Varenicline for Methamphetamine Dependence

描述（由申请方提供）：甲基苯丙胺（MA）依赖是对个人和公共健康造成有害后果的重要来源，包括HIV感染、心理困扰和心血管疾病（Cruickshank和Dyer，2009年），尤其是在美国西部。行为治疗，包括认知行为疗法（CBT）和应急管理（CM）是可用的（Lee和罗森2008），但效果有限。能够有效减少MA使用的药物可以与行为疗法相结合，这将代表治疗的重大进步。胆碱能机制在包括MA在内的兴奋剂依赖的神经生物学中很重要（Hiranita，Nawata et al. 2008;威廉姆斯和Adinoff 2008）。伐尼克兰是一种1422烟碱受体部分激动剂和17烟碱受体完全激动剂，被批准用于戒烟（冈萨雷斯，Rennard et al. 2006），并显示出治疗酒精依赖的前景（McKee，Harrison et al. 2009）。伐尼克兰可能有效治疗MA依赖，因为它具有多巴胺能效应、缓解多巴胺能和认知功能障碍以及激活烟碱胆碱能系统。基于这一基本原理和初步经验（在I期临床试验和II期试验中），研究人员提出了一项随机安慰剂对照、双盲的II期伐尼克兰MA依赖性临床试验。与戒烟治疗相似，研究药物将在一周内滴定至1 mg BID，之后受试者将在短暂的住院MA脱毒期（4晚）内服用伐尼克兰（1 mg BID）或安慰剂，随后再进行8周的门诊CBT治疗。短暂的住院戒毒是一项重要的设计创新，因为它有助于所有受试者实现短暂的戒断期，解决初始戒断症状，并允许测量伐尼克兰作为MA戒断治疗的疗效。随后的8周门诊治疗期允许研究者测试伐尼克兰在早期戒断期间预防MA复发的有效性。虽然未提供戒烟治疗，但将评估伐尼克兰对吸烟的潜在影响。

DESCRIPTION (provided by applicant): Methamphetamine (MA) dependence is a significant source of deleterious consequences to individual and public health including HIV infection, psychological distress, and cardiovascular disease (Cruickshank and Dyer 2009), particularly in the Western United States. Behavioral treatments, including cognitive behavioral therapy (CBT) and contingency management (CM) are available (Lee and Rawson 2008) but are modestly effective. Medications that have efficacy in reducing MA use that could be integrated with behavioral therapies would represent a significant advancement in treatment. Cholinergic mechanisms are important in the neurobiology of stimulant dependence including MA (Hiranita, Nawata et al. 2008; Williams and Adinoff 2008). Varenicline is a 1422 nicotinic receptor partial agonist and 17 nicotinic receptor full agonist that is approved for cigarette smoking cessation (Gonzales, Rennard et al. 2006) and shows promise for treating alcohol dependence (McKee, Harrison et al. 2009). Varenicline may be effective for the treatment of MA dependence due to dopaminergic effects, relief of glutamatergic and cognitive dysfunction, and activation of nicotinic cholinergic systems. Building upon this rationale and preliminary experiences (in a Phase I clinical trial and a pilot Phase II trial), the investigators propose a randomized placebo-controlled, double-blind Phase II clinical trial of varenicline for MA dependence. Similar to smoking cessation treatment, study medication will be titrated to 1 mg BID over one week after which participants will take varenicline (1 mg BID) or placebo during a brief inpatient MA-detoxification period (4 nights) followed by 8 additional weeks of outpatient treatment with CBT. The brief inpatient detoxification is an important design innovation, as it facilitates all subjects to achieve a brief period of abstinence, to resolve initial withdrawal symptoms, and to allow measurement of varenicline efficacy as a MA withdrawal treatment. The subsequent 8-week outpatient treatment period allows the investigators to test varenicline for efficacy in preventing MA relapse during early abstinence. Although smoking cessation treatment is not provided, potential effects of varenicline on cigarette smoking will be assessed.