Pharmacological Treatment of Cannabis Withdrawal and Dependence

大麻戒断和依赖性的药物治疗

• 批准号: 8145249
• 负责人: BARBARA J MASON
• 金额: $ 60.12万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8145249
• 关键词: Abstinence; Address; Affective; Agonist; Amygdaloid structure; Antidepressive Agents; Anxiety; Behavior; Behavior Therapy; Brain; Cannabis; Clinical; Cognitive Therapy; Collaborations; Corticotropin; Cues; Data; Dependence; Detection; Development; Double-Blind Method; Drops; Drug Addiction; Emotional; Evaluation; FDA approved; Failure; Functional Magnetic Resonance Imaging; Health Benefit; Hydrocortisone; Illicit Drugs; Impairment; Individual; Marijuana; Marijuana Dependence; Marijuana Smoking; Measures; Methods; Mission; Modeling; Moods; National Institute of Drug Abuse; Neurobiology; Neuropeptides; Outpatients; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacotherapy; Phase; Phase II Clinical Trials; Placebo Control; Placebos; Prevalence; Public Health; Randomized Clinical Trials; Rattus; Relapse; Relative (related person); Rest; Rewards; Safety; Site; Sleep; Sleeplessness; Specimen; Stress; Substance P; Symptoms; System; Testing; Treatment Protocols; United States; Urine; Withdrawal; Withdrawal Symptom; addiction; base; blood oxygenation level dependent response; cognitive function; control trial; craving; disturbance in affect; executive function; gabapentin; improved; innovation; innovative technologies; novel; public health relevance; receptor; reduce marijuana use; therapy design

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.

描述（由申请人提供）：大麻依赖（CD）是一个世界性的公共卫生问题。治疗效果有限；原因之一可能是未能解决戒断症状，​​例如渴望以及情感和睡眠障碍，这可能会促使人们重新吸食大麻（MJ）。此外，大量使用和戒断 MJ 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估新型神经激肽 1 (NK1) 受体拮抗剂 vofopitant（5 毫克/天）治疗100 名当前患有 CD 的门诊患者的 CD。抗应激 NK1 系统作为 CD 的新靶点的理论依据是基于成瘾戒断的神经生物学，其中涉及大脑压力和奖励系统的失调，即杏仁核中大脑压力系统的激活，vofopitant 被假设为激活杏仁核中的大脑压力系统正常化。在我们的初步研究中，我们发现伏匹坦显着减少了 THC 依赖性大鼠的突然戒断症状，​​并从加巴喷丁（也假设可以使大脑应激回路正常化）的原理验证对照试验中得到了积极的结果，该试验发现显着减少了 MJ 的使用和戒断症状在 50 名 CD 受试者中，与安慰剂相比，包括渴望、情绪和睡眠以及执行功能得到改善。接受测试的主要假设是，vofopitant 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 使用和与 MJ 相关的执行功能失调和 fMRI BOLD 对 MJ 线索和情绪线索的反应显着超过CD 门诊患者的安慰剂。我们将通过与 Marilyn Huestis 博士 (NIDA/IRP) 合作，应用最好的创新技术来评估 vofopitant 治疗对 MJ 使用的影响，她将提供受试者每周观察的尿液样本中 CN-THCOOH 浓度的分析，应用新的方法检测模型来识别 MJ 的新用途。该提案的另一个新颖之处是在治疗方案的背景下评估执行功能。将对 MJ 使用、MJ 退出和认知功能之间的潜在关系进行统计检验。该项目的另一个目的是确定最有可能从伏匹坦中受益的克罗恩病个体，并测量伏匹坦相对于安慰剂对这些因素的影响，从而阐明 NK1 拮抗剂对克罗恩病有效的机制。潜在的基线预测因素包括：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.) 执行职能； d.) fMRI 对 MJ 线索、情绪线索和情感 Go-No-Go 任务背景下的抑制能力以及静息状态下的功能连接的大胆反应。鉴于克罗恩病的患病率和有效药物疗法的缺乏，开发伏匹坦作为克罗恩病的新型药物可能会带来重大的公共健康益处。 公共健康相关性：大麻是美国使用最广泛的非法药物，FDA 尚未批准针对大麻依赖 (CD) 的治疗方法。本申请的目的是进行 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 的开发作为治疗 CD 的新型药物可能具有重大的公共健康益处，并且对于 NIDA 的使命具有非常重要的意义。