biorxiv.org
A multi-institutional investigation of psilocybin's effects on mouse behavior
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 multi49 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. ### Competing Interest Statement RCM is currently on leave from Stanford University serving as the Chief Scientific Officer at Bayshore Global Management. He is on the SAB of MapLight Therapeutics, MindMed and Aelis Farma. BDH is on the scientific advisory boards of Journey Clinical and Osmind and is a paid consultant to Arcadia Medicine Inc, Tactogen LLC, and Vida Ventures LLC.
