Neurobiology and Pharmacokinetics of Acute MDMA Administration

3，4-亚甲二氧基甲基苯丙胺（MDMA），俗称摇头丸，是一种合成化合物，被青少年和成年人滥用。在动物中，当给予高剂量和多次剂量的MDMA时，观察到了多巴胺能毒性。临床上，与娱乐性使用的程度相比，摇头丸相关的严重急性毒性的数量较低。一些回顾性研究的数据报告了经常与其他非法和合法物质一起滥用二亚甲基双氧安非他明的长期戒断使用者的记忆缺陷;因此，难以确定二亚甲基双氧安非他明对观察到的认知缺陷的作用。很少有前瞻性对照MDMA人体给药研究描述其在年轻人中常用剂量后的急性生理和行为效应。 我们提出了一个功能性磁共振成像（fMRI）研究，以检查大脑活动和认知能力的具体变化，并将这些变化与血浆MDMA浓度。 我们提出了一个主题内设计的变化，记忆，注意力，影响，语义处理和决策性能安慰剂和两个娱乐MDMA剂量与功能磁共振成像监测和血浆收集。 其次，将收集MDMA及其代谢物在血浆、尿液、口腔液、汗液、呼吸和毛发中分布的药代动力学数据。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能够作为急诊医学和公共安全环境中的有效诊断工具，以及治疗研究中有用的客观结果测量。 受试者人群：目前MDMA使用者和MDMA非使用者（对照组），年龄在18至40岁之间。 实验设计和方法：拟定了一项随机、平衡、双盲、受试者内药物给药研究，包括安慰剂、低剂量（1.0 mg/kg，约70 mg）和高剂量（1.6 mg/kg，约112 mg）MDMA。 另一个不接受药物的MDMA非使用者队列将允许对人群组之间的性状差异进行受试者间分析，并提供认知任务的规范性数据。而在MDMA的影响下，参与者将在fMRI扫描之前，期间和之后执行记忆，注意力，语义处理，情感和决策任务。将在整个研究期间监测生理、行为和生化指标，以确定药效学效应的发生、程度和持续时间。将采集血液、尿液、口腔液、汗液和毛发样本，通过GC/MS和/或LC/MS/MS分析MDMA和代谢物浓度，以确定MDMA的分布和药代动力学。

3,4-Methylenedioxymethamphetamine (MDMA), commonly known as ecstasy, is a synthetic compound that is abused by adolescents and adults. 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 MDMAs 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. 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 also will 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, 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.