Medication Development for Marijuana Relapse

描述（由申请人提供）：只有一小部分寻求大麻治疗的人能够实现戒断。该提案将研究大麻与潜在治疗药物之间的相互作用，其直接目标是利用这些信息来改善大麻治疗结果。我们的大麻药物开发模型是基于这样的假设：减弱大麻的积极或消极强化效应将减少复发。目的1：确定阿片类拮抗剂纳曲酮是否能降低大麻的直接作用，从而降低吸食大麻的人再次吸食大麻的可能性；复发被定义为在一段时间的戒断后自我使用大麻。假设：纳曲酮会通过减少大麻的直接影响来减少大麻的复发。目的2：确定α 2-去甲肾上腺素能激动剂Iofexidine是否能减少大麻戒断，从而减少复发。洛非昔定将与口服四氢大麻酚进行比较，后者在产生最小中毒的剂量下减少大麻戒断症状。因此，将确定Iofexidine和口服四氢大麻酚单独或联合使用的效果。假设：1)洛非西定和口服四氢大麻酚单独使用会减少大麻戒断症状的一个明显子集，并会减少大麻复发；2)洛非昔定联合口服四氢大麻酚对大麻戒断症状和复发的减少最大。目的3：比较口服四氢大麻酚和使用新开发的口腔粘膜喷雾剂给药四氢大麻酚对大麻戒断和复发的影响。假设：1)单独喷雾和口服四氢大麻酚会减少大麻戒断症状和复发；2)与口服四氢大麻酚相比，喷雾四氢大麻酚能更持续地减少个体的大麻戒断症状和复发。目的4：确定GABAB激动剂巴氯芬是否能减少大麻的直接作用和戒断，从而减少复发。假设：巴氯芬会通过减少大麻的直接影响和戒断来减少大麻的复发。大麻素、阿片和GABA受体在中枢神经系统中有明显的相互作用，但这些相互作用的性质尚不清楚。这项建议的优势在于我们利用一个受控的实验室环境来检查潜在的治疗药物对大麻的直接作用、大麻戒断和大麻复发的相互作用。

DESCRIPTION (provided by applicant): Only a small percentage of marijuana treatment seekers are able to achieve abstinence. This proposal will investigate the interaction between marijuana and potential treatment medications, with the direct goal of using this information to improve marijuana treatment outcome. Our model for marijuana medication development is guided by the hypothesis that attenuating marijuana's positive or negative reinforcing effects will decrease relapse. AIM #1: To determine if the opioid antagonist, naltrexone, decreases marijuana's direct effects, and thus decreases the likelihood that marijuana smokers will relapse to marijuana use; relapse is defined as marijuana self-administration after a period of abstinence. Hypotheses: Naltrexone will decrease marijuana relapse by decreasing its direct effects. AIM #2: To determine if the alpha2-noradrenergic agonist, Iofexidine decreases marijuana withdrawal and thereby decreases relapse. Lofexidine will be compared to oral THC, which decreases marijuana withdrawal symptoms at doses that produce minimal intoxication. Thus, the effects of Iofexidine and oral THC alone and in combination will be determined. Hypotheses: 1) Lofexidine and oral THC alone will decrease a distinct subset of marijuana withdrawal symptoms, and will decrease marijuana relapse; 2) Lofexidine combined with oral THC will result in the largest decrease in marijuana withdrawal symptoms and relapse. AIM #3: To compare the effects of oral THC to THC administered using a newly developed oro-mucosal spray on marijuana withdrawal and relapse. Hypotheses: 1) Spray and oral THC alone will decrease marijuana withdrawal symptoms and relapse; 2) Spray THC will more consistently decrease marijuana withdrawal symptoms and relapse across individuals than oral THC. AIM #4: To determine if the GABAB agonist, baclofen decreases marijuana's direct effects and marijuana withdrawal, and thereby decreases relapse. Hypotheses: Baclofen will decrease marijuana relapse by decreasing both marijuana's direct effects and marijuana withdrawal. There are clear interactions between cannabinoid, opioid and GABA receptors in the CNS, yet the nature of these interactions remains unknown. The strength of this proposal lies in our utilization of a controlled laboratory setting to examine the interactive effects of potential treatment medications on marijuana's direct effects, marijuana withdrawal, and on marijuana relapse.