Pharmacological Treatment of Cannabis Withdrawal and Dependence

项目摘要/摘要 大麻依赖是一个世界性的公共卫生问题。治疗效果有限；一种 原因可能是未能解决戒断的症状，如渴望和影响中的干扰 睡眠，这可能会刺激大麻(MJ)的恢复使用。此外，大量使用和停用MJ可能会 损害执行功能，从而干扰认知疗法的参与。的主要目的是 这项II期、单部位、为期8周、双盲、安慰剂对照的随机临床试验旨在评估 新型NK1受体拮抗剂vofopitant(5 mg/d)治疗100例CD的疗效 当前CD的门诊患者。抗应激NK1系统作为CD新靶点的理论基础是 基于成瘾戒断的神经生物学基础，成瘾涉及大脑压力和奖励的失调 系统，即杏仁核中大脑应激系统的激活，vofopitant被假设为正常化。 在我们的初步研究中，我们显示Vofopitant显着减少了大鼠的催促戒断症状 并提供加巴喷丁原则验证对照试验的阳性结果(也 假设是为了使大脑压力回路正常化)，发现显著减少了MJ的使用和戒断 症状，包括渴望，情绪和睡眠，以及相对于安慰剂的执行功能改善 研究对象。接受测试的主要假设是vofopitant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的使用和MJ相关 执行功能失调和fMRI对MJ提示和情绪提示的大胆反应显著 CD门诊患者服用安慰剂多于安慰剂。我们将应用最好的创新技术来评估 通过与Marilyn Hustis博士(NIDA/IRP)合作，对MJ的使用进行Vofopitant治疗，后者将提供 应用新方法对受试者每周观察尿样中CN-THCOOH浓度进行分析 检测模型，以识别新的MJ使用。该提案的另一个新方面是对高管的评估 在治疗方案的背景下发挥作用。MJ使用、MJ戒断和MJ退出之间的潜在关系 认知功能将进行统计检查。这个项目的另一个目标是识别CD个人最多 可能受益于vofopitant并衡量vofopitant相对于安慰剂对这些因素的影响， 从而阐明NK1拮抗剂治疗CD的作用机制。潜在基线 预测因素有：a.)P物质、ACTH、皮质醇和NE，b。)主观测量焦虑，情绪，失眠， 渴求和压力；c.)行政职能；以及d.)FMRI对MJ提示、情绪提示和 情绪性Go-No-Go任务中的抑制能力和休息时的功能连接 州政府。鉴于CD的流行和缺乏有效的药物治疗，Vofopitant的发展 作为一种治疗CD的新药，可能会对公众健康产生重大影响。

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.