Psychedelic 5-Methoxy-N,N-Dimethyltryptamine: Metabolism, Pharmacokinetics, Drug Interactions, and Pharmacological Actions

Oct 15, 2010Current drug metabolism

Metabolism, body processing, interactions, and effects of the psychedelic 5-methoxy-N,N-dimethyltryptamine

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Abstract

5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is metabolized by polymorphic cytochrome P450 2D6 (CYP2D6) to bufotenine.

5-MeO-DMT acts as a nonselective serotonin agonist, causing various physiological and behavioral changes.
Concurrent use of harmaline inhibits the deactivation of 5-MeO-DMT, leading to increased exposure to both 5-MeO-DMT and bufotenine.
The combination of harmaline, 5-MeO-DMT, and bufotenine may contribute to hyperserotonergic effects or serotonin toxicity.
CYP2D6 genetic variations can significantly affect the metabolism and pharmacokinetics of both harmaline and 5-MeO-DMT.
Risks associated with 5-MeO-DMT intoxication are discussed, particularly in the context of its interaction with harmaline.

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5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) belongs to a group of naturally-occurring psychoactive indolealkylamine drugs. It acts as a nonselective serotonin (5-HT) agonist and causes many physiological and behavioral changes. 5-MeO-DMT is O-demethylated by polymorphic cytochrome P450 2D6 (CYP2D6) to an active metabolite, bufotenine, while it is mainly inactivated through the deamination pathway mediated by monoamine oxidase A (MAO-A). 5-MeO-DMT is often used with MAO-A inhibitors such as harmaline. Concurrent use of harmaline reduces 5-MeO-DMT deamination metabolism and leads to a prolonged and increased exposure to the parent drug 5-MeO-DMT, as well as the active metabolite bufotenine. Harmaline, 5-MeO-DMT and bufotenine act agonistically on serotonergic systems and may result in hyperserotonergic effects or serotonin toxicity. Interestingly, CYP2D6 also has important contribution to harmaline metabolism, and CYP2D6 genetic polymorphism may cause considerable variability in the metabolism, pharmacokinetics and dynamics of harmaline and its interaction with 5-MeO-DMT. Therefore, this review summarizes recent findings on biotransformation, pharmacokinetics, and pharmacological actions of 5-MeO-DMT. In addition, the pharmacokinetic and pharmacodynamic drug-drug interactions between harmaline and 5-MeO-DMT, potential involvement of CYP2D6 pharmacogenetics, and risks of 5-MeO-DMT intoxication are discussed.

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Psychedelic 5-Methoxy-N,N-Dimethyltryptamine: Metabolism, Pharmacokinetics, Drug Interactions, and Pharmacological Actions

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