A pilot study of cerebral metabolism and serotonin 5-HT2A receptor occupancy in rats treated with the psychedelic tryptamine DMT in conjunction with the MAO inhibitor harmine

Klemens Egger, Frederik Gudmundsen, Naja Støckel Jessen, Christina Baun, Sandra N Poetzsch, Vladimir Shalgunov, Matthias M Herth, Boris B Quednow, Chantal Martin-Soelch, Dario Dornbierer, Milan Scheidegger, Paul Cumming, Mikael Palner, Klemens Egger, Frederik Gudmundsen, Naja Støckel Jessen, Christina Baun, Sandra N Poetzsch, Vladimir Shalgunov, Matthias M Herth, Boris B Quednow, Chantal Martin-Soelch, Dario Dornbierer, Milan Scheidegger, Paul Cumming, Mikael Palner

Abstract

Rationale: The psychedelic effects of the traditional Amazonian botanical decoction known as ayahuasca are often attributed to agonism at brain serotonin 5-HT2A receptors by N,N-dimethyltryptamine (DMT). To reduce first pass metabolism of oral DMT, ayahuasca preparations additionally contain 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 of DMT in brain via systemic MAO-A inhibition. Objectives: We measured the pharmacokinetic profile of harmine and/or DMT in rat brain, and tested for pharmacodynamic effects on brain glucose metabolism and DMT occupancy at brain serotonin 5-HT2A receptors. Methods: We first measured brain concentrations of harmine and DMT after treatment with harmine and/or DMT at low sub-cutaneous 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 effects of DMT and/or harmine (1 mg/kg each) on brain glucose metabolism with [18F]FDG-PET. Results: Results confirmed that co-administration of harmine inhibited the formation of the DMT metabolite indole-3-acetic acid (3-IAA) in brain, while correspondingly 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. We did not observe significant effects of low dose DMT and/or harmine on cerebral [18F]FDG-PET uptake. Conclusion: These preliminary results call for further experiments to establish the dose-dependent effects of harmine/DMT on serotonin receptor occupancy and cerebral metabolism.

Keywords: DMT; PKPD; [18 F]FDG-PET; ayahuasca; harmine; pharmahuasca; psychedelics; serotonin receptor.

Conflict of interest statement

KE, FG, NJ, CB, SP, VS, MH, BQ, and PC have nothing to declare. DD and MS co-founded Reconnect Labs, an academic spin-off at the University of Zurich. MP has an ongoing research collaboration with Compass Pathways Ltd. unrelated to the present study.

Copyright © 2023 Egger, Gudmundsen, Jessen, Baun, Poetzsch, Shalgunov, Herth, Quednow, Martin-Soelch, Dornbierer, Scheidegger, Cumming and Palner.

Figures

FIGURE 1
FIGURE 1
Experimental workflow in Experiments 1 and 2. (A) Experiment 1: Rats received either 2 × vehicle, harmine and vehicle, vehicle and DMT, or harmine and DMT (s.c.), then received successive injections of [3H]ketanserin (i.v.) and [18F]FDG (i.p). They were then allowed to roam freely for 45 min whereupon they were rapidly anesthetized for a PET/CT recording lasting 30 min. Next, rats were euthanized and brain samples (cerebellum and frontal cortex) were taken to measure [3H]ketanserin content by liquid scintillation counting, and the cerebral concentrations of harmine, DMT, and the metabolite 3-IAA by HPLC-MS. (B) Experiment 2: Rats received either 2 × vehicle, or harmine and DMT (s.c.), followed by [18F]MH.MZ injection (i.p). Rats were then allowed to roam freely for 45 min and then euthanized. Samples from their brain (cerebellum and frontal cortex) were taken to measure serotonin receptor occupancy/competition with a gamma counter and DMT, harmine and their metabolite concentrations with UHPLC-MS. For details, please refer to the text. DMT = N,N-dimethyltryptamine, [18F]FDG = [18F]fluorodeoxyglucose, PET = positron emission tomography. CT = computed tomography, UHPLC-MS = ultra-high performance liquid chromatography-mass spectroscopy. Figure created with BioRender.com.
FIGURE 2
FIGURE 2
Mean globally normalized SUV (SUVglob) results from experiment 1. [18F]FDG-PET data in groups of (n = 5) control and (n = 6) rats treated with harmine, DMT, or harmine + DMT (1 mg/kg s.c. each). The first two columns display a structural MRI template that was used for parcelation of brain PET data. The second column depicts the regions of interest, namely (from rostral to caudal): orbitofrontal cortex (OFC, blue), medial prefrontal cortex (mPFC, purple), nucleus accumbens (NAc, dark blue), striatum (red), anterodorsal hippocampus (dark green), posterior hippocampus (light green), thalamus (neon green), visual cortex (blue), cerebellum (yellow). The SUVglob images represent the mean of six frames of 5 minutes duration, starting at 60 min after [18F]FDG administration.

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