CB1R Availability in Synthetic Psychoactive Cannabinoid Users

项目总结 背景：人们越来越关注人工合成精神活性大麻素的娱乐用途 (SPC)作为‘香料’出售。与β-9-四氢大麻酚(THC)不同的是，它的主要精神活性成分 草本大麻，是一种药效弱、亲和力低、部分激动剂的脑部大麻受体(CB1Rs)， SPC是一种高效、高亲和力、全CB1R激动剂。与此配置文件一致，而SPC产生了一些 影响类似于大麻，它们通常更有效和不可预测；事实上，SPC一直是 与灾难性的医疗和精神不良后果有关。尽管人们对负面消息感到担忧 娱乐性香料使用的后果，关于急性或重复使用香料的影响的受控数据很少 暴露于SPC对大脑内源性大麻素系统或一般大脑功能的影响。的主要目的是 拟议的研究，是比较CB1R在香料依赖(香料使用者[SU])、大麻依赖中的可用性 (大麻使用者[CU])和健康对照(HCS)。此外，还将评估认知测试的表现 为了将受体的可用性与与“真实世界”功能密切相关的区域联系起来。考虑到过多的 香料产品及其组成的SPC、它们的药理差异以及R21的有限范围 应用，我们将需要将研究限制在研究时间附近最流行的SPC 预计将启动。后者将根据从国家法医收集的信息进行识别 实验室信息系统(NFLIS)、当地DEA办公室、当地急诊室、新闻媒体、毒物控制 关于香料使用的中心和博客(例如，药物论坛)。认知测试成绩将按顺序进行评估 将受体的可获得性与“真实世界”的功能联系起来。同样，对大麻素敏感的电生理学 信息处理措施(P300和伽马驱动)将使受体的可用性与近端相关 脑功能的生物标志物。 基本假设：与CU和HCS相比，SPICE用户的CB1R可用性较低。 探索性假设：与CUS和HCS相比，SUS的认知测试成绩更差，并且 信息加工的大麻素敏感电生理指标(P300波幅和伽马 振荡)。 方法：使用CB1R特异性PET配体[11C]Omar和高分辨率研究断层扫描 (HRRT)，CB1R可用性将在SU、CU和HCS中衡量。认知功能的评估将使用 Cantab牌电池。还将测量P300和伽马振荡。 初步结果：与大麻使用者相比，香料使用者(n=2)的CB1R可得性显著下降 对照组19例，正常对照组19例。SU和CU之间的差异的大小(效果大小d)， Hcs分别为-1.29和-6。SU和CU之间的差异在大小上相当于 CUS和HcS之间的差异(~15%，d=1.19)。

PROJECT SUMMARY Background: There is growing concern about the recreational use of synthetic psychoactive cannabinoids (SPCs) sold as `Spice'. Unlike, delta-9-tetrahydrocannabinol (THC), the principal psychoactive constituent of herbal cannabis, which is a weak efficacy, low affinity, partial agonist of brain cannabinoid receptors (CB1Rs), SPCs are high efficacy, high affinity, full CB1R agonists. Consistent with this profile, while SPCs produce some effects similar to cannabis, they are generally more potent and unpredictable; in fact SPCs have been associated with catastrophic medical and psychiatric adverse outcomes. Despite concerns about the negative consequences of recreational Spice use, there is very little controlled data on the effects of acute or repeated exposure to SPCs on the brain endocannabinoid system or brain function in general. The main purpose of the proposed study, is to compare CB1R availability in Spice dependent (Spice users [SUs]), cannabis dependent (cannabis users [CUs]) and healthy controls (HCs). Furthermore, cognitive test performance will be assessed in order to relate the receptor availability to domains germane to “real world” functioning. Given the plethora of Spice products and their constituent SPCs, differences in their pharmacology, and the limited scope of an R21 application, we will need to limit the study to the most prevalent SPC around the time around the time the study is expected to be initiated. The latter will identified based on information gleaned from the National Forensic Laboratory Information System (NFLIS), local DEA office, local emergency rooms, news media, Poison Control Centers and blogs about Spice use (e.g., Drugs-Forum). Cognitive test performance will be assessed in order to relate receptor availability to “real world” functioning. Similarly, cannabinoid-sensitive electrophysiological measures of information processing (P300 and gamma driving) will relate receptor availability to proximal biomarkers of brain function. Primary Hypothesis: Spice users will show lower CB1R availability compared to CUs and HCs. Exploratory Hypotheses: Compared to CUs and HCs, SUs will show worse cognitive test performance, and cannabinoid-sensitive electrophysiological indices of information processing (P300 amplitude and gamma oscillations). Methods: Using the CB1R specific PET ligand [11C]OMAR and High Resolution Research Tomography (HRRT), CB1R availability will be measured in SUs, CUs and HCs. Cognitive function will be assessed using the CANTAB battery. P300 and gamma oscillations will also be measured. Preliminary Results: Spice Users (n=2) show robust reductions in CB1R availability relative to cannabis users (n=11) and healthy controls (n=19). The magnitude of the differences (effects size d) between SUs vs. CUs, and HCs were -1.29 and -6, respectively. Differences between SUs and CUs were comparable in magnitude to the differences between CUs and HCs (~15%, d=1.19).