Can psychedelics treat anorexia nervosa? Effects of psilocybin on brain function and behaviour in animal models

Anorexia nervosa (AN) is characterised by extreme self-control, partly generated by exaggerated prefrontal cortex activity, which leads to inflexible thought patterns and behaviour. This feature contributes to the chronic nature of AN, which has the highest mortality rate of any psychiatric disorder. Despite an array of therapeutic strategies that have been employed over the years to treat the condition, there are currently no effective medicinal treatment strategies to ease its grip on sufferers. Therefore, new therapies are urgently needed in order to mitigate the debilitating nature of this condition. Multiple clinical trials have shown robust evidence that psychedelic medicine is a promising treatment innovation for intractable mental disorders. The U.S. Food and Drug Administration (FDA) designated psilocybin as a “breakthrough therapy” in 2018 based on its efficacy in treatment-resistant depression, part of which may relate to the disengagement of top-down cognitive processes that promote rigid behaviours and cognitive inflexibility. This is a major opportunity for its therapeutic application in AN, a key hallmark of which is a level of cognitive inflexibility that enables patients to exert extreme top-down control over the evolutionary demand to eat for survival. This project will identify the therapeutically relevant function of psilocybin for treating AN by utilising the most well-accepted animal model of AN, known as activity-based anorexia (ABA), which exploits the innate motivation of laboratory rats to run in wheels. When rats with access to running wheels are placed on a restricted feeding schedule, there is a paradoxical increase in running activity despite substantially decreased caloric intake, causing a profound reduction in body weight. We have recently revealed the specific involvement of neurocircuits controlling cognitive flexibility in the development of the ABA phenotype. Challenging this model with psilocybin and examining cognitive, behavioural and neurobiological features that are involved in the development of AN in humans and ABA in rats will fill the knowledge gap that exists in relation to the actions of psilocybin for treating AN symptoms. The use of incisive techniques including chemogenetics, optogenetics and fiber photometry to manipulate and record from specific neural circuits in combination with sophisticated cognitive testing strategies is critical to pave the way for more effective clinical trials.