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 Gaines-Smith, Alaina M Jaster, Javier González-Maeso, M Imad Damaj
Pharmacological research May 1, 2025 DOI: 10.1016/j.phrs.2025.107699 via PubMed
Summary
AI-generated from the abstractPsilocybin and a similar psychedelic, DOI, reduced pain-related behaviors in mice with chronic pain. In a mouse model of chemotherapy-induced nerve damage, both drugs reversed sensitivity to cold and touch in a dose-dependent manner, with different timing of effects. In a model of persistent inflammatory pain, they also reversed sensitivity to heat. These pain-relieving effects depended on activation of the 5-HT2A serotonin receptor. The findings suggest that classical psychedelics may be effective for treating chronic pain through this receptor pathway.
Study at a glance
| 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 |
| Keywords | Psilocybin magic mushrooms Hallucinogenic mushrooms Long-term pain Neuroscience brain research Neural studies |
| Citations | 11 |
| Key finding | 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.