Pharmacokinetics and Pharmacodynamics, Safety and Tolerability, and Therapeutic Potential of an Innovative Psychedelic Ayahuasca-Analogue containing N,N-Dimethyltryptamine and Harmine

Abstract

The psychedelic renaissance is a new wave of scientific research around psychedelics and their therapeutic potential as treatment options for mental health disorders. Specifically, psychedelic-assisted psychotherapy is a rapidly evolving field with significant therapeutic potential, and recent developments have focused on a class of serotonergic substances for their rapid-acting antidepressant and anxiolytic properties. Within this class, the Amazonian plant medicine “ayahuasca”, rich in the psychoactive compounds N,N-dimethyltryptamine (DMT) and β-carboline alkaloids like harmine or harmaline, has attracted substantial interest for its beneficial effects on affective and other mental health disorders. Yet, the use of traditional ayahuasca has been associated with several unpredictable distressing side effects in the Western medicine context, often attributed to suboptimal pharmacokinetic and pharmacodynamic (PK-PD) properties, overdosing, and intolerable plant constituents. These challenges have stimulated efforts towards refining the therapeutic application of ayahuasca components. This dissertation presents an overview of the use of ayahuasca globally and elaborates on its pharmacological and therapeutic aspects. Furthermore, we present a pioneering approach involving the development of an ayahuasca-analogue formulation, a preparation consisting of only two isolated compounds, namely DMT and harmine. With a parenteral administration form, we sought to overcome the challenges of traditional ayahuasca, to further translate its therapeutic potential into the Western healthcare system. An initial pilot study has resulted in the development of an innovative formulation, with improvements seen in the PK-PD properties and tolerability compared to traditional ayahuasca. The subsequent 2 studies presented in this dissertation are part of a double-blind, randomized, placebo-controlled within-subject study involving healthy male subjects, with each participant receiving a combination of sublingual harmine and intranasal DMT, harmine alone, or a placebo. DMT was administered intermittently in increments over a period of time to establish a more patient-oriented and better controllable drug administration. All preparations were tolerated well and the pharmacokinetic profile of DMT showed a pronounced long-lasting plateau during the intermittent administration. Moreover, based on both psychometric self-assessments and pharmacokinetic profiles, we found that intranasal DMT can be effectively activated by sublingual harmine and is the main driver of subjective effects compared to the harmine only and placebo condition. Furthermore, the combination of DMT and harmine was shown to induce a phenomenologically rich psychedelic experience, characterized by psychological insights and emotional breakthroughs, with low scores reported in challenging experiences, suggesting a generally acceptable psychological safety profile. These effects were well tolerated and were not associated with changes in personality traits, psychological flexibility, or general well-being, nor were there increases in psychopathology. Importantly, participants attributed personal and spiritual significance to the experience, with mainly positive persisting effects observed at 1- and 4-months follow-ups. These findings suggest that the standardized DMT and harmine formulation demonstrates promising PK-PD properties, psychological safety and tolerability, and induces beneficial psychological processes that could potentially augment psychotherapy. The development of new treatments for mental health disorders based on this formulation warrants further investigation in clinical trials. The successful translation of this research into clinical settings could advance the treatment of mental health disorders, adding a potent therapeutic method to the existing options for treating affective disorders.