Does Marijuana Withdrawal Syndrome Exist?

The question of whether a clinically significant marijuana (cannabis) withdrawal syndrome exists remains controversial. In spite of the mounting clinical and preclinical evidence suggesting that such a syndrome exists (Beardsley et al., 1986; Budney et al., 2001; Holson et al., 1989; Huestis et al., 2001), the DSM-IV does not include marijuana withdrawal as a diagnostic category. The clinical syndrome has been characterized by restlessness, anorexia, irritability and insomnia that begin less than 24 hours after discontinuation of marijuana, peak in intensity on days 2 to 4, and last for seven to 10 days (Budney et al., 1999; Haney et al., 1999; Mendelson et al., 1984).

The question of whether this syndrome is clinically significant is important, not only because marijuana is the most commonly used illicit drug in the United States (Johnston et al., 2001), but also because marijuana has been shown to produce dependence at rates comparable to other drugs of abuse (Kandel et al., 1997; Kessler et al., 1994) and because relapse rates among individuals seeking treatment for marijuana dependence are similar to those with other drugs of abuse (Budney et al., 1998; Stephens et al., 1993). Furthermore, many violent crimes are committed by individuals undergoing withdrawal from drugs of abuse, including marijuana (Kouri et al., 1997; Peters and Kearns, 1992). If a clinically significant marijuana withdrawal syndrome does exist, the omission of this syndrome from the DSM-IV might contribute to the perception that behavioral or pharmacological treatment regimens for marijuana dependence are not necessary.

We conducted two studies in our laboratory to determine whether abstinence from marijuana after long-term use results in withdrawal symptoms, to identify those symptoms and to quantify their severity (Kouri and Pope, 2000; Kouri et al., 1999). The first study focused specifically on whether abrupt discontinuation of marijuana following chronic use results in changes in aggressive behavior (Kouri et al., 1999). To measure aggressive behavior, we used the Point Subtraction Aggression Paradigm (PSAP). This computer test has been used to detect changes in aggressive responses following acute administration of a number of drugs, and its external validity has been demonstrated in a number of studies of male and female parolees with histories of violent behavior (Cherek and Lane, 1999; Cherek et al., 1996).

Subjects in our study were long-term heavy users of marijuana who reported a history of at least 5,000 separate episodes of marijuana use in their lifetime (the equivalent to smoking once per day for 13.7 years), were smoking at least once daily at the time of recruitment and met DSM-IV criteria for marijuana dependence without meeting criteria for a current Axis I disorder. Subjects were excluded if they reported that they had used another class of drugs more than 100 times in their lifetimes or had consumed more than five alcoholic drinks per day continuously for one month or more in their lifetimes.

The controls were composed of two groups: 1) individuals who had not smoked marijuana more than 50 times in their lives and had not smoked more than once per month in the last year and 2) individuals who had formerly smoked marijuana on a daily basis but who had not smoked more than once per week during the last three months. The rationale for using infrequent or former smokers rather than marijuana-naive subjects as controls was to minimize possible confounding variables that might differentiate individuals who had never tried marijuana from those who had. We based this decision on data from our laboratory demonstrating that heavy marijuana users do not differ from occasional users in a wide range of demographic and psychiatric measures (Kouri et al., 1995).

During the study, subjects were required to abstain from smoking marijuana and using any other drugs for 28 consecutive days. To verify abstinence, subjects had to come to the laboratory every day to provide supervised urine samples that we analyzed quantitatively for tetrahydrocannabinol (THC) metabolites. We measured aggressive responses with the PSAP on study days 0 (before abstinence), 1 (after 24 hours of abstinence), 3, 7 and 28.

Subjects were told they would be playing a computer game against an anonymous same-sex subject from the study. In fact, however, this second subject was actually a computer. During the course of each 20-minute computer session, subjects had the option of pressing one of two buttons on the PSAP response panel (labeled "A" or "B"). Pressing button A resulted in the accumulation of points that were exchanged for money at the end of the study. Pressing this button was defined as a non-aggressive response. By pressing button B, subjects could subtract points from the fictitious opponent. Points taken from the opponent, however, were not added to the subject's counter, and pressing button B was defined as an aggressive response. Aggressive responding was provoked by random subtractions of the subject's points, which were attributed to the fictitious opponent.