In vitro studies using the baculovirus expression system were used to compare the ability of two allelic variants of cytochrome P 450 isozyme 2D6 (CYP2D6) to break down a number of drugs, with CYP2D6.1 considered the "wild-type" and CYP2D6.10 a variant seen in approximately 75% of Asians. Kinetics and inhibition assays using dextromethorphan as probe substrate were performed for CYP2D6.1 and CYP2D6.10. Clearance was tested with amitriptyline, MDMA, (+) and (-) methamphetamine, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and paramethoxyamphetamine (PMA). Inhibition assays were performed with budipine, debrisoquine, fluoxetine, 2-methoxy-3,4-methylenedioxyamphetamine (MMDA-2), MDMA, norfluoxetine, paroxetine and sparteine. While CYP2D6.10 showed reduced drug clearance generally, the greatest differences in clearance between CYP2D6.1 and CYP2D6.10 were with methamphetamine and MDMA (intrinsic clearance reduced 120-fold with CYP2D6.10), whereas the lowest differences were with PMA and MPTP. When inhibition constant was compared between the CYP2D6 variants, the greatest differences in inhibition were found with norfluoxetine and MDMA. The authors conclude that people possessing the CYP2D6.10 variant should probably receive lower doses of drugs they metabolize less efficiently. The authors also hypothesized that people possessing the CYP2D6.10 variant might experience more adverse events after taking ecstasy. However, since other enzymes are involved in the demethylenation of MDMA (Maurer et al. 2000; Kreth et al. 2000) and since MDMA may inhibit wild-type CYP2D6 function, the effects of this variant may not be as great as might be expected from these studies. In other words, CYP2D6 may play only a limited role in MDMA metabolism. This possibility is supported by in vitro MDMA studies suggesting that MDMA and/or its metabolites form an inhibitory complex with CYP2D6 (e.g., Delaforge et al. 1999). In addition, plasma concentrations of MDE were not significantly increased in a "poor metabolizer" compared to 5 other volunteers in a clinical study administering 140 mg MDE (Kreth et al. 2000). Thus, it remains to be seen whether variation in CYP2D6 activity contributes to risk of acute adverse events after MDMA.