Psilocybin-induced anxiolytic effects supported by transient elevation of corticosterone

Abstract ID 128335 Poster Board 337 Investigation into the clinical use of the serotonin (5HT-2A) receptor agonist psilocybin in conjunction with psychotherapy has shown promising therapeutic results in the treatment of psychiatric disorders. Correlations between drug-induced cortisol elevation and treatment outcomes have been reported for human studies during psilocybin-assisted psychotherapy; however, the mechanistic relationship between psychedelic-associated alterations in plasma corticosterone (CORT) responses and anxiolytic efficacy remains unclear. A time course for psilocybin to induce anxiolysis in the absence of any intervention was conducted with C57/Bl6 mice and LC-MS/MS. Serum samples tested at doses of 0.3, 1, and 3 mg/kg found peak concentrations at 15 min post-injection. In the open field test 15 minutes post-injection, mice that received 3mg/kg psilocybin demonstrated decreased center time, while the 0.3 mg/kg exhibited a dose-dependent increase. However, at 4 h post-injection, the reverse was found, in that 0.3mg/kg psilocybin decreased center time. This dose-dependent interaction correlates with psilocybin-induced increases in CORT levels that peak at 15 min and return to baseline by 4 h. In addition, the non-hallucinogenic compound lisuride and NDMAR antagonist ketamine were used and demonstrated a transient increase in corticosterone concentrations at 15 min and returned to baseline by 4 h. When tested in the novelty-suppressed feeding test, all three compounds reduced the latency to feed 4 h post-injection. Although following exposure to chronic oral CORT and when administered the glucocorticoid antagonist, mifepristone, both psilocybin and ketamine lost this anxiolytic effect. Chronic exposure to CORT and mifepristone suppressed the psilocybin-induced stress response and increased CORT. At a dose of 3 mg/kg, IP psilocybin was found to have post-acute anxiolytic-like effects that were not altered by pretreatment with the non-hallucinogenic 5-HT2AR antagonist, ketanserin. These results suggest that psilocybin-induced stress response and increased plasma CORT levels are supportive of the observed anxiolytic effects. This study demonstrates that psilocybin-induced corticosterone release is a critical factor driving reductions in anxiety-like behavior in mice in the hours following drug clearance. That ongoing, unresolved glucocorticoid elevations can invert the long-term outcome of psilocybin administration on anxiety-like behavior up to seven days later. These findings point to HPA axis activation and changes in glucocorticoid concentration profiles over time as critical translational factors for mechanistic consideration when investigating classical serotonergic psychedelic-assisted therapy for the treatment of psychiatric disorders. This work was supported through funds from the UW-Madison School of Pharmacy, grant funding to C.J.W. from the National Institute of Mental Health (R01MH122742), a fellowship for N.T.J. from the National Institute of General Medical Sciences (T32GM008688), and fellowships for Z.Z. and J.R. from the National Institute of Neurological Disorders and Stroke (T32NS105602).