Psilocybin enhances sociability only in altered behavioural state and does not need an awake experience to be effective

Psilocybin, a psychoactive compound contained in certain mushrooms, can provoke profound psychedelic experiences and also exerts established and controversial therapeutic efficacy in clinical depression and other neuropsychiatric conditions respectively. Here we report that a single systemic administration of the serotonergic psychedelic psilocybin can durably promote social behaviour in the Cntnap2-knockout mouse model of autism spectrum disorder (ASD), while no increase in sociability is observed in isogenic control mice. Addressing the concern that the therapeutic actions of psilocybin may involve potentially adverse psychedelic effects, we tested drug application in anesthetised mice and found that awake brain states are not required for psilocybin’s sociability enhancing actions in ASD mice. Psilocybin shows therapeutic effects in the treatment of neuropsychiatric conditions but it can also cause strong hallucinations. Here, the authors show that psilocybin can improve social symptoms in a mouse model of autism, an effect that does not depend on wakefulness during the acute drug effects, suggesting that it might be possible to develop treatments that keep the benefits while avoiding the mind-altering side effects.