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Psilocybin induces long-lasting effects via 5-HT2A receptors in mouse models of chronic pain

Summary

Researchers found that psilocybin, the active ingredient in magic mushrooms, significantly reduced chronic pain in mice through activation of specific serotonin receptors. The effects lasted for up to two weeks after a single dose, suggesting lasting changes in how the nervous system processes pain. This study suggests psilocybin could be a promising new treatment for chronic pain conditions like neuropathy and inflammation.

Background

Chronic pain affects 20.9% of adults and current treatments lack efficacy and safety. Early studies suggest psychedelics may have analgesic potential, but clinical and preclinical controlled studies investigating classical psychedelics for chronic pain are limited.

Objective

To assess the effects of psilocybin and DOI (2,5-Dimethoxy-4-iodoamphetamine) in two mouse models of chronic pain and investigate the role of 5-HT2A receptors in mediating their antinociceptive effects.

Results

Both psilocybin and DOI dose-dependently reversed mechanical, cold, and thermal hypersensitivity in both pain models. Psilocybin produced long-lasting effects (6-14 days) while DOI effects lasted only up to 24 hours. 5-HT2A receptor antagonism completely blocked the antinociceptive effects of both compounds, demonstrating 5-HT2A receptor-mediated signaling.

Conclusion

Classical psychedelics psilocybin and DOI effectively reduce chronic pain-like behaviors via 5-HT2A receptor activation in mouse models. Psilocybin’s long-lasting effects suggest sustained changes in neural plasticity. These findings provide foundational evidence for further mechanistic studies and potential clinical applications of psychedelics in chronic pain treatment.
  • Published in:Pharmacology Research,
  • Study Type:Preclinical Animal Study,
  • Source: 10.1016/j.phrs.2025.107699, PMID: 40107634
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