The interaction of fifteen amphetamine analogs with the genetically polymorphic enzyme CYP2D6 was examined. All fourteen phenylisopropylamines tested were competitive inhibitors of CYP2D6 in human liver microsomes. The presence of a methylenedioxy group in the 3,4-positions of both amphetamine (Ki = 26.5 microM) and methamphetamine (Ki = 25 microM) increased the affinity for CYP2D6 to 1.8 and 0.6 microM, respectively. Addition of a methoxy group to amphetamine in the 2-position also increased the affinity for CYP2D6 (Ki = 11.5 microM). The compound with the highest affinity for CYP2D6 was an amphetamine analog (MMDA-2) having both a methoxy group in the 2-position and a methylenedioxy group (Ki = 0.17 microM). Mescaline did not interact with CYP2D6. O-Demethylation of p-methoxyamphetamine (PMA) by CYP2D6 was characterized (Km = 59.2 +/- 22.4 microM, and Vmax = 29.3 +/- 16.6 nmol/mg/hr, N = 6 livers). This reaction was negligible in CYP2D6-deficient liver microsomes, was inhibited stereoselectively by the quinidine/quinine enantiomer pair, and was cosegregated with dextromethorphan O-demethylation (r = 0.975). The inhibitory effect of methylenedioxymethamphetamine (MDMA) was enhanced by preincubation with microsomes, suggesting that MDMA may produce a metabolite complex with CYP2D6. These findings suggest that phenylisopropylamines as a class interact with CYP2D6 as substrates and/or inhibitors. Their use may cause metabolic interactions with other drugs that are CYP2D6 substrates, and the potential for polymorphic oxidation via CYP2D6 may be a source of interindividual variation in their abuse liability and toxicity.