Variants of the enzyme CYP2D6 were tested for their ability to metabolize MDMA, alone and in the presence of other CYP2D6 inhibitors, in human liver microsomes. Variants tested were 2D6.1, 2D6.2, 2D6.10 and 2D6.17. Other CYP enzymes were examined in cDNA expressing lymphoblast cells, including 2A6, 2B6, 2C9, 2C19, 2E1 and 3A4. Demethylenation was measured by measuring amount of DHMA in sample after application of MDMA. Findings indicate that genetic variation in CYP2D6 may reduce clearance of MDMA by human liver. MDMA was applied in concentrations of 1.95 to 5000 mcM. 2D6.2 and 2D6.10 had the lowest clearance in human liver microsomes (HLM), with clearance of 2D6.10 being particularly low. When examined in human lymphoblast cells, only CYP2D6 produced demethylenation at 10 micrograms. (No information is provided on demethylenation produced by other enzymes at higher MDMA concentrations.) Paroxetine, cocaine and fluoxetine produced the most inhibition of MDMA demethylenation, whereas citalopram did not strongly inhibit demethylenation in liver microsomes with CYP2D6.1. These findings suggest that genetic variation in structure of CYP2D6 could affect the metabolism of at least low doses of MDMA, and that some drugs taken before or shortly after MDMA may also inhibit MDMA demethylenation. However, there is some indication that at higher doses, CYP2D6 is inactivated and that other enzymes may play an equal or greater role in the breakdown of MDMA (see Pizarro et la. 2002). Hence it is unclear whether differences in CYP2D6 in humans significantly alter MDMA clearance, and whether variations in CYP2D6 are associated with differences in the toxicological, physiological or subjective effects of MDMA.