Efficacy in Relapse Prevention: Psilocybin in Alcohol Use Disorder With Depressive Symptoms (ERPPAD)

Up to 40% of individuals with alcohol use disorder (AUD) experience depression, which increases the risk of early relapse. Depression can cause relapse to occur 3 times faster in individuals with AUD who experience depressive symptoms at discharge. No treatments have been approved for individuals with both AUD and depression. Psilocybin, a psychedelic, shows promising results in treating both depression and addiction. It may be particularly effective for preventing relapse in people with AUD who also have depressive symptoms after detoxification, offering quicker action than traditional antidepressants.

The Psilocybin Alcohol Depression (PAD) pilot study, launched in February 2024, has provided critical insights for avoiding methodological flaws and demonstrated that psilocybin-assisted psychotherapy (PAP) is both feasible and acceptable. Preliminary efficacy analyses were conducted: at 12 weeks, the 25 mg group showed significantly greater reductions in drinking days (p = 0.038) and craving frequency (p = 0.045). Relapse rates were 35% in the 25 mg group and 50% in the control group (HR = 0.52 [0.16-1.65]). In the ERPPAD trial, the study authors will compare high-dose PAP with low-dose PAP in preventing relapse in individuals with AUD and depressive symptoms. The hypothesis is that high-dose PAP will be more effective than low-dose in preventing relapse over 6 months.

Study Overview

• Status: Not yet recruiting
• Conditions: Alcohol Use Disorder; Psilocybin; Depressive Sympotoms
• Intervention / Treatment: Drug: Psilocybin (high dose); Drug: Psilocybin (low dose)

• Study Type: Interventional
• Enrollment (Estimated): 172
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Amandine Luquiens; Phone Number: 04.66.68.69.98; Email: amandine.luquiens@chu-nimes.fr

Study Locations

• France
  • Bayonne, France
    • Centre Hospitalier de la Cote Basque
    • Contact: Sophie-Athéna CHARPON; Phone Number: 05 59 44 42 19; Email: sachapron@ch-cotebasque.fr
  • Besançon, France
    • CHU Besancon
    • Contact: Julie GIUSTNIANI; Phone Number: 03.81.21.90.08; Email: jgiustiniani@chu-besancon.fr
  • Bordeaux, France
    • CHU de Bordeaux
    • Contact: Mélina FATSEAS; Phone Number: 05 47 75 75 75; Email: melina.fatseas@u-bordeaux.fr
  • Brest, France
    • CHU Brest
    • Contact: Morgane GUILLOU; Phone Number: 02 98 34 23 48; Email: morgane.guillou@chu-brest.fr
  • Bron, France
    • CH le vinatier
    • Contact: Benjamin ROLLAND; Phone Number: 04 37 91 50 75; Email: benjamin.rolland@univ-lyon1.fr
  • Nantes, France
    • CHU de Nantes
    • Contact: Marie GRALL-BRONNEC; Phone Number: 02.40.20.66.40; Email: marie.bronnec@chu-nantes.fr
  • Nîmes, France, 30029
    • CHU de Nîmes
    • Contact: Anissa Megzari; Phone Number: 04.66.68.42.36; Email: drc@chu-nimes.fr
  • Saint-Priest, France
    • CHU Saint-Etienne
    • Contact: Aurélia GAY; Phone Number: 04 77 12 02 31; Email: aurelia.gay@chu-st-etienne.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Confirmed DSM-5 diagnosis of severe AUD.
• Scale BDI-II ((Beck Depression Inventory) ≥14
• The last drink must have been consumed between day(D) -60 and D -10 at the inclusion visit. The patient must have had at least 1 HDD during the last drinking period NB: The last drinking period before inclusion is defined by the last 4 weeks counted from the last drink.
• The patient must have given their free and informed consent and signed the consent form
• The patient must be a member or beneficiary of a health insurance plan

Exclusion Criteria:

• The subject is participating in an interventional study, a clinical trial, or a clinical investigation or is in a period of exclusion determined by a previous study
• The subject refuses to sign the consent
• It is impossible to give the subject informed information
• The patient is under safeguard of justice or state guardianship
• Patient unable to give informed consent.
• Participants planning to donate sperm within three months of psilocybin administration
• Positive pregnancy test at inclusion for participants of childbearing age.
• Patient who is pregnant, breastfeeding, or wishing to become pregnant during participation in the study.
• Any use of classical psychedelic in the last year
• Other current substance use disorder (except tobacco)
• Diagnosed schizophrenic or bipolar disorder
• High emotional lability (clinician-judged)
• On antipsychotics treatment that may interfere with psilocybin.
• Need for monoamine oxidase inhibitor (MAOI) treatment, which may interfere with psilocybin.
• Severe suicidal ideation (high risk on the Columbia scale)
• 1st degree family member with a diagnosed psychotic disorder
• Severe cognitive impairment (clinician-judged)
• CIWA-AR > 8
• Medical conditions that would preclude safe participation in the trial, for example: seizure disorders; significant impairment of hepatic function; coronary artery disease; history of arrhythmia; Abnormal QT interval prolongation (QTc > 470 ms for women and >450 ms for men); heart failure; uncontrolled hypertension (greater than 165/95 mmHg at screening); history of stroke; severe asthma; hyperthyroidism; narrow-angle glaucoma; stenosing gastroduodenal ulcer; pyloroduodenal obstruction; symptomatic prostatic hypertrophy or bladder neck obstruction; uncontrolled type I or type II diabetes, or a history of ketoacidosis, hyperglycemic coma, or severe hypoglycemia with loss of consciousness.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: High dose psilocybin; 2 administrations of high-dose psilocybin (25 mg) 3 weeks apart	Drug: Psilocybin (high dose); 2 administrations of high-dose psilocybin (25 mg) 3 weeks apart
Placebo Comparator: Low-dose psilocybin; 2 administrations of low-dose psilocybin (3 mg) 3 weeks apart	Drug: Psilocybin (low dose); 2 administrations of low-dose psilocybin (3 mg) 3 weeks apart

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of relapse between groups	Relapse Yes/no, where relapse is defined as the 1st heavy drinking day, assessed using the Timeline Follow-Back (TLFB) method	Month 6
Time to relapse between groups	Days until relapse, where relapse is defined as the 1st heavy drinking day, assessed using the Timeline Follow-Back (TLFB) method	Month 6

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Sex		Day 0
Change in relapse rate between groups	Assessed using the Timeline Follow-Back (TLFB) method	At weeks 3, 9, 15, 21, 27 compared to baseline
Change in rate of heavy drinking days between groups	Percent; Assessed using the Timeline Follow-Back (TLFB) method	At weeks 3, 9, 15, 21, 27 compared to baseline
Change in total alcohol consumption between groups	Grams, assessed using the Timeline Follow-Back (TLFB) method	At weeks 3, 9, 15, 21, 27 compared to baseline
Change in number of drinking days between groups	Days, assessed using the Timeline Follow-Back (TLFB) method	At weeks 3, 9, 15, 21, 27 compared to baseline
Change in craving between groups	Assessed using the Craving Experience Questionnaire (CEQ), measuring strength and frequency of craving with a score ranging from 0 to 110, whereby a higher score denotes more craving.	At weeks 3, 9, 15, 21, 27 compared to baseline
Change in alcohol-related quality of life between groups	Alcohol Quality of Life Scale- brief, a 7-item questionnaire assessing the negative impact of alcohol across 7 dimensions: social relationships, activities, living conditions, self-care, negative emotions, sleep, and loss of control.	At weeks 3, 15, 21, 27 compared to baseline
Change in anxiety between groups	Beck Anxiety Inventory (BAI)	At weeks 3, 9, 15, 21, 27 compared to baseline
Change in emotional dysregulation between groups	Difficulties in Emotion Regulation Scale (DERS), a 36-item questionnaire	At weeks 3, 9, 15, 21, 27 compared to baseline
Change in rejection sensitivity between groups	Adult Rejection Sensitivity Questionnaire (A-RSQ)	At weeks 3, 9, 15, 21, 27 compared to baseline
Change in post-Traumatic Stress Disorder between groups	Post-Traumatic Stress Disorder Checklist for DSM-5 (PCL-5), where a score of 44 is highly sensitive to diagnose PTSD	At weeks 3, 9, 15, 21, 27 compared to baseline
Visual Perspective task (VPT)	This task allows calculation of the egocentric bias index, the altercentric bias index and the egocentric egocentric bias	Day 0
Visual Perspective task (VPT)	This task allows calculation of the egocentric bias index, the altercentric bias index and the egocentric egocentric bias	Week 3
Visual Perspective task (VPT) for participants opting for a third dose	This task allows calculation of the egocentric bias index, the altercentric bias index and the egocentric egocentric bias	Week 28
Request for a 3rd dose of psilocybin between groups	Yes/no	Week 27
Reason for 3rd dose request	Relapse in AUD/ risk of relapse in AUD/low self-efficacy/ relapse in depression/ personal development/ other	Week 27
Administration of 3rd dose	Yes/no	Week 28
Relapse rate in relapsers between groups	Assessed using the Timeline Follow-Back (TLFB) method	At weeks 33, 39, 45, 51 compared to week 27
Rate of heavy drinking days in relapsers between groups	Percent; Assessed using the Timeline Follow-Back (TLFB) method	At weeks 33, 39, 45, 51 compared to week 27
Total alcohol consumption in relapsers between groups	Grams, assessed using the Timeline Follow-Back (TLFB) method	At weeks 33, 39, 45, 51 compared to week 27
Change in number of drinking days in relapsers between groups	Days, assessed using the Timeline Follow-Back (TLFB) method	At weeks 33, 39, 45, 51 compared to week 27
Change in craving in relapsers between groups	Assessed using the Craving Experience Questionnaire (CEQ), measuring strength and frequency of craving with a score ranging from 0 to 110, whereby a higher score denotes more craving.	At weeks 33, 39, 45, 51 compared to week 27
Change in alcohol-related quality of life in relapsers between groups	Alcohol Quality of Life Scale- brief, a 7-item questionnaire assessing the negative impact of alcohol across 7 dimensions: social relationships, activities, living conditions, self-care, negative emotions, sleep, and loss of control.	At weeks 33, 39, 45, 51 compared to week 27
Change in depressive symptoms in relapsers between groups	Beck Depression Inventory-II (BDI-II). The total score is the sum of the 21 item scores, ranging from 0 to 39. Higher scores indicate greater severity of depression.	At weeks 33, 39, 45, 51 compared to week 27
Change in anxiety in relapsers between groups	Beck Anxiety Inventory (BAI)	At weeks 33, 39, 45, 51 compared to week 27
Change in emotional dysregulation in relapsers between groups	Difficulties in Emotion Regulation Scale (DERS), a 36-item questionnaire	At weeks 33, 39, 45, 51 compared to week 27
Change in rejection sensitivity in relapsers between groups	Adult Rejection Sensitivity Questionnaire (A-RSQ)	At weeks 33, 39, 45, 51 compared to week 27
Change in post-Traumatic Stress Disorder between groups	Post-Traumatic Stress Disorder Checklist for DSM-5 (PCL-5), where a score of 44 is highly sensitive to diagnose PTSD	At weeks 33, 39, 45, 51 compared to week 27
Adverse Childhood Experiences	The Adverse Childhood Experiences (ACE) Questionnaire	Day 0
Attachment style	The Relationship Scale Questionnaire (RSQ) for attachment style (secure, fearful, preoccupied, dismissing)	Day 0
Severity of aocohol use disorder	The Clinical Global Impression- Severity (CGI-S)	Day 0
Cognitive impairments	Montreal Cognitive Assessment (MoCA)	Day 0
Features of the psychedelic experience	Acceptance/Avoidance Promoting Experience Questionnaire (APEQ)	Prior to integration session in Week 0
Features of the psychedelic experience	Acceptance/Avoidance Promoting Experience Questionnaire (APEQ)	Prior to integration session in Week 3
Features of the psychedelic experience	Acceptance/Avoidance Promoting Experience Questionnaire (APEQ)	Prior to integration session in Week 28 if third dose
Age	years	Day 0
Currently under antidepressant at the inclusion	Yes/no	Day 0
Diagnosed with ADHD	Yes/no	Day 0
In menstruating participants, point of the menstruation cycle at psilocybin administration		Dosing session in week 0
In menstruating participants, point of the menstruation cycle at psilocybin administration		Dosing session in week 3
In menstruating participants, point of the menstruation cycle at psilocybin administration		Dosing session in week 28 if third dose
Safety and tolerance of psilocybin	List of adverse events	End of study, week 51
Change in gamma-glutamyl transferase (GGT) between groups and subgroups	fL	At week 28 compared to baseline
Change in carbohydrate-deficient transferrin (CDT) between groups and subgroups	U/L	At week 28 compared to baseline
Change in mean corpuscular volume (MCV) between groups and subgroups	Percentage	At week 28 compared to baseline
Guess the group	Two-item questionnaire developed from the EPIsoDE framework	After dosing session Week 0
Guess the group	Two-item questionnaire developed from the EPIsoDE framework	After dosing session Week 3

Collaborators and Investigators

• Sponsor: Centre Hospitalier Universitaire de Nīmes
• Investigators: Principal Investigator: Amandine Luquiens, Centre Hospitalier Universitaire de Nîmes

Study record dates

Study Major Dates

• Study Start (Estimated): June 1, 2026
• Primary Completion (Estimated): June 1, 2030
• Study Completion (Estimated): June 1, 2030

Study Registration Dates

• First Submitted: June 5, 2026
• First Submitted That Met QC Criteria: June 5, 2026
• First Posted (Actual): June 10, 2026

Study Record Updates

• Last Update Posted (Actual): June 10, 2026
• Last Update Submitted That Met QC Criteria: June 5, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Substance-Related Disorders; Chemically-Induced Disorders; Alcohol-Related Disorders; Alcoholism; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Alkaloids; Indoles; Indole Alkaloids; Indolizidines; Indolizines; Tryptamines; Psilocybin
• Other Study ID Numbers: PHRC-N/2024/AL-01; 2025-525069-65-00 (Ctis)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No