Quetiapine Pharmacotherapy for Cannabis Dependence

描述（由申请人提供）：尽管公众的看法是良性的，但大麻使用障碍代表了一个重大的公共卫生问题。由于治疗大麻依赖的唯一现有循证临床策略是行为干预，因此开发安全有效的大麻依赖药物治疗是一项重要的未满足的公共卫生需求。对大麻依赖的理想药物治疗是：1)对使用大麻的患者安全且耐受性良好；2)减少大麻摄入量并促进戒断；3)治疗大麻戒断症状。开发安全有效的药物治疗大麻依赖是一项重要的未满足的公共卫生需求。喹硫平是一种有效的非典型抗精神病药，通过阻断血清素2A型、多巴胺2型、组胺1型和肾上腺素能受体起作用，是一种很有前景的药物使用障碍治疗方法。在动物模型中，喹硫平阻断了可卡因对奖励的增强，这可能是由于其对多巴胺和非多巴胺神经传递的作用。喹硫平的临床研究表明，它有益于治疗酒精和可卡因使用障碍。从概念上讲，喹硫平在临床上的突出作用，即镇静、焦虑、情绪稳定和食欲刺激，与大麻戒断症状很好地匹配。最重要的是，我们的研究小组进行了一项关于喹硫平治疗大麻依赖的开放标签剂量研究，确定喹硫平耐受性良好，与大麻使用减少有关，这表明喹硫平是一种有前途的药物，值得在大麻依赖门诊患者中进一步研究。该研究项目是一项随机双盲安慰剂对照临床试验，旨在评估喹硫平治疗大麻依赖的疗效，为期12周。所有参与者都将接受医疗管理，这是一种以药物依从性为重点的社会心理干预，有助于遵守研究药物和其他研究程序，促进对大麻和其他物质的戒断，并鼓励相互支持的小组出席。所有参与者都将获得奖券奖励，以奖励他们遵守研究访问考勤、归还研究药物瓶和完成其他研究程序，目的是使样本高度符合要求。这项II期临床试验的目标是建立在我们有前景的开放标签试点研究结果的基础上，并在安慰剂控制的双盲条件下，使用戒断开始模型，检查喹硫平对参与者大麻消费的功效，参与者将在研究开始时定期使用大麻，减少使用，然后实现戒断。该项目的具体目的是确定喹硫平是否优于安慰剂：1)减少大麻的使用；2)实现戒断。

DESCRIPTION (provided by applicant): Despite a benign public perception, marijuana use disorders represent a significant public health problem. Because the only existing evidenced-based clinical strategies for treating marijuana dependence are behavioral interventions, the development of safe and effective pharmacotherapy for marijuana dependence is an important unmet public health need. The ideal pharmacotherapy for marijuana dependence would: 1) be safe and well tolerated when administered to patients using marijuana~ 2) reduce marijuana intake and promote abstinence~ and 3) treat the symptoms of marijuana withdrawal. The development of safe and effective pharmacotherapy's for marijuana dependence is an important unmet public health need. Quetiapine, an effective atypical antipsychotic that acts by blocking serotonin type 2A, dopamine type 2, histamine type 1, and adrenergic receptors, is a promising treatment for substance use disorders. In animal models, quetiapine blocks the enhancement of reward by cocaine, which is likely due to its actions on both dopamine and non-dopamine neurotransmission. Clinical studies of quetiapine have shown benefit for the treatment of alcohol and cocaine use disorders. Conceptually, the clinically prominent effects of quetiapine, namely sedation, anxiolysis, mood stabilization and appetite stimulation, are a good match for the symptoms of marijuana withdrawal. Most importantly, an open-label dose-finding study of quetiapine for the treatment of marijuana dependence conducted by our research group determined that quetiapine was well-tolerated and associated with reductions in marijuana use indicating that it is a promising agent deserving of further study in marijuana-dependent outpatients. The proposed research project is a randomized double-blind placebo-controlled clinical trial to evaluate the efficacy of quetiapine for the treatment of marijuana dependence over a 12-week period. All participants will receive Medical Management, a medication adherence focused psychosocial intervention that facilitates compliance with study medication and other study procedures, promotes abstinence from marijuana and other substances, and encourages mutual-support group attendance. All participants will receive voucher incentives for compliance with study visit attendance, returning study medication bottles, and completing other study procedures, with the objective of achieving a highly compliant sample. The goal of this phase II clinical trial is to build on our promising open-label pilot study results and examine th efficacy of quetiapine on participants' marijuana consumption under placebo-controlled double-blind conditions using an abstinence-initiation model, where participants will be using marijuana regularly at study entry, reduce their use, and then achieve abstinence. The specific aims of the projects are to determine whether quetiapine is superior to placebo in 1) reducing marijuana use and 2) achieving abstinence. PUBLIC HEALTH RELEVANCE: Marijuana dependence is the most prevalent illicit drug dependence in the U.S. and is a significant public health problem responsible for substantial health and economic costs. There are no available medication treatments for marijuana dependence~ the only available evidence-based treatments are psychosocial interventions with limited efficacy. The development of effective pharmacotherapy for marijuana dependence would increase both the availability and accessibility of treatment for marijuana dependence.