Blocking 5-HT2B receptors abolishes psilocybin’s efficacy in the rat forced swim test
Journal of Psychopharmacology June 23, 2026 Lenka Seillier, Alexandre Seillier, Morgan A. Zvolska et al.
Psilocybin produces rapid and sustained antidepressant-like effects in rats, as measured by reduced immobility and increased climbing in the forced swim test. Blocking the 5-HT2B receptor with the antagonist RS-127445 dose-dependently reversed these behavioral effects, indicating that 5-HT2B receptors are necessary for psilocybin's antidepressant-like activity. However, the same antagonist did not affect psilocybin-induced head-twitch responses, a proxy for psychedelic effects, suggesting that the antidepressant-like and psychedelic effects of psilocybin can be dissociated via different serotonin receptor subtypes.