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.
Cited by
This article is cited by 3 publications
-
Krupp, K. T., Yaeger, J. D. W., Ledesma, L. J., Withanage, M. H. H., Gale, J. J., Howe, C. B., Allen, T. J., Sathyanesan, M., Newton, S. S., & Summers, C. H. (2024). Single administration of a psychedelic [(R)-DOI] influences coping strategies to an escapable social stress. Neuropharmacology, 252, 109949. https://doi.org/10.1016/j.neuropharm.2024.109949
-
Lerer, E., Botvinnik, A., Shahar, O., Grad, M., Blakolmer, K., Shomron, N., Lotan, A., Lerer, B., & Lifschytz, T. (2024). Effects of psilocybin, psychedelic mushroom extract and 5-hydroxytryptophan on brain immediate early gene expression: Interaction with serotonergic receptor modulators. Frontiers in pharmacology, 15, 1391412. https://doi.org/10.3389/fphar.2024.1391412
-
Harari, R., Chatterjee, I., Getselter, D., & Elliott, E. (2024). Psilocybin induces acute anxiety and changes in amygdalar phosphopeptides independently from the 5-HT2A receptor. iScience, 27(5), 109686. https://doi.org/10.1016/j.isci.2024.109686
Funding Source
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).