Neurobiology/Pharmacokinetics-Acute MDMA Administration

3，4-亚甲基二氧基甲基苯丙胺(MDMA)，俗称摇头丸，是一种合成化合物，近年来年轻人滥用的情况急剧增加。在动物中，当给予高剂量和多剂量的MDMA时，观察到5-羟色胺能毒性。临床上，与娱乐使用程度相关的与摇头丸相关的严重急性毒性的数量很低。一些回顾研究的数据报告了经常与其他非法和合法物质一起滥用MDMA的禁欲长期使用者的记忆缺陷；因此，很难确定MDMA对观察到的认知缺陷的贡献。很少有前瞻性对照研究描述MDMA在年轻人常用剂量后的急性生理和行为影响。我们提出了一项功能磁共振成像(FMRI)研究，以检查大脑活动和认知表现的特定变化，并将这些变化与血浆MDMA浓度相关联。 目标：主要目标是确定MDMA对人脑功能的影响，并阐明这些影响与血浆MDMA浓度的关系。我们提出了一种受试者内设计，研究在服用安慰剂和两次休闲服用MDMA后，记忆、注意力、情感、语义加工和决策能力的变化，同时进行fMRI监测和血浆采集。其次，将收集MDMA及其代谢物在血浆、尿液、口腔液体、汗液、呼吸和头发中的药代动力学数据。需要这些数据来准确解释替代生物基质中的药物浓度，以便药物测试在药物滥用治疗、执法、军事和工作场所药物测试计划中起到威慑药物使用的作用。药代动力学数据还将使药物测试在急诊医学和公共安全环境中成为有效的诊断工具，并在治疗研究中作为有用的客观结果衡量标准。 研究对象：年龄在18岁至40岁之间的当前MDMA使用者和非MDMA使用者(对照组)。 实验设计与方法：采用随机、平衡、双盲、受试者内给药试验，分别给予安慰剂、低剂量(1.0 mg/kg，约70 mg)和高剂量(1.6 mg/kg，约112 mg)的MDMA。另外一组不使用摇头丸的人将不会接受药物，这将允许对人群组之间的特征差异进行受试者之间的分析，并为认知任务提供标准数据。而在MDMA的影响下，参与者将在fMRI扫描前、中和之后执行记忆、注意力、语义加工、情感和决策任务。在整个研究过程中，将监测生理、行为和生化指标，以确定药效作用的开始、程度和持续时间。将采集血液、尿液、口腔液体、汗液、呼吸和头发样本，通过GC/MS和/或LC/MS/MS分析MDMA及其代谢物浓度，以确定MDMA的处置和药代动力学。

3,4-Methylenedioxymethamphetamine (MDMA), commonly known as ecstasy, is a synthetic compound that has shown a steep increase in abuse by young people in recent years. In animals, when high and multiple doses of MDMA were given, serotonergic toxicity was observed. Clinically, the number of severe ecstasy related acute toxicities is low in relation to the extent of recreational use. Data from some retrospective studies report memory deficits in abstinent chronic users who often abuse MDMA with other illicit and licit substances; therefore, it is difficult to determine MDMA's contribution to observed cognitive deficits. There are few prospective controlled MDMA human administration studies that describe its acute physiological and behavioral effects following doses commonly used in young adults. We propose a functional magnetic resonance imaging (fMRI) study to examine specific changes in brain activity and cognitive performance and to correlate these changes with plasma MDMA concentrations. Goals: The primary goals are identification of MDMA effects on human brain function and elucidation of the relationship of effects to plasma MDMA concentrations. We propose a within-subject design of changes in memory, attention, affect, semantic processing and decision-making performance following placebo and two recreational MDMA doses with simultaneous fMRI monitoring and plasma collections. Secondly, pharmacokinetic data will be collected on the disposition of MDMA and metabolites in plasma, urine, oral fluid, sweat, breath, and hair. These data are needed to accurately interpret drug concentrations in alternative biological matrices in order for drug tests to function as a deterrent to drug use in drug abuse treatment, law enforcement, military, and workplace drug testing programs. Pharmacokinetic data will also enable drug tests to serve as valid diagnostic tools in emergency medicine and public safety settings, as well as useful objective outcome measures in treatment research. Subject Population: Current MDMA users and MDMA non-users (control group) between the ages of 18 and 40. Experimental Design and Methods: A randomized, balanced, double blind, within-subject drug administration study with placebo, low (1.0 mg/kg, approximately 70 mg) and high (1.6 mg/kg, approximately 112 mg) doses of MDMA is proposed. An additional cohort of MDMA non-users, who will not receive drug, will allow for a between-subjects analysis for trait differences between the population groups, as well as provide normative data for the cognitive tasks. While under the influence of MDMA, participants will perform memory, attention, semantic processing, affect and decision-making tasks before, during, and after fMRI scanning. Physiological, behavioral and biochemical measures will be monitored throughout the study to determine onset, magnitude and duration of pharmacodynamic effects. Blood, urine, oral fluid, sweat, breath, and hair specimens will be collected for analysis of MDMA and metabolite concentrations by GC/MS and/or LC/MS/MS to determine the disposition and pharmacokinetics of MDMA.