Two administrations of psilocybin given 3 weeks apart. The treatment day will begin around 9 a.m. with a brief interview. Patients will be invited to relax and music will be played through speakers and headphones.

One 1 mg capsule of Psilocybin will be given approximately 30 minutes to 1.5 hours later.

The patient is accompanied throughout the session (minimum 6 hours depending on the effects felt). The patient will benefit from a preparation session the day before dosing, and an integration session the day after. Intensive relapse prevention program will be dispensed between the 2 dosing sessions (treatment as usual).

• Rest EEG prior to first treatment administration
• EEG during first treatment administration
• Rest EEG during integration session after second treatment administration

Three 7ml EDTA tubes will be taken in the morning on an empty stomach at day 0 and at 3 weeks.

Stool sampling at day 0 and 3 weeks Analysis of intestinal microbiota is carried out on a stool sample, which is stored at -20°C for a maximum of 24 hours. The sample is then transferred cold to the CRB of the Nîmes University Hospital, where it is stored at -80°C until the microbiology laboratory can perform a group analysis.

MRI functional and cerebral at day 0 and 3 weeks

Rate (%) of eligible patients who are included in the study.

Rate (%) of patients included who had at least one treatment administration session

Rate (%) of assessment sessions that were completed.

Duration of assessment sessions (minutes).

Number of patients leaving the study prematurely for any reason.

Qualitative description of reasons cited by patients

Decrease in the percentage of days of heavy drinking days during previous 4 weeks versus baseline

Decrease in the percentage of days of heavy drinking days during previous 4 weeks versus baseline

Decrease in the percentage of days of heavy drinking days during previous 4 weeks versus baseline

Total alcohol consumption during previous 4 weeks

Total alcohol consumption during previous 4 weeks

Total alcohol consumption during previous 4 weeks

Days

Days

Days

Days

Days

Days

Craving Experience Questionnaire (CEQ) score; the CEQ evaluates intensity and frequency of craving from 11 intensity items in blocks a-c. Each item is rated between 0 ("Not at all") and 10 ("Extremely") for a total score between 0 and 110. The higher the score, the more intense the craving. A frequency of craving score is calculated by adding the values obtained from 11 items in blocks d-f. Each item is rated between 0 ("Never") and 10 ("Constantly") for a total craving frequency score between 0 and 110.

Craving Experience Questionnaire (CEQ) score; the CEQ evaluates intensity and frequency of craving from 11 intensity items in blocks a-c. Each item is rated between 0 ("Not at all") and 10 ("Extremely") for a total score between 0 and 110. The higher the score, the more intense the craving. A frequency of craving score is calculated by adding the values obtained from 11 items in blocks d-f. Each item is rated between 0 ("Never") and 10 ("Constantly") for a total craving frequency score between 0 and 110.

Alcohol quality of life scale (AQoLS); the 34-item questionnaire measures the negative impact of the relationship with alcohol on quality of life through 7 dimensions: social relationships, activities, living conditions, etc. self-care, negative emotions, sleep and loss of control on a scale of 0 (not at all) to 3 (very much), for a total score of 102. There is no threshold value.

Alcohol quality of life scale (AQoLS); the 34-item questionnaire measures the negative impact of the relationship with alcohol on quality of life through 7 dimensions: social relationships, activities, living conditions, etc. self-care, negative emotions, sleep and loss of control on a scale of 0 (not at all) to 3 (very much), for a total score of 102. There is no threshold value.

Beck Depression Inventory (BDI II); a 21-item scale. Each item consists of 4 sentences corresponding to 4 degrees of increasing intensity of a symptom, rated from 0 to 3. Only the highest rating chosen for a given series is retained. The total score ranges from 0 to 39; with a higher score indicating greater intensity of depression.

Beck Depression Inventory (BDI II); a 21-item scale. Each item consists of 4 sentences corresponding to 4 degrees of increasing intensity of a symptom, rated from 0 to 3. Only the highest rating chosen for a given series is retained. The total score ranges from 0 to 39; with a higher score indicating greater intensity of depression.

Beck Anxiety Inventory (BAI); a 21-question score of common symptoms of anxiety, such as numbness and tingling, and sweating. Responses are rated on a scale of 0 (not at all) to 3 (severely). Higher total scores indicate more severe anxiety symptoms. Thresholds are: 0-7: Minimal; 8-15: Light; 16-25: Moderate; 26-63: Severe.

Beck Anxiety Inventory (BAI); a 21-question score of common symptoms of anxiety, such as numbness and tingling, and sweating. Responses are rated on a scale of 0 (not at all) to 3 (severely). Higher total scores indicate more severe anxiety symptoms. Thresholds are: 0-7: Minimal; 8-15: Light; 16-25: Moderate; 26-63: Severe.

Difficulties in Emotion Regulation Scale (DERS); a 36-item questionnaire assessing multiple aspects of emotion dysregulation. The measure gives a total score and six subscores:1. Non-acceptance of emotional responses (NON-ACCEPTANCE); 2. Difficulties in adopting goal-oriented behavior (GOALS); 3. Difficulty controlling impulses (IMPULSE); 4. Lack of emotional awareness (AWARENESS); 5. Limited access to emotion regulation strategies (STRATEGIES); 6. Lack of emotional clarity (CLARITY), with a final score 0-100.

Difficulties in Emotion Regulation Scale (DERS); a 36-item questionnaire assessing multiple aspects of emotion dysregulation. The measure gives a total score and six subscores:1. Non-acceptance of emotional responses (NON-ACCEPTANCE); 2. Difficulties in adopting goal-oriented behavior (GOALS); 3. Difficulty controlling impulses (IMPULSE); 4. Lack of emotional awareness (AWARENESS); 5. Limited access to emotion regulation strategies (STRATEGIES); 6. Lack of emotional clarity (CLARITY), with a final score 0-100.

Adult Rejection Sensitivity Questionnaire (A-RSQ); rejection sensitivity score calculated for 9 situations by multiplying the level of rejection concern by the level of rejection expectation. The total rejection sensitivity score is the average of the rejection sensitivity scores for the 9 situations.

Adult Rejection Sensitivity Questionnaire (A-RSQ); rejection sensitivity score calculated for 9 situations by multiplying the level of rejection concern by the level of rejection expectation. The total rejection sensitivity score is the average of the rejection sensitivity scores for the 9 situations.

Meaning in Life Questionnaire (MLQ); a 10-item score assessing two dimensions of meaning in life rated on a seven-point scale ranging from "absolutely true" to "absolutely false." The "Presence of Meaning" subscale measures the extent to which respondents believe their lives have meaning. The "Search for Meaning" subscale measures respondents' engagement and motivation in their efforts to find meaning or deepen their understanding of the meaning of their lives, with a final score of 5-35

Meaning in Life Questionnaire (MLQ); a 10-item score assessing two dimensions of meaning in life rated on a seven-point scale ranging from "absolutely true" to "absolutely false." The "Presence of Meaning" subscale measures the extent to which respondents believe their lives have meaning. The "Search for Meaning" subscale measures respondents' engagement and motivation in their efforts to find meaning or deepen their understanding of the meaning of their lives, with a final score of 5-35

Meaning in Life Questionnaire (MLQ); a 10-item score assessing two dimensions of meaning in life rated on a seven-point scale ranging from "absolutely true" to "absolutely false." The "Presence of Meaning" subscale measures the extent to which respondents believe their lives have meaning. The "Search for Meaning" subscale measures respondents' engagement and motivation in their efforts to find meaning or deepen their understanding of the meaning of their lives, with a final score of 5-35

Meaning in Life Questionnaire (MLQ); a 10-item score assessing two dimensions of meaning in life rated on a seven-point scale ranging from "absolutely true" to "absolutely false." The "Presence of Meaning" subscale measures the extent to which respondents believe their lives have meaning. The "Search for Meaning" subscale measures respondents' engagement and motivation in their efforts to find meaning or deepen their understanding of the meaning of their lives, with a final score of 5-35

Conflict indices and task focus of the Visual Perspective Task (VPT); participants evaluate either the number of red dots that in a scene from their own point of view (self-perspective condition), or the number of dots that another no one present in the scene can see (self-perspective condition).

Conflict indices and task focus of the Visual Perspective Task (VPT); participants evaluate either the number of red dots that in a scene from their own point of view (self-perspective condition), or the number of dots that another no one present in the scene can see (self-perspective condition).

Montreal Cognitive Assessment (MoCA); measuring attention, concentration, executive functions, memory, language, visuoconstructive abilities, abstraction abilities, calculation and orientation. Score 0-30.

Posttraumatic Stress Disorder Checklist for DSM-5 (PCL-5), a 17-item scale assessing the intensity of 17 PTSD symptoms. Each question is rated between 1 and 5 depending on the intensity and frequency of symptoms over the previous month. Three scales: Intrusion (items 1 to 5); Avoidance (items 6 to 12); Hyperstimulation (items 13 to 17). Total score 17-85, with threshold of 44 for PTSD diagnosis.

RSQ (Relationship Scale Questionnaire); a 30-item questionnaire classifying into four categories of attachment (secure or autonomous, avoidant or detached, preoccupied or ambivalent, fearful or disorganized). Score 13-65.

Concomitant Selective serotonin reuptake inhibitors yes/no

Concomitant Selective serotonin reuptake inhibitors yes/no

Concomitant Selective serotonin reuptake inhibitors yes/no

Concomitant Selective serotonin reuptake inhibitors yes/no

5D-ASC (5-Dimensional Altered States of Consciousness Questionnaire) dimension score after psilocybin sessions. A 94-item questionnaire (to be translated and retrotranslated) administered 5 to 6 hours after drug administration; visual analog scale of five main dimensions: "The absence of oceanic boundaries", "fear of ego dissolution", "restructuring of vision", "auditory alterations" and "reduction of vigilance".

5D-ASC (5-Dimensional Altered States of Consciousness Questionnaire) dimension score after psilocybin sessions. A 94-item questionnaire (to be translated and retrotranslated) administered 5 to 6 hours after drug administration; visual analog scale of five main dimensions: "The absence of oceanic boundaries", "fear of ego dissolution", "restructuring of vision", "auditory alterations" and "reduction of vigilance".

Electroencephalogram parameters: alpha coherence in the resting state

Electroencephalogram parameters: alpha coherence in the resting state

Electroencephalogram parameters: alpha coherence in the resting state

Hallucinogenic experience assessed through qualitative analysis of audio-recorded verbatim of the integration session.

Hallucinogenic experience assessed through qualitative analysis of audio-recorded verbatim of the integration session.

Evaluate participants' immune profiles in both groups through the microbiota before the first dose with circulating 16sDNA assay.

Evaluate the evolution of the immune profiles of participants in both groups through the microbiota before the first dose with circulating 16sDNA assay.

Evaluate the immune and inflammatory profiles in the 2 groups using cerebral structural and functional MRI prior to the first psilocybin administration.

Evaluate the immune and inflammatory profiles in the 2 groups using cerebral structural and functional MRI 3 weeks after to the first psilocybin administration.

Evaluate the evolution of the immune and inflammatory profiles in the 2 groups using cerebral structural and functional MRI to the first psilocybin administration.

Evaluate the evolution of the immune and inflammatory profiles in the 2 groups using cerebral structural and functional MRI 3 weeks after to the first psilocybin administration.

Evaluate participants' immune profiles in both groups through the microbiota before the first dose with circulating 16sDNA assay.

Evaluate the evolution of the immune profiles of participants in both groups through the microbiota before the first dose with circulating 16sDNA assay.

Evaluate participants' inflammatory profiles in both groups through cytokine TNF alpha before the first dose. A tube of blood will be taken. The sample is transported to the laboratory at room temperature within 4 hours.

Tubes are then centrifuged at 2000g for 10 min at room temperature, then aliquoted by 500µL into 1.5 mL Eppendorf LoBind Protein tubes for storage at -80°C prior to batch analysis.

Evaluate participants' inflammatory profiles in both groups through cytokine TNF alpha before the first dose. A tube of blood will be taken. The sample is transported to the laboratory at room temperature within 4 hours. Tubes are then centrifuged at 2000g for 10 min at room temperature, then aliquoted by 500µL into 1.5 mL Eppendorf LoBind Protein tubes for storage at -80°C prior to batch analysis.

Patients will provide a stool sample, stored at -20°C and transported in an insulated bag to the hospital. The sample will be frozen at -80°C. The number of species detected in the intestinal microbiota will be recorded

Patients will provide a stool sample, stored at -20°C and transported in an insulated bag to the hospital. The sample will be frozen at -80°C. The number of species detected in the intestinal microbiota will be recorded

Patients will provide a stool sample, stored at -20°C and transported in an insulated bag to the hospital. The sample will be frozen at -80°C. The distribution of the various bacterial species detected in the intestinal microbiota will be recorded

Patients will provide a stool sample, stored at -20°C and transported in an insulated bag to the hospital. The sample will be frozen at -80°C. The distribution of the various bacterial species detected in the intestinal microbiota will be recorded

Patients will provide a stool sample, stored at -20°C and transported in an insulated bag to the hospital. The sample will be frozen at -80°C. The diversity index according to the number of species will be recorded

Patients will provide a stool sample, stored at -20°C and transported in an insulated bag to the hospital. The sample will be frozen at -80°C. The diversity index according to the number of species will be recorded

Evaluate participants' inflammatory profiles in both groups through cytokine IL-1b before the first dose. A tube of blood will be taken. The sample is transported to the laboratory at room temperature within 4 hours.

Tubes are then centrifuged at 2000g for 10 min at room temperature, then aliquoted by 500µL into 1.5 mL Eppendorf LoBind Protein tubes for storage at -80°C prior to batch analysis.

Evaluate participants' inflammatory profiles in both groups through cytokine IL-1b before the first dose. A tube of blood will be taken. The sample is transported to the laboratory at room temperature within 4 hours.

Tubes are then centrifuged at 2000g for 10 min at room temperature, then aliquoted by 500µL into 1.5 mL Eppendorf LoBind Protein tubes for storage at -80°C prior to batch analysis.

Evaluate participants' inflammatory profiles in both groups through cytokine IL-6 before the first dose. A tube of blood will be taken. The sample is transported to the laboratory at room temperature within 4 hours.

Tubes are then centrifuged at 2000g for 10 min at room temperature, then aliquoted by 500µL into 1.5 mL Eppendorf LoBind Protein tubes for storage at -80°C prior to batch analysis.

Evaluate participants' inflammatory profiles in both groups through cytokine IL-6 before the first dose. A tube of blood will be taken. The sample is transported to the laboratory at room temperature within 4 hours.

Tubes are then centrifuged at 2000g for 10 min at room temperature, then aliquoted by 500µL into 1.5 mL Eppendorf LoBind Protein tubes for storage at -80°C prior to batch analysis.

Evaluate participants' inflammatory profiles in both groups through cytokine IL-8 before the first dose. A tube of blood will be taken. The sample is transported to the laboratory at room temperature within 4 hours.

Tubes are then centrifuged at 2000g for 10 min at room temperature, then aliquoted by 500µL into 1.5 mL Eppendorf LoBind Protein tubes for storage at -80°C prior to batch analysis.

Evaluate participants' inflammatory profiles in both groups through cytokine IL-8 before the first dose. A tube of blood will be taken. The sample is transported to the laboratory at room temperature within 4 hours.

Tubes are then centrifuged at 2000g for 10 min at room temperature, then aliquoted by 500µL into 1.5 mL Eppendorf LoBind Protein tubes for storage at -80°C prior to batch analysis.

Evaluate participants' inflammatory profiles in both groups through cytokine IL-10 before the first dose. A tube of blood will be taken. The sample is transported to the laboratory at room temperature within 4 hours.

Tubes are then centrifuged at 2000g for 10 min at room temperature, then aliquoted by 500µL into 1.5 mL Eppendorf LoBind Protein tubes for storage at -80°C prior to batch analysis.

Evaluate participants' inflammatory profiles in both groups through cytokine IL-10 before the first dose. A tube of blood will be taken. The sample is transported to the laboratory at room temperature within 4 hours.

Tubes are then centrifuged at 2000g for 10 min at room temperature, then aliquoted by 500µL into 1.5 mL Eppendorf LoBind Protein tubes for storage at -80°C prior to batch analysis.