Medication Development for Marijuana Relapse

描述(申请人提供)：只有一小部分寻求大麻治疗的人能够实现戒烟。该提案将调查大麻和潜在治疗药物之间的相互作用，直接目的是利用这一信息来改善大麻治疗结果。我们的大麻药物开发模型是以一种假设为指导的，即减弱大麻的正面或负面强化作用将减少复发。目的1：确定阿片类拮抗剂纳曲酮是否能减少大麻的直接影响，从而降低吸烟者重新吸食大麻的可能性；复发的定义是戒断一段时间后大麻的自我管理。假设：纳曲酮将通过减少其直接影响来减少大麻复发。目的#2：确定α2去甲肾上腺素能激动剂碘非西定是否能减少大麻戒断，从而减少复发。洛非西定将与口服THC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，将确定碘非西定和口服THC单独或联合使用的效果。假设：1)洛非西定和口服THC单独使用将减少大麻戒断症状的一个明显亚组，并将减少大麻复发；2)洛非西定联合口服THC将导致大麻戒断症状和复发的最大程度的减少。目的#3：比较口服THC和使用新开发的口腔黏膜喷雾剂对大麻戒断和复发的影响。假设：1)喷雾和口服THC单独可以减少大麻戒断症状和复发；2)喷雾THC将比口服THC更一致地减少大麻戒断症状和个人复发。目的#4：确定GABAB激动剂巴氯芬是否能减少大麻的直接影响和大麻戒断，从而减少复发。假设：巴氯芬将通过减少大麻的直接影响和大麻戒断来减少大麻复发。在中枢神经系统中，大麻素、阿片和GABA受体之间存在明显的相互作用，但这些相互作用的性质尚不清楚。这项建议的力量在于我们利用受控的实验室环境来检查潜在治疗药物对大麻的直接影响、大麻戒断和大麻复发的交互作用。

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.