Single-dose psilocybin rapidly and sustainably relieves allodynia and anxiodepressive-like behaviors in mouse models of chronic pain
Ahmad Hammo, Stephen Wisser, Joseph Cichon
Nature Neuroscience October 2, 2025 DOI: 10.1038/s41593-025-02068-0 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical study Peer reviewed |
|---|---|
| Population | Adult male and female mice |
| Interventions | Psilocybin Psilocin |
| Dose | a single dose |
| Topics | Psilocybin |
| Keywords | Chronic pain Anterior cingulate cortex Allodynia Prefrontal cortex Hyperalgesia Glutamate receptor Hallucinogen Antidepressant Nmda receptor Mood disorders |
| Citations | 20 |
| Key points | A single dose of psilocybin induces rapid and sustained reversal of both mechanical allodynia and anxiodepression-like states in mice with chronic pain, mediated by psilocin's partial agonism at 5-HT2A and 5-HT1A receptors in prefrontal cortical circuits. |
Abstract
Chronic pain and mood disorders co-occur, exacerbate one another and share neurobiological mechanisms, but whether a single intervention could promptly alleviate both conditions remains unclear. Here, in two chronic pain models, we show that a single dose of psilocybin induces a rapid and sustained reversal of both mechanical allodynia and anxiodepression-like states in adult male and female mice. Using local psilocin injections, the key active metabolite of psilocybin, we show that the engagement of prefrontal cortical circuits is critical for the concurrent alleviation of both conditions. Two-photon calcium imaging reveals that psilocin rapidly normalizes chronic pain-associated hyperactivity in anterior cingulate cortex layer 2/3 pyramidal neurons. Pharmacologic manipulations with full agonists of 5-HT2A and 5-HT1A receptors replicated some, but not all, of psilocin's cellular and behavioral effects, suggesting that psilocin's actions arise from partial agonism at these receptors within shared circuits governing pain and mood processing.
Comparable studies
Other preclinical and animal studies on psilocybin, 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 | |
| Harnessing psilocybin: antidepressant-like behavioral and synaptic actions of psilocybin are independent of 5-HT2R activation in mice Mice | 2021 | Experimental study | |
| Psychedelics reopen the social reward learning critical period Mice | 2023 | Experimental study in mice | |
| Correlation between the potency of hallucinogens in the mouse head-twitch response assay and their behavioral and subjective effects in other species. C57BL/6J mice | 2020 | Experimental study with dose-response experiments | |
| Effects of psilocybin on hippocampal neurogenesis and extinction of trace fear conditioning Mice | 2013 | Experimental study |
Citations in the library
Cited by 16
- No evidence of immediate or persistent analgesic effect from a single dose of psilocybin in three mouse models of pain Nature Communications January 22, 2026
- Current status and future prospects of research on psilocybin's regulation of neurotransmitters and their receptors related to the pathogenesis of tinnitus. Hearing research August 1, 2026
- Classic Psychedelics for Treating Chronic Pain: Mechanism and Clinical Translation Molecules July 27, 2026
- α2-Adrenergic receptor modulates 5-HT2A-mediated behavioral effects of MDMA and psilocybin in mice. Molecular Psychiatry July 7, 2026
- Classic Psychedelics for Chronic Pain: A Critical Review of the Literature and Practical Advice for Clinicians. Drugs June 4, 2026
and 11 more in the library
Cites 15
- Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Neuron July 5, 2021
- Single-Dose Psilocybin Treatment for Major Depressive Disorder JAMA August 31, 2023
- Psychedelics reopen the social reward learning critical period Nature June 14, 2023
- Psilocybin: from ancient magic to modern medicine The Journal of Antibiotics May 12, 2020
- Identification of 5-HT2A receptor signaling pathways associated with psychedelic potential. Nature Communications December 15, 2023
and 10 more in the library