IDENTIFYING THE NEUROPHYSIOLOGICAL MECHANISMS UNDERLYING THE POTENTIAL THERAPEUTIC EFFECTS OF PSYCHEDELIC COMPOUNDS
UNC Libraries May 21, 2026 Gavin Schmitz
Psychedelics are being investigated as therapeutic tools, but their brain-region-specific effects and signaling mechanisms are not fully understood. A comprehensive study of about 40 diverse psychedelic substances from the tryptamine, phenethylamine, and lysergamide classes found that all tested compounds activate the 5-HT2A serotonin receptor, while also showing serotonergic, dopaminergic, and adrenergic activity. The 5-HT2A receptor is enriched in layer V pyramidal neurons in rodent and human cortices. Electrophysiological studies identified a population of 5-HT2A receptor neurons in the prelimbic and anterior cingulate regions of the prefrontal cortex. Psilocin and a 5-HT2A-preferring compound increased firing in these neurons via a 5-HT2A- and Gαq-dependent mechanism, whereas the non-hallucinogenic LSD analog 2-bromo-LSD reduced firing in both 5-HT2A and non-5-HT2A neurons through a different mechanism.