Despite observed correlations between acute glucocorticoid release, self-reported anxiety, and long-term treatment outcomes for human studies using psilocybin-assisted psychotherapy approaches, the mechanistic relationship between psychedelic-dependent stress and subsequent behavioral responses remains unclear. Using rodents, direct manipulation of stress-associated hormone responses can be achieved with established pharmacologic models for the assessment of antidepressant and anxiolytic therapeutics. Here, chronic oral corticosterone-induced suppression of the hypothalamic-pituitary-adrenal axis is used to assess the relevance of drug-induced glucocorticoid release on the acute, post-acute, and long-term effects of psilocybin in male C57BL/6J mice. In these studies, psilocybin-induced acute anxiogenesis was found to be correlated to post-acute anxiolysis in a dose-dependent manner. Psilocybin also displayed acute increases in plasma corticosterone, but a post-acute anxiolytic effect in the novelty suppressed feeding test. Both effects were lost when psilocybin was administered in animals pre-exposed to chronic oral corticosterone. A similar long-term interaction between chronic corticosterone and psilocybin administration was observed in an open field test occurring one week after drug administration. Psilocybin administration alone led to more time spent in the center of the arena, but animals spent less time in the center with chronic corticosterone exposure. Intriguingly, these interactive effects were absent in animals exposed to brief isoflurane anesthesia after drug treatment.
Overall, these experiments identify acute glucocorticoid release as a relevant biological modifier for the post-acute and long-term behavioral effects of psilocybin in mice. Rodent studies are thus suggested as a tractable means to address neuroendocrine mechanisms supporting context-dependent psychedelic effects in mammalian species.