Behavioural Effects of High Doses of Psilocybin in Female Rats

Depression and anxiety are two of the most predominant mental disorders and leading causes of disability. The World Health Organization estimated that 3.8% of the world's population suffers from depression, and between 0.4% and 3.6% have an anxiety spectrum diagnosis. Psychedelics, particularly psilocybin, have been extensively studied as new and promising treatments, showing long-lasting positive results when combined with psychotherapy for patients with depression and anxiety, among other disorders. However, pre-clinical trials investigating the precise neurobiological mechanisms underlying these results are still scarce, especially with female subjects. Additionally, emerging evidence suggests that hormonal fluctuations may influence the drug's efficacy, potentially providing a protective effect.

This study utilised adult female rats to examine the behavioural effects of high doses of psilocybin on locomotor activity and on depression and anxiety-like measures. Symptomatology was induced using either early maternal separation or a genetic reduction in the serotonin transporter. The open field (OFT) and affective disorders test (ADT) were employed to assess the effects of doses of 4, 8, or 16 mg/kg of psilocybin. Additionally, the effects of the phase of the oestrous cycle when animals were injected were evaluated. Results showed a significant effect of psilocybin on locomotion activity in the OFT 3 hours and 24 hours post-injection but not after 8 days. No robust effects on depression and anxiety-like measures were observed at any of the doses tested. However, trends were observed in both depression and anxiety-like measures with doses of 4 and 8mg/kg. Moreover, a preliminary evaluation in small groups revealed an interaction between treatment and the phase of the oestrous cycle, suggesting that female hormones might have some protective effect against the effects of the drug in depression-like measures.