Psilocybin Enhances Cued Fear Extinction and Extinction Recall in Stress-Naïve, Acutely Stressed, and Chronically Stressed Mice

Noelle Cataldo; John A. Razidlo; Cody J. Wenthur

doi:10.1021/acsptsci.5c00462

Psilocybin Enhances Cued Fear Extinction and Extinction Recall in Stress-Naïve, Acutely Stressed, and Chronically Stressed Mice

Noelle Cataldo, John A. Razidlo, Cody J. Wenthur

ACS Pharmacology & Translational Science September 11, 2025 DOI: 10.1021/acsptsci.5c00462 (opens in new tab)

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Study at a glance

AI-extracted from the abstract

Characteristics	Preclinical experimental study Peer reviewed
Population	Male mice
Intervention	Psilocybin
Topics	Psilocybin
Citations	2
Key findings	Psilocybin enhanced fear extinction and promoted extinction recall in both stress-naïve and stressed male mice.

Abstract

Serotonergic psychedelics have shown promise in clinical trials for treating an array of mental health disorders, including depression, anxiety, and post-traumatic stress disorder. Despite these findings, our understanding of how these drugs mechanistically exert their therapeutic effects remains incomplete. While researchers have regularly employed rodent preclinical models to assess such mechanisms, many of these findings arise from stress-naïve animals. Given that prior environmental stress is a critical component for the mental health disorders being studied in clinical trials of psychedelics, understanding the performance of these drugs in animals previously exposed to acute or chronic stress is of strong translational relevance. In this study, we examined the effects of psilocybin in male mice that were stress-naïve, as well as in those that underwent either single-prolonged stress (SPS) or chronic restraint stress (CRS). The effects of these treatments on corticosterone release, extinction of freezing behavior, and recall of extinction in Pavlovian fear conditioning were examined for each group. We observed that psilocybin challenge transiently increased serum corticosterone in stress-naïve mice relative to saline; however, this effect was not observed in SPS and CRS animals. Interestingly, psilocybin treatment enhanced fear extinction and promoted extinction recall 24 h later not only in stress-naïve animals but also in stressed animals. These findings indicate psilocybin's ability to acutely enhance fear extinction and promote enhanced extinction recall across animals with diverse environmental stress experiences prior to exposure.

Comparable studies

Other preclinical and animal studies on psilocybin, most cited first.

Study	Year	Design
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

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