Transient Elevation of Plasma Glucocorticoids Supports Psilocybin-Induced Anxiolysis in Mice
Zarmeen Zahid, Zhen Zheng, N. Jones, Sean M. Grady, Ziyad W. Sultan, John A. Razidlo, Matthew I. Banks, Cody J. Wenthur
ACS Pharmacology & Translational Science August 2, 2023 DOI: 10.1021/acsptsci.3c00123 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | C57BL/6 male mice |
| Interventions | Psilocybin lisuride glucocorticoid receptor antagonist 5-HT2A antagonist |
| Dose | 3 mg/kg IP psilocybin |
| Duration | 4 hours and 7 days post-treatment |
| Topics | Psilocybin |
| Keywords | Anxiolytic Corticosterone Antagonist Endocrinology Pharmacology Glucocorticoid receptor Antiglucocorticoid Hallucinogen |
| Citations | 50 |
| Key findings | Acute psilocybin-induced corticosterone release drives postacute anxiolytic-like effects in mice, and chronically elevated corticosterone abolishes the long-term anxiolytic effect. |
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.
Comparable studies
Other preclinical and animal studies on psilocybin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Mice | 2021 | Observational cohort | |
| Harnessing psilocybin: antidepressant-like behavioral and synaptic actions of psilocybin are independent of 5-HT2R activation in mice Mice | 2021 | Experimental study | |
| Psychedelics reopen the social reward learning critical period Mice | 2023 | Experimental study in mice | |
| Correlation between the potency of hallucinogens in the mouse head-twitch response assay and their behavioral and subjective effects in other species. C57BL/6J mice | 2020 | Experimental study with dose-response experiments | |
| Effects of psilocybin on hippocampal neurogenesis and extinction of trace fear conditioning Mice | 2013 | Experimental study |
Citations in the library
Cited by 46
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- Associations between hypothalamic-pituitary-adrenal (HPA) axis hormone levels, major depression features and antidepressant effects of ketamine. Journal of Affective Disorders March 15, 2025
- Psilocybin for the treatment of Alzheimer’s disease Frontiers in Neuroscience July 10, 2024
- Psilocybin induces acute anxiety and changes in amygdalar phosphopeptides independently from the 5-HT2A receptor iScience April 9, 2024
- Psilocybin reduces heroin seeking behavior and modulates inflammatory gene expression in the nucleus accumbens and prefrontal cortex of male rats Molecular Psychiatry October 21, 2024
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Cites 36
- Human hallucinogen research: guidelines for safety. Journal of Psychopharmacology July 1, 2008
- Quality of Acute Psychedelic Experience Predicts Therapeutic Efficacy of Psilocybin for Treatment-Resistant Depression Frontiers in Pharmacology January 17, 2018
- Survey study of challenging experiences after ingesting psilocybin mushrooms: Acute and enduring positive and negative consequences Journal of Psychopharmacology August 31, 2016
- Psychedelic effects of psilocybin correlate with serotonin 2A receptor occupancy and plasma psilocin levels Neuropsychopharmacology January 26, 2019
- Set and setting, psychedelics and the placebo response: An extra-pharmacological perspective on psychopharmacology Journal of Psychopharmacology November 16, 2016
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