Nabilone decreases marijuana withdrawal and relapse in the human laboratorY

Abstract

Background: Few individuals seeking treatment for their marijuana use achieves sustained abstinence, and no pharmacotherapy has yet been shown to improve treatment outcome. Although the synthetic cannabinoid receptor agonist, dronabinol (tetrahydrocannabinol; THC), decreases marijuana withdrawal symptoms, it has not been shown to decrease relapse in either the laboratory (Haney et al., 2004, 2008) or the clinic (Levin et al., 2011). Dronabinol has low bioavailability (4-20%), which may contribute to its poor clinical efficacy. The FDA-approved synthetic analog of THC, nabilone, has: 1) higher bioavailability (60-90%; Lemberger and Rubin, 1982), 2) a longer duration of action and 3) clearer dose-linearity than dronabinol (Bedi et al., submitted) . The objective of this study was to determine if maintenance on nabilone decreases marijuana withdrawal symptoms and relapse relative to placebo capsules. Methods: Daily, nontreatment-seeking marijuana smokers (8 M, 3F), who reported smoking 8.4 +/- 3.0 marijuana cigarettes/day, were enrolled in this within-subject, randomized, double-blind, study; 1 additional enrolee left the study early. Participants completed three, 8-day inpatient phases, with each phase testing a different dose of nabilone in counter-balanced order [ 0 mg BID, 4mg BID, 6mg in the AM and 0mg in the PM]. The effect of marijuana and nabilone dose conditions on a range of behavior was measured each day. On the first inpatient day, participants repeatedly smoked experimenter-administered, active marijuana (5.6% THC). For the next 3 days, they had the opportunity to selfadminister placebo marijuana (0.0% THC; Marijuana Withdrawal phase), followed by 4 days in which active marijuana was available for self-administration (Marijuana Relapse phase). Participants had to pay for self-administered marijuana using study earnings. Each inpatient phase was separated by a 7-day outpatient, washout phase. Results: Data are preliminary, including only those who completed all phases to date (n=7). Marijuana Withdrawal Phase: Nabilone dose-dependently (p<0.05) reversed withdrawal-related sleep disruption relative to placebo, significantly increasing objective measures of sleep time, and improving ratings of 'Slept Well', and 'Fell Asleep Easily,' while decreasing ratings of 'Woke Often.' Craving for marijuana was decreased by nabilone, as were ratings of 'Irritable,' 'Angry' and 'Miserable' during withdrawal. However, nabilone increased ratings of fatigue and confusion, and worsened performance of certain cognitive tasks, particularly at the higher daily dose. Nabilone had no effect on ratings of capsule 'liking' or desire to take again relative to placebo. Marijuana Relapse Phase: Both active nabilone doses significantly decreased marijuana relapse (p< 0.01), i.e., the amount of marijuana self-administered after a period of abstinence, relative to placebo. Discussion: These preliminary results suggest that nabilone maintenance produces robust attenuation of marijuana withdrawal symptoms, craving and relapse in daily marijuana smokers. Nabilone's long duration of action resulted in many positive significant effects even when only one active dose per day was administered. These data support clinical testing of nabilone for patients seeking treatment for their marijuana use.