Psilocybin-assisted Therapy for Treatment of Alcohol Use Disorder

Study Overview
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Brief Summary
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Note: The trial is only eligible for citizens of Denmark. The purpose of this project is to assess the treatment efficacy of a single high dose of psilocybin administered within a protocol of psychological support to patients diagnosed with alcohol use disorder (AUD).

Detailed Description
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To establish efficacy, we will investigate a single dose of psilocybin versus placebo in a randomised, double-blinded, placebo-controlled 12 weeks clinical trial. 90 patients, aged 20-70 years, diagnosed with alcohol use disorder and treatment seeking will be recruited from the community via advertisement and referrals from general practitioners and hospital units. The psilocybin or placebo is administered within a protocol of psychological support before, during and after the dosing. Outcome assessments will be carried out one, four, eight- and 12 weeks post dosing. The primary outcome is reduction in the percentage of heavy drinking days from baseline to follow-up at 12 weeks. Key secondary outcomes include 1) phosphatidyl-ethanol as an objective biomarker for alcohol consumption 2) plasma psilocin, the active metabolite, to establish a possible therapeutic range and 3) the acute subjective drug experience as a possible predictor of treatment outcome. Furthermore, we will investigate the neurobiological underpinnings of the possible treatment effects by use of functional magnetic resonance brain imaging one week post dosing.

Official Title
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The QUANTUM Trip Trial - Psilocybin-assisted Therapy for Reducing Alcohol Intake in Patients With Alcohol Use Disorder: A Randomized, Double-blinded, Placebo-controlled Clinical Trial.

Conditions
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Alcohol Use Disorder

Intervention / Treatment
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* Drug: Psilocybin
* Drug: Maltodextrin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Bodyweight of 50-110 kg AUD according to DSM-5 criteria and alcohol dependence according to ICD-10. AUD Identification Test (AUDIT) ≥ 15. ≥ 5 heavy drinking days in the past 28 days prior to inclusion. Exclusion Criteria: Current or previously diagnosed with any psychotic disorder or bipolar affective disorder. Immediate family member with a diagnosed psychotic disorder. History of delirium tremens or alcohol withdrawal seizures. History of suicide attempt or present suicidal ideation at screening. Withdrawal symptoms at screening (>nine on the Clinical Institute Withdrawal Assessment of Alcohol Scale, Revised (CIWA-Ar) (43). Present or former severe neurological disease including trauma with loss of consciousness > 30 min. Impaired hepatic function (alanine transaminase >210/135 units/l men/women) Cardiovascular disease defined as decompensated heart failure (NYHA class III or IV), unstable angina pectoris, myocardial infarction within the last 12 months or uncontrolled hypertension (systolic blood pressure >165 mmHg, diastolic blood pressure >95 mmHg). Present or former abnormal QTc (>450/470 ms men/women). Treatment with disulfiram, naltrexone, acamprosate and nalmefene within 28 days of inclusion. Treatment with any serotonergic medication or drugs within one month prior inclusion. Any oOther active substance use disorders (except nicotine) defined as a Drug Use Disorder Identification Test score >six/two (men/women) and investigator's clinical evaluation. Women who are pregnant, breastfeeding, or intend to become pregnant or are not using adequate contraceptive measures considered highly effective (44). Unable to speak or understand Danish. Any other condition that the clinician estimates can interfere with trial participation.

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: single-centre, randomised, double-blinded, placebo-controlled, 1:1 parallel-group clinical trial
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Psilocybin-assisted therapy<br>45 patients will receive a single administration of 25mg psilocybin given in a protocol of psychological support before, during and after dosing. | Drug: Psilocybin<br>* Psilocybin-assisted therapy<br>|
| Placebo Comparator: Placebo-assisted therapy<br>45 patients will receive a single administration of placebo (lactose) given in a protocol of psychological support before, during and after dosing. | Drug: Maltodextrin<br>* Placebo-assisted therapy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in percentage of heavy drinking days | Heavy drinking is defined as days with five drinks/60 grams of alcohol or more for men, four drinks/48 grams of alcohol or more for women. Data will be collected using the Timeline Followback Method (TLFB) which is a widely used, calendar-based retrospective measure of self-reported use of alcohol. The number of days drinking assessed is 28 days. | Baseline to week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in total alcohol consumption | Total grams of alcohol consumed per day as measured by TLFB. | Baseline to week 12 | 
| Change in days of abstinence | Percentage of days without any alcohol consumption as measured by TLFB. | Baseline to week 12 | 
| Change in phosphatidyl-ethanol (PEth) | PEth is formed only in the presence of alcohol and is correlated with the amount of alcohol consumed the past month. PEth concentrations will be measured by peripheral blood test. | Baseline to week 12 | 
| Change in Alcohol Use Disorders Identification Test (AUDIT) | AUDIT is a 10-item questionnaire that measures alcohol use. The score range is 0-40, with higher scores indicating a more problematic use of alcohol. | Baseline to week 12 | 
| Change in Penn Alcohol Craving Scale (PACS) score | PACS is a 40-item questionnaire that measures alcohol craving severity. The score range is 0-30, with higher scores indicating more severe symptoms. | Baseline to week 12 | 
| Change in Alcohol Abstinence Self-efficacy Scale (AASE) score | AASE is a 40-item questionnaire that measures two scales: the temptation to drink and the confidence in the ability to avoid drinking. The score range for each scale is 0-80, with higher score indicating greater temptation or confidence, respectively. | Baseline to week 12 | 
| Change in Fagerstrom Test for Nicotine Dependence (FTND) | FTND is a 6-item questionnaire that measures the quantity of cigarette consumption, the compulsion to use, and dependence. The score range is 0-10, with higher scores indicating a more severe dependence. | Baseline to week 12 | 
| Change in Drug Use Disorders Identification Test (DUDIT) | DUDIT is an 11-item questionnaire that measures drug use. The score range is 0-44, with higher scores indication a more problematic use. | Baseline to week 12 | 
| Change in Major Depression Inventory (MDI) | MDI is a 12-item questionnaire that measures depression severity. The score range is 0-50, with higher scores indicating greater severity. | Baseline to week 12 | 
| Change in Short-Form 36 (SF-36) | SF-36 is a 36-item questionnaire that measures the quality-of-life. The score range is 0-100, with higher scores indicating better health status. | Baseline to week 12 | 
| Change in Mindful Attention Awareness Scale (MAAS) | MAAS is a 15-item scale that measures core characteristic of mindfulness. The score range is 1-6, with higher scores indicating greater mindfulness. | Baseline to week 12 | 
| Change in Acceptance and Action Questionnaire (AAQ) | AAQ is a 7-item questionnaire that measures psychological flexibility. The score range is 7-49, with higher scores indicating lesser flexibility. | Baseline to week 12 | 
| Change in NEO-Personality Inventory (NEO-PI= | The NEO-PI is a 240-item personality instrument that measures the five factors in the Five Factor Model. It consists of 30 eight-item facet scales, 6 for each of the five basic personality factors: Neuroticism (N), Extraversion (E), Openness (O), Agreeableness (A), and Conscientiousness (C), rated by use of a 5-point Likert-type scale ranging from strongly disagree to strongly agree. | Baseline to week 12 | 
| Persisting Effects Questionnaire (PEQ) | PEQ is a 143-item scale aiming to assess changes in attitudes, moods, behavior, and spiritual experience | Week 12 | 
| Neuroplasticity and inflammation | Neuroplasticity and inflammation as measured by mean concentrations of plasma serum brain-derived neurotrophic factor (BDNF) and plasma cytokines, respectively. | Baseline to week 12 | 
| Subjective effects of psilocybin: Subjective Drug Intensity (SDI) | SDI will be regularly assessed asking the patients how intense is the experience right now on a 0-10 Likert scale where 0 = not intense at all, 10 = very intense. | 0-6 hours post dosing | 
| Pharmacokinetics- and dynamics of psilocybin | Pharmacokinetics- and dynamics of plasma psilocin, serum BDNF and plasma cytokines, as determined by concentration-time curves of mean plasma concentrations | 0 - 6 hours post dosing | 
| Subjective effects of psilocybin: Mystical Experience Questionnaire (MEQ) | MEQ is a 30-item questionnaire that measures experiential aspects of psilocybin. The patients are asked to rate the items on a 6-point scale going from 0= none; not at all to 5=extreme; more than ever before in my life and stronger than 4. | Completed once the effects are fully subsided or at least 6 hours after dosing | 
| Subjective effects of psilocybin: 5-Dimensional Altered State of Consciousness scale (5D-ASC) | 5D-ASC is a 94-item questionnaire that measures experiential aspects of psilocybin. The patients are asked to rate the items by placing marks on a horizontal visual analogue scale (100 millimeters in length) going from no, not more than usual (on the left) to yes, very much more than usual (on the right). | Completed once the effects are fully subsided or at least 6 hours after dosing | 
| Subjective effects of psilocybin: Ego Dissolution Inventory (EDI) | EDI is a 8-item questionnaire that measures the experiential aspects of psilocybin. The patients are asked to rate the items by placing marks on a horizontal visual analogue scale (100 millimeters in length) going from no, not more than usual (on the left) to yes, very much more than usual (on the right). | Completed once the effects are fully subsided or at least 6 hours after dosing | 
| Subjective effects of psilocybin: Emotional Breakthrough Inventory (EBI) | EBI is a 6-item questionnaire that measures the experiential aspects of psilocybin. The patients are asked to rate the items by placing marks on a horizontal visual analogue scale (100 millimeters in length) going from no, not more than usual (on the left) to yes, very much more than usual (on the right). | Completed once the effects are fully subsided or at least 6 hours after dosing | 
| Subjective effects of psilocybin: Awe Experience Scale (AWE-S) | AWE-S is a 30-item questionnaire that measures the experiential aspects of psilocybin. The patients are asked to rate the items on a 7-point scale going from 1= Strongly Disagree to 7= Strongly Agree. | Completed once the effects are fully subsided or at least 6 hours after dosing | 
| Brain imaging | The blood-oxygen-level-dependent differences between the two treatment arms with respect to resting-state functional connectivity, alcohol vs neutral cue-reactivity within mesocorticolimbic pathways and habitual vs goal-directed activity within corticostriatal pathways | 1 week post dosing | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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psilocybin, alcohol dependence, addiction, randomized controlled trial, brain imaging