Evaluation of Psilocybine Efficacy in Alcohol Use Disorder with Comorbid Depression: A Randomized, Double-Blind, Controlled Pilot Study

The primary objective of this study is to assess the **feasibility** of a trial comparing psilocybin with a very low-dose psilocybin (control) in individuals with **alcohol use disorder** and depressive symptoms. This is clinically relevant as it explores the potential therapeutic effects of psilocybin, a psychedelic compound, in managing alcohol use disorder, which is often complicated by comorbid depression. Understanding the feasibility of such a trial is crucial for designing future studies that could lead to novel treatment approaches.

Secondary objectives include:

• Assessing the feasibility of the trial through other paraclinical variables.
• Evaluating patient acceptability of psilocybin treatment in both study groups.
• Assessing the impact of psilocybin treatment on drinking outcomes, craving, and alcohol-related quality of life.
• Evaluating the impact on dimensions of psychological and cognitive functioning.
• Investigating the role of psychological factors, other treatments, and the quality of the hallucinogenic experience on the evolution of heavy drinking days.
• Evaluating immune and inflammatory profiles and their evolution using microbiota, plasma markers, and structural and functional brain MRI.

The clinical trial focuses on individuals diagnosed with **alcohol use disorder** and depressive symptoms. The study population includes both male and female participants, aged 18 years and older. The general health status of participants is characterized by a confirmed DSM-5 diagnosis of severe alcohol use disorder, with a Beck Depression Inventory II score of 14 or higher. Participants must have consumed their last alcoholic drink between 60 and 14 days prior to the inclusion visit and have experienced at least one heavy drinking day during their last drinking period. The trial does not target a vulnerable population. The sponsor has not provided information regarding the total number of participants. Participants were selected based on specific inclusion criteria, including the requirement for informed consent and health insurance coverage. Lifestyle considerations such as diet and physical activity are not specified in the available data.

The clinical trial is designed to evaluate the feasibility of using **psilocybine** in patients with **alcohol use disorder** and comorbid depressive symptoms. This study is a randomized, double-blind, controlled pilot trial. Participants will be randomly assigned to receive either psilocybine or a very low-dose psilocybine as a control. The trial is set to commence on January 1, 2024, with an estimated completion date of January 1, 2026. The trial will involve a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a DSM-5 diagnosis of severe alcohol use disorder and a Beck Depression Inventory (BDI II) score of 14 or higher.

Participants will be required to attend multiple follow-up visits, including two psilocybine intake sessions, to assess the primary endpoint of feasibility, which is determined by the number of patients completing both sessions. Secondary endpoints will include various measures such as the number of patients screened and included per month, changes in heavy drinking days, and scores on several psychological assessments. The study will also involve blood sampling for biomarker analysis and EEG recordings to evaluate brain activity.

The expected duration of participant involvement is approximately 12 weeks, with assessments conducted at baseline, week 3, week 6, and week 12. Conditions that may lead to early termination from the study include non-compliance with study procedures, adverse events, or withdrawal of consent. The end-of-study visit will mark the conclusion of the participant's involvement, where final assessments and data collection will occur. The trial aims to provide insights into the potential therapeutic effects of psilocybine in this patient population, with a focus on safety and efficacy.

The clinical trial involves the administration of **psilocybine** in two different dosages to evaluate its effects on alcohol use disorder with comorbid depression. The experimental medication, **psilocybine**, is provided in the form of a capsule for oral use. The primary treatment group receives a dosage of 25 mg of psilocybine, administered orally. The maximum daily dose is 25 mg, and the treatment period is limited to a single day. The active substance, psilocybine, is of chemical origin and is manufactured by CHU DE NÎMES. Participant compliance with the dosing schedule is monitored to ensure adherence to the protocol.

The comparator treatment in this study is a very low-dose psilocybine, also provided in capsule form for oral use. Participants in this group receive a dosage of 1 mg of psilocybine, administered orally. Similar to the primary treatment group, the maximum daily dose is 1 mg, and the treatment period is restricted to one day. This low-dose psilocybine serves as a control to assess the feasibility and effects of the higher dosage in the context of the study. The chemical origin and manufacturing details remain consistent with the primary treatment, ensuring uniformity in the trial's methodology.

The efficacy of the clinical trial titled "Psilocybin in alcohol use disorder with comorbid depression - Randomized double-blind controlled pilot study" will be assessed through a series of primary and secondary endpoints. The primary endpoint focuses on the feasibility of the trial, specifically the collection of the number of patients who completed the two planned **Psilocybin** intake sessions. This serves as an approximation of the trial's feasibility.

Secondary endpoints include a variety of measures to evaluate efficacy. These encompass the decrease in the percentage of heavy drinking days in the last four weeks prior to week 6 and at week 12 compared to baseline, as well as total alcohol consumption during these periods. Additional parameters include the time to first drink and the time to the first day of heavy drinking. Patient-reported outcomes will be collected using validated scales such as the Craving Experience Questionnaire (CEQ), Alcohol Quality of Life Scale (AQoLS), Beck Depression Inventory (BDI II), Beck Anxiety Inventory (BAI), and others at specified timepoints including D0, W3, W6, and W12.

Further assessments involve the collection of EEG parameters, blood sampling for biomarker analysis, and qualitative analysis of integration session verbatim. These measures will be collected at various stages, including before and during psilocybin administration, and during the integration session. The trial will also assess brain anatomical anomalies and volume differences in certain brain regions. The comprehensive collection and analysis of these endpoints will provide insights into the efficacy of psilocybin in treating alcohol use disorder with comorbid depression.