Neurobiology and Pharmacokinetics of Acute MDMA Administration

3,4-亚甲基二氧甲基苯丙胺（MDMA），俗称摇头丸，是一种被青少年和成年人滥用的合成化合物。在动物中，当给予高剂量和多剂量MDMA时，观察到血清素能毒性。临床上，与娱乐性使用相比，与摇头丸相关的严重急性毒性的数量很低。一些回顾性研究的数据显示，经常与其他非法和合法物质一起滥用MDMA的戒断慢性使用者存在记忆缺陷；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MDMA人体给药研究描述其急性生理和行为影响后，通常在年轻人中使用剂量。我们提出一项功能性磁共振成像（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浓度联系起来。

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.