5-HT2A receptor and psychedelics: a trip through the mechanisms of action and therapeutic potential in mental disorders
Muhammad Asim, Julia A. Galiza Soares, Jason M Tucciarone
Translational Psychiatry September 14, 2026 DOI: 10.1038/s41398-026-04455-y (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Topics | Serotonin |
| Key findings | The authors argue that psychedelics act as 5-HT2A receptor agonists, producing profound alterations in cognition, perception, and mood that are hypothesized to stem from circuit-specific modulation of neurotransmission and promotion of neuroplasticity. They contend the receptor is a promising therapeutic target for psychiatric disorders, but note that the precise neural circuits linking 5-HT2AR activation to specific behavioral outcomes remain unmapped, calling for further research. |
Abstract
Serotonin (5-hydroxytryptamine; 5-HT) modulates a vast array of brain functions via its diverse receptor subtypes. Among these, the serotonin 5-HT2A receptor (5-HT2AR) has garnered intense recent interest for its pivotal role in mediating the effects of psychedelic compounds. Substantial evidence indicates that psychedelics act as agonists at the 5-HT2AR, triggering profound alterations in cognition, perception, and mood. These effects are hypothesized to stem from the receptor’s circuit-specific modulation of neurotransmission and its capacity to promote neuroplasticity. This review synthesizes current knowledge on the neuroanatomical distribution of 5-HT2ARs, their associated signaling pathways, and their implicated role in psychiatric pathophysiology. We further evaluate the receptor’s promise as a novel therapeutic target. While several mechanistic models are discussed, a critical outstanding challenge is the precise mapping of neural circuits that translate 5-HT2AR activation into specific behavioral outcomes. This synthesis underscores the imperative for further research to elucidate the 5-HT2AR’s role in neuropsychiatric disorders and to advance the development of targeted psychedelic-based therapies.