Above the threshold, beyond the trip: the role of the 5-HT2A receptor in psychedelic-induced neuroplasticity and antidepressant effects

Serotonergic psychedelics like psilocybin and LSD show promise for treatment-resistant depression by rapidly inducing neuroplasticity, but the molecular mechanisms are debated. This narrative review examines evidence on whether the serotonin 5-HT2A receptor, which mediates hallucinogenic effects, is also required for neuroplasticity. It covers how decreased neuroplasticity relates to depression, how psychedelics promote dendrito-, spino-, and synaptogenesis, and whether these effects are regionally selective. The review critically assesses conflicting studies on the necessity of 5-HT2A signaling for neuroplastic effects and presents a model of the molecular mechanisms involved.

Study at a glance

Abstract

Serotonergic psychedelics, including the recreationally used psilocybin and LSD, have become promising therapeutic agents for the treatment of treatment-resistant depression. While it is generally agreed that they exhibit their antidepressant effects by inducing rapid and sustained neuroplasticity, the molecular mechanisms responsible are widely debated. In particular, the role of the serotonin 5-HT2A receptor, known to mediate the hallucinogenic effects of psychedelics, is under scrutiny. However, many studies remain in conflict on whether action at the receptor is also required for neuroplastic effects. In this narrative review, we examine the available evidence for the involvement of the 5-HT2A receptor in neuroplasticity induction and the possibly antidepressant effects of psychedelics. Firstly, we review the role of decreased neuroplasticity in depression, the evidence for dendrito-, spino- and synaptogenesis promotion by psychedelics, and for its possible regional selectivity. We then discuss the current knowledge on psychedelic action at the 5-HT2A receptor, including its role in promoting hallucinogenic effects. Finally, we critically assess the studies testing the necessity for 5-HT2A signalling for neuroplastic effects and present a model of molecular mechanisms responsible for psychedelic-induced neuroplasticity.