Clinical TrialDepressive DisordersPsilocybinPlaceboNot yet recruiting

Psilocybin-assisted Therapy for Comorbid Major Depressive Disorder and Alcohol Use Disorder

This Phase II, randomised, quadruple-masked trial (n=30) will evaluate the safety and efficacy of psilocybin-assisted therapy (PAT) in adults aged 18 to 65 with comorbid Major Depressive Disorder (MDD) and Alcohol Use Disorder (AUD). Participants will be randomly assigned to receive either a single oral dose of 25 mg psilocybin or a placebo, with the primary aim of assessing the feasibility and safety of the intervention by monitoring recruitment, retention, tolerability, and safety outcomes. Participants will attend a total of 14 visits, both in-person and remotely, during which they will receive PAT at five different time points. Key outcome measures include adherence, depression severity assessed by the Montgomery-Asberg Depression Rating Scale (MADRS) and Hamilton Depression Rating Scale (HAMD-17), and alcohol use tracked through the Alcohol Timeline Followback (TLFB) and other scales. The trial is set to begin in March 2026 and is expected to conclude by June 2028.

Target Enrollment
30 participants
Study Type
Phase II interventional
Design
Randomized, quadruple Blind

Detailed Description

The goal of this clinical trial is to determine the safety and efficacy of psilocybin assisted Therapy (PAT) in individuals with comorbid Major Depressive Disorder (MDD) and Alcohol Use Disorder (AUD). The main question it aims to answer is:

\- What is the feasibility and safety of administering PAT in adults with MDD-AUD by evaluating recruitment, retention, tolerability, and safety?

Researchers will compare the psilocybin (25 mg) and placebo groups to see if there are any significant differences in frequency of dropouts or serious adverse events.

Participants will:

* be randomized to receive either psilocybin (25 mg) or placebo
* visit the site (in-person and remotely) for a total of 14 times to complete study tasks
* receive psilocybin-assisted therapy (PAT) at five various timepoints

Study Arms & Interventions

Psilocybin (25 mg)

experimental

Participant is administered one oral capsule (25 mg psilocybin) with water.

Interventions

  • Psilocybin25 mg
    via Oral• single dose

Placebo

inactive

Participant is administered one oral capsule (0 mg psilocybin) with water.

Interventions

  • Placebo0 mg
    via Oral• single dose

Participants

Ages
18 – 65
Sexes
All

Inclusion Criteria

  • Be between the ages of 18-65
  • Must be deemed to have capacity to provide informed consent;
  • Ability to read and communicate in English, such that their literacy and comprehension is sufficient for understanding the consent form and study questionnaires, as evaluated by study staff obtaining consent;
  • Stated willingness to comply with all study procedures;
  • Be deemed in health compatible with the study procedures according to study physician;
  • Ability to take oral medication and be willing to adhere to the PAT regimen;
  • Individuals who are capable of becoming pregnant: use of highly effective contraception for at least 1 month prior to screening and agreement to use such a method during study participation;
  • Fulfil Diagnostic and Statistical Manual of Mental Disorders (5th Edition) (DSM-5) criteria for a primary diagnosis of current single or recurrent episodes of MDD of at least moderate severity but without psychotic features and a comorbid AUD diagnosis (moderate or severe) using the SCID-5;
  • A score of at least 14 on the Hamilton Depression Rating Scale for Depression (HAMD);
  • Participants should not be interested in initiating standard pharmacotherapies for MDD or AUD. The need to start/resume standard pharmacotherapies will be reassessed at Week 6.
  • Individuals who are willing to and tapered off current antidepressant or IMAOs, antipsychotic and anti-alcohol/anti-craving medications for a minimum of 2-weeks (or more depending on the medication) prior to Baseline (V2) and for the duration of the study and whose physician confirms that it is safe for them to do so;
  • Individuals who are willing to and have tapered off current inhibitors of 5'-diphospho-glucuronosyltransferase (UGT)1A9 and 1A10, aldehyde dehydrogenase inhibitors (ALDHs) and alcohol dehydrogenase inhibitors (ADHs) for a minimum of 2-weeks (or more depending on the medication) prior to Baseline (V2) and for the duration of the study and whose physician confirms that it is safe for them to do so;
  • Agreement to adhere to Lifestyle Considerations (section 4.5) throughout study duration.

Exclusion Criteria

  • Pregnant as assessed by a urine pregnancy test at Screening (V1) and Baseline (V2) or individual's that intend to become pregnant during the study or are breastfeeding;
  • Presence of a relative or absolute contraindication to psilocybin, including a drug allergy, recent stroke history, uncontrolled hypertension (over 160/100 mmHG), low or labile blood pressure, recent myocardial infarction, cardiac arrhythmic, severe coronary artery disease, or moderate to severe renal or hepatic impairment.
  • Diagnosis of cirrhosis, AST or ALT elevations \> 3x upper limit of normal; significant abnormal liver function that would preclude administration of psilocybin based on the judgement of the QI (assessed notably by bilirubin, albumin, alkaline phosphatase, GGT, and INR functions)
  • Any DSM-5 lifetime diagnosis of a schizophrenia-spectrum disorder; obsessive-compulsive disorder, psychotic disorder (unless substance induced or due to a medical condition), bipolar I or II disorder, paranoid personality disorder, borderline personality disorder, or neurocognitive disorder as determined by medical history and the SCID-5 clinical interview;
  • Any first-degree relative with a diagnosis of schizophrenia-spectrum disorder; psychotic disorder (unless substance-induced or due to a medical condition); or bipolar I or II disorder as determined by the family medical history form and discussions with the participant;
  • Clinical Institute Withdrawal Assessment for Alcohol, revised (CIWA-Ar) score \> 9, or any other indication that the participant may experience medically complicated withdrawal from alcohol, such as a score of ≥4 in the Prediction of Alcohol Withdrawal Severity Scale.
  • Use benzodiazepines (with the exception of use of up to 2mg of lorazepam equivalent per day for insomnia and anxiety if it is not taken within 12 hours before the psilocybin dose (Week 2).
  • Have a DSM-5 diagnosis of substance use disorder (excluding alcohol, cannabis, tobacco and caffeine) within the preceding 6 months;
  • Presence of baseline prolonged QTc (more than 0.45 seconds for males and 0.47 seconds for females) or Torsade de Pointes as measured by the ECG or a history of long QTc syndrome or related risk factors;
  • Use of aldehyde dehydrogenase (ALDH) inhibitors and UDG modulators;
  • Use of hallucinogens in the past 5 years; or total hallucinogen use ≥10 times)
  • Current suicidality risk as indicated during the conduct of the Columbia Suicide Severity Rating Scale (C-SSRS) with concurrence after a study physician's evaluation if the response to C-SSRS questions 1 or 2 is "yes")
  • Any other clinically significant physical illness including chronic infectious diseases or any other major concurrent illness that, in the opinion of the investigator, may interfere with the interpretation of the study results or constitute a health risk for the participant if they take part in the study.
  • Participants that are responding to anti-alcohol or anti-craving medications

Study Details

  • Status
    Not yet recruiting
  • Phase
    Phase II
  • Type
    interventional
  • Design
    Randomizedquadruple Blind
  • Target Enrollment30 participants
  • Timeline
    Start: 2026-03-01
    End: 2028-06-01
  • Compounds
    PsilocybinPlacebo
  • Topic
    Depressive Disorders

Study Team

Sponsors & Collaborators

Locations

Centre for Addiction and Mental Health — Toronto, Ontario, Canada

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