Pharmacokinetics and pharmacodynamics of dextromethorphan: clinical and forensic aspects

Dextromethorphan (DXM), a common cough suppressant in over-the-counter medications, can produce psychoactive effects at high doses, leading to abuse. This review describes DXM's metabolism, including sequential O-demethylation and N-demethylation by enzymes to produce dextrorphan (the major active metabolite) and other compounds, as well as glucuronide conjugation. Genetic variations in metabolizing enzymes and drug interactions cause large differences between individuals in DXM's effects and toxicity. Understanding this metabolism helps explain variable responses and avoid adverse effects.

Study at a glance

Abstract

Abstract Dextromethorphan (DXM) is a safe and effective antitussive agent present in several over the counter cough and cold medications. At higher doses, it causes psychoactive effects, making it appealing for abuse. In this work, the pharmacokinetics and pharmacodynamics of DXM with clinical and forensic relevance were extensively reviewed. DXM and related known metabolizing enzymes and metabolites were searched in books and in PubMed (U.S. National Library of Medicine) without a limiting period. Major metabolic pathways include sequential O-demethylation and N-demethylation of DXM, yielding dextrorphan (DXO), the major active metabolite, and 3-hydroxymorphinan, the bi-demethylated product, respectively. The demethylation order described may reverse being the resultant mid product 3-methoxymorphinan. UDP-glucuronosyltranferase produces glucuronide conjugates. Genotypic variations in enzymes and interactions with other drugs can result in large inter-individual variability in the pharmacological and toxicological effects produced. Knowing the metabolism of DXM may help to better understand the inter-individual variability in the pharmacokinetics and pharmacodynamics and to avoid adverse effects.