What Addicts Need

Addictive drugs like cocaine and heroin flood the brain with the neurotransmitter dopamine, a chemical that induces a sensation of pleasure and trains the subconscious to remember everything that preceded that sensation. Together with alcohol, nicotine and amphetamines, these make up the five drugs generally considered the hardest to give up; right now, some 22 million Americans are hooked on at least one of these substances. While each causes a distinct form of intoxication and a different range of side effects and health problems, all five hijack the same pathway, deep within the brain. It's the pathway that conditions us to eat, have sex, form emotional attachments and carry out the other activities essential to our species' survival. But the agents of addiction are far more powerful than any of those natural highs. Just one dose of cocaine, for example, can release two to 10 times the amount of dopamine produced by your favorite meal, person, song or sight. Take a drug like that consistently enough, and your brain and body will come to depend on it—first for euphoria, then for normalcy. Eventually, the pursuit and consumption of drugs will become as instinctive as the pursuit and consumption of food—only far more urgent and destructive.

People vary in their innate sensitivity to dopamine, which may partly explain why addiction runs in families. A gene that codes for a dopamine receptor designated D2 (one of at least five dopamine receptors that have been identified so far) comes in several different versions, and each produces a different concentration of receptors. People with fewer receptors may receive less stimulation from their naturally occurring dopamine, and therefore be more inclined to seek an artificial high from drugs. Unfortunately, tinkering directly with the dopamine system to control addiction hasn't worked out very well. Dopamine is crucial to voluntary movement and interfering with it can cause symptoms resembling Parkinson's.

So far, other neurotransmitters that play a role in addiction have been easier to tackle. Gamma-aminobutyric acid, or GABA, exerts an inhibitory effect on neurons, telling the body to stop instead of go. Addicts' brains are deficient in GABA, so researchers are investigating a drug called Vigabatrin, which stimulates its production. In December, the pill cleared its first double-blind, placebo-controlled trial; 30 percent of patients who took Vigabatrin stayed off cocaine during the nine-week study, compared with just 5 percent in a control group. "It's the best efficacy signal that we've seen in any clinical trial for cocaine treatment," says Frank Vocci, director of the pharmacotherapies division at NIDA. "And it's worked on what many have written off as an intractable population—hard-core, long-term cocaine addicts." A drug called Campral, which is already on the market as a treatment for alcoholism, works on yet another brain chemical, glutamate. While the early stages of addiction are driven by pleasure-seeking—hence the importance of dopamine—the motive eventually shifts to avoiding the pain of withdrawal; at that point, drug-seeking behavior is fueled by glutamate. By suppressing this neurotransmitter, Campral has the potential to reduce cravings and help prevent relapses during recovery. Researchers think these drugs hold enormous promise. "The treatment of depression was revolutionized by medications that manipulate serotonin concentrations," says Alan Leshner, former head of NIDA, referring to Prozac and its cousins. "Drugs that act on GABA and glutamate could do the same thing for addiction."

If you're trying to quit drinking, you are advised not to hang out in bars, and if you're trying to kick cigarettes, you probably should avoid French movies from the 1950s. One reason addictions are so hard to break is that the pleasure of taking the drug becomes associated with all the situations and activities around it, which then become cues for a relapse. Researchers at the University of Pennsylvania found that showing cocaine addicts pictures of drugs or crack pipes for just 33 milliseconds—below the threshold of conscious awareness—was enough to trigger cravings. Beverly Dyess, 58, learned this last year when, after six months of sobriety—her longest stretch in 15 years—she went into a supermarket and discovered that her favorite brand of Scotch was on sale. She was seeing a therapist daily, but "as soon as I saw the label, everything else went out the window," she says. For the next two months she rode a roller coaster of frenzied drinking and crushing guilt. Some days she would get up early enough to get drunk and then sober up in time for her evening counseling session. Other days she would run to the store, buy a bottle of whisky and then, her resolve mysteriously stiffened, pour it down the sink when she got home. By suppressing the surge of glutamate that directed her to the Scotch aisle in the first place, Campral helped ease the pain of withdrawal and allowed the counseling and behavioral therapy to work. "I still do the talk therapy," she says. "But Camparal really helps, because everything is still a cue for drinking."

Of course, you can't protect yourself against every encounter with a bottle, or, in some environments, heroin, cocaine or amphetamines. So researchers are working on ways to break the association that was Dyess's downfall. A drug called D-cycloserine, or DCS, has the remarkable effect of helping to erase learned fear responses. The classic example, in animals, is the association of a particular place with an electric shock. If you stop giving the shock, the animal eventually "unlearns" the response and is no longer afraid; DCS makes this happen faster. It has been successfully tested in people as a treatment for acrophobia (fear of heights). Now researchers want to see if it can be used to wipe out the association between visual or social cues and the impulse to relapse into addiction. So far, it's been tested only on cocaine, but if it works there it might work for other addictions as well.

Neuroscientists don't talk about "willpower," which is a philosophical concept, but they are starting to get a handle on the parts of the brain involved in self-control, the ability to impose a rational calculus on behavior. They distinguish three kinds of selfcontrol, and, unsurprisingly, addicts score poorly on all of them, although it isn't clear whether taking drugs is the cause or consequence of this deficiency, and which of the three types plays the biggest role in addiction has yet to be determined. These are: