PSYCHOTROPIC EFFECTS OF DEXTROMETHORPHAN ARE ALTERED BY THE CYP2D6 POLYMORPHISM - A PILOT-STUDY

Dextromethorphan is a nonopioid antitussive metabolized by cytochrome P450 2D6 (CYP2D6) to an active metabolite, dextrorphan. CYP2D6 is poly morphically expressed in humans, with 5 to 10% of Caucasians being hom ozygous deficient for the active form of the enzyme. In a pilot study, the authors investigated the pharmacologic effects of dextromethorpha n in individuals phenotyped and genotyped as extensive metabolizers (E Ms, N = 4) and poor metabolizers (PMs, N = 2) of CYP2D6 substrates. De xtromethorphan doses ranged from 0 to 6 mg/kg based on individual subj ect tolerance. All EMs tolerated 3 to 6 mg/kg dextromethorphan, wherea s PMs barely tolerated 3 mg/kg dextromethorphan and therefore received lower doses. As shown in previous studies, plasma kinetics show profo und differences in dextromethorphan metabolism between EMs and PMs. De xtromethorphan produced qualitatively and quantitatively different obj ective and subjective effects in the two groups. Objectively, PMs had greater psychomotor impairment, as measured by a joystick tracking tas k, compared with EMs on 3 mg/kg dextromethorphan (mean performance +/- SE, 95 +/- 0.5% for EMs vs. 86 +/- 6% for PMs; p < 0.05). At this dos e, EMs also reported greater abuse potential compared with PMs (p < 0. 05), and PIMs reported greater sedation and dysphoria compared with EM s (p < 0.01). These data provide preliminary evidence that dextrorphan contributes to dextromethorphan abuse liability, and therefore PMs ma y be less likely to abuse dextromethorphan.