Pharmacokinetic and pharmacodynamic interactions of indolealkylamine drugs of abuse
The FASEB Journal April 1, 2012 DOI: 10.1096/fasebj.26.1_supplement.849.2 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | In vitro and in vivo study Peer reviewed |
|---|---|
| Population | Human hepatocytes and mouse models |
| Intervention | harmaline |
| Dose | 5 mg/kg of harmaline plus 2 mg/kg of 5-MeO-DMT; 10 mg/kg of 5-MeO-DMT alone |
| Topics | Serotonin |
| Keywords | Harmaline Pharmacology Monoamine oxidase Pharmacokinetics Monoamine neurotransmitter Harmine |
| Key points | Harmaline coadministration blocks 5-MeO-DMT elimination and potentiates hyperthermia, indicating both pharmacokinetic and pharmacodynamic interactions that increase intoxication hazards. |
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.
Comparable studies
Other preclinical and animal studies on serotonin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Mice | 2021 | Observational cohort | |
| Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. Rats (implied by typical neurochemical study context) | 1987 | Experimental study | |
| Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors In vitro and in vivo (rodent) models | 2023 | Experimental study | |
| 3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites. Rat brain | 1987 | Animal experiment | |
| Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs Human and mouse dopamine, norepinephrine, and serotonin transporters expressed in cells | 2006 | In vitro laboratory study |