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Pharmacokinetics and Pharmacodynamics of an Innovative Psychedelic N,N-Dimethyltryptamine/Harmine Formulation in Healthy Participants: A Randomized Controlled Trial

Mueller, Michael J; Aicher, Helena D; Dornbierer, Dario A; Marten, Laurenz; Suay, Dila; Meling, Daniel; Elsner, Claudius; Wicki, Ilhui A; Müller, Jovin; Poetzsch, Sandra N; Caflisch, Luzia; Hempe, Alexandra; Steinhart, Camilla P; Puchkov, Maxim; Kost, Jonas; Landolt, Hans-Peter; Seifritz, Erich; Quednow, Boris B; Scheidegger, Milan (2025). Pharmacokinetics and Pharmacodynamics of an Innovative Psychedelic N,N-Dimethyltryptamine/Harmine Formulation in Healthy Participants: A Randomized Controlled Trial. International Journal of Neuropsychopharmacology, 28(1):pyaf001.

Abstract

Background
Recent interest in the clinical use of psychedelics has highlighted plant-derived medicines like ayahuasca showing rapid-acting and sustainable therapeutic effects in various psychiatric conditions. This traditional Amazonian plant decoction contains N,N-dimethyltryptamine (DMT) and β-carboline alkaloids such as harmine. However, its use is often accompanied by distressing effects like nausea, vomiting, and intense hallucinations, possibly due to complex pharmacokinetic/pharmacodynamic (PK-PD) interactions and lack of dose standardization.

Methods
This study addresses these limitations by testing a novel pharmaceutical formulation containing pure forms of DMT and harmine in a double-blind, randomized, placebo-controlled trial with 31 healthy male volunteers. We evaluated PK-PD by monitoring drug and metabolite plasma levels, subjective effects, adverse events, and cardiovascular parameters. Each participant received three randomized treatments: 1) 100 mg buccal harmine with 100 mg intranasal DMT, 2) 100 mg buccal harmine with intranasal placebo, and 3) full placebo; using a repeated-intermittent dosing scheme, such that 10 mg of DMT (or placebo) was administered every 15 minutes.

Results
DMT produced consistent PK profiles with Cmax values of 22.1 ng/ml and acute drug effects resembling the psychological effects of ayahuasca with a duration of 2–3 hours. Likewise, buccal harmine produced sustained-release PK profiles with Cmax values of 32.5 ng/ml, but lacked distinguishable subjective effects compared to placebo. All drug conditions were safe and well tolerated, indicating the formulation's suitability for clinical applications.

Conclusion
This study underscores the potential of a patient-oriented pharmaceutical formulation of DMT and harmine to reduce risks and improve therapeutic outcomes in treating mental health disorders.

Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Psychiatric University Hospital Zurich > Clinic for Psychiatry, Psychotherapy, and Psychosomatics
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:January 2025
Deposited On:13 Jan 2025 09:00
Last Modified:31 Jan 2025 08:48
Publisher:Cambridge University Press
ISSN:1461-1457
OA Status:Gold
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1093/ijnp/pyaf001
PubMed ID:39774840
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  • Language: English
  • Licence: Creative Commons: Attribution 4.0 International (CC BY 4.0)

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