Grant: Project Grant

Depression is one of the main causes of disability and early death in Canada. Unfortunately, many existing treatments take weeks to work and fail to help about two-thirds of patients. This has created an urgent need for new treatments that act more quickly and effectively. One promising option is psilocybin; the active compound found in certain "magic mushrooms." Recent clinical studies suggest that psilocybin may work rapidly to improve mood, and its effects can last for a long time. Because of this potential, the U.S. Food and Drug Administration (FDA) has given psilocybin "breakthrough therapy" status, and Health Canada has allowed its use for patients with severe depression or those at the end of life. Large international trials are now underway, but we still do not fully understand how psilocybin works in the brain. Our project aims to answer this question. Specifically, we will study: 1.Which receptors in the brain are responsible for psilocybin's antidepressant effects. 2.Which brain circuits are involved, with a focus on connections between the prefrontal cortex (the brain's "thinking center") and the raphe nuclei, a key source of serotonin, which regulates our mood. 3.Which molecular pathways support psilocybin's long-lasting benefits, including those involved in brain plasticity, the brain's ability to change and adapt. This research will be carried out by an experienced team of Canadian scientists with expertise in depression, drug discovery, brain circuits, and molecular biology. By uncovering how psilocybin works, our project will provide essential knowledge for developing new, fast-acting antidepressants. It will also give patients, caregivers, clinicians, and policymakers the scientific information they need to make informed and safe decisions about psilocybin treatment.