Psilocybin reduces anxiety-like behavior in male mice four hours after treatment, an effect that depends on a temporary spike in the stress hormone corticosterone. Blocking the corticosterone rise or the glucocorticoid receptor eliminated the short-term anxiolytic effect. A nonpsychedelic drug that also raised corticosterone produced similar anxiety reduction, as did stress-induced hormone release alone. The anxiolytic effect lasted seven days after a single psilocybin dose, but this long-term benefit was lost in mice with chronically elevated corticosterone. The findings suggest that an acute, resolvable glucocorticoid surge is necessary for psilocybin's postacute anxiety relief, while chronic stress hormone elevation undermines its lasting effects.
Acute release of the stress hormone corticosterone modifies the lasting behavioral effects of psilocybin in male mice. Psilocybin caused an initial anxiety-like response and a rise in plasma corticosterone, followed by a later reduction in anxiety in the novelty suppressed feeding test. Both the acute and delayed effects disappeared when mice were first given chronic oral corticosterone to suppress their own stress-axis. One week later, psilocybin-treated mice spent more time in the center of an open field, but this long-term anxiolytic effect was also blocked by prior chronic corticosterone exposure. Brief isoflurane anesthesia after psilocybin eliminated these interactions. The findings identify glucocorticoid release as a biological modifier of psilocybin's post-acute and long-term behavioral effects in mice.