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.

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Desrosiers, Nathalie A; Barnes, Allan J; Hartman, Rebecca L et al. (2013) Oral fluid and plasma 3,4-methylenedioxymethamphetamine (MDMA) and metabolite correlation after controlled oral MDMA administration. Anal Bioanal Chem 405:4067-76
Schwaninger, Andrea E; Meyer, Markus R; Barnes, Allan J et al. (2012) Stereoselective urinary MDMA (ecstasy) and metabolites excretion kinetics following controlled MDMA administration to humans. Biochem Pharmacol 83:131-8
Schwaninger, Andrea E; Meyer, Markus R; Huestis, Marilyn A et al. (2011) Development and validation of LC-HRMS and GC-NICI-MS methods for stereoselective determination of MDMA and its phase I and II metabolites in human urine. J Mass Spectrom 46:603-14
Barnes, Allan J; Scheidweiler, Karl B; Kolbrich-Spargo, Erin A et al. (2011) MDMA and metabolite disposition in expectorated oral fluid after controlled oral MDMA administration. Ther Drug Monit 33:602-8
Schwaninger, Andrea E; Meyer, Markus R; Barnes, Allan J et al. (2011) Urinary excretion kinetics of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) and its phase I and phase II metabolites in humans following controlled MDMA administration. Clin Chem 57:1748-56
Scheidweiler, Karl B; Ladenheim, Bruce; Barnes, Allan J et al. (2011) (±)-3,4-methylenedioxymethamphetamine and metabolite disposition in plasma and striatum of wild-type and multidrug resistance protein 1a knock-out mice. J Anal Toxicol 35:470-80
Scheidweiler, Karl B; Ladenheim, Bruce; Cadet, Jean Lud et al. (2010) Mice lacking multidrug resistance protein 1a show altered dopaminergic responses to methylenedioxymethamphetamine (MDMA) in striatum. Neurotox Res 18:200-9
Mueller, Melanie; Kolbrich-Spargo, Erin A; Peters, Frank T et al. (2009) Hydrolysis of 3,4-methylenedioxymethamphetamine (MDMA) metabolite conjugates in human, squirrel monkey, and rat plasma. Anal Bioanal Chem 393:1607-17
Mueller, Melanie; Peters, Frank T; Huestis, Marilyn A et al. (2009) Simultaneous liquid chromatographic-electrospray ionization mass spectrometric quantification of 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy) and its metabolites 3,4-dihydroxymethamphetamine, 4-hydroxy-3-methoxymethamphetamine and 3,4-methylenedioxya Forensic Sci Int 184:64-8
Barnes, Allan J; De Martinis, Bruno S; Gorelick, David A et al. (2009) Disposition of MDMA and metabolites in human sweat following controlled MDMA administration. Clin Chem 55:454-62

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