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

doi:10.3389/fphar.2023.1140656

A pilot study of cerebral metabolism and serotonin 5-HT_2A receptor occupancy in rats treated with the psychedelic tryptamine DMT in conjunction with the MAO inhibitor harmine

Front Pharmacol. 2023 Sep 28:14:1140656. doi: 10.3389/fphar.2023.1140656. eCollection 2023.

Authors

Klemens Egger^{1

2

3}, Frederik Gudmundsen^{4

5}, Naja Støckel Jessen^{4

5

6}, Christina Baun^{4

5}, Sandra N Poetzsch⁷, Vladimir Shalgunov^{6

8}, Matthias M Herth^{6

8}, Boris B Quednow^{1

2}, Chantal Martin-Soelch⁹, Dario Dornbierer¹, Milan Scheidegger^{1

2}, Paul Cumming^#^{3

10}, Mikael Palner^#^{4

5

11}

Affiliations

¹ Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric University Hospital Zurich, University of Zurich, Zurich, Switzerland.
² Neuroscience Center Zurich, University of Zurich and Swiss Federal Institute of Technology Zurich, Zurich, Switzerland.
³ Department of Nuclear Medicine, Bern University Hospital, Bern, Switzerland.
⁴ Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
⁵ Department of Nuclear Medicine, Odense University Hospital, Odense, Denmark.
⁶ Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark.
⁷ Department of Forensic Pharmacology and Toxicology, Zurich Institute of Forensic Medicine, University of Zurich, Zurich, Switzerland.
⁸ Department of Clinical Physiology, Nuclear Medicine and PET, Copenhagen University Hospital, Copenhagen, Denmark.
⁹ Department of Psychology, University Fribourg, Fribourg, Switzerland.
¹⁰ School of Psychology and Counselling, Queensland University of Technology, Brisbane, Australia.
¹¹ Neurobiology Research Unit, Copenhagen University Hospital, Copenhagen, Denmark.

^# Contributed equally.

Abstract

Rationale: The psychedelic effects of the traditional Amazonian botanical decoction known as ayahuasca are often attributed to agonism at brain serotonin 5-HT_2A 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-HT_2A 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-HT_2A 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-HT_2A 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.

Grants and funding

This research was funded by the Swiss National Science Foundation grant number 320030-204978.