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 via OpenAlex
Summary
MDMA (ecstasy) strongly inhibits the liver enzyme CYP2D6, which is responsible for metabolizing many drugs. In a controlled trial with 15 healthy men, a single 1.5 mg/kg oral dose of MDMA increased blood levels of the probe drug dextromethorphan about tenfold and reduced its breakdown product dextrorphan. The urinary metabolic ratio rose nearly 100-fold, and two-thirds of participants temporarily showed a metabolic profile typical of poor metabolizers. CYP2D6 activity recovered after 10 days, with a half-life of 46.6 hours. Users should be warned that MDMA can dangerously alter the metabolism of other medications.
Study at a glance
| 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 |
| Citations | 68 |
| Key finding | 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.