Gabapentin Treatment of Cannabis Dependence

说明（由申请人提供）：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，如消极情绪状态和睡眠障碍，这些症状可能促使过度使用。此外，大量使用和戒断大麻会损害认知功能，从而干扰对认知疗法的参与。加巴喷丁（Neurontin）是一种氨基丁酸（GABA）的烷基化类似物，用于治疗癫痫和疼痛。过度使用和戒断大麻被假设为杏仁核中央核神经元功能失调，导致大脑情绪和动机系统失调。评估加巴喷丁作为大麻依赖治疗的关键理由是其能够使杏仁核中GABA机制的功能正常化，从而恢复在大麻戒断中变得失调并激发过度使用的大脑情绪机制的内稳态。一项探索性项目（R21DA020766）发现，与安慰剂相比，加巴喷丁可显著减少大麻戒断和过度使用的急性和长期症状，并改善大麻依赖受试者的睡眠、情绪和认知功能。这项II期研究的目的是在这些试点数据的基础上，通过一项充分有力的、随机的、安慰剂对照试验，评估加巴喷丁作为大麻依赖的潜在药物治疗的疗效。主要假设是加巴喷丁会减轻大麻戒断症状，特别是影响睡眠，并且比安慰剂更能显著减少过度使用。进一步的假设是，通过其对大麻戒断和使用的影响，加巴喷丁将减少大麻对认知功能的损害。研究对象将是150名目前患有DSM IV大麻依赖的门诊患者，随机分配到一个为期12周的双盲安慰剂对照试验中，加巴喷丁的灵活靶向剂量为1200mg /d。同时，所有受试者将接受动机增强治疗（访视-1和0）以促进禁欲，以及认知行为治疗（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解决和任何反弹效应的观察。大麻使用的疗效终点来自时间轴随访访谈，每周进行尿液毒理学确认。每周使用大麻戒断检查表（MWC）、大麻渴望问卷、状态-特质焦虑量表、贝克抑郁量表、匹兹堡睡眠质量指数和活动记录表评估大麻相关戒断症状。参与者将在基线、第4周和第12周接受认知测试。鉴于大麻依赖的普遍存在和缺乏有效的药物疗法，开发加巴喷丁作为大麻依赖的药物疗法可能对公共卫生有重大好处。

DESCRIPTION (provided by applicant): 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 (MWC), 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. PUBLIC HEALTH RELEVANCE: 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 be associated with excessive use. Building on positive findings from a smaller pilot study, results will provide information about the efficacy of gabapentin (Neurontin) as a pharmacotherapy for reducing cannabis withdrawal severity and excessive cannabis use in individuals with cannabis dependence.