Marijuana Relapse: Influence of Tobacco Cessation and Varenicline

描述(申请人提供)：对大麻治疗的需求远远超过了治疗策略的发展。我们的人体实验室研究表明，药物可以：减少大麻戒断症状和复发(洛非西定和屈诺比诺)，不影响任何结果(巴氯芬、米氮平)，或增加对大麻的渴望和复发(奎硫平)。此外，吸烟者(占样本的54%)再次吸食大麻的可能性是不吸烟者的9.5倍。这项提案将评估吸烟和药物治疗对大麻戒断和复发的影响，目的是利用这些数据来改善大麻治疗结果。目标1：比较吸食大麻的人在吸食大麻时和戒烟后的戒断和复发。在我们的住院模型中，每天吸食大麻的烟草依赖者将接受戒烟和正常吸烟两种情况下大麻复发的测试。我们假设，吸烟直接增加了大麻复发的可能性，因此吸食大麻的人在戒烟期间的复发频率将低于正常吸烟阶段。如果戒烟可以减少大麻的复发，那么就有充分的理由将戒烟纳入大麻治疗，以改善结果。如果戒烟对复发没有影响，那么未来的研究可以专注于为这一更难对付的大麻吸烟者群体开发强化大麻治疗策略。目的#2：确定烟碱型乙酰胆碱受体(NAChR)部分激动剂varenicline单独以及与大麻素激动剂Dronabinol联合使用是否能减少大麻的戒断和复发。依赖烟草的大麻吸烟者将戒烟(使用应急管理)，并随机接受安慰剂或瓦伦尼克林。在住院期间，安慰剂组和Varenicline组都将按平衡顺序给予活性和非活性的屈诺比诺。我们假设，与大麻素激动剂联合使用将最有效地减少该人群中的大麻复发。探索性目标3：为了评估应激反应和有针对性的基因多态作为复发和大麻效应的预测因子，所有参与者都将贡献一份DNA样本并接受特里尔社会压力测试(TSST)。我们预测：(1)对TSST表现出较大反应(皮质醇、心率)的个人将更有可能再次吸食大麻，(2)特定的基因多态将预测大麻中毒、渴望和复发加剧。这些研究的结果可能被用来更好地针对易受伤害的亚型大麻吸烟者进行靶向治疗。影响：由于大多数日常吸食大麻的人都吸烟草烟，而且吸烟预示着大麻的复发，这项提案将针对这一难以控制且数量可观的吸食大麻的人群，从而有助于大麻治疗的结果。 公共卫生相关性：对大麻治疗的需求远远超过了有效治疗战略的制定。来自我们的大麻依赖人体实验室模型的最新数据显示，每天吸食大麻的人也抽烟草香烟(占样本的54%)的人再次吸食大麻的可能性是不吸烟者的9.5倍。我们将直接评估吸烟和药物维持对大麻戒断和复发的影响，目的是利用这些数据来改善大麻治疗结果。

DESCRIPTION (provided by applicant): Demand for marijuana treatment has far outpaced the development of treatment strategies. Our human laboratory studies have shown that medications may: decrease marijuana withdrawal symptoms and relapse (lofexidine and dronabinol), not affect either outcome (baclofen, mirtazapine), or increase marijuana craving and relapse (quetiapine). Further, cigarette smokers (54% of sample) were 9.5 times more likely to relapse to marijuana than nonsmokers. This proposal will assess how cigarette smoking and medications influence marijuana withdrawal and relapse, with the aim of using these data to improve marijuana treatment outcome. Aim #1: Compare marijuana withdrawal and relapse when marijuana smokers are currently smoking cigarettes and after they have quit. Tobacco-dependent, daily marijuana smokers will be tested in our inpatient model of marijuana relapse during both a Quit and a Smoking-as-Usual condition. We hypothesize that cigarette smoking directly increases the likelihood of marijuana relapse, so that marijuana smokers will relapse less frequently in the Quit than in the Smoking-as-Usual phase. If quitting cigarettes decreases marijuana relapse, there would be a strong rationale for incorporating smoking cessation into marijuana treatment to improve outcome. If tobacco cessation has no effect on relapse, then future studies could focus on developing intensive marijuana treatment strategies for this more intractable subset of marijuana smokers. Aim #2: Determine if the nicotinic acetylcholine receptor (nAChR) partial agonist, varenicline, alone and in combination with the cannabinoid agonist, dronabinol, decreases marijuana withdrawal and relapse. Tobacco- dependent, marijuana smokers will quit smoking cigarettes (using contingency management) and be randomized to receive Placebo or Varenicline. While inpatient, both the Placebo and the Varenicline group will be given active and inactive dronabinol in counter-balanced order. We hypothesize that varenicline combined with a cannabinoid agonist will most efficaciously decrease marijuana relapse in this population. Exploratory Aim #3: To assess stress-responsivity and targeted genetic polymorphisms as predictors of relapse and marijuana effects All participants will contribute a DNA sample and undergo the Trier Social Stress Test (TSST). We predict that: (1) individuals who show a large response (cortisol, heart rate) to the TSST will be more likely to relapse to marijuana, and (2) specific genetic polymorphisms will predict enhanced marijuana intoxication, craving and relapse. The outcome of these studies may be used to better target treatment for vulnerable subtypes of marijuana smokers. Impact: Because most daily marijuana smokers smoke tobacco cigarettes, and because cigarette smoking is predictive of marijuana relapse, this proposal will contribute to marijuana treatment outcome by targeting this intractable and sizable population of marijuana smokers. PUBLIC HEALTH RELEVANCE: Demand for marijuana treatment has far outpaced the development of effective treatment strategies. Recent data from our human laboratory model of marijuana dependence show that daily marijuana smokers who also smoke tobacco cigarettes (54% of sample) were 9.5 times more likely to relapse to marijuana than nonsmokers. We will directly assess how cigarette smoking and medication maintenance influence marijuana withdrawal and relapse, with the aim of using these data to improve marijuana treatment outcome.