose tolerance in diabetes, possesses valuable antioxidant properties, and best of all, burns fat. Unfortunately, human studies are fewer, but they offer some opposing concerns—it may raise blood pressure in women, does not burn fat, and lowers glucose unless rats also eat fructose (or presumably people drink soft drinks). Clearly, more work is needed to understand the benefits and risks of taurine supplementation. Similarly, carnitine is also an important normal constituent of the body that is necessary for the production of energy by mitochondria, and a lack of carnitine caused by a genetic deficiency can have extremely adverse effects on brain function. There are some published studies of carnitine supplements in various neural disorders including Alzheimer’s disease and Parkinson’s disease with mixed results at best. Does this mean that giving dietary supplements to healthy young adults improves memory? Again, we have no evidence, and many compounds that show marginal effects in impaired populations have even less action in healthy adults. So will these “energy” drinks give you a better edge mentally in studying for exams? Perhaps, but the reason may be the 100 to 280 milligrams of caffeine that they contain! Many other “nutraceuticals” including SAMe (S-adenosylmethionine) and various vitamins often appear in supplements and benefit people who are deficient—not normal, well- nourished adults.

Nevertheless, hope springs eternal that we will find the natural product to optimize mental function or stave off the effects of aging. The findings that resveratrol, a molecule present in red wine, prolongs life and improves functioning in aging mice led to another wave of hope until we learned that the amounts required equal the resveratrol in 750 to 1,500 bottles of wine a day! Does this mean that no natural products can help delay cognitive function decline associated with aging, or help individuals who are impaired by lack of sleep or other conditions? It means that research is scanty, a good

bit of it is supported by manufacturers, and quality is not up to current standards.


Most of the herbal preparations that people use are innocuous, and some are effective, especially in people with deficiencies in the molecule that is in the supplement. Additionally, there is some benefit in taking a milder, endogenous version of a prescribed drug that may have intense side effects. However, some have real dangers. Of the group mentioned here, stimulants related to ephedrine pose the greatest risk, because people can easily take enough to cause high blood pressure, stroke, or heart attack. Often, the marketers of the herbal preparations recommend taking excessive doses. Such supplements are clearly dangerous for someone already experiencing high blood pressure or any kind of cardiovascular problem.

Some of the nutritional supplements can be quite dangerous for people with certain medical conditions, or those taking certain drugs. Taking anything that increases the production of monoamine neurotransmitters (for example, phenylalanine or tyrosine) is dangerous for someone who is taking a certain type of drug to treat depression (the monoamine oxidase inhibitor class, such as Nardil or Eldepryl). These drugs prevent the breakdown of monoamine neurotransmitters, and dangerous high blood pressure can result if they are taken in combination with nutritional supplements that increase the production of these same neurotransmitters. Furthermore, taking phenylalanine can be dangerous for a person who suffers from phenylketonuria, a disease that prevents the normal metabolism of phenylalanine, which can build up in the blood to dangerous levels. The long-term effects in otherwise healthy people of taking high doses of many herbal drugs are not known. The current enthusiasm for herbal remedies will provide the data that we need but, unfortunately, at the likely expense of unwary users of these products. Our advice is to keep your eyes on the scientific research about nutritional supplements and brain function, because science is catching up fast.

Drug Class: Mixed



Individual Drugs: nitrites (butyl or amyl); anesthetics (nitrous oxide— Whippets; gaseous anesthesia agents used for surgery—halothane, ether); solvents, paints, sprays, and fuels (toluene, gasoline, glues, canned spray paint, computer cleaner, etc.)

Common Terms: bolt, bullets, climax, locker room, rush, poppers, snappers, aimes

The Buzz: The chemicals in this category have very little in common in chemical structure, pharmacology, or toxic effects, except that they are all taken by inhalation.

The nitrites relax the smooth muscle tissue that regulates the size and shape of blood vessels, the bladder, the anus, and other tissues. The relaxed blood vessels produce a drop in blood pressure, an increased heart rate, and a sense of warmth and mild euphoria. Visual distortions can also occur.

Nitrous oxide is by far the mildest of the anesthetics; it produces mild euphoria, reduction of pain, and reduction of inhibitions, followed by

drowsiness as the concentrations increase. Other anesthetics produce the same effects but cause major sedation at modest levels.

Solvents produce effects similar to those of alcohol, with stimulation, loss of inhibitions, and mild euphoria, followed by depression. Distortions of perception and hallucinations may occur.

Overdose and Other Bad Effects: The risk of a lethal overdose with inhaled nitrites is small. Because they dilate blood vessels, nitrites cause a reduction in blood pressure. This can produce heart palpitations (rapid, hard heartbeats), loss of consciousness upon moving from lying down to standing up, and headaches. No one who has heart or blood vessel disease should use these compounds without the supervision of a physician. Long-term use of nitrites can produce negative effects that are described later. And when they are ingested, nitrites can cause major medical problems, including death.

The overdose risk for anesthetics ranges from relatively low (nitrous oxide) to very high (modern surgical anesthesia agents). For nitrous oxide, the major risk is not breathing enough oxygen while breathing the gas. For the others, the risk is disruption of heart function and the suppression of respiration, followed by death. Anyone who has inhaled enough anesthetic to become unconscious is in danger and should receive medical attention immediately.

Serious solvent intoxication is like that of alcohol, with muscular incoordination, headache, abdominal pain, nausea, and vomiting. Many of these agents are flammable, so serious burns can occur. The risk of a lethal overdose with solvents is significant. Death usually occurs because the heart rhythm is disrupted (cardiac arrhythmia) or because there is a lack of oxygen. Accidents and suicide are also significant risks. A significant percentage of people who die from inhalants are first-time users.

Dangerous Combinations with Other Drugs: As with alcohol and sedatives, it is dangerous to combine inhalants with anything else that makes a person sleepy. This includes alcohol and other sedative drugs, such as opioids (for example, heroin, morphine, or Demerol), barbiturates (for example, phenobarbital), Quaaludes (methaqualone), Valium-like drugs (benzodiazepines), and cold medicines, including antihistamines.

Drugs can become deadly when taken together. Even dose combinations that do not cause unconsciousness or breathing problems can powerfully impair physical activities such as playing sports, driving a car, and operating machinery.


What They Are and How They Work Toxicity
Tolerance and Withdrawal

Nitrous Oxide and Other Gas Anesthetics What They Are and How They Work Nitrous Oxide
Nitrous Oxide Toxicity and Tolerance

Solvents and Propellants
What They Are and How They Work Toxicity

Of all the chemicals and drugs described in this book, it is disturbing that those used by the youngest people are the most toxic. Because of their easy access to glues, gasoline, solvents, paints, and sprays, many children begin to use drugs by inhaling these common chemicals. They get a buzz, but along with that buzz comes toxic effects that would horrify any chemical safety expert. As this is written, about 9 percent of eighth grade students report

using inhalants at least once in their life.* The good news is that this percentage has dropped from about 20 percent reporting use of these drugs in 1998, the first year we published Buzzed.

While inhaling substances for highs has been with us since the Greeks, it has only been since the late 1700s, when nitrous oxide was first synthesized, that people used a chemical regularly for this purpose. This “laughing gas” was prominent in England and was even offered at London theaters for recreational purposes. A fascinating account of individual experiences with nitrous oxide has been published as “Oh Excellent Air Bag” by PDR Press. One entry from that book is a note from the poet Robert Southy to his brother,

Thomas, on July 12, 1799. He wrote, “Oh Tom such a Gas has Davy discovered! the Gazeous Oxyd! oh Tom! I have had some. It made me laugh & tingle in every toe and fingertip. Davy has actually invented a new pleasure for which language has no name. oh Tom! I am going for more this evening—it makes one strong & so happy! So gloriously happy! & without any after debility but instead of it increased strength & activity of mind and body—oh excellent air bag. Tom I am sure the air in heaven must be this wonder working gas of delight.”

As science and industry progressed, a number of volatile compounds, such as gasoline, became readily accessible to the public, and serious inhalant abuse and toxicity became prominent in the 1920s. Beginning in the 1950s, glue sniffing was recognized as a problem, and as more and more chemicals have been marketed, the menu for abuse has grown.

Because of the diversity of the chemicals in this group, we have divided this chapter into three parts—the nitrites, the anesthetics, and the solvents. The anesthetics and some of the nitrites are made for human consumption, and at least we understand the effects these have on body function. The solvents, including gasoline, sprays, glues, paints, and cleaning fluids, were never intended for human use. We consider these among the most toxic substances used for drug recreation, and we believe that they should never be used by anyone under any circumstances.


These chemicals are yellow, volatile, and flammable liquids that have a fruity odor. The nitrites are part of a large class of drugs (including amyl nitrite, butyl nitrite, isobutyl nitrite, and the nitrates like nitroglycerin) that relax the smooth muscles that control the diameter of blood vessels and the iris of the eye, keep the anus closed, and keep us from dribbling urine. When these muscles relax, the blood vessels enlarge and blood pressure falls, more light is let into the eye, and the bowels are let loose.

The medical uses of these compounds have a long and successful history, beginning with the synthesis of nitroglycerin in 1846. That’s right— nitroglycerin, the explosive that we all know about, is also a very important

drug. Chemists first noticed that just a bit of it on the tongue produced a severe headache (they did not know that this was because it dilated blood vessels); within a year it was medically used by placing it under the tongue to relieve heart pain caused by blocked blood vessels. Like all of these compounds, nitroglycerin relaxes blood vessels, and today it is very commonly used to relieve the pain that patients with heart disease feel when one of the vessels supplying blood to their heart has a spasm (angina pectoris). Remember the scene in movies when an old person grabs his heart, falls to the floor, and struggles to get his medicine out of his pocket? Then the bad guy takes the medicine away and the victim dies? Almost certainly, it was nitroglycerin that he needed.

The nitrites, like the amyl nitrite “poppers” that some people use for recreation, have the same basic effects as nitroglycerin. They were first synthesized and used medically in 1857, but soon physicians found them to be short lasting and unreliable, so nitroglycerin under the tongue has remained the medicine of choice. Amyl nitrite is now used clinically only when the very rapid absorption through inhalation is necessary for some cardiac medical procedures.

The side effects of nitrates and nitrites are common and consistent, and they are related to the dilation of blood vessels. When physicians prescribe these drugs, they tell their patients to expect headache, flushing of the skin, dizziness, weakness, and perhaps loss of consciousness if body position is changed rapidly.

As with almost all drugs, there is a lot we don’t know about how they work. In this case, we really don’t know exactly why the nitrites have the mental effects that make them attractive for some people to use. Users report a physical sensation of warmth, a giddy feeling, and a pounding heart. The psychological sensations are the removal of inhibitions, skin sensitivity, and a sense of exhilaration and acceleration before sexual orgasm. There is a rather common visual disturbance consisting of a bright yellow spot with

purple radiations.† These effects may arise from the dilation of some blood vessels in the brain. Finally, some people use these drugs not for the mental effects but for their muscle-relaxing properties to permit anal intercourse.


Only amyl nitrite is specifically manufactured and packaged for legitimate medical use in humans. Unless a product is approved by the FDA, it should be considered an industrial chemical not manufactured for human consumption, because even if it is supposed to be pure, it may contain contaminants that are harmful.

Compared to many drugs, amyl nitrite has less toxicity as long as it is inhaled as intended. Of course, there is always the possibility that the dilation of the blood vessels will cause someone with blood circulation problems to have a bad experience. As with all drugs, check with your physician before taking it.

However, there is a major toxicity problem with nitrites if they are swallowed rather than inhaled. When they are ingested, nitrites can cause major medical problems by interfering with the ability of the blood to transport oxygen. Blood carries oxygen to the tissues by way of the red blood cells, which contain hemoglobin to bind the oxygen and then release it to the cells of the body. If the hemoglobin cannot bind oxygen, then a person will die rapidly because the tissues will be suffocated. This is the way that cyanide (as used in Nazi gas chambers) works, although nitrites, when ingested, interact a little differently with hemoglobin than cyanide does.

This danger from nitrites is illustrated by an unfortunate incident that occurred in New Jersey in 1992. On October 20 of that year, forty children in an elementary school visited the school nurse because their lips and hands were turning blue, they were vomiting, and they had headaches after lunch. They had a hemoglobin disorder produced by nitrite poisoning. This was not caused by drug abuse but by something much more surprising. The boiler in their school was used to heat the water, and somehow the boiler fluid, which contained a lot of nitrites, was mixed with the hot water used for preparing their soup. Fortunately, the kids received medical care and recovered completely.


Frequent and repeated use of nitrites and nitrates can produce tolerance and symptoms upon withdrawal. Workers in the explosives industry are a case in point. When a worker first goes on the job and is exposed to nitroglycerin in the environment, the worker might experience headaches, weakness, and dizziness. After a few days, these symptoms disappear as tolerance

develops. However, when not working on the weekend, the person might suffer headaches and other symptoms due to withdrawal. A few workers have been found to have cardiac and circulatory problems upon withdrawal, and these were treated by giving them nitroglycerin. Since the advent of the nitroglycerin patch for continuous administration of the drug to heart patients, many people have been continuously exposed to nitroglycerin and have developed tolerance to it. The medical profession has become quite concerned because tolerance reduces the effectiveness of the compound, and withdrawal can produce cardiac problems.


One of the most important drug experiences anyone can have is that of proper anesthesia in the operating room. Most surgery could not be carried out without proper anesthesia, because it serves three important functions: pain relief, muscular relaxation, and loss of consciousness. All of the gas anesthetics produce the loss of consciousness, and some of them produce the muscle relaxation and pain relief. The reason for pain relief is obvious: No one would want to be cut and probed without pain suppression. Because most general anesthetics produce only loss of consciousness and not pain relief, a pain suppressor is added by an anesthesiologist. Muscular relaxation is required so that involuntary muscle contractions will not get in the way of the surgeon’s work. Finally, the loss of consciousness provides the patient relief from the anxiety and boredom of the operating room and perhaps some very welcome amnesia for the whole experience. It is probably this characteristic of gas anesthetics that leads to their abuse.

Surgery wasn’t always so easy. Until 1847 it was carried out without the help of anesthetic agents. Before then, there might have been a little help from alcohol or opium, but mostly the patient was held down by an array of strong men while the surgeon worked in spite of the patient’s screams. But in 1847 things changed at the Massachusetts General Hospital when ether was first used. Ether had been synthesized recently, and dentists had begun to notice that it had anesthetic properties. A dentist named Morton claimed that he could produce surgical anesthesia with this miracle compound and that he would demonstrate it at Mass General. With the observation gallery full and

the men arrayed to hold down the patient as usual, the dentist appeared with the anesthesia machine he had invented to administer the ether. For the first time a patient underwent major surgery while asleep but with his heart and respiration safely intact. Within a month the word had spread and ether

became a powerful part of medicine and surgery.‡

Ether was a great general anesthetic because it fulfilled the requirements for anesthesia, but it was flammable and could cause operating room fires. Modern nonflammable anesthetic agents, like halothane, are both effective and potent, and anesthesia is achieved by breathing air containing just a small percentage of these gases. This makes them great for the operating room and bad for drug abusers, because it is so easy to overdose with them. As higher levels of anesthesia are achieved, three significant systems are impaired: respiration, blood pressure, and heart contractions.

Breathing is produced by the firing of a group of nerve cells deep in the brain. They are a little resistant to anesthetics, but at high levels their activity is suppressed, and respiration is depressed. Also, the smooth muscle cells that keep blood vessels at a set diameter relax, and this causes a drop in blood pressure. Finally, anesthetics can have a direct effect on the ability of the heart to contract, so it becomes weaker and prone to disruptions of its rhythm. Halothane is particularly tricky because the difference between the concentration that is effective and the one that causes problems is small.

Lots of chemicals and gases can be anesthetic agents, ranging from inert gases like xenon to the most modern compounds. Scientists still do not know exactly how anesthetics work. We know that they suppress the firing of nerve cells, and some can relax various muscles. At this point the best evidence is that, in part, they suppress consciousness by increasing the action of the neurotransmitter GABA (see the Brain Basics chapter for an explanation of GABA), which inhibits excitable activity in neural networks.

When an anesthetic gas is inhaled, the sequence of responses is fairly uniform for many of the agents. There can be a brief period of excitation or stimulation, like after the first drink of alcohol. This is followed by pain relief, dizziness, weakness, and general depression of functions. At higher levels, reflexes such as eye blinking, swallowing, and vomiting can be lost. Finally, heart function and respiration are lost and the person dies. Some agents (such as enflurane) have more excitatory effects at overdose, and at

high levels these effects can cause epileptic seizures. Other agents produce little in the way of stimulation and only depress the nervous system.

The window of concentration between anesthesia and death is very narrow for these drugs. In medical settings the gases are carefully mixed with oxygen and survival body functions are monitored continuously. The anesthesiologist is fully capable of maintaining breathing for the patient or administering cardiac stimulants if necessary. Even with this level of care, problems can occur. Without careful surveillance, a person is at enormous risk of either dying or sustaining permanent brain damage.


Nitrous oxide was first synthesized in the late 1700s as a colorless and almost odorless gas, and its anesthetic and pain-relieving properties were appreciated almost immediately. For quite a while it remained out of the mainstream of medicine, being used mostly for recreation and entertainment at carnivals. The first medical usage of this gas came in the mid-1800s when dentists found it to be an excellent way to suppress pain.

One cannot easily achieve deep surgical anesthesia with nitrous oxide alone, unless it is applied in an environment where the atmospheric pressure is raised. Now it is used medically only to augment other anesthetics and sedatives, or for minor procedures that do not require the loss of consciousness. When nitrous oxide is inhaled in sufficient quantity, there is a euphoric feeling that comes along with the pain relief. The term laughing gas arises from the giddy state that it produces. By comparison to any of the other drugs that people inhale for recreation, nitrous oxide is less toxic, because it has little effect on critical body functions including respiration; brain blood flow; and liver, kidney, and gastrointestinal tract processes.

The pharmacological mechanisms of nitrous oxide have not been completely determined. Certainly it acts like a general anesthetic and under high pressure can cause loss of consciousness, so, as we suspect with other anesthetics, it may increase GABA inhibition of nerve cells. Part of its effect may also be through the brain’s built-in opioid system—the same receptors that morphine and heroin activate. One of the best bits of data that support this is that the specific opioid antagonist naloxone blocks the pain-relieving properties of this gas in animal experiments.

The latest research studies suggest that nitrous oxide may also act on a neuronal receptor for the neurotransmitter glutamate, the N-methyl-D- aspartate (NMDA) receptor. This is the same site at which ethanol and ketamine act to produce their dissociative effects—that feeling of being out of your body.


As we described, in clinical settings nitrous oxide is rather free of toxic effects. However, for recreational users, there are four dangers: not getting enough oxygen, getting hurt if the gas-delivery device works improperly, experiencing a vitamin B12–related problem that might occur with repeated use, and suffering possible brain toxicity if nitrous oxide is used in combination with other drugs that are NMDA antagonists.

First, remember that nitrous oxide is an anesthetic gas that can cause unconsciousness, or at least make you so disoriented that you lose good judgment. Major problems occur when the user arranges some sort of mask or bag to deliver pure gas and then becomes unconscious and breathes only nitrous oxide: the person is asphyxiated by lack of oxygen.

Second, there is the physical damage to tissues exposed to any gas that is expanding. Anyone who has ever held a hand in front of an air or gas jet knows that expanding gas is cooling. That’s the principle underlying air- conditioning units. Some users try to inhale the gas right out of the tank with no regulation of the flow rate, actually injuring their mouths, tracheas, and lungs from the cooling gas. Also, there is the direct physical risk of overexpanding (blowing up) the lungs as the gas flows at a high volume and pressure.

Third, there is an odd complication of prolonged nitrous oxide use that is similar to a vitamin B12 deficiency. A B12-dependent enzyme is inactivated by nitrous oxide, and that leads to the destruction of nerve fibers (a neuropathy) and thus neurological problems. These can include weakness, tingling sensations, or loss of feeling. There are several case reports in the medical literature of nitrous oxide causing severe nerve damage. Some dentists who regularly administer this gas have been found to experience this type of neuropathy.

Fourth, animal studies now suggest that NMDA-receptor blockers like nitrous oxide can be neurotoxic in certain brain areas. The combination of ketamine and nitrous oxide suggests that using these drugs together might be particularly problematic. In animals, they are synergistic, producing much more damage together than would be expected from the simple combination of the two drugs. This should serve as a strong caution to recreational users of nitrous oxide not to combine that use with any other NMDA antagonist like ketamine or ethanol.

Tolerance to nitrous oxide can develop, and the euphoric properties diminish with repeated usage. However, in the recreational setting, where it is used only occasionally, tolerance is unlikely.


If there were ever a drug category to “just say no” to, this is it. This category of chemicals is literally a wastebasket of anything that anyone can get in vapor form and then inhale. It consists of all sorts of industrial chemicals, such as toluene, benzene, methanol, chloroform, Freon and other coolants, paints, glues, and gases. We take the position that these compounds are so toxic to both the first-time user and the long-term user that they should never be used under any circumstances. However, we all know that people do inhale these chemicals, and so in the paragraphs that follow, we will describe a few of the more common agents and talk about their toxicity.


These compounds have only two characteristics in common (other than their toxicity). First, they form gases that can be inhaled. Second, they produce more or less the same feelings that alcohol and anesthetics do.

Solvent abusers usually inhale these chemicals through crude methods, generally called “huffing.” They soak rags with the chemicals and breathe through the rags, or put the chemicals in a can or cup and breathe the fumes. As with inhalational anesthetics, once the user begins to inhale, the blood levels peak in a few minutes and most of the agents are absorbed by body fat. As blood levels rise, there is dizziness, disorientation, perhaps an initial period of stimulation followed by depression, and a sense of being light-

headed. Some users describe changes in their perception of objects or time and/or have delusions or hallucinations involving any of the senses. Muscular incoordination occurs as levels increase, along with ringing in the ears (tinnitus), double vision, abdominal pain, and flushing of the skin. These are followed by the standard symptoms associated with chemical depression of the central nervous system: vomiting, loss of reflexes, cardiac and circulation problems, suppression of respiration, and (possibly) death.

The most dangerous effect of inhalant use is “sudden sniffing death,” which occurs during the abuse of coolants and propellants (like Freon), and fuel gases (like butane and propane), which induce abnormal heart rhythms. Death may occur because the chemicals depress the excitability of the heart cells that set the beating pattern, while at the same time increasing the sensitivity of these and other heart cells to the stimulant epinephrine (adrenaline). In addition, there are continual reports of deaths and serious illness from the inhalation of spray products for cleaning electronic devices, often containing the propellant difluoroethane. Heart toxicity, kidney damage, and bone disorder have recently been found, along with freezing damage to the airway of the user.

We do not know exactly how these compounds produce their mental effects. However, based on the physical effects, we can assume that they work in the same manner as anesthetics.


There is such a large number of diverse compounds that it is impossible to list all of the toxic effects of every one of them. Also, long-term inhalant users almost always use other drugs, so it is difficult to sort out which toxic effect belongs to which drug or which combination of drugs. But there is one common thread that runs through all of these compounds. Many users are injured not from direct toxic effects of these agents but from trauma related to their use. Disorientation and loss of muscular coordination make accidents more likely, and because many of these chemicals are flammable, serious burns occur. In one well-respected study, 26 percent of deaths associated with inhalant use were from accidents.

Also, people commit suicide under the influence of inhalants. In the same research study, 28 percent of the deaths associated with inhalant use were from suicide. Did the inhalants cause depression and suicide, or did the

suicide-prone individuals use inhalants to relieve their pain? Both are probably true, as is the case with so many other drugs.

First-time users can and do die. In a British study of 1,000 deaths from inhalant use, about one-fifth of the deaths were to first-time users. The deaths were from a variety of causes, but each was associated with inhalant use. This is a remarkable statistic, and it should make anyone wary of ever trying these chemicals.

If a person lives long enough to be classified as a chronic inhalant user, what are the long-term effects? Many research studies have been published on this subject, but almost all of them involve case studies of people that were referred with specific medical problems. There are no broad studies covering large numbers of inhalant users without reported medical problems. So we don’t know from a statistical perspective what the long-term toxic risk is. However, the medical studies of individuals who do report problems are sobering. One neurological study of abusers referred for medical treatment showed that thirteen out of twenty people (65 percent) studied had central nervous system damage as revealed by clinical examination and neurological imaging. Another study showed damage in 55 percent of a different group of people.

One of the best-studied chemicals is toluene. It is a common industrial solvent and a component of glues. In one study of chronic abusers, eleven out of twenty-four patients had damage to the part of the brain called the cerebellum. This area of the brain is well known for controlling fine, delicate muscle movements, and new studies suggest that it might also play a part in learning. Whether cerebellar impairment clears when the abuse stops has not been determined. Some studies suggest that the cells in this area die. Other brain areas, including the visual and other nerve pathways, are affected as well, but we caution that complete and controlled human studies are impossible to do.

Tests of intellectual function show that abusers have problems with memory, attention, and concentration. Like the physical studies, these studies also considered small numbers of patients who were ill, so we have to be careful in the interpretation of these results. However, there is no question that some people get very sick and suffer substantial central nervous system damage from the chronic use of inhalants.

Other body functions also suffer. The combined list of compounds and the body functions they impair is huge, and it gets larger every day as research shows new effects of these chemicals. It is enough to say that long-term usage of inhalants can damage the heart, lungs, kidneys, liver, blood, and many other areas, in addition to the nervous system. These chemicals are truly not for human consumption.

* Monitoring The Future Study (

† This description of nitrite effects is taken from a paper titled “The Psychosexual Aspects of the Volatile Nitrites” by Thomas P. Lowry, MD, which appeared in the Journal of Psychoactive Drugs, vol. 14 (1–2), pp. 77–79.

‡ This description is taken from chapter 13, “The History and Principles of Anesthesiology,” in Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 11th ed., edited by Joel G. Hardman and Lee E. Limbird (New York: McGraw-Hill, 2006).



Drug Class: No specific class, but legally considered a Schedule I narcotic at the federal level (classified by the Drug Enforcement Administration as having a high potential for abuse and no accepted medical uses). State laws vary.

Individual Drugs: low-grade marijuana (average 1 to 3 percent delta-9- tetrahydrocannabinol [THC]); high-grade marijuana—sinsemilla (average 10 percent THC, up to about 20 percent); hashish (7 to 20 percent THC); hash oil (up to 70 percent THC); “tinctures” or other liquids used in vaping systems (up to 90 percent); wax (a wax-like marijuana substance made by extracting marijuana with butane)

Common Terms: marijuana, reefer, pot, herb, ganja, grass, old man, Blanche, weed, sinsemilla, bhang, dagga, smoke (dried plant material); hash, tar (hashish); hash oil, oil, charas (extracted plant resin); vape

The Buzz: People’s experiences with marijuana vary widely and depend upon the potency of the drug taken. In general, smoking or vaping marijuana first relaxes a person and elevates his or her mood. These effects are usually

felt within a few minutes and followed about a half hour later by drowsiness and sedation. Some people experience this as stimulation followed by a relaxed feeling of tranquility. Users may shift between hilarity and contemplative silence, but these swings often reflect the user’s situation.

When hashish or high-grade marijuana is eaten, the effects take much longer to be felt (up to one to two hours), compared to smoking, and may produce a more hallucinogenic-type response. The same is true for commercially produced edibles, though they can be made in ways that enhance absorption and result in a more rapid onset of effects, compared to eating the plant material itself.

The effects of marijuana on mental functions, including learning and memory, can last far beyond the feeling of being high. Because it takes so long for the body to eliminate THC and its by-products (some of which also affect brain function), a person’s cognitive functions can be affected for a day or more after a single dose.

Overdose and Other Bad Effects: Lethal overdose is virtually impossible. Occasionally people report feeling anxious or fearful soon after smoking or after a particularly heavy dose. Relaxed and reassuring conversation with the user is often the best treatment for such an episode.

Although no one has ever died from an overdose of marijuana, it does impair judgment and the kinds of complex coordination needed to drive a car. Automobile accidents and dangerous mistakes are the largest risks of marijuana intoxication. However, people with heart disease or high blood pressure may be at risk because marijuana use increases the heart rate and places a greater workload on the heart. Marijuana can also endanger unintended users. There have been reports of small children unknowingly eating large amounts of cannabis in cookies and going into a coma. The risk of inadvertent exposure has increased in recent years as more edible cannabis products (some of which look like candy) have been introduced into both the legal and illegal markets.

There is evidence that the repeated use of marijuana during adolescence may result in long-term effects on some brain systems such as those controlling certain aspects of vision. In addition, adolescents may be at greater risk than adults for THC-induced impairment of learning and memory and that prolonged use during adolescence may increase the risk of

psychological difficulties later in life (more on these emerging studies later). Finally, there is a troubling association between the incidence of schizophrenia and early onset cannabinoid use. We don’t yet understand if this is a causal relationship or merely a correlation.

Dangerous Combinations with Other Drugs: Possible dangers include interactions with heart or blood pressure medications or with drugs that suppress the function of the immune system. In addition, one study shows that the combination of marijuana with cocaine can lead to very dangerous effects on the heart. Also, because THC affects concentration and information processing, combining it with alcohol or other sedative drugs could have additive effects on these mental functions.


A Brief History
The Cannabis Plant and Its Products
Drug Preparations: From “Headache Pot” to “Hospital Pot” How THC Moves through the Body
Effects on the Brain

The Brain Receptor for THC The Hippocampus
Other Brain Regions

Effects on Other Body Parts The Immune System The Heart
The Lungs

The Gastrointestinal System

The Reproductive System
Subjective Effects: The “Internal” Experience Tolerance, Dependence, and Withdrawal Effects on Memory and Other Mental Functions

Acute Effects

“Residual” and Chronic Effects
Does Marijuana Promote Aggression? Effects on Motor Performance and Driving Medical Uses

Nausea Glaucoma


All of the marijuana preparations people use for their psychoactive properties derive from the cannabis plant. The first written accounts of cannabis cultivation appear in Chinese records from as far back as 28 BCE, though the plant was likely cultivated for thousands of years before that. The Chinese writings indicate that the plant was grown for fiber, but they also recognize its intoxicating and medicinal properties. In fact, THC (and also nicotine and cocaine) have been identified in the internal organs of an Egyptian mummy from approximately 950 BCE. By around 1000 CE, use of the cannabis plant as an intoxicant had spread to the eastern Mediterranean region, and European explorers to this area returned with fascinating stories of the effects of hashish.

Cannabis had been introduced to eastern Europe much earlier (around 700 BCE), but not until Napoleon ventured to Egypt in the early nineteenth century did European culture fully acquaint itself with hashish. By the 1840s, recreational use of cannabis products (as well as a number of other drugs) had grown to be quite chic among the artists and intellectuals of France, many of whom used the drug in their search for new ways to enhance creativity and to view the world.

Although the original European explorers brought cannabis seeds to the New World to produce hemp for rope and cloth, it was not until the early twentieth century that marijuana began to impact United States society directly.

Seizure Disorders
Legislative Actions for Medical and Recreational Use

The Question of Legalization
Attitudes and Laws in the United States The Consequences of Illegality
Voices for Decriminalization
The Swinging Pendulum
What Will Happen Next?

“Synthetic” Marijuana


Cannabis is a highly versatile plant. Hemp, a strong fiber in the stem, has been used to make rope, cloth, and paper. When dried, the leaves and flowers are used as marijuana for their psychoactive and medicinal effects. The roots of the plant have also been used to make medicines, and the ancient Chinese used the seeds as a food. Cannabis seeds are still used for oil and animal feed.

The two most prevalent species of cannabis are Cannabis sativa and Cannabis indica. In years past, people cultivated C. sativa to make hemp. Under natural conditions, it will grow as high as a lanky fifteen to twenty feet, and it still grows wild as a weed across the southern United States. C. indica has been cultivated throughout the world mostly for the psychoactive properties of its resins. These plants generally grow to no more than a few feet in height and develop a thicker, bushier appearance than C. sativa.

The cannabis plant contains more than four hundred chemicals, and several of them are psychoactive. By far the most psychoactive of these is delta-9-tetrahydrocannabinol (THC), found in the plant’s resin. The resin is most concentrated in the flowers. In an unfertilized plant, it provides a sticky coating that protects the flowers from excessive heat from the sun and enhances contact by grains of pollen. The vegetative leaves contain a small amount of resin, as do the stalks, but the concentrations in these parts of the plant are so low as to have little intoxicating effect.

Today, much cultivation of “drug” strain marijuana plants has occurred, but the amount of THC present in the flowers of individual plants varies considerably. In addition to the genetic makeup of the plant, the growing conditions, timing of harvest, drying environment, and storage environment can all significantly influence the potency of the final product. As the plant matures, the balance of various chemicals in the resin changes, as does the amount of resin secreted at the flowering tops of the plant. Early in maturation, cannabidiolic acid (CBDA) predominates and is converted to cannabidiol (CBD), which is converted to THC as the plant reaches its floral peak. The extent to which CBD is converted to THC largely determines the “drug quality” of the individual plant. When the plant matures into the late floral and senescent stages, THC is converted to cannabinol (CBN). A plant that is harvested at the peak floral stage has a high ratio of THC to CBD and

CBN, and the psychoactive effect is often described as a “clear,” or “clean,” high, with relatively little sedative effect. However, some cultivators allow the plants to mature past this peak to produce marijuana with a heavier, more sedative effect. The difference between the feelings associated with peak- versus late-harvested marijuana has been described as the difference between being “high” and being “stoned.”

Burning marijuana for smoking produces hundreds of additional compounds. So when someone smokes a single joint, hundreds upon hundreds of chemical compounds enter the body. We know that many of these compounds act on various organs and systems in the body, but we don’t know what effects most of them have, either acutely or after prolonged use. Many scientific studies have, therefore, restricted their attention to THC, allowing us to evaluate at least some of the effects of cannabinoids on the brain and behavior.


The products made from marijuana plants for psychoactive effects vary markedly in their THC content and therefore in their psychoactive potency.

Low-grade marijuana is made from all the leaves of both sexes of the plant. These vegetative leaves contain very little THC compared to the pistillate flowers of the female plant or to the smaller leaves adjacent to them. The THC content of such a preparation may be only 1 percent or lower. Smokers sometimes call this “headache pot” because smoking it can produce more of a headache than a high.

Medium-grade marijuana is made from the dried flowering tops of female cannabis plants raised with and fertilized by male plants. Fertilization limits the psychoactive potency of the resulting marijuana because the female flowers secrete THC-containing resin only until fertilization. After that time the flower no longer needs the protective resin, and it begins to produce a seed.

High-grade marijuana is made from the flowering tops, or “cola,” of female plants raised in isolation from male plants. The resulting marijuana is called sinsemilla, which means “without seeds.” As the female flowers

mature without fertilization, they continually secrete resin to coat the delicate flowers and small leaves surrounding them; the flowers grow in thick clusters, heavy with resin. When these “buds” are harvested and dried, they contain an average of around 12 to 16 percent THC. Some samples of sinsemilla test as high as 24 percent. This represents a marked increase in potency compared to forty or fifty years ago, but THC concentrations in this range have been commonplace for the past ten years without a great deal of change during that interval.

Such powerful marijuana has been called “hospital pot” because occasionally an unsuspecting smoker, expecting the usual gentle high of medium-grade marijuana, gets frightened by the sudden and powerful high of sinsemilla, panics, and winds up in the emergency room. Actually, the best treatment for such a scare is a calm and reassuring “talk down” by a friend. The feeling of panic often arises from an unexpected sense of loss of control, and the individual needs only to be reassured that he or she is safe and there is no threat.

Some cultivators in the United States, using well-controlled indoor growing conditions, produce marijuana with THC concentrations as high as 24 percent, but the THC content of most marijuana in the United States is around 15 percent. In recent years United States marijuana has been touted as being ten times more potent now than it was in the 1960s and 1970s. This claim isn’t exactly true. Since the 1970s the THC content of marijuana seized by US law-enforcement officials has been measured by the Potency Monitoring Project in Mississippi—a government-funded project. In the early 1970s they generally reported that samples of seized marijuana contained low concentrations of THC—in the range of 0.4 to 1 percent—but those samples often came from low-potency, high-volume Mexican “kilobricks,” which probably contained considerably less THC than most of the marijuana that was actually being smoked in those days. Also, it was not until the late 1970s that the higher-potency cannabis products available to smokers, such as buds and sinsemilla, were included in the samples analyzed by the Potency Monitoring Project. Thus, estimates of THC content in the 1970s probably underestimated the average THC content of the marijuana smoked during that period. When independent laboratories analyzed marijuana samples during the 1970s, THC contents were often considerably higher than those reported by the Potency Monitoring Project—in the 2 to 5 percent range—though lower than most marijuana samples today. After 1980

the seized marijuana tested by the Potency Monitoring Project included more representative samples of what was available on the street, and between 1981 and 2000 the THC content hovered between 2 and 5 percent— consistent with the average range of independently tested samples during the 1970s. Still, marijuana cultivators have gotten better at their business, and THC concentrations in recreationally used marijuana have increased significantly. They may continue to increase as well. The recent changes in both medical marijuana and recreational marijuana laws in some states will probably help to fuel further refinements in both genetic plant selection as well as growing techniques. Although there are alternatives to smoking marijuana, such as eating it or vaporizing it, most marijuana is still smoked, and for most people the less smoke they need to take in, the better. The higher the concentration of cannabinoids in marijuana, the less needs to be smoked, so our bet is that cultivators will be motivated to continue looking for ways to increase the cannabinoid content in marijuana.

Hashish is produced when the resin of the cannabis plant is separated from the plant material. The purest form of hashish is virtually 100 percent resin. In India this pure material is called charas. Most hashish, however, is not pure resin and contains varying amounts of plant material as well. It often appears as a dark-colored gummy ball that is rather hard, but not brittle. The average THC content of hashish is around 8 percent but can vary quite a bit —up to 20 percent. Hashish is often smoked in a pipe or rolled into a cigarette along with tobacco or lower-grade marijuana. A more traditional means of smoking hashish is to ignite a small piece and let it burn under a glass or cup. The user then tilts back the glass and inhales the smoke from underneath.

Hash oil is the most potent of the preparations made from the cannabis plant. After the plant is boiled in alcohol, the solids are filtered out, and when the water evaporates, what’s left is hash oil. Hash oil is generally a thick, waxy substance that is very high in THC content—ranging from 20 to 70 percent. It can be scraped onto the inner rim of a pipe bowl for smoking or used to lace tobacco or marijuana cigarettes.

With the introduction of electronic vaping systems like e-cigarettes and “MODs” for vaping nicotine (see the Nicotine chapter), many different liquids have been formulated for delivering cannabinoid-containing vapor. How do these compare in potency to marijuana, hashish, or hash oil? You

name it, and the potency options are there. There are “e-liquids” that contain relatively little THC, and those that are extremely potent. But THC potency is not the only variable when it comes to e-liquid; the balance of different cannabinoids can also vary widely. The number of possible potency/cannabinoid mixture combinations is endless, so it’s very important for users to know what they are vaping in order not to be taken by surprise. Many cannabinoid vaping systems have built-in regulators that cut off the flow of vapor after several seconds—as if to say, “that’s a pretty good hit you just got, how about taking a few minutes to see how it affects you?” That’s probably good advice, even if it does come from a vaping MOD you can stick in your pocket.


When marijuana is smoked, the rich blood supply of the lungs rapidly absorbs the THC. This applies to marijuana that is “vaporized” as well. Even though it is not burned, the THC that is mobilized from the plant material in the vaporizer, or from the e-liquid in a cannabis vaping system, is absorbed through the lungs. Because blood from the lungs goes directly from the heart to the brain, the high, as well as the effects on heart rate and blood vessels, occurs within minutes. Much of the THC is actually gone from the brain within a few hours after smoking. However, THC also accumulates in significant concentrations in other organs, such as the liver, kidneys, spleen, and testes. THC readily crosses from the blood of a pregnant woman into the placenta and reaches the developing fetus.

How the smoker smokes makes a difference in how much of the THC from the marijuana actually gets to the body. A cigarette allows for approximately 10 to 20 percent of the THC in the marijuana to be transferred. A pipe is somewhat more efficient, allowing about 40 to 50 percent to transfer, and a water pipe (or bong) is quite efficient. Because the water pipe traps the smoke until it is inhaled, theoretically the only THC lost is what the smoker exhales. Vaporizers allow a very efficient transfer of THC because, in addition to taking advantage of the rich blood supply in the lungs, vaporized pot does not create smoke that can be irritating to the lungs and cause a person to limit his inhalation or to cough out a “hit” that is too big. This can be a problem as well, particularly when a smoker first switches to a

vapor system. Smokers are used to the feeling of smoke in their lungs and often use that feeling as a gauge by which they estimate their intake. The vapor does not irritate the lungs nearly as much as smoke, so that gauge is missing and some new vapor users take in far more THC than they intend until they figure out a new way to estimate their intake. Another consideration is that e-liquids vary widely in their THC concentrations, so it is very important to know the potency of the particular THC source in a vaping system before using it.

Although much of the high wears off relatively soon after smoking or vaping, THC remains in the body much longer. About half of the THC is still in the blood twenty hours after smoking. And once the blood carrying the THC passes through the liver, some of the THC is converted into other compounds that may remain there for several days. Some of these metabolites have psychoactive effects as well, so that although the initial high may disappear within an hour or two, some of the effects of marijuana on mental and physical functions may last for days.

Not only may THC and its metabolites stay in the blood for days but they also stay in the fatty deposits of the body much longer because they are very lipid-soluble—they easily get absorbed into and stored in fat. THC stored in fatty deposits is released from these tissues slowly over a rather long period of time before finally being eliminated. What all this means is that about 30 percent of ingested THC (and its metabolites) may remain in the body a full week after smoking and may continue to affect mental and physical functions subtly. In fact, the remnants from a single large dose of THC may be detectable up to three weeks later.

All of these rules also apply when marijuana is eaten instead of smoked or vaped, except that less THC gets to the brain and it takes a lot longer for it to get there. When marijuana (or any drug) is taken into the stomach, the blood that absorbs it goes to the liver before flowing to the rest of the body (including the brain). This means two things: First, the liver breaks down some of the THC before it ever has a chance to affect the brain. Second, the remaining THC reaches the brain more slowly because of its indirect route through the bloodstream. However, because the body absorbs THC more slowly when marijuana or other cannabis products are eaten, the peak levels of the drug last longer (though they are lower than they would be if the same amount were smoked or vaped).

Whether the user takes in cannabis through the lungs or stomach, the accompanying differences in the way THC is distributed and metabolized appear to have a substantial impact on the kind of experience the user has. Rather than experiencing a sudden change from being straight to being high, the marijuana eater experiences a slow and gradual shift that lasts longer. Many experienced users report that what happens after eating marijuana is more reminiscent of a mild mushroom or LSD trip; it’s not simply “getting high.” Because high levels of THC can cause hallucinogen-like experiences, people who have eaten marijuana and reported such feelings may actually have achieved higher levels of THC than many smokers—despite the fact that some of it is metabolized by the liver before it gets to the brain—because they ate a larger amount than they would likely have smoked.


One of the most striking findings from research on cannabinoids was the discovery of a cannabinoid receptor in the brain in the early 1990s. In recent years there has been a marked increase in studies of the brain’s natural cannabinoid receptors and the chemicals that our brains make to interact with them (the “endocannabinoids”). There is a lot of interest in how these receptors work and what they do. The research is evolving, but it seems that they play a role in a number of important functions such as learning, control of anxiety, and maybe responsiveness to other drugs, like alcohol. This is not the first time that researchers had located a specific brain receptor for a plant material. The opioid receptor, which was discovered years ago, is involved in the modulation of pain and possibly of stress in a broader sense as well. But while it makes sense that our brains have evolved a chemical system for dealing with pain, it was less clear why it would evolve a receptor for THC and what the implications of this study are for human beings. As the research on endocannabinoids became more focused on how these chemicals influence single neurons, studies began to show that they have a subtle but very important role in regulating how neurons communicate with one another in brain circuits. They essentially act as moment-by-moment feedback systems between communicating neurons that shift the intensity of the signals traveling between those cells. This allows brain circuits to react to changes

in the intensity of their communications—a kind of self-regulation of the communication between cells. This is important because it influences how messages are sent and received by a cell. Obviously, for a communication system like this to work, delicate balances of endocannabinoid concentrations are required within neural circuits. When additional, exogenous (“from the outside”) cannabinoids are added to the mix by a person using cannabis products, those delicate concentrations can get ramped way up, disrupting the normal process of communication between neurons. While this disruption is part of what causes the feeling of being high, it also compromises the function of neural circuits in ways that disrupt learning and memory as well as other aspects of information processing.

Because the brain provides its own cannabinoid receptors, it must also provide its own compound to activate those receptors. Anandamide (the name comes from ananda, the Sanskrit word for bliss) is one compound, found naturally in the brain, that binds with cannabinoid receptors. Another is called 2-AG. It also activates THC receptors in the brain and is present there in amounts 170 times greater than anandamide. There are likely several other such naturally occurring compounds, because several different subtypes of cannabinoid receptors have been discovered.


Although we must leave it to the anthropologists and ethnobotanists to figure out why we have cannabinoid receptors, we do know where they are in the brain, and that might help us to understand the effects of marijuana. The hippocampus is critically involved in the formation of new memories (as we discussed in the Alcohol chapter) and has a very high concentration of cannabinoid receptors. Not surprisingly, the inhibition of memory formation by marijuana is its most well-established negative effect on mental function.

In animal studies, when rats are given THC, they show significant deficits in memory formation—not the ability to recall previously learned information, but the ability to store new memories. In fact, an animal treated with THC performs a memory task as poorly as an animal with a damaged hippocampus. Normally the cells in the hippocampus become active and communicate with one another while an animal learns such a task. However, the hippocampal cells in the animals under the influence of THC did not activate in normal ways. These experiments make a compelling case that the

memory deficits associated with acute marijuana use are due to the THC suppressing the activity of hippocampal cells and hindering the acquisition of new memory. After the animals’ bodies eliminated the THC, their memory and hippocampal function returned to normal. The compound 2-AG, which exists naturally in the brain and stimulates THC receptors, also decreases the ability of the hippocampus to carry out some of its memory-related functions.

But the story is more complicated. Other studies have shown that several of the effects of THC are quite different in adolescents compared to adults. For instance, with respect to learning and memory, THC disrupts the learning ability in adolescent animals far more potently than it does in adult animals. It appears that this is due to THC producing more potent effects on the memory-related actions of the hippocampus in the adolescent brain compared to the adult brain. In addition, THC produces fewer unpleasant side effects like anxiety and aversiveness in adolescents than in adults. Consider that whether users continue to use a drug often depends on whether the pleasure outweighs the pain. So, if the negative effects of THC are felt less by adolescents, they might simply find it more pleasant to use THC than adults do, thus increasing adolescents’ risk for more frequent use and the negative consequences that can follow, just as with alcohol.

Whether talking about effects in adults or adolescents, these studies raise an important question about the effects of repeated marijuana use. Does marijuana kill brain cells? At present the weight of the scientific evidence suggests that at the doses, and for the periods of time, that most people use marijuana, the answer is no. A number of studies in rats have investigated the effects of THC on various areas of the brain, including the hippocampus, by giving the rats very large doses of THC for very long periods. While some of these studies suggest that some damage can occur, the way the experiments were done raises questions about the relevance of the results. The studies that show these effects on hippocampal cells generally exposed animals to high concentrations of THC nearly every day for several months (a substantial percentage of the life span of a rat). In many animal studies of this kind, the doses given are hundreds of times higher than a human user would take at any given time. When researchers gave lower doses, far less severe effects were observed in the hippocampus, even when the drug was given for more than twice as long. And even the low doses in many of these animal studies were much higher, were administered much more frequently, and were administered for longer periods of time than most cannabis users would

ever self-administer the drug. One study did use realistic concentrations of THC to see if they would decrease the chances of young hippocampal cells from rats surviving in culture (that is, growing on their own in an artificial medium outside the body). Indeed, the presence of THC did appear to decrease the chances of those brain cells surviving. Another study also showed that THC-like drugs decreased the ability of cultured hippocampal cells to make connections with other cells in the culture. While these studies should raise some flags about marijuana use, it’s very important to take these results with a grain of salt because the circumstances under which the effects were observed were so unusual.

Generally, science of this sort progresses first by finding significant results in rats or mice and then by attempting to see if the effects show up in nonhuman primates, such as rhesus monkeys, whose brains (and behavior) are more similar to those of humans. Some experiments have used rhesus monkeys to assess the effects of daily exposure to a reasonable amount of marijuana smoke for one year. At the end of the study, the animals’ brains were examined, and no evidence was found of permanent gross changes in neurons or of neuronal death. Chronic exposure to THC could conceivably cause long-lasting changes in the organization of the brain, or in the chemistry of neurons, but that would be hard to detect. If the prolonged THC exposure occurred while the brain was maturing (childhood or adolescence), then the changes might be quite important. As we will see later, some human studies show that prolonged marijuana use can have long-lasting effects even after people quit using the drug, and subtle brain changes may underlie these effects.

So what do we make of the animal research? It’s not perfect and cannot give us final answers, but there are good reasons to take the results seriously. This is particularly true for studies of the hippocampus, because that structure in the rat is remarkably similar to that in the human, both in how it looks and in what it does (that is, promote memory). Although profound damage to the hippocampus, as observed in those studies, is unlikely to occur in any but the heaviest of marijuana users, less severe effects could occur with more moderate use. The user might risk subtly damaging hippocampal circuits without causing obvious memory deficits. Brain circuits might just be less sharp than they otherwise would have been. We don’t know for sure.


Two other areas of the brain particularly rich in cannabinoid receptors are the cerebellum and the basal ganglia. These regions help to coordinate and fine-tune our movements, and marijuana is known to disrupt these functions as well. Cannabinoid receptors, however, are not found in the brain stem, which is critical for breathing. That may be why it’s virtually impossible to take a fatal overdose of marijuana.


THC receptors are located in many different places outside the brain and affect body functions in a range of ways. One of these is the immune system —the complex of structures, cells, and chemicals that fight infection and disease. In fact, two different main types of cannabinoid receptors have been identified: one that is highly concentrated in the brain, and one that is highly concentrated in certain immune-system cells.

Some animal studies indicate that THC can reduce immunity to infections, but the doses used in these studies were far greater than any human user would take. Unfortunately, at present, there are not enough reliable studies of the effects of THC on human immune function to make a convincing case either way. One early study in the 1980s, which used a rigorous double-blind, placebo-controlled design, observed no alterations to the immune function of people who were given THC. But a more recent study of medical marijuana users showed several indicators of suppressed immune function and identified several specific chemical pathways through which that effect is likely to occur. Still, although more research is starting to suggest THC effects on immune function, it’s still too early to draw specific conclusions. Though it seems clear that there are effects, we will have to wait for more conclusive research before we can reach a definitive understanding of their implications for human health and disease.


Smoking marijuana increases the heart rate. Laboratory studies have shown that this increase measures in the general range of twenty to thirty beats per minute. Relatively frequent smokers do develop some degree of tolerance to

this effect, but even tolerant individuals experience substantial increases in heart rate after smoking. There have been a number of good studies showing that marijuana also increases heart rate and lowers the heart’s pumping efficiency during exercise—essentially increasing the workload on the heart. Clearly these effects on the function of the heart could pose a risk for some individuals, particularly those with heart disease or high blood pressure, or those who take medications that alter heart rhythms. Still, there is no clear evidence that marijuana smoking leads directly to heart disease or produces heart attacks.


Two separate and important questions bear on this topic: Does chronic marijuana smoking impair the functioning of the lungs? Does chronic marijuana smoking promote lung cancer?

The answer to the first question is yes. Some studies of chronic, heavy marijuana smokers show that their lungs do not produce as much airflow as the lungs of nonsmokers, and one study indicated that chronic marijuana smokers who smoke three to four joints per day suffer from chronic bronchitis as often as cigarette smokers who smoke a pack or more per day. In addition, solid studies have found both an abnormal clinical appearance and an abnormal organization of cells in the airways of heavy marijuana smokers relative to nonsmokers and to those who smoked tobacco alone.

Although there have been rumors that marijuana smoke is ten or even one hundred times more toxic to the lungs than tobacco smoke is, the truth is that marijuana smoke and tobacco smoke are rather similar. Many of the toxic compounds, such as tar, carbon monoxide, and cyanide, are found in comparable levels in both types of smoke. One known carcinogen, benzopyrene, is found in both but occurs in greater concentration in marijuana smoke, while tobacco-specific nitrosamines appear only in tobacco. So far, no definitive evidence links marijuana smoking with lung cancer. One study measured DNA damage (thought to be a precursor to the development of cancer) in lung cells from marijuana smokers, tobacco smokers, and nonsmokers. The study found a trend toward DNA damage in cells from marijuana smokers regardless of whether they also smoked tobacco. This finding would seem to suggest that marijuana smoking alone might predispose a person to developing lung cancer. But a recent study with

over 5,000 subjects found no association at all between marijuana smoking and lung cancer risk, even among long-term smokers. There is evidence that people who smoke both tobacco and marijuana regularly may run a greater risk of developing lung cancer, and at an earlier age, than smokers of tobacco alone. However, the consensus of evidence at present indicates no increased lung cancer risk for marijuana smokers unless they also smoke tobacco.

Of course, marijuana and tobacco are smoked in very different ways. Very few marijuana smokers inhale even a significant fraction of the amount of smoke a typical cigarette smoker does in a given day. On the other hand, marijuana is smoked differently from tobacco. The amount of marijuana smoke inhaled per puff is two-thirds larger than a typical puff of a tobacco cigarette. Marijuana smoke is also inhaled more deeply into the lungs and is held in the lungs four times as long. So, the toxins in the marijuana smoke get greater access to the lungs. One study showed that a marker for carbon monoxide in the blood measured five times higher after smoking a marijuana cigarette than it did after smoking a tobacco cigarette of comparable size. The amount of tar inhaled from the marijuana cigarettes was three times higher and, of that amount, one-third more was retained in the respiratory systems of the subjects who smoked marijuana than in those who smoked tobacco.

Some of these factors may account for the decreases in lung function among marijuana smokers that we noted above, but they do not appear to increase lung cancer risk.


In 2004 a strange syndrome was first described in chronic cannabis users. It was characterized by recurrent episodes of nausea and vomiting. These patients would often show up in the emergency department after days or weeks of nausea and vomiting, dehydrated and in need of intravenous fluids and antinausea drugs. They were feeling miserable, and the only thing that many of these patients had found to provide limited relief was taking frequent hot baths or showers. This syndrome has been studied a little bit across the years since 2004 and has come to be called cannabinoid hyperemesis syndrome (CHS) (“emesis” means vomiting). It can be quite dangerous because the resulting imbalances in electrolytes and dehydration can lead to kidney failure. Unfortunately, the commonly used antinausea drugs are usually

ineffective. The only known, effective, long-term treatment is to stop using cannabis products. Because this syndrome has not been studied extensively, it’s hard to know how many people are affected, but many believe that its prevalence has been increasing in recent years as cannabis products have been legalized in many states and use seems to be increasing. One 2018 study at a public hospital in New York City identified patients eighteen to forty- nine years of age who reported using marijuana on twenty or more days per month. They were not at the hospital complaining of gastrointestinal problems, nor for anything related to marijuana use. But among those subjects, about one-third were found to have had symptoms of CHS. There are over 8 million daily or near daily marijuana users in the United States. If the New York sample is an accurate reflection of the national prevalence of CHS symptoms, it could mean that as many as 2 to 3 million people in the country have suffered from such symptoms. It’s not clear what causes CHS, and so the development of new treatments has been slow. For now it seems wise for consistent users to look out for symptoms of nausea and vomiting, and not hesitate to get supportive medical help for hydration if those symptoms persist.


Although marijuana does not make people sterile, as some rumors have asserted, long-term use of marijuana does have some effects on reproductive function. Through its effects on the brain, marijuana suppresses the production of hormones that help to regulate the reproductive system. In men this translates to decreased sperm counts and, occasionally, erectile dysfunction (impotence) from high doses over a long period of time. A woman who uses marijuana regularly over a long period of time may experience irregular menstrual cycles. Though these effects almost never cause complete infertility, they could decrease the probability of conception.

Another hormonal effect of marijuana in men may result in the development of breast tissue (the scientific term for this is gynecomastia), an effect that is generally not enjoyed by men. This is caused by marijuana’s ability to increase secretion of the hormone prolactin.


As a drug, marijuana defies characterization. It does not fit neatly into any of the general categories into which most other psychoactive drugs can be placed. However, it shares characteristics with many of them. So, rather than try to squeeze the effects into a simple category, we will first describe the range of effects and then try to unify the information in a practical way.

Until recently many, perhaps most, people didn’t even get high the first few times they used marijuana. What’s different now is that THC concentrations in much of the available marijuana and THC e-liquids can be much higher than in the mid-grade marijuana that was predominant in years past. Still, for those who start with lower concentrations, this unusual lack of effect may be due to the need to learn the techniques of smoking, such as inhaling the proper amount and holding the smoke in the lungs. It also appears that the user has to learn how to appreciate or perceive the high that the drug provides. This is in marked contrast to most drugs, whose effects lose power with repeated use (tolerance). But, again, the very high-concentration cannabinoid preparations that are available today may simply override this initial resistance to THC effects.

People’s subjective experiences of THC vary widely. Most people report that the high is intellectually interesting, emotionally pleasing, or both. The “interesting” aspect of the high may relate to what many people call an improvement in sense perception. Some people say that they hear subtleties in speech or music that they wouldn’t have recognized without the drug. To some, visual images may seem more intense or more meaningful. Likewise, feelings often seem more intense to the user, or differ from what they’d be without the drug. Generally, the user interprets these changes in cognition and feeling as positive, but the interpretation also depends on the situation in which they occur. A sense of emotional well-being and intellectual stimulation could switch to something less pleasant in other surroundings.

It’s difficult to assess the accuracy of reports of enhanced perception, cognition, or emotional insight because the high does not generally translate well into straight language. Many people who report having tried to write down the subtleties of their thoughts and feelings while on marijuana find afterward that the words they wrote just don’t convey the experience. Even if, while they were high, they thought they had captured the moment, the resulting account seems to miss the substance of the experience.

What does this translation problem mean? Are the feelings and thoughts that one has while high not as profound as they seem in the moment? Are they just what one would have thought or felt otherwise, but given a false importance by the drug? Perhaps the drug produces a relaxed and open state in which normal feelings and thoughts can be experienced more fully; but the effect can’t be due to relaxation alone because drugs like Valium clearly do not impact perception, thinking, and emotion the way marijuana does. The difference could relate to the effects of THC on memory and the perception of time.

A number of early research reports indicated that marijuana altered the user’s perception of time, seeming to slow it down. Users sometimes refer to being on “pot time,” when rather brief events seem to stretch on and on; that might be due to wandering concentration or disjointed memory. Perhaps because THC makes it harder to remember ideas and feelings, only the most salient or important parts stick in the memory, changing the user’s interpretation of the experience. The memory deficiencies that marijuana causes could also contribute to the sense of wonder that many users report. If memory is not being formed as normal, and the usual time-line that a person experiences is thereby distorted, things that might otherwise fall from the person’s attention may remain interesting. A musical phrase, an idea, or a painting might captivate attention for far longer than usual if memory is compromised. Is this a bad thing? On one hand it seems reasonable that if the brain isn’t functioning normally, then the resulting perceptions are inaccurate and thus may lack true value. On the other hand, it could be argued that such a cognitive “compromise” may afford a person an opportunity to appreciate aspects of an experience that would otherwise be passed over.


Although users do develop a tolerance to marijuana, this development is not as simple or as clear-cut as it is in the case of some other drugs. Frequent smokers generally report less of a feeling of being high than infrequent users after smoking a marijuana cigarette or taking oral THC. Interestingly, frequent users also report feeling high after smoking an inactive placebo cigarette (though less so than after a real one). These findings indicate that tolerance to the subjective effects of marijuana does develop and that there is

a significant learning effect associated with chronic marijuana use. Perhaps frequent smokers associate the feeling of being high with the various environmental stimuli that surround the act of smoking, so that smoking a joint (even an inactive one) and expecting to get high leads them to feel high despite the lack of drug.

Dependence can be measured in a variety of ways, but in general it seems that even heavy marijuana users do not become dependent in all of the ways that users of some other drugs do. For example, one way to assess dependence is to determine if the individual craves the drug so much that it comes to control much of her or his behavior. The dependent person will have difficulty in controlling their use of the drug and will sacrifice much to get it. The number of people who have this level of difficulty with marijuana is relatively small, and there does not appear to be a significant degree of craving associated with marijuana. It’s also important to clearly define what we mean by “craving.” In the context of drug addiction it means a consistent and irrepressible urge or need to find and use the drug—almost regardless of the risks or costs associated with getting it. People who simply want to get high might use the term “craving” to describe their wish, but that’s an entirely different matter. Still, some individuals have reportedly experienced psychological dependence, but these cases are hard to assess because each is unique and there have been no truly well-controlled studies.

Withdrawal occurs when, after chronic use, a drug is abruptly withdrawn and the user suffers a kind of rebound of unpleasant, often dangerous, effects. The classic symptoms are the agitation and illness associated with opioid withdrawal and the anxiety, and sometimes tremors and seizures, associated with alcohol withdrawal. Even after the most intense exposure, the effects associated with marijuana withdrawal are pretty mild. For example, in one study people consumed ten- or thirty-milligram doses of THC by mouth every three to four hours around the clock for up to twenty-one days. These are very large doses (even taken orally), given continuously over a long time, and do not model the intake of any but the most extreme users of marijuana. When they stopped, the subjects most frequently showed irritability and restlessness. Less prominent symptoms were insomnia, sweating, and mild nausea. When THC was re-administered to these subjects, the symptoms went away, indicating that they had been the result of the THC withdrawal. Another study of people who had smoked several times daily for about fourteen years indicated that they experienced a number of clinically

significant symptoms when they quit smoking for a period of three days. These symptoms included irritability, decreased appetite, and difficulty sleeping—the kinds of problems expected after withdrawal from heavy marijuana use. This study is important because it documents that there are clinically significant symptoms that accompany the abrupt cessation of marijuana use. There’s a lot more to addiction than withdrawal symptoms, but it will always be tempting for a person to use a drug again if quitting results in uncomfortable withdrawal effects.

One area of the brain that is involved in the rewarding (and possibly addicting) effects of some drugs is the nucleus accumbens, which contains cells that use the neurotransmitter dopamine (please see the Addiction chapter). Until recently there was no evidence that THC had any effect on dopamine activity in this region, leading many people to believe that marijuana carried no risk of addiction at all. Although the jury is still out on whether marijuana is addictive in the classic sense, there are some studies in animals that indicate it can increase dopamine levels in the nucleus accumbens. Remember that when it comes to science, it is never wise to bank on the results of just a few studies, but those reports at least raise the possibility that THC has some effect on the brain’s reward systems. If so, then marijuana may join the long list of other things that stimulate these circuits, including nicotine, food, heroin, sex, and alcohol. We expect that scientific research will eventually show that anything pleasurable (even a good biscuit) will evoke dopamine, and if the pleasurable experience is repeated enough, then withdrawal from it will produce discomfort. (Who wants to give up tasty food?) But the key here is a matter of degree. Maybe food, sex, and marijuana release some dopamine in the reward circuit, but cocaine is so much more effective that it is therefore much more addicting. As we continue to emphasize, good information is critical to making healthy decisions, and just because someone concludes that marijuana may stimulate the reward circuit, we should not infer that this drug is the pharmacological equivalent of other drugs like cocaine or heroin.


Although researchers cannot stick electrodes into the brains of human subjects to see exactly how marijuana affects memory, some have conducted revealing studies on the memory effects of acute marijuana intoxication. In general these studies show what the animal studies predicted they would. While people are high, they are significantly less able to store new information than when they aren’t. In fact, the single most common and reproducible cognitive effect of marijuana is this interference with memory processing. It is important to emphasize that, as with alcohol exposure, the deficit is not in the ability to recall old, well-learned memories, but rather in the ability to form new ones.

For example, after smoking one joint, people in their twenties were significantly impaired in their ability to recall the details of a story that they both read and listened to while high. However, if they learned the story the day before they smoked the joint, then the subjects could recall the story with no trouble. So, it’s probably the case that marijuana compromises the ability to learn new information but not the ability to recall previously learned information.


Because THC remains in the body (and thus the brain) for so long, it is important to know how long memory (and other cognitive functions) may be affected. Researchers have undertaken a considerable number of studies, but most of them are flawed because they fail to control for influences such as smoking experience or intelligence. Even so, when all the findings are boiled down, marijuana appears to have residual effects on cognitive functions (including memory) for up to forty-eight hours. It is therefore probably not wise to take a challenging test or to fly an airplane within a day or two after smoking marijuana. Furthermore, a person who smokes marijuana every few days is probably never completely free of its effects on thinking and problem solving, living consistently in a somewhat compromised cognitive state.

In one well-controlled study, investigators recruited college students in two distinct groups: “heavy” users (those who had used marijuana nearly every day during the month before the study and had THC in their blood when they came to the laboratory) and “light” users (those who had used marijuana on average only once in the thirty days before coming to the laboratory and had no THC in their blood when they arrived). The students

spent the night under supervision and were given a battery of mental tests the next morning. The intent was to assess the cognitive function of the heavy users, but a number of interesting differences (and similarities) appeared between the backgrounds of the heavy- and light-using groups. The heavy users tended to come from more affluent families with higher incomes. There were no differences between heavy and light users in psychiatric history: neither group had more psychological problems than the other. However, when their present emotional state was assessed, the heavy users were happier (remember, though, that they still had THC in their systems).

The mental tests revealed two important findings. First, the heavy users showed much less mental flexibility in problem solving than did the light users. They often made the same mistake over and over again on one test, indicating that they tended to become locked in to a particular problem- solving strategy and had a hard time generating new ones even when the current one no longer worked for them. The heavy users also showed impaired memory function, but this problem did not appear on all of the memory tests that they took. They were as good as light users at remembering a short story that was read to them. However, male heavy users (but not female heavy users) did not perform as well as light users at recalling figures that they were shown and then asked to draw from memory. The heavy users also had significantly more trouble learning lists of words over time.

So, what we know from this study is that about one day after their last dose, people who smoke daily are significantly impaired on some measures of memory for words and pictures, and make more errors than would be expected on a problem-solving test that requires mental flexibility. But because none of the light users had THC in their systems when they came to the lab, we do not know the effects of marijuana one day after use in people who use the drug less than daily. The other thing we don’t know is how long the residual impairment of heavy users lasts, or if there is any permanent impairment that is due to brain damage rather than residual THC in their brains.

This study did try to address the second question. The investigators looked a bit more closely at the light users and found that although they had all used marijuana very little during the month before the study, some had used it more than others across their lifetimes (and some quite heavily earlier in their lives). When the light users were divided up into subgroups based on

their life histories of marijuana use, there was no relationship between the scores they got on the mental tests and how much marijuana they had used in the past. With no THC in their systems at the time of testing, it did not matter how much these subjects had smoked in the past—there were no apparent permanent effects. But once the light users were subdivided, the number of subjects in each subgroup became rather small. So, from a purely statistical point of view, the lack of effects should be interpreted cautiously until more studies are done with larger numbers of subjects.

Another project studied people who had smoked almost daily (about two joints per occasion) for either an average of ten or twenty-four years, and compared their mental performance to a group of nonusers. Some learning deficits were found among the longer-term users, but there were some problems with the study. First, the users were all individuals who were seeking treatment for drug problems, and many of them had chronically used other drugs in addition to marijuana. Even more troubling, the average time between when the subjects had last smoked and when they were tested was only seventeen hours. Clearly, the outcomes reflected residual effects of recently smoked marijuana, so it’s impossible to attribute the observed effects to a permanent effect of chronic marijuana use.

A better study looked closely at the cognitive function of two distinct groups of users and comparable control groups of nonusers. The people in the first group were in their midforties and had been smoking heavily (about five joints per day) for an average of thirty-four years. The people in the second group were younger (average twenty-eight years old) and had been smoking about four joints per day for eight years. The performance of these groups was compared to age-matched control subjects who were not marijuana users. The older group of chronic users performed worse than the other groups on tests of verbal learning and memory as well as on a test of divided attention. There are several important points about this study. First, it indicates that after many years of very heavy marijuana use, there are some cognitive deficits that appear to be permanent. But the people who had been smoking heavily for eight years showed no deficits. There is another way in which the two user groups were different—the age at which they started using marijuana. The older group had started using at about twelve years of age while the younger user group had started at about twenty years of age. Starting so young may have had something to do with the deficits that they experienced as adults.

Does this finding suggest that repeated exposures to THC during adolescence may result in damage or deficits that would not occur with the same levels of exposure in adulthood? For now the best answer is that we don’t know, but there are some studies that are worth thinking about. One study of visual function suggested that smoking marijuana at an early age may change the way the visual system develops. Regular smokers and nonsmokers were asked to perform a task that forced them to visually scan what they were shown and identify important features of what was presented. This type of visual scanning ability is known to develop quite rapidly between the ages of twelve and fifteen. The investigators found that visual scanning performance was impaired in some of the smokers, and the factor that predicted deficits was the age at which the person had started smoking. Deficits were associated with smoking initiated before age sixteen; those who started after age sixteen showed no deficits. This study is not without its difficulties, though. Again, there is a chance that the smokers may have had acute effects—the average time between their last joint and testing was about thirty hours. Still, the results suggest that those who start smoking marijuana in their early teens may be at greater risk for long-term impairment than are those who start later.

One recent study followed nearly 2,000 twins in England from ages five to eighteen, measuring IQ at five, twelve, and eighteen, and also measuring executive function (which relies on frontal lobe maturity) at age eighteen. They found that at eighteen, subjects who had used cannabis as adolescents had lower IQs at age eighteen than those who hadn’t, but that they had also had lower IQs in childhood, before initiating cannabis use. Even subjects who had been diagnosed with cannabis dependence showed no evidence of IQ decline between ages twelve and eighteen. But one of the executive function tests (“working memory,” which tests the ability to keep a new memory accessible while working on a different task) was lower in the eighteen-year-olds who had significant cannabis use history. When the investigators looked at pairs of twins with different cannabis use histories, they found that the twins who had used cannabis more frequently did worse than the twins with a lower use history. This suggests that regular cannabis use during adolescence can degrade this aspect of executive function regardless of a person’s genetic predisposition to do well or poorly on the task. Other studies have shown that heavy use in young people results in deficits in several cognitive functions such as the ability to learn new

information, the ability to think abstractly, and information processing speed. These effects appear to last a couple of days, but not much longer. This is consistent with previous studies that have shown effects lasting several days, but it does not suggest permanent cognitive deficits after cannabis use by adolescents or young adults.

The issue of permanent, or at least very long-lasting, effects of cannabis use remains controversial, but there is some evidence that teens may be more vulnerable than adults to experiencing long-term declines in cognitive function after a history of heavy marijuana use. It’s very hard to do the types of studies that can answer questions about long-lasting effects because they take a long time to complete and require large numbers of subjects. One well-conducted study assessed IQ and other more specific measures of cognitive function in a group of 1,037 thirteen-year-olds. Then they followed the subjects while they went through adolescence and early adulthood. During those years, they kept track of their marijuana use by interviewing the subjects at ages eighteen, twenty-one, twenty-six, thirty-two, and thirty-eight. At age thirty-eight, they also retested their IQ and cognitive functioning. The subjects who had been diagnosed with cannabis dependence across those years showed significant declines in IQ and on a number of other cognitive functions, like the ability to think abstractly and process information quickly. Because people who become cannabis dependent often wind up with less education, it was important that the study control for this difference. But even when the education level was controlled in the statistical analysis, those subjects with histories of cannabis dependence did significantly worse than those without. There were also two additional factors that predicted the amount of cognitive decline in marijuana users—the persistence of their use and the age at which they began using. The more times a subject had been diagnosed as dependent on cannabis between the ages of thirteen and thirty- eight, the greater his or her amount of cognitive decline. This makes sense, of course, but what was really striking was that significant cognitive decline was only observed in subjects who had started using marijuana weekly (or received a cannabis dependence diagnosis) before the age of eighteen. Among those who started using in adulthood, there were not significant declines in cognitive function. This finding is important and is consistent with the results of other studies that have shown deficits in higher order cognitive functions and verbal IQ among chronic cannabis users who started in adolescence but not among those who started in adulthood. And the

difference was noticeable. When people who knew the participants well were asked, they reported having observed cognitive problems among the participants who had shown cognitive decline on the formal tests. Finally, and importantly, quitting cannabis use did not fully restore neuropsychological functioning among the subjects who had started using cannabis during adolescence, suggesting that regular marijuana use during adolescence may actually cause long-term damage to the brain.

We went into detail about this recent study because we think it was well done and the results are important. But it’s also important to recognize that the study was done in one region, and that although there was a large number of subjects overall, some of the groups of cannabis dependent users had only forty to eighty subjects each. This is still a good number, but it’s not huge, so some caution is warranted when trying to generalize the results. Another factor to consider is that the subjects who showed cognitive declines were pretty heavy users—having received at least one diagnosis of cannabis dependence and/or engaged in weekly use before the age of eighteen. So these results may not apply to those who engage in occasional, recreational use of marijuana. Regardless, teens and their parents should take this study very seriously. In our view, it represents one of the good reasons why young people should think very carefully before using marijuana.

In recent years some reports have suggested that early marijuana use may increase a person’s chances of developing psychological disorders later in life. The kinds of disorders indicated are serious—including delusions and other symptoms characteristic of schizophrenia—so we must take this possibility seriously. These studies raise the question of whether exposure to THC during adolescent brain development changes the trajectory of that development in ways that compromise later mental health. The statistical risk of developing these disorders is quite modest, and the vast majority of marijuana users do not develop psychotic disorders, so scientists speculate that for a subpopulation of people who are predisposed to psychosis, perhaps based on genetic characteristics, repeated marijuana smoking in adolescence conveys a relatively high risk of developing a psychological disorder later. Specifically, in people who have abnormal expression of a gene that gives rise to the brain enzyme catechol-O-methyltransferase (COMT—an enzyme that breaks down the neurotransmitters dopamine and norepinephrine), the association between adolescent marijuana use and later psychotic symptoms appears to be higher than in the general population. The

relationship between early marijuana use and later psychotic symptoms depends on multiple factors, including the amount of marijuana used, the age at which the use is initiated, and a person’s genetic vulnerability. It’s complicated. But psychosis is serious and can be life-threatening, so teens need to understand this risk. Clearly, more work needs to be done to understand the long-term cognitive and psychological effects of adolescent THC use, but evidence is accumulating of some lasting negative effects, and this should help to inform potential users in their choices.

These and other recent studies that underscore the risks of marijuana use in adolescence occur at a time when teens’ perceptions of the harmfulness of marijuana use have been declining. There has been a significant increase in the percentage of twelfth graders who believe that marijuana is not harmful at all—about 21 percent hold this belief. Correspondingly, multiple surveys in recent years have shown increasing marijuana use by teens, which is probably associated with their decreasing perception of its harmfulness. This could be related to the increasing public conversation about medical uses for marijuana and the legalization of recreational use in some states. (See the chapter on legal issues for more discussion of the recent changes in marijuana laws.)

It will take time for science to fill in the gaps in this research; meanwhile, it is our view that these findings should be taken as a strong caution about adolescents using marijuana.


In a word, no. In the late 1920s and 1930s, as US society was beginning to recognize marijuana use, articles appeared in some newspapers associating marijuana with crime. Some government agencies of the time promoted the idea that marijuana use led to aggressive behavior. Even the editors of Scientific American wrote in 1936 that when marijuana was combined with other intoxicants, it made the smoker vicious and prone to kill. (It is interesting, given the political climate of the time, that the editors of Scientific American chose to attribute the viciousness to the effects of marijuana and not to any of the other “intoxicants,” which included alcohol.) This image of marijuana effects is very inconsistent with the 1960s image of a dreamy-eyed, smiling young woman at Woodstock offering a joint to the

camera. Though there lingers some debate about the effects of marijuana on aggressive behavior, a clever laboratory study shows clearly that, if anything, marijuana decreases aggressive behavior in people when they are provoked. The study is worth explaining.

Researchers brought young men into the laboratory and showed them two buttons on a table. They were told that by pressing button A, they would accumulate points that would result in a reward. They were also told that pressing button B would remove points from another subject in a different room who would be engaged in the same task (there was actually no other subject). As the men worked at pressing their buttons, every so often they would see that they were losing points. This was attributed to the actions of the other (fictitious) subject. The experimenters could arrange to have more or less points removed to create the impression that the other subject was being mildly or highly aggressive to the actual subject. Not surprisingly, as the fictional subjects became more aggressive, the real subjects began to press button B to retaliate. Then the subjects smoked either a marijuana cigarette or a placebo cigarette that tasted like marijuana but had no THC and continued the button exercise. After smoking the marijuana cigarettes, the subjects showed a clear decrease in aggressive response to the highly provoking actions of the “other subject.” Although this was obviously not a study of aggression on the street, it does have the scientific advantage of well-controlled treatments and well-defined measurements. Moreover, it is consistent with the vast majority of anecdotal reports about marijuana effects, which claim that it makes people more peaceful.


Some people believe that marijuana does not impair the ability to drive. The truth is that it does. The decrease in attention and concentration that marijuana produces makes operating any kind of heavy machinery very dangerous. A marijuana smoker’s reflexes may be in good enough shape to control a car, but that may not be of much use if they stop paying close attention to the road. Similarly, the marijuana-induced changes in perception and sense of time may be entertaining on the couch in the living room but could be deadly on the highway. Laboratory studies using driving simulators have shown that marijuana significantly impairs both the ability to

concentrate and the ability to make corrections. This appears to be true on the real road as well. One study showed that young people who reported driving frequently while on marijuana were twice as likely to be involved in accidents as their nonsmoking peers. The best bet is never to drive while using any drug (legal, illegal, or prescription) known to impair motor or cognitive skills.


This was a hot-button issue not so long ago. However, during the past ten years or so enough scientific evidence has accumulated to show that there are valid medical uses for cannabis products, and the debate has subsided. Still, the history of this debate is informative. Prior to 1900, cannabis products were used frequently as appetite stimulants, muscle relaxants, and analgesics (pain relievers). In the early twentieth century, though cannabis was still used, its prevalence began to decline as competitive drugs became available. Finally, in 1937, the Marijuana Tax Act effectively stopped all legal medical use. Marijuana is currently categorized in Schedule I under the Controlled Substances Act, passed in 1970. This schedule lists drugs that have a high potential for abuse, lack an accepted medical use, and are unsafe for use even under medical supervision. In 1972 the National Organization for the Reform of Marijuana Laws (NORML) began a campaign to have marijuana moved to Schedule II so that it could be legally prescribed. NORML asked the Bureau of Narcotics and Dangerous Drugs (now called the Drug Enforcement Administration—DEA) to begin the process of rescheduling the cannabis products. It took more than a decade, but the required public hearings were initiated in 1986. After two years of hearings, the administrative law judge for the DEA, Francis L. Young, wrote that marijuana was “one of the safest therapeutically active substances known to man” (an overstatement, of course, but he made his point) and that marijuana fulfilled the legal requirement of currently acceptable medical use. However, his order that marijuana be moved to Schedule II was overruled by the DEA.

As the debate progressed, the demand for marijuana for medical uses grew, and the Food and Drug Administration (FDA) was persuaded to issue a handful of approvals for patients under a special permission called an Individual Treatment Investigational New Drug Application (sometimes

called a Compassionate Use IND). By the late 1980s the number of requests for Compassionate Use INDs increased markedly as AIDS patients and their physicians asked for permission to use marijuana to enhance appetite to combat the physical wasting associated with AIDS. However, in 1991 the program was halted because it was at odds with the (first) Bush administration’s anti–drug abuse policies. Many AIDS patients were left in the position of having to break the law to use marijuana to fight their physical wasting. In 1997 a group of physicians and researchers in San Francisco, who were trying to initiate controlled studies of the clinical effectiveness of marijuana for this purpose, estimated that there were two thousand AIDS patients in San Francisco alone who were using marijuana in this way. In 1999 the Institute of Medicine of the National Academy of Sciences conducted a study that concluded that marijuana had both potential therapeutic value and potential harmful effects. The harmful effects that were of particular concern were related to smoked marijuana. Thus, marijuana was cast in the same light as many drugs that are under investigation for human medical use. The study recommended that more research be conducted on the effects of marijuana and on the development of nonsmoking delivery systems. This call for more research on medical marijuana usage was echoed by the American Medical Association in 2001.

Two of the chief concerns about smoked marijuana as a medical treatment are the risk to lung function and the presence of carcinogens. Although cancer patients might use marijuana only once every few weeks, AIDS or glaucoma patients would use it much more frequently. Many of these concerns have been assuaged recently by the rapid emergence of noncombusting systems for delivering marijuana vapors as well as edibles. Although the long-term health effects of vaping are not yet known (see the Nicotine chapter), it is very likely that they are far less harmful than smoking combusted plant material, and thus may bypass the concerns about carcinogens that are mobilized by combustion altogether. Another concern about medical cannabis use relates to possible toxic effects to the immune system, particularly in AIDS patients who are already immunocompromised. Although this subject is currently debated in the medical literature, one large- scale study of HIV-infected men found no evidence that marijuana accelerated the process of immune-system failure, and while cannabis use does appear to influence some immune functions in healthy people—as many

things do—whether those effects result in any direct health problems remains unclear.


Although chronic, heavy marijuana use can cause nausea (see our discussion of CHS on page 190), under certain circumstances cannabis products can be helpful in treating acute nausea. One of the more unpleasant side effects of cancer chemotherapy (treatment with drugs to kill the cancer cells) is that the medicines make many people feel quite nauseated. THC clearly helps to control this side effect. In fact, THC has been available since 1985 in capsule form for use by cancer patients under the brand name Marinol (dronabinol), categorized by the DEA under Schedule II. Marinol has been shown to help control nausea and also to help patients gain weight. However, some physicians and patients argue that, compared to marijuana (which they use illegally for the same purpose), Marinol’s dosage and duration of effect (because it is taken orally rather than smoked) are harder to control and that it is simply not as effective. This might be so because cannabidiol, a component of natural marijuana that is not present in Marinol, has antianxiety effects that patients find helpful in addition to THC’s purely antinausea effects. In the past, proponents had argued that until a synthetic THC preparation can be made that truly reproduces the effects of the various cannabinoid compounds in marijuana, marijuana cigarettes should be made available for medical use. But with the emergence of e-liquids and edibles that contain cannabinoids, the need to smoke marijuana for nausea treatment has diminished markedly. In addition, recent advances in antinausea treatments that don’t contain cannabinoids have been of great help to chemotherapy patients. So now there are good options of both types, and nausea associated with cancer chemotherapy has been diminished markedly.


Research in the 1970s found that marijuana significantly reduced the high and potentially damaging pressure of the fluid within the eye in glaucoma patients. At present, however, neither marijuana nor Marinol is used as a treatment, and the American Academy of Ophthalmology does not recommend cannabis products for the treatment of glaucoma. One of the problems with cannabis-based treatments is that a single dose only lowers

the pressure in the eye for a few hours, and glaucoma needs to be treated all the time. So in order to have a real benefit one would need to have cannabinoids on board twenty-four hours a day. Also, cannabinoids affect blood pressure in ways that might actually make glaucoma worse. Scientists are studying whether THC-like compounds might be effective treatments if kept exclusively in the eye to treat intraocular pressure, but there are other treatments that ophthalmologists can offer, so cannabinoid products are not likely to come into common use for the treatment of glaucoma.


There have been some high-profile cases of children with intractable seizures (those that cannot be treated with conventional anticonvulsant medications) being successfully treated with cannabis. The case of Charlotte Figi gained international attention in 2013. She began having seizures at about one month of age and by the time she was five years old, she was having three hundred seizures per week, her cognitive function had declined, and her parents were told there was essentially nothing that could be done. Desperate, her parents tried cannabis, and it essentially put a stop to the seizures. It turned out that the particular strain of cannabis they used had little appeal to recreational users because it didn’t create much of a high. It was low in THC but rich in CBD—which is not known to be psychoactive. Studies had shown that both THC and CBD have anticonvulsant properties in animal models, but they control seizures through different mechanisms. It turns out that Charlotte’s case may have been a watershed moment in the national debate about medicinal cannabis. Since then, medical marijuana use has been legalized more broadly, and some commercial growers are generating strains of marijuana to be used specifically for medicinal purposes with no intent to get the user high. Much more research will be needed to fully explore the potential for marijuana as an antiseizure medication. It might only work in the most severe cases, or maybe only in children, but it seems clear that seizure disorders represent a wide-ranging set of medical problems for which very helpful cannabinoid preparations can be developed.


Spasticity is a disabling movement disorder, associated with multiple sclerosis and other conditions. The drugs that are typically used to treat it— including anticonvulsants and benzodiazepines—are helpful but limited in their effectiveness. Recently, clinicians in Spain and the United Kingdom have begun using a cannabinoid drug, called Sativex, as an “add on” medication in adult patients for whom the usual treatments are not adequate. Like the strain of marijuana that was effective against seizures in the aforementioned children, Sativex has a balance of THC and CBD that diminishes the psychoactive effects of the THC. Studies are under way to evaluate its possible benefits and risks. Early reports indicated that it has long-term clinical benefits for that group of patients without any serious side effects. The current bottom line seems to be that certain cannabis products, with the right THC/CBD balance, are generally safe in people with spasticity and might be of moderate use for spasticity—though they do have some side effects that may limit their usefulness.

Marijuana is by no means the only drug that is effective in treating the aforementioned conditions, but there certainly is an argument for the value of marijuana as medicine. Multiple sclerosis and other disorders that produce spasticity with impaired muscle control (marijuana works as a muscle relaxant), seizures, chronic pain, and migraine headaches have also been reported to respond positively to marijuana. The proponents of marijuana as medicine point out that it is hard to beat in terms of safety. As we described, it is next to impossible to overdose on marijuana, and its relative lack of addictive properties makes it safer on that score than many medicines currently used as muscle relaxants or for pain management. On the other hand, to relieve pain, sufferers would have to use enough marijuana to become stoned, which would greatly impact their ability to work or go to school. Many currently accepted pain-relieving medicines don’t have such a strong effect on mental function. And, importantly, as it has become clear that children and adolescents are likely at greater risk than adults for negative long-term effects of repeated cannabinoid use, the idea of using daily cannabinoids in young patients seems unadvisable, except perhaps in extreme circumstances.


In November 1996, Arizona and California passed propositions related to the medical use of marijuana. In California, the Compassionate Use Act of 1996 (Proposition 215) passed by a margin of 12 percent—56 percent to 44 percent. Essentially, the proposition stated that patients or defined caregivers who possess or grow marijuana for medical treatment as recommended by a physician were exempt from laws that otherwise prohibit the possession or cultivation of marijuana. It also stated that physicians who recommend the use of marijuana should not be punished in any way for doing so. The language of this proposition indicated that marijuana need only be “recommended” by a physician and did not specify the conditions for which it may be recommended. The proposition went on to state that persons using marijuana for medical purposes could still be held liable if they engaged in conduct that endangered others or if they diverted marijuana for nonmedical purposes. Still, it is clear from a reading of the proposition that nearly twenty years ago, California voters endorsed a very loose interpretation of which uses might be considered “medical.”

In Arizona, the Drug Medicalization, Prevention, and Control Act of 1996 (Proposition 200) passed by a vote of 65 percent to 35 percent. This proposition offered a similar bottom line as far as it concerns the medical use of marijuana, but it went considerably further in that it enabled physicians to recommend the use of other drugs currently grouped with marijuana under Schedule I of the DEA classification. Schedule I drugs include LSD, heroin, and other notorious drugs of abuse. Many people believe that marijuana should not be listed on Schedule I in the first place, arguing that it is not addictive and is far less powerful than most of the drugs on the list. Aside from that debate, however, the Arizona proposition raised serious concerns about other Schedule I drugs potentially being used as medicine.

Within two months of the passage of these two propositions, the US Congress conducted hearings on the issue, and the Clinton administration crafted a response. The DEA (a federal agency) has always issued licenses to physicians that allow them to prescribe controlled substances that are approved for medical use, so that without this DEA license, physicians would be limited in terms of what drugs they could prescribe. To discourage physicians in California and Arizona from recommending marijuana for medical use, the federal government has stated that it may investigate physicians who recommend marijuana and potentially withdraw their DEA

licenses. Several physicians, health organizations, and patients sued the government in response.

How things have changed! As of 2019, nine states and the District of Columbia have legalized both medical and recreational cannabis, and nineteen states have legalized medical cannabis. All of these initiatives have generated some degree of conflict with federal laws that strictly forbid marijuana use or possession for medical or personal use. The result has been an ongoing series of legal challenges and responses between state and local interests on one hand and federal authorities on the other. The ultimate outcome of these challenges remains to be seen, but they raise very powerful questions about patients’ rights, states’ rights, and the role of science in determining medical policy and law. In a marked shift from the past policies of past administrations, President Obama asked the Justice Department to refrain from enforcing the marijuana laws in certain circumstances for states that permit its possession. In 2017, the Justice Department (predictably) made moves to reverse that position, though the current president has (predictably) waffled on the issue.

Some people and agencies believe that medical marijuana propositions are thinly veiled maneuvers toward legalizing drugs. The concern is that once a drug (or a group of drugs) is approved for medical use, the next step could be legalization for nonmedical uses. Whether or not this is a legitimate concern, the potential usefulness of cannabinoid products as medicine and the aforementioned initiatives have added considerable fuel to another even more emotional debate: the outright legalization of marijuana.


The subject of the legal status of marijuana (and all drugs of abuse, for that matter) still evokes strong emotional responses in some people. But in recent years, the tone of the debate has shifted away from emotional and moralistic arguments and more toward a discussion that looks closely at the issues from a broad perspective, which includes pharmacological, social, and economic viewpoints. The legal status of any drug depends heavily on the culture in which that drug is evaluated and the prevailing social conventions relative to that drug. For example, in the United States today at the federal level, we persist in categorizing marijuana as a Schedule I narcotic and keeping it

illegal, while we allow the sale and advertisement of known addictive drugs such as nicotine and alcohol. Other societies have chosen to prohibit alcohol consumption vigorously while placing little or no sanction on the use of cannabis products. We should recognize the three principal factors that change attitudes and laws about drugs: culture, time, and money. Currently, the twenty-seven states (plus DC) that have some provision for legality of cannabis products are beginning to be able to quantify the revenues and job creation associated with that legalization. They are also beginning to be able to assess questions about whether legalization causes increases in cannabis use, traffic crashes, addiction to other drugs, etc. But the answers to those questions will take some time to emerge.


What had been a fascination with marijuana in the nineteenth century among artists and intellectuals was quickly overshadowed in the United States by fears about an association between marijuana and crime, particularly violent and sexual crime. Although we now know that there is no such relationship, by the mid-1920s the popular media had seized on this idea, and concern began to grow. Although then, as now, there were no scientific data to support the conclusion that the use of marijuana led to violent behavior, by the mid-1930s all the states of the union had laws regulating the use of marijuana. As we mentioned, even magazines devoted to interpreting the science of the day got on the bandwagon. Both Popular Science Monthly and Scientific American published articles in 1936 portraying marijuana as a “menace” to American society, particularly to the young.

A major player in elevating marijuana to the status of “national menace” was Harry Anslinger, who served as commissioner of narcotics in the 1930s. Mr. Anslinger began something of a crusade against marijuana, skillfully using congressional testimony, the medical establishment, and the popular media to warn of the dangers of marijuana to American society. He was successful, and in 1937 congressional hearings were held to address the association between marijuana and crime. By this time it was clear that Congress was ready to limit the use and possession of marijuana, and it passed the Marijuana Tax Act of 1937, which did not outlaw marijuana but created a tax structure around the cultivation, distribution, sale, and purchase

of cannabis products, which made it virtually impossible to have anything to do with the drug without breaking some part of the tax law.

Interestingly, almost immediately after the passage of the Marijuana Tax Act, the pendulum began to swing the other way. In the early 1940s, studies were published that indicated that marijuana was relatively harmless and that any relationship to criminal behavior was likely due to marijuana’s association with the use of alcohol, which proved to be the prime cause of aggression. Other studies during that time began to show that although acute marijuana use impaired cognitive function, it did not change the personality of the user, and that it affected thinking and feelings more than behavior. By the late 1960s, when the Marijuana Tax Act was ruled unconstitutional by the US Supreme Court, Mr. Anslinger’s assertions about the relationship between marijuana and violent crime were discredited. Still, marijuana was illegal, and this label alone implied “dangerous” for most people. What has developed since that time has been an interesting tension between a legal status that implies danger and a scientific literature that consistently suggests that marijuana (used in the ways it is generally used) is a relatively safe drug for adult users.

Little scientific work was done with marijuana through the 1950s and 1960s, though its use increased. The media during the 1960s increasingly focused on “hard” drugs such as LSD (which was legal until 1966, and placed on Schedule I in 1967), while marijuana became a symbol of youthful rejection of “the establishment.” The acceleration in marijuana use began in the late 1960s and by the spring of 1970, the National Institute of Mental Health estimated that as many as 20 million individuals had used marijuana at least once. In December 1970, the Gallup organization estimated that 42 percent of college students had smoked marijuana. Perhaps the social association between marijuana and hallucinogens during the 1960s can account for its continued inclusion with LSD and heroin under the category of Schedule I narcotics, despite the profound differences in the potency of its effects on (and risks to) individuals. The use of the drug decreased in the 1980s as social and political conservatism grew but rose again in the 1990s as the perceived risks of using it again dropped. In recent years, marijuana use appears to have leveled off, with slight declines among some age groups, including middle and high school students. But the recent changes in the legal status of marijuana and other cannabis products could change that (in either direction). The most recent national surveys show some interesting use

patterns. Clearly, most marijuana use is by people eighteen to twenty-five years of age. Among that group, 33 percent have used it in the past year and 21 percent have used it in the past month. People between twelve and seventeen years of age, and those over twenty-six, use it much less. Among those groups, about 12 percent have used it within the past year and about 7 percent have used it in the past month. It will be interesting to see whether changes in the legal status of cannabis products increases use in any of these groups.


Because people continue to use marijuana recreationally and, in most states, still cannot buy it legally along with their coffee, cigarettes, and beer, criminal distribution networks continue thriving to meet the demand. Growing out of the competition within these networks comes the violent crime so common to our daily news reports. At the same time, users, by definition, become criminals. We spend a considerable amount of money each year to apprehend, prosecute, and imprison people on marijuana charges. These costly laws do not hinder marijuana use, particularly among young people. The most recent Monitoring the Future survey shows that 37 percent of US twelfth graders have used marijuana, and 6 percent use it every day. Clearly, as a society we are not ready to endorse the use of marijuana by selling it in the corner drugstore, but both conservative and liberal sectors are increasingly calling for a dramatic rethinking of marijuana laws and policies, and those calls have been heeded in a growing number of states.

Aside from the criminal issue, many people feel they have been lied to by the government agencies responsible for educating and interpreting science to the lay public. In the 1960s, as more and more young people tried marijuana and discovered that it did not turn them into insane, violent killers, they began to resent and distrust the authorities who had presented those images. Authority began to lose its credibility relative to drugs. Nearly sixty years later, that credibility has not been fully regained, in part because the scientific truth about marijuana (and other drugs) is often lost among political and moral agendas.


In 1970, a commission that was formed to take a closer look at marijuana laws recommended that the private possession of small amounts of marijuana for personal use no longer be considered an offense, but that selling marijuana or driving under its influence still be punishable. The same year that that report was released, the American Medical Association and the American Bar Association suggested the reduction or elimination of criminal penalties for the possession of very small amounts of marijuana. Soon thereafter, individual states began taking steps to decriminalize marijuana for personal use, and in 1977, President and Mrs. Jimmy Carter called for the decriminalization of the possession of small amounts of marijuana. The general view of many who supported decriminalization in the 1970s was that the laws against marijuana were more harmful than the drug itself.


The “Reagan Eighties,” however, brought a new get-tough attitude to the issue of illegal drug usage. The trends toward decriminalization were abruptly reversed and replaced by the War on Drugs. States began to reinstitute tougher policies and penalties. During the 1980s the number of people aged eighteen to twenty-five who reported using marijuana steadily decreased while alcohol usage increased and the use of powder, and then crack, cocaine began to skyrocket. Crack became a major scourge of the urban underclass and for both pharmacological and social reasons has been a major contributor to violent urban crime.

Still, in the early 1990s marijuana use significantly increased, particularly among young people. In just the two years between 1992 and 1994, the use of marijuana by adolescents twelve to seventeen years of age nearly doubled. Perhaps this was just the pendulum swinging back from the more conservative and reactionary 1980s. Or maybe a new generation of users was exploring drugs. Cocaine was the drug of the 1980s, a decade that more than a few financial writers refer to as the “Go-go Eighties.” Cocaine is clearly a “go-go” drug, whereas marijuana has a considerably more mellowing and contemplative effect, perhaps reflecting a change in the spirit of the times.


As a society we have much bigger drug problems to deal with than marijuana. A rational and convincing chorus of voices across the political spectrum, including medical and scientific professionals, political pundits, and members of the business community, are urging a restructuring of our legal response to marijuana and other cannabis products, and voters are paying attention. The legal debate over marijuana is still complicated. On one hand, it is now obvious that there are beneficial medical uses for the drug, and it obviously does less social and medical harm than our legal drug of choice, alcohol, or the scourge of the opioid epidemic that is currently raging in the country. One report indicates that marijuana is the largest cash crop in the United States, larger than those for corn and wheat combined, and the revenues from its controlled cultivation, sale, and taxation could be significant, turning the loss of resources for prohibition and prosecution into gains in the legal economy and national and state coffers. The states that have already legalized medical or recreational cannabis use will soon have had those laws on the books long enough to study their fiscal impact in detail. For now, we know that Colorado, Washington, and Oregon (where marijuana has been legal the longest) have seen a total of $1.3 billion in tax receipts related to marijuana sales so far. Perhaps even more important, legalization would likely eliminate the need for a criminal production and distribution network, along with its violent and antisocial consequences. Again, as time passes in the states that have already legalized, we will learn more about the social impacts of legalization.

On the other hand, marijuana is not harmless, as some of its proponents would claim. Just because it may not be as harmful as other drugs that are now legal does not mean it should go unregulated. It has relatively long- lasting effects after even a single dose, it may carry significant risks for adolescent users, and the jury is out on whether it produces brain damage, or whether smoking combustible marijuana increases the risk of lung cancer. As cannabinoid “vaping” systems become more and more popular, there are also questions about the possible health effects of the various components of the vapor, other than THC. (See the Nicotine chapter for a discussion of vaping systems in general) Finally, despite its benign profile relative to other drugs, marijuana is currently illegal in many states, and that label alone is a difficult obstacle to overcome in the public (and political) mind.

So, the debate remains open and passionate, but our guess is that the twenty-year trend toward decriminalization and legalization of marijuana and

cannabis products will continue—maybe more rapidly now that so many states have already legalized it for medical or recreational use.


Before closing this chapter, we need to address the rising use of a group of drug mixtures that are often referred to broadly as “synthetic” marijuana. There are nearly two hundred chemical mixtures that have been marketed as “synthetic marijuana,” but they are definitely not marijuana from a chemical standpoint and have many effects that marijuana does not (most of them quite bad). These chemical mixtures go by many names, including Spice, K2, fake weed, Yucatan Fire, Skunk, Moon Rocks, Black Mamba, Mr. Smiley, Incense, and Blaze. In fact, in addition to the varied chemical compositions, there are nearly seven hundred street names for these chemicals, so trying to assess safety by the name of the product is impossible. They contain any number of different psychoactive compounds, including cannabinoids, though they do not contain marijuana, per se—thus, the term synthetic. Indeed, part of the problem with these drugs is that it is impossible to know what is in the mixture, and the specific chemicals and their amounts vary in each batch, so the actual chemical makeup of any given product is always a moving target. Users are essentially playing a game of “drug grab bag” when they take it. Although the packaging of these drugs often states that the contents are “natural,” and they do contain dried plant material, the truth is that their active ingredients are synthetic compounds. Another problem is that the cannabinoids these drug mixtures contain generally bind with the brain’s natural cannabinoid receptors either more powerfully or in different ways than THC or the other natural cannabinoids, and this can lead to far more powerful effects. As we discussed with respect to the newly emerging medical uses of marijuana, our understanding of the cannabinoid receptors in our bodies is just beginning to be understood. There are still a lot of unknowns. So when you start messing around with those receptors with new and very powerful compounds, bad things can happen and the user can be in for a wild and very dangerous ride.

Sometimes users of these drugs report experiences that are similar to those produced by marijuana, such as relaxation and changes in perception, but they also often report very dangerous effects like paranoia,

hallucinations, extreme anxiety, agitation, suicidal thoughts, and confusion. Vomiting, rapid heart rate, increased blood pressure, and decreased blood supply to the heart are also observed. There have been multiple reports in the media of users ending up in hospital emergency departments with such extreme symptoms, and some have attributed death to the use of synthetic marijuana. One recent study indicated an annual rate of 28,500 ER visits linked to the use of these drugs. Interestingly, 70 percent of these were for male users and 30 percent for females, and the majority of the ER visits (78 percent) were by adolescents and young adults (ages twelve to twenty-nine). It is very hard to know, however, what actually caused the symptoms in those patients, because many of the compounds that are found in the drugs are so new and so unusual and new ones emerge so rapidly on the market that the usual hospital toxicity screens do not even look for them. So, many times it’s not until the patient is stabilized, or a friend comes forward with information, that anyone even knows what the person took. This can lead to an emergency department guessing game that is in nobody’s best interest. The bottom line on these drugs is that it’s probably best to steer clear.



Drug Class: No specific class—prescription and nonprescription medication for smoking cessation. Legal for use in any form by adults.

Individual Drugs: tobacco, nicotine gum, nicotine skin patch, chewing tobacco, snuff, cigarettes, cigars, pipe tobacco, e-cigarettes, MODs

The Buzz: Nicotine is a specific kind of stimulant that increases attention, concentration, and (possibly) memory. Many people also report that nicotine has a calming or antianxiety effect as well.

Overdose and Other Bad Effects: Dangerous overdose from nicotine is quite rare, but it is possible. A serious overdose would cause tremors (shaking) and seizures that could paralyze muscles needed for breathing, and kill a person. Less serious nicotine poisoning results in dizziness, weakness, and nausea, which disappear as the drug is eliminated. Many people experience such side effects when they first smoke, vape, or use nicotine gum for the first time in a smoking-cessation program (the gum delivers quite a bit more nicotine than a cigarette).

As with many drugs, nicotine reaches the fetus in a pregnant woman and can cause permanent damage. If the mother smokes, then many of the bad effects specific to smoking also impact the fetus.

Dangerous Combinations with Other Drugs: Nicotine powerfully stimulates the heart and circulation. It can cause problems in combination with other drugs that increase heart rate or blood pressure or that reduce the oxygen-carrying capacity of the blood. Nicotine and cocaine taken together put far more stress on the heart than either drug alone does. This combination increases the risk of sudden death from heart attack.


A Brief History
How Nicotine Moves through the Body

Getting In Getting Around Getting Out

Is Nicotine Addictive? Reinforcement


W ithdrawal
Subjective Effects
Effects on the Brain and Mental Function Smoking and Emotional Function
Effects on the Heart
Secondhand, Thirdhand, and Sidestream Smoke Prenatal and Postnatal Effects
Health Risks of Smokeless Tobacco
Vaping: “MODs” and “ENDS”

Vaping and Teens
“ENDS” Facts and Figures


Like many drugs that are used recreationally today, nicotine has a history of being used as medicine. In the 1500s tobacco was used to treat a number of ailments, from headaches to colds. So revered was tobacco for its medicinal properties during that time that it became known as a holy plant. In 1828 French chemists isolated the active ingredient in tobacco and called it nicotine, after Jean Nicot, the French diplomat who brought tobacco from Portugal to France. Although tobacco continued to enjoy rave reviews from some quarters for its supposed medical properties, others were beginning to voice the concern that it might be bad for people’s health. By the 1890s nicotine was no longer a compound prescribed as medicine in the United States.

All this was before smoking tobacco became at all popular in the United States. In the mid-1800s the vast majority of tobacco factories produced chewing tobacco rather than tobacco for smoking. It was not until the early 1900s that smoking began to replace chewing, at first in the form of cigars, which provided a transitional opportunity to both chew (the cigar is often left in the mouth, allowing nicotine to be absorbed orally) and smoke at the same time.

Cigarettes did, however, catch on, and per capita sales of cigarettes to adults in the United States reached a peak in the early 1960s when about 40 percent of US adults were smokers. Since then smoking has decreased to about 16 percent of the adult US population. This decline is likely due to compelling research showing that smoking causes cancer and other health problems; the use of these research findings in truthful and believable public educational campaigns about smoking; and the ban on TV advertising for cigarettes.

But there are some other factors that are associated with smoking. We now know that there is a clear relationship between educational level and smoking—the more educated the person, the less likely she or he is to smoke. The percentage of college graduates who smoke cigarettes is about a third the percentage of smokers among people who have not attended college, and in general men (18 percent) are slightly more likely than women (14 percent) to smoke. According to recent statistics, daily smoking increases steadily with age, from 2 percent among eighth graders to over 9 percent among twelfth graders, and it increases markedly after that as well. Data from the US Centers for Disease Control indicate that people forty-five to sixty-four years

of age are the most likely to be smokers (18 percent), though people twenty- five to forty-four are close behind at 17.6 percent. It is a sad irony that smoking is higher among adults living below the poverty level (25.3 percent) than among those who do not live in poverty (14.3 percent), because the cost of cigarettes has gotten quite high—averaging more than $6 per pack across the United States.

Why do people still smoke, and why is smoking initiated so often by young people? We don’t know, but it could be a combination of effective non-TV advertising and the sense among many young people that they are not vulnerable to the adverse health effects of cigarettes. They may have a parent or other relative who has suffered those ill effects but believe that those are “old people.” This is a tough point to argue with because the negative health effects are relatively far off for the young smoker. But the young person will get older, and the time will come when health decisions made in high school may have a powerful impact on quality of life. Nicotine is clearly an addictive drug, and it appears that people who start smoking as adolescents put themselves at very high risk for addiction. In fact, almost all addicted smokers started as adolescents. In studies involving rats, nicotine caused adults to decrease their activity level but did not have the same effect on adolescents. Because rats are quite sensitive to their internal state and tend to become less active when they experience something that is threatening or potentially dangerous, it appears that the adolescents experienced less of the aversive effects of the drug than did the adults. Consistent with this interpretation are the findings of an important study that showed that adolescent rats will self-administer far more nicotine than adults when given the opportunity. Perhaps the adolescents like the reinforcing effects of nicotine more, they experience fewer negative side effects, or both. The bottom line for humans is that by the time a young smoker begins to think about the future or feel some of the ill effects of smoking, addiction is probably in place. Quitting is then a problem—not impossible, but a problem.


The speed and efficiency with which nicotine enters the blood and is transferred to the brain depends very much on how it is administered. When a person smokes tobacco, or inhales nicotine using an e-cigarette or MOD, the nicotine is absorbed very rapidly into the blood through the lungs and passes within seconds to the brain. The amount of nicotine in a typical cigarette is enough to kill a child or make an adult very sick, but because not all of it gets into the blood through the lungs—most of it is lost in exhaled or uninhaled smoke—a cigarette does not threaten an overdose.

If a person takes nicotine by mouth in the form of snuff (smokeless tobacco), the absorption of nicotine may be more complete than it is with smoking, but the dose is delivered over a much longer period of time. For example, the typical dose of nicotine from a cigarette is about one milligram. However, a plug of snuff maintained in the mouth continuously for thirty minutes delivers a dose in the three- to five-milligram range. The mucous membranes of the mouth are a good site for absorption because a lot of blood flows nearby, but the process is still much slower there than it is in the lungs. So, while snuff delivers a larger total dose over time than a cigarette does, they both result in about the same peak concentration of nicotine in the blood.

Nicotine gum delivers less nicotine than snuff. Even if it is chewed for thirty minutes continuously, nicotine gum generally delivers only about 1.5 milligrams of nicotine. Several tobacco companies have developed tobacco- free oral nicotine delivery devices. One, called “Verve,” is a spit-free, oral “disk” that the user either chews or holds in the mouth for ten to fifteen minutes. It contains nicotine and mint flavoring, but no tobacco. As smoking has diminished across several decades in the United States, tobacco companies have done research that indicates that about 30 percent of adult smokers are interested in smokeless products, but many of them are not comfortable with chewing tobacco or snuff, so the companies are designing more creative tobacco-free nicotine products that can deliver nicotine orally. Regardless of the specific oral delivery system, if the nicotine is getting absorbed from inside the mouth, its route into the body will be the same.

Cigars present an interesting case in nicotine absorption, because generally the smoker doesn’t inhale. Although some of the smoke still makes it to the lungs, most of it comes into contact with membranes in the mouth and upper airways, across which nicotine can be absorbed. How much nicotine gets absorbed through the direct contact of the cigar tobacco with the mouth

depends largely on the style of smoking. Those folks who stick a cigar in their mouth and leave it there until the end looks like the end of a dipstick from an old lawn mower engine will absorb much more nicotine through the mouth than those who hold the cigar in their hand and puff intermittently.


Once nicotine is absorbed, how is it distributed? Again, this depends on how it is taken. Smoking a cigarette results in a peak concentration in the lungs, blood, and brain within about ten minutes. But these concentrations decline rapidly as nicotine is redistributed to other body tissues. Twenty minutes after smoking, the nicotine concentration in the blood and brain is down to half of what it had been just ten minutes earlier. With snuff the distribution is slower, but the peak nicotine concentrations are quite similar to those obtained after smoking a cigarette.


Studies on animals that have very closely followed the concentrations of nicotine in the brain have shown very high levels five minutes after administration, declining to near nothing thirty minutes later. Nicotine’s rapid absorption from the lungs, coupled with this pattern of distribution to the brain, allows the smoker a lot of control over the peaks and valleys of nicotine exposure. In this sense, cigarettes offer a very effective drug- delivery system.

These characteristics also set up the smoker for addiction in two ways. First, nicotine’s rapid route to the brain provides a quick and potent hit. Second, the rapid redistribution out of the brain means that the brain areas that control the behaviors associated with smoking are ready for more nicotine soon after the smoker finishes the last cigarette. After nicotine is absorbed and distributed throughout the body, the liver breaks most of it down into two inactive metabolites: cotinine and nicotine-N-oxide. The kidneys eliminate these metabolites through the urine. Cotinine is the marker used in urine screens for nicotine because it stays in the body for several days.


Yes. Any honest and thorough appraisal of the scientific and medical literature on nicotine must conclude that this is a drug that causes physical dependence and addiction. At least three related lines of evidence lead to this conclusion.


In the language of psychology, a reinforcer is something that motivates an individual to work toward getting more. Nicotine is known to promote the release of the neurotransmitter dopamine in brain regions that mediate reinforcement (see the Addiction and Stimulants chapters). It is not surprising, then, that laboratory animals will work for nicotine. When rats have the opportunity to press a bar to self-administer small doses of nicotine, they will do so. And, as we noted, adolescent animals will do this much more than adults.

Humans, too, will work for nicotine once they have been smoking for a while. In fact, all smokers do, given that they spend their money on cigarettes. The willingness to work for them was typified in an old advertisement for cigarettes that centered on the phrase “I’d walk a mile for a Camel.”


Studies have demonstrated the rapid development of tolerance to the effects of nicotine. When people begin to smoke, they experience a range of rather unpleasant effects, such as dizziness or nausea, but these disappear over days or weeks as the smoker continues to smoke. Tolerance to other effects of nicotine develops even more rapidly. For example, when a group of smokers was given two equal doses of nicotine sixty minutes apart, they experienced more pronounced elevations of their heart rates and reported greater subjective effects from the first dose compared to the second.


On reporting for his first morning of smoking-cessation treatment after a required day of abstinence, one of my patients summed up his feelings by saying, “I want to hurt something.” As I scanned the room for sharp objects, I realized that he was in nicotine withdrawal. Although not all smokers are so

extreme (or honest) in their feelings soon after quitting, most report powerful cravings and irritability during the first two to three weeks after their last cigarette. These are clearly symptoms of withdrawal.

As with tolerance, withdrawal from nicotine has both short- and long- term aspects. For example, most smokers report that their first cigarette of the day is the one that makes them feel best. This effect can be seen as the termination of a mini-withdrawal after the overnight abstinence.


Although nicotine, particularly as administered by smoking, is clearly addictive, it also clearly differs from many other addictive substances. It lacks the obvious mind-altering effects of alcohol, stimulants, or opioids. People don’t use nicotine because it provides a rush or a high. Rather, most users report that it calms them and reduces anxiety. But even these effects are more complicated than they may seem.

Because the vast majority of nicotine users obtain it by smoking, we should consider smoking as a particular kind of drug delivery. Many people derive considerable comfort and calming from small personal habits or rituals—such as tapping a foot or humming to themselves—and many such habits become associated with nicotine delivery during smoking. Lighting up, holding the cigarette, moving it to and from the mouth and puffing—any or all of these small rituals could calm the smoker in and of themselves and become associated with the pharmacological effects of nicotine. The use of e-cigarettes or MODs—which deliver nicotine but contain no tobacco— involves many of the same habits associated with smoking and delivers nicotine to the lungs like cigarettes do. So the experience is very much like actual smoking—without the smoke, or most of the seven thousand or so chemicals that are released when tobacco is burned. Adding these habits to nicotine delivery makes it hard to determine what role the nicotine alone plays in the reported calming effect. Another consideration is that the people who report the antianxiety and calming effects of smoking are most often people who have been smoking for a while. Thus, it is hard to know whether the calming is a primary effect of nicotine or simply the reduction of an addicted person’s craving.

Another commonly reported effect of smoking is the suppression of appetite. Again, it is not clear if this effect is principally due to the nicotine or the smoking, but animal studies show that nicotine can reduce eating when it is given in the absence of smoke. In humans, smoking one cigarette has been shown to diminish hunger contractions in the stomach. It is also possible that the appetite is suppressed in part because smoking reduces the function of the taste buds in the mouth. Other possibilities include the effects of smoking on energy metabolism and blood-sugar levels. The fact is that we do not know exactly why smoking suppresses appetite, but it seems clear that for some people it does. Of course, there is another side to this coin: when smokers quit smoking, their appetites often increase and they gain weight. This could be due to the effects of the physical withdrawal of nicotine from the system or to the need to replace the oral habits associated with the act of smoking.


Before the 1980s, it was not at all clear how nicotine affected the brain. We now know that nicotine stimulates a specific subtype of receptor for the neurotransmitter acetylcholine—the nicotinic acetylcholine receptor. These receptors are distributed rather widely on nerve cells throughout the brain, so nicotine has effects on a wide variety of brain structures. In general, it excites nerve cells and increases cell-to-cell signaling. Several studies have shown that nicotine increases the activity in brain regions that are associated with memory and other mental functions, as well as in some structures involved with physical movement.

When acetylcholine receptors in the brain are blocked, animals (and people) have a difficult time remembering new information. Conversely, some reports show that stimulating these receptors improves memory somewhat. Because nicotine promotes the release of acetylcholine and also activates its own subtype of acetylcholine receptors, some investigators predicted that nicotine might enhance memory function. This appears to be generally true in studies with animals, and a number of studies have been undertaken to determine whether nicotine can help patients with memory deficits, like those with early Alzheimer’s disease. In such studies researchers generally administer nicotine either by injecting it or by using a

patch that allows it to be absorbed slowly through the skin. Although it’s still uncertain whether nicotine may be of use to Alzheimer’s patients, some convincing studies show that nicotine does improve some mental functions for at least a brief time after its use. In a study that used the nicotine patch, patients with mild to moderate Alzheimer’s disease showed increased attention while exposed to nicotine.

This does not mean, however, that a person should smoke cigarettes or chew nicotine gum while studying or during an exam or other activity that demands concentration or memory. The carbon monoxide in the cigarette, combined with the lack of oxygen exchange in the lungs due to the smoke, would likely lead to other side effects, such as dizziness, which could easily overpower any potential attention- or memory-enhancing effects of the nicotine. In addition, chewing nicotine gum often delivers enough nicotine to make even experienced smokers feel nauseated the first time or two.

Another potential medical use for nicotine is in the treatment of adult attention deficit/hyperactivity disorder (ADHD). Although work on this problem is not extensive, one study indicates that nicotine patch treatments reduce ADHD symptoms in both smokers and nonsmokers. When nicotine patches were used for four weeks, the capacity for attention in both children and adults with ADHD was improved.

Nicotine may also prove helpful in people with schizophrenia—not as a treatment for the psychotic symptoms but rather as an aid for cognitive function. Schizophrenics often suffer learning and other cognitive deficits that are likely due to impaired nicotinic receptors in the hippocampus. The thinking is that if nicotine is given, it will make up, in part, for that deficit in the function of the hippocampus and thus improve cognitive function in the patient. Although further research is required to form conclusive takeaways on this topic, there is some compelling evidence that nicotine may indeed diminish some cognitive deficits in adult schizophrenics.

Although these studies appear promising and may lead to more effective treatments for these disorders, it is critical to remember three things. First, the studies we mentioned have not yet led to any approved medical uses for nicotine beyond its approval for use in smoking cessation. Second, several of the studies have involved injections of nicotine, which, of course, should never be undertaken without medical supervision. Third, those results should

never be interpreted as a reason to smoke. The health costs of smoking far outweigh any potential health benefits of nicotine.


Depression is a common problem among adolescents. As many as 15 to 20 percent of adolescents may become depressed at some time during this period. Smoking has generally been regarded as a consequence of depression in young people, but it may be that smoking leads to depression in some. It turns out that adolescents who are smokers are twice as likely as nonsmoking adolescents to suffer an episode of major depression, and that teens with long-term depression are more likely to be smokers than teens without depression. We also know that depression at the age of fourteen predicts smoking progression as teens age from fourteen to eighteen. This suggests that increased smoking during the teen years could represent a form of self- medication for depression. Although these findings do not tell us why a teen smoker is more likely to become depressed or vice versa, they may provide valuable warning signals. A young person who has problems with depression may be at higher risk than normal for smoking, and it may be wise for such people to take special care to avoid situations in which smoking is prevalent. Likewise, a teen who smokes may be more susceptible to depression and should watch for early signs of it so that antidepressant treatment can be started, if necessary. It is not clear whether some of these factors related to adolescence and depression may be at play in motivating teens to vape nicotine. Like many of the questions about vaping, there is simply not yet any reliable research upon which to base conclusions.


It is well known that smoking causes lung cancer and other chronic lung diseases. What is less well known is that smoking also contributes to diseases of the heart and vascular system, which actually kill more people in the United States annually than any cancer. Nicotine affects the heart in several ways. The heart is a big muscle, and like all muscles it needs a rich supply of oxygen to do its work pumping blood throughout the rest of the body. When nicotine is in the system, it results in the release of adrenaline,

which increases heart rate and blood pressure. The heart then needs more oxygen to increase its workload, but its oxygen supply doesn’t increase, so it must do extra work with no extra help.

What’s worse, the carbon monoxide in smoke also decreases the ability of the blood to carry oxygen, making the situation even more stressful for the heart. Repeatedly stressing the heart in these ways leads to damage and compromises its function. Cigarette smoke is also directly toxic to the inner lining of the blood vessels. Something in the smoke makes them hard and inflexible, adding to the cardiovascular problems. It is estimated that as many as 30 percent of the deaths attributed to heart and vascular disease relate to smoking.

All of these negative effects on heart and circulatory functions may have another, less dangerous but unwanted effect. Smokers develop thinner skin. Over 20 years ago, a study of identical twins in which one twin smoked and one did not showed that the smokers had skin that was thinner than that of their twin siblings. Investigators think that this may be why some smokers tend to have more wrinkles and look older than they are. One possible explanation for this effect on the skin is that smoking can decrease the blood supply to the topmost layer of the skin and thus damage it.


There are two sources of smoke from cigarette smokers: the smoke they exhale (secondhand) and the smoke rising off the lit cigarette, cigar, or pipe itself (sidestream). It is worth knowing that sidestream smoke has a higher concentration of carcinogens than either secondhand smoke or the smoke that a smoker takes into his lungs through a cigarette filter. Whatever the source, smoke can cause disease. The Environmental Protection Agency, after considerable study of this issue, determined that secondhand smoke is indeed a carcinogen in and of itself and is responsible for a significant number of lung cancer deaths each year in the United States. Of course, the amount of exposure to secondary smoke is a critical factor in the risk of developing lung disease (as is the smoker’s own amount of exposure), and a few parties in smoky rooms will probably not kill anyone. However, people who spend a lot of time in smoky places, like bars, or who live with smokers are clearly placing themselves at some risk for lung disease.

The effects of secondhand smoke on the development of heart disease are even more alarming. We’ve known for over twenty years that regular exposure to secondhand smoke can double a person’s risk of heart disease. The study that showed this effect looked at more than 30,000 women and suggests that as many as 50,000 people may have been dying at that time in the United States as a result of heart attacks related to secondhand-smoke exposure. Of course, smoking has decreased since then, and most public places are now smoke-free, but the problem of secondhand smoke persists in smokers’ homes and other private spaces where people smoke.

In enclosed areas where smoking occurs, the residue of the nicotine on surfaces can react with normal chemicals present in the air to create carcinogens that are found in tobacco. This toxic feature is referred to as “thirdhand” smoke, though obviously it is not smoke per se. The actual health risks of such residues are not clear. But some public health researchers are concerned that toddlers and young children may be at greater risk of exposure because they are more likely than adults to touch and explore surfaces and put their hands in their mouths or eat without washing their hands first.


As with most psychoactive drugs, nicotine passes to the fetus in the blood of the pregnant woman who smokes (or otherwise uses nicotine). Babies born to smoking moms have been shown to have levels of cotinine in their urine that are nearly as high as those of active smokers. As time passes after birth and their nicotine levels fall, these babies show symptoms of nicotine deprivation. The pregnant smoker also passes along cyanide and carbon monoxide to her baby, both of which are very bad for the developing fetus. Remember that carbon monoxide reduces the ability of blood to carry oxygen and thereby depletes body tissues of oxygen. Also, nicotine constricts blood vessels bringing blood to the fetus, further limiting oxygen supply. In the fetus, this oxygen depletion is thought to account for the fact that babies born to smoking mothers are smaller, lighter, and have smaller head circumferences than babies born to nonsmoking mothers. In addition, as with alcohol, smoking during pregnancy likely has lasting (perhaps permanent) effects on the brain and mental function of the child after birth. Some studies have linked maternal smoking with difficulties in verbal and mathematical

abilities and hyperactivity during childhood. There’s also a greater likelihood of nicotine addiction in adulthood for people whose mothers smoked during their pregnancy. Interestingly, maternal smoking did not change the likelihood of people trying cigarettes, but it did significantly increase the chances of them becoming addicted if they did initiate cigarette use. This finding may suggest that while experimenting with smoking may be driven largely by social forces, the liability to addiction may be tied more closely to specific biological characteristics.

Once a baby is born, an immense amount of brain development is still going on. Exposure of babies and small children to secondary smoke should also be avoided. For example, some studies have suggested that there is an increased risk of sudden infant death syndrome (SIDS) in babies of smoking mothers and that this could be due to smoke in the environment. It is also possible that this could be due to damage that the baby suffered before birth due to the mother’s smoking or to the combination of prenatal and postnatal exposure.

Studies also indicate that the children of fathers who smoke are more likely to develop childhood cancers than the children of nonsmoking dads. Based on the Oxford Survey of Childhood Cancers, the study of some three thousand parents showed that fathers who smoked twenty or more cigarettes per day had a 42 percent increased risk of having a child with cancer and that those who smoked ten to twenty cigarettes per day increased the risk by 31 percent. The risk was increased by 3 percent for fathers who smoked fewer than ten cigarettes per day. These results suggest that smoking may damage sperm in ways that could lead to cancer-causing alterations of the DNA.

The message is very clear—babies are best raised in a smoke-free environment.


We should also stress that the chewing of tobacco and snuff represent significant health risks in their own right. In addition to the nicotine they deliver, their prolonged use can increase the likelihood of cancers of the mouth and esophagus. Many users develop thickening lesions in the mouth that may develop into cancer of those tissues. Smokeless tobacco also causes gum disease, which can result in inflamed and receding gums and can expose

the teeth to disease. In addition, because smokeless tobacco products generally contain very high amounts of sugar, they also promote the development of dental cavities. In short, smokeless tobacco is not a safe substitute for smoking.

It is also not a good “performance-enhancing” drug for athletes, though a lot of them use it that way. Many young people believe that the nicotine in smokeless tobacco products increases their physical reaction times and the power of their movements in various sports like baseball, track and field, and football. This is actually not true. There is no evidence of significant gains in reaction time, and there are studies that indicate that nicotine actually decreases the speed and force of leg movements during reaction-time studies. Its negative effects on heart function also argue against the use of nicotine during athletic activities.


Not so many years ago, the prevailing wisdom was that the ability to quit smoking was a matter of simple willpower. This attitude implied that smoking was not really an addiction, that no special techniques were required for quitting, and that anyone who could not quit simply lacked the internal fortitude to do so. We now know that none of this is true. Nicotine is an addictive drug, and quitting is a complicated change of behavior that is not easy.

Many former smokers report having quit on their own, but there are also plenty of treatments available to help. Unfortunately, there is no one treatment that works for everyone. Probably because the behavioral habits of smoking are tied up with the physiological addiction to nicotine, many people require a number of different treatment strategies to address the whole problem. On the behavioral side, these can include educational counseling, group or individual smoking-cessation training, hypnosis, or stress-management training. On the medical side, they can include the use of nicotine chewing gum or nicotine skin patches. Also, a medication called Zyban, which is also used as an antidepressant under the name Wellbutrin, is sometimes used as one component of smoking-cessation programs, and a number of other drugs are being actively studied or are in initial clinical trials. One of the drugs approved for use in smoking cessation is Chantix, and while it’s not a magic

bullet for quitting, it is helpful as part of a broad approach to cessation. It interacts directly with one of the subtypes of nicotine receptor in the brain and has been shown to help reduce nicotine cravings after one quits smoking.

Some of the clinical trials of innovative ways to help smokers quit have revealed some interesting twists that might be of great value. It turns out that starting nicotine replacement therapy (the patch, specifically) a couple of weeks before the planned “quit date” can increase the likelihood of successfully quitting. Studies sponsored by the National Institute on Drug Abuse have demonstrated this, and ongoing studies are looking for the optimal time at which therapy should begin relative to the quit date. Other studies are exploring the value of taking a flexible view of which medications to use, and when, in the quitting process. Some people have more success than others with different treatments, and current studies are looking for the best ways to “rescue” smoking-cessation patients who are not having success with one approach by replacing it with another at just the right time in the quitting process.

These findings have given rise to a new approach to smoking cessation, called “adaptive treatment.” The core concept is simple—not every smoker is the same, and so treatments need to be adapted to the specific characteristics of the addiction presented by each patient. Some smokers (about 20 percent) are very highly physically dependent on nicotine and may need higher doses of medications, multiple medications, or higher- concentration patches to get through the initial stages of quitting. Quite a few smokers who relapse after quitting do so in reaction to stresses in their lives. So an effective treatment program will identify stress reactivity early on and adapt to these patients’ needs by providing stress management treatments in conjunction with their initial quit attempt rather than wait for a relapse to derail them. These are just two examples of specific needs that smokers may have. Ongoing research is aimed at finding ways to fine-tune the adaptive treatment process and give patients their own personal best chance for success.

As smoking-cessation treatments become more sophisticated and the options for treatment multiply, it becomes more and more valuable to seek professional consultation about quitting. The best first step to quitting is to get a referral from a physician, psychologist, or pharmacist to an established smoking-cessation program. Sometimes these are run in hospitals or clinics,

but they may also be operated as part of a community mental health clinic or by a private practitioner. In North Carolina, for example, there is an intensive training program available for professionals who wish to become certified as tobacco treatment specialists. The training is quite broad and focuses on the medical, psychological, and social aspects of tobacco addiction. As training programs of this type spread, they will enable patients to identify providers who are specifically trained to provide effective cessation treatment.

The bad news is that even though treatments are evolving rapidly, and will continue to get better, nicotine addiction is a tricky problem, and many people return to smoking within six months. It appears that programs that use multiple approaches (like the adaptive model we described) have a somewhat better record of keeping people off cigarettes longer than single- method programs do. Still, many people in multiple-approach programs return to smoking within a year. Why is this the case? We’re not sure, but it probably has to do with how much behavioral habit the act of smoking involves, and how many places, people, and things out in the real world the smoker has associated with the act of smoking over the years. The very uncomfortable cravings for nicotine diminish rapidly, within days of quitting, and nicotine gum or skin patches can help during this time. The first few days are clearly the worst, but most people report that by about two weeks the cravings are mostly gone. What remain are all the cues that used to be associated with smoking—the morning cup of coffee, the evening beer, the talk with a friend on a break at work (the list can go on and on).

These are powerful stimuli that can exert considerable control over behavior. Many people will report that they felt well on their way to really kicking the habit when an old friend with whom they used to smoke came back for a visit, or that they went back to a bar where they used to smoke and drink and have fun, and before they knew it, the cigarette was back in their hand. A smoking-cessation program must anticipate these situations and provide strategies for dealing with them before they lead to relapse. It’s a valuable help to schedule follow-up sessions to talk such things over, learn strategies, and get support. This can be particularly helpful for people who smoke to manage their stress, a characteristic that can easily be identified in an initial clinical interview before the person sets a quit date. One final point on quitting: if at first you don’t succeed, try again. Every person is different and every addiction is different. If trying on your own did not work, a

treatment program might. If one treatment program did not work, a different one might. Enough types of help are available that there is a good chance one will work for any motivated person who wants to quit smoking.


Before leaving the topic of the behavioral and environmental cues that perpetuate smoking and challenge those who try to quit, it’s important to discuss e-cigarettes and other devices that deliver nicotine vapor. The term that lumps these devices together for convenience is Electronic Nicotine Delivery System, or “ENDS.” The term e-cigarette generally refers to a type of ENDS that has the general appearance of a cigarette. Similarly shaped ENDS are also called “vape pens.” Some e-cigarettes look very much like cigarettes, right down to the red LED that turns on and looks like a glowing cigarette ember when the user draws air into it. A sensor turns the device on when the user creates a drop in internal pressure by taking a drag. Powered by a rechargeable battery, an atomizer converts liquid nicotine (mixed with other chemicals and flavorings) into a warm mist, allowing it to be drawn into the lungs. The user then exhales a mist that looks a lot like smoke. But ENDS come in many shapes and sizes, and they can look like anything from a tiny thumb drive to a giant bong. The term “MOD” often refers to a larger and more powerful form of a vape pen that has been modified, but the smaller devices are also often referred to as MODs. Whatever you call them, they are efficient devices for delivering nicotine into the lungs (as well as into the mouth, esophagus, and stomach, by the way), and have become quite popular, particularly among young people.

The reason we chose to discuss ENDS in the context of smoking cessation is that they were initially developed with smoking cessation in mind—as a possible tool to help people quit smoking. The idea was that a nicotine delivery system that mimicked the behavioral actions of smoking might be a better cessation tool than a nicotine patch or gum, because it would allow the smoker to continue engaging in smoking-like behaviors and also deliver some nicotine to blunt the effects of nicotine withdrawal after quitting smoking. So, are ENDS helpful for smoking cessation? We don’t know yet. There are lots of people getting lots of media attention on both sides of the argument, but the truth of the matter is that the research has not

been done well enough yet to say for sure whether ENDS are helpful for smoking cessation. Some studies show helpful effects of ENDS for smoking cessation, indicating that they are more effective than earlier nicotine replacement therapies like skin patches, while other studies show no effects. For better or worse, we’re just going to have to wait for research to address this question thoroughly. Meanwhile, ENDS are not formally recommended for use in smoking cessation clinics, though many people use them on their own for that purpose.

But if we put aside the question of smoking cessation, do ENDS have value as a smoking alternative? There are a lot of angles to this issue, but if we look at it purely from the standpoint of harm reduction in current smokers there’s an argument to be made for ENDS. They deliver nicotine, which is addictive, of course, but it does not cause cancer (there are vaping systems that do not deliver nicotine, but the vast majority that are used do contain it). A striking number of people in the United States believe that nicotine causes cancer, which it absolutely does not. Cigarette smoke contains about 7,000 different chemicals, and 70 of them cause cancer. Nicotine is not one of those 70 cancer-causing chemicals. By contrast, the vapor that is produced by ENDS has far fewer chemicals, but they can include certain flavorings and some trace metals that can be bad for lung function. Benzene (a carcinogen) is also found in the vapor of some ENDS, though in far lower concentrations than in combusted tobacco products. Of course, nicotine, no matter how it’s delivered, still has its effects on heart and blood vessel function, though with ENDS these effects are not compounded by the effects of carbon monoxide, as they are with combusted tobacco.

So ENDS are clearly not harmless, and they do contain some chemicals that would be best left out of peoples’ lungs. But ENDS are not all the same, and they are evolving rapidly. It may be that as newer generations of ENDS hit the market, they can be made even less potentially harmful. To give an idea of the ambiguous state of our current understanding, a 2016 surgeon general’s report stated that ENDS vapor contains some chemicals that may represent a threat to health, while a 2018 report from the American Cancer Society states that although the long-term effects of ENDS are not known, current-generation ENDS are markedly less harmful than combustible tobacco products. The American Cancer Society also called for more studies to assess the potential for ENDS as smoking cessation aids. Clearly those

who have studied the issue believe the potential is there and that, relative to cigarette smoking, ENDS are far less harmful.

Some would argue that even if ENDS don’t turn out to help people break the nicotine habit, they may have value as a smoking alternative. The idea is that if ENDS are less likely to cause cancer and lung disease than cigarettes, why not switch? But there are concerns about people starting nicotine addiction through e-cigarette use: e-cigarettes could serve as a “gateway” to smoking for those who have never smoked, or as a path back to smoking for those who have quit. Once a person becomes addicted to nicotine, it might be easy to slip from e-cigarette use into (or back into) smoking. If that were the case, then e-cigarettes would clearly be causing great harm. On the other hand, if ENDS turn out to be safe (or future generations of them are made with safety as a priority), turning smokers into “vapers” could improve people’s lives and public health markedly—not to mention saving our health- care system lots of money that would not get spent caring for people with smoking-related lung disease. We will know more as research studies address this issue.


One public health aspect of ENDS use that needs to be addressed urgently, however, is their use by children and adolescents. Regardless of whether ENDS turn out to have value as smoking alternatives or cessation aids, they should not be used by children and teens, because most of them deliver nicotine, which is highly addictive, and the young brain is still developing and likely more vulnerable to addiction than the adult brain. Because ENDS are essentially unregulated at this point, they can be infused with flavors that would be attractive to children, and built to appeal to young people in the way they look, feel, and function. It doesn’t take much looking to find media reports about schoolchildren sneaking thumb drive–sized ENDS into school to share among friends and even sneak hits in the classroom. Back in the day when kids would sneak cigarettes at school there was always the telltale smoke and smell to give it away. ENDS and vapor are far more stealthy. The most recent surveys indicate that 9.5 percent of eighth graders, 14.0 percent of tenth graders, and 16.2 percent of twelfth graders have used ENDS in the past month, with twice as many boys as girls using them. There are a few studies suggesting that teens who use ENDS are more likely to start smoking

within a year than teens who don’t vape, and those studies have gotten a lot of media attention, but they should be interpreted cautiously because they really don’t account for all the variables involved, and it’s easy to fall into the trap of assuming cause when all that’s really shown is correlation. In other words, just because a certain sample of teens ended up trying cigarettes after using ENDS does not mean that the ENDS use caused the smoking. Plenty of teens smoke, and those subjects might have started smoking anyway. It’s also the case that many who vape actually started out smoking—and some do both—so it’s a very tricky type of research to do. We’re just going to need to see more data, across a wide range of samples, before any firm conclusions can be drawn about whether vaping leads to smoking in teens.


There are currently hundreds of ENDS products available. The early versions were disposable and looked a lot like cigarettes. The more popular models that have been developed since then feature a refillable tank for holding the e-liquid, which is heated by a small battery to produce vapor. The e-liquids can contain varying concentrations of nicotine as well the chemicals that enable the nicotine to be aerosolized (turned into vapor), and various flavorings. Propylene glycol, glycerin, along with flavorings and sweeteners are the usual components of e-liquids. Some people make the mistake of thinking that propylene glycol is the stuff that’s used in antifreeze. It’s not—that’s ethylene glycol. Propylene glycol is an FDA-approved food additive, although it’s not clear whether it is also completely safe when heated and inhaled. It’s also good to remember that ENDS are currently unregulated, and so it’s hard to know the exact contents of any given e-liquid. The nicotine content of vapor varies considerably, generally from 1.2 percent (a little less than cigarette smoke) up to about 5 percent, which is well above the concentration in cigarette smoke. There is a lot of variability in nicotine delivery between ENDS products, and it is wise to check on nicotine concentrations.

There are nearly 8,000 e-liquid flavors available. Since each of these flavors potentially has unique chemical characteristics and can be used in any number of ENDS with different heating and delivery systems, the task of determining safety is extremely complex. Until good regulation is in place,

the use of ENDS will remain a personal decision, and it will be on the users to exercise their best judgment about safety based on the available facts.



Drug Class: Opioid analgesics. Most of the drugs mentioned in this chapter are scheduled by the Drug Enforcement Administration, but they vary from Schedule I (heroin) to Schedule IV (propoxyphene) based on their likelihood of abuse and medical use.

Individual Drugs: Opium, heroin, morphine, codeine, hydromorphone (Dilaudid), oxycodone (Percodan, OxyContin), meperidine (Demerol), hydrocodone (Vicodin), fentanyl (Sublimaze), buprenorphine (Suboxone), propoxyphene (Darvon), Tramadol (Ultram), Tapendatol (Nucynta), diphenoxylate (Lomotil), loperamide (Imodium), desomorphine (Krokodil), Kratom

Common Terms: Chinese molasses, dreams, gong, O, skee, toys, zero (opium); Big H, dreck, horse, mojo, smack, white lady, brown (heroin); speedballs (heroin and cocaine); Oxys, OCs, Hillbilly heroin (oxycodone)

The Buzz: Opioids are drugs that produce effects like those of the opium poppy and its active agent morphine. They can be natural products from the poppy, or synthetic molecules created in laboratories. People who inject

opioids experience a rush of pleasure and then sink into a dreamy, pleasant state in which they have little sensitivity to pain. Their breathing slows, and their skin may flush. Pinpoint pupils are another hallmark of opioid effects. Opioids taken by ways other than injection have the same effect, except that a pleasant drowsiness replaces the rush. Nausea and vomiting can accompany these effects, as well as constipation. An injected heroin/cocaine combination (speedball) causes intense euphoria, the dreaminess of heroin, and the stimulation of cocaine. People who take opioids by mouth experience the same effects, but the pleasure has a slower onset and is less intense.

Overdose and Other Bad Effects: Opioid overdose can be lethal whether users inject it or take pills. This is not a cumulative effect of years of misuse —it can happen the first time. Breathing slows to the point that it ceases. Fortunately, the opioid antagonist naloxone (Narcan) can almost immediately reverse the dangerous effects of opioids if the user gets medical help quickly. Opioid overdoses are most common with injectable forms of a drug or when a user takes opioids from an illegal source that contains a more potent opioid than the user thinks is present (fentanyl instead of oxycodone, for example), but can occur with any dosage form if enough is taken. Medical attention is critical.

Dangerous Combinations with Other Drugs: Opioids are especially dangerous when used in combination with other drugs that suppress breathing. These include alcohol, barbiturates (for example, phenobarbital), Quaaludes (methaqualone), Pregabalin (Lyrica), and Valium-like drugs (benzodiazepines).


Where Opioids Came From
What Opioids Are
How People Take Opioids
How Opioids Move through the Body
Opioid Effects on the Brain and the Rest of the Body How Opioids Work in the Brain

Natural High: Our Own Endorphins Addiction, Tolerance, and Dependence


Even Dorothy of The Wizard of Oz has experienced the effects of opioids (remember the field of poppies?). As we saw in The Wizard of Oz, you pretty much have to lack a brain to resist the effects of opioids. For those with a more classical bent, morphine derives its name from Morpheus, the Greek god of dreams, who was often depicted with a handful of opium poppies. Use of opioids began in prehistoric times, probably with teas prepared from opium poppies. The oldest historical references to the medicinal use of opioids arise from the Sumerian and Assyrian/Babylonian cultures (about five thousand years ago). Opium pipes recovered from archeological sites in Asia, Egypt, and Europe document the smoking of opium between 1000 and 300 BCE. Arab traders introduced opioids to China between CE 600 and CE 900. Paralleling developments in Europe, medical use gradually evolved into recreational use, and the number of opium addicts grew. The importation of opium into China became a major source of trade for England and helped start a war between China and England when China banned its importation in the early nineteenth century.

Use (and abuse) of opioids in Europe was common during the Middle Ages. One agent of its popularity was Paracelsus, who coined the term laudanum—meaning “to be praised”—for an opioid preparation. Later, many poets (Samuel Taylor Coleridge and Elizabeth Barrett Browning, among others) used and abused opium. Coleridge reported an opium experience in his famous “Kubla Khan.”

Opium has been used widely in the United States throughout its history. Immigrants from both Europe and Asia arrived with previous experiences of using opium products, either in the form of laudanum or other “medicinal” preparations, or smoked as opium. Opium was a major ingredient in many of the patent medicines available during the 1800s before the FDA was started, and the average housewife was a major consumer in nineteenth-century

Patterns of Use: Are You a Junkie? Opioid Overdose and Toxicity

Short-Term Effects

Long-Term Effects
Treatment for Overdose and Addiction

America. As in the story of cocaine, the rising availability of increasingly potent preparations led to greater recognition of the drug’s toxicity and addictive qualities.

In 1805 morphine, the major active ingredient in the opium poppy, was purified; in 1853 Alexander Wood invented the hypodermic syringe. The first major wave of addiction to injectable narcotics followed the wide use of injected morphine during the American Civil War. The final improvement came courtesy of the Bayer Company in 1898, when the company’s scientists discovered that adding an extra chemical group onto morphine made it more soluble in fat, so that it would enter the brain faster. This produced heroin, once a trade name for the narcotic produced by Bayer.

Today, opioid drugs are a mainstay of the medical treatment of pain. There just aren’t substitutes for their effectiveness at reducing pain. However, all opioid drugs are addictive. Some doctors so fear addiction in their patients that they withhold needed treatments. This was the reason for the introduction of national programs that rightly promoted the use of adequate medication to treat pain. Unfortunately, this opened the door to the current opioid epidemic. Well-meaning physicians started dispensing more valid prescriptions for strong opioids like methadone, morphine, and oxycodone. In addition, a number of unscrupulous doctors, likely with tacit cooperation from pharmaceutical companies, ran “pill mills” that prescribed these drugs to patients with very little verification of their medical need for such medication. This led to a rapid rise in the total number of opioid pills available and rapidly rising rates of overdose deaths, especially with long- lasting drugs like methadone. Growing public awareness led to action by the medical establishment and legislators to begin to curb excessive opioid prescribing, and the number of valid prescriptions began to fall.

However, a new market now existed, and two trends rapidly emerged. First, some people who could no longer get their opioid of choice, like oxycodone, began to switch to heroin (which was cheaper). Then, other opioid drugs from non-US sources (mostly China, according to the Drug Enforcement Agency) began flooding the market with illegally manufactured derivatives of the drug fentanyl, which were dramatically more potent than oxycodone and heroin. Some of these were manufactured to look like oxycodone, and the rates of overdoses skyrocketed as users who thought they were taking heroin or oxycodone instead took the far more powerful drugs.

The musician Prince may have died from an overdose of fentanyl that he thought was the much less potent prescription drug Vicodin. Fortunately, more widespread availability of the opioid-reversing drug naloxone (Narcan) has saved many lives. However, scientists are still trying to help an expanded population of opioid-dependent people and save more lives that are threatened by potent fentanyl derivatives.


Opioid drugs are any drugs, natural or synthetic, that produce the characteristic opioid effects: the combination of a dreamy, euphoric state; lessened sensation of pain; slowed breathing; constipation; and pinpoint pupils. Current usage has evolved from opiates to the more generic term opioids, which includes drugs resembling the substances in the opium poppy as well as endogenous opioids that serve as neurotransmitters in the brain.

Opium refers to a preparation of the opium poppy (Papaver somniferum). It is obtained in a very low-tech, labor-intensive manner throughout the world. Opium farmers cut the developing seedpod of the opium poppy and collect the gummy fluid that oozes out of the cut over the next few days. The sap is refined in several ways. It may be dried into a ball and used directly (gum opium) or dried and pounded into a powder (opium powder). Raw opium appears as a brown tarry substance. Opium can also be made into an alcohol-water extract called tincture of opium. This is the famous laudanum of your great-great-grandmother’s era, or the paregoric of that age.

Morphine, which is one of the mainstays for pain management, is a major constituent of the seedpod. It is a potent opioid and is used in injectable or pill form to relieve pain after surgery and for extreme pain, such as in advanced cancer. Codeine is a much less potent opioid that is used mainly in pill form for milder pain. Doctors often prescribe it as an acetaminophen- codeine preparation for dental pain or in prescription cough medicine. To compensate for the lower potency of codeine, some drug abusers simply drink an entire four-ounce bottle, which does contain an intoxicating amount. These cough syrups used to be available over the counter until recreational use became too popular. Now most states require a prescription for codeine- containing cough syrups.

Heroin is a chemically modified form of morphine that is created from partially purified morphine, usually in “refineries” close to sites of opium production. It is broken up into small amounts and usually appears on the street in bags of loose powder containing about one hundred milligrams. The color ranges from white to brown to black depending upon the source and quality of the preparation technique. Highly purified heroin hydrochloride is a white powder that is prized for its purity, while heroin at the other end, Mexican “black tar,” is recognized by its black appearance. The user either snorts the powder directly or dissolves it in saline and injects it. The actual composition of the powder depends upon the supplier and can range from 10 to 70 percent heroin with various contaminants, including talc, quinine, and baking powder, making up the balance.

Opium poppies grown in Southeast Asia (Burma and Thailand), Afghanistan, South America (Colombia), and Mexico provide the starting material for illegal heroin that enters the United States. Southeast Asian poppies mostly provide heroin for Europe, although some makes its way to the United States. Heroin production from Afghanistan still represents the majority of worldwide production (tenfold more than the next highest supplier, which is Mexico), but heroin in the United States mainly comes from South America (East Coast) or from Mexico (West Coast) (US Department of Justice National Drug Intelligence Center, Threat Assessment 2015).

The purity of heroin varies widely; the concentration sold on the street can range from 5 percent to 66 percent. In the most recent report from the DEA (from 2015), the average purity in the United States was 30 percent for heroin from South America and about 60 percent for heroin from Mexico. If heroin is just morphine that has been slightly changed chemically, what advantage does it have? In fact, once heroin enters the brain, it is converted back to morphine. However, the improved fat solubility gets heroin into the brain faster. Scientists have made many derivatives of morphine. The original hope was to find a drug that would eliminate pain but not cause tolerance or addiction. That mission has been unsuccessful—all of the effective opioid analgesic drugs are also addictive. However, the attempt has led to many man-made opioids with desirable characteristics for particular clinical uses. There are at least five important opioid analgesics that are either direct products of the seedpod of the opium poppy or minor modifications of it. These chemically modified drugs are widely used in

medicine, and prescription opioid abuse has been a major contributor to the current opioid crisis. Ten times more people abuse prescription opioids than abuse heroin, although rates of abuse and overdose deaths attributed to both have increased dramatically in the last ten years. Therefore, we will spend some time describing them in detail.

Some of the most widely used and abused prescription narcotics are modifications of morphine. These are hydromorphone, oxycodone, and hydrocodone. Hydromorphone (Dilaudid), a very strong opioid, is an effective analgesic that is widely abused. Oxycodone is synthesized from a nonanalgesic chemical in opium (thebaine) and ranks between morphine and codeine in its effectiveness against pain. Its use spread dramatically in the United States during the 1990s due in part to its appropriate use to treat pain and in part due to aggressive marketing of the sustained release preparation OxyContin, factors that led to current widespread abuse. It is also sold in combination with aspirin under the prescription name Percodan. Hydrocodone (Vicodin) is a moderately strong opioid that is also widely abused.

Meperidine (Demerol) is used like morphine for intense postsurgical pain, but it works well even with oral use. Meperidine has a definite downside: it can cause seizures at high doses—a feature that has led to decreased use by physicians in recent years. Methadone is a long-lasting opioid that is taken as a pill. Its unique time course makes it particularly useful for replacement therapy for treating opioid addiction as well as chronic pain. The gradual and mild onset of action staves off withdrawal signs but doesn’t provide a “high.” Its use for these purposes is controversial in some circles: although tolerance and physical dependence clearly develop, it provides safe and effective treatment without the same liability for abuse. One important characteristic of methadone is its very long half-life —it remains in the body for hours. This is a helpful characteristic in suppressing opioid withdrawal and in treating chronic pain. However, it also represents a danger to people who do not follow instructions about its use. Overdose deaths from methadone increased dramatically as physicians began to prescribe it more for chronic pain, and most deaths occurred in people with valid prescriptions, not drug abusers.

Buprenorphine is the other main opioid drug used to treat opioid addiction. It does not activate the receptor as well as other opioids, and so it

is not the first choice for pain, but it does so enough to suppress withdrawal. Since it can cause intoxication if a user takes enough, it is widely prescribed for a variety of abuse-deterrent formulations. These include tablets or films that dissolve in the mouth, but if someone tries to dissolve and inject, then they activate the opioid antagonist naloxone, which triggers immediate (and unpleasant) withdrawal. It is also used in the form of once-monthly injections or implants, additional strategies that are difficult if not impossible to abuse.

Fentanyl (Sublimaze) and its relatives are very fat-soluble, very fast- acting analgesics that anesthesiologists use when they put patients to sleep. Fentanyl is also used in patches that release the drug slowly through the skin to provide more long-lasting pain relief. Its most unusual formulation is a lollipop designed to deliver the drug to young children before surgery. Many addicts use fentanyl in its injectable form, and it is a common cause of overdose. Fentanyl’s high comes on fast and is intense, brief, and just a step away from fatal suppression of breathing. Unfortunately, fentanyl, sufantanil, and a number of novel fentanyl derivatives including 3-methylfentanyl, 4- Methoxy-Butyryl Fentanyl, Acetyl Fentanyl, Carfentanil, Fluorobutyrfentanyl, Flurofentanyl, and others arriving from bootleg laboratories in China have been flooding the illegal market as alternative sources of this very potent opioid.

Then, there is propoxyphene (Darvon). This drug is such a poor opioid that most physicians won’t use it, because clinical studies find it to be no more effective than a placebo. However, some people swear by it, although it’s really little stronger than aspirin.

Tramadol and tapentadol are drugs with multiple actions. Both cause analgesia through opioid effects and blockade of norepinephrine uptake. Tramadol also blocks the reuptake of serotonin, and its opioid actions are weak enough that it has little abuse liability. Tapentadol is a more efficacious opioid and so has some abuse liability. For both drugs, the combined actions seem to provide better pain relief with fewer side effects and less abuse.

“Krokodil” is an infamous bootleg heroin substitute that first emerged in the Ukraine and Russia. The main active opioid is called desomorphine, which has never been used medically in the United States. According to recent research, there also may be many other previously unknown codeine derivatives in mixtures as well. “Krokodil” is most well known not for its opioid-like qualities but for the terrible skin and muscle necrosis and the

crocodile-like skin lesions that users may develop around the site of injection. These likely have nothing to do with the opioid, but rather with the reaction ingredients that remain in the crude mixture that users inject.

Finally, in Thailand, the leaves of the kratom tree have traditionally been used to treat pain, diarrhea, and cough. Recently it has become available on the web for sale in many countries, including the United States. This plant is the object of controversy between enthusiasts, who claim it is a panacea that can treat opioid addiction, and the DEA, which considers it a potentially dangerous opioid. The scientific facts place it somewhere between these extremes. One of the molecules in the plant, mitragynine, is itself a very weak opioid, but it is metabolized to 7-hydroxy mitragynine, a molecule with more opioid actions. It causes analgesia and constipation that are blocked by naloxone, and so can be classified as an active opioid. There are anecdotal stories from Thailand that its use can both suppress opioid withdrawal (which makes sense since it contains an active opioid) and lead to dependence. People typically use it as a tea, powdered leaves, or capsules filled with powdered leaves. It is not yet scheduled by the DEA, but it may well be in the future. All the opioid drugs bind to the same molecule in the brain, but they do so with varying degrees of success. What follows is a list of drugs that bind very well, bind intermediately well, and bind poorly. The clinical use of these drugs is determined in large part by this quality. Obviously, a drug like codeine won’t do much good with the pain caused by major abdominal surgery, and hydromorphone would be overdoing it for a simple headache. Therefore, the form in which each of these is prepared and administered is tailored to its typical use.

High Efficacy

morphine hydromorphone meperidine fentanyl


Medium Efficacy

hydrocodone oxycodone

Low Efficacy

codeine propoxyphene



Most opioid drugs enter the bloodstream easily from many different routes because they dissolve in fatty substances and so can cross into cells. Heroin and fentanyl represent one extreme—they are so fat-soluble that they can be absorbed across the mucosal lining of the nose. Most other opioids are not quite that fat-soluble and cannot be absorbed well after snorting. However, some opioids including the natural ingredients of the opium poppy form a vapor if heated and can be absorbed into the body if they are smoked—that is the basis of the use of the “opium pipe” as the traditional device of ancient as well as more recent history. Almost all opioids can be absorbed from the stomach, although injection is a much more efficient route for some, like morphine, that are more poorly absorbed from the stomach than others.

Intravenous injection is the route that delivers opioids into the bloodstream the fastest. Because intravenous injection is more difficult and more dangerous than other routes, many users do not start this way. Instead, they start by skin-popping—injecting drugs subcutaneously (just beneath the skin). Heroin powder can be dissolved and injected. Morphine, fentanyl, and meperidine typically appear in illegal markets through diversion from medical use. Snorting heroin is another common route for new drug users. In part, users are avoiding the stigma—and risk of infectious diseases including hepatitis and AIDS—that come with injecting a drug. They may also mistakenly believe that they cannot become addicted if they don’t inject drugs. Prescription opioids like codeine, hydromorphone (Dilaudid), oxycodone (Percodan, OxyContin), meperidine (Demerol), and, of course, methadone (Dolophine) are available as pills. Sometimes drug users grind up pills of codeine, hydrocodone, or methadone and inject the suspension when they cannot get opioids any other way. This is an extremely risky business because the other pill components do not dissolve in saline. Injecting particles into a blood vessel can irritate the blood vessel, thus setting off a chain of reactions that lead to vascular inflammation and permanent damage. In addition, a pill particle can lodge in a small vessel and block off the blood supply to an area of the body.


The rate at which opioids enter the brain depends mainly on how the user takes them. The fastest way to get high is to inject the drug directly into the bloodstream. The second fastest is to smoke it. When users smoke or inject opioids, peak levels in the brain occur within minutes. Fentanyl is the most fat-soluble and achieves maximum brain concentrations in seconds. Heroin is a little slower; it takes a couple of minutes. Morphine is slower still, but not by much (five minutes). The faster the buzz, the greater the danger of death by overdose, because drug levels in the brain can rise so quickly. Snorting heroin causes slower absorption because the drug must travel through the mucous membranes of the nose to the blood vessels beneath.

Opioid effects after ingestion of a pill begin more slowly because the drug must be absorbed from the small intestine into the bloodstream, then pass through the liver, which can metabolize much of a dose, before it ever gets into the circulation. This process takes about thirty minutes, so there’s no “rush” after oral administration. This lack of a “rush” is why methadone is so useful in treating addicts, and as a pain medication. Sometimes users figure out how to circumvent opioid preparations that are designed to have a slow onset—the original formulation of OxyContin provides a now-notorious example. OxyContin is a delayed-release form of oxycodone that is designed to release drug gradually, providing pain relief over hours. However, when it was first introduced, users discovered that crushing the pills causes a quick release of drug and gives a “high” that the manufacturer did not intend. Following its introduction in 1996, OxyContin rapidly gained a reputation as the hot “new” drug of abuse. It has since been reformulated to make abuse more difficult.

The length of time an opioid high lasts depends upon how quickly the drug-metabolizing enzymes in the liver degrade the particular drug. Most of the drugs mentioned last for four to six hours. The exact time can vary from two hours (morphine) to up to six or so (propoxyphene), but all opioids are pretty similar. There are two important exceptions. Methadone lasts for twelve to twenty-four hours, so it can be given as a single daily dose. Fentanyl goes to the other extreme: the effects are over within an hour.


Morphine hits the backs of the legs first, then the back of the neck, a spreading wave of relaxation slackening the muscle away from the bones so that you seem to float without outlines, like lying in warm salt water. As this relaxing wave spread through my tissues, I experienced a strong feeling of fear. I had the feeling that some horrible image was just beyond the field of vision, moving, as I turned my head so that I never quite saw it. I felt nauseous. A series of pictures passed, like watching a movie: a huge neon-lighted cocktail bar that got larger and larger until streets, traffic and street repairs were included in it; a waitress carrying a skull on a tray; stars in the clear sky. The physical impact of the fear of death; the shutting off of breath; the stopping of blood. I dozed off and woke up with a start of fear. Next morning I vomited and felt sick until noon.

The character in William Burroughs’s novel Junkie describes his first experience with morphine fairly accurately. The only thing missing from this description is the “rush” that comes with intravenous injection that most users compare to orgasm.

All opioids cause a pleasant, drowsy state in which all cares are forgotten (nodding off), and there is a decreased sensation of pain (analgesia). The feelings are the most intense after injection, which brings the “rush.” After the orgasmic feeling, sexual feelings usually diminish, and people experience decreased sexual desire and performance. This happens because opioids affect the release of hormones and neurotransmitters involved in the regulation of sexual behavior. People under the influence of opioids will often say that they just don’t worry about their troubles anymore: they are in a special, safe place where cares are forgotten. The allure is understandable, and at the beginning it is impossible to understand the misery of addiction and withdrawal.

While the opioid user is in a dreamy, pleasant state, breathing slows, pupils constrict, and the person typically experiences nausea and perhaps even vomits. Although the effects on breathing can be quite dangerous, the other physiologic effects are fairly benign. For example, opioids do not produce big changes in blood pressure in healthy individuals. Most of the effects of narcotic drugs are caused by effects of the drugs on specific opioid receptors in the parts of the brain involved with the control of breathing and

other involuntary functions. For example, opioid users can vomit because morphine stimulates a center in the brain (the chemoreceptor trigger zone) whose job it is to cause vomiting in response to the ingestion of a toxic substance. So, in the movie Pulp Fiction the injection of adrenaline into the heart to reverse opioid overdose was not accurate. The effects on breathing that were causing the woman to OD were happening in the brain, and injecting a drug directly into the heart to get it started again was good theater, but bad pharmacology. Injecting an opioid receptor–blocking drug (naloxone, or Narcan) into the bloodstream instead would have effectively treated the OD. The movie Trainspotting does a much better job of depicting the reversal of opioid effects with naloxone. The protagonist is dumped at the doors of a hospital emergency room, taken into a room, and given naloxone. In a matter of seconds, he leaps up from the gurney.

One very important effect of opioids on the body has made life easier for generations of foreign travelers. Opioids increase the tension in certain muscles in the gastrointestinal tract so that the normal propulsive movements that move food along cannot operate effectively—hence their well-known ability to cause constipation. This can be a good thing if you are in Mexico and have traveler’s diarrhea. Through a similar action, opioids constrict the muscles of the urinary bladder and can cause difficulties in urination.

Diphenoxylate (Lomotil) or loperamide (Imodium) take advantage of a neat chemical trick to stop diarrhea without affecting the brain. The typical opioid molecule is slightly changed so that it is not fat-soluble enough to enter the brain well. This gives you a very safe, very effective medicine that can treat mild diarrhea without the risk of addiction. This safety is not absolute, especially if loperamide is used. Some users who were desperate to blunt their opioid withdrawal signs have tried to take as many as one hundred loperamide pills, enough to cause a fatal overdose. There is active research ongoing to improve this strategy to develop drugs that bind to mu receptors (see next page) that are not behind the blood-brain barrier but still can suppress pain. This could be the holy grail of narcotics research—a nonaddictive narcotic drug.


The efforts of the opium poppy to make opium alkaloids may reflect ingenious plant evolution to match the biology of their predators/pollinators. The poppy plant evolved to make a compound that acted in their brains. The poppy is not alone—many plants make compounds that are psychoactive. The marijuana plant, numerous species of hallucinogenic mushrooms, and the coca shrub, to name a few, also influence the behavior and physiology of animals that ingest them. Furthermore, the production of opioids is not limited to plants—certain frogs produce opioid-like compounds in their skin, perhaps for the same reason(s).

Opioids act on specific receptor molecules for the endorphin/enkephalin class of neurotransmitters in the brain. These endogenous opioids are chemical neurotransmitters that control movement, moods, and physiology. They help to control many bodily activities, including digestion, regulation of body temperature, and breathing. They also help to process pain sensations, and they activate reward circuits (see the Addiction chapter), which is why stimulating them makes you high. All of these behaviors arise when neurons in different parts of the brain release endorphins or enkephalins. Normally, each neuron is doing its job, firing away only if it is called upon; activation of all the endogenous opioid neurons virtually never happens. Taking heroin is like every endogenous opioid neuron in the brain firing all at once.

Which of the many endogenous opioid neurons in the brain are responsible for the opioid high? The first is a small group of neurons in the hypothalamus of the brain. The neurons that use the main opioid neurotransmitter, beta-endorphin, start here and they spread out throughout the brain. These neurons become active during extremely intense stress, perhaps for the purpose of calming us down. The theorists speculate that in the body’s most extreme time of stress, when it is on the verge of death, a sense of calm relaxation is helpful. The beta-endorphin neurons fire like crazy and induce an opioid-like pleasant state. Injecting beta-endorphin in the brain creates many aspects of this state, including slowed breathing, analgesia, and drowsiness.

The enkephalins are a different story. Many different kinds of neurons use enkephalins to communicate with other neurons. They appear in parts of the brain involved in processing painful sensations, controlling breathing, and other actions influenced by the opioids. They are also found in the gastrointestinal tract, where they regulate digestive function. Most important,

they are found in several places involved in the reward system. However, they probably do not function as a cohesive unit like endorphin neurons.

Endorphins and enkephalins are different members of a closely related “family” of neurotransmitters. Dynorphins, the third member of the family, share some actions, like analgesia, but actually cause unpleasant rather than pleasant feelings. These three opioid neurotransmitters share receptors. This is perhaps a resourceful evolutionary trick played by the brain to get the most “bang for the buck” out of neurotransmitters and their receptors. By combining different opioid peptides with their receptors, a large number of possible combinations can produce a great diversity of effects.

The main opioid receptor (named with the Greek letter mu) provides the major effects of opioids: analgesia, euphoria, respiratory depression. The second major receptor (delta) cooperates with mu in some places to help produce these same effects. The third receptor (kappa) is the weird one. The drugs that are specific for this receptor produce analgesia, but they do not produce a high. This should be the perfect nonaddicting analgesic drug. There is only one problem: stimulating this receptor alone causes the opposite of euphoria—dysphoria. Unfortunately, all of the clinically useful drugs we have now are specific for the mu receptor, and they are all addictive—the addicting properties of opioids cannot be distinguished from their painkilling properties.


Are the joys of nature (music, sex, meditation, whatever) as great as drugs? There may be a crumb of truth in this. The brain does produce its own opioids—the enkephalins and endorphins. If we inject these into animals, they cause the same effects as morphine or heroin. Are they released in circumstances in which we feel great? Can we learn to release them ourselves? The latter question is a premise of the science fiction book Earth, by David Brin, which depicts a future world where drug abuse no longer exists: the new social outcasts are the brain addicts who have learned to release their own opioids.

Naturally released endorphins do affect behavior. One enterprising scientist showed that the release of endorphins went up in animals undergoing experimental acupuncture, lending credence to this ancient

Chinese healing technique. How can we tell if we are releasing endorphins? First, we could give a drug like naloxone (Narcan) and see if the endorphin high stopped. This approach has actually been tested on people listening to their favorite music, who found that they didn’t enjoy the music as much if they were treated with an opioid antagonist (and pleasure is in the ear of the beholder—it has to be music the listener likes, whether it is Beethoven or Florence and the Machine). However, playing the music instead of listening to it may be even more effective. A recent study that used increased pain threshold as a surrogate for endorphin activity in the brain showed that playing music or drumming elevated the pain threshold of the musician. How about runner’s high? Do endorphins kick in at the end of a marathon? A recent experiment suggests that may happen. Scientists showed that endogenous opioids were released in the brains of people who had just completed a two-hour endurance run.

Overall, endogenous opioids play an important role in suppressing pain and in promoting reward. Recent studies showed that animals with no beta- endorphin will not take care of their babies, implicating endorphins as a critical element in nurturing behavior as well. These neurotransmitters are crucial to an important and related group of behaviors essential to human survival. Dynorphins also have an important role to play, telling us that stressful experiences make us feel bad, hopefully teaching us to avoid such experiences in the future.


While the buzz from opioids might sound alluring, it comes at a cost. Opioid drugs stimulate all opioid systems simultaneously, so there are many unwanted effects that accompany the desirable ones. One of these is the cycles of withdrawal that opioid users experience. People who take opioids for a while (weeks) can develop significant dependence and addiction and undergo withdrawal when they stop. Most opioid addicts use heroin or other opioids several times a day. With this pattern of use, tolerance develops to many of the actions of opioids, but it develops to different effects at different rates. Experimental studies in both animals and humans show that tolerance develops quickly to the ability of opioids to suppress pain. However, patients experiencing intense, chronic pain like that associated with terminal

cancer can actually show little tolerance to the analgesic effects of opioids. Tolerance also develops fairly well to the suppression of breathing (this is why opioid users can tolerate higher and higher doses). However, the constipation remains, and the pinpoint pupils are slow to change. The latter is fortunate because it provides a useful sign of OD in a comatose patient and can help identify even a longtime user. While tolerance develops to opioid- induced euphoria, the drug keeps providing enough pleasure that users still get high.

Part of the tolerance results from chemical changes in how cells respond to opioids. The normal chain of events initiated by opioids adapts to the continuous presence of the drug. The adaptation becomes so thorough that cells function normally even though the drug is present. Another part of tolerance is purely a conditioned response. Pharmacologists have learned from animal studies that if you give animals a dose of heroin every day in the same room, they tolerate higher and higher doses. However, if you move them to a strange environment, the dose that they usually tolerated kills them. We think this occurs because conditioned responses permit their bodies to anticipate and counter the effects of the drug. This conditioning effect probably does apply to humans. Frequently, very experienced opioid users who OD do so because they took the drug in an unfamiliar environment. Finally, tolerance is never absolute, and some intriguing recent research suggests that even tolerant opioid users can OD if they combine opioids with certain sedatives like alcohol or diazepam.

Opioid withdrawal is miserable but not life-threatening (unlike alcohol withdrawal). Again, in Junkie, William Burroughs provides a good description:

The last of the codeine was running out. My nose and eyes began to run, sweat soaked through my clothes. Hot and cold flashes hit me as though a furnace door was swinging open and shut. I lay down on the bunk, too weak to move. My legs ached and twitched so that any position was intolerable, and I moved from one side to the other, sloshing about in my sweaty clothes. . . . Almost worse than the sickness is the depression that goes with it. One afternoon I closed my eyes and saw New York in ruins. Huge centipedes and scorpions crawled in and out of empty bars and cafeterias and drugstores on

Forty-second Street. Weeds were growing up through cracks and holes in the pavement. There was no one in sight. After five days I began to feel a little better.

The earliest signs of withdrawal are watery eyes, a runny nose, yawning, and sweating. When people have been using opioids heavily, they experience mild withdrawal as soon as their most recent dose wears off. As withdrawal continues, the user feels restless and irritable and loses his appetite. Overall, it feels like the flu. As withdrawal peaks, the user suffers diarrhea, shivering, sweating, general malaise, abdominal cramps, muscle pains, and, generally, an increased sensitivity to pain. Yawning and difficulty sleeping gradually become more intense over the next few days. The worst of the physical symptoms abates after a few days.

If flu symptoms were all that happened when addicts stopped using, treating heroin addiction would be easy. Unfortunately, there is another symptom that is more intangible but much longer lasting. There is a dysphoria (the just-feeling-lousy feeling), which may be the reverse of opioid-induced euphoria. Users experience a craving for the drug that can be so strong that it becomes the only thing they can think about. The craving for a fix can last for months or longer, long after the physical symptoms have abated. This is the symptom that usually triggers relapse.

Most of these withdrawal signs are the opposite of acute drug effects. For example, opioids cause constipation, and diarrhea occurs when people go through withdrawal. The body of the addict adapts to maintain a level of intestinal tract movement despite the presence of the opioid that is constipating. Remove the opioid, and the underlying processes that were counteracting it to keep things normal suddenly find themselves unhindered. The character in the movie Trainspotting experienced this effect, which necessitated his mad dash for the bathroom in one scene. This represents the sort of yin-yang response the body has to any disruption. (If you shiver and feel cold when you are withdrawing from opioids, what do opioids usually do to body temperature?)

Many addiction researchers think that once people have a long history of taking opioids, the desire to avoid withdrawal maintains addiction more than the pleasurable effects of the drug. Obviously, when people first get addicted, they haven’t been taking the drug long enough to go through intense

withdrawal. However, after several months or years, the withdrawal is stronger and may contribute more to an addict’s continued drug taking. If you know taking the drug will solve the problem, it seems an easy solution, doesn’t it? In the end, it is a combination of changes in the brain that create the overwhelming compulsion to keep using opioids (or any other highly addictive drug). Researchers think that the craving for a drug may result from chemical changes in two parts of the brain that unfortunately combine their efforts: the parts of the brain that seek reward are chemically changed to respond strongly to drug cues, and the parts of the brain that create anxiety and bad feelings start firing as soon as the drug wears off.


Many people use opioids occasionally for the high. They take a pill, drink cough syrup, or inject heroin or fentanyl, for example. Some people develop a habitual pattern of daily use that accelerates over a period of time and then stabilizes at a certain level. These people take opioids every few hours. After the first week or two, they are tolerant to many of the effects of the drug; every time the drug wears off, withdrawal signs begin and the cycle of use starts again.

What pattern of use defines an addict? Can a person be addicted after the first dose? The answer for opioids isn’t very different from the answers for all of the other drugs we discuss. It is not determined by whether a user injects drugs, or uses them only on weekends, or has never shared a needle, or has ever blacked out. The answer is that people are addicted when they have lost control of use: when they must continue to pursue whatever pattern of use they have set. For some, this loss of control might come from taking oxycodone pills or smoking heroin; for others, injecting or snorting heroin; and for still others, even drinking codeine-containing cough syrup or taking fifty loperamide pills in desperation to avoid withdrawal. Research indicates that about 10 percent of people using opioids to treat chronic pain develop addiction to pain medication, but only a small percentage (5 percent) switch to heroin. However, once someone initiates heroin use, the likelihood is higher (20 percent) that they will proceed to abuse.

Is a person an addict if he or she goes through withdrawal? Or, conversely, if the person doesn’t go through withdrawal, is he or she not a

junkie? This is a common rule that many people use. As we have said, opioid users will go through withdrawal if they have been taking the drug regularly enough that their bodies have adapted to it. Usually, such adaptation means the person is in a regular use pattern, but a user can be addicted before having taken the drug long enough to show strong withdrawal signs. Conversely, a pattern of use might be compulsive but low, and the withdrawal might be so mild it isn’t noticeable. Withdrawal happens also in patients who take opioids as prescribed for pain if they take the drug for a period of days or weeks. This doesn’t mean they are addicts—just that their bodies have adapted to the opioids.

The National Institute on Drug Abuse has accumulated statistics about “addiction careers,” or the typical drug-use pattern of people who are addicted to opioids. Usually, use begins with occasional experimentation and then gradually accelerates over a period of months to continuous administration at intervals of four to six hours. The surprising part about opioid addiction careers is that they often end. Many opioid users follow this pattern for about ten to fifteen years and then quit, often without prolonged treatment. The reasons are not entirely clear but probably include a host of social and physical factors.


The other downside to taking opioids is that there are many physical effects of stimulating all opioid receptors in the body simultaneously. Death by overdose is a major possibility. The most dangerous thing about the opioid drugs by far—and the usual cause of death—is the suppression of breathing, which can be fatal within minutes after an injection. It’s not the result of cumulative toxicity but can happen with a single dose. Usually at this point the patient has become sedated and sleepy and has pinpoint pupils. The most common reason for overdose with opioids is that the user has received a dose that is much higher than expected. The composition of street heroin varies widely, from as high as 70 percent pure to as low as 10 percent. In the current environment, the user may not even know the drug they are taking. As mentioned earlier, heroin can contain highly potent fentanyl derivatives, or these derivatives can be disguised as oxycodone pills. Seizures can develop

with extremely high doses, especially in infants and children who have OD’d by ingesting a drug intended for an adult. Seizures are much rarer in ordinary adult users but obviously can be dangerous. Using opioids in combination with other depressants like alcohol raises the risk of death even in regular opioid users. A rash of deaths in Texas from 2005 to 2007 resulted from a black-market combination of black tar heroin and crushed-up cold medication that contained the antihistamine diphenhydramine. This combination of narcotic and antihistamine has long been a favorite of addicts because the antihistamine augments the narcotic high. For the uninitiated teenagers who were taking the drug, the combination proved to be lethal.

The other side effects of opioids are uncomfortable but not dangerous: nausea and vomiting, constipation, and difficulty urinating. Sometimes opioids cause a flushing of the skin and itching. This happens because morphine probably releases histamine, one of the molecules that mediates allergic reactions in the skin.

If opioid addicts were in perfect health, these would be little to worry about. Unfortunately, this is often not the case. Addicts are frequently undernourished, generally in ill health, often addicted to alcohol or other drugs, and if they inject drugs, infected with HIV or hepatitis. For example, in most people the effects of opioids on blood pressure are minor. However, these effects can be worse in people who already have problems with their cardiovascular system. Similarly, the constriction of the bile ducts can cause them to spasm, which is extremely painful in users with bile duct problems.

The existence of contaminants in illegally prepared injectable forms of heroin represents another major hazard. Depending upon the source (which is almost never known), heroin can be contaminated with quinine or other inactive ingredients, including talc. Some apparent heroin overdoses are actually problems caused by these contaminants.


What are the long-term effects, and which of them are dangerous? The answer might surprise you. One of our teachers, a wise and ancient British pharmacologist named Frederick Bernheim, was fond of getting up in front of the medical school class and saying that if you didn’t mind being impotent and constipated, opioid addiction really wasn’t too bad. He probably wouldn’t be so blithe about it today, but there is some truth to this assertion.

The long-term consequences for your major body systems of taking opioids every day are, as our teacher implied, somewhat benign. Yes, addicted men can become impotent, and sexual and reproductive function can be impaired in male and female addicts. Women often stop having menstrual cycles, and in men sperm production falls. The people who use opioids over the long term are also chronically constipated, as he described. Users typically lose weight because they spend so much time chasing down the drug, they don’t eat well. Otherwise, the opioids themselves are not damaging to organ systems, in marked contrast to regularly ingested alcohol. The death of Jerry Garcia of the rock group the Grateful Dead is a case in point: he was a longtime opioid addict, but he died from complications of his diabetes, not from the heroin. Even more dramatic was the quite amazing long life of William Burroughs, from whose books we have quoted extensively. He died at the age of eighty-three of natural causes, despite living much of his life addicted to opioids.

None of this sounds too bad. However, there are other major considerations. First of all, with any pattern of compulsive drug use, users tend to ignore anything but obtaining the drug. Therefore, they tend to neglect their health, usually eat poorly, and suffer all of the other complications of not taking care of themselves. Furthermore, addicts often engage in risky behaviors associated with obtaining and using the drug. Many women addicts engage in unprotected sex to obtain money for their drug habit, and thereby increase their risk of contracting sexually transmitted diseases. Many people who inject drugs share the needles, which greatly increases their risk of contracting HIV and hepatitis. In New York City, a substantial percentage of all heroin addicts who inject heroin are infected with hepatitis and HIV. In fact, the recent popularity of snorting heroin is motivated in large part by the desire to avoid needles. These people don’t avoid addiction, but they do avoid a potentially lethal side effect from needle-transmitted disease. In the context of HIV and other sexually transmitted diseases, the potential effects of opioids on the immune system present a real concern. Opioids do seem to suppress immune function, and most immune cells are loaded with opioid receptors: numerous recent studies have shown changes in immune-cell function if they are exposed to opioids. There are some other toxicities associated with long-term opioid use. As mentioned earlier, injecting particles or using unsterilized needles can cause an inflammation of the veins, which in turn can cause serious damage to the blood vessels.

New research has shown that the brains of regular opioid users don’t work normally. First, many narcotics addicts have trouble with complex decision making—they tend to make poor choices and have some trouble learning new information. We are not sure yet whether this is a cause or a result of the drug taking, but the fact that these problems are worse in people who have used drugs for a long time makes it likely that it is related to the drug. Stimulant abusers have the same troubles, suggesting that changes in the brain reward system that are activated by both types of drugs may be the reason.

The repeated suppression of breathing that is caused by continuous opioid use represents another risk factor for dangerous long-term outcomes of opioid use, because it can produce changes in the brain associated with hypoxia (low blood oxygen). Long-term addicts simply don’t breathe enough to maintain normal levels of blood oxygen. While this problem is not unique to opioids, it is a potential side effect that could have long-term consequences, including impaired cognitive function.


In case of overdose, the opioid antagonist naloxone (Narcan) almost immediately reverses the life-threatening suppression of breathing. Treating opioid addiction is another matter. As with other addictions, there is no easy solution. People have tried many of the strategies used for alcoholics. A number of groups, such as Narcotics Anonymous, emphasize abstention, attendance at meetings, and so forth.

In addition, two drugs have proved to be very effective in treating narcotic addiction. Methadone is a long-acting opioid that can be given on an outpatient basis to patients in treatment programs. The idea of this strategy is to allow the addict to avoid withdrawal and the constant need to procure the drug. The other advantages of methadone are that the drug is given orally, without the risks of IV administration, and that the dose is controlled and can gradually be worked down. Although some complain that this method just substitutes one addiction for another without addressing the social and psychological reasons for the addiction, patients’ lifestyles do improve. The bottom line is that methadone works—it helps users abstain and get back to productive lives and decreases mortality compared to users receiving non-

drug-based therapy. Recently, buprenorphine, another opioid drug, has been approved for the treatment of opioid addiction in the form of a pill or film that you place under the tongue or in your cheek, or an implant placed under the skin to provide the drug constantly. It is somewhat different from methadone. It also stimulates opioid receptors and provides a “substitution” strategy. But when an addict takes buprenorphine, it keeps effective agonists like heroin from getting to the receptors. So it has just enough activity to stave off withdrawal. The addict doesn’t get high on buprenorphine and can’t get high on heroin. Some formulations of buprenorphine are combined with naloxone, so if users inject it rather than taking it by the proper route, they cannot get high and likely will experience withdrawal symptoms. The goal of this formulation is to decrease potential abuse. One reason for this formulation is that buprenorphine, unlike methadone, can be prescribed by a doctor outside of a clinic. Methadone can only be used in conjunction with a clinic visit: this is a real turnoff to long-term clients who complain that the only time they are around the old drug-taking environment is when they are forced to visit the clinic to receive their medication.

Pellets containing long-term-release preparations of the opioid antagonist naltrexone are also available. Like buprenorphine, they are implanted under the skin and provide the drug continuously. In this case, they keep the user from getting high as long as they last—and that’s the problem. The pellets wear out, and the user simply goes back to getting high. The success of this strategy is less than those using methadone or buprenorphine.

Scientists continue to explore pharmacologic treatments for opioid addiction. Ibogaine is one molecule of interest. It is a chemical contained in an African shrub that has been touted by users saying that one ibogaine experience led them to give up opioids forever. Ibogaine is a hallucinogen, and although research is progressing, it seems unlikely that it will pan out to be a mainstream treatment for opioid addiction. While there are numerous clinics around the world, the National Institute on Drug Abuse decided that it has too many side effects to commit resources to studying its potential, and so there is little about it in the scientific literature.



Drug Class: Sedative, hypnotic, anxiolytic. All of the drugs mentioned in this chapter are legally considered Schedule II–IV drugs (classified by the Drug Enforcement Administration as having some potential for abuse as well as accepted medical uses), except for GHB, which is Schedule I as a recreational drug and Schedule III as a prescription drug (Xyrem).

General Sedatives: Barbiturates (phenobarbital, pentobarbital [Nembutal], secobarbital [Seconal], amobarbital [Amytal]), chloral hydrate (Notec, Somnos, Felsules), glutethimide (Doriden), others (Equanil, Miltown, Noludar, Placidyl, Valmid, methaqualone [Quaaludes])

Benzodiazepines: Flunitrazepam (Rohypnol), diazepam (Valium), chlordiazepoxide (Librium), Ativan, Dalmane, Xanax, Serax, Tranxene, Verstran, Versed, Halcion, Paxipam, Restoril (there are hundreds more)

Drugs Designed Specifically to Induce Sleep: zolpidem (Ambien), eszopiclone (Lunesta), ramelteon (Rozerem), suvorexant (Belsomra)

GHB: Gamma-hydroxybutyrate (Xyrem)

The Buzz: All of the sedatives, except those designed specifically to promote only sleep, produce about the same psychological effects. First there is a sense of relaxation and a reduction of anxiety—a general “mellow” feeling. At higher doses, this is followed by light-headedness, vertigo, drowsiness, slurred speech, and muscle incoordination. Learning is impaired, and memory for events that occurred while under the influence of these chemicals, especially the benzodiazepines, may be impaired. The duration of action can vary from a couple of hours to more than a day, so it is important to be alert to the possibility of prolonged impairment. Unexpected side effects such as anxiety, nightmares, hostility, and rage (the opposite of the calming effects the drug is expected to have) occasionally occur. All of these drugs impair the ability to drive, and in general, their effects are increased by alcohol. A person who has had a sedative and a drink of alcohol should never drive.

Overdose and Other Bad Effects: With benzodiazepines the risk of fatal overdose is small if they are taken alone. High doses simply cause prolonged sleep and perhaps memory impairment for the period they are active. However, if they are combined with any other sedating drug, fatal suppression of respiration can result. If a person has taken a benzodiazepine and is difficult to arouse, it is best to assume that some other drug may be present and to seek medical attention immediately.

Almost any of the sedatives except the benzodiazepines will cause death by suppression of breathing and heart failure if taken in sufficient quantity. The progression of symptoms is as follows: drowsiness and muscular incoordination with slurring of speech; deep sleep from which the person cannot be aroused; loss of reflexes such as blinking, gagging, and withdrawal from a painful stimulus; suppressed breathing; and death. If a person has taken a sedative and cannot be aroused, seek medical attention immediately.

Dangerous Combinations with Other Drugs: As with alcohol, opioids, and inhalants, it is dangerous to combine any sedative, including benzodiazepines, with anything else that makes a person sleepy. This includes alcohol and other drugs that have sedating properties, such as opioids (for example, heroin, morphine, or Demerol), general anesthetics (nitrous oxide, halothane), or solvents. Some cold medicines include antihistamines, and sedatives consumed in combination with them can

produce depression of heart rate and breathing. Recently there has been a strong FDA warning about mixing benzodiazepines and opioids because of a remarkable number of opioid overdoses when benzodiazepines are also present.

Even drug combinations that do not cause unconsciousness or breathing problems can powerfully impair physical activities such as playing sports, driving a car, and operating machinery.

There are reports that GHB (“Easy Lay”) and flunitrazepam (Rohypnol, or “roofies”) have been added to drinks to cause sedation leading to rape or sexual assault. If a person begins to feel weak, dizzy, light-headed, or mentally confused after a drink that should not produce such feelings, consider getting that person medical help.


General Sedatives
What They Are and How They Work Toxicity
Tolerance and Withdrawal

What They Are and How They Work Problems with Benzodiazepines

Drugs Designed Specifically to Induce Sleep Ambien

Belsomra Lunesta Rozerem

Gabapentin GHB

What It Is and How It Works Toxicity
Tolerance and Withdrawal Other Sources of GHB

A Cautionary Note

For all of recorded history, people have sought ways to reduce their anxiety and make themselves peaceful and calm: through meditation, religious practice, psychotherapy, and all kinds of chemicals. Historically, the chemical of choice has been alcohol, and for many it still is. But as biology and medicine have progressed in this century, there has been a growing understanding of how we can manipulate our consciousness with very specific drugs to induce unconsciousness for surgery, to induce sleep, or to reduce anxiety.

The modern pharmacology of sedation began in the mid-1800s with the synthesis of chloral hydrate, a sedative that is still used today. It was followed by barbital, the first of the barbiturates, in 1903. The barbiturates turned out to be a wonderful group of compounds, because small modifications to the chemical structure of the basic compound produced a variety of sedatives with different properties. For example, phenobarbital had antiseizure properties at doses that did not make patients too sleepy. Some barbiturates were extremely short-acting, while others produced anesthesia sufficient for surgery. More than 2,500 barbiturates were synthesized, and at least 50 reached the commercial market. Not only was this an important milestone for patients and physicians but it also demonstrated to scientists that slight changes in a basic molecule could create drugs with very different effects.

As important as the early sedatives were, they had a deadly side effect. At high doses they depress the brain functions that support life, particularly breathing. This was a major risk, and thus they could not be safely prescribed to anxious and depressed individuals who might use them to commit suicide. This changed in 1957 with the synthesis of the first benzodiazepine-like compound (chlordiazepoxide, or Librium). It quickly became clear that this was a remarkable group of drugs. They could specifically reduce anxiety without making a person too drowsy and, best of all, they did not excessively suppress respiration. They were much safer. Even though at that time no one knew how these drugs worked, they clearly worked very well, and a huge number of different variations of these compounds were synthesized (more than three thousand).



Almost all of the general sedatives that are used for recreational purposes are compounds that have been manufactured for medical use and are diverted from legitimate sources. These drugs are obtained by illegal prescriptions, by theft, or by importing them from countries where they can be bought without a prescription. Thus, they almost always appear as pills, packaged liquids, or preparations ready for injection. There is nothing distinctive about their appearance; however, the potency of drugs in this group can vary considerably.

Our best understanding of the general sedatives comes from studies of the barbiturates. The barbiturates and other drugs act by increasing the inhibitory function of the neurotransmitter GABA at its binding site on the nerve cells (see the Brain Basics chapter for a discussion of GABA). So, if a signal comes along that releases a bit of GABA onto a cell or network of cells, then in the presence of the barbiturates that same packet of GABA can be much more effective. They do this by increasing the time that the channels in the cell membrane are open. If they are open longer, then more inhibiting ions flow, and the cell is inhibited from firing action potentials for a longer time. If there is enough GABA and enough barbiturate, then the cells cannot fire at all, and the network shuts down.

With a sedative, shutting down is exactly what we want to have happen, but only in certain areas. What we don’t want is for those areas responsible for life to shut down, and there is the secret to good pharmacology—finding a drug that will do exactly what you want and not what it must not do. The barbiturates and other general sedatives are terrific if you know just how to use them, and they can be deadly if you don’t.

For instance, the barbiturate phenobarbital is a great barbiturate for mild sedation and perhaps an antiseizure medicine. A clinically appropriate dose of phenobarbital will make you feel a little drowsy and maybe a bit less anxious. More of it will make you sleep, but it takes quite a bit to stop critical life functions such as respiration, and it is not good for surgery. Now assume that a person has experience with phenobarbital and knows how many pills he or she can take, but cannot get it, so the person takes pentobarbital instead. Pentobarbital tends to have a much greater effect on GABA inhibition and is great for surgery, but it does not spare the nerve networks that control respiration. The same dose of pentobarbital that would

be appropriate for phenobarbital can fatally suppress breathing. Our experimenter is in real danger of having a lethal overdose.

The message from this is that all of these sedatives are alike in their mechanism of action, but they can be very different in their potency, and maybe even in their specific potency on critical life-support networks. Anytime you take a sedative, know exactly what you are taking and the appropriate dose for that drug.


The barbiturates, being manufactured for human consumption, do not contain known toxic agents, and in general their toxicity is not great if they are used at clinically appropriate doses. We have already talked about what can happen at high doses—death by respiratory depression. At normal doses, the major concern is that they can have sedative effects that outlast their sleep- inducing properties so that, for example, driving, flying an airplane, or performing other activities requiring muscle coordination can be impaired for up to a day after a single dose. Also, as with any drug that sedates, there is the possibility that excitation rather than sedation will develop. No one knows why this happens, but it seems that some people react as though some part of their nervous system is actually stimulated.

If barbiturates are used for a long period of time, the liver systems that metabolize them become enhanced. This may cause some tolerance to develop, but it also causes other drugs to be metabolized more effectively, including steroids, ethanol, and vitamins K and D. So, when a user is taking barbiturates with other prescribed drugs, there may be a problem with getting an adequate concentration of those other drugs, and a physician might need to increase the dosage of those other drugs.

Chloral hydrate is a liquid that can irritate mucous membranes in the mouth and stomach and may cause vomiting. It can also cause disorienting feelings, such as light-headedness, vertigo, muscle incoordination, and even nightmares. There are also reports that chronic users can experience sudden death, perhaps due to overdose or to liver damage. (When the liver becomes damaged, its ability to metabolize and detoxify a compound is impaired, and what may be a normal drug dose becomes toxic.)

In general, all of these drugs are safe if taken under the guidance of a physician and not mixed with other sedating compounds. People who experiment with any of them should be aware that the safety window between the effective dose and the lethal dose may be rather small.

A recent example of the danger of using anesthetic sedatives outside of the hospital is the death of Michael Jackson. It appears that Mr. Jackson had great difficulty sleeping and thus hired a physician to sedate him with propofol, a general anesthetic used for both major and minor operative procedures. Propofol is generally a very safe drug, but allegedly in this case it was administered outside of a medical setting without proper equipment for anesthesia and recovery. In addition, there are claims that Mr. Jackson might have also been under the influence of other sedative drugs.


Tolerance will develop to all sedatives if they are used in sufficient doses for a period of weeks or more. There is a real risk with sudden withdrawal, because the central nervous system adapts to the drugs by turning down the inhibitory systems that these drugs enhance. It’s like if the brakes have been on in a car and the driver has been compensating by pressing the accelerator more, and then suddenly the brakes are off and the driver cannot let up on the gas. The car goes faster and faster and then out of control. That’s what happens to the brain. The GABA system stops being enhanced and is in a weakened condition, so the brain, out of control, becomes overexcited and can have electrical discharges that produce epileptic seizures.

Then there is the problem of psychological dependence or, simply, learning to live in a sedated state. Some people who are chronically anxious or agitated may get some relief from these drugs, but upon withdrawal, they are miserable because they have not cured their problems but only suppressed them.


The benzodiazepines are remarkable because they are one of the closest drugs we have to a “magic bullet” for anxiety. Used in the proper way,

benzodiazepines can provide significant relief from anxiety without disrupting normal functions. Most important, they are quite safe from the risk of overdose if they are used alone and not in combination with any other sedating drug, including alcohol and opioids. While there are a few known deaths from benzodiazepines, in the vast majority of these cases the person had used them with something else.

The mechanism of action of these drugs is just about the same as that of the general sedatives—the enhancement of GABA inhibitory systems. So, the question arises of why they don’t suppress respiration and cause death. It’s because they work through a special benzodiazepine-binding site on the GABA receptor molecule (the place where GABA interacts with the nerve cell), and the nerve cells that control respiration and other impor-tant functions do not have many benzodiazepine sites on their GABA receptors. They might appear to be almost the perfect drug, because the receptors are on cells that participate in thinking and worrying but not on those that keep us alive. It is no wonder that these are among the most prescribed drugs on earth.


So, is it a perfect class of drugs? No. First, benzodiazepines often cause drowsiness and muscle incoordination, at least during the first few days of use. So, operating machinery such as cars, airplanes, or saws is a really bad idea when you are first taking them. Also, they cause problems with learning, and they can cause amnesia.

Significant tolerance develops to all of these drugs and, over the long term, increasing doses are required. When use is stopped, a long withdrawal period ensues. Some people start using benzodiazepines, become tolerant and increase their dose, experience withdrawal and are definitely dependent, but would not reach criteria for addiction (compulsive, out of control use).

If one is very tolerant and abruptly stops, there is a significant risk of seizures. Thus, cessation of benzodiazepine use should be done with the help of a physician. This dependence/withdrawal property of benzodiazepines often leads to people having great difficulty stopping their use.

Are benzodiazepines actually addictive? Our current understanding of addiction is that drugs and behaviors that promote the actions of the

neurotransmitter dopamine have the capacity to produce not only dependence, but addiction. There is some new data that benzodiazepine can promote dopamine function and thus may cause more than just dependence.

Because they enhance inhibition in the central nervous system, benzodiazepines can impair the process of neuroplasticity that we talk about in the Brain Basics chapter. That is, they can prevent the brain from recording and adapting to new information by preventing it from changing its wiring pattern. See the discussion on pages 324–6 about how long-term potentiation of synapses may underlie learning. Benzodiazepines suppress this process. The general sedatives do this, too, but few people take them chronically, while a lot of people take benzodiazepines for prolonged periods. Because general learning is a problem, it is unrealistic for people who need to learn new information to expect to do so to their full potential if using these drugs. Once people stop taking benzodiazepines, however, this effect on learning disappears and they return to normal function.

The really dark side of not learning is amnesia—not remembering something important. Benzodiazepines can cause amnesia, and this is part of the major controversy about their abuse in social situations. There are reports of benzodiazepines being put into the drinks of women who are then raped but have amnesia for the whole event. This may have become more prominent because of the availability of flunitrazepam (the brand name is Rohypnol, commonly called roofies), which is an especially potent benzodiazepine. A very small amount (two milligrams) will easily disappear in a drink but be quite effective. This is the worst kind of drug abuse because it is inflicted on someone who does not choose it.

Flunitrazepam is widely distributed in the underground market, and the US government has banned importation of it. As far as we can determine, it does exactly what the far more common benzodiazepine Valium does and nothing more. However, it takes only about two milligrams of flunitrazepam to do what ten milligrams of Valium will do; it more easily disappears into a drink; and if mixed with a lot of alcohol, it could lead to a serious overdose.

A new problem with benzodiazepines has been discovered because of the current high levels of abuse of opioids. Studies have shown that many opioid abusers also use benzodiazepines, and it appears that benzodiazepines increase the propensity for opioid overdoses. Because of this recent finding,

the FDA has issued a warning about combining benzodiazepines and opioids and recommended against prescribing them together.

As for other problems with benzodiazepines, they are about the same as those for the general sedatives—light-headedness, vertigo, poor muscle coordination, nightmares, and so forth. That said, as with alcohol, most people use benzodiazepines for short periods and do not become dependent or addicted.


Problems with sleeping are a huge issue in our society, and the pharmaceutical companies are responding with new drugs that may be less problematic than the general benzodiazepines. Four of these drugs are zolpidem (Ambien), eszopiclone (Lunesta), ramelteon (Rozerem), and suvorexant (Belsomra).


Ambien (zolpidem) is an interesting drug because, although it is chemically unrelated to the benzodiazepines, it acts on a benzodiazepine receptor that induces sleep. It does not, however, seem to reduce anxiety, so it is thought to be less rewarding and thus less prone to cause dependence than normal benzodiazepines like Valium. It also has a very short lifetime in the body—its effects are diminished within a few hours—which some scientists argue is what prevents the development of tolerance problems.

Zolpidem received FDA approval in 1993 and now has been on the market long enough for any problems to emerge. In general, it appears to be a reasonably safe drug if, as with all prescription drugs, it is taken as prescribed by a doctor—that is, it should be taken just before sleep, and then the user should actually get in bed and go to sleep. If the user stays awake, zolpidem’s hypnotic properties will impair driving or other activities requiring coordinated functions. And like other agents that act at the benzodiazepine receptor, it can produce amnesia for any activities that occur during the time it is effective.

It should not be taken with any other sedating drug, such as alcohol, and its use should be limited to a short period of time—seven to ten days.

Epidemiological studies indicate that the abuse potential of this drug is, in fact, lower than that for benzodiazepines, but caution should be used in prescribing it for individuals who have a history of sedative abuse or dependence.

As with all drugs, however, surprises do occur. There are an increasing number of reports of individuals who take zolpidem and then partially wake up enough to engage in fairly complex activities for which they later have no memory. These include sleep driving, sleep eating, sleep shopping, sleep emailing, sleep sex, and even criminal activity carried out in a twilight state. We do not know why this happens, but we speculate that for some reason, the sleep-maintaining effects of the drug diminish faster than the effects of the drug on other brain areas. This leaves the user in a twilight state in which some behaviors are possible but high-level cognitive functions are still impaired. One person told us of repeated episodes of sleep shopping from websites. Another reported sending inappropriate emails to a friend of the opposite sex. We have consulted on criminal cases that involved driving offenses, the display and firing of a gun, and even murder—all committed while the person was under the influence of zolpidem, and in every case, the person had amnesia for the events.

In 2013 the Drug Abuse Warning Network* released a report concerning reports of adverse effects of zolpidem from 2005 to 2010. The report commented on a marked increase in emergency department visits related to the use of zolpidem. The report goes on to state that “patients typically use zolpidem to benefit from temporary sedative effects that aid them in attaining restful sleep. Adverse reactions have occurred, including daytime drowsiness, dizziness, hallucinations, behavioral changes (e.g., bizarre behavior and agitation), and complex behaviors such as sleepwalking and ‘sleep driving’ (i.e., driving while not fully awake).” It is very likely that many more people experience unexpected effects with zolpidem than the number that actually go to the emergency department of hospitals, so our advice is to be cautious in the use of this drug, especially in combination with other drugs.


Belsomra (suvorexant) is different from any of the other sleep-inducing agents. It was brought to market in 2014 as a sleep-inducing product that acts

on a different receptor system from that of all other such drugs. Suvorexant blocks the action of wake-promoting neurotransmitters, the orexins, secreted by a relatively small number of neurons in the hypothalamus. When the actions of the orexins are blocked, animals and humans are unable to stay awake. A particularly interesting disorder, narcolepsy, involves difficulty staying awake for normal periods, and a lack of neurons that secrete orexins appears to be the cause.

Suvorexant has been on the market for such a short period of time that there has been relatively little postmarketing information about its efficacy and side effects. The prescribing information regulated by the FDA contains nearly the same cautions as for all the other sleep-inducing agents. However, drug interactions with the orexin receptors have been studied only recently, and there may be side effects not currently recognized. Our advice is to use this drug only with the guidance and advice of a physician experienced in its use.


Lunesta came to the market in 2005 and is similar to Ambien. It is not a benzodiazepine but acts at benzodiazepine receptors to induce sleep. Like Ambien, it is reported to have lower abuse potential than benzodiazepines, but the same cautions apply. The same warnings are given for Lunesta as for zolpidem.


Rozerem is an entirely different sleep-inducing agent that works through melatonin receptors. It is discussed in the chapter on herbal drugs. Prescribing information offers warnings similar to those for zolpidem.


Gabapentin is a drug that lives up to the mantra of pharmacologists: “Every drug has two effects, the one you know about and the one you don’t.” It was approved in 1993 as a treatment for seizures and nerve pain following shingles (a herpes infection) and marketed as Neurontin. Over time, it has been used “off label” for many types of pain caused by nerve irritation or

damage. Because it has a molecular structure similar to that of the inhibitory neurotransmitter GABA, it was thought to interact at that receptor to inhibit nerve signaling. However, subsequent research has shown it likely blocks the entry of calcium into neurons, particularly at the synaptic terminals that release neurotransmitters. It is included here because it has significant sedative effects and is increasingly used as a recreational drug, alone or in combination with other drugs.

For years, probably until about 2010, gabapentin was considered a benign drug that could suppress pain without the negative effects of opioids. Then the number of prescriptions began to increase. There were 18 million prescriptions for gabapentin in 2004 and 43 million in 2015. Often gabapentin is prescribed to individuals also receiving opioids and/or benzodiazepines.

Drug abuse reports have indicated that opioid users are adding gabapentin to their drug regimen for an increased “high.” At this point we do not know if there is any pharmacological interaction in which gabapentin enhances opioid effects, or if users simply take it for added sedative effects. As of this writing, the US government has not scheduled it as a controlled substance, but the state of Kentucky has because of its use by opioid addicts.


GHB emerged on the scene of popular culture when Time magazine made it a hot topic. On September 30, 1996, Time reported the death of a seventeen- year-old Texas girl. An outstanding athlete and a highly responsible student, she went to a dance club, had a couple of soft drinks, then went home complaining of a headache and nausea. Twenty-four hours later she was dead from an overdose of GHB. There was no other toxic agent in her body and no evidence that she knew she took the drug. The speculation is that GHB was slipped into her drinks.

GHB is now a common drug of abuse for teenagers and young adults. The internet is full of descriptions (many very inaccurate) about the effects of the drug, and there are even instructions for making it in home laboratories. GHB can be lethal, it is easy to manufacture, and it is difficult to detect in a drink —a perilous and dicey combination.


GHB—gamma-hydroxybutyrate—is most often available as an odorless and colorless liquid, occasionally with a salty taste. It is used as a general anesthetic in Europe, and it has been sold in health-food stores for bodybuilding, but that is now illegal in most areas, having been banned by the US Food and Drug Administration for over-the-counter sales in 1990. Now most of the illicit market is found in nightclubs and at all-night dance parties (“raves”). GHB is available by prescription (Xyrem) for treating the sleep disorder narcolepsy (a disease in which the patient falls asleep repeatedly during the day).

Originally this drug was thought to work by binding to the GABA receptor on nerve cells and activating that receptor. It does that, but GHB may itself be a neurotransmitter in the brain. It meets many of the requirements that neurobiologists have established for a transmitter. It is synthesized in the brain, it has specific receptor sites and specific receptor locations, and its effects can be blocked by specific receptor antagonists. Thus, it may have a very specific role in the brain, although we don’t know what that is. Even so, there is nothing very remarkable about this, and it should not make much difference to anyone but neuroscientists, except for one unusual fact: it easily crosses from the blood to the brain.

Under normal circumstances, the brain is remarkably insulated from the rest of the body by the blood-brain barrier. To get into the brain, substances must dissolve easily in fat to move through tissues. Most neurotransmitters will not cross the blood-brain barrier, and so no matter how much of them is ingested, they never reach the brain. This is a very important property of the body because neurotransmitters are present in much of what we eat, and if we had meals that included a huge amount of a particular neurotransmitter, we would die of either overexcitation or too much inhibition.

So, what does it mean that GHB can cross from the blood to the brain? It means that whatever role GHB plays in normal brain function will be modified by added GHB moving into the brain. Instead of having a normal circuit that is wired and functioning in an orderly manner, the circuit could become disordered as the GHB receptors get randomly activated as the drug courses through the brain. This is a bit different from other sedatives that simply increase the activity of a receptor, more or less preserving the orderliness of the network.

Whatever the neuropharmacology of GHB turns out to be, it is clearly a potent drug. In general, it can be thought of as a major sedative on the basis of its effects. It produces relaxation, mild euphoria, then headache, perhaps nausea, drowsiness, loss of consciousness, seizures, and coma or even death. Given its amnesiac properties, it probably produces subtle effects on learning and memory at doses that don’t produce loss of consciousness.

Is GHB addictive? When GHB is used clinically as a treatment for narcolepsy, it is not. However, when it is used recreationally, at doses that are higher than recommended and at frequent intervals, a profound dependence syndrome can develop, as we discuss in what follows.


As illustrated by the Time article, GHB can be quite toxic. We then did not know much about toxicity from long-term effects of its use, but the short-term effects were clear. Overdose can occur easily. The overdose signs are similar to those for other sedatives, with drowsiness, nausea, vomiting, headache, loss of consciousness, loss of reflexes, and suppression of breathing, leading up to death. Epileptic seizures may also occur. Please be aware that routine toxic screens in the emergency room are often not set up to detect GHB. Therefore, if anyone shows signs of these problems, it is critical to get medical help and tell the medical personnel that GHB may be present.

Often GHB is taken with ethanol, and this violates the cardinal rule of not combining sedatives. A very recent pharmacological study in humans indicates that toxic effects of the two drugs are additive, lowering blood pressure and decreasing blood oxygen.


Perhaps the worst problem with GHB is the development of tolerance and withdrawal. When the first edition of this book was written, we knew nothing about the effects of long-term use of GHB, but now we know a lot, and the news is very bad.

Here’s how the problem typically develops, according to a psychiatrist who regularly treats GHB-dependent patients. A person will discover that GHB produces a high somewhat like alcohol, and with higher doses, sedation. That person uses the drug recreationally, at social events, for the

euphoria. Then one night the person has trouble falling asleep and turns to GHB as a sedative. After many uses, the person reaches the point that he or she is using the drug every few hours, twenty-four hours a day, seven days a week. Typically a person in this state can sleep no more than two to four hours before waking and needing more of the drug.

The GHB withdrawal process can be devastatingly difficult for a highly tolerant and dependent person. Within hours of stopping GHB, the person experiences insomnia, anxiety, and perhaps psychosis. The physical symptoms are somewhat like those associated with profound ethanol withdrawal—tremors, agitation, high heart rate, and high blood pressure. Often the person cannot withdraw without medical help, and usually this means admission to a hospital where physicians skilled in addiction medicine can taper the dosing of GHB and administer high doses of sedatives to allow the person to slowly come out of withdrawal.


GHB is synthesized in the brain through several metabolic pathways, and this has provided a way for people to get a GHB-like high without having to purchase the now-illegal substance itself. The solvents GBL (gamma- butyrolactone) and 1,4 BD (1,4 butanediol) are metabolized in the brain to GHB; when ingested, they both produce the same effects as GHB itself. There’s a real problem with 1,4 BD—the metabolism of 1,4 BD to GHB is inhibited by ethanol. So if a person drinks alcohol and takes 1,4 BD, then the conversion to GHB is delayed until the ethanol is eliminated, and the user can have an unexpectedly delayed GHB effect.


Because GHB is growing in popularity, easy to manufacture, readily found in nightclubs, and hard to detect in a drink, it is important to be alert to the possibility that someone may add it to a drink. If a person begins to feel weak, dizzy, light-headed, or mentally confused after a drink that should not produce such feelings, consider getting that person medical help. At this point, there is no FDA-approved antagonist for GHB. Good medical support early on can prevent most of the problems that ingesting GHB will cause.




Drug Class: Anabolic steroids. All of the drugs mentioned in this chapter are legally considered Schedule III drugs (classified by the Drug Enforcement Administration as having some potential for abuse but having accepted medical uses).

Individual Drugs: testosterone; methyltestosterone; boldenone (Equipoise); methandrostenolone (Dianabol); stanozol (Winstrol); nandrolone (Durabolin, Dex-Durabolin); trenbolone (Finajet); ethylestrenol (Maxibolin); fluoxymesterone (Halotestin); oxandrolone (Anavar); oxymetholone (Anadrol); androstenedione, dehydroepiandrostenedione (DHEA); selective androgen receptor modulators (SARMs), including ostarine, andarine, ligandrol, cardarine, and enobosarm

Common Terms: steroids, roids, juice

The Buzz: Steroids do not cause a buzz immediately when they are taken because they don’t take action for hours. After a typical “stacking” regimen lasting several weeks, some users report feelings of euphoria, great energy,

and increased combativeness/competitiveness. Such users complain of depression when they stop using anabolic steroids.

Overdose and Other Bad Effects: Anabolic steroids do not cause death by acute overdose in the same way that opioids or other psychoactive drugs do. However, they cause many changes in body function that can lead to serious injury or death. Serious heart damage and even death from heart attacks or stroke have occurred in people using high-dose anabolic steroids for a prolonged period of time.


What Are Anabolic Steroids?
Normal Testosterone Effects
A Brief History of Anabolic Steroid Abuse
How Are Anabolic Steroids Used and Are They Effective? What Are the Hazards of Anabolic Steroid Use?
Are Anabolic Steroids Addictive?


Testosterone and drugs that act like testosterone in the body are called anabolic steroids. The term steroid refers to their chemical structure, and the term anabolic refers to their ability to promote muscle growth. Testosterone production during adolescence is responsible for both sexual maturation and the growth in height and muscle mass that men experience at this time. Physicians prescribe anabolic steroids to men who have inadequate testosterone production. Male and female athletes, both professional and amateur, use anabolic steroids illegally for their ability to increase muscle mass. There are other natural steroid hormones, but they are not anabolic steroids. Estrogen and progesterone are the reproductive steroids that are present in females, and cortisol is a catabolic hormone that breaks down muscle and is normally released by the adrenal gland under conditions of stress. Normally, the main anabolic steroid present in the body is testosterone. Obviously, men have much more than women, but women

produce a small amount of testosterone as well. The steroids that people take to treat asthma and other inflammatory conditions are not anabolic steroids; instead, they are variations on cortisol. So asthma sufferers who take steroids for their condition should not worry that they are using a dangerous drug.

Nearly all anabolic steroids, as well as their precursors and derivatives, are Schedule III according to the DEA, and available only by prescription. The only exception is the precursor dehydroepiandrosterone (DHEA), which is a normal hormone in the human body, and can be converted to both estradiol and testosterone, although not in amounts that improve athletic performance. Most of the steroids used illegally have been diverted from appropriate medical or veterinary use, or have been prepared by clandestine labs and packaged in a way that resembles the real product. Testosterone itself appears as pills or as injectable solutions. There are also topical testosterone preparations including creams, gels, and skin patches that release small amounts of hormone that are absorbed through the skin. Testosterone is a natural hormone, and so it has the advantage of not having unexpected toxicities. For users, its disadvantage is that the body eliminates it quickly. There are numerous synthetic derivatives; the most common ones in the clandestine market include boldenenone, methandrostenolone, stanozol, nandrolone, and trenbolone. Each of these has the same effects as testosterone but remains active longer.

There are a number of steroid hormone precursor products on the clandestine market, including androstenediol, DHEA (dehydroepiandrosterone), and norandrostenedione, all used for the common goal of increasing the production of testosterone or other androgenic hormones that normally exist in the body in trace amounts. And they all share a common problem: it is difficult (but not impossible) to achieve anabolic levels of the hormones by taking these supplements.

Finally, biomedical scientists have developed several “SARMs,” or specific androgen receptor modulators, that specifically target anabolic actions of testosterone in the muscle and bone, without effects on reproductive organs. These include ostarine, andarine, ligandrol, and cardarine. None of these has been approved yet by the FDA, and they exist only as research chemicals (and in the clandestine market). They may prove to have the advantage of not suppressing reproductive function or raising concerns about prostate cancer. Finally, supplement manufacturers remain

busy selling testosterone “look-alikes” which mostly contain vitamins and various amino acids and herbs that are touted as “testosterone raisers,” including tribulus, agmatine, higenamine, stinging nettles, and many others. While some of the ingredients like aspartic acid cause extremely small increases in testosterone in medically healthy but sedentary men, they are ineffective in highly trained men, and the increases were not enough to change muscle metabolism in a meaningful way.


In a normal man, testosterone is present from the time of fetal life. During fetal development, it is responsible for the development of the male genitalia, and it contributes to the differentiation of brain functions that are different in men and women, like reproduction and sexual behavior. During puberty, testosterone production increases dramatically in men, causing the rapid growth in height, the thickening and coarsening of body hair, the lowering of the voice, genital development, acne, and the muscle growth that happens at that stage of life. It influences the production of fat-carrying proteins in the blood and lowers levels of the “good” lipid-carrying protein that can protect against heart disease. Testosterone also contributes to the increase in libido that occurs at this age. Once puberty is over, testosterone levels tend to be fairly constant until the third decade, and decline slowly after that.


Physicians use testosterone to treat men whose bodies don’t produce enough due to delay in pubertal development, disease, or surgical removal of the testes. These men tend to be anemic, a serious condition that is easily reversed with hormone treatment. It is also used for its anabolic properties to facilitate tissue regrowth in burn patients and in AIDS patients who have severe weight loss. Recently, some doctors are using testosterone to restore libido and energy in men with “low T,” although this may be as much an advertising gimmick as a clinical condition. Testosterone can also be used to facilitate the development of secondary sex characteristics in individuals undergoing female-to-male sex conversions. Its use in intersex individuals

who wish to attain male phenotype is less well-established because many aspects of this condition do not respond to hormone treatment.

The Cold War introduced anabolic steroids into international athletic competition. The Communist countries of Eastern Europe started giving anabolic steroids to their athletes during training for international competition to improve performance in the 1950s and 1960s, and the improvement in performance was not lost on the rest of the world. Some of the athletes (for example, women swimmers from then East Germany) have since claimed that they were given these substances without their knowledge, although they recognized that they were receiving a very active drug because of the dramatic changes they noticed in their bodies. Other countries caught on, and by the mid-1960s, this use was common. By the early 1970s almost three-quarters of the athletes involved in middle- or short-distance running or in field events admitted to using steroids, and most of the weight lifters also used steroids. The use of anabolic steroids in Olympic competition was banned, and testing after competition began in 1976. Different amateur and professional sports associations have gradually adopted similar prohibitions. The National Football League started testing players in 1989. Major league baseball in the United States did not ban steroids until 1991 and started testing athletes in 2003. As a result of rigorous testing, the percentage of amateur and professional athletes who use steroids has declined markedly. Testing has become increasingly successful but has also resulted in a “shell game” in which athletes either use products that are not yet recognized by testers or learn how to stop use long enough before a tournament to avoid detection. The controversy surrounding the designer steroid tetrahydrogestrinone (THG) synthesized by BALCO (Bay Area Laboratory Cooperative) is a recent example. This molecule is a testosterone derivative that had never been used before and so was not banned. When a coach turned in a syringe filled with this unknown steroid, the hunt was on by the testing laboratory of Dr. Don Caitlin at UCLA. He identified the molecule in 2003, and since then, urine from a number of elite athletes has tested positive for THG, and a number of track and field records have been thrown into question. Growing concerns about the rapid spread of anabolic steroid use led Congress to place them under the Controlled Substances Act in 1991. This ban is gradually having some effect, and the number of high school students admitting to anabolic steroid use has gradually declined since 2000 to a current level of about 1 to 2 percent. However, the “shell game”

continues, and the newest members of this class of drugs, the SARMs, are appearing in athlete urine samples.

Unfortunately, the use of anabolic steroids has entered the mainstream. The online marketplace provides many opportunities to buy these drugs illegally. A Google search by an anabolic steroid researcher revealed 328,000 hits for “steroids for sale” in a 2014 article, and a similar search today comes up with 76,200,000 hits. The typical user is involved in weight lifting or other fitness activities and starts during his midtwenties. Recently, there have been rising reports of use by military personnel (despite an official ban on all anabolic steroids) and by police in urban areas. Use by women is rare because of the irreversible side effects (see below). Much steroid use is undetected, because these drugs do not cause immediate overdoses that lead to ER visits, as opioids do, and doctors generally do not ask about them (nor do users typically volunteer the information).


Normally, testosterone is released constantly by the testes, and when doctors try to treat male patients who have inadequate testosterone, they try to provide steady, low levels. This is not how steroid users typically use them. One way that sophisticated users take anabolic steroids in preparation for or during competitions is by using creams or skin patches to temporarily boost levels of the natural hormone testosterone to levels in the top of the normal range: this can evade some testing approaches. Testers figured out how to thwart this strategy by testing the ratio of testosterone to a minor metabolite, epitestosterone, which is present at no more than a 4:1 ratio normally. When the ratio is very high (over 6:1), it almost always indicates testosterone use. Then sophisticated athletes started using T:E combinations. Testers most recently base assessment on the ratio of C13:C12 in testosterone precursor and metabolites in urine: testosterone from synthetic sources has a different ratio than that produced by the body. Both tests caught Floyd Landis cheating in the 2006 Tour de France. Another way that athletes cause a temporary boost in the body’s production of testosterone is by using natural hormones that stimulate the pituitary (gonadotropin-releasing hormone, GnRH) or testes

(luteinizing hormone, LH, or human chorionic gonadotropin, HCG) to make more testosterone.

Usually, athletes use anabolic steroids in a “stacking” regimen: a cycle that lasts four to eighteen weeks, starting with low doses of several steroids, gradually increasing the dose every few weeks, then taking some weeks off. The amounts they take are huge in comparison to normal regimens used by doctors. A normal replacement regimen would be about seventy-five to one hundred milligrams of testosterone a week, while a comparable regimen of self-administered testosterone can be from ten to a hundred times the normal medical dose. Some of the anabolic agents used in this way are listed at the start of the chapter, but the list is always changing and expanding.

The huge doses that users often take may explain the difference between public perception and scientific results. For many years, the scientific establishment denied that anabolic steroids could cause any real improvement in athletic performance. This conviction was based on results of controlled scientific studies done on men who were not particularly fit and who already had optimal levels of testosterone. They put them all on an exercise regimen and gave some men testosterone and others a placebo. All of the men usually improved in performance because of the exercise regimen. Because the male body makes about the optimal amount of testosterone, adding a little usually has little impact.

The situation for bodybuilders and others who use anabolic steroids is quite different—they are maximally fit to start, just looking for that slight edge, and taking huge amounts does improve performance enough for that winning edge. Although testosterone normally works only on its own receptor to build muscle, when such huge amounts are taken, scientists have speculated that it “spills over” onto the catabolic steroid receptor and prevents the effects of cortisol. So instead of just muscle building, huge amounts of anabolic steroids might prevent muscle breakdown, too. Finally, it is possible that just the sense of energy that anabolic steroids can give, or even the psychological boost of taking a performance-enhancing drug, can have a real impact on performance in sports. In a highly competitive environment of optimally trained athletes, the appearance of advantage may be all that is necessary.

Anabolic steroids definitely improve muscle deposition in women, even in normal amounts; in the amounts taken by athletes, the improvement in

muscle deposition can be dramatic. Because muscle deposition promoted by testosterone tends to be greater in the upper body, this provides the greatest effects (and therefore the greatest likelihood of abuse) for sports like swimming that rely on upper-body strength.


There is no question that anabolic steroid use can cause bad health consequences. However, extravagant claims on both sides of this argument have flown back and forth in the media. What is the scientific evidence? In women the evidence is clear-cut. Women usually make a small amount of testosterone, so the very high levels that result from taking anabolic steroids lead to the emergence of masculine characteristics: extra muscle deposits, a deeper voice, thicker and coarser body hair, male pattern baldness, and an enlarged clitoris. The anatomical changes caused by steroid use (deeper voice and enlarged clitoris) are irreversible. Also, women experience changes in the profile of blood proteins that promote heart disease and lose the normal protective effects of their sex on the heart and blood vessels. Similarly, in adolescent males, use of anabolic steroids can cause a premature end to puberty, including a stop to the rapid growth stimulated in part by testosterone during this phase of life. Some of the effects in adolescent boys, like those in women, are irreversible. Normally, the rise in testosterone during puberty stimulates skeletal growth and finally stops it by causing the growing ends of the bone to “close over” and stop lengthening. After this closing over has happened, no further increase in height is possible. Use of anabolic steroids can speed up this process, leading ultimately to a shorter height than expected.

In adult men, the doses that many athletes use suppress libido and halt sperm production. A growing number of case reports indicate that damage to the heart occurs in some users. It is also clear that levels of fat-carrying proteins in the blood of both male and female users change to a pattern that promotes heart disease, although this pattern reverses when steroid use is stopped. The combination of hypertrophy (increased growth) of the heart, increased tendency of the platelets to clot, and increased levels of lipids in the blood likely contributes to the increased risk of heart attack in men who use anabolic steroids to improve athletic performance. There are isolated

cases of liver disease and liver cancer that have been attributed to the use of particular steroids. On rare occasions, certain anabolic steroids cause the appearance of blood-filled cysts in the liver that can rupture and cause dangerous internal bleeding. Finally, testosterone can actually cause some feminizing effects in men. Breast development is the most common. This happens because a little bit of the testosterone in the body is converted to the female hormone estradiol. This condition commonly develops in weight lifters who use anabolic steroids. Most important, death (from any cause) is more common in men who use anabolic agents than in men of comparable age and health who do not.

What about “roid rage”? Do anabolic steroids really make people incredibly aggressive and prone to uncontrollable outbursts of rage and violence? This is the most controversial effect of these drugs. There is no question that anabolic steroids can affect behavior. They have been used successfully to treat depression in experimental studies, and there have even been a number of cases of anabolic steroid-induced manic episodes. Furthermore, as we note in the following, stopping use can cause depression.

However, evidence for the specific effects of testosterone on aggression is hard to find in controlled studies in humans. There have been small, much- publicized studies showing that testosterone levels were high in a subset of criminals who were known to have committed particularly violent crimes. There are many studies in rats and some in monkeys that show that high levels of steroids can affect aggressive behavior in specific tests. The behavior they describe is not the sort of irrational destructiveness that is so popular in the lay press. Instead, animals often simply compete better or fight more quickly when provoked. To extrapolate from these studies to explain the behavior of individual men requires a leap. For the moment, we are left with reports of users who describe their own absolutely uncharacteristic impulsive aggressive behavior while under the influence of anabolic steroids. Learning from the wrong conclusions scientists drew from their first inadequate experiments with muscle deposition, we should take these reports seriously because there simply aren’t controlled laboratory studies of the behavioral effects of the tremendous dosage regimens that some athletes use.


Anabolic steroids certainly meet the first criterion of addiction—that users take them in the absence of medical need and despite the knowledge of negative health consequences. This was the basis for their being placed under the Controlled Substances Act. But are they addictive? Users do feel differently when they take steroids, and the feelings are mostly positive. They also experience a withdrawal syndrome when they stop. Some users report fatigue, depression, loss of appetite, insomnia, and headaches as the effects of the drugs wane. However, users don’t report a rush of euphoria when they take steroids; there are no recognizable effects of taking an injection. Furthermore, laboratory studies show that animals generally don’t self- administer them, although there are some interesting exceptions. Anabolic steroids don’t cause the kinds of changes in the brain caused by other addictive drugs like cocaine and heroin. However, it is clear that people develop a compulsive reliance on them and willingly tolerate negative health consequences when they are using them—both of which are criteria for drug dependence. Finally, a few intriguing experiments in hamsters have shown that some animals will voluntarily take anabolic steroids. Because the effects of sex hormones in the brain can be very species-specific, we are awaiting confirmation in a wide array of species before we extend these results to humans.

Are there good health reasons for anabolic steroids to be illegal in sports? Given the real health problems caused by these drugs, this ban does make sense. In the end, the normal male body produces optimal amounts of testosterone for health and vitality, and providing suprapharmacologic amounts provides a scant benefit in terms of slightly better muscle deposition at a great health cost. The focus on success at any price, even in amateur athletics, has encouraged the use of anabolic steroids worldwide. Better education about the consequences should make people wary of using or recommending them.



Drug Class: Stimulants. All of the drugs mentioned in this chapter are legally considered Schedule I or II drugs by the Drug Enforcement Administration. Drugs that are used to treat ADHD (amphetamine, methamphetamine, methylphenidate) have a valid medical use and are Schedule II. Others are Schedule I. Purchasers must show identification to purchase stimulant precursors like pseudoephedrine.

Individual Drugs: cocaine, amphetamine (Adderall, Dexedrine), methamphetamine, methylphenidate (Ritalin), cathinone, methcathinone, 4- methylmethcathinone (mephedrone), 3,4-Methylenedioxypyrovalerone (MDPV), 3,4-methylenedioxymethcathinone (methylone), alpha- pyrrolidinovalerophenone (alpha-PVP, flakka)

Common Terms: coke, blow, candy, crack, jack, jimmy, rock, nose candy, whitecoat (cocaine); crank, bennies, uppers (amphetamine); meth, crystal, crystal meth, ice (methamphetamine); Ritalin (methylphenidate); cat, khat, crank, goob (methcathinone); Ivory Wave, Bliss, Bubbles, Meow, Explosion, Vanilla Sky (bath salts); gravel, flakka (alpha-PVP)

The Buzz: Stimulants are aptly named: these drugs cause a sense of energy, alertness, talkativeness, and well-being that users find pleasurable. At the same time, users experience signs of sympathetic nervous system stimulation, including increased heart rate and blood pressure and dilation of the bronchioles (breathing tubes) in the lungs. These drugs also cause a stimulation of purposeful movement that is the reason for their description as psychomotor stimulants. When injected or smoked, these drugs cause an intense feeling of euphoria. With prolonged and high-dose use, the locomotor activity often becomes focused in repetitive movements like drawing repeating patterns.

Overdose and Other Bad Effects: There are three kinds of dangers with the stimulants. First and most important, at high doses (these are doses a person could take accidentally), death can result. High-dose cocaine use can lead to seizures, sudden cardiac death, stroke, or failure of breathing. Lethal doses of amphetamine sometimes cause seizures but more often can cause lethal cardiac effects and/or hyperthermia (fever). As with opioids, any of these drugs can cause death with a single dose, and this is particularly easy with cocaine. The second kind of danger is psychiatric. With repeated use of high doses of stimulants over days to weeks, a psychotic state of hostility and paranoia can emerge that cannot be distinguished from paranoid schizophrenia. With some of the new, particularly effective “bath salts,” a toxic delirium with psychotic-like behavior can occur as a result of a single very high dose. Finally, addiction can develop to any stimulant.

Dangerous Combinations with Other Drugs: Stimulants can be dangerous when taken with over-the-counter cold remedies that contain decongestants, because the effects of the two can combine to raise blood pressure to a dangerous level. Also, stimulants can be dangerous in combination with the antidepressants known as monoamine oxidase inhibitors, because they will enhance the effects of the stimulants. Cocaine is dangerous with anything that would affect heart rhythm, such as medication taken for certain heart diseases, because these drugs would act in an additive way with the effects of cocaine on the heart. Cocaine is also dangerous in combination with anything that makes people more sensitive to seizures, such as the prescription medication buspirone (BuSpar) or extremely high levels of xanthines, like caffeine or theophylline.


The yuppies of the eighties certainly did not invent cocaine use. Cocaine has been used for centuries by the natives of South America. Amphetamine, on the other hand, was the product of the pharmaceutical industry—the result of successful attempts to improve upon ephedrine as a drug for treating asthma.


Cocaine appears in the leaves of several species of plants, including the shrubby plant Erythroxylum coca, that grow in the Andes Mountains in South America. Coca use as early as the sixth century is documented in archeological relics from South America, but it probably started much


The History of Stimulant Use
The Story of Cocaine
The Story of Ephedrine and Amphetamine

What Stimulants Are Used Today? How Stimulants Move through the Body

Amphetamine and Methamphetamine Ephedrine and Ephedrine Substitutes Methylphenidate

What Stimulants Do to the Brain
What Stimulants Do to the Rest of the Body

Effects on the Fetus

Methylphenidate and Use of Stimulants to Treat Attention Deficit/Hyperactivity Disorder

How Stimulants Work
Stimulants Prevent Monoamine “Recapture”
How Is Amphetamine Different from Methylphenidate or Ephedrine? Cocaine Can Cause Seizures

Addiction, Tolerance, Dependence, and Withdrawal Diet Pills
Stimulant Toxicities and Overdoses

earlier. The natives of South America chewed coca leaves for their alerting effects and their ability to increase endurance, particularly at the high altitudes in which many of these peoples lived. This practice continues to the present day. When the Spaniards conquered the Incas in the sixteenth century, they attempted to ban its use until they realized that the Indians working in the silver mines would work harder if given their daily allotment of coca.

With the importation of coca to Europe and the purification of cocaine from the leaves by the German scientist Albert Niemann in 1860, a new era began. The Corsican chemist Angelo Mariani was partly responsible for popularizing the use of cocaine by inventing Vin Mariani in 1869. Vin Mariani was a “medicinal” wine made by steeping coca leaves in wine, and it became the rage of Europe. Soon thereafter, the American pharmaceutical industry took note, and Parke-Davis started manufacturing a cocaine- containing tonic. The success of this tonic spawned a host of imitators, including Georgia pharmacist John Pemberton’s Coca-Cola, a tonic containing a (still) secret formula that included cocaine. Another pharmacist, Asa Candler, realized the financial potential of this concoction and purchased the rights to the formula. The rest is history, as his Coca-Cola Company became a fixture in the American landscape and now the world.

Sigmund Freud, known to most as the father of psychoanalysis, was also one of the major forces in the popularization of cocaine in Europe. Freud studied cocaine using the well-accepted practice of the time—self- experimentation. He took the drug and recorded his experiences. His initial reports were overwhelmingly positive: he enjoyed the sense of euphoria and energy and found little in the way of toxic effects. His enthusiasm caused him to encourage his friend Ernst von Fleischl-Marxow to try cocaine in an attempt to free himself from morphine addiction. This turned out to be a misguided idea, as his friend quickly substituted morphine dependence with cocaine dependence. His pattern of use escalated to intravenous injections of larger and larger doses until he developed psychotic symptoms, one of the first recorded cases of stimulant psychosis. Freud was also responsible for noting the ability of cocaine to produce local anesthesia (numbing), and his mention of this quality to a friend, ophthalmologist Carl Koller, led to the widespread use of cocaine in certain types of eye, ear, and nose operations that persists to the present day.

Why isn’t there still cocaine in Coca-Cola? The tale is familiar in today’s environment of public activism about product safety. During the early 1900s, unregulated sales of “tonics” containing potent ingredients such as opium and cocaine boomed. Some of these formulations contained so much cocaine (hundreds of milligrams per milliliter instead of the 0.5 milligrams per milliliter in the original Parke-Davis formula) that toxicities became widespread. The medical establishment finally took note. Unfortunately, a scare campaign with racist overtones also contributed to the public furor. Reports that cocaine made African Americans powerful and uncontrollable contributed to the wave of negative publicity. In 1906, the Pure Food and Drug Act required that manufacturers list the ingredients on all tonics, and in 1914, the Harrison Narcotic Act imposed severe restrictions upon the distribution of opium and cocaine products. Today, Coca-Cola contains only caffeine, and clinical cocaine use is restricted to a few surgical procedures.


The story of ephedrine and amphetamine is not dissimilar. The Chinese drug mahuang was long known to help treat the breathing symptoms of asthma. Dr. K. K. Chen of the Eli Lilly Company in the 1920s identified the compound ephedrine as the active agent in mahuang, and ephedrine quickly became an important treatment for asthma. At the time it was first identified, it was a useful medicine. However, there was not an easy way to make synthetic ephedrine, so it had to be extracted from the native plant, which was in short supply. A few years later, a chemist named Gordon Alles synthesized amphetamine in an attempt to develop a synthetic form of ephedrine. Little did he realize that he had succeeded too well. Amphetamine was quickly marketed in several forms, including a volatile preparation. Nasal amphetamine inhalers gained quickly in popularity, in part because amphetamine proved to do much more than simply dilate the bronchioles—it produced a stimulation and euphoria that ephedrine lacked almost completely. Use of amphetamine for these properties spread rapidly during the 1930s. In a parallel development, Japanese scientists synthesized methamphetamine marketed as Philopon with the same enthusiasm in Japan. Soldiers of many countries, including Germany, Japan, and the United States, used amphetamine during World War II to maintain alertness during long tours of duty. After World War II, amphetamine and methamphetamine use

moved even more widely into the civilian populations, and Japan experienced the first known wave of stimulant addiction. Episodes of abuse of these highly addictive stimulants have occurred ever since. In the 1960s, amphetamine use had become widespread enough that the dangerous effects of stimulants were rediscovered and given voice in the slogan “Speed kills.” The “meth” epidemic in the United States and Asia today represents the most recent of three postwar waves of amphetamine abuse. Amphetamine is still popular with the military, too. Soldiers in the Gulf War used amphetamines, and recent reports have suggested that American fighter pilots in Afghanistan maintained the tradition.

Our lack of cultural memory is remarkable: we keep rediscovering the beneficial and toxic effects of psychomotor stimulants. As soon as the popularity of amphetamine waned, the cocaine abuse of the 1970s began. The widespread availability of a volatile form (crack) that could be inhaled led to a remarkable rise in addiction and toxicity, in a manner reminiscent of the Benzedrine craze of the 1930s. Then, as the dangers of crack emerged and its popularity dwindled, a new drug appeared on the horizon. “Ice,” the volatile form of methamphetamine (an amphetamine derivative), spread rapidly during the mid-1990s, sparking a new wave of addiction and toxicity. Amphetamine-related emergency room admissions increased 460 percent from 1985 to 1994 in California alone, and another 67 percent from 1994 to 2001. In 2006, law enforcement personnel in the United States listed meth as the number one drug problem they face, and today, most law enforcement officials rate it second only to heroin. In 2010 to 2011, the new wave of “bath salt” abuse led to a rapid rise in ER admissions for these novel psychostimulants. This continues today, with continual addition of new “designer” stimulants with novel structures that are intended to evade legal restrictions, but which also have unknown actions. As abuse of prescription opioids has finally begun to fall, an alarming increase in methamphetamine and cocaine abuse is occurring in some of the same communities that still suffer most from the oxycodone/heroin/fentanyl epidemic. The National Survey of Drug Use and Health reported that 1.1 million Americans started using cocaine in 2016, a 60 percent increase from 2013. Although this survey could not measure the number of new meth users due to a change in the survey, changes in admission to treatment, overdose deaths, and other metrics suggest that comparable increases have occurred in methamphetamine use,

although the total number of new users (192,000) in 2016 was lower than in 2015 but rebounded in 2017.


The major stimulants used in the United States today (aside from caffeine, discussed separately in its own chapter) are cocaine, amphetamine, and methamphetamine. Although the press from law enforcement might indicate otherwise, new cocaine users still outnumber new meth users almost five to one. Abuse of methylphenidate (Ritalin), normally prescribed to treat attention deficit disorder, is rising in student populations. Recent studies show that up to 30 percent of college students in some surveys have used a prescription stimulant either as a study aid or recreationally. The most troublesome news on the stimulant abuse front is the rapid spread of designer psychostimulants that are so potent that they are associated with a rising number of ER visits for toxic delirium and psychotic symptoms as well as overdose deaths. These are often marketed as bath salts or plant food, labeled not for human consumption.

Cocaine is used medically as a local anesthetic, but on the street, the two most common forms are the white powder that is either snorted or dissolved for injection, and crack, a solid chunk of cocaine that is heated directly in a pipe to form a vapor that is inhaled into the lungs. Both the powdered cocaine and crack are prepared from leaves of the coca plant, which are mixed with solvents and processed through several steps to remove the cocaine from the leaves and purify it as crystals. Crack is prepared from the powder by boiling it with sodium bicarbonate. Chunks of cocaine base precipitate from this solution. This simple process has a tremendous impact on the speed with which cocaine is absorbed, as we will see in the following. Colombia is the source of most of the cocaine that arrives in the United States.

The powdered form of cocaine is usually diluted with other white powders such as cornstarch, talcum powder, lactose, or mannitol, and/or with other local anesthetics, caffeine, or, sometimes, amphetamine. The purpose of the inert powders is economic: to dilute an expensive drug with cheap substances. These ingredients provide some semblance of the sensations associated with cocaine but with cheaper drugs—caffeine or

amphetamine for alertness, and local anesthetics for the numbing sensation that users associate with real cocaine. However, the purity of cocaine has been steady for several years; it was about 50 percent in 2016, the most recent year for which the DEA provides statistics.

Users usually snort powdered cocaine, which then enters the body by absorption through the mucous membranes and into the blood vessels of the nose. Sometimes it is applied to other places, including the mouth, rectum, penis, or vagina. The purpose here is the same: to promote absorption across highly vascular mucous membranes.

Amphetamine and methamphetamine appear in diverse forms: pills, powders of varying colors, or chunks that look like cocaine. While there is some diversion from medical sources, the majority is from clandestine labs. Mexican “superlabs” have provided much of the methamphetamine in the last few years since the crackdown on small, local labs in the United States. However, local labs have not vanished, as manufacturers find alternative supplies of the precursor pseudoephedrine, which has been strongly regulated in the United States since the 2006 law that required customers to show identification for any purchase of cold products containing pseudoephedrine or phenylpropanolamine. Methamphetamine is sold in many forms, including loose forms like powders or “rocks,” as well as in capsules or tablets of various types. Many college students buy amphetamine or methamphetamine pills intended for the treatment of attention deficit disorder. The smokable form appears as chunks called “ice,” which are heated and smoked like the crack form of cocaine. Methylphenidate (Ritalin) is the well-known drug prescribed to treat attention deficit disorder. It is also a psychomotor stimulant that is used for studying as well as recreation by a growing number of students. Most users obtain it in pill or tablet form from someone who has a valid prescription for its use, or from underground sources that have diverted it from clinical use.

There is an alphabet soup of amphetamine derivatives, including trimethoxyamphetamine (TMA), 2,5 dimethoxyamphetamine, 4- methamphetamine (or Serenity, Tranquility, Peace), methoxyamphetamine (STP), methylenedioxyamphetamine (MDA), and paramethoxyamphetamine (PMA), which are all chemically related to amphetamine. These are synthesized in bootleg laboratories and appear in diverse forms. Most of these drugs have effects like those that MDMA or hallucinogens produce

rather than like those of amphetamine and are discussed in the Hallucinogens chapter.

There are also a number of synthetic stimulants with more typical stimulant effects that enjoyed temporary popularity as appetite suppressants or asthma medications until their abuse potential became recognized. Bootleg versions of many of these are available in some places (4-Methylaminorex [4-MAX, U4EU] and pemoline are two such drugs). The synthetic stimulants are sometimes called “designer drugs” because they are produced by altering the molecular structure of parent drugs so that they have a different profile of action. Some of these structural variants have been synthesized for legitimate research purposes, while others have been created by illegal producers or drug abusers to satisfy specific preferences.

Khat (also spelled “qat” or “quat”) is a stimulant in a leafy plant that grows in Africa. For centuries native peoples in Africa and the Middle East have used khat in social settings to promote conversation and improve social interactions. With the urbanization of many native populations in Africa, khat use in certain groups has extended to Europe, Great Britain, and, recently, the United States. The active ingredient in khat is cathinone, an amphetamine-like stimulant. Synthetic variants of cathinone (methcathinone, 4 methylcathinone, or mephedrone) have become more prevalent among bath salts. They are much more potent stimulants with amphetamine-like actions.

The most common are 3,4-methylenedioxypyrovalerone (MDPV), 3,4- methylenedioxymethcathinone (methylone), and 4-methylmethcathinone (mephedrone). MDPV is the stimulant that appears most often in the United States. Mephedrone is found more in European drug samples. Methylone appears increasingly in pills sold as “Molly” or MDMA. There are many similar variants, including para-methoxymethcathinone (methedrone), 4- fluoromethcathinone (flephedrone), 3-fluoromethcathinone (3-FMC), naphyrone, butylone (bk-MBDB), and buphedrone, to name the most common. It is worth mentioning that alpha-PVP (flakka), which has received sensationalistic news reports of people “gone mad,” is another member of the bath salts group of stimulants. Its effects are similar to those of high doses of most other stimulants.

The DEA has scheduled all of these molecules as Schedule I (high potential for abuse, no currently accepted medical use). As with cocaine, the mild stimulant properties of chewing khat leaves have been replaced by the

intense high of the pure chemical substance. In an interesting “back migration” of substance-abuse habits, there are increasing reports of adverse effects from excessive khat chewing, especially among urban populations in Africa. The majority of bath salts come from China. Before they received Schedule I status, most were marketed quite openly as “bath salts, not for internal use” in head shops, but internet sources have also become more common.


The different purification methods that produce powdered cocaine and crack have a huge impact on how they are delivered to the body. Because cocaine constricts the very blood vessels that absorb it, snorting is a relatively slow way to deliver cocaine to the bloodstream. Blood cocaine levels rise relatively gradually and don’t reach a peak until about thirty minutes after snorting. Cocaine in its “crack” form, in contrast, forms a vapor that users inhale. This delivers cocaine as quickly to the circulation as injecting the drug intravenously. Maximum levels occur within a minute or two, and blood levels of cocaine at this time are much higher than ever observed after snorting comparable doses. Users often prefer the fast and intense rush that results from smoking crack. However, this rapid delivery of more drug also means a greater risk of addiction or overdose.

Liver and blood enzymes degrade about half of a cocaine dose in about an hour. This means that a user is usually ready for another dose in about forty minutes or less. The rapid rise in blood levels, followed by a rapid fall —a rush followed by a crash—often leaves the user wanting to reexperience the original high. This rush-and-crash phenomenon can lead the cocaine user to keep taking additional doses until blood levels accumulate to toxic levels. This “run” often continues until the user either runs out of drug or has a seizure or some other sign of toxicity.

Ingesting cocaine is a much less effective route of delivery. The process is slower, and the liver degrades much of the drug before it ever reaches the circulation. For this reason, the average blood levels of cocaine in people chewing leaves is very low compared to the amounts present in the blood after smoking crack or snorting powder. Similarly, single doses of the

original patent formulas, like Vin Mariani, with fairly low levels of cocaine (six milligrams per ounce) probably resulted in relatively low blood levels of the drug with a single dose.


Amphetamine and methamphetamine, like cocaine, enter the bloodstream very quickly when users smoke or inject them. This leads to a rapid high and to a greater likelihood of toxicity. Unlike cocaine, amphetamine and methamphetamine are also effective if they are ingested as pills, because they are destroyed more slowly in the liver and enter the circulation effectively. Amphetamine and methamphetamine are degraded more slowly than cocaine, and so effects last at least two to four hours. This leads to less of the rush- and-crash pattern of injecting the drug. However, heavy users still tend to use in binges over several days followed by a period of exhaustion that they call “tweak and crash.”


Ephedrine is almost always ingested as either a pill or tea, and it enters the circulation easily. Ephedrine reaches its peak effect in about an hour and lasts for three to six hours. However, many supplement manufacturers have replaced ephedrine with somewhat similar molecules, including dimethylamylamine, beta-phenylethylamine, and synephrine (bitter orange). These are supplied mainly as pills that users ingest to improve athletic performance. Most of these molecules are well absorbed, but only betaphenylethylamine enters the brain well. These are discussed in more detail in the Herbal Drugs chapter.


Methylphenidate exists typically in pill form. It is well absorbed from the intestine. The drug effects last two to four hours in a simple pill, although there are many different extended-release preparations. Addicts have been known to crush the pills and inject them. This practice is extremely dangerous because the other components in the pill can lodge in tiny blood vessels in the lung and eye and cause serious damage. Students have tried to crush the pill and snort it in the hopes that a high would result. However,

absorption from this form is slow enough and the dose of most pills low enough that the buzz, if any, is not particularly different from taking a pill. Methylphenidate enters the brain but more slowly than cocaine and amphetamines, which may be one reason that compulsive abuse of methylphenidate is fairly rare.


Khat in its native form is ingested as a tea or chewed as leaves of the native plant. However, users today typically snort or inject purified cathinone. Similarly, users snort bath salts (MDPV), and both MDPV and methylone appear often in tablet form. These pills often contain a variety of compounds, sometimes with other drugs thrown in. The distribution of these drugs in the human body has not been extensively studied, but all enter the brain quickly. The high lasts for several hours, longer for some like MDPV.


Amphetamines and cocaine are best known for their ability to increase attention, cause alertness, and eliminate fatigue. Amphetamines are popular in the United States to increase attention and delay sleep and as medical treatments for attention deficit disorder and narcolepsy (a disease in which the patient falls asleep repeatedly during the day). Even Freud commented that the most probable use of cocaine would be for these properties: “The main use of coca will undoubtedly remain that which Indians have made of it for centuries: it is of value in all cases where the primary aim is to increase the physical capacity of the body for a given short period of time and to hold strength in reserve to meet further demands. . . . Coca is a far more potent and far less harmful stimulant than alcohol, and its widespread utilization is

hindered at present only by its high cost.”* People who have taken stimulants are often talkative and full of energy, movement, and confidence to the point of being restless and grandiose in thinking that they can accomplish anything.

If stimulants simply increased energy and alertness, they indeed would be the miracle medicine that Freud proposed. However, these drugs also cause an unmistakable euphoria and sense of well-being that is the basis of addiction. People who inject or smoke cocaine describe a rush of intense

physical pleasure that they often compare to orgasm. When these drugs are taken in a form that is absorbed more slowly (snorting or taking a pill), this feeling is much less intense and may simply be recognized as a feeling of well-being.

Stimulants also cause an increase of movement, which is the reason for their name. Stimulant users are in constant motion—talking, moving, exploring, and generally fidgeting. At higher stimulant doses, this motion becomes a more focused, repetitive action. People who have taken high doses of amphetamine will doodle in repetitive patterns or engage in repetitive tasks or even pick at their skin repeatedly. Laboratory animals do the same thing. At low doses, amphetamine-treated animals move incessantly about the cage, as if they are constantly searching the environment. After a high dose, animals will sniff back and forth in one spot in the cage, or engage in repetitive grooming or chewing.

At very high doses, or after prolonged use, stimulants can cause a psychotic-like state that resembles paranoid schizophrenia except that the symptoms usually resolve quickly when the user is hospitalized. These symptoms often occur when a user is at the end of a “run” of some days and blood levels are very high. However, people with excited delirium with psychotic behaviors are also showing up in emergency rooms from the new bath salt preparations. One reason may be that these drugs are often supplied as a powder, and as relatively new drugs on the scene, users are inexperienced and tend to overdose. While the conventional wisdom states that these symptoms go away when the user stops drugs, there is some suspicion that this can take a very long time in a chronic stimulant user (months to years).

People sometimes use cocaine or methamphetamine in combination with heroin or other opioids. This combination is called a “speedball.” The effect on the brain and behavior is somewhat like the addition of the two. The dreaminess of opioids is added to and cuts the edginess and arousal caused by cocaine. This combination can be particularly dangerous: often people who are injecting cocaine slow down their intake of the drug when the jitteriness gets too great, but in the presence of heroin, these feelings are not so obvious, increasing the risk of an overdose (of either cocaine or heroin). This is the combination of drugs that comedians Chris Farley and John Belushi and rap performer Chris Kelly were taking when they died. New

speedball versions have emerged from the current opioid epidemic in which users combine cocaine or methamphetamine with heroin or fentanyl.

Psychostimulants decrease appetite through actions in the brain. Amphetamine was the first diet pill and was popular for this use in the 1950s and 1960s. Its dependence-producing effects became a real problem in its use in diet aids, and psychomotor stimulants are not used for this purpose today; nonaddicting alternatives have been developed. All stimulants do this, and weight loss is a consequence of high-dose chronic use.


The aphorism “Speed kills” is well deserved. It reflects the understanding that the sixties drug subculture had of the effects that cocaine and amphetamine derivatives have on body functions. Cocaine and amphetamines mimic the effects of the sympathetic nervous system: they initiate all the bodily responses of the fight-or-flight syndrome. They increase blood pressure and heart rate, constrict (narrow) blood vessels, dilate the bronchioles (breathing tubes), increase blood sugar, and generally prepare the body for emergency. These effects can be beneficial. The effects on the lungs can actually improve the symptoms of asthma. Furthermore, fat is broken down to help mobilize energy, and this effect in combination with the suppression of appetite and excessive physical activity may contribute to the weight loss these drugs can cause. However, the effects on the heart can be so excessive that they may result in a disordered heartbeat or, eventually, failure of the cardiovascular system. Most of the stimulants mentioned in this chapter have these effects, and overdose deaths from cocaine, amphetamine, and bath salts typically result from their cardiovascular effects.

Most of the stimulants also increase body temperature, which presents a real problem when amphetamines are used in situations involving exercise. At the same time, amphetamines and cocaine seem to increase the capacity for muscular work. Whether this represents a real improvement in muscle function, a better delivery of sugar to fuel muscular work, or simply the perception of greater energy, these drugs have been popular with some endurance athletes, like cyclists, and with those attending all-night rave dance parties to permit dancing all night. Extreme physical exertion increases

body temperature even without the amphetamine; with amphetamine added, the increase in body temperature can become fatal.


Effects on “crack babies”—babies born to women who abuse crack or other psychomotor stimulants during pregnancy—have probably stimulated more public scrutiny and more public outcry than any other consequence of drug addiction in the United States. The alarms are again being raised for meth babies. Are the minds and bodies of these infants destroyed by their prenatal exposure to the drug? The answer is very hard to know, partly because almost no person abuses only one drug. The pregnant women who abuse cocaine almost invariably smoke cigarettes and abuse alcohol as well. Furthermore, they tend to have poor access to health care and as a result often do not receive adequate prenatal care. It is very difficult to distinguish the role of cocaine itself in any problems the infants experience.

Nevertheless, exposure to these drugs in utero can cause serious problems. Many cocaine- or methamphetamine-exposed babies are born prematurely and with low birth weight; a few have experienced catastrophic events, like strokes, before they were born. Cocaine use is also associated with premature separation of the placenta from the uterus, a condition that can cut off the baby’s blood supply and result in brain damage or death. However, if babies are carried to term, the consequences for many may not be drastic. There are small increases in the rate of birth defects, but this is not the major problem that it is for babies exposed to high levels of alcohol during pregnancy. Many stimulant-exposed infants are extremely irritable and overly sensitive to any form of sensory stimulus at birth. This condition usually improves, and the infants develop pretty normally. Many of the effects at birth (low birth weight, increased frequency of prematurity) are not unique to cocaine but also happen in babies whose mothers smoked tobacco during pregnancy. Nicotine and cocaine have something in common that explains this: both powerfully constrict blood vessels that supply blood to the fetus during pregnancy and deny the infant vital nutrients.

What is the prospect for these children as they grow up? As the first waves of cocaine-exposed children are moving through school, researchers are finding a higher incidence of learning disabilities and ADHD, much like the children of women who smoke heavily during pregnancy. However, they

are not significantly different from peers who share a low socioeconomic status and chaotic home lives. Nor do we have a clear answer as to whether exposing children to drugs in utero increases the likelihood that they will abuse drugs as adults. Likewise, we don’t know whether or how prenatal experience with drugs will affect later responses to drugs as these babies become adults: some studies find increased sensitivity to drugs in adulthood, and others find decreased response. Furthermore, biology is not destiny: many factors go into the development of drug use—not just brain biochemistry. In this regard, these children can be at an added disadvantage because they may well grow up in drug-using homes.


Methylphenidate (Ritalin) may be the most controversial stimulant in America today. It is not the most dangerous, nor the most abused. However, scientists, parents, teachers, and counselors all have opinions about its value as a medication. Methylphenidate is the most frequently prescribed medication for treatment of attention deficit/hyperactivity disorder (ADHD) in the United States, although amphetamine and several other stimulant and nonstimulant drugs may be used. There is little disagreement, at least in the scientific community, about whether these drugs improve attention. They do so in almost every clinical study that has been conducted. Furthermore, they do so for everyone. The myth of the “paradoxical” effects of stimulants is just that—a myth. Stimulants improve attention in normal people and in people who have poor attention. College students have discovered this, and some buy methylphenidate from other students, the internet, or sometimes even from cooperative doctors to study better. In some high-pressure academic environments, including colleges and medical schools, students view methylphenidate as a necessary tool in the competition for good grades.

Human imaging studies are providing new knowledge about how stimulants improve attention. We have learned that parts of the frontal cortex are active while we are paying attention and deciding whether to act upon information. This same area is also active when we are processing emotions. This part of the brain does our highest level of thinking; it is where we “think about thinking.” Stimulant medication affects these areas, and scientists think that maybe it corrects a deficiency in activity that exists in some people.

These are just hypotheses, and the way that stimulants work to improve attention is still uncertain. So what is the controversy? The controversy arises from the difficulty in diagnosing ADHD. There is a difference between a healthy, active child and an impulsive, impaired, constantly active child. Because teachers or parents often make the call, lack of classroom obedience often goes to the top of the list of “diagnostic criteria.” Many are concerned that we are medicating our children into submission, while health-care professionals argue persuasively that we need to treat children whose behavior is severely disordered. The role of medication in therapy is also a contentious issue. Health-care professionals insist that medication is not the sole solution and that it is best used in combination with appropriate behavioral strategies and lots of work with the family. It is unlikely that this controversy will be solved anytime soon. However, scientists are working hard to learn if there are any observable differences in the brain anatomy or function of people with ADHD and are studying possible genetic causes for ADHD. Studies emerging from this research have shown that certain parts of the brain that are the target of dopamine in children with ADHD reach “normal” adult structure at a later age than those of children without this diagnosis. These studies provide some tangible evidence that ADHD is a real phenomenon that merits treatment. Finally, the use by students assumes that if it helps people with ADHD to be normal, it can help a normal person to be better than normal. Unfortunately, this is unlikely. Your frontal cortex likes just the right amount of stimulation—too little or too much causes a deterioration in its function. Furthermore, the evidence that stimulants improve learning and memory is controversial. They may keep students awake to study and help children with ADHD focus on a task (like a test) so that they can complete more answers and score better. However, the
evidence that learning per se is better is contradictory.


What do euphoria, blood pressure, appetite, and attention have in common that causes them all to be affected by stimulants? These behaviors/bodily functions are all regulated by a related group of neurotransmitters—the biogenic amines, or monoamine, neurotransmitters. Norepinephrine, epinephrine, dopamine, and serotonin are the monoamine neurotransmitters.

They are related in structure, but each is a neurotransmitter in its own right that regulates a particular set of behaviors. Psychomotor stimulants increase the amount of monoamine neurotransmitters in the synapses. They vary widely from each other in terms of which monoamines they raise and how much they raise them. Some, like cocaine, raise all three. These stimulants mimic what would happen if every one of the neurons that released a monoamine fired at once. It’s no wonder that the effects of stimulants are so complicated. Others, like MDPV, raise only dopamine and norepinephrine, so the effects are more restricted. Research has shown that the behavioral and physiological effects of stimulants, from khat to bath salts, track predictably with the amount of each monoamine that the drug enhances.

Norepinephrine, as we mentioned earlier, is the chemical transmitter of the sympathetic nervous system. Epinephrine (or adrenaline) is the transmitter of the adrenal medulla, a special part of the sympathetic nervous system that is particularly important in fight-or-flight responses. Norepinephrine also exists in certain neurons in the brain. Norepinephrine neurons organize the behavioral part of the fight-or-flight response. They prepare the body and brain for emergency. This includes paying attention to your environment (not doing simple body maintenance things, like eating) and deciding whether the risk is so great that you should run away. This prepares the body for physical activity: making the heart beat faster, bringing glucose and oxygen to muscles, and widening the breathing tubes to facilitate breathing. Dopamine neurons do several important jobs. These neurons are responsible for reinforcement, or reward—the sense of pleasure—as we discuss in the Addiction chapter. In addition, these neurons control purposeful movement and influence release of some hormones. The loss of dopamine neurons in Parkinson’s disease causes the gradual loss of voluntary movement that is so incapacitating. Dopamine neurons also contribute to the improvement in attention and planning/prioritizing (executive function) that psychomotor stimulants cause. Serotonin is involved in the regulation of sleep and mood and also in controlling appetite, body temperature, and more “vegetative” functions, as they are strangely called (since when did a carrot control its body temperature?).

Imagine what happens when a person takes amphetamine: the body prepares for fight-or-flight both physically, by increasing heart rate and blood pressure, and mentally, by becoming hyperalert (via norepinephrine); the person explores the environment, moves around (perhaps purposefully,

perhaps not), feels euphoric (courtesy of dopamine), and stops eating; body temperature rises, and the release of many hormones increases. Some of these actions seem to conflict with each other. For example, in preparing for physical activity, it would be better if your body were attempting to lose excess heat instead of experiencing an increase in temperature. This is why the excessive use of stimulants can be so dangerous physically.


Stimulants work by interfering with the mechanism that monoamine neurons have for stopping neurotransmission and “recycling” their products. Normally, monoamine neurons fire impulses and release their neurotransmitters, which go across the synapse and act on their receptors. Then the monoamine neurons recapture them by “pumping” them back into the neuron. This process eliminates the monoamines from the synapse and is the main way that these neurons “turn off” neurotransmission once it is started. Stimulants like cocaine, amphetamines, and bath salts block this pump. The result is that the norepinephrine, dopamine, and serotonin all stay in the synapse much longer once they are released. There is a subtle but important difference between cocaine and the amphetamines: the amphetamines use this pump themselves to enter the nerve terminal and, once inside, cause a massive “dump” of neurotransmitter into the synapse. Therefore, they increase levels of neurotransmitters much more than cocaine does. Any stimulant that releases these neurotransmitters can have more dramatic effects than the stimulants that only block uptake.


Norepinephrine Increase in blood pressure and heart rate Relaxation of bronchioles

Activation of fat breakdown Arousing effects



Appetite effects

Increase in body temperature Appetite effects

Locomotor activation Euphoria: addiction Attention



Amphetamine and methamphetamine, cocaine, ephedrine, and methylphenidate differ from each other in the range of psychomotor stimulant effects that they cause. What determines the differences in effects of the stimulant drugs? First of all, drugs that don’t get into the brain affect only the peripheral nervous system. Ephedrine is a good example because it enters the brain poorly; therefore, its effects on the cardiovascular system and other “body” systems are much stronger than its effects on mood or appetite. However, amphetamine, cocaine, and methylphenidate all enter the brain, but they do not cause exactly the same effects. Cocaine and amphetamine cause all the possible actions of psychomotor stimulants; they increase attention and alertness and cause the pleasurable effects that become addicting. These drugs also mimic activation of the sympathetic nervous system, causing increased breathing, heart rate, and blood pressure because they increase levels of all the monoamines. In contrast, methylphenidate affects dopamine more than norepinephrine, so it has much smaller effects on heart rate and breathing. Understanding these underlying mechanisms has helped scientists quickly unravel the actions of the new bath salts. Some, like MDPV, inhibit dopamine and norepinephrine only and are extremely reinforcing and cause dangerous cardiovascular stimulation. Others, like mephedrone, act like amphetamine to release all monoamines. Methylone and mephedrone are much more like MDMA (see the Ecstasy chapter) in having large effects on dopamine and serotonin, but they also release norepinephrine. These drugs are reinforcing, cause significant sympathetic stimulation, and also elevate

body temperature, as would be predicted from this profile of action. For many of the others, the research still hasn’t been done, but it is likely that all of them will inhibit dopamine uptake to some extent; the balance of dopamine, norepinephrine, and serotonin will dictate their end results. All drugs that inhibit dopamine uptake or release dopamine will be potentially addictive. All drugs that inhibit norepinephrine uptake or release norepinephrine will stimulate the sympathetic nervous system and have potentially dangerous cardiovascular side effects. Drugs that also affect serotonin will have a touch of MDMA-like “entactogen” action and potentially have more dangerous effects on body temperature.


Drugs with effects on all monoamines

Drugs with effects mainly on dopamine and norepinephrine

Drugs with effects mainly on norepinephrine


Cocaine, MDPV, mephedrone, methylone

Methylphenidate, amphetamine, methamphetamine, methcathinone, MDPV, alpha-PVP



Cocaine has a unique effect all its own. Remember the initial use of cocaine by Freud’s friend? He used it to cause local anesthesia—to block the transmission of pain stimuli. Physicians use cocaine for this purpose much less today because drugs that have this effect but not cocaine’s addicting properties are available. However, the local anesthetic effects of cocaine may account for a toxicity that is unique to cocaine. At doses not much greater than those that cause maximal effects on mood, cocaine causes seizures. Other stimulants don’t do this at all, or only at extremely high doses. Because other local anesthetics also can cause seizures, we think that this effect of cocaine is a result of its anesthetic action.


Cocaine addiction could be viewed as a problem created by successful science. Cocaine addiction is basically unknown in the South American cultures where the drug has been used for millennia to increase endurance and the ability to work. Chewed with an alkaline substance and delivered to the stomach and then absorbed slowly, coca leaves provide only a mild stimulant effect. The rush doesn’t happen, and the drug is relatively safe.

The situation is quite different with the cocaine and amphetamine formulations available today. Part of the addictiveness of cocaine may have much to do with how it is delivered to the body. The extremely fast rise in blood levels may be the important factor. Just as cigarettes deliver nicotine to the bloodstream rapidly, smoked cocaine (crack) delivers cocaine rapidly to the brain. The recent explosion of addiction to ice, the smokable form of methamphetamine, lends credibility to this notion. Bath salts may prove to be the most lipophilic of all and enter the brain very fast even when snorted.

Animal experiments point out how uniquely compelling cocaine can be. Animals will press a lever hundreds of times to deliver a single intravenous dose of cocaine or methamphetamine (and very recent data suggest that they will press even more to receive MDPV). In contrast, most animals will not voluntarily ingest dangerous amounts of alcohol or nicotine and tend to limit their intake of heroin to a steady pattern. Recovering cocaine addicts usually say that the only thing that stops a serious addict during a binge is running out of cocaine. One user described it like this: “If I had been in a room full of cocaine, I would have kept using it until it was all gone, and I still would have wanted more.”

Does this mean that everyone who uses stimulants becomes addicted? There are thousands of people, ranging from children with ADHD to truck drivers, who regularly use psychomotor stimulants but never develop a compulsive pattern of use. Good prescribing practice by the physician usually leads to safe use for clinical purposes. Taking the drug according to a schedule instead of “as needed” helps to avoid a pattern of self-medication that can become compulsive. Similar differences have been observed in the laboratory. When monkeys have free access to cocaine, their intake increases to toxic levels, but if access is restricted to a few hours a day, their intake can remain stable for months. Another factor is the reasons for taking the drug

and the environment. Usually, truck drivers and college students use stimulants only while engaged in a particular task in a particular environment (that is, when on the road or pulling an all-nighter). When placed in a different environment, without all the typical stimuli associated with drug use, it is easier for them to abstain.

There is no question that psychomotor stimulants are addictive. As described in the Addiction chapter, the dopamine neurons on which they act play a primary role in addiction, and taking amphetamine or cocaine can be viewed simply as substituting drugs for natural reinforcers, such as food and sex. No other drugs in this book act so directly on reward systems or are so commonly addicting. Can some individuals use stimulants recreationally without addiction? Probably so, and yet we know that the drive to use cocaine or amphetamine is considerably stronger than that for any of the other addictive drugs.

Tolerance develops to some stimulant effects, such as the suppression of appetite, and develops more easily with continuous use than with irregular use. This is one reason why amphetamine isn’t very useful as a diet pill. Tolerance also develops during a single run, so that the high becomes harder and harder to reach. This is why people keep taking more frequent injections (“chasing the high”). However, this rapidly developed tolerance also reverses rapidly, so a few days of abstaining can restore sensitivity. Some effects actually become progressively greater over time. The locomotor stimulation is one of the behavioral patterns that become more and more exaggerated. While people rarely show intense repetitive behaviors the first time they take amphetamine, it is a common behavioral effect on the longtime user. Do stimulants become more addictive over time? We really don’t know the answer for sure, although the pattern of use probably plays an important role.

Is stimulant withdrawal dangerous? Although there are definite symptoms of stimulant withdrawal, it is not life-threatening. When people stop using at the end of a long run, they crash. There is a period of exhaustion, with excessive sleep, often depressive symptoms, and a rebound in appetite that probably results from a prolonged period of inadequate food intake. During this period, the craving for the drug is very strong. One particularly difficult symptom is the inability to feel pleasure (anhedonia). This is not a big surprise if a person has been artificially and intensely stimulating his

pleasure center with a drug. When the drug is removed, so is its artificial stimulus of the brain’s pleasure center. There seems to be a suppression in dopamine neuron activity during the first few days after withdrawal. No one ever died from a few days without pleasure, but in the absence of any positive feelings, the temptation to use the drug to feel better becomes stronger and stronger. Anhedonia is thought to be a major reason why people start using stimulants after a period of attempted abstinence. We don’t know for sure how long these symptoms last, but in very longtime users the craving for the drug can last for months.


Amphetamine was the original diet pill. This use was based on the ability of amphetamine and drugs like it to suppress appetite. Unfortunately, it was impossible to separate the appetite-suppressing qualities from the addictive potential. The search for an effective nonaddicting diet pill fueled millions of dollars’ worth of pharmaceutical company research, resulting in a new understanding of the neural mechanisms regulating appetite. The appetite- inhibiting effects of amphetamine probably result from the release of norepinephrine and serotonin, and its addictive qualities from the release of dopamine. The newer medication sibutramine (Meridia) worked more selectively on norepinephrine and serotonin, and so lacked the abuse potential of amphetamine. However (see page 303), the effects on norepinephrine led to predictable cardiovascular stimulation with sibutramine, and it has been withdrawn from the market. The most recent appetite-reducing drug on the market, lorcaserin (Bleviq), works very specifically on one of the many serotonin receptors (5-HT2c) and is very effective without the cardiovascular side effects of drugs that increase norepinephrine, or the potentially addictive qualities of drugs that increase dopamine. Furthermore, the explosion of information about other mechanisms involved in the regulation of food intake have led to the development of other new drugs that don’t target monoamine systems at all.

All effective drugs that suppress appetite require a prescription. However, there are many over-the-counter drugs marketed as effective that really have minimal or no effectiveness. Chromium is one favorite in health- food stores today for its supposed ability to burn fat—a claim based on

modest research about its ability to increase the actions of insulin. However, these effects are slight at best, and the safety of long-term use has not been established.

Ephedrine was another favorite, for both its ability to suppress appetite and its thermogenic properties. There is a little more truth to this, but not much. If ephedrine is taken in safe amounts, it does not get into the brain and thus cannot suppress appetite. It might increase energy metabolism a little, but not without significant effects on heart rate and blood pressure. The ephedrine substitutes on the market (bitter orange, for example) do not enter the brain well either, so they share its effects on cardiovascular function but are not very effective as anorectics (see the Herbal Drugs chapter).


Psychomotor stimulants can cause three kinds of severe health problems. First, single-dose toxicities can cause death through overdose. Second, chronic use of escalating doses leads to particular behavioral problems. Finally, there are a myriad of health problems associated with long-term use that are not specifically caused by the drug but that result from the stimulant- using lifestyle.

All of these drugs can kill at doses that people take recreationally. A single clinically appropriate dose of amphetamine, methamphetamine, cocaine, methylphenidate, or ephedrine would rarely cause death unless an individual had an underlying health problem (aneurysm, coronary artery disease, etc.). Yet people using drugs obtained from clandestine sources rarely know the dose they are taking. Also, blood levels can gradually accumulate to toxic levels during the runs of repeated drug injections or inhalations at fairly closely spaced intervals, which are a common pattern of stimulant administration. It is commonplace for people to keep taking cocaine or amphetamine until they experience unpleasant side effects, but such warning signals may come too late if the drug accumulates in the body rapidly. This uncertainty is proving particularly problematic with the new bath salt drugs, which are often supplied as loose powder: the combination of inexperienced users and bulk marketing is leading to frequent dangerous overdoses. What happens as blood levels rise to toxic levels? The first effects are simply exaggerations of the typical drug response: energy and

alertness become jitteriness or even paranoia and hostility, and increased movement becomes repetitive aimless activities, such as drawing closely spaced lines, taking watches apart and putting them back together, or talking constantly without listening. A mild increase in heart rate becomes palpitations or chest pains as the heart rhythm is disturbed, and the skin becomes flushed as body temperature rises. Headaches are common, often from effects on blood vessels. Nausea and vomiting can accompany these changes. These toxic levels can also result in strokes, heart attacks, or fatal elevations in body temperature. For cocaine, the pattern is a little different. Elevated body temperature is relatively rare, but seizures are commonplace —so much so that an adolescent or young adult arriving at an emergency room with a seizure without a previous history is almost always screened for cocaine use. Scientists once argued that the repeated use of cocaine led to an increased sensitivity to seizures, but this theory has not held up in continued study. Seizures can happen at any time during a cocaine-using “career”—the first, twentieth, or hundredth time. Many longtime users eventually have a seizure. Rather than some permanent change in the brain, the reason may be the escalating pattern of use that leads to higher and higher blood levels of the drug.

Like alcohol, in the words of Shakespeare, stimulants provoke and unprovoke. Stimulants, especially cocaine, can increase interest in sex, but sexual activity can become more difficult. Stimulants constrict blood vessels in the penis in a way that makes it difficult to maintain an erection and can delay ejaculation. In fact, this latter characteristic of cocaine is occasionally exploited by local application of cocaine to the head of the penis to prolong sexual activity!

There are also serious social consequences to chronic psychomotor stimulant use. The increasing hostility, paranoia, and belligerence associated with higher blood levels of stimulants result in more overt violence. Many high-dose stimulant users become increasingly convinced that people are “out to get them,” while they also become more agitated and inclined toward action. In a country with liberal gun laws, this combination can be lethal and often is. The incidence of gun-related violence is substantial for stimulant users.

Additional problems develop with chronic use. As use escalates into more and more frequent runs, the bizarre, repetitive movements become more

extreme. They can take the form of very self-directed behaviors such as picking at imaginary insects under the skin or assembling and taking apart equipment, or more social forms such as repetitive sexual or conversational activity. The picking behavior leads people eventually to create large wounds in the skin that often become infected. When paranoid and hostile behavior takes over, a person in the midst of extreme chronic amphetamine intoxication resembles a paranoid schizophrenic patient, although the disordered thinking of schizophrenia is usually not present. After a few days of hospitalization, the person often returns to normal, although sometimes the behavioral change persists.

What are the effects of long-term amphetamine use on major body functions? Part of the answer depends on how the drug is administered. Cocaine and amphetamine are powerful vasoconstrictors, and so they cut off the blood supply to the area where the drug is delivered. Snorting cocaine can cause ulcers in the lining of the nose from inadequate blood supply, while smoked cocaine or amphetamine can cause bleeding in the lungs as small blood vessels burst. Stomach ulcers or damage to the intestines can occur with long-term oral or even intranasal use. Heart problems are also fairly common. Long-term stimulant use seems to accelerate the development of atherosclerosis (development of fatty plaques that block blood vessels) and may cause direct damage to the heart muscle from lack of oxygen. Longtime stimulant use is also associated with many problems not caused directly by the drug. Because these drugs suppress appetite, stimulant users are often undernourished and experience all the ill effects of that condition. The incidence of hepatitis, HIV, and other infectious diseases is high in users who share dirty needles or engage in sex to obtain money for drugs.

Finally, research points to the possibility that chronic use of methamphetamine may cause long-term neurotoxic damage. High-dose methamphetamine causes long-lasting damage to the dopamine nerve endings of neurons. The nerves do not die, but the nerve endings are “pruned,” or cut back, leaving a deficit in the density of nerve terminals and the amount of dopamine and serotonin available for use. What is the functional implication of this loss? Right after the loss, the system probably can compensate enough that no behavior problems are obvious. However, as people age and experience the normal aging-related loss of dopamine neurons, this deficit could potentially be revealed in movement or mood disorders. Imaging studies show that some recovery in dopamine nerve terminals occurs.

However, other abnormalities have been shown in the brains of heavy stimulant users: evidence of damage and attempted repair by the glial cells has been reported, resembling that seen with loss of blood supply, aging, or diabetes. These differences in brain structure seem to be associated with the difficulties with memory and decision making seen in heavy methamphetamine users. We don’t know yet the extent to which these behavioral changes are reversible. One final question that has been raised but not answered is this: Does long-term use of ADHD medications have any of these effects? The answer is no for most of the worst effects because these result from very high doses. However, we don’t know if the brain adjusts to the long-term use—likely it does in some ways (changes in receptor sensitivity, etc.). Research in this area is ongoing. One good bit of news is that most studies show that kids with ADHD who get effective treatment (behavioral or drug) are less likely to become addicted to drugs.

* Freud’s comments are from Über Cocaine, quoted by S. H. Snyder in Drugs and the Brain (New York: W. H. Freeman and Co., 1995).

Part II



NOTHING CHANGES THE way we feel or the way we perceive the world unless it interacts with our central nervous system (CNS). Whether we take a sip of wine, snort a line of cocaine, or see an attractive person, our CNS is the place where the action occurs. To understand how any drug works, we need to understand some very basic principles governing brain function.


1. The brain is not only the organ that tells us who we are, what we are doing, and what we have done, but it is with our brains that we sense the world, control our actions, and maintain basic body functions such as heart rate, blood pressure, and breathing. Drugs can strongly affect all of these functions.

2. The brain is an extraordinarily complex structure, with thousands of different sites for drug action on thousands of different kinds of nerve cells. This complexity can cause different people to have very different experiences with the same drug.

3. The CNS, especially in children and young adults, has a remarkable capacity to change in response to experience; this is called plasticity. We see it happen every day as learning and remembering, but the CNS, in response to a variety of influences, can undergo changes that occur without our awareness of them.

4. The ability of the CNS to undergo plasticity can be modified by chemicals, whether taken for medical benefit or for recreational purposes.


Single Nerve Cells
Connections between Nerve Cells

The Role of Receptors
Collections of Neurons Form Specialized Brain Areas The Central Nervous System Controls Many Functions Plasticity in the CNS—Learning from Experience

Do All Parts of the Brain Learn? The Developing Brain
Drugs and Plasticity

The Latest Brain Imaging
Why Should Anyone Care about All of This?


It is laughable to think that anyone completely understands how the brain functions. Every time neuroscientists make a discovery that explains some property of the nervous system, that discovery opens new doors and raises new questions. For example, no one knows exactly how the CNS stores memories, but we do know a lot about how to alter the storage process.

Often the brain is compared to a computer. That analogy is overworked, but in one way, it is not such a bad one. Most people know how to use a computer, but they do not know precisely how the circuits inside the computer do the job. However, not knowing just how the circuits work does not prevent the user from knowing what to type on the keyboard, how to

access the internet, and how to run a program. Likewise, there is a lot to know about the nervous system, and a little knowledge can help you keep yours healthy.

The first step is to appreciate what an amazing structure the brain is. One of the most amazing things is that such a complex structure can function so well even under some of the terribly difficult conditions that we impose on it. It has an ingenious balance of excitatory and inhibitory influences coursing through it. It’s like a sports car moving along a winding country road with just the right amount of pressure on the accelerator (excitation) and the brakes (inhibition). In the brain, the brakes are the release of inhibitory chemicals. They suppress the firing of nerve cells by opening channels in the cells’ membranes, letting ions flow in a direction that causes the cells’ electrical potential to move away from the point at which it would fire a signal (an action potential). Without action potentials, there is no action, so we say that that cell or network of cells is inhibited. An inhibited network cannot carry out its function, so that function is lost. The lost function might be thinking, feeling anxiety, staying awake, having reflexes to pain, adjusting the circulatory system, or breathing. An overly excited network is like a pot of boiling water, or like that sports car out of control at high speed. There is a chaos of discharges that randomly fire in many parts of the brain, leading to all sorts of feelings and movements. Yet in most of us, for most of the time, the brain maintains the delicate balance of excitation and inhibition that permits a normal life.

The first step to understanding that delicate balance, and how drugs disrupt it, is to understand the building blocks of the CNS—the nerve cells, or neurons. There are many other CNS cells that support the neurons, but the neurons are where the information is stored, where feelings are sensed, and where actions are initiated.

Neurons look a little like trees. There’s the trunk and the top with many branches and the leaves that receive the sunlight. Then there is the root system that is equally branched, with a large taproot going off into the earth. Under the microscope, many neurons look the same way. They have a “top” receiving area called the dendrites, where connections from other neurons make contact. Then they have a “trunk” area, where the body of the nerve cell is located, containing the genetic information for that cell. Finally, out of the cell body emerges the axon of the cell (like the root of a tree), which goes off

and branches to make contact with other nerve cells or muscle cells and transmit signals to them.

Like all cells, a nerve cell is held together by its cell membrane, which is a mixture of lipids (fats) and proteins. Many nonneuronal cells (for example, blood cells, muscle cells) have cell membranes that are more or less the same all over. The cell membranes of neurons, however, are vastly different in different parts of the cell. These differences allow a cell to receive different types of signals from many other cells, integrate these signals, and then send out signals of its own. Even a single neuron is a very complicated bit of biochemical machinery, but this complexity is what allows the enormous information storage and processing capacity of the human brain to exist in such a compact form.


The dendritic, or receiving, area of neurons is where axons (transmitting fibers) from other nerve cells make contact. These points of contact are called synapses. A single synapse is, in itself, a complex structure, consisting of the presynaptic and the postsynaptic regions. The presynaptic region is the termination point of the axon of the transmitting cell, and at that point the axon balloons from a very small fiber to a group of bulblike endings called the presynaptic terminals. These terminals contain chemicals— neurotransmitters—that are released into the space between the presynaptic terminal and the dendrite of the postsynaptic (receiving) cell. The neurotransmitter molecules react with special receptors that are sensitive only to that neurotransmitter on the postsynaptic cell, and, in just thousandths of a second, these receptors cause electrical and/or biochemical signals within the receiving cell.

A single neuron can have a large number of synapses on its dendrites, and it is the job of the neuron cell body to take in signals from all of those synapses and make a decision. That decision is whether to fire electrical signals itself down its transmitting fiber—its axon. The signals that are transmitted down the axon are called action potentials because they can cause action somewhere else. If they come from a nerve cell synapsing onto a muscle cell, they can cause the muscle cell to contract. If they come from a nerve cell connecting to another nerve cell, they can cause that follower

nerve cell to either fire or stop firing, depending on what kind of signal it gets from the neurotransmitter molecules.

The input to a neuron is from synaptic connections from other neurons, while the output is a series of action potentials firing down its axon. The action potentials are all the same, just quick (about one-thousandth of a second) discharges of electrical activity. The information is carried at the rate by which these discharges occur. So, if a neuron fires lots of action potentials in a brief period (up to four hundred in one second), it can have a large influence on its follower cells, while slow firing would have less influence.

Some drugs may affect the generation and spread of action potentials down the axon, but that is not a common site of drug action. These drugs usually produce drastic and often toxic changes because they can completely stop a neuron from firing. One such toxin that does this is the chemical present in the ovaries of puffer fish, which are delicacies in Japan. This chemical, called tetrodotoxin, is so toxic that eating just part of a fish can paralyze the muscles responsible for breathing and lead to death. Japanese restaurants have chefs who are specially trained and licensed to remove the ovaries before the fish is served. This same class of toxin is also thought to be used in Haitian voodoo rituals to induce zombie-like behavior.

Most drugs act either at the presynaptic terminal, where the neurotransmitter is released, or at the postsynaptic membrane on the neurotransmitter receptor. The synapse is the primary site of action of the majority of drugs that affect human brain functions. So to understand how drugs affect our CNS, we must understand the synapse.

The presynaptic terminal is the place where neurotransmitters are synthesized, packaged, and released. When action potentials travel from the cell body of the transmitting neuron down to the terminal area, the electrical signals cause changes in the shape of protein molecules that reside in the terminal area. These molecules sense the electrical signals and, within thousandths of a second, reconfigure themselves to form pores, or channels, in the terminal membrane. Calcium ions flow into the terminal through these pores, and the calcium initiates a chain of biochemical reactions. The result of this biochemical sequence is that packets of neurotransmitter molecules break through the terminal membrane and move toward the postsynaptic area of the receiving cell.

What happens to the neurotransmitter molecules after they are released? After all, if they stayed around forever, the postsynaptic neuron, or muscle fiber, would constantly be under their influence and further signaling would be impossible. Removal of neurotransmitters is accomplished in three ways. First, the molecules just diffuse away into other areas where there are no receptors and are removed by the general circulation of fluids in the brain. Second, there can be specific chemicals that break the neurotransmitters into inactive parts that are returned to the cells. Finally, there are specific sites on the presynaptic terminal that attach to the active neurotransmitter molecules and transport them back into the terminal for release again. These transport sites are often places where drugs act to prolong the presence of the transmitter in the postsynaptic area, therefore increasing its effect. Cocaine is an excellent example of such a drug, because it suppresses the uptake of the transmitter dopamine, which is important in the reward center of the brain.

This entire neurotransmitter-release process can be controlled by neurochemicals active at the presynaptic terminal. In some cases there are receptors for the transmitter being released that serve to suppress further release of the transmitter and thus limit the action at that synapse. In other cases there are receptors for different neurotransmitters that can regulate release. Any of these sites could be important places for drugs to act.


Next, consider the postsynaptic region of the cell, where the neurotransmitter receptors are located. The postsynaptic region contains the proteins bound in the lipid cell membrane that react with the neurotransmitter molecules. These proteins are, in themselves, very complex structures. They are three- dimensional molecules that have sites into which the neurotransmitter molecules can fit. In fact, this arrangement is just like a lock-and-key mechanism. The neurotransmitter molecules from the presynaptic cell are the keys and the postsynaptic receptors are the locks. When the key “enters” the lock by binding to the receptor molecule, the lock operates and the bioelectrical activity is initiated.

The lock-and-key analogy is good to a point, but it’s certainly too simplistic. Unlike a lock, which usually has only one action (to throw a bolt into a door), a receptor can have numerous actions, and each one of these

steps can be changed by drugs. The first two actions that occur at a receptor are electrical and biochemical.

The fastest signal is the electrical process. Once the neurotransmitter binds, the receptor molecule can change its shape and open channels (pores) into the cell on which it is located. These channels allow the flow of charged molecules (ions) into or out of the cell, and this movement of electrical charge causes an electrical signal to develop across the cell membrane.

Normally neurons have an electrical charge so that the inside of the cell is negative (about 0.1 volt) compared to the outside. This is called the resting potential, and when a neuron is at rest, it fires no action potentials. When the inside of the cell at the point of the cell body becomes considerably less negative (about 0.04 volts), then action potentials begin to fire and the cell is then transmitting to its follower cells.

Neurotransmitters released at the synapse change the charge across the membrane near the postsynaptic receptors, and so control whether a cell starts to fire action potentials. If a receptor opens a channel that lets in ions that make the cell less negative, then the electrical potential of the cell moves in the direction of firing action potentials. If the receptor opens a channel that causes the cell to become more negative inside, then the cell becomes less able to fire. Every cell has many synapses, and when all of this electrical activity together adds up, the sum of it determines whether a cell fires its own action potential. This addition of pro- and anti-firing (excitatory and inhibitory) currents occurs in and around the cell body of the neuron, in a place where action potentials originate. Thus, all of the synaptic activity of the cell converges to the cell body, where the cell makes the decision to fire or not to fire, depending on the voltage across its cell membrane.

The two most common neurotransmitters in the CNS are the amino acids GABA (gamma-aminobutyric acid) and glutamate. These are referred to as inhibitory (GABA) and excitatory (glutamate) amino acid neurotransmitters. These neurotransmitters are responsible for much of the second-to-second processing in the CNS. If either of these is significantly blocked, the proper functioning of the CNS is dramatically disrupted. There are many subtypes of these receptors, and each of these subtypes has different characteristics. Some of the most interesting drug effects come from activating just a particular subtype of a receptor rather than the whole class of receptors.

Receptors can initiate a cascade of biochemical events within neurons. Either by letting calcium ions into cells or by activating intracellular enzymes directly, activated receptors can profoundly change the biochemical environment of a cell. These biochemical signals can alter the numbers of receptors for different transmitters, change the degree to which they recognize their transmitters, or even change the systems that regulate the function of the cell—literally, thousands of different processes. It is no wonder that drugs that interact with receptors can be so specific and so powerful.

This diversity of receptors and biochemical signaling pathways is what makes the brain infinitely more complex than a computer. There may be as many as one hundred neurotransmitters in the human brain. Instead of just a single plus or negative signal, there is an almost infinite variety of signals, each generated by a different neurotransmitter—from a tiny, fast excitation as described above, to a prolonged, slow, and powerful inhibition. This diversity also allows humans to devise drugs that have quite specific effects. Throughout this book there are references to actions of a drug at a specific receptor, receptor regulation site, or biochemical-signaling pathway. Although we know much about the way these chemicals operate, it is important to remember the mantra of every pharmacologist: “Every drug has two effects—the one I know about and the one I don’t know about.”


While neurons are the basic components of the brain, the ways in which they are connected determine what functions will occur. An old cartoon shows a neurosurgeon in the operating room saying, “Well, there go the piano lessons.” Like most humor, it’s somewhat based on fact. The brain is organized into specialized areas that control speech, hearing, vision, fine movements, gross movements, learning, anger, fear, and much more.

It would be very useful to know which neurotransmitters and receptors carry the information for all of these functions, because then we could design specific drugs to modulate them with great precision. However, we are far from having that information, and even if we did have it, there is another complication—the pattern of connections between neurons. While neurochemistry is important, the patterns in which neurons connect are

equally important. This is where the computer analogy holds up: in fact, neuroscientists call the web of connections that mediate specific brain functions “neural circuits.”

Behaviors, even simple ones, are possible because neuronal connections are very specific and complex. Even the simplest reaction, such as blinking when a dust particle gets in your eye, involves several nerves connected to each other. So, when a drug alters one process, the effect it has depends on how that process participates in the function of the network. Thus, our ignorance of nerve-cell connections accounts for some of the uncertainty in knowing the effects of drugs.


In the following section, we will talk about some of the most exciting parts of brain function, learning, and memory. But it is crucial to understand that the central nervous system controls almost everything about us: how we perceive the world through our senses (vision, hearing, smell, taste, touch); how we organize movement from the moment we are motivated to do something to the completion of the act; our motivation and emotional states (are we sad, excited, depressed, anxious, elated, bewildered, and so on); and how we organize these functions. For example, when you smell a doughnut, your mouth waters, you feel hungry, and perhaps cheery at the prospect of eating. You become motivated to find the doughnut, use your other senses to do so, and activate your motor systems to get there. The brain also controls some very important body functions that sustain life. These are boring functions until they fail, and then they get attention right away. The three most vital functions that the CNS controls are the circulatory system (heart and blood vessels), the respiratory system (breathing), and the reflex system (which instantly, and without thinking, causes you to respond to a threat).

The circulatory system is maintained in a stable condition by its own built-in control system. However, the brain can easily modify this set point. For example, during periods of anger or excitement, the heart beats rapidly and blood pressure rises. The CNS also stimulates the respiratory system and causes breathing to increase. The brain has decided that the “normal” status is incorrect and that the body needs to be prepared for fight or flight. In

contrast, when the mind is at peace, and perhaps meditative, the heart rate falls, blood pressure falls, and breathing is slowed.

The CNS reflex system is equally important but often forgotten. People who think about drugs and safety often mention hearts and breathing, but they don’t put as much emphasis on how reflexes keep us safe. Take, for example, how we jerk our hand back from a hot surface. This is a pure reflex action that is signaled in the spinal cord. The sensing nerves in the fingers and hand send a powerful signal to the spinal cord. This signal excites neurons that cause movement and withdrawal of the hand. This all happens before the pain signals are even interpreted by the conscious brain.

A more important example is the reflex to clear the airway for breathing. Notice how fast and how strongly the body responds when something touches the airway in the back of the throat. This is a critical reflex to sustain life. If this reflex were suppressed by a drug, then something (such as vomit) could easily block the airway and it would not be cleared. The person would die of asphyxiation. The list of basic body functions that can be impaired by drugs goes on and on. This is not a particularly glamorous or fascinating area of drug effects, but it is one that everyone must understand.


The third principle of this chapter stated that the CNS responds to experience by learning—that is, it reorganizes some of its neurochemistry and connections so that the experience is remembered. It is very important to understand that this plasticity is a broad concept. Not only does the CNS remember events that are consciously experienced, but it also changes in response to all sorts of signals, such as the constant presence of drugs.

The most familiar plasticity in the CNS is the simple remembering of experiences—faces, odors, names, classroom lectures, and lots more. The neurobiological mechanisms through which this kind of learning happens are not completely understood, but we have some clues. One important site of learning appears to be the synapse.

As discussed, synapses of nerve cells are quite complex, and there is extensive biochemical machinery in both the presynaptic and the postsynaptic areas. We think memory is built one synapse at a time: some synapses that are

stimulated repeatedly change how they function (learn) and maintain that change for a long time. There is an electrical manifestation of this learning that scientists call long-term potentiation (LTP). It is a long-lasting strengthening (potentiation) of the electrical signal between two neurons that occurs when the synapse between them is stimulated.

We’re not sure how this happens, but it is likely through a series of biochemical changes in how the first neuron releases its neurotransmitter and how the second neuron responds to the neurotransmitter. On the presynaptic side, a synapse could be strengthened by increasing the number of presynaptic terminals, by releasing more transmitters from the same number of terminals, or by a reduction in transmitter removal. On the postsynaptic side, strengthening could occur with an increase in the number of receptors, a change in the functional properties of the receptors, a change in how well the postsynaptic site is coupled to the remainder of the neuron, or a change in the biochemistry of the postsynaptic neuron. There is scientific controversy about the true mechanisms of LTP, and the issue may not be clear for a number of years.

Almost every neuron can modify many aspects of its function to adapt to new conditions—by making more or less neurotransmitter, by changing the number of receptors on the surface of its cells, by changing the number of molecules responsible for the passage of the electrical stimulus down the axon, and so forth. If a neural circuit is being overstimulated, it can reduce the stimulation by removing some of the receptors for the neurotransmitter stimulating it. Therefore, even if the neural circuit is being sent lots of signals, they don’t get through. Alternatively, if a neural circuit is receiving much less stimulation than usual, it can adapt by becoming more sensitive to each stimulus. This is how the brain stays in balance.

This type of biochemical plasticity goes on all the time and is part of normal brain function. However, these same changes can cause abnormal brain function. For example, we think that the tremendous mood changes in depression might result from changing numbers of neurotransmitter receptors following changing stimulation of specific neurons in the brain.

If neurons and synapses learn, do they also forget? The answer appears to be yes. We just described how stimulating a neural pathway in a certain way can cause it to “learn” to respond to stimulation differently. Stimulating it in another way (slowly, and for a long time) can cause a process called

depotentiation, which appears to be the opposite of long-term potentiation. Why is this interesting? Depotentiation could be quite important because it may represent the synaptic equivalent of amnesia. Depotentiation can be produced by prolonged slow activity or by very strong high-frequency activity, like that which occurs in seizures. It may be a protective mechanism by which the CNS prevents a seizure or brain trauma from encoding new information into the circuits. Again, it is almost certainly under the control of cell-signaling pathways and thus could be manipulated by drugs.

This gradual change in the electrical strength of a connection seems subtle, but it makes intuitive sense that memories could form in this way. Can the brain actually change physically? We used to think that once a person was mature, the brain didn’t change anymore. However, more and more research shows that actual changes in the shapes of neurons also can happen in response to earlier experiences. We know that the shape of certain neurons in the brain changes when different hormones become available. For example, at least in animal studies, treatment with hormones can stimulate the production of little protuberances, or “spines,” on the dendrites of neurons. Other research has shown that synapses actually remodel themselves over time after different levels of activity. So, connections actually get lost or remade. For example, prolonged stress seems to actually shrink the dendrite on neurons, perhaps explaining the cognitive difficulties people encounter during prolonged stressful periods.

It has been known for a long time that this happened in lower animals. For example, as songbirds learn new songs, the structure of certain parts of their brains changes. It was once thought that the brains of mammals did not have this type of structural plasticity. However, more recent studies have shown similar changes in rats, and scientists think that they probably occur in all mammals.

One of the most exciting findings about neuronal plasticity is that the brain can actually make new neurons. This process, called neurogenesis, was long thought to occur mostly during prenatal development, but now we find that it is happening in adult mammals. Neurogenesis results from the conversion of neural stem cells into functional neurons. The rate of conversion seems to increase in response to injury or other pathologies and decrease in response to chronic stress. As with most neuroscience research,

the data come primarily from animal experiments, usually rats, and as always, relevance to humans needs to be established.

There have been some intriguing findings regarding the effects of drugs on neurogenesis in animals. It appears that depression reduces neurogenesis and subsequent treatment with antidepressants restores it. More relevant to this book, the laboratory of Fulton Crews at the University of North Carolina has made the startling discovery that binge exposure to alcohol dramatically suppresses rat neurogenesis, particularly in the adolescent forebrain, which is a brain area in rapid development. The potential implications of this are enormous, because adolescents tend to be binge drinkers. Is this behavior impairing their brain development? What other drugs affect these processes? Does this really happen in humans? These questions should and will be answered by future research, but for now they alert us to the possibility that drug abuse could have profound effects on teenage brain development.


The processes that we just described do not happen in just one part of the brain. There are indeed specialized neural networks, especially in a part of the brain called the hippocampus, where learning occurs and memories are created. (People who have had damage to this part of the brain have great difficulty learning new things, although they can readily remember things that happened before.) However, most forms of plasticity can occur all over the brain and affect all brain function.

For us to be able to function normally, all brain processes need to proceed unimpaired. All of the neurotransmitter systems need to be working. The brain needs to change with time to reflect previous experience—that is, learn—to restore balance if it is over- or understimulated.


While the brains of adults change all the time, what goes on in adults is trivial compared to the phenomenal changes that occur while the brain is developing. The brain assembles itself carefully through the process of neurons growing out, and through chemical signals around them, gradually finding their way to the correct destination, where they make the connections that they then maintain. During this time of life, the physical changes in the

brain are dramatic. New synaptic connections are being made at a high rate every day. The growing brain also has its own way of “forgetting.” Many of the neurons growing out never reach their destination and die in the process. Others reshape their connections until they are correct. Through all of this furious growth, neurons must remain active or they can fail to make their appropriate connections. Therefore, changes in neuronal function that in an adult would simply shut down a pathway for a while can have more drastic consequences in a developing brain.

Growing neurons are affected by processes that don’t affect the neurons of adult brains. Exposure to substances that inhibit cell growth has some impact on an adult brain but a devastating impact on the developing brain. The neurotoxic element mercury provides a good example. Mercury affects the function of the adult brain and can lead to serious, but largely reversible, disruption of brain function. However, exposure of the brain of the developing fetus to mercury disrupts brain development so totally that severe mental retardation results. For example, an industrial spill of mercury into the water near a small, coastal Japanese town called Minamata contaminated the fish that were the local food source. While many adults experienced diseases that eventually resolved, many children born during this time frame had terrible disruption of normal brain development and remained mentally retarded throughout their lives.

Recently, medical imaging techniques have made it possible to study the development of the human brain at various points from birth to adulthood. Some of the most interesting studies use magnetic resonance imaging (MRI) with the machine set to reveal the white matter of the brain, the myelin insulation on the nerve cell axons. As the brain matures, the connections between cells become permanent, and then they are insulated with myelin. So, imaging for the myelin tells the scientist just how much development has occurred in a brain area. The big news is that the human brain is not fully developed until early in adulthood. And among the last parts to develop are the frontal lobe areas that give us the capability of inhibiting inappropriate behavior, handling complex tasks, and planning ahead. When we lecture about this, we often make the point that from the standpoint of the brain, adolescents are not “young adults,” but rather, “big kids.”

We believe it is very important to teach kids that their brains are still developing through adolescence. This means that they have the opportunity to

take some control of the final development of some of the most critical areas of their brains.

There are an increasing number of studies examining the effects of drugs on the adolescent brain from our laboratories and others. Most of these studies have focused on the acute effects of alcohol and other drugs, but some epidemiological studies have examined the associations between drug use and brain pathology. We have discussed these issues in the appropriate chapters, primarily those dealing with alcohol and marijuana.


Whatever the exact mechanisms are that underlie learning, there is strong evidence that supports the correlation between synaptic changes, neuroplasticity, and learning. The best of this evidence comes from drug studies. Chemicals that block the development of LTP tend to block other manifestations of neuroplasticity and, in particular, can block learning.

For example, a drug called AP-5 (D-2-amino-5-phosphonopentanoate) blocks a certain subtype of the excitatory neurotransmitter glutamate. This particular subtype, the NMDA (the N-methyl-D-aspartate) receptor, has the very special property of letting calcium into the cell only when the cell is receiving excitatory signals through other synapses. The calcium causes LTP to occur at those synapses. Thus, the NMDA receptor is like a memory switch. When the cell is receiving a signal and the NMDA receptor is activated, the cell “remembers” the signal by strengthening that synapse.

We were fortunate to find the NMDA receptor, because it appears to be one of the most important receptors for learning and other forms of neuroplasticity. It may teach us much about how memory occurs and how some drugs disrupt it. For example, in laboratory experiments, if we chemically block the NMDA receptor so that glutamate cannot bind there, LTP does not occur, rats do not learn mazes, and the CNS does not reorganize its neuronal connections following injury. There is increasing evidence that such learning and neuroplasticity can be suppressed in humans.

Alcohol in rats blocks NMDA receptors, suppresses LTP, and suppresses maze learning. So, now we may know why we forget what we did when we were drunk (see the Alcohol chapter for more information).

Many drugs affect the ability of the brain to learn—there is no question about it. But which drugs have which effects, and for how long? One of the best stories about the effects of drugs on learning was told to one of us by a drug company representative during an airplane trip. It seems that some of the professional staff from his company were making a quick trip overseas to a meeting, and they needed to sleep during the plane ride because their lectures were scheduled almost as soon as they were to arrive. So, this group had a few alcoholic drinks and then took one of their newly marketed sedatives (a benzodiazepine) to get to sleep. Everything went well, including the lectures, and the scientists returned home in a couple of days. The only problem was that when they returned, they remembered nothing of the meeting—not their lectures or those of anyone else. They did not know that the drug they chose, in the dose they chose, would have powerful amnesiac effects, especially when mixed with alcohol.

This story is legend in the pharmaceutical industry, and whether it is exactly true does not make any difference. It illustrates the point that even the people who develop and manufacture drugs by the highest standards may not know every effect they can have and how long these effects can last.

There are basically three ways in which drugs can affect learning: they can impair the ability of the brain to store information (amnesia), they can distort reality, or in some cases, they can stimulate the brain to increase learning.

By far the most common effect of drugs is to suppress learning. Almost all of the drugs that have sedative or anxiety-reducing properties impair the retention of information. Although we do not know exactly how this happens, there are three mechanisms that have been proposed at the synaptic level.

The first of these is increased inhibition. We know that many sedative drugs increase GABA-mediated synaptic activity, which inhibits the firing of neurons. The experimental data suggest that this increase in inhibition can reduce the effects of the type of neuronal firing that is usually necessary for LTP, and thus prevent neuroplasticity.

The second of these mechanisms is reduced excitation. Some drugs, such as alcohol, not only increase GABA function (and thus inhibition) but also suppress the glutamate-mediated excitatory channels (the NMDA receptor channels) that let calcium ions into the neurons. This reduction in calcium

entry prevents the signaling mechanisms within the neurons that lead to long- term synaptic changes.

Finally, there are drugs, such as the THC in marijuana, that act through their own receptors to change cell biochemistry so that learning is impaired. From what we know of their biochemistry, they may directly regulate the signal-processing pathways within the cell that govern the strength of synaptic activity, perhaps by suppressing the signals that mediate LTP or, alternatively, by enhancing the processes underlying LTD and/or depotentiation.

Now that we know about LTD and depotentiation, it is easy to imagine that there would be reasons for the CNS to reduce activity in some pathways and thus “forget” some neuroplastic changes. Therefore, it is completely reasonable that some drugs could enhance this type of signaling, reducing the ability to learn.

On a brighter note, neurobiologists are exploring ways to use drug therapy to enhance learning. This research is particularly important for the many people who suffer from Alzheimer’s disease or other brain disorders that impair learning. Most of the rest of us would also relish the ability to learn more or faster. There are some tantalizing clues that this may be possible.

One of the most interesting clues comes from an experience that almost all of us have had. It’s the “Do you remember what you were doing when . . . ?” question. Every generation has at least one of these questions. For older people, it’s what they were doing when they heard that JFK was assassinated. Nearly everyone recalls the fateful morning of 9/11. Think of an example: the first time you had a very important and emotional experience, either positive or negative.

Why is it that we remember some experiences so well, and not only the event but maybe what clothes we wore, what the room looked like, what we ate? Ongoing experiments shed a lot of light on this phenomenon. Dr. James McGaugh (of the University of California at Irvine) took two similar groups of people and placed them in separate but similar rooms with all sorts of cues, or decorations. The goal was to subject the groups to an emotional story and to see how well they remembered the story and the environment (the room) in which they experienced the event.

What makes this experiment interesting is that one group was given a drug (propranolol) that blocks a subtype of the adrenaline receptor—the beta-adrenaline receptor. This receptor is the one responsible for the increase in heart rate and blood pressure that occurs under physical or emotional stress; the blocker, propranolol, is used to control blood pressure and heart problems in some patients. So, one group was completely normal, while the other group had their excitatory adrenaline activity blocked.

The experimental subjects were then told a heartbreaking story about an injured child. After a period of time the two groups were removed from their rooms and then asked to recall the story and the details of their environment in the room. Both groups remembered the story. However, only the normal (undrugged) group remembered the details of the room. The treated group remembered very little of their environment.

What does this teach us? We all know that we tend to learn what interests us, and we know that we remember emotional events. Now we know why. The brain interprets an event as important and activates circuits that facilitate learning and remembering the environment associated with an emotionally powerful event. This is probably a critical characteristic for both humans and other animals to have, because it tends to help us remember events and places that were either wonderful or threatening, and thus adjust our future behavior accordingly. So, now it is clear why a smell or a face or a place might make you feel good or bad, even if you cannot immediately recall why: your brain is recalling an emotional experience.

This insight into learning is useful in several ways. First, it illustrates how important it is to be alert and interested in what we are trying to learn. When we are sleepy or depressed we are poor learners, in part because we are not so sensitive to stimuli. To really learn or teach something, we must include an emotional component.

In addition, this experiment suggests that there may be ways to facilitate learning through manipulating brain chemistry. Neuroscientists already know that learning is controlled by multiple neurotransmitters and neural circuits. However, increasing the function of any of these systems has proven difficult to achieve without producing unacceptable side effects.

At this point, no drug has yet been approved to increase learning. Until then, readers, you’ll have to “trick” your brain by studying what is exciting and by getting excited about what you must study!

What about other kinds of learning and memory besides what you learned in school or “where was I when . . .”? Multiple neurotransmitters and circuits participate in the neuroplasticity of the brain, and the outcomes are not always helpful.

Posttraumatic stress disorder (PTSD) is a prime example of pathological neuroplasticity. When a person experiences extremely frightening or distressing events repeatedly, the fear system of the brain becomes hyperreactive. People with PTSD then find themselves extremely vigilant and quick to react to stimuli that would not normally disturb a person. It could be sensory stimuli or psychological stimuli. Unfortunate examples are members of the military who have experienced the horrors of war, or children who have been repeatedly abused. At the time of this writing, there is no known way of reversing this plasticity, any more than one can reverse a pleasant memory. But there are significant research efforts under way to find solutions to PTSD that will offer relief to the individuals.

Another example of neuroplasticity and “learning” by the brain is epilepsy. In many cases, epileptic seizures begin with a lesion at one site in which the neurons fire in a hyperexcited, coordinated pattern. This neuronal excitability is transmitted to other, normal areas of the brain that, in turn, “learn” to fire in the same way. Eventually enough of the brain “learns” to fire in this way, and generalized seizures develop. Drugs called anticonvulsants can suppress the hyperexcitability, but we have no drugs that can erase the “learned” tendency to generate the seizure activity.

In the Addiction chapter we talk about another type of pathological neuroplasticity—how the reward system learns to crave a drug or a pleasurable behavior. All of these forms of neuroplasticity involve basic alterations of neuronal behavior, and all of them depend on a number of different neurotransmitters besides GABA and glutamate. Recreational drugs can alter the function of different neurotransmitters, often in subtle but damaging ways. While the details of all of the possibilities are beyond the scope of this book, it is important to understand that if a drug is altering your perception of the world or your reactions to your environment, there is a good chance that drug has the capacity to enable the brain to change in a permanent way that is likely not to be good in the long run.


It’s hard to find a media story about the brain that doesn’t refer to the latest technology for imaging the activity of the brain, most often using functional magnetic resonance imaging (fMRI). This is a powerful tool for imaging ongoing brain activity in humans as well as animals. As with structural MRI that yields “still” images of the brain, fMRI uses magnetic fields rather than radiation to image the tissue. So, as far as we know, there is no safety issue about long or repeated exposures (unless you have something in your body that can be magnetized).

fMRI depends on a particularly useful property of hemoglobin, the molecule in red blood cells that carries oxygen to all tissues, including those in the brain. As you may have learned in biology class, oxygen is bound to hemoglobin in the blood and is released from hemoglobin as blood perfuses tissues that need oxygen for producing energy. The magnetic properties of hemoglobin change as the hemoglobin releases oxygen to tissues. Thus, the fMRI system looks for changes in magnetic signals as tissues consume oxygen. The signal is called the blood oxygen level dependent (BOLD) signal.

When neural circuits are active, blood flow increases in those areas and oxygen is stripped from hemoglobin in the blood. Thus the BOLD signal changes to reflect that shift in the amount of hemoglobin that has oxygen bound to it. So literally, a person can lie in an fMRI machine and decide to wiggle a thumb and watch the brain activity associated with that movement. What is being displayed is blood flow and oxygen-consumption changes in the brain areas that control that movement—not the electrical activity of the brain. The BOLD signal lags the neuronal activity for one to two seconds, and there is still controversy about what exactly triggers the increased blood flow and oxygen delivery. But it is safe to say that fMRI is at least measuring a correlate of brain activity.

fMRI has its limits. First, there is the time issue we just mentioned, because the signal lags the neural activity for a long time compared to the firing rate of neurons. Then there is the issue of spatial resolution. The very best fMRI resolution (at this writing) is a cube that’s about 0.9 millimeter on each side—and that requires a machine with a very strong and expensive magnet. That small cube contains many neurons and synapses between them. So, using an fMRI to examine brain circuits is a bit like looking at a low- resolution TV—there is information there, but not as much as one would like.

Another problem is that it is not possible to determine whether a BOLD signal in a brain area is a result of that area transmitting information or receiving information. All we can say is that the area is active. Furthermore, we don’t know the result of that activity—it may be stimulating or shutting down its neighbor by activating neurons that normally slow down cells they contact.

Finally, the BOLD signals are very small compared to the background activity. This requires that the fMRI system average the images to reveal the relevant activity of an area. To further emphasize the active area, colors are used and the contrast is enhanced. Those techniques are very helpful to scientists but can produce images that are misleading to nonscientists. One of us was consulted by a major television network talk show about the effects of Ecstasy as shown by brain images (not fMRI, but it doesn’t matter) of individuals who had used the drug. The images had very high contrast, and it appeared that the Ecstasy users had “holes” in their brains. In fact, there was just a small percentage difference in the true signals, but the images had been enhanced to emphasize those differences. Nevertheless, they talked about Ecstasy producing holes in the brains of users.

fMRI has been used to monitor brain activity in a vast array of studies, ranging from epilepsy to lie detection. It has also been used to image the response of the brain to various drugs as scientists try and determine where in the brain a drug acts to produce a change in behavior. To some extent this works. For example, one can show pictures of cocaine to nonusers and compare their response to the response of cocaine addicts. The BOLD images can vary remarkably between brain areas. But it is hard to know exactly what these changes mean.

First, individual variations make it hard to draw conclusions about a particular individual’s responses. Doing studies with groups of people and averaging the group results produces reliable images, but we are not yet at the point of being able to image one individual and draw firm conclusions. Second, even if a brain area is reliably activated in some circumstance, we don’t know enough about the brain to know exactly what each area does. Probably most important, brain activities are executed by coordinated signaling between a variety of areas, and fMRI may not be able to tell us the direction of signal flow or what role an area is playing. Finally, variations in signal strength may obscure proper interpretations. This could easily happen

if a very small collection of neurons exerted powerful effects on a much larger circuit. The BOLD signal from the small number of neurons initiating the activity might not even be visible, while the larger circuit would dominate and appear to be the source of the activity.

All of this is not to say that fMRI and other brain imaging tools should be ignored. They are truly fantastic tools to begin to understand the relationship between behaviors and brain activities. As they become more refined, they may be able to reveal individual differences that have diagnostic meaning. But our advice at this moment is to view the nonscientific media with a degree of caution and to not be seduced by pretty pictures.


We hope that this chapter offers some good reasons to develop a respect for the brain and the body that supports it, as well as some insight into why drugs do what they do. This is especially important for teenagers, because as every teenager knows, they are different from adults.

What adults may not know is that the teenagers are right. For some time we have known that the very immature brain, as in babies, has a number of characteristics that are different from the adult brain. Now we are finding that the adolescent brain may be different also. It may respond differently to drugs, and it may learn differently.

A psychologist at Duke University, Dr. David Rubin, carried out a fascinating series of experiments showing just how different young people may be. The basic experiment was to take adults at various ages and ask them questions about events that occurred in every ten-year period of their lives, including a lot of trivia. Of course, recent events were remembered fairly well, but other than those, the events best recalled were those that occurred during young adulthood (from age eleven to age thirty). This means that a senior citizen recalled his life events and what was going on in the world during his adolescence even better than those events that had occurred just a few years earlier.

If our conclusions from this research are correct, then there is something very special about either our brain biochemistry or our psychological state during adolescence that enables us to store our experiences for life.

Whatever the explanation, the implications are clear—the experiences, good or bad, that we have during our youth are very well stored in our “sober” memory systems and can be recalled for the rest of our lives. Thus, when teenagers say they are different, they are right, and when adults say that these are formative years, they, too, are right.



UNDERSTANDING DRUGS AND their effects on our bodies begins with some very simple principles.


1. A drug is any chemical put into the body that changes mental state or bodily function.

2. Howadrugentersthebodycanmakeahugedifferenceinitseffects. Ingesting a drug is usually the slowest route to the brain, and inhaling and intravenous injection are the fastest routes. If a drug is potentially lethal, then rapid administration of the drug by inhaling it or injecting it is the most dangerous way to take it and could result in death.

3. Thelengthoftimeadrugaffectsthecentralnervoussystemvaries tremendously across drugs. Some drugs are removed in only a few minutes, while others stay around for weeks. With any compound, it is crucial to know how long its effects will last—even those effects you do not notice.

4. The effects of drugs can change with time as our bodies adapt to the drug. This is called tolerance. As a result, when drug use is stopped, these changes cause bodies to work abnormally once the drug is no longer present. This is called withdrawal.


How Drugs Work: Receptors
How Well Drugs Work: Dose Response How Drugs Move through the Body

Getting In Where They Go Getting Out

The Effects of Drugs Change over Time
How the Body’s Responses to Drugs Change What Happens When We Stop Taking Drugs?

The term drug means one thing to politicians trying to get elected, another thing to high school students, and yet another to physicians. A drug is any substance that changes mental state or bodily function. This can mean megadoses of vitamins, herbal medications from health-food stores, birth control pills, over-the-counter cold remedies, aspirin, or beer. Psychoactive drugs are those that affect the brain. People use psychoactive drugs from a number of sources including foods or beverages (like coffee), prescriptions from doctors to treat illnesses of the brain (like epilepsy), and from a variety of sources from the grocery store to the corner pusher for recreational purposes. There are thousands of compounds that fit this simple definition of drugs. Try to make a list of all the drugs you have ever taken. It will probably number at least twenty, even for those readers who “don’t take drugs.”

Some argue that certain foods are drugs (favorite culprits are sugar and chocolate). Likewise, some addiction-treatment programs view behaviors such as compulsive sex, shopping, playing video games, and gambling as similar to drugs. In this book, we assume that neither foods nor behaviors qualify as drugs. However, research over the last few years has provided some compelling evidence that there actually may be some overlap. Some

behaviors like gambling, overeating, and sex as well as some foods (for example, sugar) activate the same reward system that cocaine does (see the Addiction chapter). At least one study shows that the brains of overeaters show a profile of low dopamine receptors that resembles patterns seen in alcoholics, suggesting that engaging in this behavior might have changed receptors like the drug does. However, there just isn’t enough information to know for certain, and these changes may just reflect normal adaptations the brain makes to excessive stimulation with natural stimuli. That doesn’t mean they are drugs.

A toxin, in distinction from a drug, is a substance that causes bodily harm. Pharmacologists joke that the only difference between a drug and a toxin is how much you take. There is a grain of truth in this. Many drugs produce good effects at one dose and bad effects at a higher dose. There is another difference between drugs and toxins, however. Drug taking is usually purposeful. This is not necessarily true of toxins. We are frequently exposed without choice to toxins including pesticide residues on our food, air pollutants, and vapors we inhale when we put gasoline in our cars. This last example shows how blurred these definitions can be. One of the substances present in gasoline in trace amounts (toluene) is the active ingredient in inhalants that some people sniff to get high. Is it a toxin or a drug? It is both, and it is toxic to the body regardless of the intent of the drug user.


Drugs work by interacting with a particular molecule called a receptor. Many different molecules can be receptors for drugs. Proteins on the surface of a cell that normally respond to hormones circulating in the blood, enzymes that control the flow of energy in a cell, even structures like the microscopic tubes (microtubules) that give the cell its shape can all be receptors. They can occur anywhere in the body: brain, heart, bone, skin. A drug can affect any bodily function if it can bind to some element of the cell that influences that function.

When a drug binds to its receptor and activates it, the drug is called an agonist. This means that the drug has an effect. Some drugs attach to a receptor and do not activate it but keep other molecules from getting to the receptor—often the molecule that normally would be stimulating it. These

drugs are antagonists. They act by preventing normal processes from happening. Many of the psychoactive drugs we have discussed in this book work by preventing the action of normal neurotransmitters.

The toxins used in poison darts provide a vivid example. One active compound in these poisons, curare, prevents the neurotransmitter acetylcholine from working on its receptor. Acetylcholine is necessary to transmit from brain to muscle the information that permits muscle contraction. When curare blocks the action of acetylcholine, the muscles are paralyzed and the dart’s victim dies from paralysis of the muscles responsible for breathing.


How well a drug works depends on how much a user takes. The larger the dose, generally, the bigger the effect, until a maximum is reached. Usually this maximum is reached because all the available receptors are occupied by the drug, or the processes the receptor stimulates are functioning at maximal capacity. Taking more drug than this is pointless.

Why do we take more of some drugs than others? Advertisements on TV are proud of bragging that just one tiny pill of brand X has the same effect as three pills of brand Y. Some drugs bind so tightly to their receptor that it takes very little to activate all the available receptors. Such a drug is very potent. LSD is a good example of a very potent drug—only millionths of a gram can cause hallucinations. So, should you be happy to take brand X instead of brand Y? It depends on how much they cost. If brand X costs three times more and you take one-third as much, you have gained nothing!

What difference between brand X and brand Y could matter? Some drugs don’t bind very well, but a large enough dose can activate all available receptors very well. Others bind very tightly but don’t activate the receptor very well. Efficacy means how well a drug does what it does—how well it changes receptor function. It does matter if brand X has more efficacy than brand Y, because then the one pill would have more effect than three of brand Y. For example, both aspirin and a strong opioid like morphine diminish the sensation of pain. However, no amount of aspirin will match the pain relief from morphine, because aspirin has less efficacy for this particular action. So, why take aspirin instead of morphine? First of all, a morphine dose can

kill you because the difference between an effective dose and a toxic overdose is not great. Second, morphine is addictive. For a garden-variety tension headache, the risks associated with using morphine are not worth the potential benefit. However, for pain relief after surgery, sometimes the greater efficacy of opioid drugs is necessary.


Drugs must get to their receptors to act. Even a skin cream like a cortisone ointment that relieves the itch of poison ivy must be able to pass through the fatty membrane that surrounds most cells to heal the cells that are irritated by poison ivy toxin.

Most drugs must go much farther than the skin to act. Drugs used to treat tumors deep inside the body must travel from where they are placed, through the bloodstream, to be delivered to distant organs. A few drugs pass through cells so well that when they are rubbed on the skin they travel through all the skin layers down to the layer of the skin where the smallest blood vessels (capillaries) are, through the capillary walls, and into the bloodstream. Nicotine is one, which is why the nicotine skin patch works to help people stop smoking. Some oral contraceptive hormones are also able to easily pass from a skin patch through the skin and enter the bloodstream. What is unique about such drugs is their ability to pass through a cell membrane that is very fatty. However, most drugs just don’t dissolve well enough in these fatty membranes to travel all that distance. Such drugs prefer water to oil, and they have a great deal of trouble passing through cells: these often only enter the body well after injection.

Applying drugs to the mucous membranes is an effective way to get some drugs into the body, because the mucous membrane surfaces of the body (as in the nose) are much thinner, and the capillaries are much closer to the surface. For these reasons, placing drugs in the nose, mouth, or rectum provides a pretty efficient route for administering some drugs. Cocaine and amphetamine enter the bloodstream easily from these sites, which is why people snort them. In contrast, antibiotics, an example of drugs that prefer water to oil, cannot cross through cell membranes and cannot be given nasally.

The most efficient way to get a drug into the bloodstream is to put it there directly. The invention of the hypodermic syringe provided the most direct means we have of getting drugs into the body: we inject them directly into a vein. The drug then goes to the heart and is distributed throughout the entire body by the circulation system. After intravenous injection, peak drug levels in the bloodstream occur within a minute or two. Then levels begin to fall as the drug crosses the capillaries and enters the tissues.

There are other places that drugs can be injected. Most immunizations are done by injecting the vaccine into the muscle (intramuscular). The drug is delivered a little more slowly this way, because it must leave the muscle and enter capillaries before it is distributed to the body. Drugs can also be injected beneath the skin (subcutaneously). This “skin-popping” is a route used by many beginning heroin users who have not yet started injecting heroin intravenously.

Inhaling drugs into the lungs can deliver a drug to the circulation almost as quickly as intravenous injection. Anyone who smokes tobacco takes advantage of this characteristic to deliver nicotine to the brain. The drug simply has to dissolve through the air sacs of the lungs and into the capillaries. The surface area of the lungs is very large, and fat-soluble drugs like nicotine can move quickly across a large surface. In addition, the blood supply of the lungs goes directly to the heart and then out to the other tissues. Therefore, smoking can deliver the drugs to the tissues very quickly. However, only certain drugs enter the body efficiently this way. They must be very fat-soluble, and they must form a vapor or gas when they are heated. Several drugs, including cocaine and methamphetamine, easily form vapors if they are in their uncharged form, which occurs when they are crystallized from an alkaline (basic) solution. In this case, the nitrogen that is present in each molecule is uncharged (it has no positive charge from a hydrogen ion). These qualities allow drugs to cross into the circulation very quickly. Drug users call this method of delivery “freebasing.” Cigarette manufacturers create the same effect by making tobacco leaves alkaline (basic).

The most common way that people get drugs into their system is by swallowing them. Drugs that enter this way must pass through the walls of the stomach or intestine and then enter the capillaries. A large portion of any drug dose that is swallowed never gets to the rest of the body because it is removed by the liver and destroyed. The liver is placed cleverly to do this

job. All the blood vessels that take nutrients from the intestine to the body must go through the liver first, where toxic substances can be removed. This protects the body from toxic substances in food. Swallowing may be the easiest way to deliver drugs, but it is the slowest way to deliver a drug to the body. That is why your headache is not gone five minutes after you take an ibuprofen tablet.

To recapitulate, the way people take a drug (the route of administration) and the amount they take determine the drug’s effects. Injecting drugs intravenously or smoking them results in nearly instantaneous effects because the levels of drug in the blood rise very rapidly. This speed accounts for the lure of injecting heroin intravenously or smoking crack. Injecting a drug intravenously or smoking it also offers the greatest risk of overdose. Drugs like heroin can be lethal because they take effect so quickly after intravenous injection that the drug user can reach fatal drug levels before it would be possible to get help. The same dose of drug taken orally will never exert as great an effect—some of it will be lost to metabolism because the process of absorption is gradual.


Once drugs are in the circulation, getting into most tissues is no challenge. There are big holes in most capillaries, and drugs are free to go into most tissues. The brain is an important exception because it has an especially tight defense—the blood-brain barrier—that prevents the movement of many drugs into it. All of the drugs we discuss in this book are psychoactive, in part because they easily pass through this blood-brain barrier.

Although there are myths that drugs “hide” in specific places in the body (such as Ecstasy or LSD hiding in the spinal cord for months), they don’t really. Because most psychoactive drugs are fat-soluble enough to enter the brain, they also accumulate in body fat. THC (the active component in marijuana) and PCP (phencyclidine, or angel dust) are particularly prone to accumulate in fat. As the drug eventually leaves the fat, it enters the bloodstream again and can enter the brain but usually at levels so low it produces negligible effects.

There is a legal consequence to this storage in fat. Drugs like THC are so well stored in fat that they remain detectable in urine for weeks after the last time the drug was used. It is common in drug-treatment programs for people

who have been testing “clean” to show drugs in their urine suddenly if they have been losing weight during their rehabilitation. The drug is simply driven out of the fat as the fat deposits shrink.


Most drugs do not leave the body the way they came in. Although a few drugs, like the inhalants, enter and leave through the lungs, most leave through the kidneys and the intestine. Many are changed in the liver to a form that is easily excreted in the urine. This process of metabolism and excretion in the urine determines how long the drug effect lasts. It is very difficult to change this rate, so once a dose of drug is ingested, there is no hurrying the recovery. In extreme cases, there are emergency room procedures that can accelerate the removal of some drugs by the kidneys, but otherwise we must wait.

Some drugs, like cocaine, leave the brain and bloodstream quickly. The combination of quick onset of action and rapid removal can lead to cycles of taking the drug repeatedly. Drug levels shoot up, then plummet, taking the user to an intense high followed by a “crash,” which provides motivation to take another dose of the drug. Some cocaine users get into “runs” of repeated doses and end up using grams of cocaine in a single sitting. This pattern often leads to overdosing—the user takes another dose as the drug effect wanes but before the earlier dose has been completely eliminated. Drug levels in the brain gradually accumulate to dangerous levels.

Marijuana presents the opposite problem. THC, the active compound, is extremely fat-soluble (and thus accumulates in body fat), and its breakdown products are also active compounds. So, as the body tries to remove it, the metabolic products continue to have psychological effects. These two characteristics of marijuana mean that users can be under its influence for many hours or even days after it is smoked.


When people recall the first time they drank alcohol, most remember that they got drunker than they would now if they drank the same amount. This isn’t all just fading memory. Many drugs cause much smaller reactions in the body

when someone uses the same drug regularly. This change is called tolerance. Usually the lesser reaction is due to previous experience with that drug or a similar drug, but even intense stress might change the reactions to some drugs.

Think about all the drugs we take that keep working even with many doses: our morning cup of coffee, an occasional aspirin for a headache (imagine how much aspirin we all take over a lifetime!), an antacid to calm the stomach after a spicy meal. Why do these drugs keep working? The reason is that we usually take them only for a short time, or intermittently. The more frequently we take the drug, and the higher the dose, the more likely it is that tolerance will develop. So, with just one aspirin once a week or even once a day, the body has plenty of time between doses to return to normal.

Caffeine continues to provide that pleasant arousing effect that people associate with their morning cup of coffee or tea for years. However, bodies do adapt to the daily cup of coffee (see the Caffeine chapter), so that people who are regular coffee drinkers have smaller effects from (show tolerance to) caffeine compared to someone who never ingests it. So, tolerance builds up, but the normal daily dose is high enough that the effect does not go away entirely.

Tolerance to some drugs can be dramatic. For example, heroin addicts rapidly build up tolerance to the ability of opioid drugs to suppress breathing (the cause of overdose death). Longtime heroin addicts will take doses that would have killed them the first time they used the drug. This tolerance can last as long as several weeks or months. Tolerance lasts this long because addicts typically take many doses a day, every day, sometimes for years, and some of the body’s changes are very long-lasting. Opioids also exemplify the fact that different tissues adapt at different rates to drugs: While tolerance develops to effects of breathing, the ability of opioids to constrict the pupils is fairly resistant to tolerance. This can be helpful in overdose situations, because medical personnel can quickly assess whether opioid drugs might be involved. But we are also learning, unfortunately, that tolerance to the ability of opioid drugs to suppress pain also develops fairly easily, and so the effects of these drugs become diminished with prolonged use.

What about antibiotics? Everyone probably remembers being exhorted to be sure to take every one of the two weeks’ worth of pills, and tried (and

perhaps failed) to be careful to take a dose every six to eight hours. Although no one bacterium adapts to the drug, the population as a whole often does adapt. Bacteria replicate between one and many times a day, so new generations are constantly appearing. When an individual bacterium appears that happens to be resistant to the drug, this individual and its offspring survive, and the infection becomes resistant. With the rising use of antibiotics (antibiotics in beef, antibiotics for many childhood diseases, etc.), more and more humans are carrying resistant populations of bacteria in their body that are difficult to treat with currently available antibiotics. This is drug tolerance playing out at the population level rather than the individual level, and it is becoming more of a problem worldwide.

Some drugs actually become more effective over time. Cocaine is an example. Some of its effects become greater with each passing dose. There could be a beneficial side to this effect: drugs that gradually become more active could be delivered only occasionally and still be effective. This certainly would be cheaper! Some researchers have proposed that antidepressant drugs fit into this category, and that daily treatment may not be necessary.

Fortunately, many of the drugs we rely on to treat disease are given in doses that do not cause the development of tolerance, so they can continue working over a long period of time. This is especially important for drugs that are used to treat diseases like high blood pressure, which are lifelong conditions that require therapy for years.


How do tolerance and sensitization happen? Bodies tend to adapt to the continuous presence of drugs, so bodily functions remain normal despite the presence of drugs. We will describe the three most important ways that this happens.

The first adaptation to long-term drug use happens in the liver, which inactivates drugs with certain enzymes that change the drugs into forms that the kidneys can excrete. The enzymes that inactivate drugs are not very specific. If they were, hundreds upon hundreds of them would be needed— one for each drug. Instead, humans have between fifty and sixty, which are responsible for metabolizing all drugs.

The activity of these enzymes changes with experience. When the liver encounters frequent doses of a drug that one of the enzymes must inactivate, its cellular machinery “tools up” to deal with the excess drug by making extra enzyme to get rid of the drug. As a result, the drug gets eliminated more quickly. This process causes tolerance in a simple way: less of the drug gets to the tissue where the receptors are. Smokers, who inhale many different substances each time they smoke cigarettes, typically metabolize many drugs much more quickly than nonsmokers because the constant presence of the substances in smoke results in increases in many drug-metabolizing enzymes. This can present problems when treating diseases in smokers. In the same way, the livers of heavy alcohol drinkers metabolize many drugs more quickly.

Nasal decongestants provide a great example of the second major tolerance process. The over-the-counter medications that people use to treat stuffy noses accomplish their effect by attaching to receptors on the blood vessels in the nose. These receptors are activated by the drug and cause the blood vessels to constrict. This decreases the volume of blood in the nose and helps to reduce the inflammation and swelling. This works well for a while. However, the cells that have these receptors resist being overstimulated. To reestablish balance, they simply remove some of the receptors from the surface of the cells. The result is that the nasal decongestant stops working! The warnings on the bottle about not using the drug for more than a few days are based on the reality that the drug will stop working anyway. This kind of change is a very common source of tolerance. The brain adapts in much the same way: overstimulation of receptors causes neurons simply to remove receptors and bring the level of stimulation back down to normal. Likewise, if the drug prevents receptors from working, the cell simply makes more.

Pavlov’s dogs salivating when they heard a bell ringing to signal the arrival of dinner provides an example of the last tolerance mechanism. Our brains “learn” to expect the drug, and act accordingly. Sometimes this means activating processes that tend to oppose the effects of drugs. If people take drugs in a familiar environment (as do many people who take addictive drugs), they learn to associate the typical environment of drug taking with the experience of the drug. For example, a heroin addict might usually buy from the same dealer and take the drug to a “shooting gallery” to inject it. Soon, this environment becomes associated with the drug experience. When the

heroin addict enters the shooting gallery, he or she will start breathing faster to offset the slowing that will happen once heroin is injected. This process is powerful. Often, when people overdose after taking a dose of drug that they normally tolerate, it is because they took it in an unfamiliar place.

Unfortunately, this type of expectation can also work the opposite way. When heroin addicts have been in recovery and then return to their homes, many times simply being on the street where they used to take the drug will reawaken those same sensations and reawaken drug craving. This becomes a very strong urge and is the reason why many treatment programs urge addicts to change their lifestyle in a dramatic way and avoid people and places that they associate with drug use.


When the drug is no longer present, all of these marvelous adaptations are counterproductive. Let’s go back to the nose of the earlier example. Imagine that someone has been taking decongestants for two weeks. The person probably is taking more and more to overcome the tolerance that is developing to the drug. What happens upon stopping? The blood vessels of the nose don’t have their normal number of receptors anymore. They are staying unstuffy only because the decongestant has been stimulating the few that are left like crazy. Once the drug is gone, the few receptors left are not enough to do the job, and there is a huge rebound in nasal congestion. So, the cure has become the disease.

This process is called withdrawal, and it is really the flip side of tolerance. The person is not addicted to nose drops, but simply tolerant: the nose is dependent on the drug. This is one of the commonest misconceptions about withdrawal and addiction (more about this in the Addiction chapter). A person can be dependent and go through withdrawal even from drugs that are not addicting, like nose drops.

The consequences of withdrawal from some drugs can be life- threatening. For example, alcohol is a sedative drug that slows the firing of neurons. Imagine a neuron prevented from firing every day by alcohol. A logical response would be for it to do whatever it could to fire more often. Now imagine many cells in the brain affected in this way. They adapt by increasing receptors that stimulate neural firing and decreasing receptors that

inhibit firing. Now imagine an alcoholic who enters treatment and stops drinking abruptly. All these neurons are very excitable and the result is a tremendous overexcitation of the nervous system. This overexcitation can actually lead to seizures and death. Fortunately, there are medications that can be given to detoxifying alcoholics to keep these withdrawal symptoms at bay while the brain returns to normal.

Understanding how drugs work is not simply a matter of which drug does what, although that is the first thing to know. Everyone needs to understand how safe it is to take a drug in a particular way, how fast it gets in, how long it hangs around, and how it gets out; and we all need to understand the consequences of prolonged use of, and withdrawal from, anything we take.

How quickly does any tissue, including the brain, return to normal when a person stops using a drug? The answer depends on how much drug the person took, how long she or he took it, and the extent and kind of changes that occurred. Some changes reverse very quickly. The nose drop user will have a normal nose a few days after stopping the use of nose drops. Even some of the receptor changes in chronic alcoholics reverse so quickly that the worst of the withdrawal symptoms are over in a matter of days. However, other changes take longer to reverse. The longest changes may be the responses that rely on learning mechanisms—like Pavlov’s dogs. These do eventually reverse—if you expect something to happen often enough and it never happens, very gradually your brain changes its response. But this can take weeks or even years. This type of change is one of the changes that develop in addiction that make recovery such a long-term process.




1. Addiction is the repetitive, compulsive use of a substance despite negative consequences to the user.

2. Addictive drugs initially activate circuits in the brain that respond to normal pleasures, like food and sex. Every brain has these circuits, so every human could potentially become addicted to a drug.

3. Drug taking accelerates and becomes compulsive for many reasons, including changes in the brain, the desire to experience pleasure from the drug, and the desire to avoid the discomfort of withdrawal.

4. Many different factors in the life of an individual, such as family history, personality, mental health, social and physical environment, and life experience, play a role in the development of addiction.

What Is Addiction?



Addiction (or psychological dependence, as some people call it) is the repetitive, compulsive use of a substance by a person despite negative consequences to their life and/or health. Use of cocaine or heroin is illegal and unhealthy, but not everyone who uses those substances is addicted to them. Addiction differs from physical dependence: simply undergoing changes when substance use is stopped (like the headache that many coffee users experience when they miss their morning cup of coffee) is a sign of physical dependence, but it is not necessarily a sign of addiction. Both addiction and physical dependence coexist in people who are strongly addicted to some drugs.

This definition of addiction obviously applies to the compulsive, repetitive use of alcohol, nicotine, and opioid drugs like heroin, as well as cocaine and other stimulants. But what about activities like overeating, gambling, and sex? Some people engage in these activities to the point that there are negative consequences for themselves (and their families). Some people gamble away everything they have, or engage in promiscuous sex to the extent that they risk infection with HIV or other sexually transmitted diseases. These behaviors resemble drug-seeking behaviors in an addicted person, and more and more research shows that the same neural circuits may be involved.

How Addiction Starts: The Neural Circuits of Pleasure Drugs and the Pleasure Circuit
The Special Role of Dopamine
The Dark Side: Pain, Not Pleasure

Cucumbers and Pickles: Changes in the Brain Is There a Deficient Brain Chemistry in Addicts? Personality and Drug Addiction
Life Experience and Drug Addiction
Mental Illness and Drug Addiction
The Bottom Line on Addiction
Using Drugs to Stop Drug Use


What would lead someone to abandon their job, family, and life or to ignore the most basic, life-sustaining impulses to eat and reproduce? There must be something fundamentally different about “addicts” that leads them into such an extremely dysfunctional lifestyle. Addiction has been attributed to personal characteristics, including a lack of “morals” or self-control, having different brain chemistry, experiencing mental illness or extreme trauma, or hanging out with the wrong friends. While all of these factors influence addiction, something more primal is at work. The neural mechanisms by which addictive drugs act are present in every brain. Addiction is so powerful because it mobilizes basic brain functions that are designed to guarantee the survival of the species. Because these mechanisms exist in every brain, potentially any human being could become a drug addict. The reason lies in a complicated neural circuit through which we engage in behaviors that feel good. The job of this neural circuit, presumably, is to cause us to enjoy activities or substances that are life-sustaining. If it is successful, then it is more likely that we will engage in the activity again.

How does this “pleasure circuit” work? Let’s use food as an example. A person who has a really great pastry at a bakery will go to this bakery again because the food tasted good. The good-tasting food is a reinforcer because it increases the likelihood that the person will engage in the same behavior (going to the bakery). Animals, including humans, will work to gain access to food, water, sex, and the opportunity to explore an environment (perhaps to find food, water, or sex). These are the “natural reinforcers”—events or substances in the world that motivate behavior.

In a laboratory, animals can learn to press a lever to obtain a food pellet. This is the laboratory equivalent of the bakery scenario. There is a critical neural circuit in the brain that makes this happen. If this circuit is damaged, even animals that are extremely hungry will not press the bar. We think that this neural circuit is the pathway that causes the animal or person to experience the reinforcers as pleasurable. It is sometimes called the reward pathway. When this pathway is destroyed, an animal loses interest in food, in sex, and in exploring its environment. It is still capable of doing all these things; it is just not motivated. Conversely, an intact animal will work very hard (pressing a bar or whatever) to turn on a gentle electrical current that

stimulates this pathway. It acts like it enjoys having the pathway stimulated electrically. This is called self-stimulation.


It won’t surprise anyone that addictive drugs are reinforcers. The experimental evidence is overwhelming. Most experimental animals (pigeons, rats, monkeys) will press a lever to get an injection of cocaine, methamphetamine, heroin, nicotine, and alcohol. They will not press a lever for LSD, antihistamines, or many other drugs. Even fruit flies and zebra fish will hang out in an environment in which they have previously received a reinforcer—another test of the potential addictiveness of a substance. This list of drugs for which experimental animals will work matches exactly the list of drugs that are viewed as clearly addictive in humans.

We know that the same pathway mediates the pleasurable effects of addictive drugs. There are two particularly convincing arguments. First, if this pathway is damaged in an animal, the animal will not work for drugs. Second, animals with an electrode placed in the reward pathway find smaller currents more “enjoyable” if the animal has received an injection of cocaine or heroin, for example. The same system is activated by drugs or stimuli associated with drugs in the brains of addicts. When cocaine addicts looked at pictures of cocaine or handled crack pipes while the activity of their brains was monitored, they reported a craving for cocaine, and at the same time, their brains showed activation in the reward pathway of the brain.

Addictive drugs (stimulants, opioids, alcohol, cannabinoids, and nicotine) can actually substitute for food or sex. This explains why rapid injection of cocaine or heroin produces a “rush” of pure pleasure that most users compare to the pleasure of orgasm. This isn’t just true for certain people who lack willpower or who are engaged in a deviant lifestyle. It is true for everyone who has a brain. It automatically becomes easier to understand why addiction is such a common problem across cultures.

Although the news media have overdone the “what is the most addictive drug?” contest, it is clear that animals will work much harder to get some drugs than others. For example, rats will press a bar up to two to three hundred times for one injection of cocaine and perhaps even more for the bath salt MDPV. Both animals and humans consume less of some drugs, like

alcohol and nicotine, that have unpleasant effects on the body at high doses. However, if you judged the most addictive drug by the largest number of people who have trouble stopping their use of it, then nicotine would be the clear leader. The reason, as we explain below, is that there are two sides to the addiction process: the pleasure of starting, and the pain you experience when you stop. Both can powerfully influence drug-taking behavior.


The neurotransmitter dopamine plays an important role in the normal process of reinforcement and in the actions of most addictive drugs. One group of dopamine neurons runs directly through the reward circuit we just described. If the dopamine neurons in this circuit are destroyed, then animals will not work for food, sex, water, or addictive drugs. Furthermore, both natural reinforcers and most addictive drugs increase the release of dopamine from these neurons. Our favorite experiment was conducted by a scientist in Canada who measured the release of dopamine in the brain of a male rat before and after providing it with a female partner. Not surprisingly, access to a sexually receptive partner caused a large rise in dopamine levels in this part of the brain.

If this same experiment is done with drugs instead of natural reinforcers, the results are the same. Cocaine, morphine, nicotine, cannabinoids, or alcohol will cause large increases in dopamine in the same area of the brain in which sex causes a rise. Most neuroscientists think that addictive drugs affect neurons that connect, one way or another, with this critical dopamine circuit to stimulate its activity.

Anyone who has ever enjoyed a muffin knows that dopamine going up when something pleasant happens is not the whole story of addiction. It is not even the whole story of how dopamine is involved. To explain that, we are going back to the bakery for a second visit. The first time you went to the bakery, dopamine went up when you had an unexpected treat—a tasty muffin. The second (or the third, or fifth) time, you started to anticipate the muffin when you saw the bakery sign. We know from experiments in monkeys that dopamine starts going up in anticipation of a reward rather than when the reward arrives. Scientists now think that one important role dopamine plays is this anticipation for a known reward. The first step toward addiction may

be when you expect the muffin and begin to organize your walk to work to make sure it happens. Dopamine probably contributes to that decision- making process. However, it is still not addiction. You could change your route if you needed to.

Furthermore, dopamine neurons are not “the end of the line” for detecting pleasure, but they clearly connect with other neurons. We are just beginning to understand how these other areas of the brain play a role.


Enjoying the rush of pleasure from a drug is only part of addiction. For addicts, there is an opposing force, a yang for the yin. Once the body adapts to the drug and physical dependence develops, a daily cycle of drug taking, pleasure, gradual waning of drug effect, and the onset of withdrawal symptoms emerges. Withdrawal symptoms are different for each drug, and minimal for some (much of this is covered in detail in the chapters on individual drugs). For example, the waning of opioid effects causes an ill feeling similar to the onset of the flu. The drug user has chills and sweats, a runny nose, diarrhea, and a generally achy feeling. An alcoholic will feel restless and anxious. However, there is a common underlying feeling of withdrawal from all addictive drugs: an unpleasant feeling that is the reverse of the good feeling that the drug once gave and can be accompanied by a strong craving to take more of the drug. Avoiding the unpleasant feelings of withdrawal and satisfying the desire for more drug can eventually become even stronger motives for drug taking than simply feeling good.


Once you are a real muffin addict, you wait at the bakery door until opening time each day, neglecting your job or forgetting to take your children to school. You do this even if the muffin tastes lousy. It is this sort of compulsive, repetitive involvement in drug taking despite negative consequences that most experts view as addiction.

Use of addictive drugs can be viewed in a similar way. Many people drink alcohol occasionally, or even sometimes use cocaine at parties.

However, for some people, the first social experiences with drugs gradually evolve into more continual use. Alcohol use provides an example. While 50 percent of the adult population of the United States drink alcohol occasionally, of these about 10 percent drink heavily and about 5 percent engage in addictive patterns of drinking.

Clearly, something happens in addicts that makes the need to consume drugs so great that they will go to extreme lengths to obtain the drug. What changes in the brain explain this? We have heard recovered addicts compare the change in their behavior and lives to the change from a cucumber to a pickle. Once a cucumber is turned into a pickle, it cannot be turned back. Is this a real analogy? If so, then the Alcoholics Anonymous approach of lifetime abstinence from drugs becomes a convincing solution to alcoholism.

Most scientists think that changes gradually occur in the reward circuit of the brain as it adapts to the continuous presence of the drug. The simplest change is easy to understand: with daily stimulation by addictive drugs, the reward system comes to “expect” this artificial stimulus. When people stop using drugs abruptly, the reward system is shut down—it has adapted to the daily “expectation” of drugs to maintain its function. We know of one biochemical change in the brains of all addicts that may explain this result. The brains of alcoholics, methamphetamine addicts, heroin addicts, and even compulsive eaters show a common biochemistry—they have low levels of one of the receptors that normally receive dopamine. This makes sense—in response to a constant barrage of dopamine, the cell that receives it is just trying to shut down. Recovering heroin addicts often report that every time they inject heroin, they are trying to recapture the feeling of their early experience with the drug, which gave a pleasure that they never quite reached again.

Furthermore, some successfully recovering addicts often say that they do not feel pleasure in anything for a while after they stop using cocaine. Imagine how difficult it must be to stop using a drug that gives incredible pleasure, when even things that are usually enjoyable give no pleasure during withdrawal. This inability to feel pleasure may be one of the powerful reasons why people have great difficulty giving up cocaine. If there is a substance at an addict’s fingertips that can increase the feeling of well-being immediately, clearly the impulse to take it can become overwhelming. We think that the loss of dopamine receptors described above is one change in

the brain that contributes to the anhedonia (inability to experience pleasure). However, in contrast to our pickle analogy, these receptors normalize within weeks after someone becomes drug-abstinent. Research has shown that many changes like this occur in the brains of animals that have become addicted to drugs, and many of these changes reverse when the animal stops. Unfortunately, scientists haven’t pinpointed the critical changes and confirmed which of them are reversible.

Some of the changes in the brain of a person who uses addictive drugs repeatedly are just a result of normal learning in the brain. Let’s go back to our bakery one more time. As our imaginary muffin addict approaches the store each day, they remember the route and look forward to the smell of newly baked muffins wafting down the street. Pretty soon, the smell of the bakery alone can cause an intense longing for the pastries before they arrive at the door. What happens when our muffin addict decides that the daily search for muffins is taking too long, or when the bakery raises prices too high? An addict who goes “cold turkey” and quits muffins altogether had better find another way to go to work, because the route to the bakery, the smell of the muffins, and many of the experiences associated with going to the bakery will cause an intense longing for a muffin. This type of longing has ruined many a diet, and this type of learning plays an important role in addiction as well. Simply showing a former cocaine user a photograph of a crack pipe will trigger a strong craving for the drug, and recent studies of brain activity show that areas of the brain involved in memory are activated while the person looks at these pictures.

There is another kind of “learning” that happens in the brains of addicts that makes it hard for them to stop using drugs. This involves the part of the brain that plans for the future. Under normal circumstances, if an animal or person finds a reinforcer, the brain remembers where and how it happened and plans to check back the next time food or sex is needed. This ability to plan for the future is perhaps the most sophisticated thing our brain does. However, in a crack user, what this part of the brain focuses on is finding crack—the repeated stimulation with this one reinforcer can also “hijack” these planning centers in the same way. So it isn’t simply the pleasure the drugs cause that motivates drug use but our ability to remember and plan for future pleasure. This may be one of the most long-lasting changes that happen in the brain.

New research shows that there is a final step in addiction: when taking the drug becomes as automatic as tying your shoes. Scientists have shown that another part of the dopamine system that is important for the transition of this learning to something automatic gradually changes, too, but more slowly. Eventually, hitting the bar to get an injection of drug becomes a habit. This behavior has become an automatic and controlling part of your behavior.


If everyone with a brain can become an addict, why are there (relatively) so few addicts? Could there be a unique group of people whose pleasure circuits are abnormal in some way so that these drugs feel particularly good? Or could there be a group of people whose pleasure circuits don’t work very well, so that they are inclined to drink alcohol, smoke, or take cocaine to feel normal? There are probably people in each of these categories. In studying these questions in human addicts, there is a real “chicken and egg” problem. If brain function is abnormal, it is impossible to know whether the abnormality was caused by years of substance abuse or was present before. This is one challenge about the aforementioned dopamine receptor finding. Some scientists have tried to solve this problem by studying the children of alcoholics. There are certain EEG (brain wave) changes that have been noted in some alcoholics and in their sons. However, we don’t really understand the significance of this EEG anomaly yet. The only way to be sure is to study these children until they become adults to see if this difference predicted alcoholism. Such studies are under way, but they take a long time. We can do these experiments in animals, and we have found that even with free access to cocaine, only a certain percentage of animals (about a fifth) progress to the stage of compulsive use.

Are these differences due to a deficient gene that could simply be repaired? The mapping of the human genome has really speeded up the search for genes related to addiction as well as other diseases. Many candidates have been identified. Some are specific to specific addictions. A variant of one gene for the receptor through which ethanol acts is associated with alcoholism, and a variant for a receptor that opioids act upon is associated with opioid addiction. Others, like the dopamine D2 receptor, are related to all addictions. Others have been surprises. One of the best genetic

“predictors” of nicotine dependence is a gene that controls the breakdown of nicotine in the liver—not anything related to brain function at all. Finally, there are genes that seem to protect people from addictions. Two genes involved in alcohol degradation fit into this category (see the Alcohol chapter). So, as many scientists predicted, drug addiction is a complicated disorder that can involve many genes. Can we fix the affected genes? Not yet. Do we want to? Because most of these genes affect normal brain activities, we are not close to knowing if changing them would treat addiction without causing other troubles. And even if we could, the ethical questions raised by such manipulations are huge.

Finally, it is important to realize that biology is not destiny. People are more than bags of genes that produce behavior. They are influenced by their environment and can control their behavior voluntarily. Simply possessing a particular gene that has been found in the brains of some alcoholics does not mean that an individual must become an alcoholic. If he or she abstains from alcohol, for one thing, there will never be a problem. Maybe these slightly abnormal genes provide some benefit to the person that we don’t fully understand. On the other hand, people with no genetic predisposition may experience such traumatic life circumstances (being sexually abused during childhood, for example) that they develop compulsive use of alcohol or other substances in an attempt to self-medicate their psychological trauma. The bottom line is that everyone with a brain can become an addict. Given the diversity of human brains, it is likely that some people will find the experience more compelling than others, but we have not really defined exactly what brain chemistry leads to this vulnerability yet.


How many people reading this book have worried about the possibility that they or a loved one may have an “addictive personality”? Although this concept is a favorite of some drug-abuse treatment professionals, psychology classes, and self-help books, there seems to be little agreement about what an addictive personality is. Furthermore, the personality type prone to substance abuse changes with the times. In years gone by, the obsessive-compulsive personality was described as prone to drug abuse. Today, there is concern that risk-taking and impulsive people are more likely to develop substance-

use problems. Many of these theories probably have a grain of truth to them. For example, a person who is uninhibited about trying new experiences, including those that are risky, may be more likely to take drugs the first time. The risk of addiction in these people might arise from the greater likelihood that they will experiment with drugs. As with genetic arguments, it is important to remember that such traits do not condemn a person to drug addiction. Many risk takers channel their energies into daring activities like bungee jumping.


Life experience can contribute to addiction as well as protect potential addicts. The life histories of people who have entered drug-treatment facilities show that certain characteristics appear more frequently in substance users than in people without substance-use problems.

Substance abusers are more likely to have grown up in a family with a substance-using parent. Alcoholism can be passed on by the experience of living with an alcoholic parent (although almost as often this experience will motivate a life of abstinence). Do people growing up in an alcoholic household simply learn to respond to stress with alcohol? Possibly. Children of alcoholics also are more likely to experience physical and emotional abuse at the hands of their parents, and a past history of physical and emotional abuse is another characteristic of many substance abusers. This is particularly true among women. In studies of hospitalized alcoholics, 50 to 60 percent typically report having experienced childhood abuse.

Why should bad early experience lead to adult substance use? One group of theories suggests a psychological origin for the substance use. However, a biological theory was developed from experimental work done on monkeys. Scientists at the National Institutes of Health and elsewhere have shown that when infant monkeys are neglected or abused by their mothers, they have a number of behavioral problems as they grow up. As adults, they tend to get into fights, and if given the chance to drink alcohol, they drink to excess. This is not just a genetic tendency, because infants from perfectly normal mothers will show these tendencies if they are raised by neglectful mothers. None of this is surprising. What is surprising is that these behavioral problems are accompanied by changes in the brain. The alcohol-drinking monkeys show

lower levels of the neurotransmitter serotonin in their brains. This study indicates that this early life experience may produce long-lasting changes in the brain that contribute to these behaviors.

We know that associating with drug-using peers increases the chances that a person will choose to try drugs. Also, early use of cigarettes, alcohol, or marijuana is associated with later use of other drugs. This association has led to the popular “gateway theory” of drug addiction. This theory is based on evidence that most people who use illegal addictive drugs first used drugs like alcohol, tobacco, or marijuana. These drugs are viewed as a gateway to the use of more dangerous drugs. However, the vast majority of people using cigarettes, alcohol, and marijuana never use “harder” drugs. Although the statistics are correct, this situation reminds us of our favorite statistics teacher, who is fond of saying that statistics don’t prove how things happen. It is possible that people who are risk takers, or mentally ill, or living in chaotic families, or hanging out with deviant friends are more likely to experiment with many deviant behaviors, including drug use. The drug use could just as likely be a symptom as a disease.


Depression and some other mental illnesses also occur more frequently in substance users. Did the drugs cause the problem, or did the problem cause the drug use? Once someone’s life has become complicated by substance addiction, the turmoil that has been created can certainly contribute to the development of depression. This fact makes it very difficult to understand the complicated relationship between mental illness and drug addiction. However, some recovering addicts will describe an opposite cycle: that their anxious or depressed mood led them to drink or to use other substances to deal with feelings of inadequacy or despair. Then, as time passed and substance use became more frequent, the substance use became the dominant problem. This “self-medication” process probably contributes to addiction in many people.


The bottom line on addiction is that anyone with a brain can get addicted to drugs. However, most people don’t, and there are a lot of reasons. First and foremost, if a person does not experiment with addictive drugs, then the person won’t get addicted. Second, if a person is mentally healthy, has a stable family and work life (including supportive and non-drug-using peers), and has no family history of substance abuse, then some important risk factors are absent and the person is less vulnerable. However, the individual still has a brain and so is not immune to addiction. During the cocaine craze of the 1970s and 1980s, plenty of constructive, highly educated, well- employed professionals became addicted to cocaine despite positive factors in their lives.

Finally, there may be some people for whom the pleasurable experience of these drugs is exceptionally high, and the drive to use the drugs is thus more compelling than for others. If these people do not try drugs, this underlying quality will not present a problem. However, if they have access to them, and if they do choose to use them, they are at significant risk. It is no accident that the rate of drug addiction among professionals in the United States is highest among medical personnel, who have easy access to such drugs.


Anyone who has ever dieted knows how hard it is to lose weight and maintain the loss, despite the many strategies available: self-help books, diet products, web-based tutoring, group support, physician help, even diet drugs. Despite all of this help, most of us find that controlling our eating behavior is the hardest change to make in our lives. One reason: our reward system has us “wired” to eat. This is a strong, neurobiological imperative to help us survive. Given the overlap between the neural circuits that control the pleasurable aspects of eating and using drugs, drug treatment of overeating might be considered as a metaphor for drug abuse treatment.

As when dieting, there are a multitude of approaches to treating drug addiction. These range from trying to go “cold turkey” to treatments that include inpatient rehab, physician-assisted counseling, outpatient group or individual therapy, support groups like Alcoholics Anonymous and Narcotics Anonymous, etc. And similarly, most people try over and over again before

successfully stopping. Some research estimates that the average smoker tries five to ten times to quit before successfully quitting.

We are not going to try to compare all of these different approaches, but we want to address the use of pharmacotherapy in treatment of addiction. There are a number of drugs that can help suppress the craving associated with quitting drugs. Most are based on a simple principle: they aim to provide a small bit of drug, just enough to curb craving, but not enough to get “high.” These approaches are intended for use for a period of time that allows those brain changes that can reverse to do so. Typically, as the brain changes, the amount of the drug is gradually tapered down to a very low dose, or nothing at all. The nicotine patch is probably familiar to most: a skin patch that releases nicotine slowly to suppress craving for cigarettes. There are other products like nicotine-containing gum, nasal spray, etc. The goal with any of these products is to gradually lower the nicotine dose until the person is successfully nicotine-free.

Similarly, there is effective pharmacotherapy for opioid addiction. Decades ago, the opioid methadone was shown to suppress craving, decrease drug use, and help people resume normal living. A newer drug, buprenorphine, does much the same thing. Both drugs work by providing a small, constant dose of opioid to prevent craving while the patient gradually normalizes. Similarly, acamprosate provides the same “substitution” for alcohol. All of these pharmacotherapies have been shown to help drug- dependent patients remain abstinent. Unfortunately, no such drug exists for stimulant addiction at the present time, but researchers are working hard to find one.

What about the common criticism of drug therapy for addiction that by using a drug, you are “maintaining the addiction”? Let’s go back to our definition of addiction to dispute this assumption. Addiction is the repetitive, compulsive use of a drug despite negative consequences. A person who is taking a pill each morning, going to work, sustaining healthy relationships, and functioning well in society does not fit this description! The pharmacotherapy is making the person’s life better, not worse.

Consider again our dieting analogy. There are now several drugs that can effectively help people lose weight by decreasing appetite. These are based on a sound scientific understanding of the neural circuits involved in regulation of eating. Despite effective pharmacotherapy, most people regain

weight after using drugs to help control their appetite. Similarly, many people relapse to drug taking despite pharmacotherapy. Has the drug just been a “crutch” that is not useful in the long run? Just like drugs used to treat appetite, the drugs used to treat addiction are not intended for lifelong use, but to give the patient’s brain time to change as much as possible and to give the patient time to learn alternative strategies to deal with his or her behavior. Much as overweight patients must learn better eating habits and how to exercise, people with drug dependencies must learn how to cope with life without resorting to their addictive drug of choice. This is where all of the strategies listed above become invaluable. Research shows that recovery from addiction is most likely to be successful with a combination of counseling and drug therapy.

One of the most useful alternative definitions of addiction we have ever heard is the one coined by the former head of ONDCP (Office of National Drug Control Policy), Tom McClellan, who defines drug addiction as a “chronic relapsing disorder of phased neuroplasticity.” This is the process we have described in this chapter. If we define obesity as an eating disorder, it certainly seems relevant to call addiction a disorder too. We do not need to invoke a “disease” definition, which some people find inappropriate. And extending this comparison, why not use all the strategies we have available to help people recover and live normal lives?



IT IS SAID that your life can change forever in a matter of seconds. When a person mixes alcohol or other drugs and the legal system, the combination can easily become life-changing. For a variety of reasons, the lawmaking bodies of most countries, especially the United States, control illegal drug use by making drug laws harsh and certain. All who deal with drugs in an illegal manner are thus at risk for penalties that can disrupt their own lives and those of their families.

The use of almost all the drugs discussed in this book could involve violations of the law, depending on the circumstances. Many of these drugs are illegal in all circumstances—manufacturing, distribution, and possession. Others are legal when prescribed, but not for recreational use. Still others, such as alcohol, can be legal for adults, but their use is prohibited for underage individuals and for activities such as driving a car or operating a boat.

This chapter is written to inform readers about very basic laws and principles that come into play around drug issues. It is not intended to give advice about dealing with the law-enforcement community or the judicial system. If you feel that you need that advice, find a good lawyer to answer all of your questions before you become legally involved.


1. While laws exist regarding the rights of a law officer to search someone’s car or home, this very complicated issue is often decided in the courts in individual cases. Generally you have the greatest “expectation of privacy” in your home. There is less expectation of privacy in a car, and the least when you are out in public.

2. If a law-enforcement officer suspects you of a crime and really wants to search you or your car, you will be searched, whether or not you give permission. If you give your permission, the search will almost certainly be considered legal. If you refuse permission, the search may or may not be legal, but it may happen anyway. The debate over whether the search was permitted and legal will begin in the court system. The easiest way to avoid trouble is to avoid situations in which a random and unexpected search will yield anything illegal.

3. A person who is innocent of any crime and has not taken, distributed, or even possessed drugs, but is with someone arrested for possessing drugs may become involved with the legal system until proven innocent. By that time, the person may have incurred large financial burdens (for example, an expensive lawyer), terrified family members, and spent some time under arrest.

4. The penalties for drug-related activities can be horrendous, especially in the United States federal judicial system, and particularly for selling drugs. Many casual drug users do not realize that simple possession of a modest amount of a drug can automatically be considered “intent to distribute,” whether or not they actually plan to sell the drug. Intent to distribute is a crime itself and can carry significant penalties.

5. You do not have to be on government property to be in violation of federal law. The federal drug laws apply everywhere in the United States and US territories at all times.

6. State and federal laws can be extremely strict about the use of guns in the commission of crimes. The possession of a gun—even just having one in the vicinity of a drug-law violation—can add many years onto the sentence for the original crime.

7. Manypeoplebelievethattheyare“safe”fromseriouslegal consequences because they know the local officials, or because they

believe the penalties are not serious. They are wrong. First, a local official who interferes with a prosecution could be prosecuted for obstruction of justice or public corruption. Second, an arrest by a state or local officer can easily be referred to federal prosecutors not subject to local political influence. Third, in many states and in the federal system there is no parole. Even worse, in some cases “minimum mandatory” sentencing laws give the judges practically no leeway for reduced sentences.

8. Your rights as a US citizen do not apply in foreign countries, and the legal consequences of drug-law violations in some places can literally mean death.


Drug Laws
Getting Searched
Illegal Acts
Getting Caught
Getting Convicted: The Penalty Box Where Do We Go from Here?


The drugs in this book are subjected to a variety of laws. Tobacco and alcohol are legal to possess and use in the United States, as long as you are at least eighteen years old (for tobacco) or twenty-one years old (for alcohol). In a few states marijuana is legal to possess for recreational purposes by adults, and in more states it is legal to possess for medical purposes. The laws are changing so fast that we advise you check with local officials before you make any decisions. But federal law still states that marijuana possession is illegal everywhere, and the consequences of violating that can be significant, as we discuss later.

There are some controls on many of the over-the-counter cold medications that can be used as precursors of methamphetamine and for

dextromethorphan—if you show identification and are at least eighteen years old, you can possess amounts for personal use. Most herbal drugs we discuss (except ephedrine) can legally be purchased and possessed by anyone.

Most of the other drugs are covered by the Controlled Substances Act. According to this federal law, some substances cannot be purchased or possessed by anyone, while others can be used if they have a prescription from a doctor. There are different “schedules” that are based on the danger of abuse and the medical use. These are described in what follows. These drugs can be purchased and possessed only with an appropriate license from the Drug Enforcement Administration (DEA) or a prescription from a physician.

• Schedule I: Drugs in this class have no currently accepted medical use in the United States, a lack of accepted safety for use under medical supervision, and a high potential for abuse. Some of the drugs in this category are all forms of marijuana (natural and synthetic), heroin, all serotonin-related hallucinogens (LSD, psilocybin, and all their derivatives), MDMA and all its congeners, and all cathinone derivatives (bath salts). These drugs can be possessed only for research purposes with an appropriate license. If you are not a researcher, you cannot purchase them legally.

• Schedule II: Substances in this schedule can be used to treat medical conditions of symptoms in appropriate circumstances, but they have a high potential for abuse that may lead to severe psychological or physical dependence. These drugs include many opioids, such as methadone, morphine, opium, oxycodone, fentanyl, meperidine, and codeine; some sedatives like pentobarbital; and stimulants that are used clinically, including amphetamine, methamphetamine, and methylphenidate.

• Schedule III: Substances in this schedule have a potential for abuse less than substances in Schedules I or II, and abuse may lead to moderate or low physical dependence or high psychological dependence. Drugs in this class include combination products containing some opioids like hydrocodone with acetaminophen; buprenorphine formulated with naloxone (Suboxone), which is used to treat opioid addiction; the anesthetic ketamine; and testosterone.

• Schedule IV: Substances in this schedule have a low potential for abuse relative to substances in Schedule III. Drugs in this category include many benzodiazepine sedatives, including diazepam (Valium), alprazolam (Xanax), and triazolam (Halcion).

• Schedule V: Substances in this schedule have a low potential for abuse relative to substances listed in Schedule IV and consist primarily of preparations containing limited quantities of certain narcotics.
This list is not comprehensive, but it provides enough examples. The penalties that result from purchasing or possessing them vary by the schedule and by how much you have in your possession, so you should consider this only as an introductory guideline. You need to understand that if you purchase or possess anything in these schedules without a doctor’s prescription, you are breaking the law. In addition, state laws may differ from federal laws. For example, marijuana is scheduled much lower by most states, but many states have broadly liberalized availability for medical purposes (although it is not completely legal in any state).
We have a word of caution about the scheduling of drugs. While this list describes the various schedules for drugs, placement at a given level in the list does not necessarily represent the degree of safety of the drug. For example, marijuana is a Schedule I drug, but it is almost impossible to die from it acutely. On the other hand, benzodiazepines are Schedule IV drugs, and with regular use over a period of time, an individual can become very tolerant to them. At that point, stopping their use can be almost impossible without medical help. If you take one of these drugs, get good information about it and don’t depend on the level of scheduling to keep you safe.
Not all psychoactive drugs are controlled substances and, therefore, are on these schedules, but they do require a prescription. In most situations, you are breaking the law if you possess these drugs without a prescription and particularly if you give or sell them to another person.
There’s this joke about a very large canary: Where does an eight-hundred- pound canary sit? Anywhere it wants to! Likewise, a law-enforcement officer

will search just about anywhere if they really want to do it. Eventually the courts could decide whether the search was legal, but an officer who has reason to believe that a crime is being committed may well initiate the search process and let the lawyers settle the issue later.

Laws in the United States on the subject of a search are extremely complicated, in part because the legal rights of individuals have been defined over the years by many different court cases. However, there are a few general principles that govern when someone can legally be detained and searched.

First is the “expectation of privacy.” The expression “A man’s home is his castle” applies here. To search a residence usually requires more stringent legal prerequisites than searching elsewhere. Often a search warrant signed by a judge is required, unless there is evidence of a major and immediate threat to public safety.

Next is the automobile. This is the place where most individuals confront the law. An officer will see a traffic violation in progress, stop the vehicle, and then come to suspect that illegal drug activity is being carried out. If an officer reasonably believes that a crime is being committed, then the officer probably has the right to detain the occupants of the car until a legally proper investigation can be carried out. Remember, this officer can stop and hold someone if he or she believes that a crime is being committed, even if the officer is wrong!

A court official gave us an extreme example: Say a murder has been committed in the course of a bank robbery and the killer is driving away in a 2017 blue four-door sedan. In the heat of the moment, an incompetent 911 operator becomes confused and broadcasts that the killer is leaving the scene in a 2013 red pickup truck. An officer down the road sees a 2013 red pickup truck and stops it, removes the occupants, and searches the truck for weapons. The officer finds illegal substances. Was the search legal? Probably, because the officer had reason to suspect that the occupants were criminals. The officer was wrong, but with good reason, and the occupants may well be convicted for whatever offense they committed.

There are equally odd outcomes in which convictions are not possible because the officer was found to have no reason to search a vehicle. That is why most officers ask permission to search a car before doing so. That permission usually makes the search legal and any evidence is thus legally

obtained. If permission is not given, then the officer may choose to detain the individuals further and call for a drug dog or other assistance to examine the vehicle. This issue then gets very complicated.

The practical side of all this is that a law officer has quite a lot of power to detain and arrest, because the lawmakers have decided it is in the public good to be able to temporarily detain potential criminals and, to some extent, to ask questions later. Even if an officer is eventually found in court to be wrong, the suspected individuals would have suffered loss of time and perhaps arrest, legal bills, and considerable life discomfort.

Finally, there is the situation when a person is out in public and walking about. This is the least “private” act, and so there is the least expectation of privacy. In this case a law officer has much more leeway in searching a person for the protection of the officer and of the general public. For example, imagine that an officer sees a person walking down the street in and out of traffic, in an erratic manner. The officer has the right to stop and talk to that person to ensure that the person and the driving public are safe. If in the process of that stop the officer suspects that the individual may be carrying a weapon, the officer could conduct a pat-down search. If in the course of that search the officer feels something recognizable as an illicit drug, the officer can seize the drug. Can the person be convicted of a drug-law violation? It is very likely that the person can because the search was legal.

The same rules might apply at a concert. Let’s say that two students are obviously intoxicated and fighting. An officer moves to stop the fight, the students resist, they are appropriately searched for weapons, and illicit substances are discovered. If the officer chooses to charge them, there is a good probability that the charges will stick.

Do law-enforcement officers have a pathological agenda to harass drivers and students at a concert, looking for drugs everywhere? Rarely. Most law officers see their work as a job, not a mission. Think of all the traffic laws that are broken every day and how seldom stops occur. Think of how seldom someone who is innocent of any law violation is stopped in a car or interdicted at a concert. By and large, the legal community just does its job.


The drug laws are complicated, and the states differ from each other and from the federal system. So, there is no easy way to explain them in detail. However, there are a few very powerful and relatively unknown aspects of the law that should be explained to everyone.

First is the difference between a felony and a misdemeanor. A misdemeanor is a minor crime that might result in a fine, public service, or a short prison sentence—typically less than one year (in the federal system)— and usually is associated with traffic violations, minor theft, or sometimes possession of a very small amount of an illegal drug. A felony (murder, armed robbery, sale of drugs) usually carries a sentence in excess of one year and is considered such a serious crime that convicted individuals lose many rights that ordinary citizens enjoy. This includes the right to hold many kinds of highly paid jobs and to vote at least while you are incarcerated, and in some states, even after you get out. A felony conviction is truly a life- changing event. Understanding this is important for drug users because possession of some amounts of some drugs can be considered a misdemeanor, while larger amounts are always felonies.

The law always sets the level of punishment based on the amount of a drug that one possesses or distributes, and in this case size counts a lot. For example, there is a current public controversy because the federal laws are terribly tough for possession of even a few grams of crack cocaine, but they are much more lenient for powdered cocaine. Anyone who contemplates drug usage should understand the severity of the penalties that various levels of drug possession invoke. There is often discretion on the part of the prosecutor about what charges will be assessed. The problem is that this is an executive decision and can be reversed in any case and at any time. For example, we have seen cases in which the original charge for a death- associated distribution of an opioid was changed from manslaughter to second-degree murder at the discretion of the district attorney.

Most people know that conviction for selling drugs (distribution) results in stiffer penalties than for possession. What they don’t know is that simply possessing certain amounts of a drug can be considered an “intent to distribute” and thus may subject a person to the much stiffer distribution penalties. Moreover, money does not have to change hands for distribution to take place from a legal perspective. Simply handing a package of a drug to another person can be considered distribution.

Another obscure criminal area is conspiracy. In drug cases, there are many convictions for conspiracy to commit a crime because very often a drug deal involves much more than the simple transfer of money and drugs. The conspiracy laws are broad and powerful. Even people peripheral to the planning of a crime, who may not have participated in the crime itself, are often charged under these laws. Sometimes court officials do this in the hope that the charged individuals will cooperate with the court officials to convict others. Anyone hanging around individuals involved in drug possession and distribution should be aware of the risk of being charged with conspiracy for seemingly innocent acts. These can be as simple as lending a boyfriend a car, cashing a check, or allowing a friend who is a dealer to use a phone, if prosecutors can prove that in doing any of these seemingly innocent acts you knew you were helping the person who asked you to do it commit a crime. From the standpoint of law enforcement, drug dealing is considered a business (although it is illegal), and just as in a legal business, different people play different roles and have different levels of importance. In general, being around drug dealing is legally very risky.

Finally, there is the issue of the confiscation of property. Most of us have heard about auctions where the property of drug dealers is sold. This happens because of forfeiture laws that allow property used in drug dealing to be confiscated and sold by the government. The particularly devastating aspect of this is that the property of a more or less innocent individual might be confiscated because it was being used in violation of drug laws. Imagine, for example, a student distributing cocaine from their father’s home and car. Suppose the father knew something about this and told the student to stop it, the student continued, and the father just gave up trying to get him to stop. If the prosecutor could prove that the father knew that the student was distributing drugs and allowed that activity to continue, it is possible that both the father’s home and his car could be confiscated as part of the criminal prosecution against his son. Now substitute “brother” or “friend” for “father” and you can see how you yourself may fall into this trap.

What about marijuana? It’s now legal, right? Some states have “legalized” marijuana possession for medicinal purposes; others have made the possession of small amounts for recreational use either legal or punishable as a misdemeanor. But the US federal law still makes it a crime in all fifty states. In general, federal law overrules state law, so you might well be in a state in which possession is legal but prosecuted under federal law.

As we are writing this new edition, the US attorney general is enforcing marijuana laws more vigorously than in the former Obama administration. For example, there is a relatively obscure section of the federal statutes that sets a serious penalty for illegal possession of any controlled substance and a gun at the same time. To take this to the extreme, if you legally possess a gun and have a small amount of marijuana, you are subject to this federal law, even if marijuana is legal in your state. The same would apply to having pills of a controlled substance (opioids, benzodiazepines, etc.) and a gun. Of course, the specific conditions under which the federal law might be enforced may not be crystal clear. So, be aware that no matter what a state law says, federal law can be enforced in all of the United States.


Most people believe that they will not get caught. Teenagers, in particular, have the feeling that they are “beyond the law.” But it does happen. It happens to grandmothers, teenagers, lawyers, doctors, and the most ordinary people on the face of the earth.

Many drug arrests come from the most random events imaginable. In Virginia, an officer stopped a car for having something hanging off the rearview mirror. He became suspicious, legally searched the car, and found major quantities of cocaine. Another drug transporter thought he had the perfect scheme and filled fruit juice cans with cocaine, then resealed them. It is a regular practice for tourists to bring back food from vacation in the Caribbean, and he expected to walk right through customs. What he did not realize was that customs officials knew there was no reason to bring canned fruit juice from the Caribbean, where it is expensive, to the United States, where it is cheap. He was arrested and convicted for transporting millions of dollars’ worth of cocaine.

Even grandmothers are not immune to arrest. A pair of DEA agents working a bus station in North Carolina noticed an elderly woman behaving oddly. When they approached her, she moved away and they became suspicious. They conducted a legal search and found a large quantity of cocaine in her luggage.

A college student came back to her dorm room to find the place crawling with campus and city police. While she had absolutely no role in any illegal

activity, a friend of her roommate had come to town from another college with a shipment of drugs. Another student, obeying the honor code, had called the campus police. Fortunately, the innocent student was not arrested because the roommate cleared her, but it was a very close call.

The law-enforcement community is actually quite sophisticated in its drug-enforcement efforts. DEA agents work all over the world trying to prevent the transport of drugs into the United States. They have agents working major and minor airports, and even bus stations. The highway patrols of most states have drug interdiction units looking for suspicious vehicles. This is not a trivial effort, and it results in so many convictions that both the state and federal prison populations have grown dramatically.

Yet everyone realizes that most countries are overrun with drugs. It is usually easy to buy the most common illegal drugs in many areas of cities and on college campuses. So why is the legal interdiction effort perceived as failing? It is not exactly failing, but rather it is being overwhelmed. Many, many people are caught in the legal system, but there is always someone else to replace each person caught. Routine usage of cocaine, crack, or heroin can be a very expensive habit, and the only way that most people can maintain such expensive behavior is to turn to dealing. As we say elsewhere in this book, cocaine and opioids can be extremely reinforcing, and they are also expensive in the quantities that habitual users consume. The combination of dependence and expense often leads users to become dealers until they are stopped by medical intervention, arrest, or death.

What does this have to do with the average reader of this book? Anyone who can read this book no doubt has the ability to do honest and legal work and have a successful life. Such a reader might feel that he or she is above being caught, or just not in the “wrong” circle of friends. This naïveté might be the most dangerous attitude of all, because, like most jobs, illegal drug dealing depends on knowledge, skills, and having a network of people. Most casual dealers do not have the knowledge or, fortunately, are not willing to do what is necessary to involve themselves fully in the drug culture. Thus, they approach the whole issue as amateurs, and like many amateurs in anything, they fail miserably. Only in this case, the stakes are much higher. They can get caught, lose a lot of money, become victims of criminal violence, or become heavily dependent on the substance they are dealing.

As we all know, some people think they have few opportunities and only a short time to live. They will deal drugs no matter what anyone says. In their lives they see jail time as just the cost of doing business. However, a district attorney who has prosecuted thousands of drug cases had just one bit of advice: people with families, an opportunity for education, and a supportive network of friends have so much to lose from being on the wrong side of the legal system that they should never become involved with it. A felony conviction can strip a person of so many opportunities in this society and can cost families so much in pain, suffering, and financial loss that no amount of money or drug experience is worth the risk.


The penalty laws of most states and countries are built on a series of legislative acts that happened over a long period of time, and thus, they are complicated and not easily summarized. Possession of modest amounts of marijuana can result in a slap on the wrist in some states and serious jail time in others. The same is true for other drugs, although they are usually taken more seriously, even in very small amounts. In the United States, often the prosecuting attorney has some leeway about the level of crime with which to charge an individual. The problem is that it is difficult to be sure of (1) the latest changes in the law, (2) the attitude that the prosecutor is taking toward drug crimes, and (3) whether that individual will be charged under state or federal statutes. (There are several factors that determine under which statutes you can be charged, including whether a federal officer arrested you, whether the crime occurred on federal property, and whether the state and federal authorities agree that the federal government should prosecute the crime, which can happen for a whole host of reasons.) Thus, conviction for the possession of a small, recreational amount of heroin or cocaine could result in either a modest sentence or a huge fine and a long prison term, depending on the exact circumstances and the mood of the legal officials overseeing the case.

It is important to recall that in some states and in the federal system there is structured, or guideline, sentencing. That means that once an individual is convicted of some drug crimes, the sentence is regulated by law and might not be alterable by the judge, no matter what the circumstances. Coupled with

the fact that there is no parole in the federal system (and increasingly in the state systems), a conviction can mean long prison time, even if the prosecutor and judge wish it were otherwise.

Here’s an example of how things can go terribly wrong as a consequence of alcohol, a prescription drug, and harsh laws. One of us (WW) testifies as an expert in legal cases, and a recent one illustrates how the law, the prosecutor, and the courts can interact to ruin the life of an individual. A man was at a party with his neighbors outside of his home. He consumed a modest amount of alcohol throughout the evening, but at some point he decided to go to bed and took his nightly medicine, which included the sleeping pill zolpidem (generic for Ambien). Before going to bed, he came back to the party but soon appeared intoxicated. He then prepared for bed and went to sleep. Shortly thereafter, he awoke and came out of the house without his shoes, false teeth, or hearing aid, clearly having just awakened. But he had a gun, which he had retrieved from his bedside where he kept it. He fired twice as he yelled an obscenity to the individuals at the party. No one was hurt. The police were called, and he was arrested.

The man was charged with aggravated assault, and everyone thought he was intoxicated with alcohol. In the law of most states, that is considered “voluntary intoxication” and thus is not a defense against any charges. His defense team argued that he was not intoxicated with alcohol but with his prescribed zolpidem, which is known to produce odd behaviors such as sleep driving, sleep sex, sleep shopping, sleep eating, and so forth. If it were the zolpidem, that would be “involuntary intoxication,” and that is a defense against such charges.

The jury heard the case and decided that he was intoxicated by alcohol and was therefore guilty. Now, here is where the disaster occurred. In that state, commission of many crimes (such as aggravated assault) with a gun is a mandatory ten-year sentence. If the gun is fired, the mandatory sentence is twenty years. In this case the prosecutor chose to charge the man for each of the six people present at the party, and the law requires that the mandatory sentences apply to each charge and be served consecutively. This meant that the man must, by law, be sentenced to 120 years in prison. The judge has no discretion in such a case.

This is a terrible example of the interaction of intoxication, harsh laws, vigorous prosecution, and, finally, the presence of a gun where a sleepy,

intoxicated person could access it and fire it. This man had no history of behavior like this and was a decorated soldier. It is very likely that the zolpidem produced the bizarre behavior, but the prosecutor and jury did not see it that way.

But this is not the end of the story. A specialist in appealing such decisions accepted his case and wrote an effective appeal to the higher courts. They ruled that he deserved another trial, and that trial resulted in a not-guilty verdict from the jury. Although this is a happier ending, the man lost almost all of his money, almost lost his retirement funding, and had to spend some time in jail. So he certainly did not avoid serious consequences. The lesson from this is that guns and drugs (even legal ones) are an awful combination, and one should avoid this at all costs.

Another lesson from this is that if a person chooses to become intoxicated and then commits a crime, that intoxication is usually not a defense against any crime committed, no matter how impaired the person was at the time of the crime.


There is an ongoing debate in the United States, as well as in other countries, about the legalization or decriminalization of drugs by society. As of 2018, more than thirty states have passed laws that allow the use of marijuana for medical and possibly recreational purposes, with a number of other states considering similar laws. But these laws are still controversial, and there is the additional problem, discussed above, that these state laws can be in conflict with federal laws. No one knows what the outcome will be.

The international scene is as confusing as that in the United States. For example, the country of Portugal has decriminalized all recreational drugs since 2001. They have not made drugs legal, but have minimized the penalties for small amounts of all drugs. Data from the 2014 European Drug

Report* shows that the death rate from drugs in Portugal is the lowest in the European Union at 6 per million people. That compares to 185 per million people in the USA in 2016. There is also a decriminalization movement in Britain. In a recent issue of the British Medical Journal, the Royal College of

Physicians has proposed decriminalizing drugs in Britain.† On the other

hand, the president of the Philippines has instituted an extraordinary anti-drug campaign that, according to news reports, has claimed a large number of lives.

Many people believe that any effort to reduce the pressure on drug users and dealers will result in a flood of illegal substances that, in their worst nightmares, will become readily available to children. Unfortunately, drugs are already readily available to anyone, including children, from all economic levels. So, that nightmare is here right now.

To reduce demand, we need to increase education. As we have said elsewhere in this book, effective drug education is not just a matter of exhortations to refuse all drugs, because many individuals believe that the drugs they use are harmless. It is a matter of teaching the science that can help us appreciate what complex and delicate organisms our brains are, how body chemistry may vary from person to person, and how little we know about the many ways, both positive and negative, short-term and long-term, that the powerful chemicals we call “drugs” can affect us. Good education is expensive, but with it we will be healthier, and as a society, we will save the enormous costs of lost wages, law enforcement, and prisons that drugs have brought us.

* † BMJ 2018;361:k1832.


THIS BOOK AROSE from our recognition of how little most adolescents, parents, lawmakers, and even medical advisers know about drugs that we regularly use and abuse. Informal talks with Leigh Heather Wilson and Jeremy Foster (contributors to this book) about their college experiences, and our interactions with a large number of college students in our courses, led to our realization of the need for this book. These students asked hard questions, shared their experience honestly, and provided background research of their own. We thank each of them.

W. W. Norton representative Steve Hoge deserves our thanks for bringing the book to Norton’s editors. Our agent, Reid Boates, was superb. He was recommended by Dr. Redford Williams, another Duke author. Thank you, Red. The editorial staff at Norton has seen us through the ups and downs of getting a book out, and we appreciate the good advice and editing of the first edition from Alane Mason and Ashley Barnes.

Two individuals were exceptional in helping us understand the rudimentary principles discussed in the Legal Issues chapter. First we thank Mr. Rick Glaser, former first assistant United States attorney of the Northern District of Florida who is now partner, board member, and head of Government Investigation and the White Collar Crime Team for Parker Poe Adams & Bernstein in Charlotte, North Carolina. He clearly and carefully explained some important parts of the federal laws that deal with illicit drugs as well as discussed the general nature of drug prosecutions at the federal level. He was remarkably insightful and helpful. (Mr. Glaser made it clear that his views do not necessarily represent the views of the Department of Justice, the Northern District of Florida, or the Middle District of North Carolina.) The Honorable James E. Hardin Jr., former district attorney for Durham County, North Carolina (now a superior court judge in North Carolina), spoke extensively with us about drug prosecutions at the local and state levels. He was most patient with us nonlawyers and quite helpful in

explaining the basic laws regulating search and seizure as well as giving us an understanding of how local law enforcement is dealing with the drug issue.

We also thank Mr. Mark Goldrosen, a defense attorney in San Francisco, for particular insights into recent legal issues.

Despite the fact that we received the best advice we could get, we want to be clear that the words written here are those of the authors, who are not lawyers, and should not be taken as legal advice.

In addition, Cindy thanks her husband, Mark, for patient listening; her children, Elena and Eric, for stories about what young adults are doing and for their helpful advice; Dr. Donald McDonnell, chairman of the Department of Pharmacology and Cancer Biology at Duke, for facilitating her undergraduate course, Drugs and the Brain; and all of her students who ask her questions that she can’t always answer and who share information and experiences. Scott thanks Elizabeth Kaufman and his children—Sara, Nicholas, and Rita—for immensely helpful discussions as this project has evolved, and Drs. James Koury, Robert S. Dyer, Anthony L. Riley, and R. D. Myers for helping him learn how to think.

Wilkie thanks his daughter Heather, who, seeing her friends and acquaintances exposed to drugs in all sorts of social situations, was amazingly articulate in describing what she saw and absolutely relentless in pushing him to find some way to inform all of these people about the complexities of the drug issues in a user-friendly way. She became involved in this book as a research assistant, but she deserves enormous additional credit for her advice and counsel. He thanks her for her openness, her dedication to this project, and the grace she showed during some of the hard times. In addition, he thanks his wife, Linda, and his daughter Stephanie for support during some difficult moments when this book was being written. Their love is beyond description. He also thanks Joe for great discussions.


Mexican brown heroin and Southeast Asian heroin.

Demerol (meperidine).

Innovar (fentanyl).

Mexican black tar heroin.


Percodan (oxycodone).


Vicodin (hydrocodone).

Tylenol with Codeine No. 3 (codeine).


OxyContin (oxycodone).

PCP is most commonly sold as a powder (left) or liquid (center), and applied to a leafy material such as oregano (right), which is then smoked.


Marijuana rolled into cigarettes for smoking.

Collage of LSD blotter paper.

Ketamine, also known as Special K.

Marijuana abusers prefer the colas, or buds of the plant, because of their higher THC content. Leaves are discarded or used as filler.

Hollowed-out cigars packed with marijuana, called blunts.

Black, resinous sticks of hashish.

Spice (synthetic cannabis).

Amber, viscous hash oil.

Baby pot plant.

Amytal (amobarbital).

Seconal (secobarbital).

Halcion (triazolam).

Nembutal (pentobarbital).

Ativan (lorazepam).

Librium (chlordiazepoxide).

Valium (diazepam).

Sniffing an inhalant-soaked rag from a bag is a form of huffing.

Xanax (alprazolam).

GHB is a generally odorless, colorless liquid or white powder.

Rohypnol (flunitrazepam). “Roofies,” as they are known on the street, are sold inexpensively in Mexico. They are smuggled into the United States, where they have become a problem among American teens. The problem is rapidly spreading from the American Southwest to other parts of the United States.


Powdered cocaine.

Dexedrine (dextroamphetamine).

Counterfeiters duplicate packaging for black-market sales.

Ritalin (methylphenidate).



Bath salts.

Ice, so named because of its appearance, is a smokable form of methamphetamine.

Crack cocaine.

Methcathinone, or cat.


Page numbers listed correspond to the print edition of this book. You can use your device’s search function to locate particular terms in the text.

abortion, 140

spontaneous, 119
acetaldehyde, 39–40
acetaldehyde dehydrogenase, 39
acetaminophen (Tylenol), 34, 40, 46, 68, 76, 133 acetylcholine, 124, 130, 135, 141, 157–58, 223–24 acid reflux disease, 79
Adam (MDMA), 96
ADD (attention deficit disorder), 53, 293, 297 Adderall, 286
addiction, 20, 22, 27, 350–51

alternative definition for, 363

brain and, 350, 352–59, 361

compulsive, repetitive patterns and, 30, 297–98, 310, 350, 351, 355–57, 363

definition of, 351
Ecstasy and, 100, 101
gateway theory of, 360
genetic and hereditary predispositions to, 20, 54–55, 357–59 hallucinogens and, 136, 139
heroin and, 27, 29, 100, 251–54, 345, 347
life experience and, 359–61
mental illness and, 361
nicotine and, 27, 29, 219, 221–22, 228, 229–32, 234, 353

opioids and, 27, 29, 100, 239, 240, 243, 249, 250, 251–59, 362–63 personality and, 359
pharmacotherapy in treatment for, 362–63
principles of, 350

recovery from, 307
scientific information on, 17–18 steroids and, 284–85
stimulants and, 296, 297, 303, 305–7 withdrawal and, 30, 350, 355

see also specific drugs

adenosine, 75–76, 83
ADH (alcohol dehydrogenase), 39, 58
ADHD (attention deficit/hyperactivity disorder), 148, 224, 286, 301–2, 307,

312 adolescents:

alcohol and, 25, 34, 36, 38, 45, 51, 60–65 drug perspectives of, 23–26
inhalants and, 29, 163
marijuana and, 198–201, 207, 211, 212, 213 nicotine and, 30, 218–19, 225–26

vaping and, 234–35 adrenaline, 29, 80, 248 Advil, 68
Afghanistan, 242, 291 aggression, 101

alcohol and, 45, 56

decreases in, 102, 202

marijuana and, 201–2, 210 aging, 159

melatonin and, 152, 153–54

prevention of, 152, 154, 159

smoking and, 226 agonists, 339

AIDS, 279

contraction of, 246

HIV and, 204, 256, 257, 312, 351

marijuana and, 204 alcohol, 23, 144, 213, 366

absorption and elimination of, 33, 34, 37–40, 46, 58 abstaining from, 46, 50, 54, 60, 356
abstract thinking and, 48, 49
acute exposure to, 41–46, 67

adolescents and, 25, 34, 36, 38, 45, 51, 60–65 advertising of, 35, 36, 59
aggressive behavior and, 45, 56
attention, concentration and, 49–50, 53

binge drinking of, 34, 48, 60–61, 64, 326 biphasic action of, 42
blood and, 34, 37–38, 40, 41–42, 44, 58 body type and, 39, 58

breast cancer and, 58–59, 69

breathing problems and, 33, 34, 38, 41, 67

buzz from, 33, 44, 55–56

chronic exposure to, 40, 42, 46–52, 54–59, 66, 67, 68

cognitive problems and, 30, 34, 45, 47–51, 62–64

comparative amounts of, 41, 51, 54, 58, 59, 60, 66, 69

death and, 19, 28, 29, 34, 38, 41, 65, 67, 68, 69, 70

dependence on, 39, 52, 54–55, 64–65

driving and, 34, 38, 39, 42, 45, 50, 65, 66

drugs combined with, 25, 28, 34, 40, 46, 65–68, 90–91, 111, 238, 375– 76

education on, 17 emotion and, 50
food and, 37–38, 46 GABA and, 43, 44, 330

hangovers from, 45–46, 68
health benefits of, 23, 46, 68–70
heart disease and, 46, 58, 69
heavy intake of, 46, 60, 68, 69
history of, 35
intoxication with, 28, 33–34, 38, 40, 41–42, 48, 52, 68
laws on, 60, 65
light intake of, 46, 69
long-term effects of, 30, 46, 47–54, 62–63, 64
making decisions about, 36, 69
memory impairment and, 44–45, 48, 50, 57, 61, 62, 64
men and, 36, 54, 55–56, 59–60, 69
mixed drinks of, 36
moderate intake of, 46, 53, 68–70
overdose of, 19, 28, 29, 33–34
peer pressure and, 33, 36, 38
physical and mental impairment caused by, 30, 34, 37–38, 41–54, 56–68 prenatal exposure to, 28, 30, 39, 40, 53–54
religious and cultural use of, 21, 36
sedative effects of, 33, 34, 42, 62, 65–66
self-medication with, 54, 361
sex and, 45, 59–60
sleep and, 28, 29, 52
social drinking of, 47, 50–51
tolerance to, 40, 51–52, 57, 65
toxicity of, 36, 39, 40, 46
types of, 36
withdrawal from, 66
women and, 28, 30, 39, 40, 53–54, 57–59, 69

see also specific types of alcohol

alcohol amnesic disorder, 50 alcohol breath, 39

alcohol dehydrogenase (ADH), 39, 58 Alcoholics Anonymous (AA), 262, 356 alcoholism:

dementia associated with, 50 diagnosing of, 56–57
divorce rates and, 59
genetic factors and, 54–55
memory deficits and, 44–45, 48, 50 nature vs. nurture and, 55

programs and therapies for, 39, 356
risk factors for, 54–57, 65
sign of, 45, 56–57
social, medical, and psychological problems with, 30, 50, 52, 56–59

types of, 56
alcohol-use disorder, 47
ale, 33
Aleve, 68
allergies, 67
Alles, Gordon, 290
“Altered State of Consciousness,” 120 Alzheimer’s disease, 82–83, 147, 154, 330

memory loss and, 154, 155, 157–58, 224

treatment of, 154, 155, 157–58, 224
Amanita muscaria (fly agaric mushroom), 112, 124, 135, 138 Amanita phalloides, 138
Ambien (zolpidem), 34, 260, 268–70, 375–76
American Academy of Ophthalmology, 205
American Bar Association (ABA), 212
American Cancer Society, 234
American Medical Association (AMA), 204, 212
amino acids, 106, 119, 146, 157, 158, 321
amitriptyline (Elavil), 66
amnesia, see memory impairment
amobarbital (Amytal), 260
amphetamine, 18, 44, 101, 102, 125, 127, 286, 290–91, 292, 305, 306

derivatives of, 114, 293
drugs combined with, 72
history of, 290–91
physical effects of, 96, 100, 128, 131, 135–36, 295–96, 297–98 synthesis of, 29

weight loss and, 308–9 amyl nitrite, 161, 164, 165, 166 Amytal (amobarbital), 260 anabolic steroids, see steroids Anacin, 84, 93
Anadenanthera peregrina, 125 Anadrol, 276
anandamide, 184
Anavar, 276
anesthesia, 161, 162, 167–69 anesthetics, 164

dissociative, 109, 114–15
effects of, 161
gaseous, 161, 167–71
general, 131, 167, 169 hallucinogenic, 131–32, 133, 141 overdose of, 162

surgical, 161, 162, 167–69

veterinary, 27, 114, 131
angel dust, 109, 131–32, 343
angina pectoris, 165
anhedonia, 336
animal research, 28, 42, 44, 48, 54, 61–63, 65, 79, 83, 97, 100, 105, 106,

108, 133, 140, 149, 150, 151, 153, 154, 155, 156, 158, 169, 170, 185, 187–88, 195, 219, 221, 223, 224, 251, 252, 284, 298, 307, 325–26, 329, 352–53, 358, 360

animal tranquilizers, 27, 114, 131 Annual Review of Nutrition, 77 Anslinger, Harry, 210, 211 Antabuse (disulfiram), 39

antagonists, 339
antianxiety medications, 66, 68 antibiotics, 36, 345

alcohol and, 66
anticoagulants, 40, 66 antidepressants, 101, 151, 159, 230

drugs combined with, 66–67, 72, 97, 144, 151 ketamine and, 132
physical effects of, 134
tricyclic, 66

see also specific drugs

antidiabetic medications, 40, 67 antihistamines, 133, 353

drugs combined with, 25, 34, 67, 162, 256, 261 antioxidants, 89
antipsychotic medications, 67, 139
antiseizure medications, 67, 264

anxiety, 25, 52, 104, 105–6, 110, 120, 147, 148

causes of, 25, 117, 122, 126, 128, 138, 139, 142, 144, 261, 262

reduction of, 17, 66, 139, 142 anxiolytics, 260
AP-5, 328
“Apache,” 19

appetite suppression, 96, 97, 102, 223, 308–9 Apresoline, 68
Araliaceae, 155
Army, US, 97–98

“Asian alcohol-induced flushing syndrome,” 40 aspirin, 34, 46, 68, 344

stomach irritation and, 79
asthma treatments, 27, 79, 95, 130, 147, 277, 290 Atabrine (quinacrine), 66
Ativan, 260
Atropa belladonna (deadly nightshade), 109, 130 atropine, 109, 110, 111, 130

attention deficit disorder (ADD), 53, 293, 297
attention deficit/hyperactivity disorder (ADHD), 148, 224, 286, 301–2, 307,

Awake energy mints, 94 ayahuasca, 109, 114, 128–29, 142

birth defects of, 140, 228, 300
crack, 28, 30, 299–300
development delays in, 30, 228
low birth weight of, 30, 79, 300
premature, 30, 79
prenatal exposure to alcohol in, 28, 30, 39, 40, 53–54

sudden death of, 228
bacteria, 78, 82
Banisteriopsis caapi, 128 barbiturates, 18, 40, 65, 260, 263–65

drugs combined with, 162, 238

sedative effects on, 34, 42
bath salts, 286, 287, 291, 292, 294, 296, 298, 305, 307, 310, 353 Bay Area Laboratory Cooperative (BALCO), 280
Bayer Company, 239
beer, 45, 66, 70, 212

alcohol content in, 33, 37

slipping drugs into, 29
belladonna alkaloids, 109, 110, 129–31, 144

effects of, 130–31, 135
forms of, 109, 129
history of, 129, 130
lethal doses of, 130, 131, 141 medical use of, 114, 130

ritual and religious use of, 114, 130 Belsomra, 268, 270
Belushi, John, 298

Benadryl (diphenhydramine), 67, 256 benzene, 29, 171, 233 benzodiazepines, 42, 139, 141, 238

drugs combined with, 34, 66, 162

physical and psychological effects of, 262, 263, 266–67

problems with, 266–68 benzopyrene, 189
Bernheim, Frederick, 256
beta carbolines, 128
beta-endorphin neurons, 249–50, 251 beta phenylethylamine (PEA), 148 birth control pills, 151

blindness, 36, 46 blood, 156, 157

alcohol in, 34, 37–38, 40, 41–42, 44, 58 circulation of, 76, 100, 165, 166 clotting of, 68, 156
sodium in, 103

thinning of, 66
blood-brain barrier, 343
blood hemorrhage, 156
blood oxygen level dependent (BOLD) signal, 333–35 blood pressure, 138, 206

elevation of, 151
lowering of, 124, 154, 155, 158, 161, 164, 168, 273 monitoring and treatment of, 18, 68

raising of, 72, 78, 80, 96, 97, 100, 106, 111, 117, 119, 125, 126, 131, 132, 133, 141, 144, 147, 148, 149, 150

blood sugar, 67, 156, 223
blood thinners, see anticoagulants blood vessels, 168, 246

dilation and constriction of, 76, 80, 119, 164–65, 166, 228, 299, 310, 311

body temperature, 129, 130, 138, 249

elevation of, 97, 101, 102, 103, 106, 107, 110, 111, 130, 131, 132, 133, 141, 151

reduction of, 106, 153
bone density, caffeine and, 83–84
bone loss prevention, 154
booze, 33, 38
Boston Marathon of 2002, 103
Boston Tea Party, 74
brain, 22, 134–35, 152, 156, 315–36, 347

addiction and, 350, 352–59, 361
alcohol and, 28, 30, 37, 38, 40–54, 59, 61–65
blood and oxygen flow to, 18, 76
caffeine and, 75–77, 78
complexity of, 18, 47
cortex of, 47
damage of, 30, 48, 135, 173
development of, 61, 228, 327–28, 335–36
effects of drugs on, 17, 18, 19, 23, 25, 26, 27, 28, 30
frontal lobes of, 47, 49, 61–63
GHB and, 272–73, 274
hallucinogens and, 115–16, 117–18, 121, 130, 131, 133, 134–35, 140 herbal drugs and, 147, 152, 156, 157, 158
hippocampus of, 48, 62, 63, 185–87, 225
learning and memory in, 322–33
mammillary bodies of, 47, 49
marijuana and, 175, 182–87, 194–95, 196, 198–99
mitochondria of, 158
neurons in specialized areas of, 352
nicotine and, 220–21, 223–25
PEA and, 148
pleasure circuit in, 44, 352, 353, 356, 357–58
principles of, 315–16
recovery of tissue in, 47

role of receptors in, 320–22 shrinking of tissues in, 47–48 stimulants and, 296, 297–98 swelling of, 103

synapses of, 318–20, 321, 324, 325, 326, 327, 330

transgenerational effects of FAS on, 54

see also central nervous system; sympathetic nervous system brain imaging techniques, 47, 63, 328, 358
breast cancer, 58–59, 69, 79
Breathalyzer tests, 39

breathing problems, 162, 168, 169 alcohol and, 33, 34, 38, 41, 67 fatal, 67, 71, 141, 262, 263, 264 opioids and, 248, 255, 258

treatment of, 75, 79 breweries, 35

Brin, David, 251
British Medical Journal, 377 British Stamp Act of 1765, 74 bronchioles, 79, 81, 124

dilation of, 100, 130, 147, 287 Browning, Elizabeth Barrett, 239 bufotenine, 114, 126
buprenorphine, 243, 258–59, 363 Burroughs, William, 128, 247, 252–53, 257 burundunga, 130–31

businessman’s special, 109, 116, 124–25 buspirone (BuSpar), 287
butane, 172
butyl nitrite, 161, 164

B vitamins, 170 BZP, 108

caapi, 109, 128–29
cacti, see peyote cactus; San Pedro cactus

café mocha, 86
caffeine, 27, 28, 71–95, 98, 144, 145, 149, 150, 158

absorption and elimination of, 74–80, 344–45 addiction and, 28, 30, 77
brain and, 75–77, 78, 94
buzz from, 71, 86, 89

calcium and, 83–84
central nervous system and, 76, 95
children and, 71, 79
concentrations of, 27, 28, 74, 76, 84–95
death and, 71
dependence on, 76
diuretic effects of, 46, 78
drugs combined with, 72, 90–91
enhancement of physical performance with, 73, 80–81 exercise and, 80–81
headaches and, 76, 84
health benefits of, 82–83
history of, 73–74
limitation and avoidance of, 72, 77, 94
memory function and, 82, 83
overdose and, 71, 95
physical effects of, 71–83, 94–95
ritualistic use of, 77
sources of, 27, 28, 71, 73–74, 84–95
stimulant effects of, 71, 72, 73, 76, 89–90, 94–95 tolerance to, 76
toxicity of, 71, 94–95
withdrawal from, 76

see also chocolate; coffee; energy drinks; soft drinks; tea caffè latte, 86

CAGE test, 56

Caitlin, Don, 280
calcium, 83–84, 319, 321
California, University of (Irvine), 331 cancer, 46, 79, 82, 189, 283

alcohol and, 46, 58–59, 69 childhood, 228
end stage, 241
tobacco and, 218, 228, 229 treatment of, 204, 205 vaping and, 233

see also breast cancer; lung cancer
Candler, Asa, 289
cannabidiol (CBD), 178, 206, 207 cannabidiolic acid (CBDA), 178
cannabinoid hyperemesis syndrome (CHS), 190 cannabinoids, 181, 183–84, 214–15

Cannabis indica, 178 cannabis plant, 175, 177–79

cultivation and harvesting of, 178, 179, 180–81

products of, 177–81, 203

species of, 178
Cannabis sativa, 178
cappuccino, 86
capsaicin, 150
carbon monoxide, 189, 224, 226, 228
carnitine, 157, 158
Carter, Jimmy, 212
Castaneda, Carlos, 128
catecholamine, 157
cathinone, 286, 294, 296
Centers for Disease Control, US, 218
central nervous system (CNS), 116, 171, 173, 267, 321–26, 337

belladonna alkaloids and, 129
caffeine and, 76, 95
connections between nerve cells in, 318–20

functions of, 315–20, 322–27
MDMA and, 30
plasticity of, 315–16, 324–26, 329–33

single nerve cells in, 316–18 Cha de Bugre, 148
Chantix, 230
charas, 174, 181

chemicals, 21
altering thought and feeling with, 17, 35 excitatory vs. inhibitory actions of, 42–43 industrial, 163, 171–73
laboratory produced, 17
natural sources of, 17
pleasure, 157
solvent, 29, 161–62

spiritual and mystical powers ascribed to, 17 chemotherapy, 205
Chen, K. K., 290

abuse of, 360
alcohol and, 60–65
of alcoholics, 54–55, 360 anesthetics for, 114 caffeine and, 71, 95 cigarettes and, 28, 30, 228 drug use by, 27, 28, 29, 30 inhalants and, 29, 163

see also babies
China, 73, 177, 178, 239, 240, 244, 294 chloral hydrate, 260, 265 chlordiazepoxide (Librium), 66, 260, 263 chloroform, 171
chlorpromazine (Thorazine), 67, 139 chocolate, 75

baker’s, 94

caffeine in, 73, 74, 94

dark, 74

Dutch refinement process for, 74

marijuana compared with, 27, 94

psychoactive effects of, 27, 94 cholesterol:

coffee and, 78

LDL, 78

lowering of, 89 choline, 157–58 Christianity, 127, 130 chromium, 309 cigarettes, 23, 306–7

aging and, 226
children and, 28, 30, 228
cost of, 218, 222
eating of, 28, 30
habits and rituals with, 223
hashish, 181
pregnancy and, 30, 216, 227–29
secondhand and sidestream smoke from, 226–27, 228 smoking of, 23, 30, 189, 216, 218, 219, 221, 222–29, 342 “thirdhand” smoke from, 226, 227

see also nicotine; tobacco cigars, 216, 218, 220 circadian rhythm, 152 circulatory system, 67 citicoline, 158

Civil War, US, 239
Claviceps purpurea, 119
cleaning fluids, 164
Clinton, Bill, 208
CNS (central nervous system), 267

Coca-Cola, 289, 290
cocaine, 29, 44, 100, 102, 145, 176, 213, 291, 292–93, 297, 305, 319–20,

absorption and elimination of, 344
addiction to, 305–7
common terms for, 286
crack, 131, 213, 291, 292, 295, 373
dangerous effects of, 19, 23, 28, 30, 213, 287, 295, 298, 306 drugs combined with, 72, 287
history of, 289–90
injection of, 238
medical use of, 290, 292
powder, 213, 292
pregnancy and, 28, 30, 299–300

tolerance to, 345–46 cocoa, 94

codeine, 237, 241, 242, 244, 245, 246

alcohol and, 68
coffee, 30, 46, 73–74, 84–88

cholesterol levels and, 78
concentrations of caffeine in, 27, 28, 71, 76, 84–88 filtered, 78
preparation of, 78, 84–88
US consumption of, 73–74

varieties of, 74, 84–88 coffee beans, 73, 84–85 coffeehouses, 73
cognitive problems:

alcohol and, 30, 34, 45, 47–51, 62–64 brain and, 315–33
marijuana and, 30, 175
MDMA and, 105–6

sedatives and, 261

cohoba, 126
cold medicine, 25, 34, 111

drugs combined with, 34, 72, 93, 111, 162, 261

see also antihistamines; cough syrup; nasal decongestants Coleridge, Samuel Taylor, 239
coma, 65, 110, 132, 138, 175
Compassionate Use Act of 1996, 207–8

Compassionate Use IND, 204
Congress, US, 145, 147, 208, 210, 280
Conocybe, 121
constipation, 29, 238, 248, 252, 253, 257
Controlled Substances Act of 1970, 203, 280, 284, 367 cortex, 47
cortisol, 89, 277
cortisone, 341
cotinine, 221, 227
cough syrup, 115, 132, 133, 241, 256, 366
Coumadin (warfarin), 66
Crews, Fulton, 326
cross tolerance, 40
cyanide, 166, 189, 228

Dalmane, 260 DanceSafe website, 98 Darvon, 237, 244, 247

alcohol and, 68
Datura stramonium (Jimsonweed), 109, 114, 129–30 deadly nightshade (Atropa belladonna), 109, 130 dehydration, 46, 102, 103, 190

caffeine and, 81
delayed sleep disorder, 153 delirium, 71, 130, 141 dementia, 50, 154
Demerol, 237, 243, 245, 246

drugs combined with, 68, 162, 261 dental work, 68, 167, 169, 170, 229, 241

dependence, see addiction
depotentiation, 325
depression, 25, 148, 150, 151, 161, 225–26, 253

addiction and, 361 alcohol and, 66 clinical, 104

treatment of, 17, 66–67
desomorphine (Krokodil), 237, 244 detoxification clinics, 66
Dexadrine, 286
Dex-Durabolin, 276
dextromethorphan, 98, 109, 115, 132–33, 135–36

tolerance and, 133
DHEA (dehydroepiandrostenedione), 276, 278 diabetes, 156, 158, 257, 312

genetic factors and, 55

treatment of, 40, 67 Dianabol, 276

diarrhea, 29, 106, 248–49, 253
diazepam (Valium), 29, 34, 42, 66, 68, 131, 139, 141, 162, 192, 260, 268,

Dietary Supplement Health and Education Act (DSHEA), 145–46 diet pills, 308–9
difluoroethane, 172
digestive system, 37–38, 46, 74–75, 78–79, 152

see also intestines; stomach dihydroepiandrosterone (DHEA), 276, 278 Dilantin (phenytoin), 67
Dilaudid (hydromorphone), 237, 242, 245, 246 dimethoxyamphetamine (DMA), 114, 127 dimethylamylamine (DMAA), 148, 149, 150 dimethyltryptamine, see DMT diphenhydramine (Benadryl), 67, 256 diphenoxylate (Lomotil), 237, 248–49 dissociative anesthetics, 109, 114–15 dissociative experience, 128, 131–32

distillation, 35
disulfiram (Antabuse), 39
diuretics, 46, 93
dizziness, 67, 118, 148, 165, 166, 168, 171, 216, 222, 261, 265, 270 DMA (dimethoxyamphetamine), 114, 127
DMAA (dimethylamylamine), 148, 149, 150
DMT (dimethyltryptamine), 109, 110, 114, 129

effects of, 124–25 forms of, 126 phosphorylated, 121 rapid onset of, 116, 126

sources of, 126
DNA damage, 153, 154, 189
Dolophine (methadone), 240, 246, 247, 258, 259, 260, 362
DOM, 114, 127
dopamine, 44, 101, 102, 104, 108, 136, 148, 149, 157, 194, 221, 302, 303,

304, 305, 307, 308, 309, 312, 354, 356, 357 Doriden (glutethimide), 260
“downers,” see sedatives
drinking games, 33, 38

driving, 131
alcohol and, 34, 38, 39, 42, 45, 50, 65, 66, 364 marijuana and, 175, 202–3

sedatives and, 262, 265
dronabinol (Marinol), 205
Drug Abuse Warning Network (DAWN), 269–70
drug dealers, 24, 371–74, 377
drug discrimination test, 100
“drug dogs,” 369
Drug Enforcement Administration (DEA), 98, 109, 174, 203, 208, 237, 240,

242, 244, 260, 276, 293, 294, 367, 373
drug laws, 203, 210, 290, 364–77
Drug Medicalization, Prevention, and Control Act of 1996 (Arizona), 208 drugs:

absorption and elimination of, 341–44

advertisement of, 340
alcohol combined with, 375–76
arrest and conviction for use of, 365, 369–70, 372–76 availability of, 20
basic facts on, 337–49
brain imaging and, 334
“chasing the high” of, 44, 356, 357
children’s use of, 27, 28, 29, 30
college students’ perspective on, 23–26
deaths associated with use of, 19, 24, 29, 30
definition of, 29, 338
designer, 127–28
distortion of facts about, 19, 28
dosage of, 340
education and prevention programs on, 19, 21, 26, 98, 377 efficacy of, 340
freebasing of, 342
individual differences in reactivity to, 20, 24
injection of, 23, 24, 28, 29, 30, 105, 114, 131, 237–38, 341 interactions of, 22, 25, 34
involuntary use of, 29
legal issues and, 19, 20, 203–10, 364–77
long-term effects of, 19, 21
medical supervision of, 18
music and, 23–24
nightclub, 27, 28, 29, 275
overdose of, 27, 28, 29, 30
over-the-counter, 72, 76, 84, 93, 346, 366
peer pressure and, 360
plasticity and, 315–16, 324–27, 328–33
popularity of, 28, 30, 211
prescription, 18, 27, 72, 114

principles of, 337
purity of, 24, 25, 29–30, 241, 242
quiz on, 27–30
receptors for, 339–40, 341
recreational use of, 18, 20, 27–28
rising use of, 20, 24
romance and allure of, 24
“rush” of, 24, 30, 259, 355, 356
schedule classes for, 367–68
scientific vs. public understanding of, 17–19, 25, 26 self-medication with, 54, 361
side effects of, 18, 67, 68
slogans about, 18, 19, 23–24, 26, 299
smuggling of, 373
societal and economic disruption caused by, 21 stopping use of, 337, 347–49
tolerance and sensitization to, 337, 344–47
toxicity of, 339
underground scene and, 98

withdrawal from, 347–49

Drugs and Phantasy: The Effects of LSD, Psilocybin and Sernyl on College Students (Pollard), 123n

Drugs and the Brain (Snyder), 297n Duke University, 335
Durabolin, 276
dynorphins, 250, 251

dysphoria, 136, 250, 253

Earth (Brin), 251
Eastern medicine, 146, 155
Easy Lay, 29, 262
e-cigarettes, 181, 223, 232–36
Ecstasy, see MDMA
Ecstasy and the Dance Culture (Londson), 100n

EEG, 358
Egypt, 177, 239
Elavil (amitriptyline), 66
Eldepryl, 159
electroencephalograph (EEG), 76
electrolytes, 91
elemicin, 128
Eleutherococcus, 155
Eli Lilly Company, 290
emergency medical assistance, 33–34, 36, 38, 103, 116, 132, 138, 141, 215,

238, 248, 261, 291, 292, 298
endocannabinoids, 184
endogenous opioids, 251
endorphins, 248–49, 250–51
ENDS (Electronic Nicotine Delivery System), 232–36 energy drinks, 156–57

alcohol and, 90–91
buzz from, 90
caffeine in, 71, 73, 89–93, 158

contents of, 157, 158
energy formulations, 91
enkephalins, 248–49, 250
enlightenment, 17, 117, 128, 129, 136–37 entactogens, 21, 96, 101, 108
entheogenics, 113
Environmental Protection Agency (EPA), 227 enzymes, 39, 40
ephedrine, 29, 305, 309

death and, 148, 149
drugs combined with, 144, 145, 149 history of, 290–91
medicinal use of, 147, 290
physical effects of, 147–50, 296 sources and forms of, 296
weight loss and, 147, 148

ephredrine, 159 epilepsy, 67, 169

brain imaging and, 334 Equanil, 260

equilibration, 37
ergot alkaloids, 119, 140
Erythroxylon coca, 289
espresso, 85–86
estradiol, 278
eszopiclone (Lunesta), 260, 268, 270
ethanol, 36, 37, 39, 41, 171, 265, 273, 274
ether, 161, 167–68
euphoria, 71, 77, 96, 117, 120, 128, 131, 136, 161, 169, 237, 250, 253, 274,

287, 297, 302, 303 European Drug Report, 377 Eve (MDE), 96
Excedrin, 84, 93
exogenous cannabinoids, 184 eyes, 130, 152

blurred vision of, 120, 126, 161 caffeine and, 80
dilated pupils of, 100, 119, 126, 130 pinpoint pupils of, 237, 255

Farley, Chris, 298
Felsules, 260
feminization syndrome, 59–60, 283
fenfluramine, 101, 102
fentanyl, 18, 237, 238, 240, 243–44, 245, 246–47, 255, 367 fetal alcohol effects (FAE), 53
fetal alcohol spectrum disorders (FASD), 53
fetal alcohol syndrome (FAS), 53

trangenerational effects of, 54 fight-or-flight response, 100, 102, 303 Figi, Charlotte, 206
Finajet, 276

First Amendment, 127
5–Hour Energy, 90
5–methoxy dimethyltryptamine (5–MeO-DMT), 114, 124, 126
Flagyl (metronidazole), 66
flephedrone, 108
flunitrazepam (Rohypnol), 29, 260, 262, 268
fluoxetine (Prozac), 101, 106, 142
fly agaric mushrooms (Amanita muscaria), 112, 124, 138
Food and Drug Administration (FDA), 90–91, 107, 145–46, 147, 148, 149,

165, 204, 235, 239, 261, 268, 270, 272, 275, 278, 286 forskolin, 150

Foster, Jeremy, 23–26
Four Loko, 90–91
Freon, 171, 172
Freud, Sigmund, 122, 289–90, 297, 306
functional magnetic resonance imaging (fMRI), 333–35 Furoxone (furazolidone), 66

GABA (gamma-aminobutyric acid), 262, 264, 271, 321, 332

alcohol and, 43, 44, 330

enhancement of, 168, 169, 266 gabapentin (Neurontin), 271 gangrene, 119
Garcia, Jerry, 257

Garcinia cambogia, 150
gasoline, 161, 163, 164
Gatorade, 91
genetic deficiency, 158
GHB (gamma-hydroxybutyrate), 29, 260, 271–75

brain and, 272–73, 274 cautionary note on, 275 misinformation on, 20 tolerance to, 274 toxicity of, 273

uses of, 20 withdrawal from, 274

ginkgo biloba, 90, 155, 156
ginseng, 90, 143, 155–56
ginsenosides, 155
glaucoma, marijuana and, 204, 205–6
glue, 29, 161, 163, 164, 171
glutamate receptors, 43, 135, 136, 169, 170, 321 glutethimide (Doriden), 260

Goodman and Gilman’s The Pharmacological Basis of Therapeutics (Hardman and Limbird, eds.), 168n

Goody’s Powders, 84, 93 Grateful Dead, 257 Griffiths, Roland, 124 Grisactin (griseofulvin), 66 guarana, 91

Gulf War, 291 gum disease, 229

Halcion, 260
hallucinations, 100, 104, 110, 122–24, 127, 128, 129, 130, 131, 134–35,

136, 162, 215, 270
alcohol and, 52
LSD and, 110, 117–18, 119–20 treatment of, 67, 131

visual vs. aural, 113, 117
hallucinogen persisting perception disorder, 110–11 hallucinogens, 100, 101, 109–42, 144, 211, 259, 293

absorption and elimination of, 115–16, 133–36
addiction and, 136, 139
brain and, 115–16, 117–18, 121, 130, 131, 133, 134–35, 141 buzz from, 110
categories of, 110, 114–15
common terms for, 109
dangers and myths of, 137–42
death and, 110, 119, 130, 138, 141
drugs combined with, 29, 111, 141–42

enlightenment and, 117, 128, 136–37 flashbacks and, 110–11, 115, 139–40, 142 forms of, 114–15, 116
history of, 112–13, 117–18, 119 identification of, 138

medicinal use of, 114, 130, 132

myths about, 116

Native American use of, 21, 113, 126–27

overdose and, 110–11, 116

psychological and physical effects of, 110–11, 113–15, 117–18, 119–20, 122, 127, 129, 130–31, 138–41

research on, 137–38

ritual and religious use of, 21, 113, 114, 115, 121, 127, 128–29, 136–37, 138

toxicity of, 127, 133

see also specific hallucinogens

Halotestin, 276
halothane, 161, 168, 261 hangovers, 45–46, 68
Hardman, Joel, 168n
harmala alkaloids, 114
harmaline, 128
harmine, 128
Harrison Narcotic Act of 1914, 290 Harvard Medical School, 69 hashish, 174, 175, 181
hash oil, 174, 181
headache pot, 179
headaches, 30, 66, 67

causes of, 45–46, 76, 84, 103, 120, 148, 162, 164, 166, 310, 351

migraine, 84, 124

treatment of, 84
health-food stores, 28, 152, 154 heart, 131, 341, 342

alcohol and, 46, 69 caffeine and, 77–78 marijuana and, 188 nicotine and, 226

stress and, 81
heart attacks, 58, 69, 77, 78, 88–89, 103, 159, 227, 283 heartburn, 79
heart disease, 102–3, 162, 164–65, 175

alcohol and, 46, 58, 69 caffeine and, 77, 78, 81, 95 hallucinogens and, 111

smoking and, 226, 227 heart medications, 36, 67–68 heart rate, 18, 129

elevation of, 71, 96, 97, 100, 110, 117, 119, 125, 126, 129, 134, 144, 147, 148, 151, 161, 162, 188, 189, 222

irregular, 71, 72, 162

slowing of, 110, 124, 261 Helicobacter pylori, 78 hemp, 177
Hendrix, Jimi, 24

hepatitis, 246, 256, 257, 312 herbal drugs, 28, 130, 143–60

brain and, 147, 152, 156, 157, 158 buzz from, 143
Chinese, 29, 147, 155
cognitive function and, 154–55 death and, 151

definition of, 144–45
dosage of, 147, 159
drugs combined with, 144, 151 overdose of, 143
research on, 147

unregulated status of, 29–30, 143, 145–47, 154

see also specific herbal drugs

herbal remedies, 130, 144–45, 146–47
herbal sedatives, 145
herbal X-tacy, 143
heroin, 211, 237, 240, 241, 242, 245, 246, 249, 298, 307

addiction to, 27, 29, 100, 251–54, 345, 347 coming down from, 29
“cutting” of, 24, 242, 256
drugs combined with, 25, 34, 162, 261

high street value of, 24

injection of, 23, 24, 238, 246, 254, 342, 347

major risks of, 24

Mexican “black tar,” 241, 256

overdose of, 24, 29

physical effects of, 29, 259

production of, 239–40

purity of, 24, 241

relative scarcity of, 24

“rush” from, 24, 259

skin-popping and, 342

tolerance to, 345
high blood pressure, 133, 159

alcohol and, 58, 68
caffeine and, 72, 95
Ecstasy and, 97
marijuana and, 175
synthetic marijuana and, 215

treatment of, 68, 346
hippocampus, 48, 49, 62, 63, 185–87, 225 Hofmann, Albert, 117–18
hooch, 33
Hoodia, 148, 150

hospital pot, 179–80
hydrochloride, 241
hydrocodone (Vicodin), 237, 243
hydromorphone (Dilaudid), 237, 240, 242, 245, 246 hyperactivity, 53, 100

hypericum, 151
hypertension, see high blood pressure
hyperthermia, 41, 97, 101, 102, 103, 110, 111, 130, 131, 132, 133, 141, 151 hypnotics, 145, 260
hypodermic syringe, 239, 341
hyponatremia, 103
hypothermia, 41
hypoxia, 258

ibogaine, 259 ibotenic acid, 124 ibuprofen, 342

drugs combined with, 34, 46, 76
“ice,” 286, 291, 293, 307
immune system, 19, 154, 156, 176, 187–88, 205, 257 immunosuppressant medication, 151
Imodium (loperamide), 237, 248–49
Inderal (propranolol), 68, 331
India, 88, 112
indigenous peoples, 113, 115, 126–27, 128–29, 136
Individual Treatment Investigational New Drug Application, 204 inhalants, 161–73, 341

buzz from, 161–62, 163
common terms for, 161 contaminants in, 166
death and, 162, 168, 170, 171–72 drugs combined with, 162–63 overdose of, 162

physical and psychological effects of, 161–73 three types of, 164–73

toxicity of, 163, 164, 165–66, 169, 170–73

young people’s use of, 29, 163

see also specific inhalants

insomnia, 20, 67, 148, 153
Institute of Medicine, 204
insulin, 309
internet, 20, 119, 147
intestines, 37, 38, 74–75, 115, 152, 343 intrauterine stroke, 30

ischemia, 83, 158 isobutyl nitrite, 164 isopropyl alcohol, 36

Jack Daniel’s Black Label, 25 “Jackpot,” 19
Jackson, Michael, 265 Jamestown, Va., 129

Japan, 290–91
Jell-O shots, 33, 38
jet lag, 152, 153
Jimsonweed (Datura stramonium), 109, 114, 129–30 jitteriness, 75, 94, 97, 102, 110, 117, 144, 147, 151, 310 Jobs, Steve, 137
Joplin, Janis, 24
Julien, R. M., 120n
(Burroughs), 247, 252–53
Justice Department, US, 209, 372
“Just Say No,” 23, 24, 171

kava, 145
Kelly, Chris, 298 Kennedy, John F., 330 Ketalar, 131
ketamine, 29, 109, 114

drugs combined with, 171
effects of, 132, 133, 135–36, 171

medical use of, 131–32

see also Special K ketanserin, 139

khat, 294, 296–97, 302
kidneys, 75, 116, 169, 172, 221, 343

caffeine and, 75, 78

damage and failure of, 97, 102, 138, 190 Koller, Carl, 290
Kratom, 237
kraton tree, 244

Krokodil (desomorphine), 237, 244 “Kubla Khan” (Coleridge), 239 Kuhn, Cindy, 25

Landis, Floyd, 281
Leary, Timothy, 137, 138
legal issues, 19, 20, 28–30, 133, 137, 364–77

alcohol and, 60, 65, 364
arrests and, 369, 372–74
conviction and imprisonment and, 365, 369–70, 374–76 crime and, 365, 369, 370–72, 374, 376
law enforcement officers and, 365–66, 368–70
lawyers and, 364
marijuana and, 19, 21, 203–10
personal rights and, 365, 368–70
principles of, 364–77
searches and, 365, 368–70

state vs. federal laws and, 368, 372, 376–77 Leshner, Alan, 18, 21
Librium, 66, 260, 263
life-support machines, 65

Limbird, Lee E., 168n liquor, 70

alcohol content of, 33, 36

home-distilled, 36
liver, 75, 115, 116, 121, 148, 150, 151, 169, 221, 247, 342, 343

alcohol and, 39, 40

long-term drug use and, 346
liver damage, 138, 182, 183, 265, 283

alcohol and, 34, 46, 58, 68
Lloyd’s of London, 73
Lomotil, 237, 248–49
Londson, Nicholas Saunder, 100n
long-term potentiation (LTP), 324–25, 328–30 loperamide (Imodium), 237, 248–49 Lophophora williamsii, 126

Love (MDA), 96
Lowry, Thomas P., 165n
LSD (lysergic acid diethylamide), 117–21, 129, 207, 211, 340, 353

absorption of, 115–16
common terms for, 109
contamination of, 111
drugs combined with, 29, 111, 141–42 forms and doses of, 114, 115, 118–19 legal status of, 113, 137

long-lived effects of, 115, 116, 120

“microdoses” of, 137

misinformation about, 111

overdose of, 28, 29, 110, 138

physical and psychological effects of, 110, 115, 117–18, 119–20, 121, 122, 125, 127, 133–35, 137, 138–41, 183

synthesis of, 117, 119, 120, 138

tolerance to, 121

toxicity of, 138
LSD, My Problem Child (Hofmann), 117–18 Lunesta, 260, 268, 270
lung cancer, 214, 226

marijuana and, 188–90

lysergic acid amide, 119
lysergic acid diethylamide, see LSD

mace, 128
magic mushrooms, 109
mahuang, 29, 290
mandrake root (Mandragora officinarum), 109, 130 MAO inhibitors, 72, 150

drugs combined with, 97, 142, 144 marathon runners, 103, 251
Mariani, Angelo, 289
marijuana, 174–215, 249, 344, 377

acute effects of, 195
addiction and, 27, 29
adulteration of, 142
aggression and, 201–2, 210
brain and, 30, 175, 182–87, 194–95, 196, 198–99 buzz from, 174–75

as cash crop, 213
chocolate compared with, 27, 94
chronic use of, 193, 195–98
cognitive problems and, 30, 175
common terms for, 174
controversy over, 19, 21, 203–11, 214
crime and, 210–11, 212
crusade against, 210, 213
dependence and, 193
drugs combined with, 111, 115, 126, 131, 141–42, 175–76 forms of, 175, 179, 180, 181
gastrointestinal system and, 190
high-grade, 174, 175, 179–80
history of, 177
legalization campaign for, 19, 21, 203, 206, 213

legal status of, 203, 206, 207–14, 366, 372 low-grade, 174, 179, 180
medical, 180
medical uses of, 21, 203–9, 213 medium-grade, 179, 180

memory impairment and, 30, 175, 192, 195–201

motor performance and, 175, 202–3

overdose of, 175

physical and psychological effects of, 19, 27, 28, 30, 94, 174–75, 182– 203, 214

popularity and symbolism of, 30, 211 popular media and, 210
reproductive system and, 190–91 residual and chronic effects of, 195–201 tolerance to, 193

vaporization of, 181, 182

withdrawal from, 193–94

young people’s use of, 211, 212, 213

see also THC marijuana, synthetic, 214–15

death and, 215
Marijuana Tax Act of 1937, 203, 210–11
Marinol (dronabinol), 205
Marplan, 72, 150
Massachusetts General Hospital, 167
masturbation, 46
Maxibolin, 276
McClellan, Tom, 363
McGough, James, 331
mCPP, 108
MDA, 96, 97, 98, 101, 127
MDE, 96, 98, 101
MDMA (Ecstasy), 27, 96–108, 127, 128, 294, 305, 334, 343

absorption and elimination of, 99

addiction and, 100, 101
biochemical profile of, 101–2
brain and, 25, 30, 99–102
buzz from, 96
clinical use of, 106–7
common terms for, 96
contaminants in, 98, 99
death and, 97, 103, 106
drugs combined with, 97, 103, 111
fake, 98, 133
heavy use of, 103, 104, 105
history of, 97–98
memory and, 104
overdose of, 97
physical and psychological effects of, 25, 30, 96–108, 158, 293 protection from, 106–7
psychotherapy and, 27, 29, 98
“rave” dance parties and, 97, 98, 100, 102, 106
substitute for, 147, 148
substitutions for, 107–8
tolerance to, 100

toxicity of, 97, 98, 102–7
MDPV, 294, 296–97, 302, 305, 307, 353 melatonin, 143, 146, 152–54

aging and, 152, 153–54 dosage of, 152, 154 fertility and, 153, 154 safety of, 154

sleep and, 152–53, 154, 155
memory formation, 45, 48–49, 62, 83, 135, 145 memory impairment, 27, 173, 267, 269

alcohol and, 44–45, 48, 50, 57, 61, 62, 64

Alzheimer’s disease and, 154, 155, 157–58, 224 blackouts and, 44–45
hallucinogens and, 129, 132, 135
marijuana and, 19, 30, 175, 192, 195–201 sedatives and, 267

treatment of, 158, 159, 224
menstrual cycles, 191
mental illness, 18, 113, 145, 352, 361
mental retardation, 28
meperidine (Demerol), 68, 162, 237, 243, 245, 246, 261 Merck, 97
Meridia (sibutramine), 309
mesc, 109
mescal, 109
mescaline, 109, 114, 116, 127, 133, 134, 138

drugs combined with, 111

see also peyote cactus
methadone (Dolophine), 240, 246, 247, 258, 259, 260, 362 methamphetamine, 98, 104, 286, 291–92, 293, 305, 307

brain and, 104, 312 drugs combined with, 72 forms of, 293

physical effects of, 295–96 methandrostenolone (Dianabol), 276 methanol, 36, 171
methaqualone, 34, 65, 260

drugs combined with, 162, 238 methcathinone, 286 methylenedioxyamphetamine, see MDA methylenedioxyethylamphetamine, see MDE methylenedioxymethamphetamine, see MDMA methylone, 107, 294

methylphenidate (Ritalin), 286, 292, 293, 296, 301–2, 305, 310 methyltestosterone, 276
metronidazole (Flagyl), 66

Mexico, 119, 121, 126, 127, 129, 242, 248, 293 milk, 118, 158
Miltown, 260
mitragynine, 244

MODs, 181, 223, 232
Molly (MDMA), 96, 103, 294

contaminants in, 98–99
Monitoring the Future Study, 98, 212
monoamine oxidase, 148, 149, 150
monoamine oxidase inhibitors, see MAO inhibitors monoamines, 150, 159, 302, 303–4
moonshine, 36
morning glory seeds, 119
morphine, 237, 239–40, 241, 242, 243, 245, 246, 247, 256

drugs combined with, 34, 68, 162, 261 Morrison, Jim, 24
Motrin, 34
muscarine, 124, 135

muscimol, 124 muscle mass, 149 muscles, 80, 106

injury and weakness of, 102, 119, 126, 162

relaxation of, 161, 164, 165, 167, 168

stimulation of, 135, 282 mushrooms, 141–42

ancient use of, 121

cautionary note on, 124–25, 138

dried, 115, 121

genera of, 121

hallucinatory effects of, 112, 121–25, 138, 249

home growing of, 121

see also fly agaric mushrooms; psilocybin mushrooms myristicin, 128

naloxone, 139, 244

naltrexone, 259
naphyrone, 108
Napoleon I, Emperor of France, 177
Narcan (naloxone), 29, 169, 240, 248, 251, 258, 259
narcolepsy, 20, 272, 297
Narcotics Anonymous, 258, 362
Nardil, 72, 150, 159
nasal decongestants, 111, 149, 346, 347–48
National Academy of Sciences, 204
National Cancer Institute, 82
National Center for Complementary and Alternative Medicine, 147 National Institute of Mental Health, 211
National Institute on Drug Abuse, 18, 230, 255, 259
National Institutes of Health, 147, 360
National Organization for the Reform of Marijuana Laws (NORML), 203 National Survey of Drug Use and Health, 291
Native American Church, 127
Native Americans, 113, 115, 126–27
nausea, 106, 117, 119, 120, 122, 124, 127, 128, 133, 148, 162, 190, 216,

222, 238, 247, 248, 256, 310

marijuana treatment of, 205
Nembutal (pentobarbital), 260, 264
nerve damage, 170
neuroanatomists, 47
neurogenesis, 326
Neurontin, 271
neuropharmacology, 23, 25
neurotransmitters, 30, 101, 134–36, 152, 156, 157–58, 159, 169–70, 302,

321–22, 324–25, 332
alcohol and, 42–44
blocking actions of, 75
caffeine and, 75
catecholamine, 157
hallucinogens and, 130, 133–36, 141

release of, 319 Nichols, Dave, 98

Nicot, Jean, 218
nicotine, 135, 177, 216–36, 306–7, 341

absorption and elimination of, 219–21
addiction and, 27, 29, 219, 221–22, 228, 229–32, 234, 353 appetite suppression and, 223
brain and, 220–21, 223–25
buzz from, 216
drugs combined with, 216–17
emotional function and, 225–26
forms of, 216
history of, 217–19
medicinal use of, 217–18, 224–25
memory and, 216, 224
overdose of, 216
physical and psychological effects of, 30, 216–17, 219–30 potential health benefits of, 216, 224–25
pregnancy and, 216, 227–29
skin and, 226
smoking delivery of, 23, 30, 189, 216, 219, 223–28 subjective experience of, 222–23
tobacco-free oral delivery of, 220
tolerance to, 222
toxicity of, 30, 216
vaping and, 225–26, 232–36
withdrawal from, 222, 228
young people and, 30, 218–19, 225–26

see also cigarettes; tobacco
nicotine chewing gum, 216, 220, 230 nicotine-N-oxide, 221
nicotine poisoning, 30, 216
nicotine skin patch, 216, 224, 233, 341, 362 nicotinic acetylcholine receptor, 223–24 Niemann, Albert, 289

nitrites, 161, 162, 164–67
definition of, 164
physical and psychological effects of, 165–66 tolerance to, 166–67
toxicity of, 165–66

withdrawal from, 166 nitroglycerin, 68, 164–65, 166–67 nitrous oxide, 161, 162, 261

as “laughing gas,” 163, 169

recreational use of, 163, 164, 169

tolerance to, 170–71

toxicity of, 169, 170–71
NMDA receptors, 136, 169–70, 171, 328–29

alcohol and, 43, 329 Noludar, 260

norepinephrine, 101, 102, 108, 148, 150, 157, 303, 304, 305, 309 North Carolina, University of, 326
Notec, 260
nuclear hormone receptors, 152

nutmeg, 128
nutritional supplements, 90, 145, 146, 147, 158–59, 160, 278

Obama, Barack, 209, 372
obesity, 95, 145, 148
Office of National Drug Control Policy (ONDCP), 363 “Oh Excellent Air Bag,163–64
ololiuqui, 119
opioids, 136, 237–59

absorption and elimination of, 242, 243–47 addiction to, 27, 29, 100, 215–59, 362–63 blocking of, 29
brain and, 247–50

breathing problems and, 248, 255, 258 buzz from, 237–38, 247

classification of, 237
common terms for, 237
death and, 240, 243, 255
drugs combined with, 34, 162, 238, 256 forms of, 34, 237–38, 239–45

history of, 239–40
injection of, 23, 24, 237–38, 245
long-term effects of, 256–58
medical uses of, 239, 240, 241, 242, 243
natural, 240, 249–51
overdose of, 116, 238, 243, 248, 249, 252, 255–59 physical and psychological effects of, 237–38, 246–58 relative efficiency of, 245
tolerance to, 251–54, 345
toxicity of, 255–59
withdrawal from, 243, 249, 252–55

see also specific opioids

opioids, endogenous, 251
opium, 237, 239–42
opium pipes, 245
opium poppy (Papaver somniferum), 239–40, 241, 245, 249 orexims, 270

organ transplant rejection, 151
Orinase (tolbutamide), 67
out-of-body experience, 110, 117, 118, 127, 132 Oxford Survey of Childhood Cancers, 228 oxycodone, 237, 238, 240, 242, 245, 246, 247

drugs combined with, 34
OxyContin, 237, 242, 246–47
oxygen, 18, 153, 162, 166, 224, 228, 258, 311, 333

pain, 162
sensitivity to, 131, 136 suppression of, 167–71

pain relievers, 17, 164
alcohol and, 34, 40, 46, 68
caffeine in, 71, 73, 84, 93
narcotic, 68, 242, 243, 244, 247, 248, 250 non-narcotic, 34, 68, 84
over-the-counter, 71, 76, 84, 93

side effects of, 34, 68 paint, 29, 161, 163, 164, 171 panacea, 158, 244 Panaeolus, 121
Panax, 155
pancreas, 58
panic attacks, 104, 116

caffeine and, 71, 80
Papaver somniferum (opium poppy), 239–40, 241, 245, 249 Paracelsus, 239
paralysis, 126, 216
paramethoxyamphetamine (PMA), 103
parasympathetic nervous system, 124, 130, 147
Parke-Davis, 289
Parkinson’s disease, 158, 303
Parnate, 72, 150
parsley, 115
Pavlov’s dogs, 347, 349
Paxipam, 260
PCP, see phencyclidine
PEA (beta phenylethylamine), 148
PeaCe pills, 109
Pemberton, John, 289
pentobarbital (Nembutal), 260, 264
perceptual distortion, 110, 113, 117, 120, 122, 128, 139–40, 141, 162 Percodan, 237, 242–43, 246
performance enhancement, 147, 148

caffeine and, 73, 80–81 nicotine and, 229

steroids and, 277, 279–82 peyote cactus, 109, 114, 116

dried button of, 109, 115, 126–27

physical and psychological effects of, 127

ritual and religious use of, 127 pharmaceutical companies, 18, 289, 329 pharmacology, 161, 259, 263, 264, 339 pharmacotherapy, 362–63
phencyclidine (PCP), 109, 114–15, 131–32, 343

drugs combined with, 111, 142
effects of, 110, 122, 131–32, 135–36, 141 forms of, 109, 114–15, 131

overdose of, 116 phenethylamine, lethal dose of, 141 phenobarbital, 260, 264

drugs combined with, 34, 162, 238

sedative effects of, 42, 263, 264 phenylalanine, 157, 159 phenylephrine, 149 phenylketonuria, 159 phenylpropanolamine, 72

phenytoin (Dilantin), 67
Philippines, 377
Philopon, 290
PHPD (posthallucinogen perceptual disorder), 139–40, 142 pineal gland, 152

piperzines, 108
pipe tobacco, 216
Piptadenia peregrina, 125, 126 placebo effect, 145, 155, 202 placebos, 193
Placidyl, 260
PMA (paramethoxyamphetamine), 103 Pollard, J. C., 123n
Pondimin, 101
Popular Science Monthly, 210

porter, 33
Portugal, 277
posthallucinogen perceptual disorder (PHPD), 139–40, 142 posttraumatic stress disorder, 107, 124, 125, 332
Potency Monitoring Project, 180
pre-gaming, 38
pregnancy, 79, 151

alcohol and, 28, 30, 39, 40, 53–54 caffeine and, 79
cocaine and, 28, 30, 299–300 LSD and, 140

premature placental separation in, 30, 300

smoking and, 30, 216, 227–29

stimulants and, 299–300
Primer of Drug Action, A (Julien), 120n Prince, 240
Prohibition, 21
propane, 29, 172
propofol, 265
propoxyphene (Darvon), 68, 237, 244, 247 propranolol (Inderal), 68, 331
propylene glycol, 235
protein, 157
Prozac (fluoxetine), 101, 106, 142 pseudohallucinations, 110, 117
psilocin, 114, 121, 133
Psilocybe, 121
Psilocybe cyanescens, 121
Psilocybe mexicana, 121
psilocybin, 107, 113, 114, 121–25

therapeutic potential of, 124
psilocybin mushrooms, 109, 114, 116, 121–25, 144

brain and, 121
physical and psychological effects of, 121–25, 138–39 ritual use of, 121

psychedelics, 113
“Psychosexual Aspects of the Volatile Nitrites, The” (Lowry), 165n psychosis, 110, 113, 115, 138, 139, 201, 274, 298 psychostimulants, designer, death and, 292
psychotherapy, 27
psychotomimetics, 113
Psychotria viridis, 128
p-Synephrine, 148, 149
Pulp Fiction, 28, 29, 248
punch, 33
Pure Food and Drug Act of 1906, 290

Quaaludes, 260

alcohol combined with, 65

drugs combined with, 34, 162, 238 quinacrine (Atabrine), 66
quinine, 241, 256
Quinlan, Karen Ann, 65

ramelteon (Rozerem), 260, 268, 271
“rave” dance parties, 97, 98, 100, 102, 106 Reagan, Ronald, 213
Red Bull, 90, 92
Religious Freedom Restoration Act of 1993, 127 Restoril, 260
Revolutionary War, 74
Rhodiola rosea, 150, 151
Rig-Veda, 112
risky behaviors, 63, 104, 110
Ritalin, 286, 292, 293, 296, 301–2, 305, 310 Rohypnol, 29, 260, 262, 268
“roofies,” 18, 29, 262, 268
Royal College of Physicians, 377
Rozerem, 260, 268, 271
Rubin, David, 335

St. Anthony’s fire, 119

St. John’s wort, 151–52
salivation, 124, 347
Salvia (Salvia divinorum), 109, 115, 129, 136, 139
Salvinorin A, 129, 136
SAMe (S-adenosylmethionine) levels, 158–59
San Pedro cactus (Trichocereus pachanoi), 127
Santo Daime, 129
SARMS (selective androgen receptive moderators), 276, 278, 280 Sativex, 207
schizophrenia, 113, 148, 175

paranoid, 141, 311

treatment of, 17, 224–25 Schultes, Richard, 121, 128 Scientific American, 201–2, 210 scopolamine, 109, 110, 130, 131 secobarbital (Seconal), 260 sedatives, 29, 33, 260–75

buzz from, 260–61
classification of, 260
death and, 261, 263, 264, 265
driving and, 262, 265
drugs combined with, 65–68, 261–62 general, 260, 261, 263–66
overdose of, 261, 264
physical and psychological effects of, 263–85 tolerance to, 265–66
toxicity of, 264–65
withdrawal from, 265–66

see also specific sedatives

seizure disorders, 206, 207
seizures, 134, 138, 271, 287, 310, 332

causes of, 52, 66, 67, 71, 95, 103, 110, 132, 141, 169, 256, 267, 306

prevention and treatment of, 66, 67, 325 self-stimulation, 352

Serax, 260
Sernyl, 131
serotonin, 30, 104–6, 108, 125, 130, 134–35, 151, 152, 244, 302, 303, 304,

305, 309, 360

phosphorylated, 121

release of, 101–2, 104 serotonin-2a, 134 serotonin neurons, 134–35

damage of, 97, 104–6
serotonin receptor blocking drugs, 102
serotonin receptors, 134–35, 139
serotonin-specific reuptake inhibitors (SSRIs), 97, 100, 101, 106, 142, 151 serotonin syndrome, 97, 106, 108, 142, 151
serotonin transporters, 104–6
Seville oranges, 149
sex, 354

alcohol and, 45, 59–60 compulsive, 338
orgasm and, 100, 165, 311

promiscuous, 351 Shakespeare, William, 311 shock, 124
Shulgin, Alexander, 98, 125 Siberian ginseng, 155 sibutramine (Meridia), 146, 309 sigma receptors, 136
sildenafil (Viagra), 146 sinsemilla, 174, 179, 180
sleep, 134

alcohol and, 28, 29, 34, 52, 66
sleep disorders, 20, 25, 28, 29, 52, 94–95, 153, 253, 272
sleep medications, 20, 34, 66, 67, 146, 152–53, 154, 260, 268–71 smart drugs, 143, 146, 156–59
smoking, see cigarettes; hashish; marijuana; nicotine; tobacco smoking cessation, 219

programs and medication for, 216, 220, 222, 225, 229–33, 234

snuff, 126, 216, 219–20, 221, 229 Snyder, S. H., 297n
sodium, 103
soft drinks:

caffeine in, 73, 74, 75, 89, 92–93

diet, 89, 92

see also energy drinks; sports drinks solvents, 29, 171–73

chemicals in, 29, 161
drugs combined with, 261 effects of, 161–62, 163, 171–73 toxicity of, 171–73

see also specific solvents

Soma, 112
Somnos, 260
South America, 113, 114, 125–26, 127, 128, 130, 242, 289 Southy, Robert, 163–64
Southy, Thomas, 163
soy phospholipids, 150
Spain, 207
spasticity, 206–7
Special K, 29, 109
spirits, 33, 37
sports drinks, 91
stanozol (Winstrol), 276
state laws, federal laws vs., 368, 372, 376–77
steroids, 276–85

addiction to, 284–85 aggression and, 283–84 banning of, 280, 284 buzz from, 276 classification of, 276 common terms for, 276 death and, 283

hazards of, 282–84
medical use of, 277
overdose of, 276–77
performance enhancement and, 277, 279–82 physical effects of, 276, 277–84

women and, 281, 283 stimulants, 17, 71, 169, 286–312

addiction to, 296, 297, 303, 305–7 brain and, 296, 297–98, 311
buzz from, 286–87
chronic use of, 310–12

common terms for, 286
death and, 97, 287, 298, 309
“designer,” 291–92, 294
drugs combined with, 287, 298
forms of, 286
history of, 288–92
monoamine recapture and, 303–4
natural, 145
neurotransmitters and, 303–4
overdose of, 287, 298, 309–12
physical and psychological effects of, 286–87, 295–312 pregnancy and, 299–300
tolerance to, 308
toxicity of, 295, 309–12
violence and, 311

see also specific stimulants

stink weed, 109
stomach, 74–75, 79, 115, 130

alcohol and, 34, 37–38, 46, 58, 68 caffeine and, 78–79
food in, 38, 46

irritation and bleeding of, 34, 46, 68, 78–79, 89, 94, 95, 311 STP, 114, 127

stress, 156, 157 caffeine and, 80, 89 heart and, 80

reduction of, 89
stroke, 58, 83, 103, 135, 141, 149, 158, 287, 310 Stropharia, 121
Sublimaze, 237, 238, 240, 243–44, 245, 246 sudden infant death syndrome (SIDS), 228
sugar, 90
suicide, 25, 172, 215
Supreme Court, US, 127, 211
suvorexant (Belsomra), 268, 270
sweating, 103, 122
sympathetic nervous system, 125, 130, 299 synesthesia, 117

talc, 241, 256, 292 tapentadol, 244
tar, 174, 189
taurine, 90, 157, 158
tea, 75, 88–89, 126, 129, 150

black, 88–89
caffeine in, 73, 88
green, 88–89
health benefits of, 88–89 herbal, 89, 114, 115, 147 preparation of, 88–89

taxes on, 74
Teachings of Don Juan, The (Castaneda), 128
teeth clenching, 97, 102
teonanactl, 121
testosterone, 276, 277, 278, 280, 281, 282, 283, 284 tetrahydrogestrinone (THG), 280

tetrodotoxin, 319
TFMPP, 108
Thailand, 244
THC (delta-9-tetrahydrocannabinol), 174, 175, 178–88, 191–93

absorption and elimination of, 175, 182–83, 343 antinausea effects of, 205
brain and, 28, 94, 179, 182–87, 194, 196 by-products of, 28, 175, 182

fat solubility of, 28, 183, 344 marijuana levels of, 174, 178, 180–81 subjective experience of, 191–93

see also marijuana
Theobroma cacao, 94
theobromine, 75, 94
theophylline, 75, 79, 81, 95, 287 THG (tetrahydrogestrinone), 280 Thorazine (chlorpromazine), 67, 139 Time, 271–72, 273

“tinctures,” 174
tlitlitzin (Ipomoea violacea), 119 TMA (trimethoxyamphetamine), 114 toads, 126
tobacco, 189, 366

advertising of, 218, 219
cancer and, 218, 228, 229
chewing, 218, 229
declining use of, 218
drugs combined with, 115, 181, 216–17 educational levels and, 218

forms of, 216–17

smokeless, 229 tolbutamide (Orinase), 67 toluene, 29, 161, 171, 173 topi, 109

Tour de France, 281
Trade Revenue Act of 1767, 74
Trainspotting, 28, 248, 253
Tramadol (Ultram), 237, 244
Tranxene, 260
tremors, 52, 71, 119, 128, 148, 216 Trichocereus pachanoi (San Pedro cactus), 127 tryptophan, 106, 146
Turbina corymbosa, 119
TWEAK test, 57
2-AG, 184
2C-B, 125
Tylenlo (acetaminophen), 76
Tylenol (acetaminophen), 34, 40, 46, 68 tyrosine, 157, 159

Über Cocaine (Freud), 297n ulcers, 78–79, 311
Ultram, 237, 244
unconsciousness, 162, 165, 167–71

alcohol and, 33–34, 38, 41, 65 Uniao do Vegetal (UDC), 128–29 United Kingdom, 98
“uppers,” see amphetamine urination, 78, 81

Valium, 42, 68, 131, 139, 141, 192, 260, 269

drugs combined with, 34, 66, 162, 238, 268

memory impairment and, 29 Valmid, 260

vaping, 225–26, 232–36

adolescents and, 234–35 vegetal, 109, 128–29 Versed, 260
Verstran, 260

Verve, 220
Viagra (sildenafil), 146

Vicodin, 237, 240, 243 Vin Mariani, 289, 295 vitamin, D, 265 vitamin B12, 170 vitamin E, 153

vitamin K, 265
Vivarin, 71, 93 Vollenweider, Franz, 125 vomiting:

causes of, 34, 41, 66, 71, 95, 103, 119, 125, 127, 128, 133, 148, 162, 166, 190, 215, 238, 256, 265, 310

suffocation and, 34 voodoo, 319

Wall Street Journal, 126 warfarin (Coumadin), 66 War on Drugs, 213 Wasson, R. Gordon, 121 water, 103, 106

weight loss, 28, 146–47, 149, 150, 362, 363 amphetamines and, 308–9
appetite suppression and, 96, 97, 223, 308

ephedrine and, 147, 148 Wellbutrin, 230
Whippets, 161
whiskey, 35

alcohol content of, 33, 40 Wilson, Leigh Heather, 23–26 wine, 70

alcohol content in, 33, 37 coca, 289
fortified, 33
health benefits of, 23

pregnancy and, 28, 30, 53 Winstrol, 276

Wizard of Oz, 239 Wood, Alexander, 239

X, 96
Xanax, 260 xanthines, 75, 79, 287 XTC, 96
Xyrem, 260, 272

yage, 109, 128–29
Yage Letters, The (Burroughs), 128 Yemen, 73
yopo, 126
Young, Francis L., 203

zolpidem, 34, 260, 268–70, 375–76 Zyban, 230

Praise for Buzzed
“This is a well-written and well-organized book that is highly recommended

for health-care professionals, health educators, and even parents.”

Dr. Charles E Yesalis, professor of health policy and administration at Penn State University and coeditor of Performance Enhancing Substances in Sport and Exercise “Students need clear, detailed, comprehensive factual information in order to make smart decisions, and Buzzed provides it all in an easy-to-understand format. What a great resource!”

Ellen Gold, former chair of the Alcohol, Tobacco, and Other Drug Task Force at the American College Health Association “A well-written book that dispels some of the myths associated with drug

abuse. I would recommend it to anyone looking for a readable, factual account of the physiological and behavioral effects of drugs of abuse.”

Dr. Charles Schuster, director of clinical research on substance abuse at the Wayne State University School of Medicine, and former director of the National Institute on Drug Abuse “Buzzed is one of the most important books I’ve ever read. . . . So comprehensive and so readable that I recommend everybody who’s interested in this area—kids who are taking drugs, parents, professionals . . . and, most of all, politicians and legislators—to read it.”

Irvine Welsh, author of Trainspotting “A unique, up-to-date, and useful source for all those interested in the workings of and effects of legal and illegal drugs, regardless of whether you are a concerned mother or Irvine Welsh!”

The British Psychological Society “Everyone who is interested in drugs will enjoy reading this. . . . The authors approach the subject with neither bias nor exaggeration. . . . A wonderfully interesting and accurate handbook of drug information.”

Carlton K. Erickson, director of the Addiction Science Research and Education Center at the University of Texas at Austin, and author of The Science of Addiction: From Neurobiology to Treatment “Lively, highly informative, unbiased, thorough, and nothing but straight talking on an issue which is often condemned without being fully understood or sufficiently explained to our youth. Its breadth of scope yet clarity of detail place this book in contention for the coveted title of the ‘only drug book you’ll ever need.’ I have not read a fuller, more illuminating text on the influence of drugs on physical and psychological functioning.”

Christopher Russell, research fellow at the University of Glasgow’s Centre for Drug Misuse Research “Well written and easy to read. [Buzzed] could be used as a resource to be consulted, dipped into simply for interest’s sake, or read from cover to cover. . . . If you are looking for an up-to-date, accessible source of information regarding drugs of abuse, this book would be a good starting point.”

The Ulster Medical Journal “Drug education ought to be sober but it doesn’t have to be dour. The authors [of Buzzed] have come up with an informative book about the ways people get high. It is also realistic and interesting to read.”

Dallas Morning News

CYNTHIA KUHN is a professor of pharmacology at Duke University Medical Center and heads the Pharmacological Sciences Training Program at Duke. She is married with two children.

SCOTT SWARTZWELDER is a professor of psychology and neuroscience at Duke University and a clinical professor of psychiatry and behavioral sciences at Duke University Medical Center. He is also a senior research career scientist with the US Department of Veterans Affairs. He is married with three children.

WILKIE WILSON is a professor of prevention science at the Duke University Social Science Research Institute and the Center for Child and Family Policy. He is married with two daughters.

LEIGH HEATHER WILSON is a graduate of Meredith College with a degree in Spanish language and literature. She is pursuing a career in educational consulting.

JEREMY FOSTER is a graduate of the University of North Carolina, Chapel Hill, with a degree in journalism and mass communication. He is currently working as a specialist in international development.

Copyright © 2019, 2014, 2008, 2003, 1998 by Cynthia Kuhn, Scott Swartzwelder, and Wilkie Wilson

All rights reserved
For information about permission to reproduce selections from this book, write to Permissions, W. W. Norton & Company, Inc.,
500 Fifth Avenue, New York, NY 10110

For information about special discounts for bulk purchases, please contact W. W. Norton Special Sales at or 800-233-4830

Book design by JAM Design

Cover Design by Pete Garceau

Cover Illustrations ©

The Library of Congress has cataloged the printed edition as follows:

ISBN: 978-0-393-35646-5 (pbk.)

ISBN: 978-0-393-35647-2 (ebk.)

W. W. Norton & Company, Inc., 500 Fifth Avenue, New York, N.Y. 10110

W. W. Norton & Company Ltd., 15 Carlisle Street, London W1D 3BS

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