Transient Elevation of Plasma Glucocorticoids Supports Psilocybin-Induced Anxiolysis in Mice
ACS Pharmacology & Translational Science – August 02, 2023
Source: OpenAlex
Summary
Psilocybin's long-term anxiolytic effects stem from a temporary stress hormone surge, not its hallucinogenic properties. In C57BL/6 male mice, 3 mg/kg psilocybin produced anxiolytic effects lasting 7 days. This pharmacology was blocked by a glucocorticoid receptor antagonist, an antiglucocorticoid, or suppressing corticosterone. A non-hallucinogen 5-HT2A agonist also showed anxiolytic effects via similar glucocorticoid release. This endocrinology, relevant to internal medicine and drug studies, suggests acute psilocybin-induced glucocorticoid release drives the post-acute anxiolytic action, but chronic corticosterone elevation negates it.
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.