Cannabis Dependence: Imaging and Medication Development

描述（由申请人提供）：本申请响应RFA-DA-04-014大麻相关疾病的药物开发，从两个角度解决大麻依赖问题：1）使用脑成像（EEG/ERP，fMRI和MRS）量化大麻的急性，慢性和戒断作用，2）使用这些数据作为探索大麻药物开发新策略的基础。目前还不清楚大麻如何影响大脑功能，无论是急性还是慢性使用后，因此大麻依赖和戒断期间大脑功能变化的知识将大大有助于我们了解大麻滥用的神经生物学基础，因此将成为开发新药物治疗这种疾病的重要基础。新的和改进的脑成像技术，如功能磁共振成像和磁共振波谱为我们提供了一个独特的机会，以查看这些微妙的，但重要的变化，大脑功能。作为设计药物治疗大麻依赖的第一步，我们建议仔细记录急性施用大麻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，因此将作为基线，以评估一种新型药物，胞苷-5 '-二磷酸胆碱（CDP-胆碱，胞二磷胆碱）在减少大麻使用，逆转大麻中毒和戒断期间发生的精神表现缺陷，记忆丧失和睡眠障碍方面的疗效。我们选择胞磷胆碱是基于我们的偶然发现，它不仅减少了我们正在进行的临床试验中可卡因的使用，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临床研究中获得的结果，沿着飞行员MR数据。如果是积极的，这些结果可能对大麻依赖的药物治疗以及与慢性大麻使用相关的神经生物学损伤的一级和二级预防具有重要意义。此外，拟议项目的成果可为了解大麻依赖的病理生理学和过程（以及可能对其他药物依赖性疾病）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设计来测试胞磷胆碱和认知行为疗法（CBT）联合治疗失眠作为大麻依赖的有效治疗方法。最后，鉴于胞磷胆碱没有任何副作用，这些结果也可能为扩大弱势群体（如孕妇、药物依赖母亲所生子女和青少年）相对有限的治疗选择提供重要线索。

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 These effects will be compared to the acutely withdrawn brain and thus will serve as baselines to assess the efficacy of a novel medication, cytidine-5'- diphosphate choline (CDP-choline, citicoline) in reducing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.