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

This research presents a proposal for a randomized, double-blind, controlled clinical trial with an experimental, prospective, and comparative methodology, involving both quantitative and qualitative analysis, to determine whether there are differences in psychedelic, antidepressant, and adverse effects between the combination of Psilocybe cubensis mushrooms and fluoxetine, a selective serotonin reuptake inhibitor (SSRI), compared to the administration of mushrooms alone. The condition investigated is Major Depressive Disorder, diagnosed according to the DSM-5-TR, considered refractory (or treatment-resistant), a subgroup of patients who do not adequately respond to conventional antidepressant treatment (therapeutic failure to two or more antidepressant regimens of different classes, despite adequate dose, duration, and treatment adherence). The investigational product is Psilocybe cubensis mushrooms, that will be collected in their natural state, identified and characterized by mycologists, and samples of these mushrooms will be chemically analyzed to determine the specific amounts of psilocybin in each sample. Participants are divided into two groups: an intervention group, which will receive fluoxetine treatment (20mg/day for 4 weeks) 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 research questions focus on determining whether there is a difference in antidepressant effects between the intervention with mushrooms alone and the intervention with mushrooms combined with fluoxetine, whether the acute effect of the subjective psychedelic experience is altered by treatment with fluoxetine, whether antidepressant effects are correlated with the quality of the subjective psychedelic experience, and whether the combination with fluoxetine reduces adverse effects associated with mushrooms intake. The general objectives of the study are to investigate whether there are differences in psychedelic, antidepressant, and adverse effects between interventions with mushrooms alone and mushrooms combined with fluoxetine in people with treatment-resistant depression. Specific objectives include evaluating the effects of interventions on depressive symptoms using the Montgomery-Åsberg Depression Rating Scale (MADRS), examining the effects on cognitive inflexibility of depression with the Decentering Experiences Questionnaire (Decenter-EQ), and investigating the relationship between the quality of the subjective experience during the psychedelic experience and therapeutic effects using the States of Consciousness Questionnaire (SOCQ) and the Mystical Experience Questionnaire (MEQ-30). Additionally, it will be assessed whether the combination with fluoxetine mitigates or intensifies the adverse effects of psilocybin. Primary outcomes include the change in total MADRS score from baseline to four weeks after the initiation of interventions. Secondary outcomes include the proportion of participants showing at least a 50% improvement in the total MADRS score, depression remission (defined as a total MADRS score ≤10) at Week 4, and maintenance of antidepressant effects at Week 6. Exploratory outcomes will also be analyzed, such as the effects of interventions on cognitive inflexibility, the quality of the subjective psychedelic experience and its correlation with antidepressant effects, and differences in adverse effects related to psilocybin administration between groups.