This randomised, quadruple-blind, placebo-controlled Phase I/II trial (n=50) will investigate the antidepressant, psychedelic, and adverse effects of Psilocybe cubensis mushrooms (equivalent to 30 mg of psilocybin) with or without daily fluoxetine (20mg) in adults with treatment-resistant depression (TRD).
Conducted by the Federal University of Latin American Integration in Brazil, the COGUNILA trial addresses whether combining a selective serotonin reuptake inhibitor (SSRI) like fluoxetine with psilocybin impacts the therapeutic and psychedelic experience.
Participants will be divided into two groups: one will receive fluoxetine for four weeks alongside one psilocybin-assisted psychotherapy session, while the control group will receive the same psilocybin session but with a placebo instead of fluoxetine. All participants will engage in preparation and integration therapy sessions. The primary aim is to assess changes in depressive symptoms using the Montgomery–Åsberg Depression Rating Scale (MADRS) from baseline to Week 4. Secondary outcomes include rates of remission, sustained effects at Week 6, and the relationship between the quality of the psychedelic experience (measured via tools like the Mystical Experience Questionnaire) and clinical outcomes. The study also explores whether fluoxetine moderates or intensifies psilocybin’s effects or side effects, offering crucial insights into the safety and compatibility of combining psychedelics with conventional antidepressants.
Trial Details
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.Trial Number NCT06898606