Cellular mechanisms of serotonergic psychedelics - apical hypercontextualisation.

Abstract

Classical serotonergic psychedelics primarily exert their profound effects through agonism at the serotonin 2A (5-HT2A) receptor, which is abundantly expressed in many cortical regions, particularly in layer V pyramidal neurons of associative and visual areas. At the cellular level, these receptors are predominantly localized postsynaptically on the soma and apical dendrites. This review synthesizes evidence from distinct subfields of psychedelic cognitive neuroscience to illuminate how 5-HT2A agonism at apical dendrites of layer V pyramidal neurons disrupts the usual boundaries of conscious mental representations, boosting their interaction with surrounding contextual influences. We propose "apical hypercontextualisation" as a unifying hypothesis, whereby enhanced apical signaling amplifies relational processing over direct stimulus representation. Finally, we overview key psychedelic phenomenological features - such as perceptual distortions, associative cognition, and self-alterations - demonstrating how they emerge from contextual amplification, with implications for therapeutic mechanisms in mental health disorders.