Cannabis Dependence: Imaging and Medication Development

描述(申请人提供)：针对RFA-DA-04-014《大麻相关疾病药物开发》，本申请从两个角度解决大麻依赖问题：1)利用脑成像(EEG/ERP、功能磁共振成像和MRS)量化大麻的急性、慢性和戒断影响；2)使用这些数据作为探索大麻药物开发新策略的基础。目前尚不清楚大麻是如何影响大脑功能的，无论是急性还是长期使用，因此了解大麻依赖和戒断过程中大脑功能的变化将极大地帮助我们理解大麻滥用的神经生物学基础，从而成为开发治疗这种疾病的新药的重要基础。新的和改进的脑成像技术，如功能磁共振成像和MRS，为我们提供了一个独特的机会来观察这些微妙但重要的大脑功能变化。作为设计治疗大麻依赖药物的第一步，我们建议仔细记录急性给药对局部脑血流和脑化学的影响。这些效果将与急性戒断的大脑进行比较，因此将作为评估一种新型药物--胞苷-5‘-二磷酸胆碱(CDP-胆碱，胞二磷胆碱)--在减少大麻使用和扭转在大麻中毒和戒断期间发生的精神运动表现缺陷、记忆丧失和睡眠障碍方面的效果的基线。我们选择胞二磷胆碱是基于我们的偶然发现，在我们正在进行的临床试验中，它不仅减少了可卡因的使用，而且似乎也减少了大麻的吸烟。我们的实验利用了我们正在进行的可卡因依赖受试者的临床研究中获得的结果以及试点磁共振数据。如果呈阳性，这些结果可能对大麻依赖的药物治疗以及与长期使用大麻有关的神经生物学损害的一级和二级预防具有重要意义。此外，拟议项目的结果可以为大麻依赖的病理生理学和病程(以及潜在的其他药物依赖障碍)提供重要的见解。由于治疗药物滥用的多学科方法是最成功的，我们将使用2×2设计来测试胞二磷胆碱和认知行为疗法(CBT)联合治疗失眠作为治疗大麻依赖的有效方法。最后，鉴于胞二磷胆碱没有任何副作用，这些结果也可能为扩大相对有限的弱势人群的治疗选择提供重要线索，如孕妇、依赖药物的母亲所生的儿童和青少年。

DESCRIPTION (provided by applicant): This application, in response to RFA-DA-04-014 Medication Development for Cannabis-Related Disorders, addresses cannabis dependence from two perspectives: 1) quantifying the acute, chronic and withdrawal effects of cannabis using brain imaging (EEG/ERP, fMRI and MRS) and 2) using these data to serve as a foundation for exploring new strategies for cannabis medication development. It is unclear how cannabis affects brain function, either acutely or after chronic use so knowledge of the changes in brain function during cannabis dependence and withdrawal will aid greatly in our understanding of the neurobiological bases of cannabis abuse and will thus serve as an important foundation for developing new medications to treat this disorder. New and improved brain imaging techniques such as fMRI and MRS offer us a unique opportunity to view these subtle, yet important changes in brain function. As a first step in devising a medication to treat cannabis dependence we propose to carefully document the effects of acutely administered cannabis on regional cerebral blood flow and brain chemistry. These effects will be compared to the acutely withdrawn brain and thus will serve as baselines to assess the efficacy of a novel medication, cytidine-5'- diphosphate choline (CDP-choline, citicoline) in reducing cannabis use, and reversing the psychomotor performance deficits, memory loss and sleep disorders that occur during cannabis intoxication and withdrawal. We chose citicoline based on our serendipitous findings that it reduces not only cocaine use in our ongoing clinical trial, but appears to reduce marihuana smoking as well. Our experiments capitalize on the results obtained in our ongoing clinical studies of cocaine-dependent subjects along with pilot MR data. If positive, these results could have important implications for the pharmacotherapy of cannabis dependence as well as primary and secondary prevention of neurobiological damage associated with chronic cannabis use. Furthermore, the outcome of the proposed project could offer important insights into the pathophysiology and course of cannabis dependence (and potentially on other drug dependence disorders). As multidisciplinary approaches to treating drug abuse have been the most successful, we will use a 2 x 2 design to test the combination of citicoline and cognitive behavioral therapy (CBT) for insomnia as an effective treatment for cannabis dependence. Lastly, given the lack of any side effects of citicoline, these results also may provide important leads for expanding the relatively limited treatment options for vulnerable populations such as pregnant women, children born to drug dependent mothers, and adolescents.