Pharmacological Treatment of Cannabis Withdrawal and Dependence

描述(申请人提供)：大麻依赖(CD)是一个世界性的公共卫生问题。治疗的效果有限；一个原因可能是未能解决戒断症状，如渴望以及情感和睡眠方面的障碍，这些症状可能会促使重新开始使用大麻(MJ)。此外，大量使用和停用MJ会损害执行功能，从而干扰认知疗法的参与。这项II期、单部位、8周、双盲、安慰剂对照的随机临床试验的主要目的是评价一种新型的神经激肽1(NK1)受体拮抗剂vofopitant(5 mg/d)治疗100例门诊CD患者的疗效。抗应激NK1系统作为CD的新靶点的理论基础是基于戒除成瘾的神经生物学，其中涉及大脑应激和奖励系统的失调，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显著减少了THC依赖大鼠的催促戒断症状，并从加巴喷丁(也被假设为正常化大脑应激回路)的原则验证对照试验中提供了积极的结果，该试验发现在50名CD受试者中，MJ的使用和戒断症状显著减少，包括渴望、情绪和睡眠，与安慰剂相比，执行功能得到改善。接受测试的主要假设是，在CD门诊患者中，vofopitant将显著改善大麻戒断症状，特别是渴望、焦虑、情绪和睡眠，并减少MJ的使用和与MJ相关的执行功能失调，以及对MJ提示和情绪提示的大胆反应，明显高于安慰剂。我们将通过与Marilyn Huestis博士(NIDA/IRP)的合作，将最佳创新技术应用于评估Vofopitant治疗对MJ使用的影响，Marilyn Huestis博士将提供受试者每周观察的尿样中CN-THCOOH浓度的分析，应用新的检测模型来识别新的MJ使用。该提案的另一个新方面是在治疗方案的背景下对执行职能进行评价。MJ使用、MJ退出和认知功能之间的潜在关系将被统计检验。该项目的另一个目的是确定最有可能从vofopitant中受益的CD个体，并测量vofopitant对这些因素相对于安慰剂的影响，从而阐明NK1拮抗剂在CD中的作用机制。潜在的基线预测因素有：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；行政职能；以及d.)FMRI对MJ提示的大胆反应，情绪提示和情绪性Go-No-Go任务背景下的抑制能力，以及休息状态下的功能连接。鉴于CD的流行和缺乏有效的药物治疗，开发vofopitant作为一种治疗CD的新型药物可能会对公众健康产生重大好处。 与公共卫生相关：大麻是美国使用最广泛的非法药物，目前还没有FDA批准的治疗大麻依赖(CD)的方法。本申请的目的是进行一项II期临床试验，以评估新型NK1拮抗剂vofopitant作为CD新疗法的疗效。Vofopitant作为一种治疗CD的新药的开发可能会对公众健康产生重大影响，并对NIDA的使命具有重要意义。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Cannabis is the most widely used illicit drug in the US and there are no FDA-approved treatments for cannabis dependence (CD). The purpose of this application is to conduct a Phase II clinical trial to assess the efficacy of a novel NK1 antagonist, vofopitant, as a new treatment for CD. The development of vofopitant as a novel medication for CD may have major public health benefits and is highly significant for the mission of NIDA.