Interaction Between Reboxetine and 3,4-Methylenedioxymethamphetamine: Pharmacodynamics (PD) and Pharmacokinetics (PK)
MDMA releases dopamine, serotonin, and norepinephrine in the brain. Serotonin uptake inhibitors have been shown to interact with 3,4-Methylenedioxymethamphetamine (MDMA) and to decrease its psychoactive and cardiovascular stimulant effects. This finding indicates that MDMA acts in part by releasing serotonin through the serotonin uptake site. However, in vitro studies show that MDMA binds more potently to the norepinephrine uptake site that to the the serotonin or dopamine uptake transporter. In addition, norepinephrine uptake site blockers such antidepressant drugs attenuate some of the behavioral effects of MDMA in animals. These preclinical data indicate that norepinephrine may also contribute to the response to MDMA in humans. To test this hypothesis this study evaluates the interacting effects of the selective norepinephrine transporter inhibitor reboxetine on the subjective and cardiovascular stimulant effects of MDMA in healthy volunteers.
Drug: Reboxetine, 8 mg
|Study Design:||Allocation: Randomized
Endpoint Classification: Pharmacodynamics Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Basic Science
|Official Title:||Pharmacological Interaction Between Reboxetine and 3,4-Methylenedioxymethamphetamine (MDMA, Ecstasy): Pharmacological Effects and Pharmacokinetics|
- Effect of reboxetine on subjective responses to MDMA [ Time Frame: 24h ] [ Designated as safety issue: No ]
- Effect of reboxetine on physiological responses to MDMA [ Time Frame: 24h ] [ Designated as safety issue: No ]
- Effects of reboxetine on pharmacokinetics of MDMA [ Time Frame: 24h ] [ Designated as safety issue: No ]
- Tolerability of MDMA and reboxetine [ Time Frame: 7 days ] [ Designated as safety issue: Yes ]
- Effect of reboxetine on neuroendocrine responses to MDMA [ Time Frame: 24h ] [ Designated as safety issue: No ]
- Genetic polymorphisms [ Time Frame: assessed after study completion ] [ Designated as safety issue: No ]Effects of genetic polymorphisms on the response to MDMA
|Study Start Date:||April 2009|
|Study Completion Date:||March 2010|
|Primary Completion Date:||December 2009 (Final data collection date for primary outcome measure)|
Reboxetine, MDMA, Placebo
Cross-over within-subjects design with all treatment conditions tested in the same subject. This design has 1 arm but two (actually 4) treatment conditions in the same subject.
125 mg, single doseDrug: Reboxetine, 8 mg
two doses 12h and 2h before MDMADrug: Placebo
capsules identical to MDMA or Reboxetine
The study will use a randomized double-blind cross-over design with four experimental sessions. Reboxetine (8 mg) or placebo will be administered the night before the experimental session and 1 h before the administration of MDMA (125 mg) or placebo to 16 healthy volunteers. Subjective and cardiovascular responses and plasma samples for pharmacokinetics will be repeatedly assessed throughout the experiments.
We hypothesize that the highly selective norepinephrine uptake inhibitor reboxetine will attenuate subjective and especially heart rate and blood pressure responses to MDMA. Such a result would indicate that norepinephrine is critically involved in the pharmacology of MDMA and may provide helpful in the use and development of treatments for Ecstasy intoxications.
|Principal Investigator:||Matthias E Liechti, MD||Department of Internal Medicine, Division of Pharmacology & Toxicology, University Hospital Basel, Switzerland|