Toward an Understanding of the Therapeutically Relevant Mechanisms of Psilocybin for Anorexia Nervosa

Abstract Background Psilocybin, the psychoactive compound produced by so-called “magic” mushrooms has shown promise in alleviating symptoms of a range of psychiatric conditions including depression, anxiety and substance use disorder. Recently, a small Phase 1 trial showed psilocybin to be safe and tolerable for individuals with anorexia nervosa (AN), with 4/10 participants experiencing long-lasting improvements in eating disorder symptoms. Aims & Objectives A major challenge in understanding the mechanisms through which psilocybin acts to cause enduring changes in brain function and behaviour is that it is impossible to effectively blind participants to treatment, making clinical studies particularly susceptible to placebo effects. Method Animal models are necessary for this mechanistic investigation, and this presentation will focus on data accumulated in the lab over recent years using an animal model known as activity-based anorexia in combination with operant learning paradigms, behavioural pharmacology, RNAscope and in-vivo fiber photometry. Results We demonstrate that psilocybin elicits a specific improvement in cognitive flexibility to improve body weight outcomes in activity-based anorexia. Moreover, we show effects of psilocybin on learning are mediated by actions at specific serotonin receptor subtypes, the transcription of which is transiently altered in the prefrontal cortex across the 24 hours after psilocybin administration. Finally, we applied computational modelling to understand how performance strategies are altered by psilocybin over time and reveal that enhanced cognitive flexibility is underpinned by altered dopamine signalling in the ventral striatum. Discussion & Conclusions Our results are translationally relevant for the clinical application of psilocybin for AN, considering these individuals display both impaired cognitive flexibility and diminished reward processing.