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The Consequences of 3,4-Methylenedioxymethamphetamine Induced CYP2D6 Inhibition in Humans

Brian O’Mathúna, Magı́ Farré, Amin Rostami‐hodjegan, Jiansong Yang, Elisabet Cuyàs, Marta Torrens, Ricardo Pardo, Sergio Abanades, Silvana Maluf, Geoffrey T. Tucker, Rafael de la Torre

Journal of Clinical Psychopharmacology September 12, 2008 DOI: 10.1097/jcp.0b013e318184ff6e (opens in new tab)

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Study at a glance

AI-extracted from the abstract
Characteristics Controlled clinical trial Peer reviewed
Sample size 15
Population Healthy male subjects
Interventions MDMA Dextromethorphan
Dose 1.5 mg/kg MDMA
Duration 10 days
Topics MDMA
Keywords Dextrorphan Dextromethorphan Cyp2d6 Pharmacology Pharmacokinetics Active metabolite Cyp1a2 Cmax Trihexyphenidyl Amphetamine Cytochrome p450 Dopamine Metabolism
Citations 68
Key findings A single oral dose of 1.5 mg/kg MDMA produced a near 100-fold increase in the urinary metabolic ratio of dextromethorphan to dextrorphan, indicating profound inhibition of CYP2D6 activity that recovered with a half-life of 46.6 hours.

Abstract

3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) is a widely abused substituted amphetamine. MDMA is predominantly O-demethylenated in humans by cytochrome P450 isoforms 2D6 and 1A2 (CYP2D6 and CYP CYP1A2, respectively). MDMA is also a mechanism-based inhibitor of CYP2D6. A controlled clinical trial was conducted in 15 healthy male subjects whereby a probe drug, dextromethorphan (DEX), was administered after an oral dose of 1.5 mg/kg MDMA. The pharmacokinetics of DEX and its metabolites were used to evaluate changes in CYP2D6 activity. The urinary metabolic ratio of DEX and dextrorphan was used to calculate a recovery half-life of CYP2D6. After MDMA, DEX Cmax and area under the curve increased approximately 10-fold with corresponding decreases in dextrorphan pharmacokinetic parameters. The metabolic ratio increased almost 100-fold from 0.0061 +/- 0.0056 to 0.4322 +/- 0.2848 after MDMA administration, with 67% of the subjects having a value greater than the antimode of 0.3 for assigning the poor metabolizer phenotype. CYP2D6 activity recovered after 10 days with a recovery half-life of 46.6 hours. In addition to the possible long-term serotonergic effects of MDMA, users must be warned of the consequences of such an inhibition.

Comparable studies

Other non-randomized and open-label trials on MDMA, most cited first.

Study Year Design Participants
Durability of improvement in post-traumatic stress disorder symptoms and absence of harmful effects or drug dependency after 3,4-methylenedioxymethamphetamine-assisted psychotherapy: a prospective long-term follow-up study. Adults with chronic, treatment-resistant PTSD 2013 Long-term follow-up of a completed trial n = 19
First study of safety and tolerability of 3,4-methylenedioxymethamphetamine-assisted psychotherapy in patients with alcohol use disorder. Patients with alcohol use disorder (AUD) following community alcohol detoxification 2021 Open-label safety and tolerability proof-of-concept study n = 14
MDMA-facilitated cognitive-behavioural conjoint therapy for posttraumatic stress disorder: an uncontrolled trial. Couples in which one partner was diagnosed with PTSD 2020 Pilot study n = 6
Culturally informed research design issues in a study for MDMA-assisted psychotherapy for posttraumatic stress disorder People of color with posttraumatic stress disorder 2019 Phase 2 open-label multisite study
First study of safety and tolerability of 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy in patients with alcohol use disorder: preliminary data on the first four participants. Patients with alcohol use disorder 2019 Open-label safety and tolerability proof of concept study n = 4

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