Pharmacological Treatment of Cannabis Withdrawal and Dependence

描述（由申请人提供）：大麻依赖（CD）是一个全球性的公共卫生问题。治疗效果有限；一个原因可能是未能解决戒断症状，如渴望、情感和睡眠紊乱，这可能会促使大麻（MJ）重新使用。此外，重度MJ使用和戒断会损害执行功能，从而干扰认知治疗的参与。该II期单点、8周、双盲、安慰剂对照随机临床试验的主要目的是评估一种新型神经激肽1 （NK1）受体拮抗剂伏伏匹坦（5mg/天）治疗100例门诊CD患者的效果。抗应激NK1系统作为CD的新靶点的理论基础是基于成瘾戒断的神经生物学，其中涉及大脑应激和奖励系统的失调，即：激活杏仁核中的大脑应激系统，伏伏匹坦被假设使其正常化。在我们的初步研究中，我们发现伏伏匹坦显著减少了四氢大麻酚依赖大鼠的急性戒断症状，并从加巴喷丁（也假设使脑应激回路正常化）的原理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，与安慰剂相比，显著减少了MJ的使用和戒断症状，包括渴望、情绪和睡眠，并改善了执行功能。被检验的主要假设是，伏福匹坦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使用和MJ相关的执行功能失调，以及fMRI BOLD对MJ线索和情绪线索的反应，显著高于安慰剂。我们将通过与Marilyn Huestis博士（NIDA/IRP）的合作，应用最好的创新技术来评估福匹坦治疗对MJ使用的影响，Marilyn Huestis博士将提供受试者每周观察尿液标本中CN-THCOOH浓度的分析，应用新的检测模型来识别新的MJ使用。该建议的另一个新颖方面是在治疗方案的背景下评估执行功能。MJ使用、MJ戒断和认知功能之间的潜在关系将在统计学上进行检验。该项目的另一个目的是确定最有可能受益于伏伏匹坦的乳糜泻患者，并测量伏伏匹坦相对于安慰剂对这些因素的影响，从而阐明NK1拮抗剂对乳糜泻有效的机制。潜在的基线预测因子是：P物质、ACTH、皮质醇和NE， b)焦虑、情绪、失眠、渴望和压力的主观测量；c)执行功能；d. fMRI BOLD对MJ线索、情绪线索和情感Go-No-Go任务背景下的抑制能力的反应，以及静息状态下的功能连接。鉴于乳糜泻的流行和缺乏有效的药物治疗，开发伏福匹坦作为乳糜泻的新型药物可能具有重大的公共卫生益处。

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.