Above the threshold, beyond the trip: the role of the 5-HT2A receptor in psychedelic-induced neuroplasticity and antidepressant effects
Adam J. Drewko, Ron L. P. Habets, Tibor M Brunt
Molecular Psychiatry August 23, 2025 DOI: 10.1038/s41380-025-03169-9 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Narrative review Peer reviewed |
|---|---|
| Topics | Neuroplasticity Serotonin |
| Keywords | Antidepressant Vortioxetine Psychotherapist Hippocampus |
| Citations | 4 |
| Key findings | The role of the 5-HT2A receptor in psychedelic-induced neuroplasticity remains debated, with conflicting evidence on whether action at this receptor is required for neuroplastic effects. |
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.
Comparable studies
Other narrative reviews on neuroplasticity, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| A neurotrophic hypothesis of depression: role of synaptogenesis in the actions of NMDA receptor antagonists | 2012 | Review | |
| Towards an understanding of psychedelic-induced neuroplasticity. Review of preclinical and clinical studies | 2023 | Review | |
| Buddha's Brain: Neuroplasticity and Meditation [In the Spotlight] | 2008 | Review | |
| Neuroplasticity as a convergent mechanism of ketamine and classical psychedelics | 2021 | Review | |
| Psychedelics in Psychiatry: Neuroplastic, Immunomodulatory, and Neurotransmitter Mechanisms | 2020 | Review |
Citations in the library
Cited by 5
- Psilocybin-assisted therapy for major depressive disorder: Perspective from meta-analysis. Journal of Affective Disorders August 1, 2026
- Inhibition of cortico-amygdala projections underlies affective bias modification by psilocybin bioRxiv (Cold Spring Harbor Laboratory) March 4, 2026
- Distinguishing 4- vs 5-Hydroxy- N , N -Dimethyltryptamine (Psilocin vs Bufotenine) Using Hydrogen–Deuterium Back-Exchange Journal of the American Society for Mass Spectrometry December 30, 2025
- Psychedelics for the Treatment of Substance Use Disorder Pharmaceutical Science October 13, 2025
- Experience, plasticity, and context: Beyond single-level models of antidepressant action. Journal of Psychopharmacology August 17, 2026
Cites 58
- Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder JAMA Psychiatry November 4, 2020
- Psychedelics Promote Structural and Functional Neural Plasticity Cell Reports June 1, 2018
- Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action Neuroreport December 1, 1998
- Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Neuron July 5, 2021
- The Subjective Effects of Psychedelics Are Necessary for Their Enduring Therapeutic Effects. ACS Pharmacology & Translational Science December 10, 2020
and 53 more in the library