A single dose of psilocybin at 0.32 mg/kg, but not lower or higher doses, produced short- and long-term antidepressant-like effects in Wistar rats, as measured by the forced swim test, and also increased social interaction and sucrose preference. Higher doses of 1.0 and 3.2 mg/kg lacked antidepressant-like activity and instead reduced body temperature, locomotor activity, and weight gain. Brain-derived neurotrophic factor (BDNF) levels in the hippocampus and prefrontal cortex increased linearly with dose, dissociating from the inverted-U-shaped behavioral effects. The findings suggest a narrow therapeutic window for psilocybin, with the intermediate dose providing benefits without adverse effects seen at higher doses.
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.