Pharmacokinetic and pharmacodynamic interactions of indolealkylamine drugs of abuse

Indolealkylamine drugs like 5-MeO-DMT act on serotonin neurotransmission and are often co-abused with harmaline. Concurrent use of harmaline, a monoamine oxidase inhibitor, blocks the metabolic elimination of 5-MeO-DMT, leading to increased and prolonged exposure. In mice, coadministration of harmaline and 5-MeO-DMT produced more severe hyperthermia than a higher dose of 5-MeO-DMT alone, indicating that harmaline interacts at both pharmacokinetic and pharmacodynamic levels. These results suggest that combining a monoamine oxidase inhibitor with 5-MeO-DMT heightens the risk of serotonin toxicity and intoxication.

Study at a glance

Abstract

Indolealkylamine (IAA) drugs are a major class of serotonin analogs that have high impact as substances of abuse. Among them, 5‐methoxy‐ N,N ‐dimethyltryptamine (5‐MeO‐DMT) was placed into Schedule I controlled substance status in the United States as of January 19, 2011, which is often co‐abused with harmaline. IAA drugs acts mainly on the serotonin neurotransmission system. Overdose of one IAA substrate or concomitant use of two IAA drugs, e.g., harmaline and 5‐MeO‐DMT, causes the excess of 5‐HT or agonists or both, and induces hyperserotonergic effect or Serotonin Toxicity. Monoamine oxidase A (MAO‐A)‐catalyzed deamination is the predominant route for 5‐MeO‐DMT metabolic elimination. In vitro studies using human hepatocytes indicate that concurrent harmaline, an MAO inhibitor (MAOI), blocks 5‐MeO‐DMT substrate depletion. In vivo studies with mouse models show that coadministration of harmaline leads to an increased and prolonged exposure to 5‐MeO‐DMT, as well as a potentiation of 5‐MeO‐DMT‐induced hyperthermia. Interestingly, a more severe hyperthermia is shown in mice treated with 5 mg/kg of harmaline plus 2 mg/kg of 5‐MeO‐DMT than that treated with 10 mg/kg of 5‐MeO‐DMT alone, which is in contrast to the higher exposure to 5‐MeO‐DMT in mice treated with 10 mg/kg of 5‐MeO‐DMT. These findings support that harmaline interacts with 5‐MeO‐DMT not only at the pharmacokinetic level but also at the dynamic level, and concurrent use of MAOI will increase the hazards of 5‐MeO‐DMT intoxication.