Cellular mechanisms of serotonergic psychedelics - apical hypercontextualisation.
Karl Kristjan Kaup, Javier Hidalgo Jiménez, Jaan Aru
Neuroscience & Biobehavioral Reviews July 1, 2026 DOI: 10.1016/j.neubiorev.2026.106876 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Topics | Serotonin |
| Key findings | Proposes that 5-HT2A agonism at apical dendrites of layer V pyramidal neurons causes 'apical hypercontextualisation', amplifying relational processing over direct stimulus representation, which may underlie psychedelic phenomena and inform therapeutic mechanisms. |
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.
Comparable studies
Other narrative reviews on serotonin, most cited first.
Citations in the library
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