Interaction Between Duloxetine and 3,4-Methylenedioxymethamphetamine (MDMA, Ecstasy)

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to determinate the effect of a pre-treatment with the combined serotonin (5-HT) and norepinephrine (NE) transport blocker duloxetine on the pharmacodynamics and pharmacokinetics of 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy). The investigators hypothesize that duloxetine will attenuate the subjective and cardiovascular response to MDMA.

Detailed Description
-----------------
3,4-methylenedioxymethamphetamine (MDMA, ecstasy) is widely used by young people for its euphoric effects. MDMA releases serotonin (5-HT), norepinephrine (NE), and dopamine through an interaction with the corresponding presynaptic monoamine uptake transporter. 5-HT transport inhibitors block MDMA-induced 5-HT release in vitro or in animals and also attenuate the subjective and cardiovascular response to MDMA in humans. NE transport inhibitors similarly prevent the MDMA-induced release of NE in cell assays and attenuate behavioral effects of MDMA in animals. Effects of the NE transporter inhibitor reboxetine on the response to MDMA in humans are currently investigated. Here we suggest evaluating effects of pretreatment with the combined 5-HT and NE transport blocker duloxetine on the pharmacodynamics and pharmacokinetics of MDMA. The study will use a randomized double-blind cross-over design with four experimental sessions. Duloxetine (120 mg) or placebo will be administered 16 h and 4 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.

Official Title
-----------------
Pharmacological Interaction Between Duloxetine and 3,4-Methylenedioxymethamphetamine (MDMA, Ecstasy): Pharmacodynamics (PD) and Pharmacokinetics (PK)

Conditions
-----------------
Mood Disorder, Substance-Related Disorders, Amphetamine-Related Disorders

Intervention / Treatment
-----------------
* Drug: 3,4-Methylenedioxymethamphetamine
* Drug: Duloxetine
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Sufficient understanding of the German language Subjects understand the procedures and the risks associated with the study Participants must be willing to adhere to the protocol and sign the consent form Participants must be willing to refrain from taking illicit psychoactive substances during the study. Participants must be willing to drink only alcohol-free liquids and no xanthine-containing liquids (such as coffee, black or green tea, red bull, chocolate) after midnight of the evening before the study session. Subjects must agree not to smoke tobacco for 1 h before and 4 hours after MDMA administration. Participants must be willing not to drive a traffic vehicle in the evening of the study day. Women of childbearing potential must have a negative pregnancy test at the beginning of the study and must agree to use an effective form of birth control. Pregnancy tests are repeated before each study session. Body mass index: 18-25 kg/m2 Exclusion Criteria: Chronic or acute medical condition including clinically relevant abnormality in physical exam, laboratory values, or ECG. In particular: Hypertension (>140/90 mmHg). Personal or first-grade history of seizures. Cardiac or neurological disorder. Current or previous psychotic or affective disorder Psychotic or affective disorder in first-degree relatives Prior illicit drug use (except THC (Tetrahydrocannabinol)-containing products) more than 5 times or any time within the previous 2 months. Pregnant or nursing women. Participation in another clinical trial (currently or within the last 30 days) Use of medications that are contraindicated or otherwise interfere with the effects of the study medications (monoamine oxidase inhibitors, antidepressants, sedatives etc.)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: duloxetine, MDMA, placebo<br>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. | Drug: 3,4-Methylenedioxymethamphetamine<br>* 125 mg, single dose<br>* Other names: Ecstasy;Drug: Duloxetine<br>* 120 mg two doses 12h and 2h before MDMA<br>* Other names: Cymbalta (r);Drug: Placebo<br>* capsules identical to MDMA or duloxetine<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effect of duloxetine on the subjective response to MDMA |  | 24h | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effect of duloxetine on cardiovascular effects of MDMA |  | 6h | 
| Effect of duloxetine on pharmacokinetics of MDMA |  | 6h | 
| Effect of MDMA on duloxetine pharmacokinetics |  | 6h | 
| Tolerability of MDMA and duloxetine |  | 7 days | 
| Effect of duloxetine on neuroendocrine responses to MDMA |  | 6h | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
MDMA, serotonin, norepinephrine, Ecstasy, stimulant