Oral psilocybin produces rapid and long-lasting antidepressant-like effects in adolescent rats of both sexes, alongside hallucinogenic-like head-twitch responses. Acute doses of 0.3 and 1 mg/kg induced fast behavioral changes in the forced-swim test that coincided with the timing of hallucinogenic effects. Repeated daily dosing for seven days increased hippocampal neurogenesis markers—Ki-67 (cell proliferation), NeuroD1 (neural progenitors), and BrdU (cell survival)—measured one day later. Antidepressant-like effects persisted up to 15 days after treatment and paralleled continued regulation of NeuroD1. These findings suggest oral psilocybin may offer a fast-acting, long-lasting treatment for adolescent depression, with NeuroD1 as a potential biomarker of long-term neural plasticity.
Adolescent depression is a major public health problem, but treatment options are limited, partly because antidepressants work differently depending on age and sex. In adolescent rats, a single oral dose of psilocybin produced rapid antidepressant-like effects within 30 minutes in both males and females, shown by less immobility and more escape behavior in the forced swim test. After 7 days of daily dosing, males maintained these effects for at least 15 days at both doses tested. Females showed dose-dependent effects that lasted only up to 8 days at the highest dose. These findings suggest psilocybin may offer fast and lasting antidepressant action during adolescence, a period of high depression vulnerability and poor response to conventional treatments, and highlight the need to tailor therapies to biological sex.