Pharmacological Treatment of Cannabis Withdrawal and Dependence

大麻戒断和依赖性的药物治疗

• 批准号: 8305013
• 负责人: BARBARA J MASON
• 金额: $ 57.35万
• 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/8305013
• 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; abstracting; addiction; base; blood oxygenation level dependent response; cognitive function; control trial; craving; disturbance in affect; executive function; gabapentin; improved; innovation; innovative technologies; novel; receptor; reduce marijuana use; therapy design

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.

项目概要/摘要 大麻依赖（CD）是一个世界性的公共卫生问题。治疗效果有限；一 原因可能是未能解决戒断症状，​​例如渴望和情感障碍 和睡眠，这可能会促使人们恢复吸食大麻 (MJ)。此外，MJ 的大量使用和退出可以 损害执行功能，从而干扰认知治疗的参与。主要目标 这项 II 期、单中心、为期 8 周、双盲、安慰剂对照随机临床试验旨在评估 新型神经激肽 1 (NK1) 受体拮抗剂 vofopitant（5 毫克/天）治疗 100 例 CD 的疗效 现有 CD 的门诊患者。抗应激 NK1 系统作为 CD 新靶点的理论依据是 基于成瘾戒断的神经生物学，涉及大脑压力和奖励的失调 系统，即激活杏仁核中的大脑应激系统，推测 vofopitant 可以使该系统正常化。 在我们的初步研究中，我们发现 vofopitant 显着减少了诱发的戒断症状 THC 依赖性大鼠，并从加巴喷丁的原理验证对照试验中获得了积极的结果（也 假设可以使大脑压力回路正常化），发现 MJ 的使用和戒断显着减少 50 CD 中相对于安慰剂，症状（包括渴望、情绪和睡眠）以及执行功能得到改善 科目。所测试的主要假设是伏匹坦将显着改善以下症状： 大麻戒断，特别是渴望、焦虑、情绪和睡眠，并减少 MJ 使用和 MJ 相关的 执行功能和功能磁共振成像的失调 对 MJ 线索和情绪线索的大胆反应 在 CD 门诊患者中的疗效超过安慰剂。我们将应用最好的创新技术来评估效果 通过与 Marilyn Huestis 博士 (NIDA/IRP) 合作，对 MJ 使用进行 vofopitant 治疗，她将提供 应用新方法分析受试者每周观察的尿液样本中的 CN-THCOOH 浓度 检测模型来识别 MJ 的新用途。该提案的另一个新颖之处是对执行人员的评估 在治疗方案的背景下发挥作用。 MJ 使用、MJ 退出和 MJ 之间的潜在关系 认知功能将进行统计检查。该项目的另一个目标是确定最常 CD 个体 可能受益于 vofopitant 并测量 vofopitant 相对于安慰剂对这些因素的影响， 从而阐明 NK1 拮抗剂对 CD 有效的机制。潜在基线 预测因素包括：a.) P 物质、ACTH、皮质醇和 NE，b.) 焦虑、情绪、失眠的主观测量， 渴望和压力； c.) 执行职能； d.) fMRI 对 MJ 线索、情绪线索和 在情感“Go-No-Go”任务中的抑制能力，以及休息期间的功能连接 状态。鉴于 CD 的流行和缺乏有效的药物治疗，伏匹坦的开发 作为治疗克罗恩病的新型药物，可能具有重大的公共健康益处。