Cover Story

New research in nonhuman animals and humans is showing that marijuana withdrawal can produce symptoms such as irritability, anxiety and depressed appetite. The findings provide the most compelling evidence yet that people can become physically dependent on the drug--perhaps contributing to continued use.

"For many years, there was resistance to the whole notion of marijuana dependence," says Columbia University psychologist Margaret Haney, PhD. "Neither society nor scientists viewed marijuana as an important drug of abuse. It paled in comparison to cocaine or heroin. I think that resistance has now lessened."

But the research also indicates that physical dependence on marijuana is far from universal, even among longtime users. Although withdrawal is only one indicator of drug dependence, findings like these may nonetheless help resolve some of the confusion and controversy over whether marijuana is a drug of dependence and how psychologists can develop treatments for substance abusers, researchers say.

"People have this simple-minded idea that the risk of becoming dependent on marijuana is the same for every user, and that's really not the case," says Columbia University epidemiologist Denise B. Kandel, PhD. "It varies, and we have to understand the reasons for that in order to tailor prevention and treatment efforts to the needs of particular groups."

Indeed, the emerging evidence of a marijuana withdrawal syndrome in humans, along with similar findings in studies of rats and mice, has helped spur interest in developing effective treatments for marijuana abuse.

"We know that a small but significant percentage of people who ever try marijuana become dependent and may need treatment," says clinical psychologist Robert S. Stephens, PhD, of the Virginia Polytechnic Institute and State University. "Yet there have been very few randomized, controlled trials to evaluate the effectiveness of different treatment approaches--but that's finally beginning to change."

A withdrawal syndrome emerges

The studies that have sparked excitement in scientific quarters are based on the 1991 finding in rats that animals' brains possess abundant receptors for a class of chemicals known as cannabinoids--one of which is delta-9-tetrahydrocannabinol (THC), the psychoactive compound in marijuana. The receptors, subsequent research revealed, are part of an internal, or endogenous, cannabinoid system whose evolved purpose is not yet well understood.

The discovery of the cannabinoid receptors presented a new opportunity for studying marijuana withdrawal. A complication in conducting research in this area has been that THC metabolizes slowly, making subtle withdrawal effects difficult to detect. In 1995, building on the discovery of the cannabinoid receptors, Brown University and Virginia Commonwealth University researchers independently found the first clear evidence of cannabinoid withdrawal in rats.

Studying animals that had been chronically administered THC, the researchers used a procedure called precipitated withdrawal to chemically block cannabinoid receptors in the animals' brains, abruptly stopping the drug's action. The animals suffered a range of withdrawal symptoms, including paw tremors, "wet-dog shakes" and other disorganized behavior.

Following up, researchers at Virginia Commonwealth University recently learned that withdrawal effects subside when animals whose cannabinoid receptors are blocked are then given more THC. Those results, not yet published, bolster the notion that people continue to take marijuana in part to avoid withdrawal effects. Such neurobiological findings have raised a range of questions--about just how the endogenous cannabinoid system operates, what purposes it evolved to serve and how it can be exploited in medicine.

The animal studies also reignited behavioral scientists' interest in quantifying withdrawal symptoms in humans. In a 1999 study, Haney and colleagues at Columbia University gave chronic marijuana smokers alternating courses of marijuana or a placebo for 21 days, each for several days at a time.

While abstinent during placebo phases of the experiment, participants experienced anxiety, irritability, stomach pain and decreased appetite. Most withdrawal symptoms peaked on the third or fourth day and abated when participants again received marijuana. In two subsequent studies, Harvard University psychologist Elena M. Kouri, PhD, and colleagues found similar effects with marijuana smokers who were abstinent for 28 days. Kouri emphasizes, however, that many people who smoke marijuana regularly do not become dependent on the drug. In her studies, for example, about 40 percent of participants experienced no withdrawal symptoms, despite having smoked marijuana for an average of 22 years.

Columbia's Kandel echoes the sentiment. Her research, examining nationally representative samples of marijuana smokers, has indicated that the risk of dependence is different for different population groups. For example, males are more likely to become dependent than are females and adolescents are at greater risk than are adults.

Testing treatment options

The evidence that marijuana use can lead to dependence--coupled with concern over the high and growing prevalence of marijuana use, especially among youth--has underscored the societal need for effective treatment. In the first controlled study of marijuana treatment, published in 1994, Stephens and colleague Roger A. Roffman, DSW, of the University of Washington, compared the effectiveness of two treatment approaches, both of which took place in group therapy sessions.

One approach applied cognitive-behavioral treatment principles to help people identify and prevent situations in which they are most likely to use marijuana. The second approach simply provided social support to people who wanted to quit. In the study, about 60 percent of the 212 participants in both treatment groups successfully quit smoking marijuana. One year later, about 25 percent remained abstinent.

In a follow-up study involving 291 participants, Stephens's group compared a 14-session cognitive-behavioral treatment approach with a two-session "motivational enhancement" intervention, in which a therapist helped participants review their reasons for wanting to quit smoking marijuana, helped them set goals and provided written materials describing coping skills.

The results, published last year, showed that participants in both treatment conditions were more successful at quitting marijuana than were participants in a control group--and equally so. As in the first study, one year after treatment ended about 25 percent of participants were abstinent.

Although that study suggested that a brief treatment works as well as longer treatment, a recent large, multisite study funded by the federal Center for Substance Abuse Treatment (CSAT) has indicated otherwise.

That study compared 450 chronic marijuana users who were randomly assigned to a two-session motivational enhancement program or to a nine-session program that involved both cognitive-behavioral therapy and motivational enhancement. Part- icipants who received more treatment reduced marijuana consumption by about 60 percent on average, the results showed, compared with 30 percent for those in the brief-intervention condition.

Although the reasons for the treatment differences remain uncertain, University of Connecticut psychologist Thomas F. Babor, PhD, one of the study's lead investigators, says the results are heartening.

"Consistent with earlier findings," he observes, "the CSAT study suggests that treatments for marijuana dependence are effective, even for people who are long-time, chronic marijuana users."

Another recent CSAT-funded study addressed marijuana treatment for youth. The study, involving 600 adolescents, evaluated the effectiveness of five different treatment strategies currently in use. They included brief and extended cognitive-behavioral and motivational treatments as well as programs that supplemented such therapy with discussions about family dynamics, community-reinforcement programs or family therapy.

Preliminary results released last fall indicate that all five treatment strategies are equally effective. After six months, about 70 percent of teen-agers had reduced their marijuana use and about 50 percent had reduced consumption by half or more. After one year, more than one-third of participants were abstinent.

"All five of the treatments did two- or three-fold better than evaluations of existing practice and cost less than current treatment options," says lead investigator Michael L. Dennis, PhD, a research psychologist at Chestnut Health Systems in Bloomington, Ill. The results were so encouraging, in fact, that CSAT plans to release manuals for all five treatment methods in the coming months.

But, cautions Dennis, "Let's not kid ourselves. Two-thirds of these teens were not out of the woods 12 months after treatment. There's lots of room for improvement."

In a departure from traditional cognitive-behavioral and motivational enhancement approaches, clinical psychologist Alan J. Budney, PhD, and colleagues at the University of Vermont have tested another strategy for treating marijuana dependence. The treatment, modeled after programs they and others have used to treat cocaine and opiate addiction, hinges on an old behavioral standby: reinforcement for positive behavior.

In a 1999 study, the Vermont group examined the effectiveness of supplementing traditional motivational and behavioral therapy with voucher incentives, rewarding people for marijuana abstinence. They found that participants who were randomly assigned to the therapy-plus-voucher condition remained abstinent for longer than did those who received only motivational or behavioral therapy, or both.

Another recent study, reported in the Archives of General Psychiatry (Vol. 58, No. 4) in April, explored a new method of treating marijuana dependence by chemically blocking people's cannabinoid receptors, dulling the effects of the drug.

In the study, Marilyn A. Huestis, PhD, and colleagues at the National Institute on Drug Abuse gave 63 participants either a "cannabinoid antagonist" known as SR141716 or a placebo. Two hours later, participants smoked a marijuana cigarette. Results showed that the participants who had received the cannabinoid antagonist reported feeling less "high" after smoking the marijuana than did participants who had been given a placebo. In addition, they showed less increase in heart rate after smoking the marijuana than did participants in the control group.

Such findings are promising, to be sure. But one of the most instructive findings in the treatment literature so far, many researchers observe, has concerned not treatment outcomes, but treatment turnout. In the past, few treatment programs specifically addressed marijuana dependence, and researchers were initially uncertain whether many people would seek treatment for marijuana use. That question can now be put safely to rest.

When his group began recruiting participants for its first treatment study, Stephens remembers, "We were almost overwhelmed by people coming out of the woodwork who wanted treatment for marijuana. I think it was very useful for these people to realize there were other people seeking treatment."