Psychedelic 5-methoxy-N,N-dimethyltryptamine: metabolism, pharmacokinetics, drug interactions, and pharmacological actions

Abstract

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.

Figures

Figure 1

5-MeO-DMT biotransformation and the metabolic interactions with harmaline. O-demethylation of 5-MeO-DMT by CYP2D6 produces an active metabolite bufotenine. Both 5-MeO-DMT and bufotenine are readily deaminated by MAO-A to indoleacetic acid derivatives. The MAOI harmaline, which is inactivated by CYP2D6, blocks the deamination metabolism of 5-MeO-DMT and bufotenine.

Figure 2

Hyperserotonergic effects may be induced when harmaline blocks 5-HT degradation, and the concurrent 5-MeO-DMT activates 5-HT receptors within the synaptic cleft, beside their pharmacokinetic interactions.

Figure 3

Harmaline (5 mg/kg, i.p.) co-administered with 5-MeO-DMT (2 mg/kg, i.p.) markedly alters blood concentrations of the parent drug 5-MeO-DMT (A), the active metabolite bufotenine (B), and the ratio of their systemic exposures (C) in wild-type and/or Tg-CYP2D6 mouse models [37].

Figure 4

Studies using wild-type and Tg-CYP2D6 mouse model demonstrate that CYP2D6 status has significant impact on harmaline pharmacokinetics (A) and harmaline-induced hypothermia (B) [113].