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Letter to the Editor

Editor, – In the case report on serotonin syndrome precipitated by an over-the-counter cold remedy (Aust Prescr 2006;29:71), several mechanisms that may have caused this were proposed. I would like to add another contributing mechanism which relates to the patient taking methadone 70 mg daily. Although not a cytochrome P450 2D6 (CYP2D6) substrate, methadone is a potent CYP2D6 inhibitor.1 It is possible that methadone is able to convert a CYP2D6 extensive metaboliser to a poor metaboliser. This process is known as phenocopying. There are very few data on methadone altering the pharmacokinetics of dextromethorphan in plasma. However, another CYP2D6 inhibitor, quinidine, can raise plasma dextromethorphan concentrations about 40-fold.2 Hence, the combination of several drugs individually increasing the brain serotonin concentration and the likelihood of methadone increasing the dextromethorphan concentration may also have contributed in part to the patient developing serotonin syndrome.

Andrew Somogyi
Professor and Deputy Head
Discipline of Pharmacology
The University of Adelaide


  1. Shiran MR, Chowdry J, Rostami-Hodjegan A, Ellis SW, Lennard MS, Iqbal MZ, et al. A discordance between cytochrome P450 2D6 genotype and phenotype in patients undergoing methadone maintenance treatment. Br J Clin Pharmacol 2003;56:220-4.
  2. Capon DA, Bochner F, Kerry N, Mikus G, Danz C, Somogyi AA. The influence of CYP2D6 polymorphism and quinidine on the disposition and antitussive effect of dextromethorphan in humans. Clin Pharmacol Ther 1996;60:295-307.