How to Get Monkey Off Your Brain

Society has been fighting the plague of addictions without knowing how drugs, cigarettes, and alcohol hot-wire the brain's pleasure response. Now researchers may be closing in on a magic bullet.

Photograph by Ashkan Sahihi

IT STARTS RIGHT HERE The people pictured in this feature are not addicts. They were, however, photographed for a New York art exhibit by Ashkan Sahihi after they took various habit-forming substances. Sahihi wanted to strip both the heroin-chic glamour and the street-crime stereotyping from depictions of drug use and force the viewer to directly confront images of people under the influence. Many of the 11 subjects in the series were experiencing the drugs for the first time. (See the link in the right column to view more of the series.) Ecstasy (above) is a man-made "club drug" with stimulant and hallucinogenic properties; its use is growing across the country, especially among teens. Evidence suggests it causes permanent brain damage.Photograph by Ashkan Sahihi

Jeff was your everyday successful guy. He owned a thriving clothing business, had plenty of friends, and seemed to be living the sweet life in sunny Florida. Except for one thing: He was a heroin addict. It began eight years ago at a party with a snort of just one line of the drug. Within weeks, Jeff, then 30, was a frequent user and enjoying it. So much so that before long snorting didn't deliver a powerful enough high to satisfy his cravings; he moved on to smoking heroin. Next, concerned that too much of the precious drug was being wasted -"going up in smoke," as Jeff puts it-he started shooting up, regularly.

Heroin was an expensive habit in every way. At first, Jeff tried hiding the addiction from his girlfriend. But she found out and left him. He paid less and less attention to his business and eventually went bankrupt. Finally, with no friends and no money, he moved in with his sister. He felt trapped: "I was scared to quit because I knew how painful withdrawal would be."

Desperate, Jeff turned to an illegal, one-dose anti-addiction drug called Ibogaine-a combination withdrawal treatment and hallucinogen. His 30-hour Ibogaine "trip" was a gut-wrenching vision that haunts him still. As he descended deeper and deeper into himself, he realized that on heroin he'd taken on a dual personality-the nice guy whom people liked and the selfish person who alienated friends and stopped at almost nothing to get money to feed his habit. Ibogaine took Jeff back to early memories. "It made me relive painful things from my childhood and beyond," he says. "But as I came out of it, I saw myself change from two people into one." Since then, Jeff hasn't had the urge for heroin, though he's still not over the mental trauma that Ibogaine left behind.

Jeff's decision to put the chemical equivalent of a howitzer to his head to rid himself of his heroin jones speaks volumes about the sorry state of the medical establishment's approach to addiction. A handful of medicines help stem substance abuse, but their approaches border on Draconian. Antabuse, an anti-drinking pill, blocks the enzyme that breaks down alcohol in the body. For anyone taking the drug, the tiniest sip of liquor, wine, beer, or even mouthwash produces a rapid and extremely toxic buildup of alcoholic byproducts in the bloodstream. That's followed by any number of unpleasant symptoms, including nausea, throbbing headaches, respiratory difficulty, vomiting, chest pain, vertigo, and confusion.

Zyban, a quit-smoking drug that's a reformulation of the antidepressant Wellbutrin, is an indirect solution at best. The idea is that smokers suffer from underlying depression and treating it will quell the cigarette craving. Unfortunately, Zyban's potential side effects include dry mouth, dizziness, lethargy, and diminished sex drive. Perhaps the best known anti-addiction drug is methadone, used to treat heroin addicts. While a godsend for some, methadone is more habit-forming than any opiate and is also not without its discomforting side effects: low blood pressure, nausea, and insomnia.

Meanwhile, naltrexone, a treatment for alcoholism and opiate abuse, blocks drug-induced highs by shutting down sites in the brain that make people feel good-banishing not only the addiction but much of the reason for living as well. No wonder today's anti-addiction drugs are unpopular. "If we take away pleasure, no one's going to take the treatment," says Stephen Dewey, senior scientist at the Department of Energy's Brookhaven National Laboratory in Upton, New York.

Promising new research, however, may help put these primitive drugs behind us. In the past decade, investigators have learned a remarkable amount about the brain chemistry that makes mood-altering drugs so pleasant-and, thus, so difficult to quit-as well as the precise location of addiction in the brain. Once these neuro-mysteries have been fully puzzled out, researchers hope to design targeted substance abuse treatments that act more like cruise missiles than cannonballs, quelling cravings without deadening the pleasure of everyday life. Their efforts stand to improve the lives of more than 65 million Americans hooked on everything from cigarettes to crack. "Addiction will always be with us," says Frank Vocci, director of the Division of Treatment Research and Development at the National Institute on Drug Abuse, "but these new drugs are our first real opportunity to minimize it."

Brookhaven is the epicenter of this ambitious project. There are many other anti-addiction research programs-60 different compounds are being developed to treat cocaine abuse alone-at schools such as Johns Hopkins, Emory, Harvard, and the University of Pennsylvania, and at agencies like the National Institute on Drug Abuse (NIDA). But backed by an annual $5 million budget, a team of a dozen scientists at Brookhaven has launched the most elaborate effort yet to map the mechanics of the addicted brain with advanced imaging technology. Their main focus: a chemical called dopamine, the prime mover in the human pleasure pathway.

Dopamine is one of the brain's many neurotransmitters-chemicals that carry messages between brain cells. These chemicals travel through the brain by hopping from one cell to the next. After being secreted by one brain cell, a neurotransmitter must bind to a specialized receptor on the next cell in order to continue its journey. Dopamine's main job is to ferry information related to elation and pain. The joy we get from a meal, a promotion, a winning poker hand, or sex-anything that brings us happiness-is conveyed in part by dopamine. But only recently have scientists literally visualized dopamine's dark side: specifically, the role it plays as the brain's principal architect of drug addiction.

Under normal circumstances the brain produces dopamine at a relatively constant rate, and only a portion of its dopamine receptors are occupied at any given time. But under the influence of a mood-altering drug like cocaine, the brain releases an avalanche of pleasure-inducing dopamine. With so much of the chemical available, practically all of the brain's dopamine receptors become activated at once.

The result is euphoria for the user, but the brain is overwhelmed and tries to dampen the effect by switching off some of its dopamine receptors. Consequently, when the drug wears off, the user is equipped with fewer functioning receptors, so his mood will be lower than it was before he took the drug. Thus begins the negative feedback loop that leads to addiction. As dopamine receptors progressively shut down, drug users must ingest ever larger quantities in order to get high, and will feel increasingly unhappy when the drug leaves their system. Eventually, cocaine effectively becomes the puppeteer of much of the dopamine levels in the brain. Users may need to take drugs simply to feel a normal amount of well-being. Some recent research indicates, however, that when addicts stop doing drugs, the disabled dopamine receptors in their brains can repair themselves.

Through dissections of animal brains, scientists had shown that the dopamine pathway responds similarly to all habit-forming drugs. But in 1997 Nora Volkow, Brookhaven's associate laboratory director for life sciences, harnessed an emerging technology, positron emission tomography (PET), and became the first scientist to demonstrate the addiction mechanism in living people. PET scanning is a noninvasive method of observing the brain in real time. Volkow employed it and oral interviews to study 17 long-term cocaine users, and found that as the number of engaged dopamine receptors in the brain increased, the subjective experience of feeling high did too. "Volkow is very good at looking at systems we're pinpointing and, with imaging, answering questions we haven't been able to answer," says Roy Wise of NIDA.

Volkow's colleague, Stephen Dewey, made critical use of the results of this study. Aware that an epilepsy pill called Vigabatrin works in part by lowering the amount of dopamine in the brain, Dewey wondered whether the medication might also be helpful for cocaine addiction. He injected Vigabatrin into half of a group of baboons, then studied the brain scans of the entire group both before and after they ingested cocaine. In the Vigabatrin-primed baboons, the cocaine did not increase the amount of dopamine activity in the brain. The animals that had not been given the epilepsy drug, meanwhile, showed a marked increase in the level of dopamine attached to receptors. In people, of course, Dewey hopes Vigabatrin will do more than keep dopamine activity from rising with cocaine use; he hopes Vigabatrin could banish the craving for cocaine altogether. The drug's manufacturer is in negotiations to launch a study to test Vigabatrin with addicts.

An interesting result of Dewey's studies is what he unexpectedly revealed about the so-called cueing response-the desire to drink or take drugs that's sparked by familiar sights and sounds, such as the tinkling of ice in a scotch glass or the scratch of a razor against a mirror. Scientists traditionally believed that these responses were fundamentally behavioral. Recovering addicts were counseled not to rejoin friends in the old neighborhoods where their drug habits began, or risk relapsing.

But Dewey shed new light on cueing in a study of cocaine-addicted rats that were given Vigabatrin. Prior to taking the epilepsy drug, the rats habitually scurried over to the part of their cage where the cocaine was located. With Vigabatrin in their systems, the rats ran around freely and mostly ignored that spot.

"This research has fundamentally changed the traditional view that physical function and brain function are separate," says Alan Leshner, head of the American Association for the Advancement of Science. "The mind-body split is dead and now we know that all addictions are diseases of the brain."

Brookhaven researchers are certain that, though counseling and behavioral adjustments will always play a role in treating addiction, biochemistry-changing medications are the key. "Alter a protein here or there," says Volkow, "and you turn a philanderer into a monogamist."

Volkow believes some individuals may have a predisposition to addiction-a physiological one, caused by an inherent shortage of dopamine receptors. They may be born with fewer receptors, or their brains may have lost receptors over time due to negative life experiences. Such people would be victims of a double whammy: a shortage of dopamine receptors makes them prone to addiction, and then the habit disables even more receptors. In a study completed late last year, PET scans showed that 15 recovering speed addicts had 10 percent to 16 percent fewer dopamine receptors than did 20 people who never used drugs. Similar results have been obtained from studies of alcoholics and cocaine and heroin users. Cause and effect are still unclear, but Volkow believes flawed physiology is partly to blame. "A low level of receptors will drive them to where nothing else but the drug matters," Volkow says.

Brookhaven research has also recently revealed that the withered dopamine systems of addicts are consistently associated with low metabolic activity in the orbitofrontal cortex, the part of the brain that makes it possible to do several tasks at once. The full implications of this finding are unclear, but it may mean that the orbitofrontal cortex is the command center of addiction in the brain. If that's the case, the Brookhaven researchers will have unearthed the location of what some researchers call the "receptors in a haystack"-the few dopamine receptors among the tens of thousands in the brain at which a targeted addiction control drug should be aimed.

There's a certain logic to substance abuse being lodged in the orbitofrontal cortex. This part of the brain also directs obsessive and compulsive activities-and few people are more obsessive than drug addicts. Volkow's next phase of investigation will be to determine whether drug addiction and obsessive-compulsive disorders-the uncontrollable urge, for instance, to pull out each strand of hair or collect every scrap of paper-are nothing more than distortions of healthy survival instincts, distortions that are caused by dopamine-system malfunctions. "New mothers are obsessed with their babies, but that's a positive survival instinct," Volkow says. "Uncontrolled gambling, eating, or substance abuse have the same kind of drive, but they're destructive."

Still, until researchers concoct just the right formula to treat drug addiction safely, without eliminating the ability to feel pleasure and without nasty side effects, addicts will turn to other options. In the early 1960s, Howard Lotsof, a heroin addict looking for another high, discovered Ibogaine (the drug that Jeff, the Florida entrepreneur, took), which is derived from a shrub in western Africa. When Lotsof's heroin craving subsided after one dose, he told fellow users. A decade ago University of Miami neuroscientist Deborah Mash became one of the first serious researchers to champion it.

Little is known about how Ibogaine works, but it appears to stifle the creation of dopamine and cleanse the body of opiates in a frisson of frantic brain cell activity. Mash is the only scientist authorized by the U.S. government to distribute Ibogaine, but she hasn't been able to raise enough money for clinical trials. To demonstrate that the treatment works when administered by a professional and accompanied by psychotherapy, Mash is treating addicts in a private clinic in the West Indies. "I had one patient-a real party boy," she says. "While on Ibogaine, he looked down and saw that he was dressed in black and surrounded by red satin. He realized he was in a casket and this was his funeral and though he tried to explain his life to the funeral visitors, he couldn't speak." She says he stopped taking heroin immediately afterward.

Like virtually all drug treatments today, though, Ibogaine is terribly flawed. At least two people have died after taking it without professional supervision. Which is the reason for the frenetic pace of research at places like Brookhaven. These scientists are untangling complex biochemistry to achieve the simplest of goals. They want to stop people from having to take trips nearly out of this world just to kick a habit that is keeping them from living normal lives on Earth.

American Addicts

From cigs to booze to drugs, how many?

Tobacco, 65.5 million

Caffeine, 57.3 million (est.)

Alcohol, 15.4 million

Cocaine, 3.3 million

Heroin, 980,000

Speed, 356,000

SOURCES: 2000 National Household Survey on Drug Abuse (tobacco); Canadian Centre for Addiction and Mental Health (caffeine); National Institutes of Health (alcohol); Office of National Drug Control Policy (cocaine, heroin, and speed).

Estimated U.S. Deaths, Direct and Indirect

It's hard to measure the human toll of addiction, but annual fatalities are a potent indicator.

Tobacco, 430,000
Alcohol, 110,000
Cocaine, 4,864
Heroin, 4,820
Tranquilizers, 2,038
Antidepressants, 1,745

SOURCES: Centers for Disease Control and Prevention (tobacco); National Institutes of Health (alcohol); U.S. Dept. of Health and Human Services (cocaine, heroin, tranquilizers, and antidepressants). Drugs in the HHS survey were cited as contributing factors, not necessarily direct causes of death.

The Raw Costs of Addiction

The annual financial burden includes the cost of health care, law enforcement, treatment, and lost productivity.

Alcohol, $184 billion
Illegal drugs, $143 billion
Tobacco, $138 billion

SOURCES: National Institute of Alcohol Abuse and Alcoholism (alcohol); Office of National Drug Control Policy (illegal drugs); National Institute on Drug Abuse (tobacco).