Neurobiology and Pharmacokinets of Acute MDMA Administration

Background: 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: Eighteen current MDMA users will complete the neurocognitive and pharmacokinetics group. Thirty-six MDMA non-using controls will include 18 non-drug using participants and 18 drug using (primarily cannabis) participants. Controls in each group will be matched to MDMA users in the neurocognitive and pharmacokinetics group. All participants must be between the ages of 18 and 40. The estimated target enrollment, based on ecstasy use by race/ethnic group and Baltimore demographics, will be 41% female and 59% male, 83% Caucasian, 14% African American, 3% Asian, and 2% Hispanic.

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. The non-drug using and drug using control groups will be matched to MDMA users in the neurocognitive and pharmacokinetics group for sex, age, IQ, education level and intersession interval. The drug using control group will control for cannabis and other drug usage in the MDMA group. The drug using control group is necessary because many MDMA users also use other drugs, primarily cannabis. Control groups allow for a between-subjects analysis for trait differences between the population groups, as well as provide normative data for the cognitive tasks. Drug using control group participants will stay on the clinical research unit overnight prior to each of the three sessions; non-drug using control group participants will arrive the morning of each session. Participants from the MDMA group will complete three separate stays, each lasting approximately 26 hours, within one year. While under the influence of MDMA, qualified participants will perform memory, attention, semantic processing, affect and decision-making tasks before, during, and after fMRI scanning. Physiological, behavioral and biochemical measures of all MDMA users 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 from MDMA users for analysis of MDMA and metabolite concentrations by GC/MS and/or LC/MS/MS to determine the disposition and pharmacokinetics of MDMA.

Risks and Benefits: A main potential risk of this study is associated with acute cardiovascular responses to MDMA administration; however, these doses have proven safe and well tolerated in previous human studies conducted within the US and abroad. In addition, impaired cognitive function has been reported following long-term MDMA use in some but not all studies. A potential benefit of the proposed study is to understand how MDMA affects human brain function at doses employed by recreational users. Additionally, advances will be made in understanding MDMA pharmacokinetics.