Evaluation of Psilocybin's Efficacy in Reducing Alcohol Consumption in Patients with Alcohol Use Disorder: A Randomized, Double-Blind, Placebo-Controlled Trial

The primary objective of this clinical trial is to assess the impact of a single administration of **psilocybin**, a 5-HT2A receptor agonist, on the number of heavy drinking days in patients diagnosed with **Alcohol Use Disorder**. This evaluation will be conducted from baseline to a 12-week follow-up period. The study is designed as a randomized, double-blinded, placebo-controlled trial, which is crucial for determining the efficacy of psilocybin in potentially reducing alcohol intake. The clinical relevance of this objective lies in its potential to offer a novel therapeutic approach for managing alcohol use disorder, a condition with significant health and social implications.

The clinical trial focuses on individuals diagnosed with **Alcohol Use Disorder** (AUD) as per DSM-5 criteria and alcohol dependence according to ICD-10. The study population includes both male and female participants aged between 20 and 70 years, with a body weight ranging from 60 to 95 kg. Participants are required to have an Alcohol Use Disorder Identification Test (AUDIT) score of 15 or higher and must have experienced at least five heavy drinking days, defined as consuming over 60 grams of alcohol per day for men or 48 grams for women, in the 28 days prior to inclusion. The trial does not involve a vulnerable population. The sponsor has not provided information regarding the total number of participants. The selection criteria ensure that participants are representative of the target population for evaluating the effects of a single administration of the 5-HT2A receptor agonist Psilocybin on heavy drinking days over a 12-week period.

The clinical trial is designed to evaluate the effect of a single administration of **psilocybin** on heavy drinking days in patients diagnosed with **Alcohol Use Disorder**. This study is a randomized, double-blinded, placebo-controlled trial, ensuring that neither the participants nor the researchers know who receives the active treatment or placebo, thus minimizing bias. The trial is expected to run from September 2023 to April 2027, with participant involvement lasting approximately 12 weeks from baseline to follow-up.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, body weight, and diagnosis according to DSM-5 and ICD-10 standards. Following successful screening, participants will be randomized to receive either the psilocybin capsules or a placebo. The primary endpoint is the percentage of heavy drinking days during the last 28 days, with secondary endpoints including total alcohol consumption, days without alcohol, and various psychological and physiological assessments.

Study visits will include baseline assessments, the administration of the investigational product, and follow-up visits to monitor outcomes and collect data on endpoints. The end-of-study visit will conclude the participant's involvement, with comprehensive evaluations to assess the impact of the treatment. Participants may be withdrawn from the study if they experience adverse effects, fail to comply with study procedures, or withdraw consent. The trial aims to provide insights into the potential therapeutic effects of psilocybin in reducing alcohol intake among individuals with Alcohol Use Disorder.

The clinical trial involves the administration of **PEX010 Psilocybin Capsules**, which contain 25 mg of psilocybin as the active ingredient. The psilocybin is derived from a **dry extract from Psilocybe cubensis** with a concentration ratio of 15-25:1, using methanol as the extraction solvent. The pharmaceutical form of the experimental medication is capsules, and the route of administration is oral. The trial is designed to evaluate the effect of a single administration of this 5-HT2A receptor agonist on reducing alcohol intake in patients with alcohol use disorder. The administration is a one-time event, and the study is structured as a randomized, double-blinded, placebo-controlled clinical trial.

In addition to the experimental treatment, a placebo is used as a comparator to assess the efficacy of the psilocybin capsules. The placebo is designed to be indistinguishable from the active treatment in appearance and administration method, ensuring the integrity of the double-blind study design. Participants are randomly assigned to receive either the psilocybin capsules or the placebo, and compliance with the dosing schedule is monitored throughout the trial period. The primary objective is to measure changes in heavy drinking days from baseline to a 12-week follow-up.

Efficacy in this clinical trial will be assessed by evaluating the impact of a single administration of **psilocybin** on alcohol consumption patterns in patients with alcohol use disorder. The primary endpoint for efficacy evaluation is the percentage of heavy drinking days during the last 28 days, with a heavy drinking day defined as a day with an intake exceeding 60 grams of alcohol for men or 48 grams for women. This data will be collected using the Timeline Followback (TLFB) method.

Secondary endpoints include total alcohol consumption per day, percentage of days without alcohol consumption, and various psychometric scores such as the Penn Alcohol Craving Scale (PACS), Alcohol Use Disorders Identification Test (AUDIT), and Drug Use Disorders Identification Test (DUDIT). Additional assessments will include scores from the Alcohol Abstinence Self-efficacy (AASE), Quality of Life (SF-36), Major Depression Inventory (MDI), and Mindful Attention Awareness Scale (MAAS). Biomarkers such as phosphatidyl-ethanol (PEth), liver parameters (GGT, ALAT, MCV), brain-derived neurotrophic factor (BDNF), and markers of inflammation (TNF-a, IL-6) will also be measured.

Pharmacokinetic properties of plasma psilocin and key phenomena of the acute subjective experience will be assessed through questionnaires like the Mystical Experience Questionnaire (MEQ30) and the 11-Dimensional Altered State of Consciousness (11D-ASC). Emotional responses to music will be evaluated using the Geneva Emotional Music Scale (GEMS) and qualitative interviews. Persisting effects will be measured with the Persisting Effects Questionnaire (PEQ), and post-dosing fMRI analysis will be conducted to examine differences in functional connectivity during resting state and task-related activity between treatment groups.