Marijuana Withdrawal in Humans: Effects of Oral THC or Divalproex

Abstract

Abstinence following daily marijuana use can produce a withdrawal syndrome characterized by negative mood (eg irritability, anxiety, misery), muscle pain, chills, and decreased food intake. Two placebo-controlled, within-subject studies investigated the effects of a cannabinoid agonist, delta-9-tetrahydrocannabinol (THC: Study 1), and a mood stabilizer, divalproex (Study 2), on symptoms of marijuana withdrawal. Participants (n ¼ 7/study), who were not seeking treatment for their marijuana use, reported smoking 6-10 marijuana cigarettes/day, 6-7 days/week. Study 1 was a 15-day in-patient, 5-day outpatient, 15-day in-patient design. During the in-patient phases, participants took oral THC capsules (0, 10 mg) five times/day, 1 h prior to smoking marijuana (0.00, 3.04% THC). Active and placebo marijuana were smoked on in-patient days 1-8, while only placebo marijuana was smoked on days 9-14, that is, marijuana abstinence. Placebo THC was administered each day, except during one of the abstinence phases (days 9-14), when active THC was given. Mood, psychomotor task performance, food intake, and sleep were measured. Oral THC administered during marijuana abstinence decreased ratings of 'anxious', 'miserable', 'trouble sleeping', 'chills', and marijuana craving, and reversed large decreases in food intake as compared to placebo, while producing no intoxication. Study 2 was a 58-day, outpatient/in-patient design. Participants were maintained on each divalproex dose (0, 1500 mg/day) for 29 days each. Each maintenance condition began with a 14-day outpatient phase for medication induction or clearance and continued with a 15-day in-patient phase. Divalproex decreased marijuana craving during abstinence, yet increased ratings of 'anxious', 'irritable', 'bad effect', and 'tired.' Divalproex worsened performance on psychomotor tasks, and increased food intake regardless of marijuana condition. Thus, oral THC decreased marijuana craving and withdrawal symptoms at a dose that was subjectively indistinguishable from placebo. Divalproex worsened mood and cognitive performance during marijuana abstinence. These data suggest that oral THC, but not divalproex, may be useful in the treatment of marijuana dependence.

Effects of THC and lofexidine in a human laboratory model of marijuana withdrawal and relapse

“…Neither medication alone had this effect. Although THC decreases nicotine withdrawal in mice (Balerio et al, 2004), smoking behavior during marijuana abstinence was not decreased by THC either in this study or in our earlier study (Haney et al, 2004). Clonidine appears to decrease smoking in clinical trials compared to placebo, but side effects decrease clonidine's potential to treat nicotine dependence (see Covey et al, 2000).…”

“…The antidepressant, nefazodone, which is sedating compared to the stimulant-like bupropion, decreased a subset of marijuana withdrawal symptoms (Haney et al, 2003), but the medication that most effectively attenuated marijuana withdrawal was THC (dronabinol, Marinol). THC selectively decreased ratings of anxious, miserable, trouble sleeping, chills, and marijuana craving, and reversed the large decreases in food intake during marijuana abstinence as compared to placebo, while producing no cannabinoid intoxication (Haney et al, 2004). These results have recently been replicated in an outpatient setting (Budney et al, 2007).…”

“…Correspondingly, THC did not decrease marijuana relapse. Our earlier study, testing a lower THC dose (10 mg) administered frequently (5 times) throughout the day, produced no intoxication and attenuated a range of withdrawal symptoms, including marijuana craving (Haney et al, 2004). Although this might suggest that lower, more frequent doses of THC would be most effective, others have shown that in an outpatient setting, among participants who were selected because they manifested symptoms of marijuana withdrawal, higher doses of THC (30 mg tid) decreased marijuana withdrawal symptoms during marijuana abstinence (Budney et al, 2007).…”

“…In fact, half the participants went all 4 days without smoking active marijuana when maintained on THC and lofexidine (compared to 25% of participants under placebo conditions). Overall, the combination of lofexidine and THC produced the most robust medication effects on sleep, marijuana craving and relapse relative to either medication alone.Based on the literature (Haney et al, 2004;Budney et al, 2007), we had predicted that THC would decrease relapse by reducing the negative reinforcing effects of marijuana, i.e., a return to marijuana use to alleviate symptoms of withdrawal. However, under the present dose regimen, THC instead produced a mild but significant intoxication (good drug effect, mellow, capsule liking, increased willingness to take capsule again) without reducing marijuana craving, or the mood and sleep symptoms associated with marijuana withdrawal.…”

The endogenous cannabinoid system and the treatment of marijuana dependence

“…The latter consists of a constellation of symptoms similar to those seen with nicotine withdrawal, which include irritability, sleep difficulty, decreased appetite, weight loss, and increased anger and irritability (Kouri et al, 1999;Kouri and Pope, 2000;Budney et al, 2003). There have been few pharmacological attempts to alleviate this syndrome (McRae et al, 2003), but one approach using oral D 9 -THC has recently shown significant promise (Haney et al, 2004). The broad applicability of a replacement therapy may be limited, however, by undesirable psychotropic and cardiovascular side effects.…”