Mapping Endogenous Psychedelic Chemistry: Indolethylamine N-Methyltransferase (INMT) Localizes Proximal to the Golgi Apparatus of Human Neurons

Abstract

N,N-dimethyltryptamine (DMT) is a serotonergic psychedelic with a history of ethnobotanical use and emerging clinical efficacy for neuropsychiatric disorders. Following Julius Axelrod's pioneering studies showing DMT production in human tissues, DMT has been proposed as an endogenous neuromodulator because it is a serotonin 2A receptor (5-HT2A R) agonist. However, the DMT-producing enzyme, indolethylamine N-methyltransferase (INMT), has not been characterized at the protein level in the human central nervous system. Here, we validated an anti-INMT antibody and used immunocytochemistry to show that INMT localizes in close proximity to other DMT biosynthetic enzymes near the cytosolic face of the cis-Golgi network in human induced pluripotent stem cell-derived neurons, with immunoreactivity observed across multiple neuronal Golgi phenotypes. Notably, both DMT-like and 5-HT2A R immunoreactivity also partially localized in close proximity to the Golgi apparatus. Our results establish the first protein-level characterization of INMT in human neurons and identify the cis-Golgi network as a candidate microdomain for psychedelic tryptamine biosynthesis. We propose that INMT catalytic activity at the cis-Golgi network creates an enriched region of membrane-permeable psychedelic tryptamines that can access an intracellular 5- HT2A R pool. These findings provide new tools and insights that can inform efforts to understand the mechanism of action of psychedelics under clinical investigation and to target endogenous tryptamines therapeutically.