Clinical protocols for administering psilocybin-assisted psychotherapy have found a negative correlation between anxious responding and therapeutic outcomes. Despite this, few studies have directly assessed the role that corticosteroids have in altering psilocybin’s acute or delayed behavioral effects. Here, psilocybin, lisuride, and ketamine were used to assess the role of glucocorticoid release in acute threat-associated behavioral responding. Using the open field test, psilocybin's anxiogenic effects at 15 min were found to be inversely and dose-dependently correlated with anxiolytic effects at 4 h in C57BL/6J mice. This corresponded with the observed ability of psilocybin to induce plasma corticosterone release at 15 min, which returned to baseline by 4 h. Lisuride and ketamine also showed this effect. Furthermore, psilocybin, lisuride, and ketamine reduced the latency to feed in the novelty suppressed feeding task at 4 h. Psilocybin and ketamine's effects in this task were lost following chronic oral corticosterone suppression of acute corticosterone release or following pretreatment with the glucocorticoid receptor antagonist mifepristone. When delayed effects were assessed in the open field test at 7 d following administration, anxiolytic effects were again observed for psilocybin, while lisuride and ketamine did not exhibit this long-term effect. Notably, this long-term behavioral effect of psilocybin was found to interact with corticosteroid status at the time of treatment, where chronic corticosterone exposure caused psilocybin to be anxiogenic at 7 d. Intriguingly, mifepristone pretreatment did not affect psilocybin’s long-term behavior. These results suggest that drug-induced corticosteroid release is supportive of acute anxiolysis across drug classes, but this corticosterone release is neither sufficient nor necessary for long-term anxiolysis. Psilocybin's long-term anxiolysis is sensitive to elevated corticosterone concentrations at the time of drug administration. Delayed ketamine and psilocybin-enhanced fear extinction learning have also been observed and the corticosterone sensitivity of these observations is under study. Together, these observations highlight critical distinctions between drug-induced glucocorticoid release and exogenous factors causing elevated glucocorticoid concentrations on psilocybin’s behavioral effects.

Glucocorticoid release and modification of acute threat-associated behaviors by Psilocybin

ACS Spring 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.