Laboratory studies have shown that animals exhibit symptoms of drug withdrawal after cessation of prolonged marijuana administration. Some human studies have also demonstrated withdrawal symptoms such as irritability, stomach pain, aggression, and anxiety after cessation of oral administration of tetrahydrocannabinol (THC), marijuana's principal psychoactive component. Now, NIDA-supported researchers at McLean Hospital in Belmont, Massachusetts, and Columbia University in New York City have shown that individuals who regularly smoke marijuana experience withdrawal symptoms after they stop smoking the drug.

"These studies suggest that in real-world situations abstinence from daily marijuana smoking creates withdrawal symptoms similar to those of other drugs of abuse," says Dr. Jag Khalsa of NIDA's Center on AIDS and Other Medical Consequences of Drug Abuse. "Marijuana smokers may continue to use the drug to prevent the irritability and discomfort they experience when they stop."

Aggression

Dr. Elena Kouri and her colleagues at the Biological Psychiatry Laboratory at McLean Hospital found that long-term heavy marijuana users became more aggressive during abstinence from marijuana than did former or infrequent users. Previous studies of withdrawal symptoms have relied largely on patients' subjective reports of a range of symptoms, Dr. Kouri notes. "We studied measurable changes in one specific symptom-aggression," she says.

The researchers recruited two groups of male and female volunteers: 17 current long-term users of marijuana and a control group of 20 infrequent or former users. Current long-term users were smoking marijuana daily at the time of recruitment and had smoked marijuana at least 5,000 times-the equivalent of smoking once each day for more than 13 years. The infrequent or former users had not smoked more than 50 times in their life and had smoked less than once per month in the past year, or had formerly smoked at least daily but had not smoked more than once per week for the past 3 months.

At the beginning of the study, all participants were instructed to refrain from any marijuana use for 28 days. Abstinence was monitored by analysis of daily observed urine sampling. Cigarette smokers were allowed to continue their usual tobacco use.

During the first weeks of abstinence, long-term current marijuana smokers made more aggressive responses on a computerized game than did infrequent or former smokers. The graph shows the average number of aggressive responses in 17 long-term daily (Solid Square) and 20 infrequent or former (Open Square) marijuana smokers. (Star = significantly different from former smokers.)

Aggression was measured on the first day of the study and after 1, 3, 7, and 28 days of abstinence. To measure aggression, the researchers used a 20-minute computerized test that participants were told would measure motor skills and other physiological characteristics. Participants were told that pressing one button in a certain pattern would add points to their score and that pressing another button would subtract points from the score of their opponent, who could similarly add or subtract points.

In fact, Dr. Kouri says, there was no human opponent; the computer was programed to subtract points randomly in order to give the illusion of a human opponent. At the end of each session, aggressive responses-those that subtracted from the supposed opponent's points-were compared with nonagressive responses-those that added to the participant's points. Dr. Kouri notes that studies involving parolees with a history of violent behavior have shown a close correlation between performance on this game and actual aggression.

After 1, 3, and 7 days of abstinence, current marijuana users registered significantly more aggressive responses-more than twice as many on days 3 and 7-than the control group. By the 28th day, there was no significant difference between groups. Aggressive behavior was limited to responses in the test situation, Dr. Kouri notes; participants did not display overt hostility. "At this point we do not know exactly how these findings reflect changes in aggressive behavior outside the laboratory," Dr. Kouri says. "But the results demonstrate that abstinence is associated with unpleasant behavioral symptoms that may contribute to continued drug use."

Other Withdrawal Symptoms

Studies at Columbia University in New York City have demonstrated that, in addition to aggression, marijuana smokers experience other withdrawal symptoms such as anxiety, stomach pain, and increased irritability during abstinence from the drug. "These results suggest that dependence may be an important consequence of repeated daily exposure to marijuana," says NIDA-supported researcher Dr. Margaret Haney.

Dr. Haney and her colleagues investigated the effects of abstinence on 12 adult males with an average age of 28 years who, in the laboratory, smoked marijuana with THC concentrations of 3.1 percent or 1.8 percent, or marijuana cigarettes containing no active THC. All participants smoked inactive marijuana during the first 4 days of the study followed by either the high concentration, low concentration, or inactive marijuana on alternating 4-day periods. Three times each day, the participants completed a 50-item checklist that rated physical conditions such as hunger, dizziness, and headache and aspects of their mood, for example, anxiety, talkativeness, friendliness, or depression.

Abstinence from either high- or low-concentration marijuana resulted in reduced hunger, decreased ratings of "friendly" and "content," and increased ratings of "irritability," "stomach pain," and "anxiety." Moreover, Dr. Haney notes, participants receiving high-concentration marijuana rated the drug's effects higher ("good drug effect," "stimulated," "high") on the first day of exposure than on the fourth day, indicating the development of tolerance to THC.

"It appears likely that the onset of the withdrawal symptoms we observed in this study may contribute to maintaining chronic marijuana use," Dr. Haney says. "The withdrawal symptoms are not as dramatic as those associated with withdrawal from opiates or alcohol, but are still significant to the individual marijuana user. These symptoms must be taken into account in order to develop effective treatment programs for marijuana abuse."

Sources

Kouri, E.M.; Pope, H.G.; and Lukas, S.E. Changes in aggressive behavior during withdrawal from long-term marijuana use. Psychopharmacology, 143:302-308, 1999. [Abstract]

Haney, M.; Ward, A.S.; Comer, S.D.; Foltin, R.W.; and Fischman, M.W. Abstinence symptoms following smoked marijuana in humans. Psychopharmacology, 141:395-404, 1999. [Abstract]