Pharmacological Treatment of Cannabis Withdrawal and Dependence

项目总结/摘要 大麻依赖（CD）是一个全球性的公共卫生问题。治疗效果有限; 1 原因可能是未能解决戒断症状，如渴望和情感障碍 睡眠，这可能会促使恢复大麻（MJ）的使用。此外，大量使用MJ和退出可以 损害执行功能，从而干扰参与认知治疗。的主要目的 这项II期、单中心、8周、双盲、安慰剂对照的随机临床试验是为了评估 新型神经激肽1（NK 1）受体拮抗剂伏福匹坦（5 mg/天）治疗100例CD的疗效 目前患有CD的门诊患者。抗应激NK 1系统作为CD新靶点的理论基础是 基于神经生物学的戒瘾，涉及大脑压力和奖励的失调， 系统，即，激活杏仁核中的大脑应激系统，伏福匹坦被假设为使其正常化。 在我们的初步研究中，我们发现伏福匹坦显著降低了 THC依赖性大鼠，并从加巴喷丁的原理验证对照试验（也 假设大脑压力回路正常化），发现显著减少MJ使用和戒断 症状，包括渴望，情绪和睡眠，并改善执行功能相对于安慰剂50 CD 科目检验的主要假设是伏福匹坦将显著改善 大麻戒断，特别是渴望，焦虑，情绪和睡眠，并减少MJ使用和MJ相关 执行功能失调和对MJ线索和情绪线索的fMRI BOLD反应显著 在CD门诊患者中，我们将采用最先进的创新技术， 通过与Marilyn Huestis博士（NIDA/IRP）合作，对MJ使用进行伏福匹坦治疗， 采用新的方法分析受试者每周观察的尿液样本中的CN-THCOOH浓度 检测模型，以确定新的MJ使用。该提案的另一个新方面是对执行人员的评价。 在治疗方案中发挥作用。MJ使用、MJ退出和MJ之间的潜在关系 将对认知功能进行统计学检查。该项目的另一个目的是确定CD个人最 可能受益于伏福匹坦，并测量伏福匹坦相对于安慰剂对这些因素的影响， 从而阐明了NK 1拮抗剂在CD中有效的机制。潜在基线 预测因子是：a.）P物质、ACTH、皮质醇和NE，B.）焦虑情绪失眠 渴望和压力; c.）执行功能;和d.）对MJ线索、情绪线索和 在情感性Go-No-Go任务中的抑制能力，以及休息时的功能连接 状态鉴于CD的患病率和缺乏有效的药物治疗， 作为一种治疗CD的新药物可能具有重大的公共卫生益处。

Project Summary / Abstract Cannabis dependence (CD) is a worldwide public health problem. Treatments are of limited efficacy; one reason may be a failure to address the symptoms of withdrawal, such as craving and disturbances in affect and sleep, that may motivate resumed marijuana (MJ) use. In addition, heavy MJ use and withdrawal can impair executive functioning and thereby interfere with participation in cognitive therapies. The primary aim of this Phase II, single-site, 8-week, double-blind, placebo-controlled randomized clinical trial is to evaluate the efficacy of a novel neurokinin1 (NK1) receptor antagonist, vofopitant (5mg/day), for treating CD in 100 outpatients with current CD. The theoretical rationale for the anti-stress NK1 system as a novel target in CD is based on the neurobiology of abstinence in addiction which involves dysregulation in brain stress and reward systems, i.e., activation of brain stress systems in the amygdala, which vofopitant is hypothesized to normalize. In our Preliminary Studies we show vofopitant significantly decreased precipitated withdrawal symptoms in THC-dependent rats and provide positive results from a proof-of-principle controlled trial of gabapentin (also hypothesized to normalize brain stress circuitry) that found significantly reduced MJ use and withdrawal symptoms, including craving, mood and sleep, and improved executive functioning relative to placebo in 50 CD subjects. The primary hypotheses under test are that vofopitant will significantly improve symptoms of cannabis withdrawal, specifically craving, anxiety, mood and sleep, and reduce MJ use and MJ-related dysregulation of executive functioning and fMRI BOLD response to MJ cues and emotional cues significantly more than placebo in CD outpatients. We will apply the best innovative technology for evaluating the effect of vofopitant treatment on MJ use through a collaboration with Dr. Marilyn Huestis (NIDA/IRP), who will provide analysis of CN-THCOOH concentrations in subjects' weekly observed urine specimens, applying new detection models to identify new MJ use. A further novel aspect of the proposal is the evaluation of executive functioning in the context of a treatment protocol. Potential relationships between MJ use, MJ withdrawal and cognitive functioning will be examined statistically. A further aim of this project is to identify CD individuals most likely to benefit from vofopitant and to measure effects of vofopitant on these factors relative to placebo, thereby clarifying the mechanisms through which NK1 antagonists have efficacy in CD. Potential baseline predictors are: a.) Substance P, ACTH, cortisol and NE, b.) subjective measures of anxiety, mood, insomnia, craving and stress; c.) executive functioning; and d.) fMRI BOLD response to MJ cues, emotional cues and capacity for inhibition in the context of an Affective Go-No-Go task, and functional connectivity during resting state. Given the prevalence of CD and the lack of effective pharmacotherapies, the development of vofopitant as a novel medication for CD may have major public health benefits.