Citicoline-Induced Modulation of Cannabis Effects: Imaging & Mechanism of Action

描述(申请人提供)：大麻是美国最常见的滥用非法药物，但目前还没有针对其滥用或依赖的治疗方法。作为一个重大的公共卫生问题，因为它与药物滥用的门户理论有关，NIDA在过去几年的任务一直是为了找出安全有效的大麻滥用和依赖的候选疗法，特别是那些可以提供给弱势群体的疗法。这项提案的总体目标是测试天然脑部化学物质胞苷-5‘-二磷酸胆碱(胞二磷胆碱)的营养补充剂对大麻诱导的中毒和滥用模式的影响。这种补充剂最近在一项根据RFA-DA-04-014(大麻相关疾病的药物开发)授予的赠款的开放标签试验中被证明可以减少大麻的使用。由于胞二磷胆碱是哺乳动物大脑中的一种天然化学物质，它相对安全，在治疗中风和其他神经疾病方面非常有用。目前尚不清楚大麻对大脑功能的影响，无论是急性使用还是长期使用，因此拟议的研究旨在收集数据，作为探索治疗大麻滥用的新策略的基础。这些目标将通过使用脑电成像、磁共振成像等脑成像技术来实现，并将进行研究，以确定胞二磷胆碱对大麻使用的作用机制及其令人陶醉的效果。作为设计治疗大麻依赖药物的第一步，我们建议对胞二磷胆碱在自然环境下对大麻使用模式进行双盲、安慰剂对照评估。然后，我们将使用BOLD信号检测来记录急性给药大麻对局部脑血流的影响。最后，我们将研究胞二磷胆碱是否改变了大麻线索诱导的渴望。总而言之，这些研究应该会产生重要的信息，说明补充一种天然的大脑化学物质如何改变大麻的效果，从而减少它的使用。本系列研究的结果可能对大麻依赖的药物治疗以及与长期使用相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过程(以及潜在的其他药物依赖障碍)提供重要的见解。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，例如孕妇、依赖药物的母亲所生的儿童和青少年。与公共健康相关：大麻是美国最常被滥用的非法药物，但目前还没有针对其滥用或依赖的治疗方法。胞二磷胆碱是大脑中一种自然产生的化学物质，在一项试点临床试验中被证明可以减少大麻的使用。利用磁共振脑成像和脑电技术，这一应用将探索大麻依赖的作用机制，并开发新的治疗策略。

DESCRIPTION (provided by applicant): Marihuana is the most commonly abused illegal drug in the United States, yet there are no treatments for its abuse or dependence. As a significant public health problem because of its known association with the Gateway theory of drug abuse, NIDA's mission over the past few years has been aimed at identifying safe and effective candidate therapies for marihuana abuse and dependence, particularly those that can be given to vulnerable populations. The overall objectives of this proposal are to test a nutritional supplement of the natural brain chemical, cytidine-5'-diphosphate choline (citicoline) for its effects on marihuana-induced intoxication and abuse patterns. This supplement was recently shown to reduce marihuana use in an open label trial of a grant that was awarded under RFA-DA-04-014 (Medication Development for Cannabis-Related Disorders). Because citicoline is a natural chemical in mammalian brain, it is relatively safe and has been very useful in treating stroke and other neurological disorders. It is still unclear how marihuana affects brain function, either acutely or after chronic use, so the proposed studies are designed to collect data that will serve as a foundation for exploring new strategies for treating marihuana abuse. These goals will be accomplished by using brain imaging techniques such as electroencephalography, magnetic resonance imaging and studies will be conducted to identify the mechanism of action of citicoline's effects on marihuana use and its intoxicating effects. As a first step in devising a medication to treat marihuana dependence we propose to conduct a double-blind, placebo-controlled assessment of citicoline on marihuana use patterns in a natural setting. We will then document the effects of acutely administered marihuana on regional cerebral blood flow using BOLD signal detection. Finally, we will study whether citicoline alters marihuana-induced cue-induced craving. Collectively, these studies should yield important information on how supplementation with a natural brain chemical alters marihuana's effects such that its use is decreased. The results of the present series of studies could have important implications for the pharmacotherapy of marihuana dependence as well as primary and secondary prevention of the neurobiological damage associated with chronic use. Furthermore, the outcome of the proposed project could offer important insights into the pathophysiology and course of marihuana dependence (and potentially on other drug dependence disorders). 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. PUBLIC HEALTH RELEVANCE: Marihuana is the most commonly abused illegal drug in the United States, yet there are no treatments for its abuse or dependence. Citicoline, a naturally occurring chemical in the brain, has been shown to reduce marihuana use in a pilot clinical trial. Using magnetic resonance brain imaging and EEG techniques, this application will explore the mechanism of action and develop new treatment strategies for marihuana dependence.