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

Frontiers in Pharmacology

Pharmacology

Frederik Gudmundsen¹  Christina Baun¹  Naja Støckel Jessen²  Mikael Palner³  Vladimir Shalgunov⁴  Matthias M. Herth⁴  Sandra N. Poetzsch⁵  Paul Cumming⁶  Dario Dornbierer⁷  Boris B. Quednow⁸  Milan Scheidegger⁸  Klemens Egger⁹  Chantal Martin-Soelch^1,10 

[1] Department of Clinical Research, University of Southern Denmark, Odense, Denmark;Department of Nuclear Medicine, Odense University Hospital, Odense, Denmark;Department of Clinical Research, University of Southern Denmark, Odense, Denmark;Department of Nuclear Medicine, Odense University Hospital, Odense, Denmark;Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark;Department of Clinical Research, University of Southern Denmark, Odense, Denmark;Department of Nuclear Medicine, Odense University Hospital, Odense, Denmark;Neurobiology Research Unit, Copenhagen University Hospital, Copenhagen, Denmark;Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark;Department of Clinical Physiology, Nuclear Medicine and PET, Copenhagen University Hospital, Copenhagen, Denmark;Department of Forensic Pharmacology and Toxicology, Zurich Institute of Forensic Medicine, University of Zurich, Zurich, Switzerland;Department of Nuclear Medicine, Bern University Hospital, Bern, Switzerland;School of Psychology and Counselling, Queensland University of Technology, Brisbane, Australia;Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric University Hospital Zurich, University of Zurich, Zurich, Switzerland;Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric University Hospital Zurich, University of Zurich, Zurich, Switzerland;Neuroscience Center Zurich, University of Zurich and Swiss Federal Institute of Technology Zurich, Zurich, Switzerland;Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric University Hospital Zurich, University of Zurich, Zurich, Switzerland;Neuroscience Center Zurich, University of Zurich and Swiss Federal Institute of Technology Zurich, Zurich, Switzerland;Department of Nuclear Medicine, Bern University Hospital, Bern, Switzerland;Department of Psychology, University Fribourg, Fribourg, Switzerland;

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

DOI  :  10.3389/fphar.2023.1140656

 received in 2023-01-09, accepted in 2023-09-19,  发布年份 2023

来源: Frontiers

【 摘 要 】

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.

【 授权许可】

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