Beyond classical antidepressants: DMT-based therapeutics as novel drug targets for mental health disorders

Abstract

Only a limited number of innovative psychopharmaceuticals have been developed by major pharmaceutical companies for patients with affective disorders in recent years. At the same time, various psychedelic compounds with entirely novel mechanisms of action are under investigation for their potential as therapeutic agents. One particularly interesting candidate is N,N-dimethyltryptamine (DMT), a naturally occuring serotonergic psychedelic with potent consciousness-modulating properties. 

DMT, along with several harmala alkaloids (MAO inhibitors), constitutes the core ingredient of the indigenous plant medicine „ayahuasca“, which has been used for curative purposes in South America for centuries. Clinical studies indicate that ayahuasca compounds exhibit antidepressant, anxiolytic, and anti-addictive properties. Beyond their capacity to enhance brain resilience by promoting synaptic plasticity, it is postulated that the psychedelic experience facilitates emotional processing, psychological insights and behavioral flexibility. Consequently, DMT-based therapeutics may enhance the effectiveness of psychotherapy in a transdiagnostic way.

However, the utilization of botanical ayahuasca in biomedical research presents certain translational challenges due to distressing side effects such as nausea, vomiting, and overwhelming hallucinations. For clinical trials, standardized formulations with improved safety, tolerability, and pharmacokinetic profiles are therefore urgently needed. This presentation summarizes findings from neuropsychopharmacological studies and outlines pathways and potential avenues in translational drug development. The overarching objective is to refine the safety and potential clinical applicability of DMT formulations for the treatment of mental health disorders.

Biography

Milan Scheidegger has a multidisciplinary background in medicine (MD), neuroscience (PhD), philosophy (MA), and clinical psychiatry (FMH). As a senior physician, he currently leads the junior research group "Psychedelic Research & Therapy Development" at the Department for Psychiatry, Psychotherapy, and Psychosomatics at Psychiatric University Hospital Zurich. After his MD-PhD training in functional and molecular brain imaging at the Institute for Biomedical Engineering (ETH Zurich), he has been conducting research on the neurobiology and pharmacology of altered states of consciousness and the therapeutic potential of psychedelics such as ketamine, psilocybin, and DMT. As a co-founder of the UZH spin-off "Reconnect Labs" he is developing psychedelic-assisted treatment approaches for mental health. His research has been recognized with the Young Investigators Award from the Swiss Society of Biological Psychiatry (2013), the Inger Salling Prize for Psychiatry (2019), and the European Varela Award (2020).