5-HT2A receptor and psychedelics: a trip through the mechanisms of action and therapeutic potential in mental disorders

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. This work was supported by funding from K08 DA055157, Brain and Behavior Research Foundation Young Investigator Grant, Stanford University School of Medicine Department of Psychiatry & Behavioral Sciences 2024 Innovator Grants Program (JT).

Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, US Muhammad Asim, Julia A. Tucciarone Nancy Pritzker Laboratory, Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, US Correspondence to Muhammad Asim or Jason M. The authors declare no competing interests.

This study is a literature review and does not involve any human participants or animal subjects. Therefore, ethical approval was not required. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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