Psilocybin's lasting action requires pyramidal cell types and 5-HT2A receptors.
Ling-Xiao Shao, Clara Liao, Pasha A. Davoudian, Neil K. Savalia, Quan Jiang, Cassandra Wojtasiewicz, Diran Tan, Jack D. Nothnagel, Rong-Jian Liu, Samuel C Woodburn, Olesia M Bilash, Hail Kim, Alicia Che, Alex C. Kwan
Nature June 1, 2025 DOI: 10.1038/s41586-025-08813-6 (opens in new tab)
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Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study with in vivo optical imaging, chemogenetic perturbation, and cell-type-specific electrophysiology Peer reviewed |
|---|---|
| Population | Mice |
| Intervention | Psilocybin |
| Dose | a single dose |
| Topics | Psilocybin Serotonin |
| Keywords | Psychedelics Mental health Brain research Stress disorders |
| Citations | 75 |
| Key findings | Psilocybin's long-term effects on stress-related behavior and structural plasticity depend on PT neurons and the 5-HT2A receptor in the medial frontal cortex. |
Abstract
Psilocybin is a serotonergic psychedelic with therapeutic potential for treating mental illnesses1-4. At the cellular level, psychedelics induce structural neural plasticity5,6, exemplified by the drug-evoked growth and remodelling of dendritic spines in cortical pyramidal cells7-9. A key question is how these cellular modifications map onto cell-type-specific circuits to produce the psychedelics' behavioural actions10. Here we use in vivo optical imaging, chemogenetic perturbation and cell-type-specific electrophysiology to investigate the impact of psilocybin on the two main types of pyramidal cells in the mouse medial frontal cortex. We find that a single dose of psilocybin increases the density of dendritic spines in both the subcortical-projecting, pyramidal tract (PT) and intratelencephalic (IT) cell types. Behaviourally, silencing the PT neurons eliminates psilocybin's ability to ameliorate stress-related phenotypes, whereas silencing IT neurons has no detectable effect. In PT neurons only, psilocybin boosts synaptic calcium transients and elevates firing rates acutely after administration. Targeted knockout of 5-HT2A receptors abolishes psilocybin's effects on stress-related behaviour and structural plasticity. Collectively, these results identify that a pyramidal cell type and the 5-HT2A receptor in the medial frontal cortex have essential roles in psilocybin's long-term drug action.
Comparable studies
Other preclinical and animal studies on serotonin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Mice | 2021 | Observational cohort | |
| Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. Rats (implied by typical neurochemical study context) | 1987 | Experimental study | |
| Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors In vitro and in vivo (rodent) models | 2023 | Experimental study | |
| 3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites. Rat brain | 1987 | Animal experiment | |
| Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs Human and mouse dopamine, norepinephrine, and serotonin transporters expressed in cells | 2006 | In vitro laboratory study |
Citations in the library
Cited by 73
- The polypharmacology of psychedelics reveals multiple targets for potential therapeutics. Neuron July 15, 2025
- Psilocybin triggers an activity-dependent rewiring of large-scale cortical networks Cell December 5, 2025
- Psychedelic compounds directly excite 5-HT2A layer V medial prefrontal cortex neurons through 5-HT2A Gq activation Translational Psychiatry October 6, 2025
- Emerging mechanisms of psilocybin-induced neuroplasticity TIPS - Trends in Pharmacological Sciences September 16, 2025
- Psychedelic neuroplasticity of cortical neurons lacking 5-HT2A receptors Molecular Psychiatry March 1, 2026
and 68 more in the library
Cites 22
- Synaptic Dysfunction in Depression: Potential Therapeutic Targets Science October 4, 2012
- Trial of Psilocybin versus Escitalopram for Depression New England Journal of Medicine April 14, 2021
- 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
- Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression. New England Journal of Medicine November 3, 2022
and 17 more in the library