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Psychotropic Effects of Dextromethorphan Are Altered by the CYP2D6 Polymorphism: A Pilot Study

Zawertailo, Laurie A. MSc; Kaplan, Howard L. PhD; Busto, Usoa E. PharmD; Tyndale, Rachel F. PhD; Sellers, Edward M. MD, PhD

Journal of Clinical Psychopharmacology: August 1998 - Volume 18 - Issue 4 - p 332-337
Brief Reports

Dextromethorphan is a nonopioid antitussive metabolized by cytochrome P450 2D6 (CYP2D6) to an active metabolite, dextrorphan.CYP2D6 is polymorphically expressed in humans, with 5 to 10% of Caucasians being homozygous deficient for the active form of the enzyme. In a pilot study, the authors investigated the pharmacologic effects of dextromethorphan in individuals phenotyped and genotyped as extensive metabolizers (EMs, N = 4) and poor metabolizers (PMs, N = 2) of CYP2D6 substrates. Dextromethorphan doses ranged from 0 to 6 mg/kg based on individual subject tolerance. All EMs tolerated 3 to 6 mg/kg dextromethorphan, whereas PMs barely tolerated 3 mg/kg dextromethorphan and therefore received lower doses. As shown in previous studies, plasma kinetics show profound differences in dextromethorphan metabolism between EMs and PMs. Dextromethorphan produced qualitatively and quantitatively different objective and subjective effects in the two groups. Objectively, PMs had greater psychomotor impairment, as measured by a joystick tracking task, 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 dose, EMs also reported greater abuse potential compared with PMs (p < 0.05), and PMs reported greater sedation and dysphoria compared with EMs (p < 0.01). These data provide preliminary evidence that dextrorphan contributes to dextromethorphan abuse liability, and therefore PMs may be less likely to abuse dextromethorphan. (J Clin Psychopharmacol 1998;18:332-337)

Departments of (Zawertailo, Tyndale, Sellers) Pharmacology, (Sellers) Medicine, and (Sellers) Psychiatry and the Faculty of (Busto) Pharmacy, Psychopharmacology and Dependence Research Unit, (Zawertailo, Kaplan, Busto, Tyndale, Sellers) Centre for Research in Women's Health, Women's College Hospital, University of Toronto, Toronto, Ontario, Canada; (Kaplan, Busto, Tyndale, Sellers) Biobehavioral Research Department, Addiction Research Foundation, Toronto, Ontario, Canada

Received March 10, 1997; accepted after revision November 19, 1997.

Address requests for reprints to: Edward M. Sellers, MD, PhD, Dept. of Pharmacology, University of Toronto, Medical Sciences Building, Room 4334, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8. Address e-mail to:

© Williams & Wilkins 1998. All Rights Reserved.