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.

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.

Eligibility Criteria:
Inclusion Criteria:

Who meet the following criteria for Treatment-Resistant Depression:

* Over 25 years old and under 65 years old;
* Having attempted Standard Treatment (at least one antidepressant at an adequate dose and duration);
* Adequate treatment duration (for at least 6 to 12 weeks);
* Incomplete responses to Standard Treatments (residual symptoms);
* Moderate to Severe Depression according to the MADRS scale (MADRS ⩾20)

Exclusion Criteria:

* Individuals under 25 years of age or over 65 years of age;
* Pregnant or breastfeeding women;
* History of major psychiatric disorders, like bipolar, psychosis,or substance use. -Family history (first-degree relatives) of psychotic or bipolar disorders;
* Subjects unwilling to withhold interacting pharmacotherapy
* Patients with uncontrolled acute or chronic diseases;
* Smokers who use more than 10 cigarettes per day;
* Individuals who have used illicit drugs in the last 2 months (exception of THC).
* Patients who report that they are currently experiencing suicidal ideation.