Neurobehavioral and Molecular Pharmacology of Pharmahuasca ($\textit{N,N}$-dimethyltryptamine (DMT) and Harmine) in Humans – A Combined Neuropharmacological and Brain Imaging Approach

Abstract

Over the past decade, research with psychedelics has gained new momentum, leading to a psychedelic renaissance in both basic and clinical research. Among these substances is ayahuasca, an Amazonian plant medicine used for millennia by indigenous people for ritualistic and healing practices, which has recently entered research labs in the Americas and Europe. Preliminary findings indicate its therapeutic potential for treating various affective, addictive, and stress-related disorders. This thesis aims to advance our understanding of the neurobehavioral and molecular pharmacology of a simplified, standardized formulation of ayahuasca’s primary chemical constituents, N,N-dimethyltryptamine (DMT) and harmine. By investigating this formulation, I seek to unravel the mechanisms underlying its profound effects on human cognition, emotion, and brain function. This work is motivated by the growing interest in the therapeutic potential of psychedelics, particularly for mental disorders, where existing treatments often fall short. The primary objective is to combine neuropharmacological and brain imaging methodologies to comprehensively explore how DMT and harmine interact at molecular, systemic, and experiential levels. Specifically, I aim to understand the pharmacokinetic and pharmacodynamic interplay of these compounds, their effects on brain networks, and their capacity to induce altered states of consciousness in controlled, measurable ways. This research not only addresses key knowledge gaps regarding the individual and combined actions of DMT and harmine but also lays the groundwork for their future clinical applications in treating mental health conditions. The first study presented is a review article examining the known neurobiological and pharmacological mechanisms of ayahuasca, DMT, and harmine. The most fundamental role of harmine is preventing the degradation of DMT via oxidative deamination by monoamine oxidase type A (MAO-A), leading to significant differences in DMT bioavailability and its effects on human cognition when harmine is co-administered to DMT. The interplay between harmine and DMT extends beyond MAO-A inhibition and might be bidirectional, as explored in one of the research projects in this thesis. It is important to note that ayahuasca contains additional β-carboline alkaloids besides harmine, making its pharmacology more complex than the interaction between DMT and harmine alone. Additionally, the cultural context in which the botanical ayahuasca brew is used significantly influences its psychoactive effects. These fundamental differences should always be considered when ayahuasca is being explained from a purely biological or pharmacological perspective. The following sections detail three experimental research projects that investigate DMT and harmine on different biological and pharmacological levels. The first study is a preclinical project in rodents that received DMT, harmine, or both, in two different concentrations. We measured the concentrations of these compounds and their metabolites in the brain, and used radiopharmaceutical techniques to assess differences in brain glucose uptake and serotonin 2A receptor binding. As expected, DMT concentrations increased with higher administered doses and harmine concentrations, confirming a slowed down DMT metabolism induced by harmine also in the brain. Surprisingly however, no significant differences were found in glucose metabolism or serotonin 2A receptor binding. In the next study, we explored the interaction of DMT and harmine in healthy humans, administering different doses and ratios of these substances using a novel oromucosal application form. This formulation reliably induced psychedelic effects and showed a favorable adverse effect profile compared to traditional ayahuasca. We also observed bidirectional drug-drug interactions, with DMT influencing the pharmacokinetics of harmine and not only the other way. The final study was conducted in trained meditators, who received either the DMT+harmine formulation or a placebo on the second day of a three-day meditation retreat. Functional MRI was used to measure changes in brain connectivity at rest, both between drug conditions and pre- and post-retreat. Both the DMT+harmine combination and placebo affected brain connectivity, suggesting that not only our ayahuasca-inspired formulation is capable of augmenting meditation, but also that meditation has profound effects itself. Safety and tolerability data from both human studies suggest that this novel formulation is safe and warrants further investigation in future clinical trials, potentially targeting conditions such as major depression or substance use disorders. The thesis concludes with a general discussion embedding these findings into the broader literature on psychedelic research, highlighting the implications for clinical applications, and providing directions for future studies to refine and expand the therapeutic potential of DMT+harmine.