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NCT Number: NCT07638553

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

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.

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Key information

Conditions

Alcohol Use Disorder Alcohol-Related Disorders Alcoholism Chemically-Induced Disorders Depressive Sympotoms Mental Disorders Psilocybin Substance-Related Disorders

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 3

Primary location

Centre Hospitalier de la Côte Basque, Bayonne, France

Loading trial locations.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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.

Treatment and study plan

Psilocybin (high dose)

Drug

2 administrations of high-dose psilocybin (25 mg) 3 weeks apart

psilocybin (low dose)

Drug

2 administrations of low-dose psilocybin (3 mg) 3 weeks apart

Primary outcomes

  1. Incidence of relapse between groups

    Time frame: Month 6

    Relapse Yes/no, where relapse is defined as the 1st heavy drinking day, assessed using the Timeline Follow-Back (TLFB) method

  2. Time to relapse between groups

    Time frame: Month 6

    Days until relapse, where relapse is defined as the 1st heavy drinking day, assessed using the Timeline Follow-Back (TLFB) method

Secondary outcomes

  1. Change in relapse rate between groups

    Time frame: At weeks 3, 9, 15, 21, 27 compared to baseline

    Assessed using the Timeline Follow-Back (TLFB) method

  2. Change in rate of heavy drinking days between groups

    Time frame: At weeks 3, 9, 15, 21, 27 compared to baseline

    Percent; Assessed using the Timeline Follow-Back (TLFB) method

  3. Change in total alcohol consumption between groups

    Time frame: At weeks 3, 9, 15, 21, 27 compared to baseline

    Grams, assessed using the Timeline Follow-Back (TLFB) method

  4. Change in number of drinking days between groups

    Time frame: At weeks 3, 9, 15, 21, 27 compared to baseline

    Days, assessed using the Timeline Follow-Back (TLFB) method

  5. Change in craving between groups

    Time frame: At weeks 3, 9, 15, 21, 27 compared to baseline

    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.

  6. Change in alcohol-related quality of life between groups

    Time frame: At weeks 3, 15, 21, 27 compared to baseline

    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.

  7. Change in anxiety between groups

    Time frame: At weeks 3, 9, 15, 21, 27 compared to baseline

    Beck Anxiety Inventory (BAI)

  8. Change in emotional dysregulation between groups

    Time frame: At weeks 3, 9, 15, 21, 27 compared to baseline

    Difficulties in Emotion Regulation Scale (DERS), a 36-item questionnaire

  9. Change in rejection sensitivity between groups

    Time frame: At weeks 3, 9, 15, 21, 27 compared to baseline

    Adult Rejection Sensitivity Questionnaire (A-RSQ)

  10. Change in post-Traumatic Stress Disorder between groups

    Time frame: At weeks 3, 9, 15, 21, 27 compared to baseline

    Post-Traumatic Stress Disorder Checklist for DSM-5 (PCL-5), where a score of 44 is highly sensitive to diagnose PTSD

  11. Visual Perspective task (VPT)

    Time frame: Day 0

    This task allows calculation of the egocentric bias index, the altercentric bias index and the egocentric egocentric bias

  12. Visual Perspective task (VPT)

    Time frame: Week 3

    This task allows calculation of the egocentric bias index, the altercentric bias index and the egocentric egocentric bias

  13. Visual Perspective task (VPT) for participants opting for a third dose

    Time frame: Week 28

    This task allows calculation of the egocentric bias index, the altercentric bias index and the egocentric egocentric bias

  14. Request for a 3rd dose of psilocybin between groups

    Time frame: Week 27

    Yes/no

  15. Reason for 3rd dose request

    Time frame: Week 27

    Relapse in AUD/ risk of relapse in AUD/low self-efficacy/ relapse in depression/ personal development/ other

  16. Administration of 3rd dose

    Time frame: Week 28

    Yes/no

  17. Relapse rate in relapsers between groups

    Time frame: At weeks 33, 39, 45, 51 compared to week 27

    Assessed using the Timeline Follow-Back (TLFB) method

  18. Rate of heavy drinking days in relapsers between groups

    Time frame: At weeks 33, 39, 45, 51 compared to week 27

    Percent; Assessed using the Timeline Follow-Back (TLFB) method

  19. Total alcohol consumption in relapsers between groups

    Time frame: At weeks 33, 39, 45, 51 compared to week 27

    Grams, assessed using the Timeline Follow-Back (TLFB) method

  20. Change in number of drinking days in relapsers between groups

    Time frame: At weeks 33, 39, 45, 51 compared to week 27

    Days, assessed using the Timeline Follow-Back (TLFB) method

  21. Change in craving in relapsers between groups

    Time frame: At weeks 33, 39, 45, 51 compared to week 27

    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.

  22. Change in alcohol-related quality of life in relapsers between groups

    Time frame: At weeks 33, 39, 45, 51 compared to week 27

    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.

  23. Change in depressive symptoms in relapsers between groups

    Time frame: At weeks 33, 39, 45, 51 compared to week 27

    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.

  24. Change in anxiety in relapsers between groups

    Time frame: At weeks 33, 39, 45, 51 compared to week 27

    Beck Anxiety Inventory (BAI)

  25. Change in emotional dysregulation in relapsers between groups

    Time frame: At weeks 33, 39, 45, 51 compared to week 27

    Difficulties in Emotion Regulation Scale (DERS), a 36-item questionnaire

  26. Change in rejection sensitivity in relapsers between groups

    Time frame: At weeks 33, 39, 45, 51 compared to week 27

    Adult Rejection Sensitivity Questionnaire (A-RSQ)

  27. Change in post-Traumatic Stress Disorder between groups

    Time frame: At weeks 33, 39, 45, 51 compared to week 27

    Post-Traumatic Stress Disorder Checklist for DSM-5 (PCL-5), where a score of 44 is highly sensitive to diagnose PTSD

  28. Adverse Childhood Experiences

    Time frame: Day 0

    The Adverse Childhood Experiences (ACE) Questionnaire

  29. Attachment style

    Time frame: Day 0

    The Relationship Scale Questionnaire (RSQ) for attachment style (secure, fearful, preoccupied, dismissing)

  30. Severity of aocohol use disorder

    Time frame: Day 0

    The Clinical Global Impression- Severity (CGI-S)

  31. Cognitive impairments

    Time frame: Day 0

    Montreal Cognitive Assessment (MoCA)

  32. Features of the psychedelic experience

    Time frame: Prior to integration session in Week 0

    Acceptance/Avoidance Promoting Experience Questionnaire (APEQ)

  33. Features of the psychedelic experience

    Time frame: Prior to integration session in Week 3

    Acceptance/Avoidance Promoting Experience Questionnaire (APEQ)

  34. Features of the psychedelic experience

    Time frame: Prior to integration session in Week 28 if third dose

    Acceptance/Avoidance Promoting Experience Questionnaire (APEQ)

  35. Age

    Time frame: Day 0

    years

  36. Sex

    Time frame: Day 0

  37. Currently under antidepressant at the inclusion

    Time frame: Day 0

    Yes/no

  38. Diagnosed with ADHD

    Time frame: Day 0

    Yes/no

  39. In menstruating participants, point of the menstruation cycle at psilocybin administration

    Time frame: Dosing session in week 0

  40. In menstruating participants, point of the menstruation cycle at psilocybin administration

    Time frame: Dosing session in week 3

  41. In menstruating participants, point of the menstruation cycle at psilocybin administration

    Time frame: Dosing session in week 28 if third dose

  42. Safety and tolerance of psilocybin

    Time frame: End of study, week 51

    List of adverse events

  43. Change in gamma-glutamyl transferase (GGT) between groups and subgroups

    Time frame: At week 28 compared to baseline

    fL

  44. Change in carbohydrate-deficient transferrin (CDT) between groups and subgroups

    Time frame: At week 28 compared to baseline

    U/L

  45. Change in mean corpuscular volume (MCV) between groups and subgroups

    Time frame: At week 28 compared to baseline

    Percentage

  46. Guess the group

    Time frame: After dosing session Week 0

    Two-item questionnaire developed from the EPIsoDE framework

  47. Guess the group

    Time frame: After dosing session Week 3

    Two-item questionnaire developed from the EPIsoDE framework

Study contacts

Contact information is provided by the study sponsor or research team.

Amandine Luquiens

CONTACT

[email protected]

04.66.68.69.98

Sponsors and collaborators

Lead sponsor

Centre Hospitalier Universitaire de Nīmes

Other

Registry information

Acronym: ERPPAD

Important dates

Study start
2026
Primary completion
2030
Study completion
2030
First posted
Jun 10, 2026
Registry last updated
Jul 1, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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