Many people still chalk up the destructive behavior of a drug addict to a lack of willpower or weakness of character. To a neuroscientist, however, drug addiction is a psychiatric illness that develops when the repeated use of narcotics disrupts brain chemistry. Such a chemical disturbance cries out for a chemical solution—that is, a drug treatment.
Doctors have few pharmaceutical remedies for drug addiction, which is often resistant to talk therapy. Relapse rates run as high as 40 to 60 percent for many types of substance abuse. Heroin addicts often benefit from methadone, a synthetic opioid that thwarts cravings by substituting for some of heroin’s effects; naltrexone, an opioid receptor blocker, helps alcoholics kick their habit by reducing the desire for alcohol. But most victims of drug dependence are left with no antidote to the neurological havoc their habit has wrought in their brain. “We have very few medications for the treatment of addiction,” says Nora D. Volkow, director of the National Institute on Drug Abuse (NIDA), “and it’s urgent” that more such drugs are developed.
Among the most urgent needs is a pharmacological weapon to combat the abuse of cocaine, a powerfully addictive stimulant that is synthesized from a pure form found in the leaf of the Erythroxylon coca bush. About 1.7 million Americans abused cocaine in 2006, according to the Department of Health and Human Services. Such compulsive drug taking not only ruins addicts’ lives—breaking up families, for instance, or causing severe cardiovascular disease—but also exacts large costs to society, spreading crime and HIV, among other ills. If a medication could decrease cocaine use by even 10 percent, it could save the U.S. $745 million in cocaine-related expenses, such as those from the incarceration of sellers and users and medical treatment for babies born to addicted mothers, according to a 2000 study in Pharmacoeconomics.
Officials at the NIDA are gunning for such savings. The institute fronted about $15 million for drug treatments for cocaine addiction in fiscal year 2007. Those funds accounted for one third of the total money the institute doled out for pharmacological trials in that year. So far several drug candidates have emerged from this effort, including medications currently marketed for epileptic seizures and the sleep disorder narcolepsy that act in the brain to help quench or diminish an addict’s thirst for cocaine. Meanwhile scientists are also trying to enlist the immune system to prevent cocaine from entering the brain in the first place.
Too Much of a Good Thing
Cocaine exerts its insidious effects by hijacking the parts of the brain dedicated to the perception of pleasure. Whenever we eat or have sex, for example, neurons in these so-called reward centers release the chemical messenger, or neurotransmitter, dopamine. When dopamine conveys its message to the recipient neurons, their responses engender feelings of delight, satisfaction or arousal. Dopamine’s effects, however, quickly fade as the chemical is sucked back into the cells that released it by transporter molecules in a process known as reuptake.
Cocaine blocks the transporters and prevents dopamine reuptake, causing the neurotransmitter to build up in the brain. As dopamine concentrations reach double or even 10 times those the brain experiences from ordinary amusements, the neurotransmitter continually stimulates the receiving neurons, producing euphoria or a “high.” A user also may feel unnaturally energetic and alert—features of stimulants, which include methamphetamine (“speed”) as well as cocaine.
Not everyone who tries cocaine becomes addicted to it, but many people have trouble restraining their need for and use of the drug. Cocaine can perturb the brain’s reward centers such that drug-seeking behavior becomes a conditioned, almost reflexive, response. Cocaine is often the sole source of pleasure for an addict, as he or she loses the motivation to engage in other once enjoyable activities. Meanwhile any reminder of drug use, such as glimpsing a fellow user or drug-related paraphernalia, triggers a small surge of dopamine that brings on intense cravings for the drug.
In the past researchers have tried to end this brutal cycle with drugs that directly target dopamine or its receptor, but the therapies proved addictive themselves and produced other unwanted side effects. Now scientists are turning their attention to compounds that adjust the activity of other neurotransmitters—such as glutamate and gamma-aminobutyric acid (GABA)—to either satisfy an addict’s cravings or dampen reward responses in the brain, dulling the incentive to use. At least one experimental medication may also cushion the harsh withdrawal symptoms, including nausea and depression, that result from the sudden drop in dopamine that occurs when users become abstinent.
An approved narcolepsy treatment called modafinil, for example, acts as a mild stimulant that, among other effects, increases levels of the excitatory neurotransmitter glutamate in the brain. Modafinil may thus work as a cocaine replacement, safely satiating an addict’s cravings while diminishing withdrawal symptoms. In 2005 psychiatrist Charles A. Dackis of the University of Pennsylvania and his colleagues reported that 30 cocaine-dependent subjects who received modafinil steered clear of cocaine for an average of 3.4 of the eight weeks of treatment as compared with 1.9 weeks of abstinence for 32 users who received a placebo. But in an unpublished trial of 210 cocaine addicts conducted in 2007, psychiatrist Ahmed Elkashef and neuropharmacologist Frank Vocci, both at the NIDA, and their co-workers found that only 17 percent more of the addicts who took modafinil as compared with those who took a placebo were cocaine-free for at least two of the eight weeks of treatment.
Holding Back the “High”
Other possible cocaine-curbing remedies act in the opposite fashion: instead of exciting neurons, they augment the activities of the inhibitory neurotransmitter GABA. One such compound is topiramate, an antiseizure medication that also blocks the release of glutamate. In 2004 Penn psychiatrist Kyle M. Kampman and his colleagues reported that in combination with psychotherapy, topiramate led to three weeks of abstinence in 59 percent of addicts who took it for 13 weeks, whereas just 26 percent of users in the placebo group remained cocaine-free for that long. Studies suggest that addicts who are abstinent for three to four weeks will remain so for at least six months to a year.
Another GABA booster is vigabatrin (gamma-vinyl-GABA, or GVG), a drug used in some countries to treat epilepsy. GVG works by blocking an enzyme, GABA transaminase, that chemically breaks down GABA, causing the neurotransmitter to build up inside neurons. These neurons normally release their stores of GABA in response to a surge of dopamine, such as the one that accompanies a cocaine binge. By boosting GABA stores, GVG greatly enhances the inhibitory firepower of these neurons, suppressing the cocaine high and giving addicts less reason to use. GVG thus calms an overactive reward system rather than shutting it down entirely, which may reduce its potential side effects.
So far GVG is faring well in small-scale trials. According to Jonathan Brodie, a psychiatrist at the New York University School of Medicine, 14 of 50 addicts (or 28 percent) who were given GVG in an unpublished study that he and his colleagues conducted in Mexico were clean for the last three of nine weeks of treatment as compared with four of 53 addicts (or 7.5 percent) given a placebo. Catalyst Pharmaceutical Partners in Coral Gables, Fla., is now testing the compound in 180 cocaine addicts in the U.S. and expects results later this year.
A more far-reaching potential remedy taps the body’s immune system to target cocaine circulating in the blood. Because the cocaine molecules are too small to provoke a strong immune response, developers link the drug to larger molecules, such as a bacterial toxin, that powerfully invigorate immune cells. Some of these cells churn out antibodies against the attached cocaine molecules that, after immunity is established in six to 10 weeks, are poised to prevent cocaine from entering the brain whenever a person uses it, undercutting the potential high. In studies of cocaine-obsessed rats and in small-scale clinical trials, the vaccine spawned the production of anticocaine antibodies and decreased cocaine use. Unlike a neurotransmitter-based remedy, however, a vaccine is unlikely to quell cravings or ease withdrawal.
No one knows whether such a vaccine, or any of the other possible antidotes to cocaine dependence, will prove to be safe and effective in trials involving large numbers of addicts. Unfortunately, big pharma may resist sinking money into such trials. The NIDA’s Volkow warns that companies see little payoff in treating destitute drug addicts, especially because many insurance companies do not cover addiction treatments. Undeterred, neuroscientists are continuing to look for new ways of combating addiction while also fighting the false perception that compulsive drug use is a symptom of character flaws. “We can be at the mercy of drugs that inflict damage to brain tissue representing control functions,” Volkow says. But that idea, she admits, will be slow to seep into the public consciousness.