Psilocin Alleviates Acute Itch in Mice: Possible Involvement of 5-Ht2a Receptors and Kynurenine Pathway Publisher



Afrooghe A^{1, 2} ; Ahmadi E^{1, 2} ; Lesani A^{1, 3} ; Mehranjani MS¹ ; Elahi M^{1, 4} ; Babaei M^{1, 2} ; Shayan M^{1, 5} ; Shafaroodi H^{1, 3} ; Jafari RM^{1, 3} ; Foroumadi A^{6, 7} ; Manavi MA¹ ; Dehpour AR^{1, 3}
Source: Naunyn-Schmiedeberg's Archives of Pharmacology Published:2025

Abstract

We aimed to investigate whether psilocin, the bioactive metabolite of the well-known psychedelic, psilocybin, may have antipruritic effects in mice by interfering with the kynurenine pathway and interacting with 5-HT2A receptors. Eight mice were randomly assigned to each of the study groups receiving either normal saline, compound 48/80, psilocin (0.3, 1, and 3 mg/kg), or psilocin (1 mg/kg) + 1-MT (0.3 mg/kg). The scratching bouts were documented in each group. The hallucinogenic properties of psilocin were documented using the head-twitch response (HTR) test. To confirm their involvement, we also quantified the expression levels of TNF-α, TLR-4, indoleamine-2,3-dioxygenase (IDO), and 5-HT2A receptors across various study groups. We found that psilocin (1 mg/kg) exerted the most significant antipruritic and hallucinogenic effects (P < 0.0001). The activity of 5-HT2A receptors in the skin tissue of mice was confirmed by western blot. When psilocin (1 mg/kg) was given together with 1-MT (0.3 mg/kg), the antipruritic effects became more pronounced as compared to when psilocin was given alone (P < 0.05). TLR-4 and TNF-α expression levels considerably reduced after psilocin was applied, both alone and together with 1-MT (P < 0.05, P < 0.01, respectively). We also observed significantly decreased activity of IDO in the treatment groups (P < 0.05, P < 0.01 after giving psilocin alone, and together with 1-MT, respectively). To our knowledge, this is the first study to confirm the effectiveness of psychedelics in battling pruritus. Our findings offer a novel repositioning for psilocin. This may be particularly beneficial for psychological conditions accompanied by pruritus. © The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2025.