Overcoming the clinical challenges of traditional ayahuasca: a first-in-human trial exploring novel routes of administration of N,N-Dimethyltryptamine and harmine

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Abstract

Recently, the Amazonian plant medicine “ayahuasca”—containing the psychedelic compound N,N-dimethyltryptamine (DMT) and numerous β-carboline alkaloids, such as harmine—has been suggested to exhibit beneficial effects in patients with affective and other mental health disorders. Although ayahuasca ingestion is considered safe, its pharmacokinetics/pharmacodynamics and tolerability profile pose some challenges and may limit the clinical applicability in vulnerable patient populations. While overdosing and the admixture of intolerable plant constituents may explain some of the common adverse reactions, the peroral route of administration may represent another relevant source of gastro-intestinal intolerabilities and unpredictable pharmacokinetics across users. To overcome these challenges, the present work aimed at creating ayahuasca-analogue formulations with improved pharmacokinetics and tolerability profiles. To this end, we developed peroral formulas and compared them with parenteral formulas specifically designed to circumvent the gastro-intestinal tract. In more detail, peroral administration of a capsule (containing purified DMT and harmine) was tested against a combined administration of an oromucosal harmine tablet and an intranasal DMT spray at two dose levels in an open-label within-subject study in 10 healthy male subjects. Pharmacokinetic and pharmacodynamic profiles were assessed by means of continuous blood sampling, vital sign monitoring, and psychometric assessments. Common side effects induced by traditional herbal ayahuasca such as nausea, vomiting, and diarrhea were significantly attenuated by our DMT/harmine formulations. While all preparations were well tolerated, the combined buccal/intranasal administration of harmine and DMT yielded substantially improved pharmacokinetic profiles, indicated by significantly reduced variations in systemic exposure. In conclusion, the combined buccal/intranasal administration of harmine and DMT is an innovative approach that may pave the way towards a safe, rapid-acting, and patient-oriented administration of DMT/harmine for the treatment of affective disorders.

Clinical Trial Registration: clinicaltrials.gov, identifier NCT04716335

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Most cited references 38

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A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression.

Carlos A Zarate, Jaskaran Singh, Paul Carlson … (2006)

Existing therapies for major depression have a lag of onset of action of several weeks, resulting in considerable morbidity. Exploring pharmacological strategies that have rapid onset of antidepressant effects within a few days and that are sustained would have an enormous impact on patient care. Converging lines of evidence suggest the role of the glutamatergic system in the pathophysiology and treatment of mood disorders. To determine whether a rapid antidepressant effect can be achieved with an antagonist at the N-methyl-D-aspartate receptor in subjects with major depression. A randomized, placebo-controlled, double-blind crossover study from November 2004 to September 2005. Mood Disorders Research Unit at the National Institute of Mental Health. Patients Eighteen subjects with DSM-IV major depression (treatment resistant). After a 2-week drug-free period, subjects were given an intravenous infusion of either ketamine hydrochloride (0.5 mg/kg) or placebo on 2 test days, a week apart. Subjects were rated at baseline and at 40, 80, 110, and 230 minutes and 1, 2, 3, and 7 days postinfusion. Main Outcome Measure Changes in scores on the primary efficacy measure, the 21-item Hamilton Depression Rating Scale. Subjects receiving ketamine showed significant improvement in depression compared with subjects receiving placebo within 110 minutes after injection, which remained significant throughout the following week. The effect size for the drug difference was very large (d = 1.46 [95% confidence interval, 0.91-2.01]) after 24 hours and moderate to large (d = 0.68 [95% confidence interval, 0.13-1.23]) after 1 week. Of the 17 subjects treated with ketamine, 71% met response and 29% met remission criteria the day following ketamine infusion. Thirty-five percent of subjects maintained response for at least 1 week. Robust and rapid antidepressant effects resulted from a single intravenous dose of an N-methyl-D-aspartate antagonist; onset occurred within 2 hours postinfusion and continued to remain significant for 1 week.

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REBUS and the Anarchic Brain: Toward a Unified Model of the Brain Action of Psychedelics

R L Carhart-Harris, K. J. Friston (2019)

This paper formulates the action of psychedelics by integrating the free-energy principle and entropic brain hypothesis. We call this formulation relaxed beliefs under psychedelics (REBUS) and the anarchic brain, founded on the principle that—via their entropic effect on spontaneous cortical activity—psychedelics work to relax the precision of high-level priors or beliefs, thereby liberating bottom-up information flow, particularly via intrinsic sources such as the limbic system. We assemble evidence for this model and show how it can explain a broad range of phenomena associated with the psychedelic experience. With regard to their potential therapeutic use, we propose that psychedelics work to relax the precision weighting of pathologically overweighted priors underpinning various expressions of mental illness. We propose that this process entails an increased sensitization of high-level priors to bottom-up signaling (stemming from intrinsic sources), and that this heightened sensitivity enables the potential revision and deweighting of overweighted priors. We end by discussing further implications of the model, such as that psychedelics can bring about the revision of other heavily weighted high-level priors, not directly related to mental health, such as those underlying partisan and/or overly-confident political, religious, and/or philosophical perspectives. Significance Statement Psychedelics are capturing interest, with efforts underway to bring psilocybin therapy to marketing authorisation and legal access within a decade, spearheaded by the findings of a series of phase 2 trials. In this climate, a compelling unified model of how psychedelics alter brain function to alter consciousness would have appeal. Towards this end, we have sought to integrate a leading model of global brain function, hierarchical predictive coding, with an often-cited model of the acute action of psychedelics, the entropic brain hypothesis. The resulting synthesis states that psychedelics work to relax high-level priors, sensitising them to liberated bottom-up information flow, which, with the right intention, care provision and context, can help guide and cultivate the revision of entrenched pathological priors.

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Rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression: a randomized placebo-controlled trial

Fernanda Palhano-Fontes, Dayanna Patrícia de Carvalho Barreto, Heloisa Onias … (2019)

Background Recent open-label trials show that psychedelics, such as ayahuasca, hold promise as fast-onset antidepressants in treatment-resistant depression. Methods To test the antidepressant effects of ayahuasca, we conducted a parallel-arm, double-blind randomized placebo-controlled trial in 29 patients with treatment-resistant depression. Patients received a single dose of either ayahuasca or placebo. We assessed changes in depression severity with the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Hamilton Depression Rating scale at baseline, and at 1 (D1), 2 (D2), and 7 (D7) days after dosing. Results We observed significant antidepressant effects of ayahuasca when compared with placebo at all-time points. MADRS scores were significantly lower in the ayahuasca group compared with placebo at D1 and D2 (p = 0.04), and at D7 (p < 0.0001). Between-group effect sizes increased from D1 to D7 (D1: Cohen's d = 0.84; D2: Cohen's d = 0.84; D7: Cohen's d = 1.49). Response rates were high for both groups at D1 and D2, and significantly higher in the ayahuasca group at D7 (64% v. 27%; p = 0.04). Remission rate showed a trend toward significance at D7 (36% v. 7%, p = 0.054). Conclusions To our knowledge, this is the first controlled trial to test a psychedelic substance in treatment-resistant depression. Overall, this study brings new evidence supporting the safety and therapeutic value of ayahuasca, dosed within an appropriate setting, to help treat depression. This study is registered at http://clinicaltrials.gov (NCT02914769).

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Author and article information

Contributors

Laurenz Marten: URI : https://loop.frontiersin.org/people/2358467/overview

Jovin Mueller: URI : https://loop.frontiersin.org/people/2538354/overview

Helena D. Aicher: URI : https://loop.frontiersin.org/people/2295809/overview

Michael J. Mueller: URI : https://loop.frontiersin.org/people/2349558/overview

Thomas Kraemer: URI : https://loop.frontiersin.org/people/647854/overview

Hans-Peter Landolt: URI : https://loop.frontiersin.org/people/10009/overview

Erich Seifritz: URI : https://loop.frontiersin.org/people/69053/overview

Milan Scheidegger: URI : https://loop.frontiersin.org/people/76534/overview

Journal

Journal ID (nlm-ta): Front Pharmacol

Journal ID (iso-abbrev): Front Pharmacol

Journal ID (publisher-id): Front. Pharmacol.

Title: Frontiers in Pharmacology

Publisher: Frontiers Media S.A.

ISSN (Electronic): 1663-9812

Publication date (Electronic): 27 November 2023

Publication date Collection: 2023

Volume: 14

Electronic Location Identifier: 1246892

Affiliations

[1] ¹ Institute of Pharmacology and Toxicology , University of Zurich , Zurich, Switzerland

[2] ² Department of Forensic Pharmacology and Toxicology , Zurich Institute of Forensic Medicine , University of Zurich , Zurich, Switzerland

[3] ³ Department of Psychiatry , Psychotherapy and Psychosomatics , University Hospital of Psychiatry Zurich , Zurich, Switzerland

[4] ⁴ Department of Chemistry and Applied Biosciences , Zurich, Switzerland

[5] ⁵ Department of Psychology , University of Zurich , Zurich, Switzerland

[6] ⁶ Neuroscience Center Zurich , University of Zurich and ETH Zurich , Zurich, Switzerland

[7] ⁷ Department of Health Science & Technology , Zurich, Switzerland

[8] ⁸ Reconnect Labs , Winterthur, Switzerland

[9] ⁹ Institute of Pharmaceutical Technology , University of Basel , Basel, Switzerland

Author notes

Edited by: Adam Halberstadt, University of California, San Diego, United States

Reviewed by: Armando Caceres, Galileo University, Guatemala

Liz Girardi Müller, Regional Community University of Chapecó, Brazil

*Correspondence: Dario A. Dornbierer, dario-do@ 123456hotmail.com

Article

Publisher ID: 1246892

DOI: 10.3389/fphar.2023.1246892

PMC ID: 10711279

PubMed ID: 38089057

SO-VID: 33311ad9-f30e-4576-bf12-facb11aaf043

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

History

Date received : 24 June 2023

Date accepted : 10 November 2023

Funding

This work was supported by the Forschungskredit (MS, Grant No. FK-18-052) and the BioEntrepreneur Fellowship Program (DD, BIOEF-18-009) at the University of Zurich, Switzerland, the SNSF Swiss National Science Foundation (DD, BRIDGE PoC 40B1-0_198689/1; HA, Doc.CH Grant P0ZHP1_191935). The authors declare that this study received private donations from Fabian Hediger. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article, or the decision to submit it for publication.