Gabapentin Treatment of Cannabis Dependence

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Project Summary / Abstract Cannabis dependence is a major public health problem. Treatments are of limited efficacy and one reason may be a failure to address both acute and protracted symptoms of cannabis withdrawal, such as negative emotional states and sleep disturbance, which may motivate excessive use. In addition, heavy cannabis use and withdrawal can impair cognitive functioning and thereby interfere with participation in cognitive therapies. Gabapentin (Neurontin) is an alkylated analog of gamma amino butyric acid (GABA) marketed for management of epilepsy and pain. Excessive cannabis use and withdrawal are hypothesized to dysregulate neuronal function in the central nucleus of the amygdala, resulting in dysregulation of brain emotional and motivational systems. The key rationale for evaluating gabapentin as a treatment for cannabis dependence is its ability to normalize function in GABA mechanisms in the amygdala, thereby restoring homeostasis in the brain's emotional mechanisms that become dysregulated in cannabis withdrawal and motivate excessive use. An exploratory project (R21DA020766) found gabapentin significantly reduced acute and protracted symptoms of cannabis withdrawal and excessive use, and improved sleep, mood, and cognitive functioning relative to placebo in cannabis dependent subjects. The purpose of this Phase II study is to build on these pilot data and evaluate the efficacy of gabapentin as a potential pharmacotherapy for cannabis dependence in an adequately powered, randomized, placebo-controlled trial. The primary hypotheses are that gabapentin will decrease symptoms of cannabis withdrawal, specifically affect and sleep, and decrease excessive use significantly more than placebo. A further hypothesis is that, through its effects on cannabis withdrawal and use, gabapentin will decrease cannabis-related impairment in cognitive functioning. Subjects will be 150 outpatients with current DSM IV cannabis dependence randomized to a 12-week, double-blind, placebo-controlled trial of a flexible targeted dose of gabapentin 1200 mg/d. Concomitantly, all subjects will receive motivation enhancement therapy (Visits -1 and 0) to facilitate abstinence, and cognitive behavioral therapy (Visits 1-12) to support abstinence. Post-treatment assessments will occur at Week 13 to verify resolution of any side effects and observance of any rebound effects. Efficacy endpoints for cannabis use are derived from the Timeline Followback Interview, with weekly urine toxicology confirmation. Cannabis-related withdrawal symptoms are assessed weekly with the Marijuana Withdrawal Checklist, Marijuana Craving Questionnaire, State-Trait Anxiety Inventory, Beck Depression Inventory, Pittsburgh Sleep Quality Index, and actigraphy watches. Participants will receive cognitive testing at baseline, Week 4 and Week 12. Given the prevalence of cannabis dependence and the lack of effective pharmacotherapies, the development of gabapentin as a pharmacotherapy for cannabis dependence may have major public health benefits.