Characterizing psilocybin as an antidepressant for adolescence in male and female rats

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.

Study at a glance

Abstract

Abstract Adolescent depression is a significant public health concern, yet treatment options remain limited, particularly due to age- and sex-related differences in antidepressant efficacy. This study explored the rapid and long-lasting antidepressant-like potential of psilocybin in adolescent Sprague-Dawley rats, examining acute and repeated oral dosing effects while incorporating sex as a biological variable. An acute administration of psilocybin produced rapid antidepressant-like effects 30 minutes post-treatment in both male and female rats, demonstrated by reduced immobility and increased escape-related behaviour in the forced swim test. However, repeated daily administrations over 7 days revealed notable sex differences. In males, the antidepressant-like effects were sustained, at least, for up to 15 days post-treatment at both tested doses. In contrast, in females, the effects were dose-dependent and less enduring, persisting only up to 8 days at the highest dose tested. To the best of our knowledge, these results are the first ones to underscore psilocybin’s potential as a fast-acting and long-lasting antidepressant during adolescence, a developmental stage marked by high vulnerability to depression and reduced response to conventional treatments, while also emphasizing the importance of tailoring therapeutic approaches to individual biological factors such as sex.