Administration of Psilocybe Cubensis Mushrooms with or Without Fluoxetine with or Without Fluoxetine for Refractory Depression: a Randomized Double-blind Controlled Trial Controlled Clinical Trial - COGUNILA

Major Depressive Disorder is a chronic mental health condition that affects the quality of life and occupational capacity of over 300 million people worldwide, including 11 million in Brazil alone, making it the second most depressive country in the Americas. Despite advances in understanding the pathophysiological mechanisms of depression, many patients do not adequately respond to conventional treatment with antidepressants and psychotherapy, with 30% of patients considered treatment-resistant. In this context, research on new therapeutic approaches is crucial to improve depression treatment. Psilocybin, a naturally occurring psychedelic substance found in mushrooms of the genus Psilocybe, has shown promising results for the treatment of various mental disorders, including depression. However, in general, withdrawal from serotonergic antidepressant drugs is a common prerequisite for participation in clinical studies with psilocybin, due to a supposed possibility of antidepressant drugs altering the psychedelic effect. This study aims to investigate whether there are differences in the psychedelic, antidepressant, and adverse effects of concurrent or non-concurrent administration of Psilocybe mushrooms with daily fluoxetine, a serotonergic antidepressant. For this purpose, a randomized, double-blind, placebo-controlled clinical trial will be conducted, dividing participants into two groups: an intervention group, which will receive fluoxetine treatment combined with a session of psychotherapy assisted by a single dose of Psilocybe cubensis mushrooms equivalent to 30mg of psilocybin, and a control group, which will receive the same treatment with mushrooms but will use daily placebo instead of fluoxetine. The severity of depressive symptoms will be evaluated over 6 weeks primarily through the MADRS scale. It is expected that both groups will maintain the same pattern of psychedelic experience and present the same antidepressant results, demonstrating that there is no attenuation of effects by fluoxetine. The completion of this study has the potential to contribute new insights into psilocybin treatment for depression, being highly relevant for new perspectives in mental health.