Gabapentin Treatment of Cannabis Dependence

项目总结/摘要 大麻依赖是一个重大的公共卫生问题。治疗效果有限，其中一个原因可能是 未能解决大麻戒断的急性和长期症状，如阴性 情绪状态和睡眠障碍，这可能会导致过度使用。此外，大量使用大麻 戒断会损害认知功能，从而干扰认知治疗的参与。 加巴喷丁（Neurontin）是γ氨基丁酸（GABA）的烷基化类似物， 癫痫和疼痛的管理。过度使用大麻和戒断被假设为失调 杏仁核中央核的神经元功能，导致大脑情绪和 激励系统。评价加巴喷丁作为大麻依赖治疗的关键理由是 它能够使杏仁核中GABA机制的功能正常化，从而恢复杏仁核中的稳态， 大脑的情感机制在大麻戒断中变得失调，并激发过度使用。 一项探索性项目（R21 DA 020766）发现，加巴喷丁可显著减轻急性和迁延性症状 大麻戒断和过度使用，并改善睡眠，情绪和认知功能， 在大麻依赖者中使用安慰剂。第二阶段研究的目的是在这些试点数据的基础上， 评估加巴喷丁作为大麻依赖的潜在药物治疗的有效性， 有把握度的随机安慰剂对照试验。主要假设是加巴喷丁会减少 大麻戒断症状，特别是影响和睡眠，并减少过度使用显着更多 安慰剂。另一个假设是，通过其对大麻戒断和使用的影响，加巴喷丁将 减少大麻相关的认知功能障碍。受试者将为150例门诊患者， DSM IV大麻依赖随机分配至一项为期12周的双盲安慰剂对照试验， 加巴喷丁的目标剂量为1200 mg/d。与此同时，所有受试者都将获得动力增强 治疗（访视-1和0）以促进禁欲，认知行为治疗（访视1-12）以支持 禁欲治疗后评估将在第13周进行，以验证任何副作用的消退情况， 观察任何反弹效应。大麻使用的疗效终点来自时间轴 随访访谈，每周尿液毒理学确认。与大麻有关的戒断症状有 每周评估一次，使用Maritime Withdrawal Checklist，Maritime Craving Questionnaire，State-Trait 焦虑量表、贝克抑郁量表、匹兹堡睡眠质量指数和腕动计。 受试者将在基线、第4周和第12周接受认知测试。鉴于大麻的流行 依赖和缺乏有效的药物治疗，加巴喷丁作为一种 对大麻依赖的药物治疗可能对公共卫生有重大益处。

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.