Pharmacokinetics and Pharmacodynamics of an Innovative Psychedelic N,N-dimethyltryptamine/harmine Formulation in Healthy Participants: a Randomized Controlled Trial

Overview

Journal Int J Neuropsychopharmacol

Publisher Oxford University Press

Specialty Psychiatry

Date 2025 Jan 8

PMID 39774840

Authors

Michael J Mueller

Helena D Aicher

Dario A Dornbierer

Laurenz Marten

Dila Suay

Daniel Meling

Claudius Elsner

Ilhui A Wicki

Jovin Muller

Sandra N Poetzsch

Luzia Caflisch

Alexandra Hempe

Camilla P Steinhart

Maxim Puchkov

Jonas Kost

Hans-Peter Landolt

Erich Seifritz

Boris B Quednow

Milan Scheidegger

Affiliations

Soon will be listed here.

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 3 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: N,N-dimethyltryptamine 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.

Conclusions: 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.

Clinical Trial Registration Number: Neurodynamics of prosocial emotional processing following serotonergic stimulation with N,N-dimethyltryptamine (DMT) and harmine in healthy subjects (NCT04716335) https://clinicaltrials.gov/ct2/show/NCT04716335.

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