The consequences of 3,4-methylenedioxymethamphetamine induced CYP2D6 inhibition in humans

J Clin Psychopharmacol. 2008 Oct;28(5):523-9. doi: 10.1097/JCP.0b013e318184ff6e.


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.

Publication types

  • Controlled Clinical Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Area Under Curve
  • Cytochrome P-450 CYP2D6 / drug effects*
  • Cytochrome P-450 CYP2D6 / metabolism
  • Dextromethorphan / pharmacokinetics
  • Dextrorphan / pharmacokinetics
  • Enzyme Inhibitors / pharmacology*
  • Half-Life
  • Hallucinogens / pharmacology*
  • Humans
  • Male
  • N-Methyl-3,4-methylenedioxyamphetamine / pharmacology*
  • Phenotype
  • Pilot Projects
  • Time Factors


  • Enzyme Inhibitors
  • Hallucinogens
  • Dextrorphan
  • Dextromethorphan
  • Cytochrome P-450 CYP2D6
  • N-Methyl-3,4-methylenedioxyamphetamine