The bombshell dropped in 1976, when "The Natural History of Chipping" appeared in the American Journal of Psychiatry. In their article, Norman Zinberg, then clinical professor of psychiatry at Harvard, and his research assistant R.C. Jacobson described five case studies, representative of 54 identified long-term heroin users who had regularly injected the drug for from two to 23 years, yet had never become addicts. These "chippers," whose existence Zinberg had noted as early as 1964, actively developed social rituals and usage strategies that permitted stable, controlled use of heroin.

That article demolished the received wisdom of decades. Ever since 1898, when Bayer & Co. of Germany, makers of another painkiller, Bayer aspirin, introduced heroin to the pharmaceutical market, popular and scientific mythology had enshrined it as the most addictive of drugs. (The word heroin, allegedly referring to heroic feelings stimulated by the drug, was originally a Bayer trademark.) The finding that people could take heroin without forming habits challenged the whole idea that drugs themselves were addictive.

Since then, the ethos has shifted markedly. "The idea of addictive drugs makes no sense," says Howard Shaffer. "It's magical thinking to imagine that drugs have this power." Shaffer, associate professor of psychology in the department of psychiatry and director of the division on Addictions at Harvard Medical School, has studied both drug addicts and compulsive gamblers and notes, "We don't talk about addictive dice."

The old-fashioned concept of "addictive personality" has also collapsed. Today, the word addiction does not appear in standard psychiatric nomenclature. Rather, addiction seems to characterize neither a substance nor a personality type, but a form of relationship. Clinicians now speak of addiction to gambling, sex, aerobic exercise, work, day-trading, eating carrots, shopping, even excessive drinking of water. The term is vastly popular: people laughingly refer to themselves as "TV addicts" or "chocoholics." But Bertha Madras, professor of psychobiology in the department of psychiatry, objects: "The word is grossly overused. Addiction is a neurobiological disorder. Clinically, it's a very clear syndrome. If you look at all drug addictions from tobacco to heroin, there's only one clear statement that applies to all of them: uncontrolled use despite negative consequences."

Classically, drug addiction means tolerance (the need for increasing doses to obtain the same effect) and withdrawal (psychic and/or bodily ailments, sometimes lethal, that accompany sudden cessation of use). Both signs indicate neuroadaptation: repeated intake of a drug alters the brain in profound ways that both stimulate more drug use and render choice more difficult. Yet "pathological gamblers show physiological signs of tolerance and withdrawal, just like narcotic addicts," says Shaffer. "And hospital patients medicated for pain can develop tolerance and withdrawal, but don't show signs of addiction, such as drug-seeking behavior. We can't be sure if it's the drugs or the behaviors that are changing the brain chemistry." The emerging consensus, he says, is that both factors are at work.

Such riddles suggest why addiction research spans many disciplines, from neurobiology to social policy. The division on Addictions, founded in 1993, is one of nine such divisions focusing on areas that do not fit well into the Medical School's regular academic departments. Addiction is as old as human history, and remains one of the costliest and most intractable of all social problems. It confounds rationality: millions of addicts persist in their blatantly self-destructive behavior despite the loss of family, friends, jobs, money, and health. (Some studies have shown the death rate for untreated heroin addicts to be as high as 7 percent annually.) To use the analogy of professor of psychiatry George Vaillant '55, M.D. '59, the addict can resemble a cigar smoker in an elevator, oblivious to something that is obvious to everyone else. Research is now beginning to show what makes addicted brains, bodies, minds, and spirits so different.

The Addicted Brain

Most animals will gladly take any drug that humans use, excepting marijuana and certain psychedelics like LSD. "The addictive potential of drugs appears to be reflected in many mammalian species," says Madras, who studies the effects of cocaine on macaque monkey brains at the Harvard-affiliated New England Regional Primate Research Center. Pigeons, rats, and monkeys will all press levers to access cocaine or opiates, suggesting that addiction taps into widely shared neural pathways. This makes sense because psychoactive drugs generally exert their most important effects on older brain structures, those areas sometimes called the "reptile brain." In fact, some current research suggests that these pathways may have evolved even before reptiles appeared.

Biologist Tristan Darland, a postdoctoral fellow in the laboratory of Cabot professor of the natural sciences John Dowling, is currently running experiments on zebra fish--common residents of home aquariums whose brains have enough cortex to let them learn some behaviors, though far less effectively than mammals. Darland begins by having the fish swim for 30 minutes in a tank that has a wick saturated with cocaine at one end. The next day, he returns the zebra fish to the same tank for two minutes, but with no cocaine on the wick. Nonetheless, the fish usually prefer the end of the tank where they encountered the cocaine--and spend 70 to 80 percent of their time there. Even during their initial "conditioning" swim, the fish gravitate toward the cocaine end, but "prior exposure to cocaine evokes a stronger response. Evidently, they see it as pleasurable," Darland explains. Results from more than 100 fish show that at least 85 percent prefer the side they associate with cocaine.

The zebra fish may be undergoing some systematic changes in brain chemistry. Psychoactive drugs alter patterns of communication within the brain, via neurotransmitters (molecules that convey messages in the nervous system). "The chemical structure of drugs happens to resemble the chemical structure of the brain's own neurotransmitters," Madras explains. "I call them 'the great brain impostors.' They target the same communication systems as the brain's natural messages. But the complex communication and control systems in the brain are geared for the natural message, not the impostor. As a result, the brain adapts to, and compensates for, the abnormal signals generated by the drug. Here is where the addictive process begins. Brain adaptation is central to addiction. In the case of drugs that produce physical or psychological withdrawal, there is a compulsion to restore the brain to the status it had when it was awash with drugs."

A central enzymatic pathway in the midbrains of vertebrates produces an important neurotransmitter called dopamine, which occurs at high concentrations in a part of the brain called the nucleus accumbens. "All addictive drugs seem to increase dopamine release in the nucleus accumbens," says Darland. "It's been hypothesized that the dopamine system in potential addicts is somehow different. Addictive drugs cause a big increase in dopamine release, with different mechanisms involved, depending on the drug. Cocaine seems to block dopamine uptake, keeping it in circulation. Morphine apparently shuts off inhibitory neurons in the ventral tegmental area of the brain, where the dopamine pathway begins.

"Dopamine release is associated with eating, with sex--with many pleasurable states. It's a 'feel-good' molecule," Darland continues. "These pathways didn't evolve for the sake of doing drugs. They are there to keep humans procreating and eating."

Draper professor of psychiatry Joseph Coyle says, "It looks like there are some final common pathways through which addictive drugs work, in the nucleus accumbens and the amygdala, and which involve the neurotransmitters dopamine and enkephalin. This leads to some interesting things. It's rare to see an individual who uses only cocaine or heroin; these brain systems are involved in other addictive behaviors. Howard Shaffer, for example, has studied gamblers and finds that you rarely see a person who is just a pathological gambler--usually it's a gambler who also smokes and drinks too much, or may have a drug habit. Regarding treatment, it also might explain why Naltrexone, an opiate receptor antagonist, has been shown to be effective in reducing relapse among alcoholics."

To better define the sites in the brain where these molecular firestorms occur, instructor in psychiatry Hans Breiter is using magnetic resonance imaging (MRI) to view patterns of neuronal activity in the brains of cocaine addicts. He has begun to identify the brain centers that become active during euphoria (when addicts are high on the drug) and to distinguish them from those that fire when the user experiences craving (strong desire for cocaine). Some preliminary data suggest that the same brain centers may show parallel activity in compulsive gamblers, possibly indicating--as Shaffer has suggested--that addictive pathways in the brain can exist independent of drug input.

But the neuroscience of addiction is far from settled. Madras, for example, dissents from the current model that sees drug effects converging on the dopamine system. She cites the different effects of drugs, their different targets in the brain, the inability of one drug to substitute for another (cocaine will not relieve morphine withdrawal, nor is methadone an effective treatment for cocaine addiction), and the fact that adverse circumstances such as fear or electric shock also prompt the release of dopamine. "Dopamine may not be the brain's euphoriant," she says, "but the brain's adrenaline."

"In a sense, these drugs are stressors," explains Gene Heyman, Ph.D. '77, lecturer on psychology in the department of psychiatry. "Besides their hedonic properties, they shock the system when taken in these amounts. Rats on opiates, stimulants, or alcohol reliably show increases in corticosterone, a stress-related hormone. Clinical evidence shows parallel findings with heroin addicts. This suggests that opiates and perhaps other addictive drugs have a short-term effect of easing stress, but a long-term effect of increasing susceptibility to stress." Jack Mendelson, professor of psychiatry, draws a parallel between the hormonal responses caused by cocaine and those associated with thrilling or frightening pursuits like hang-gliding and bungee-cord jumping: "Cocaine triggers major stress hormones like epinephrine [adrenaline], norepinephrine, adrenocorticotropic hormone [ACTH], and serotonin. These are the same ones that surge up during bungee jumping."

Even if these chemical responses are common to all drugs of abuse, they are not uniform in degree among all individuals. Darland and Dowling are now attempting to breed zebra fish with increased cocaine sensitivity, which may help identify genetic predispositions to drug addiction. In humans, several lines of research suggest such genetic sensitivities. In the 1960s and 1970s, Scandinavian researchers followed up families of alcoholics to find that the prevalence of alcoholism was four times greater in individuals from alcoholic backgrounds. The researchers clearly demonstrated that genetic variables, rather than family behavior, were at work. More recent research has indicated that hospital patients of Asian background need relatively higher doses of opiates to relieve pain, suggesting that they may metabolize opioids more rapidly, and hence are perhaps at greater risk for opiate addiction. Differences in gene pools may influence cultural practices. "In France and Italy, children drink wine with meals at early ages, whereas in Ireland they are discouraged from drinking before age 21," says Barry Kosofsky, associate professor of neurology. "Some cultures may fear alcohol more, perhaps due to genetic predispostions for alcoholism."

Not only genes but prenatal environments may incline an organism toward drug sensitivity. Neurotransmitters "sculpt" the brain by controlling its early development. Kosofsky investigates the effect of drugs on the developing brain by studying children born to women addicted to crack cocaine. "The intrauterine environment is critical in terms of brain development," he says. "Alcohol, nicotine, or cocaine in a pregnant woman can all have great impact on the fetal brain." Kosofsky hopes to learn whether exposure to cocaine in the womb will increase the likelihood of someone becoming addicted to cocaine as an adult. "This," he says, "would raise the possibility that infants exposed to drugs before birth are more likely to beget others who are also exposed to drugs in the womb"--creating a kind of nongenetic "inheritance" of drug abuse.

Early experiences with drugs, whether in the womb or as an adult, have ineradicable effects. Drug users often describe a wish to recapture the bliss of their first high. But this goal proves elusive because once the brain has neuroadapted to drugs, it is physiologically and structurally changed. The director of the National Institute on Drug Abuse and many others argue that voluntary drug consumption alters the brain in ways that lead to involuntary drug consumption. The question of whether drug habits are voluntary or not leads us to ask how people get over their addictions, and raises some of the moral issues surrounding compulsive behavior.

The Ambivalent Addict

Even if we all have the neural wiring to become addicts, only a few of us actually do so. Bertha Madras estimates that 5 to 10 percent of those who experiment with a drug become compulsive users or abusers. (Cigarettes are the exception: data show habituation rates ranging from 10 to 70 percent.) What distinguishes that 5 or 10 percent who get hooked? Some studies indicate that children who have "personality disorders," earn poor grades, or have been sexually abused are at higher risk for drug abuse. Yet Howard Shaffer says, "I don't think there is an addictive personality, nor does the scientific literature support the concept." George Vaillant states flatly, "The 'addictive personality' probably doesn't exist," noting that "addictions tend to distort personality. You can't predict this--alcoholics look like everyone else until they become alcoholics, much as cigarette smokers do." Some theorists postulate that "novelty-seeking" or "sensation-seeking" personalities are prone to drug abuse, but Vaillant observes, "They are seeking the high, not addiction." Similarly, he adds, "People with miserable childhoods may look like addictive personalities, but they are seeking pain relief, not addiction."

Clinical professor of psychiatry Edward Khantzian has written extensively about addiction as a form of self-medication. "The nature of suffering is at times overwhelmingly intense--or elusive, vague, and beyond people's control," he says. "The drug user suddenly feels some control over what had felt uncontrollable. I do think there's a specificity involved. People with a lot of rage and irritability find the opiates very soothing. Stimulants may appeal to those individuals who are dysphoric, de-energized, or depressed. Some say that drugs hijack the reward centers of the brain, but I believe that what is hijacked is the emotional brain."

According to clinical instructor in psychiatry Stephen Bergman '66, M.D. '73, "All addictions feed the ego, the self. The ego is insatiable. If you are into your ego, you can never

get enough--not enough drugs, sex, money, alcohol, relationships, not enough anything. Enough, that is, to feel 'not bad.' Many of these people don't like it if they have to be in a room by themselves for a while. In 12-step programs, those who recover do it by asking for help. The connection has to change, from the self to a we. The only thing that helps is getting beyond yourself."

Shaffer's studies of compulsive gamblers may support Bergman's notion. "Gambling at slot machines seems to have more addictive potential than table games like cards, dice, or roulette," he says. "There's a lot of social ritual at the gaming tables, but fewer social controls available at the slot machines. Similarly with compulsive shopping: if you don't shop with other people, there are fewer social controls. The excessive shopper shops alone." Other isolated addicts come readily to mind--the solitary drinker, the solo food binges of the bulimic, the workaholic executive alone in the penthouse office at midnight. Connections with other people interrupt the addictive cycle; they redirect attention away from the self-reinforcing feedback of the addictive activity that can quickly escalate to excessive levels.

Addiction is not all pharmacology, neurotransmitters, and intrapsychic states; the social settings of drug consumption have powerful effects. They can influence basic brain chemistry--which is one reason Gene Heyman rejects the notion that "addictive behavior is insensitive to persuasion, that there's an irresistible urge to take the drug." Heyman agrees that drugs alter the brain, but disputes the idea that they change the brain in ways that make choice impossible--he does not believe, in other words, that neuroadaptation makes drug use involuntary. Exhibit A, he says, is 50 million ex-smokers who have voluntarily ended their intake of nicotine.

Many external factors can influence the choice to use drugs. Culture matters: drug intake is far less prevalent in places where religion plays a major role--Israel, Islamic nations, Mormon communities. Laws, too, have an effect: during Prohibition, the incidence of cirrhosis of the liver, probably the best epidemiological index of alcoholism, plummeted. Social class predicts some use patterns: differential quitting rates for tobacco use have strengthened the correlation between smoking and lower levels of education. Then there are social norms: the precipitous drop in the social desirability of smoking has supported quitters. And money talks: in experimental situations, social psychologists have offered addicts cash rewards--say, $50--for not smoking, drinking, or doing cocaine. "There are powerful positive results--addiction will stop in the short run," Heyman says. "If drug use really is involuntary, it doesn't matter whether it's short- or long-term. You can't pay someone not to have dandruff, not to be depressed, not to hallucinate."

One reason people believe drug use is involuntary is that recovery rates for addicts treated at clinics are quite bad. Within one year of treatment, relapse rates of 67 to 90 percent are common for alcohol, opiate, cocaine, and tobacco users. "But most of the people who become addicted to drugs don't go to clinics," says Heyman. "Actually, only 30 to 40 percent go to clinics. Yet this clinic population has greatly influenced our vision and concept of addiction."

It turns out that addicts who don't go to clinics have much higher recovery rates. Heyman cites two large community surveys, one from 1980 to 1984 and another from 1990 to 1992, that interviewed a cross-section of the general population and reliably identified individuals who met recognized criteria for drug dependence. "Most of those who had been addicts were no longer addicted," says Heyman. "Fifty-nine to 76 percent had been in remission for the previous year or longer. Smaller scale ethnographic studies of general populations also report high remission rates for addicts, and these results strongly suggest that for most, remission is permanent."

Another fascinating finding is the well-known 1975 study, conducted by Lee Robins of Washington University Medical School in St. Louis, of U.S. servicemen who became heroin addicts in Vietnam. Thousands of men got hooked, and 80 percent of those who initially took heroin more than three times became regular users, taking the drug at least once per week. Those who stayed in Vietnam longer often moved on from sniffing to injection. Yet three years after these veterans returned to the States, more than 90 percent had quit. (This contrasts sharply with relapse rates that often exceed 90 percent for heroin addicts in treatment.) The veterans' success in kicking their habits wasn't simply due to decreased drug availability: half of the Vietnam addicts used heroin at least once after they returned home. But "what's really interesting is what happened to the 6 percent of the Vietnam addicts who went into treatment," Heyman says. "For this group, the relapse rate was about 70 percent! In other words, Vietnam vets who go into treatment look pretty much like other Americans who go into treatment."

The question of how addicts who present themselves for treatment differ from other addicts is not well studied, Heyman says. "What has emerged is that treatment seekers are much more likely to have other psychiatric disorders--depression, schizophrenia, affective disorders, or conduct disorders like sociopathy. These psychiatric syndromes may undermine the mechanisms and processes that assist in recovery." Consider that 30 years ago, there was no apparent correlation between smoking and depression. Today, there is one, Heyman explains--"linked to a selective quit rate as a function of psychiatric disorders."

He suggests we "think of addiction not as compulsion, but ambivalence. Alcoholics often recognize that the alcohol is doing them in, yet they keep right on drinking. These data lead people to conclude that the drinking is involuntary, out of control, since continuing to drink doesn't make sense. Another view is that people are inconsistent and contradictory, and predictably so--it's a slightly starker view of human nature. When talking to his therapist, the guy says he wants to stop. But that's looking at his life as a whole--after all, it's hard to be a heavy drinker, or a heroin or cocaine user, without having tons of problems. Yet at a given instant, when the alcoholic is looking at a glass of wine, the frame of reference is, 'What do I want to do right now?' The situations in which they say they want to stop are different from those in which the drug or substance is presented.

"Humans are inconsistent. Their preferences change with the setting," Heyman continues. "To end an addiction, people need an alternative to drug use, something better to do. The clinic population, people with other psychiatric disorders, have a much harder time changing their situations to ones where drug use is less preferred. If you see it as preference rather than compulsion, you can account for all the data."

Lethal Liquids, and Some Ways Out

One of the foremost scholars doing longitudinal research (studies that follow up subjects over many years) in psychiatry is George Vaillant, who directs the Study of Adult Development, based at Harvard Medical School. Vaillant's 1983 book The Natural History of Alcoholism, a milestone in the field, analyzes drinking patterns in two populations of World War II era men: a group from Harvard and another group from working-class, inner-city Boston. Generations of researchers have followed these men as they have aged. "Alcohol is more often the horse and less often the cart than any other social ill I can think of," Vaillant says. "I find it terribly interesting that people are much more concerned with every other form of addiction than they are with alcoholism, which--as a problem to humanity--is as big as all other addictions combined. It costs as much as all infectious and pulmonary disease. And it has more impact on others. Drug addicts harm themselves, but that's small beer compared with 25,000 alcohol-related traffic fatalities per year."

Even though cigarette smoking is the direct cause of 400,000 American deaths annually, while alcohol directly causes only 100,000 deaths, "alcoholism is a major reason that people don't stop smoking," says Vaillant. "Those who keep on smoking after age 50 tend to be alcoholics." In hospitals, alcoholics cost six times as much as other patients. Half of all people who show up in emergency rooms with severe multiple fractures are alcoholics. "But the emergency rooms treating multiple fractures ignore blood alcohol levels," Vaillant says. "The causal link isn't made."

"No other drug of addiction impairs one's aversion to punishment the way alcohol does," he continues. "Yes, compulsive gambling impairs your aversion to being poor, and heroin use impairs your aversion to being arrested. But alcoholism goes across the board. When drinking, people are much more likely to engage in all kinds of dangerous, life-threatening behavior--wife beating, child abuse, unprotected sex with strangers, smoking, drunk driving. You can be five foot two and willing to take on anyone in the bar."

Such imperviousness to punishment also tends to forestall recovery. In any case, "the best intentions in the world don't help you with addiction," says Vaillant. "Will power is not a prognostic factor in recovery. Addiction resides in what is often referred to as our reptilian brain, and--well, alligators don't come when they're called. What does matter, over the short term, is hitting bottom and having something to lose--the employed, married, upper-middle-class drinker does better at the Betty Ford Center than the homeless alcoholic. But over the long term, inner-city men recovered twice as often from alcoholism as the Harvard men did. The difference has nothing to do with treatment, intelligence, self-care, or having something to lose. It does have to do with hitting bottom. Someone sleeping under the elevated train tracks can at some point recognize that he's an alcoholic, but the guy getting stewed every night at a private club may not."

How, then, to change addictive behavior? We may start with the new understanding of the problem--that the roots of addiction lie in both brain chemistry and behavior. "It's a wrong-headed bias to think that these are either psychological or biological problems," says Gene Heyman. Both voluntary and involuntary behaviors have biological bases. Successful treatments for addiction need to address both realms at once--say, combining a drug like Naltrexone, which influences neurotransmitters, with a healthier alternative to the drinking, drugging, or gambling life.

Vaillant's studies have convinced him that there are four factors, common to all addictions, that predict success in breaking a habit.

Find a competing behavior that is less disruptive. "Say a drinker goes to Alcoholics Anonymous, sobers up, and starts drinking a lot of coffee and smoking cigarettes," he says. "Then he quits smoking, by chewing the erasers off pencils and overeating, so he gains weight. Now his problem is obesity, so he winds up hanging around Overeaters Anonymous and drinking a gallon of water a day. It's what teachers call 'redirecting.' You may not be able to stop two four-year-olds from fighting, but you can say, 'Let's go get ice cream cones.'"

An external superego. "If I tell you you'll get liver disease if you keep on drinking, you could care less," Vaillant says. "But if I say that as an M.D. I'm going to do random checks on your urine, you may pay attention. Or if, when you drink Jack Daniels, it burns your stomach. Methadone is an external superego, since it blocks the effect of heroin. Someone who engaged in compulsive sex might not care if it hurt their spouse's feelings, but if there were an electric bracelet that could transmit a shock at crucial moments, that might make a difference."

"I get no kick from cocaine." "It's fascinating that heroin addicts get better when they fall in love with someone new," Vaillant says. "Our brains are wired for falling in love, because that's good for nature--but you can short-circuit that pathway with morphine, nicotine, caffeine. Love gets the whole brain involved. Romantic attachment not only competes with the addiction, but takes place in a nonaddictive way."

Spiritus contra spiritum. "Charismatic religions offer a conversion experience, as described by William James and C.G. Jung. Suddenly you find your higher power, and booze is no longer important," Vaillant explains. "There is also the protective wall of a human community--something that AA, for example, provides. It's important to find a new social group, since you owe money to all your old ones. Religion offers an oceanic high--the sense that a higher power loves you. To the addict, heroin, cocaine, and booze are like mother's milk. Religion is, too."