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Concurrent stress modulates the acute and post-acute effects of psilocybin in a sex-dependent manner

Chloé Galipeau, Zsolt Lenkei, Miguel Farinha‐ferreira, Catarina Miranda‐lourenço, Ana M. Sebastião

Neuropharmacology December 24, 2024 DOI: 10.1016/j.neuropharm.2024.110280 (opens in new tab)

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Study at a glance

AI-extracted from the abstract
Characteristics Experimental study Peer reviewed
Population Adult male and female C57BL/6J mice
Intervention Psilocybin
Dose 5 mg/kg
Duration 1-hour restraint during acute drug effects; behavioral tests starting 24 hours after administration
Topics Psilocybin
Keywords Hallucinogen Acute pain Pharmacology Developmental psychology
Citations 17
Key findings Psilocybin induced anxiolytic-like effects that were fully blocked by stress in males but only partially in females, with no antidepressant-like effects observed.

Abstract

There is renewed interest in psychedelics, such as psilocybin, as therapies for multiple difficult-to-treat psychiatric disorders. Even though psychedelics can induce highly pleasant or aversive experiences, depending on multiple personal and environmental factors, there is little research into how such experiences impact post-acute mood-altering actions. Here we aimed at offsetting this gap. First, we tested whether acute psilocybin effects differed between sexes. Adult male and female C57BL/6J mice received saline or psilocybin (5 mg/kg; i.p.), and head-twitch response (HTR) frequency was quantified. Notably, while psilocybin increased HTR frequency in both sexes, the effect was greater in females. We then tested if stress exposure during acute drug effects impacted post-acute psilocybin actions. Following drug treatment, mice were returned to their homecage or restrained for 1 h. Anxiety- and depression-like behaviors were assessed starting 24 h following drug administration, using the marble burying, novelty-suppressed feeding, and splash tests. Psilocybin induced anxiolytic-, but not antidepressant-like, which were fully blocked by stress in males, but only partially so in females. Lastly, we assessed the acute stress-psilocybin interaction on plasma corticosterone levels in a separate cohort of mice, treated as above. Both stress and psilocybin independently increased corticosterone levels, without additive or interactive effects being observed for either sex. Our data reveals the role of sex and peri-acute negative experiences in the acute and post-acute actions of psilocybin. These findings underline the importance of non-pharmacological factors, such as the quality of the psychedelic experience, in the mood-altering effects of psychedelics, holding significant for both their therapeutic and recreational use.

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

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Psilocybin Addiction Anxiety Depression Psychedelic-assisted therapy