IUPHAR Article: Psilocybin induces long-lasting effects via 5-HT2A receptors in mouse models of chronic pain.
Eda Koseli, Belle Buzzi, Torin Honaker, Yogesh Rakholia, Melissa Lewis, Maya C Gaines-Smith, Alaina M Jaster, Javier González-Maeso, M Imad Damaj
Pharmacological Research May 1, 2025 DOI: 10.1016/j.phrs.2025.107699 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical study Peer reviewed |
|---|---|
| Population | Male and female mice with chemotherapy-induced peripheral neuropathy or chronic inflammatory pain |
| Interventions | Psilocybin 2 5-Dimethoxy-4-iodoamphetamine (DOI) |
| Topics | Psilocybin Serotonin |
| Keywords | Psilocybin magic mushrooms Hallucinogenic mushrooms Long-term pain Neuroscience brain research Neural studies Pain therapy Preclinical Chronic pain Mice Neuropathy |
| Citations | 11 |
| Key points | Psilocybin and DOI dose-dependently reversed mechanical, cold, and thermal hypersensitivity in two mouse models of chronic pain via activation of 5-HT2A receptors. |
Abstract
Chronic pain is a debilitating disease with current treatments lacking efficacy and safety, therefore discovery of new treatments is crucial. Initial studies suggest that psychedelics may be feasible for targeting pain, however clinical and preclinical controlled studies are necessary to further investigate that possibility. In this study we assessed the effects of two classical psychedelics psilocybin and 2,5-Dimethoxy-4-iodoamphetamine (DOI) in two models of chronic pain after systemic administration in male and female mice. Psilocybin and DOI dose-dependently reversed mechanical and cold hypersensitivity in the chemotherapy-induced peripheral neuropathy (CIPN) mouse model with different time-course of action. Similarly, psilocybin and DOI dose-dependently reversed thermal hypersensitivity in the chronic inflammatory mouse model of Complete Freud's Adjuvant (CFA). The effects of Psilocybin and DOI in both models were mediated by activation of 5-HT2A receptors (5-HT2AR). Overall, the present study suggests that classical psychedelics psilocybin and DOI are effective in reducing pain-like behaviors via 5-HT2AR activation in two mouse models of chronic pain.
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 13
- Single-dose psilocybin rapidly and sustainably relieves allodynia and anxiodepressive-like behaviors in mouse models of chronic pain Nature Neuroscience October 2, 2025
- The science of psychedelic medicine. Nature Medicine February 6, 2026
- 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
- Psilocybin has no immediate or persistent analgesic effect in acute and chronic mouse pain models bioRxiv (Cold Spring Harbor Laboratory) July 7, 2025
- Advancing cancer neuroscience through stress modulation: Interdisciplinary potential of psilocybin and ketamine General Hospital Psychiatry February 25, 2026
and 8 more in the library
Cites 14
- Psychedelics Promote Structural and Functional Neural Plasticity Cell Reports June 1, 2018
- The Therapeutic Potential of Psychedelic Drugs: Past, Present, and Future. Neuropsychopharmacology April 26, 2017
- Emotions and brain function are altered up to one month after a single high dose of psilocybin. Scientific Reports February 10, 2020
- Psilocybin-Induced Decrease in Amygdala Reactivity Correlates with Enhanced Positive Mood in Healthy Volunteers Biological Psychiatry April 26, 2014
- A Single Dose of Psilocybin Increases Synaptic Density and Decreases 5-HT2A Receptor Density in the Pig Brain International Journal of Molecular Sciences January 15, 2021
and 9 more in the library