Marijuana Relapse: Influence of Tobacco Cessation and Varenicline

描述（由申请人提供）：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（洛非西定和屈大麻酚），不影响任何结果（巴氯芬，米氮平），或增加大麻的渴望和复发（喹硫平）。此外，吸烟者（占样本的54%）重吸大麻的可能性是不吸烟者的9.5倍。该提案将评估吸烟和药物如何影响大麻戒断和复发，目的是利用这些数据来改善大麻治疗的结果。目标1：比较吸食大麻的人正在吸烟和戒烟后的戒断和复吸情况。对烟草依赖的、每天吸食大麻的人将在我们的住院模型中接受大麻复发的测试，在戒烟和正常吸烟的情况下。我们假设吸烟直接增加了吸食大麻复发的可能性，因此吸食大麻的人在戒烟阶段比在正常吸烟阶段复发的频率要低。如果戒烟减少了大麻的复发，那么将戒烟纳入大麻治疗以改善结果的理由就很充分了。如果戒烟对复发没有影响，那么未来的研究可以集中在为大麻吸烟者这一更棘手的子集开发强化大麻治疗策略上。目的2：确定烟碱乙酰胆碱受体（nAChR）部分激动剂varenicline单独或与大麻素激动剂屈大麻酚（dronabinol）联合使用是否能减少大麻戒断和复发。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伐尼克兰。在住院期间，安慰剂组和伐尼克兰组将按平衡顺序给予活性和非活性屈大麻酚。我们假设伐尼克兰联合大麻素激动剂将最有效地减少这一人群的大麻复发。探索性目标#3：评估压力反应性和靶向基因多态性作为复发和大麻效应的预测因素。所有参与者将提供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）的个体更有可能再次吸食大麻；(2)特定的遗传多态性将预测大麻中毒，渴望和复发。这些研究的结果可能用于更好地靶向治疗易受伤害的大麻吸烟者亚型。影响：由于大多数日常吸食大麻的人吸食的是烟草，并且因为吸烟是大麻复发的预测因素，因此该提案将通过针对这一棘手且数量庞大的大麻吸食者群体，有助于大麻治疗的结果。

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.