Neurobiology and Pharmacokinets of Acute MDMA Administration
Condition: Substance-Related Disorders
MeSH terms: Substance-Related Disorders
Study type: Interventional
Phase: Phase 1

Summary: 
      Background:

        -  3,4-Methylenedioxymethamphetamine (MDMA), commonly known as ecstasy, is a synthetic
           psychoactive drug that has shown a steep increase in recreational use and abuse by young
           people in recent years. Research studies have reported that chronic MDMA users who also
           consume other legal and illegal substance show memory deficits; however, because of the
           combination of drugs often involved, it is difficult to determine MDMA s contribution to
           these effects.

        -  Only a few studies have examined the immediate physical and behavioral effects of MDMA
           given at dose levels commonly used in young adults. Researchers are interested in using
           functional magnetic resonance imaging (fMRI) to examine changes in brain activity and
           function in MDMA users compared with users of other drugs and non-drug-using
           individuals.

      Objectives:

      - To evaluate the effects of MDMA on thinking and brain function.

      Eligibility:

      - Individuals between 18 and 30 years of age who are (1) current users of MDMA (2), current
      drug users who do not use MDMA, or (3) healthy non-drug-using volunteers.

      Design:

        -  Participants will complete one training session and three scanning sessions.

        -  Before the start of the study, participants will complete questionnaires about medical
           and psychological history, and provide information about past or current drug use.
           Researchers will introduce the tasks to be performed during the scanning session(s), and
           will allow participants to practice the tests.

        -  Participants will provide urine, saliva, and hair samples for testing before the start
           of the study, and multiple times during each scanning session.

        -  Participants who use MDMA and participants who use other drugs will stay overnight at
           the clinical center prior to each scanning session. Participants who do not use drugs
           can spend the night prior to scanning or arrive at the clinical center on the morning of
           the scanning session.

        -  Participants who use MDMA will receive either MDMA or a placebo during the scanning
           sessions, and will not be told which one they have received. Because of the nature of
           MDMA, participants will be required to stay at the clinical center until the effects of
           the drug have worn off, and will be required to return to the clinical center on the
           following day for a follow-up examination.

        -  During the study, participants will be asked to do one or more tasks selected by the
           researchers. The tasks will be performed on a computer in an MRI machine, and may
           involve receiving monetary rewards for actions, memory and reaction-time tests, or other
           tests that involve responding to instructions on the screen.
    

Detailed description: 
      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.
    

Intervention name(s): MDMA; (+/-)3,4-methylenedioxymethamphetamine Hydrochloride, MDMA HCI Capsules
Intervention type(s): Drug; Drug
Intervention description(s): 0, 1.0 &amp; 1.6 mg/kg
Intervention MeSH terms: N-Methyl-3,4-methylenedioxyamphetamine
Allocation: Randomized
Intervention model: Crossover Assignment
Primary purpose: Other
Keywords: Ecstacy; fMRI; Alternative Matrices; Cognitive Training; Brain Imaging