Pharmacological Treatment of Cannabis Withdrawal and Dependence

大麻戒断和依赖性的药物治疗

• 批准号: 8788513
• 负责人: BARBARA J MASON
• 金额: $ 65.98万
• 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 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8788513
• 关键词: Abstinence; Address; Affective; Agonist; Amygdaloid structure; Antidepressive Agents; Anxiety; Behavior; Behavior Therapy; Brain; Cannabis; Clinical; Cognitive Therapy; Collaborations; Corticotropin; Cues; Data; 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; 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; cannabis withdrawal; cognitive function; control trial; craving; disturbance in affect; executive function; gabapentin; improved; innovation; innovative technologies; marijuana use; marijuana withdrawal; neuroregulation; 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.

项目摘要 /摘要 大麻依赖（CD）是全球公共卫生问题。治疗的功效有限；一 原因可能是无法解决戒断症状的原因，例如渴望和情感干扰 和睡眠，这可能会激发恢复大麻（MJ）的使用。此外，大量的MJ使用和提取可以 损害执行功能，从而干扰参与认知疗法。主要目的 该阶段II，单位，8周，双盲，安慰剂对照的随机临床试验是为了评估 新型Neurokinin1（NK1）受体拮抗剂，vopitant（5mg/day）的功效，用于100 现有CD的门诊病人。反应NK1系统作为CD中的新目标的理论基本原理是 基于成瘾中禁欲的神经生物学，涉及大脑压力和奖励失调 系统，即杏仁核中脑应力系统的激活，该系统被认为是vopitant的，以归一化。 在我们的初步研究中，我们表明宣传剂显着降低了沉淀的戒断症状 依赖THC的大鼠，并提供了加巴喷丁的原则对照试验证明的阳性结果（也是 假设将大脑应力电路归一化），发现MJ的使用显着降低了 症状，包括渴望，情绪和睡眠，以及相对于安慰剂在50 CD中的安慰剂的提高 主题。正在测试的主要假设是vopitant将显着改善 大麻提取大麻，特别渴望，焦虑，情绪和睡眠，并减少MJ使用和MJ相关 对MJ提示和情感提示的执行功能和fMRI大胆响应的失调大大调节 在CD门诊患者中不仅仅是安慰剂。我们将运用最佳创新技术来评估 通过与Marilyn Huestis博士（NIDA/IRP）的合作，对MJ的宣传治疗 分析受试者每周观察到的尿液标本中的CN-THCOOH浓度，应用新的样本 检测模型以识别新的MJ使用。该提案的另一个新颖方面是评估执行 在治疗方案的背景下运作。 MJ使用，MJ撤回和 认知功能将在统计上进行检查。该项目的进一步目的是确定CD大多数 可能会从vopitant中受益，并测量相对于安慰剂对这些因素的影响， 从而阐明了NK1拮抗剂在CD中具有功效的机制。潜在基线 预测因子是：a。）物质P，ACTH，皮质醇和NE，b。）焦虑，情绪，失眠， 渴望和压力； c。）执行功能； d。）fMRI对MJ提示，情感提示和 在情感上不执行任务的背景下，抑制能力和休息期间的功能连接 状态。鉴于CD的患病率和缺乏有效的药物疗法，vopitats的发展 作为CD的新药物，可能具有重大的公共卫生益处。