Transient Elevation of Plasma Glucocorticoids Supports Psilocybin-Induced Anxiolysis in Mice

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.

Study at a glance

Abstract

While correlations between drug-induced cortisol elevation, self-reported anxiety, and treatment outcomes have been reported for human studies during psilocybin-assisted psychotherapy, the mechanistic relationship between psychedelic-associated alterations in plasma glucocorticoid responses and the time course of anxious responsiveness remains unclear. Using rodents, both time-bound manipulation of glucocorticoid concentrations and assessment of anxiety-like behaviors can be achieved. Here, 3 mg/kg IP psilocybin was found to have anxiolytic-like effects in C57BL/6 male mice at 4 h after treatment. These effects were not altered by pretreatment with a 5-HT2A antagonist but were blunted by pretreatment with a glucocorticoid receptor antagonist or suppression of psilocybin-induced corticosterone elevations. Anxiolytic-like effects were also observed at 4 h following treatment with the nonpsychedelic 5-HT2A agonist lisuride at a dose causing a similar increase in plasma glucocorticoids as that seen with psilocybin, as well as following stress-induced (via repeated injection) glucocorticoid release alone. Psilocybin's anxiolytic-like effects persisted at 7 days following administration. The long-term anxiolytic effects of psilocybin were lost when psilocybin was administered to animals with ongoing chronic elevations in plasma corticosterone concentrations. Overall, these experiments indicate that acute, resolvable psilocybin-induced glucocorticoid release drives the postacute anxiolytic-like effects of psilocybin in mice and that its long-term anxiolytic-like effects can be abolished in the presence of chronically elevated plasma glucocorticoid elevations.