A multi-institutional investigation of psilocybin’s effects on mouse behavior
Odilia D Lu, Katrina White, Kendall Raymond, Christine Liu, Alexandra S Klein, Nathaniel Green, Sam Vaillancourt, Austin Gallagher, Lena Shindy, Alyssa Li, Kira Wallquist, Ruoxian Li, Mila Zou, Austen B Casey, Lindsay P. Cameron, Matthew B Pomrenze, Vikaas S. Sohal, Mazen A Kheirbek, Andrea M Gomez, Stephan Lammel, Boris D. Heifets, Robert C. Malenka
bioRxiv (Cold Spring Harbor Laboratory) April 9, 2025 preprint DOI: 10.1101/2025.04.08.647810 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Multi-institutional collaborative experimental study |
|---|---|
| Sample size | 200 |
| Population | Male and female mice |
| Intervention | Psilocybin |
| Dose | 2 mg/kg, IP |
| Duration | Acute and 24-hour post-administration |
| Topics | Psilocybin |
| Keywords | Psychedelics Psilocybin research Behavioral studies Animal testing |
| Citations | 18 |
| Post-publication review | 1 comment on PubPeer (opens in new tab) · last active May 2026 |
| Key findings | Psilocybin had robust and replicable acute effects on mouse behavior, including increased anxiety and avoidance and decreased fear expression, but did not have replicable persistent effects on anxiety- or depression-like behaviors, fear extinction, social preference, or social reward learning. |
Abstract
ABSTRACT Studies reporting novel therapeutic effects of psychedelic drugs are rapidly emerging. However, the reproducibility and reliability of these findings could remain uncertain for years. Here, we implemented a multi-institutional collaborative approach to define the robust and replicable effects of the psychedelic drug psilocybin on mouse behavior. Five laboratories performed the same experiments to test the acute and persistent effects of psilocybin (2 mg/kg, IP) on various behaviors that psychedelics have been proposed to affect, including anxiety-related approach-avoidance, exploration, sociability, depression-related behaviors, fear extinction, and social reward learning. Through this coordinated approach, we found that psilocybin had several robust and replicable acute effects on mouse behavior, including increased anxiety- and avoidance-related behaviors and decreased fear expression. Surprisingly, however, we found that psilocybin did not have replicable effects 24 hours post psilocybin administration on reducing anxiety- and depression-like behaviors or facilitating fear extinction learning. Additionally, we were unable to observe psilocybin-induced alterations in social preference or social reward learning. Overall, our comprehensive characterization of psilocybin’s acute and persistent behavioral effects using ∼200 total male and female mice per experiment spread across five independent labs demonstrates with unique certainty several acute drug effects and suggests that psilocybin’s persistent effects in mice may be more modest and inconsistent than previously suggested. We believe this unusual multi-laboratory, highly coordinated research effort serves as a model for facilitating the generation of replicable results and consequently will reduce efforts based on unreliable and spurious results.
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 19
- The ABCs of psychedelics: a preclinical roadmap for drug discovery. TIPS - Trends in Pharmacological Sciences August 28, 2025
- Psychedelic medicine: mechanisms, evidence, and translation to practice BMJ February 23, 2026
- No evidence of immediate or persistent analgesic effect from a single dose of psilocybin in three mouse models of pain Nature Communications January 22, 2026
- An exploration of the relationships between the effects of psilocybin on behavior, 5-HT 2A receptor occupancy, and neuroplastic effects in mice Journal of Psychopharmacology January 6, 2026
- Psilocybin Enhances Cued Fear Extinction and Extinction Recall in Stress-Naïve, Acutely Stressed, and Chronically Stressed Mice ACS Pharmacology & Translational Science September 11, 2025
and 14 more in the library
Cites 44
- Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial Journal of Psychopharmacology November 30, 2016
- Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial Journal of Psychopharmacology November 30, 2016
- Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. The Lancet Psychiatry May 17, 2016
- Trial of Psilocybin versus Escitalopram for Depression New England Journal of Medicine April 14, 2021
- Psilocybin-assisted treatment for alcohol dependence: A proof-of-concept study Journal of Psychopharmacology January 13, 2015
and 39 more in the library