Efficacy of High‑Dose vs Low‑Dose Psilocybin for Relapse Prevention in Severe Alcohol Use Disorder with Comorbid Depression: Randomized Controlled Trial

The primary objective is to evaluate the efficacy of two high oral doses of 25 mg psilocybin administered three weeks apart versus two low doses of 3 mg on the incidence of relapse defined by excessive alcohol consumption in patients with severe Alcohol use disorder and comorbid depressive symptoms after detoxification over a six‑month period. Secondary objectives include comparison of high‑dose and low‑dose groups during the first six months on changes in drinking outcomes, craving, alcohol‑related quality of life, depressive symptom severity, and psychological functioning; description of the proportion and characteristics of participants requesting a third 25 mg dose at week 27 and associated outcomes; assessment of maintenance of abstinence or relapse status from six to twelve months in sub‑groups receiving or not receiving a third dose; evaluation of changes from baseline to six and twelve months within the high‑dose cohort; identification of response factors; monitoring of safety and tolerance over 24 months; and performance of laboratory assessments between baseline and week 28 with reporting of values within normal ranges.

The study population comprised adult patients (≥ 18 years) of both sexes who met DSM‑5 criteria for severe Alcohol use disorder and exhibited depressive symptoms with a Beck Depression Inventory‑II score of ≥ 14. Eligible individuals had completed detoxification, with their last alcoholic drink occurring between 10 and 60 days before the inclusion visit, and reported at least one heavy‑drinking day during the preceding four‑week period. Additional requirements included affiliation with a health‑insurance plan, provision of informed and voluntary consent, and classification within the trial’s age‑range codes “3” and “4.” Lifestyle considerations were limited to post‑detoxification abstinence from alcohol; other dietary or physical‑activity factors were not specified. The sponsor did not provide information on the total number of participants enrolled.

The study is a randomized, open‑label, superiority, controlled trial evaluating two dosing regimens of oral psilocybin (high dose 25 mg vs. low dose 3 mg) administered three weeks apart in adults with severe Alcohol use disorder and comorbid depressive symptoms following detoxification. After a screening visit confirming DSM‑5 criteria, a baseline (inclusion) visit occurs (week 0) during which the first dose is given; a second dose is administered at week 3. Follow‑up assessments are scheduled at weeks 6, 9, 15, 21, 27, and a final end‑of‑study visit at week 28, with additional exploratory visits at weeks 33, 39, 45, 51 for sub‑analyses. At each visit participants complete the Timeline Follow‑Back interview, mood and anxiety scales, and safety labs; the primary endpoint is time to first heavy drinking day (≥60 g alcohol). Participant involvement spans approximately six months, with optional extended monitoring up to 12 months for specific sub‑groups. Early termination may occur due to serious adverse events, withdrawal of informed consent, or non‑adherence to protocol requirements.

The investigational product designated as “PSILOCYBINE” is supplied as a capsule for oral use containing 25 mg of psilocybin. The capsule is administered orally in a single dose, repeated once after a 3‑week interval, for a total of two administrations.

The comparator product, also labeled “PSILOCYBINE,” is provided as a capsule for oral use containing 3 mg of psilocybin. This capsule is taken orally in a single dose and repeated after a 3‑week interval, resulting in two administrations.

Both dosing regimens are delivered under direct observation at the study site to ensure accurate timing and adherence. Participants receive written dosing instructions and maintain a medication diary. Compliance is further assessed by pill count at each study visit and by verification of observed dosing records. No additional pharmacologic comparator or placebo is employed in the trial.

The primary endpoint is the time to relapse, defined as the first heavy drinking day (≥60 g alcohol). Relapse timing will be derived from alcohol consumption data collected with the Timeline Follow-Back method every six weeks throughout the 6‑month follow‑up period.

Secondary efficacy parameters include the proportion of participants requesting a third 25 mg dose of psilocybin and a series of patient‑reported outcome measures. Assessments will be performed at weeks 0, 3, 9, 15, 21, 27, and at the end of treatment (week 28) using the following instruments: the Comprehensive Effects Questionnaire (CEQ), the Alcohol Quality of Life Scale – brief (AQoLS‑brief), the Beck Depression Inventory‑II (BDI‑II), the Beck Anxiety Inventory (BAI), the Difficulties in Emotion Regulation Scale (DERS), the Affective‑Regulation Self‑Questionnaire (A‑RSQ), the PTSD Checklist for DSM‑5 (PCL‑5), and the Visual Preference Test (VPT, administered only at weeks 0, 3, and 28). The secondary endpoints also encompass changes in these measures for subgroups defined by relapse status and third‑dose administration at weeks 27, 33, 39, 45, and 51, as well as long‑term changes from baseline to 6–12 months in the high‑dose group.

Potential response factors (ACE, RSQ, MoCA) will be recorded at baseline, and serious adverse events will be monitored throughout the study. Blood sample analyses will be conducted at baseline and week 28 for both high‑dose and low‑dose groups, stratified by relapse status.