CB1R Availability in Synthetic Psychoactive Cannabinoid Users

合成精神活性大麻素使用者中 CB1R 的可用性

• 批准号: 9244957
• 负责人: DEEPAK Cyril D'SOUZA
• 金额: $ 25.13万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9244957
• 关键词: Accident and Emergency department; Acute; Address; Admission activity; Adverse event; Affect; Affinity; Age; Agonist; Animals; Automobile Driving; Behavior; Binding; Biological Markers; Brain; CNR1 gene; Cannabinoids; Cannabis; Case Study; Chronic; Clinical Laboratory Information Systems; Cognition; Data; Dependence; Down-Regulation; Electrophysiology (science); Emergency department visit; Exposure to; Forensic Medicine; Gender; Glean; Goals; Human; Individual; Kinetics; Knowledge; Label; Law Enforcement; Ligands; Literature; Long-Term Effects; Measures; Medical; Methods; Names; Pharmaceutical Preparations; Pharmacology; Platinum; Poison Control Centers; Positron-Emission Tomography; Psychotic Disorders; Reporting; Reproducibility; Research; Resolution; Seizures; Spices; Surveys; System; Testing; Tetrahydrocannabinol; Time; Time Study; adverse outcome; base; cannabinoid receptor; cognitive function; cognitive performance; cognitive testing; desensitization; endogenous cannabinoid system; high resolution imaging; illicit drug use; in vivo; indexing; information processing; marijuana user; news; performance tests; receptor; tomography

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).

项目概要 背景：人们越来越关注合成精神活性大麻素的娱乐用途 （SPC）作为“香料”出售，与 δ-9-四氢大麻酚（THC）不同，后者是主要的精神活性成分。 草本大麻，是一种弱功效、低亲和力、脑大麻素受体（CB1Rs）的部分激动剂， SPC 是高效、高亲和力的完全 CB1R 激动剂，与此相符，而 SPC 产生一些。 与大麻类似的作用，它们通常更有效且不可预测； 尽管担心负面结果，但仍与灾难性的医疗和精神不良后果有关。 娱乐性香料使用的后果，关于急性或重复性影响的受控数据非常少 暴露于 SPC 对大脑内源性大麻素系统或一般大脑功能的主要目的。 拟议的研究，是比较 CB1R 在香料依赖者（香料使用者 [SUs]）、大麻依赖者中的可用性 （大麻使用者 [CU]）和健康对照（HC） 此外，还将评估认知测试表现。 为了将受体的可用性与与“现实世界”功能密切相关的域联系起来。 香料产品及其成分 SPC、其药理学差异以及 R21 的有限范围 应用程序中，我们需要将研究限制在研究期间最流行的 SPC 预计将启动后者根据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 有关 Spice 使用的中心和博客（例如，药物论坛）将按顺序进行评估。 将受体可用性与“现实世界”功能联系起来，类似地，大麻素敏感的电生理学。 信息处理措施（P300 和伽马驱动）将受体可用性与近端联系起来 大脑功能的生物标志物。 主要假设：与 CU 和 HC 相比，Spice 用户将表现出较低的 CB1R 可用性。 探索性假设：与 CU 和 HC 相比，SU 的认知测试表现较差，并且 信息处理的大麻素敏感电生理指标（P300 振幅和伽玛 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 HC 中进行测量。认知功能将使用评估。 CANTAB 电池和伽马振荡也将被测量。 初步结果：与大麻使用者相比，香料使用者 (n=2) 的 CB1R 可用性大幅下降 (n=11) 和健康对照 (n=19) SU 与 CU 之间的差异程度（效应大小 d）， SU 和 CU 之间的差异分别为 -1.29 和 -6。 CU 和 HC 之间的差异 (~15%, d=1.19)。