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，如渴望和影响和睡眠的干扰，这可能会促使恢复大麻（MJ）使用。此外，大量使用MJ和戒断会损害执行功能，从而干扰认知治疗的参与。这项II期、单中心、8周、双盲、安慰剂对照随机临床试验的主要目的是评价一种新型神经激肽1（NK 1）受体拮抗剂伏福匹坦（5 mg/天）治疗100例目前患有CD的门诊患者的CD疗效。抗应激NK 1系统作为CD中新靶点的理论基础是基于成瘾戒断的神经生物学，其涉及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，伏福匹坦被假设为使其正常化。在我们的初步研究中，我们显示伏福匹坦显著降低THC依赖性大鼠的突然戒断症状，并提供了加巴喷丁（也假设使大脑应激回路正常化）的原理验证对照试验的阳性结果，该试验发现在50名CD受试者中，与安慰剂相比，MJ使用和戒断症状（包括渴望、情绪和睡眠）显著减少，执行功能改善。测试的主要假设是，伏福匹坦将显着改善大麻戒断症状，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和功能磁共振成像BOLD响应MJ线索和情绪线索显着超过安慰剂在CD门诊患者。我们将通过与Marilyn Huestis博士（NIDA/IRP）合作，应用最佳创新技术评估伏福匹坦治疗对MJ使用的影响，他将提供受试者每周观察尿液样本中CN-THCOOH浓度的分析，应用新的检测模型来识别新的MJ使用。该提案的另一个新颖方面是在治疗方案的背景下评估执行功能。将对MJ使用、MJ戒断和认知功能之间的潜在关系进行统计学检查。本项目的另一个目的是确定最有可能从伏福匹坦中获益的CD个体，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NK 1拮抗剂在CD中有效的机制。潜在的基线预测因子是：a.）P物质、ACTH、皮质醇和NE，B.）焦虑、情绪、失眠、渴望和压力的主观测量; c.）执行功能;和d.）功能磁共振成像BOLD反应MJ线索，情绪线索和抑制能力的情况下，情感去不去任务，和功能连接在休息状态。鉴于CD的患病率和缺乏有效的药物治疗，开发伏福匹坦作为CD的新型药物可能具有重大的公共卫生益处。 公共卫生相关性：大麻是美国使用最广泛的非法药物，没有FDA批准的大麻依赖（CD）治疗方法。本申请的目的是进行II期临床试验，评估新型NK 1拮抗剂伏福匹坦作为CD新治疗方法的疗效。伏福匹坦作为治疗CD的新型药物的开发可能具有重大的公共卫生益处，并且对于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.