How do psychedelics alter brain function and behaviour? Investigating psilocybin for therapeutic use.

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 relates to the disengagement of cognitive processes that promote rigid and inflexible behaviours that are common to many psychological conditions, including substance use disorders, obsessive compulsive disorders and anorexia nervosa. Only a short time later, in 2021, there are more than 100 ongoing clinical trials worldwide investigating the therapeutic potential of this psychoactive compound produced by so-called “magic” mushrooms. While the rapid push to clinical trials is encouraging, there remain unavoidable shortfalls in study design, including the inability to “blind” participants to the acute subjective (hallucinogenic) effects of psychedelics. A corollary of this is an expectation of efficacy based on social and experiential context that can bias towards positive outcomes. Moreover, only 50-70% of individuals display clinically significant responses to psychedelic interventions, highlighting a need to understand why therapeutic outcomes occur in some individuals but not others. This mechanistic understanding can only come from animal-based experimentation where the effects of expectation are entirely removed. Animal studies have begun to elucidate some of these mechanistic details, to show that psilocybin rapidly increases neuroplasticity in the prefrontal cortex, which persists for at least 1 month. There has also been support from animal studies for alleviation of symptoms in mouse models of OCD and post-traumatic stress disorder (PTSD), but not for alcohol relapse in rats and with conflicting results seen in different genetic rat models of depression, highlighting the importance of model selection in translational studies. This project will examine how psilocybin alters reinforcement learning and flexible adaptation in rat models to provide a crucial mechanistic adjunct to fast-paced clinical trials in patients in the absence of expectation of positive outcomes and other biases. It will also use sophisticated and cutting edge technologies to manipulate and record specific neuronal activity to examine neuronal circuit and transmitter-specific effects of psilocybin and investigate the behavioural correlates of such changes with computer vision and machine learning approaches.