Study: Oral Psilocybin Shows Fast and Lasting Antidepressant-Like Effects in Adolescents

The preclinical study, published in Biomedicine & Pharmacotherapy, tested male and female Sprague-Dawley rats and found benefits across both sexes. In the forced-swim test, a single oral dose of psilocybin (0.3 or 1 mg/kg) reduced immobility and increased active escape behaviors within 30 minutes. The team confirmed hallucinogenic-like drug engagement via head-twitch responses, consistent with 5-HT2A receptor activation, while locomotor activity remained unchanged. When psilocybin was given once daily for seven days, the antidepressant-like pattern persisted when animals were retested 1, 8 and 15 days after the final dose. Effects were stronger and more consistent at 1 mg/kg; the lower dose showed signs of waning at later time points.

Notably, repeated dosing increased several hippocampal neurogenesis markers one day after treatment: Ki-67 (cell proliferation), NeuroD1 (neural progenitors) and BrdU (cell survival). Two weeks later, NeuroD1 remained elevated, and higher NeuroD1 levels moderately correlated with greater antidepressant-like behavior, pointing to a potential biomarker of psilocybin-related plasticity. Body-weight gain tracked normally, supporting dose tolerability in adolescents of both sexes.

The authors emphasize the translational relevance of using oral dosing, which mirrors how psilocybin would be taken in clinical settings. At the same time, they caution that these are rodent data. The study relied on behavioral screens like the forced-swim test, did not include pharmacokinetic measurements of psilocin, and did not probe longer-term durability beyond 15 days. Still, the findings add to evidence that psilocybin can act quickly and that its sustained effects may track with hippocampal neurogenesis rather than continued hallucinogenic activity.