Pharmacokinetic and Pharmacodynamic Interaction of the Ayahuasca Constituents Harmine and Dimethyltryptamine (DMT) in the Rat Brain
Klemens Egger, Frederik Gudmundsen, Naja Støckel Jessen, Christina Baun, Sandra Pötzsch, Vladimir Shalgunov, Matthias M. Herth, Boris B. Quednow, Chantal Martin-Soelch, Dario Dornbierer, Milan Scheidegger, Paul Cumming, Mikael Palner
January 4, 2023 preprint DOI: 10.31219/osf.io/cv6ey (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical experimental study |
|---|---|
| Population | Rats |
| Interventions | harmine DMT |
| Dose | 1 mg/kg each or 3 mg/kg each |
| Topics | Ayahuasca 5-MeO-DMT DMT |
| Keywords | Harmine Pharmacology Harmaline In vivo Metabolite Ex vivo Biochemistry In vitro |
| Key findings | Co-administration of harmine with DMT increased cerebral DMT availability but did not result in detectable occupancy at serotonin 5-HT2A receptors. |
Abstract
RationaleThe psychedelic effects of the traditional Amazonian botanical decoction known as ayahuasca are attributed to the effects of N,N-dimethyltryptamine (DMT) at brain serotonin 5-HT2A receptors. To make oral DMT bioavailable, ayahuasca additionally contains reversible monoamine oxidase A (MAO-A) inhibitors, namely β-carboline alkaloids such as harmine. However, there is lacking biochemical evidence to substantiate this pharmacokinetic potentiation in the brain. ObjectivesTherefore, we measured the pharmacokinetic profile of harmine and DMT in the rat brain. Additionally, we investigated the pharmacodynamic properties of DMT and/or harmine. MethodsWe first measured brain concentrations of harmine and DMT after treatment with harmine and/or DMT at low doses (1 mg/kg each) or harmine plus DMT at moderate doses (3 mg/kg each). In the same groups of rats, we also measured ex vivo the effects of these treatments on the availability of serotonin 5-HT2A receptors in frontal cortex. Finally, we explored influences of DMT and/or harmine in the lower dose group on brain glucose metabolism with [18F]FDG-PET. ResultsResults confirmed that co-administration of harmine inhibited the formation of the DMT metabolite indole-3-acetic acid (3-IAA) in the brain, while increasing the cerebral availability of DMT. However, we were unable to detect any significant occupancy by DMT at 5-HT2A receptors measured ex vivo, despite brain DMT concentrations as high as 11.3 µM at moderate doses. We did not observe strong influences of low dose DMT and/or harmine on [18F]FDG-PET. ConclusionsThe present preliminary results call for further experiments to establish the dose-dependent effects of harmine/DMT on receptor occupancy and on cerebral metabolism.
Comparable studies
Other preclinical and animal studies on DMT, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| The Hallucinogen N,N -Dimethyltryptamine (DMT) Is an Endogenous Sigma-1 Receptor Regulator Mice and cell lines | 2009 | Experimental study | |
| Correlation between the potency of hallucinogens in the mouse head-twitch response assay and their behavioral and subjective effects in other species. C57BL/6J mice | 2020 | Experimental study with dose-response experiments | |
| Psychedelic N,N-dimethyltryptamine and 5-methoxy-N,N-dimethyltryptamine modulate innate and adaptive inflammatory responses through the sigma-1 receptor of human monocyte-derived dendritic cells. Human primary monocyte-derived dendritic cells | 2014 | In vitro study | |
| Inhibitory effect of chlorpromazine on the syndrome of hyperactivity produced by l‐tryptophan or 5‐methoxy‐N,N‐dimethyltryptamine in rats treated with a monoamine oxidase inhibitor Rats | 1971 | Experimental study | |
| Effects of N,N-Dimethyltryptamine on Rat Behaviors Relevant to Anxiety and Depression Adult male Sprague-Dawley rats | 2018 | Experimental study |