Cover Story

Most substance abuse researchers once believed that drug abuse and addiction are best explained by drugs' reinforcing effects. Pharmacological studies have long supported that view, showing that drugs of abuse powerfully affect the brain's dopamine system, which regulates emotional responses and plays a part in abuse by providing an emotional "reward" for continued use.

Increasingly, however, scientists are learning that the story is more complicated. Brain-imaging studies in humans and neuropsychological studies in nonhuman animals have shown that repeated drug use causes disruptions in the brain's highly evolved frontal cortex, which regulates cognitive activities such as decision-making, response inhibition, planning and memory.

"We now know that many of the drugs of abuse target not just those aspects of the brain that alter things like emotion, but also areas that affect our ability to control cognitive operations," says Herb Weingartner, PhD, of the Division of Neuroscience and Behavioral Research at the National Institute on Drug Abuse (NIDA).

The new findings hold promise for better understanding why only some drug users become addicted, why drug abusers so easily relapse even after long periods of drug abstinence and, ultimately, how prevention and treatment efforts can be tailored to people's individual vulnerabilities.

"In the past few years, people have begun to recognize that drug abuse is not a pharmacological disease--it's a pharmacological and behavioral disease," says Elliot A. Stein, PhD, a neuroscientist at the Medical College of Wisconsin. "The cognitive functions that sit in the frontal lobes play a role in drug abuse."

For treatment, he believes, that may suggest that it will be difficult to find a "magic bullet" to attack both the pharmacological and the behavioral parts of addiction.

Shifting tide

Since the 1980s, scientists have observed that many people who were addicted to drugs such as cocaine and marijuana appeared to have frontal cortex abnormalities. Such abnormalities, however, were long thought to be incidental side effects of drug abuse, explains Steven Grant, PhD, a program officer in NIDA's Division of Treatment Research and Development.

"We typically haven't thought of the influence of those processes on substance abuse and addiction," he says, "because we have been so focused on the role of reinforcement and the hedonic effects of drugs as being the driving force in drug abuse. That has been the dominant paradigm for the last two decades."

In the past five years, however, the tide has begun to turn. At a 1992 scientific conference, University of Iowa neuroscientist Antoine Bechara, PhD, described research showing that patients with frontal cortex damage had impaired decision-making abilities, reflected in their performance on a laboratory gambling task.

Grant saw Bechara's presentation and made the connection to drug abuse, hypothesizing that disruptions in the frontal cortex might be responsible for impaired decision-making and behavioral inhibition in drug abusers--and that that could help explain the compulsive drug-seeking that is a hallmark of addiction.

Using Bechara's gambling task, Grant and his colleagues tested drug abusers' decision-making abilities. Last year, they reported in the journal Neuropsychologia (Vol. 38, No. 8) that drug abusers indeed made poorer decisions on the gambling task than did participants in a control group.

More recently, Bechara and his colleagues uncovered three subgroups of drug abusers. About one-third, they found, showed no decision-making impairment on the gambling task. About 25 percent, in contrast, responded exactly as patients with frontal lobe damage have been shown to do, almost invariably choosing a higher immediate reward even knowing that their strategy would be unprofitable in the long run. Finally, about 40 percent of Bechara's study participants appeared to be hypersensitive to potential rewards--no matter whether they were immediate or long-term.

Bechara suggests that these differences in decision-making impairment reflect different vulnerabilities to drug addiction. If so, he argues, they may help shed light on treatment strategies. Drug users who show no decision-making impairment may be at least risk for becoming addicted and may be able to stop if they want to, he suggests. In contrast, he says, for those with severe decision-making impairments, "There's probably nothing you can do. You can put them in jail, but in my opinion, they're unlikely to respond."

Finally, Bechara argues, for drug users who are sensitive to both the short- and long-term consequences of drug use, heightening awareness of the negative long-term consequences of abuse may be sufficient to tip the scales and help people quit using drugs.

In other studies, researchers have used two imaging techniques, positron emission tomography and functional magnetic resonance imaging, to measure drug abusers' brain activity during craving.

In 1996, Grant and NIDA colleagues David B. Newlin, PhD, Edythe D. London, PhD, and others reported in the Proceedings of the National Academy of Sciences (Vol. 93) that cocaine craving was linked to heightened activity in areas of the frontal cortex that regulate decision-making and motivation, but not in the brain's dopamine control centers. Those findings have since been replicated and extended in other laboratories.

"Classically, people thought that drug addiction was a disease that involved the centers of pleasure--that people are taking the drug because it's pleasurable," concludes Nora D. Volkow, MD, a research scientist at the U.S. Department of Energy's Brookhaven National Laboratory. "But that's not the case--in fact, addicted people don't have as strong a pleasure response as people who aren't addicted. Recent data are showing us that addiction entails a basic disruption of motivational circuits."

Seeking clues for treatment

Evidence that craving and drug cues can trigger abnormal activity in the frontal cortex--even in the absence of drugs--has led many researchers to believe that this brain area may be especially important in relapse. Grant suggests it may be in the frontal cortex that the residual effects of drugs manifest themselves, long after dopamine effects have disappeared.

"Without a properly functioning frontal cortex," he says, "one may be unable to look beyond drugs' immediate reinforcing or hedonic aspects and consider the long-term consequences of drug use."

Bechara adds, "I think there are two mechanisms playing in addiction. One is the pharmacological reward process that we've been studying for years. But the other is the behavioral process of controlling your behavior in the face of punishment."

The growing body of research on the roles that the frontal cortex and cognitive processes such as decision making and behavioral inhibition play in addiction raises many questions about treatment:

  • What is the difference, in the brain, between drug use and addictive drug use?

  • Do some people have pre-existing, subtle abnormalities in the frontal cortex that make them more vulnerable to drug use? If so, how can such dysfunction be identified and used for early interventions?

  • What are the long-term brain consequences of drug use? Are they reversible?

  • How can the recent findings of frontal cortex activation during drug craving be exploited to develop better ways to evaluate treatment effectiveness?

"Right now, the best tool for measuring success of drug treatment is recidivism--does the person show up in the hospital again?" comments Stein. "Compare that with a field like cardiology, where a physician would never release a heart attack patient without a stress test. In drug addiction, we send people out on the street without certainty that the treatment worked."

He hopes that someday, he'll be able to put people in a craving situation and measure their brain responses. "That," he says, "will help us know if the intervention blunted the craving response."