A theoretical investigation of DMT metabolism and the formation of apotential biomarker

Abstract

N,N-dimethyltryptamine (DMT) is an endogenous psychedelic tryptamine characterizedby a short duration of action due to its rapid metabolic degradation mediated by monoamineoxidase A (MAO-A), a flavoprotein that utilizes flavin adenine dinucleotide (FAD) as a redoxcofactor. When ingested as part of ayahuasca, a traditional Amazonian decoction containingPsychotria viridis (a source of DMT) and Banisteriopsis caapi (rich in β-carbolines that inhibitMAO-A), DMT reaches the central nervous system (CNS) and produces psychoactive effects. Inthis paper a computational study using density functional theory (DFT) was performed atM06-2X/6-311+G(2d,p) level of theory to investigate the catalytic mechanism of MAO-A inDMT metabolism, focusing on the formation of indole-3-acetic acid (3-IAA), an inactivemetabolite of toxicological and forensic relevance. Single point energy calculations using apolarizable continuum model (ε = 4.0) were performed to approximate the enzymaticenvironment. A benchmark analysis identified PBE/def2-TZVP as the most suitable protocol forTD-DFT calculations, providing the lowest mean absolute deviation, MAD (0.16), and root mean square deviation, RMSD (0.21), with negligible systematic error. These findings offermechanistic insights and support the application of computational chemistry in forensic studies.