Neurobiology and Pharmacokinetics of Acute MDMA Administration

急性 MDMA 给药的神经生物学和药代动力学

基本信息

批准号：
7966817
负责人：
MARILYN A HUESTIS
金额：
$ 30.77万
依托单位：
NATIONAL INSTITUTE ON DRUG ABUSE
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7966817
关键词：
Acute Adolescent Adult Affect Age Animals Attention Behavioral Biochemical Biological Blood Brain Chronic Cognitive Cognitive deficits Collection Control Groups Data Decision Making Diagnostic Dose Double-Blind Method Drug Kinetics Drug abuse Drug usage Emergency Medicine Equilibrium Experimental Designs Functional Magnetic Resonance Imaging Goals Hair Human Law Enforcement Liquid substance Magnetic Resonance Imaging Measures Memory Memory impairment Methods Military Personnel Monitor Neurobiology Oral Outcome Measure Participant Performance Pharmaceutical Preparations Pharmacodynamics Physiological Placebos Plasma Population Population Group Randomized Reporting Research Subjects Retrospective Studies Safety Specimen Sweat Sweating Toxic effect Urine Whole Blood Workplace cohort design drug testing ecstasy programs prospective semantic processing tool trait young adult

项目摘要

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.

3,4-亚甲二氧基甲基苯丙胺 (MDMA)，俗称摇头丸，是一种被青少年和成人滥用的合成化合物。在动物身上，当给予高剂量和多次剂量的 MDMA 时，观察到血清素毒性。临床上，与娱乐性使用程度相关的严重摇头丸相关急性毒性的数量较低。一些回顾性研究的数据表明，经常与其他非法和合法物质一起滥用 MDMA 的长期戒毒者存在记忆缺陷；因此，很难确定摇头丸对观察到的认知缺陷的影响。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影响。我们提出了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 浓度相关联。我们提出了一种受试者内设计，研究服用安慰剂和两种娱乐性 MDMA 剂量后记忆、注意力、情感、语义处理和决策表现的变化，并同时进行功能磁共振成像监测和血浆采集。其次，将收集有关 MDMA 及其代谢物在血浆、尿液、口腔液、汗液、呼吸和头发中的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，以便药物测试能够在药物滥用治疗、执法、军事和工作场所药物测试项目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成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：当前 MDMA 使用者和年龄在 18 岁至 40 岁之间的 MDMA 非使用者（对照组）。实验设计和方法：提出一项随机、平衡、双盲、受试者体内给药研究，使用安慰剂、低剂量（1.0 mg/kg，约 70 mg）和高剂量（1.6 mg/kg，约 112 mg）MDMA 。另外一组不接受药物的 MDMA 非使用者将允许对人群之间的特征差异进行受试者间分析，并为认知任务提供规范数据。在摇头丸的影响下，参与者将在功能磁共振成像扫描之前、期间和之后执行记忆、注意力、语义处理、情感和决策任务。在整个研究过程中将监测生理、行为和生化指标，以确定药效学效应的发生、程度和持续时间。将收集血液、尿液、口腔液、汗液和头发样本，通过 GC/MS 和/或 LC/MS/MS 分析 MDMA 和代谢物浓度，以确定 MDMA 的处置和药代动力学。