Psilocybin, the active compound in magic mushrooms, had several clear and repeatable immediate effects on mouse behavior, including increased anxiety and avoidance and reduced fear expression. However, its effects one day later were not consistent across five different laboratories, and no reliable changes were seen in depression-like behavior, fear extinction learning, social preference, or social reward learning. Using about 200 mice per experiment across five independent labs, the findings show that psilocybin's lasting behavioral effects in mice are more modest and less reliable than previously claimed. This coordinated multi-lab approach highlights the importance of replication for producing trustworthy results.
Psilocybin can improve cognitive flexibility, but only when the impairment stems from a specific brain-circuit problem. In mice, psilocybin reversed deficits caused by abnormal signaling between the prefrontal cortex and the mediodorsal thalamus, but it did not help deficits caused by disrupted communication between brain hemispheres. The drug reduced overactivity in prefrontal-thalamic neurons during post-error exploration, an effect that lasted at least 24 hours. It also triggered lasting changes in those neurons, strengthening inputs from the thalamus while dampening afterdepolarizations that sustain aberrant signaling. These results suggest psilocybin's therapeutic effects are circuit-specific and point toward a precision-medicine approach for psychedelic treatments.