A Double-Blind Trial of Psilocybin-Assisted Treatment of Alcohol Dependence

Study Overview
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Brief Summary
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Several lines of evidence suggest that classic hallucinogens such as psilocybin can facilitate behavior change in addictions such as alcohol dependence. The proposed investigation is a multi-site, double-blind active-controlled trial (n = 180, 90 per group) contrasting the acute and persisting effects of psilocybin to those of diphenhydramine in the context of outpatient alcoholism treatment.

Detailed Description
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Two to four sites will participate in this study. Aims of the study are 1) to characterize the acute effects of PO psilocybin 25 mg/70 kg, 30 mg/70 kg, and 40 mg/70 kg in alcohol dependent patients; 2) to evaluate the effect of psilocybin treatment on drinking outcomes for 32 weeks after the first administration, relative to diphenhydramine control; 3) to test whether or not characteristics of the drug administration session experiences mediate effects of psilocybin on short-term (1 week) persisting effects and post-session drinking behavior, 4) to evaluate the explanatory value of changes in alcohol craving, self-efficacy, motivation, and other psychological domains in accounting for the observed experimental effect of psilocybin relative to diphenhydramine control, and 5) to evaluate pre-post changes in drinking in participants after they receive psilocybin in the third session. The total duration of psychosocial treatment in the double-blind period will be 12 weeks, and double-blind drug administration sessions will occur after 4 and 8 weeks. In the first psilocybin session, a dose of 25 mg/70 kg will be administered. Depending on the response in the first session, the dose for the second session may be increased to 30 mg/70 kg or 40 mg/70 kg, or held at 25mg/70kg. The dose of diphenhydramine will start at 50 mg, and may be increased to 100 mg or held at 50 mg in the second session, depending on response in the first session. Following completion of the double-blind period (34 weeks after randomization) all participants who meet interim safety criteria will be offered an additional session in which psilocybin will be administered. The drug will be administered during 8-hour sessions in an outpatient setting under close medical and psychiatric monitoring. The drug administration sessions will occur in the context of an extended version of Motivational Enhancement Therapy (Motivational Enhancement and Taking Action, META) with the addition of standardized preparation before and debriefing and follow-up after the psilocybin administration sessions. Extensive screening and baseline assessment will be completed, including thorough safety screening and assessment of participant characteristics that could potentially moderate treatment response. Within-session and short-term persisting effects will be assessed. Drinking outcomes and changes in several potential mediators of treatment effect, including motivation, self-efficacy, craving, depression, anxiety, and spiritual dimensions of the experience, will be measured until 50 weeks after the first drug administration session, for a total of 54 weeks from the initiation of treatment.

Official Title
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A Double-Blind Trial of Psilocybin-Assisted Treatment of Alcohol Dependence

Conditions
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Alcohol Dependence

Intervention / Treatment
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* Drug: Psilocybin
* Drug: Diphenhydramine
* Behavioral: Motivational Enhancement and Taking Action (META)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males and females age 25-65 with SCID (DSM-IV) diagnosis of alcohol dependence who Want to stop or decrease their drinking Are not participating in any formal treatment for alcohol dependence (12-step meetings are not considered treatment) Are able to provide voluntary informed consent Have at least 4 heavy drinking days in the past 30 days If female of childbearing potential, are willing to use approved form of contraception from screening until after the psilocybin administration sessions Have a family member or friend who can pick them up and stay with them overnight after the psilocybin administration sessions Are able to provide adequate locator information. Exclusion Criteria: Medical conditions that would preclude safe participation in the trial (e.g., seizure disorder, significantly impaired liver function, coronary artery disease, heart failure, uncontrolled hypertension (above 165/95 mmHg at screening), history of cerebrovascular accident, asthma, hyperthyroidism, narrow-angle glaucoma, stenosing peptic ulcer, pyloroduodenal obstruction, symptomatic prostatic hypertrophy, or bladder-neck obstruction) Exclusionary psychiatric conditions (schizophrenia, schizoaffective disorder, bipolar disorder, current major depressive episode, current post-traumatic stress disorder, current suicidality or history of medically serious suicide attempt) Cognitive impairment (Folstein Mini Mental State Exam score < 26) A family history of schizophrenia or schizoaffective disorder (first or second degree relatives), or bipolar disorder type 1 (first degree relatives) History of hallucinogen use disorder, or any use in the past 1 year, or >25 lifetime uses; Cocaine, psychostimulant, opioid, or cannabis dependence (past 12 months) Current non-medical use of cocaine, psychostimulants, or opioids (past 30 days) Significant alcohol withdrawal (CIWA-Ar score greater than 7. Patients presenting at screening in withdrawal may be referred for detoxification and reassessed within 30 days) Serious ECG abnormalities (e.g., evidence of ischemia, myocardial infarction, QTc prolongation [QTc > .045 for men, QTc > .047 for women]) Serious abnormalities of complete blood count or chemistries Active legal problems with the potential to result in incarceration Pregnancy or lactation Need to take medication with significant potential to interact with study medications (e.g., antidepressants, antipsychotics, psychostimulants, treatments for addictions, other dopaminergic or serotonergic agents, lithium, anticonvulsants). Allergy or hypersensitivity to psilocybin or diphenhydramine. High risk of adverse emotional or behavioral reaction based on investigator's clinical evaluation (e.g., evidence of serious personality disorder, antisocial behavior, serious current stressors, lack of meaningful social support).

Ages Eligible for Study
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Minimum Age: 25 Years
Maximum Age: 65 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
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Psilocybin<br>Psilocybin 25 mg/70 kg PO administered at week 4, 25-40 mg/70 kg PO administered at week 8. | Drug: Psilocybin<br> <br> Behavioral: Motivational Enhancement and Taking Action (META)<br>* Manualized psychosocial intervention based on motivational enhancement therapy, functional analysis, and implementation of a change plan.<br>|
| Active Comparator: Diphenhydramine<br>Diphenhydramine 50 mg PO administered at week 4, 50-100 mg PO administered at week 8. | Drug: Diphenhydramine<br> <br> Behavioral: Motivational Enhancement and Taking Action (META)<br>* Manualized psychosocial intervention based on motivational enhancement therapy, functional analysis, and implementation of a change plan.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent of Heavy Drinking Days | The Timeline Follow-back (TLFB) method is used to calculate the percent of heavy drinking days. The TLFB is a method for assessing the number of drinks of alcohol on a daily basis over the previous 30 days. For each day in the recall period, the participant indicates the number of drinks of alcohol they consumed. The TLFB provides a calendar prompt and number of other memory aids (e.g., holidays, payday, and other personally relevant dates) to facilitate accurate recall of drug use during the target period. Heavy drinking is defined as ≥4 drinks per day for women and ≥5 drinks per day for men. | Screening (Week 0) | 
| Percent of Heavy Drinking Days | The Timeline Follow-back (TLFB) method is used to calculate the percent of heavy drinking days. The TLFB is a method for assessing the number of drinks of alcohol on a daily basis over the previous 30 days. For each day in the recall period, the participant indicates the number of drinks of alcohol they consumed. The TLFB provides a calendar prompt and number of other memory aids (e.g., holidays, payday, and other personally relevant dates) to facilitate accurate recall of drug use during the target period. Heavy drinking is defined as ≥4 drinks per day for women and ≥5 drinks per day for men. | Baseline (Week 4) | 
| Percent of Heavy Drinking Days | The Timeline Follow-back (TLFB) method is used to calculate the percent of heavy drinking days. The TLFB is a method for assessing the number of drinks of alcohol on a daily basis over the previous 30 days. For each day in the recall period, the participant indicates the number of drinks of alcohol they consumed. The TLFB provides a calendar prompt and number of other memory aids (e.g., holidays, payday, and other personally relevant dates) to facilitate accurate recall of drug use during the target period. Heavy drinking is defined as ≥4 drinks per day for women and ≥5 drinks per day for men. | Follow Up (Weeks 5-36) | 
| Drinks Per Day | The Timeline Follow-back (TLFB) method is used to calculate drinks per day. The TLFB is a method for assessing the number of drinks of alcohol on a daily basis over the previous 30 days. For each day in the recall period, the participant indicates the number of drinks of alcohol they consumed. The TLFB provides a calendar prompt and number of other memory aids (e.g., holidays, payday, and other personally relevant dates) to facilitate accurate recall of drug use during the target period. | Screening (Week 0) | 
| Drinks Per Day | The Timeline Follow-back (TLFB) method is used to calculate drinks per day. The TLFB is a method for assessing the number of drinks of alcohol on a daily basis over the previous 30 days. For each day in the recall period, the participant indicates the number of drinks of alcohol they consumed. The TLFB provides a calendar prompt and number of other memory aids (e.g., holidays, payday, and other personally relevant dates) to facilitate accurate recall of drug use during the target period. | Baseline (Week 4) | 
| Drinks Per Day | The Timeline Follow-back (TLFB) method is used to calculate drinks per day. The TLFB is a method for assessing the number of drinks of alcohol on a daily basis over the previous 30 days. For each day in the recall period, the participant indicates the number of drinks of alcohol they consumed. The TLFB provides a calendar prompt and number of other memory aids (e.g., holidays, payday, and other personally relevant dates) to facilitate accurate recall of drug use during the target period. | Follow Up (Weeks 5-36) | 
| Percent of Drinking Days | The Timeline Follow-back (TLFB) method is used to calculate the percentage of days that participants drank alcohol. The TLFB is a method for assessing the number of drinks of alcohol on a daily basis over the previous 30 days. For each day in the recall period, the participant indicates the number of drinks of alcohol they consumed. The TLFB provides a calendar prompt and number of other memory aids (e.g., holidays, payday, and other personally relevant dates) to facilitate accurate recall of drug use during the target period. | Screening (Week 0) | 
| Percent of Drinking Days | The Timeline Follow-back (TLFB) method is used to calculate the percentage of days that participants drank alcohol. The TLFB is a method for assessing the number of drinks of alcohol on a daily basis over the previous 30 days. For each day in the recall period, the participant indicates the number of drinks of alcohol they consumed. The TLFB provides a calendar prompt and number of other memory aids (e.g., holidays, payday, and other personally relevant dates) to facilitate accurate recall of drug use during the target period. | Baseline (Week 4) | 
| Percent of Drinking Days | The Timeline Follow-back (TLFB) method is used to calculate the percentage of days that participants drank alcohol. The TLFB is a method for assessing the number of drinks of alcohol on a daily basis over the previous 30 days. For each day in the recall period, the participant indicates the number of drinks of alcohol they consumed. The TLFB provides a calendar prompt and number of other memory aids (e.g., holidays, payday, and other personally relevant dates) to facilitate accurate recall of drug use during the target period. | Follow Up (Weeks 5-36) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Short Inventory of Problems (SIP-2R) Score | 15-item self-report questionnaire assessing problems related to alcohol use. Items are ranked on a 4-point Likert scale ranging from 0 (never) to 3 (daily or almost daily). The total score range is 0-45; the higher the score, the more problems related to alcohol use. | Baseline (Week 4) | 
| Short Inventory of Problems (SIP-2R) Score | 15-item self-report questionnaire assessing problems related to alcohol use. Items are ranked on a 4-point Likert scale ranging from 0 (never) to 3 (daily or almost daily). The total score range is 0-45; the higher the score, the more problems related to alcohol use. | Week 36 | 
| Percentage of Participants Achieving Abstinence From Drinking | The Timeline Follow-back (TLFB) method is used in calculating abstinence from drinking. The TLFB is a method for assessing the number of drinks of alcohol on a daily basis over the previous 30 days. For each day in the recall period, the participant indicates the number of drinks of alcohol they consumed. The TLFB provides a calendar prompt and number of other memory aids (e.g., holidays, payday, and other personally relevant dates) to facilitate accurate recall of drug use during the target period. Abstinence is defined as zero drinks of alcohol over the target period. | From Week 5 (1 week after first drug administration) up to Week 36 | 
| Percentage of Participants Achieving Abstinence From Drinking | The Timeline Follow-back (TLFB) method is used in calculating abstinence from drinking. The TLFB is a method for assessing the number of drinks of alcohol on a daily basis over the previous 30 days. For each day in the recall period, the participant indicates the number of drinks of alcohol they consumed. The TLFB provides a calendar prompt and number of other memory aids (e.g., holidays, payday, and other personally relevant dates) to facilitate accurate recall of drug use during the target period. Abstinence is defined as zero drinks of alcohol over the target period. | From Week 33 up to Week 36 | 
| Percent of Participants Achieving No Heavy Drinking Days | The Timeline Follow-back (TLFB) method is used in calculating the number of heavy drinking days. The TLFB is a method for assessing the number of drinks of alcohol on a daily basis over the previous 30 days. For each day in the recall period, the participant indicates the number of drinks of alcohol they consumed. The TLFB provides a calendar prompt and number of other memory aids (e.g., holidays, payday, and other personally relevant dates) to facilitate accurate recall of drug use during the target period. Heavy drinking is defined as ≥4 drinks per day for women and ≥5 drinks per day for men. | From Week 5 (1 week after first drug administration) up to Week 36 | 
| Percent of Participants Achieving No Heavy Drinking Days | The Timeline Follow-back (TLFB) method is used in calculating the number of heavy drinking days. The TLFB is a method for assessing the number of drinks of alcohol on a daily basis over the previous 30 days. For each day in the recall period, the participant indicates the number of drinks of alcohol they consumed. The TLFB provides a calendar prompt and number of other memory aids (e.g., holidays, payday, and other personally relevant dates) to facilitate accurate recall of drug use during the target period. Heavy drinking is defined as ≥4 drinks per day for women and ≥5 drinks per day for men. | From Week 33 Up to Week 36 | 
| Percent of Participants Achieving WHO Risk Drinking Level Decrease of at Least 1 Level | For men, WHO low risk drinking (level 1) is defined as >0 grams of alcohol/day (g/d) to 40 g/d; moderate risk (level 2) as >40 g/d to 60 g/d; high risk (level 3) as >60 g/d to 100 g/d; and very high risk (level 4) as >100 g/d. For women, low risk (level 1) is defined as >0 g/d to 20 g/d; moderate risk (level 2) as >20 g/d to 40 g/d; high risk (level 3) as >40 g/d to 60 g/d; and very high risk (level 4) as >60 g/d. Abstinence was defined as no risk (level 0). | From Week 5 (1 week after first drug administration) up to Week 36 | 
| Percent of Participants Achieving WHO Risk Drinking Level Decrease of at Least 1 Level | For men, WHO low risk drinking (level 1) is defined as >0 grams of alcohol/day (g/d) to 40 g/d; moderate risk (level 2) as >40 g/d to 60 g/d; high risk (level 3) as >60 g/d to 100 g/d; and very high risk (level 4) as >100 g/d. For women, low risk (level 1) is defined as >0 g/d to 20 g/d; moderate risk (level 2) as >20 g/d to 40 g/d; high risk (level 3) as >40 g/d to 60 g/d; and very high risk (level 4) as >60 g/d. Abstinence was defined as no risk (level 0). | From Week 33 Up to Week 36 | 
| Percent of Participants Achieving WHO Risk Drinking Level Decrease of at Least 2 Levels | For men, WHO low risk drinking (level 1) is defined as >0 grams of alcohol/day (g/d) to 40 g/d; moderate risk (level 2) as >40 g/d to 60 g/d; high risk (level 3) as >60 g/d to 100 g/d; and very high risk (level 4) as >100 g/d. For women, low risk (level 1) is defined as >0 g/d to 20 g/d; moderate risk (level 2) as >20 g/d to 40 g/d; high risk (level 3) as >40 g/d to 60 g/d; and very high risk (level 4) as >60 g/d. Abstinence was defined as no risk (level 0). | From Week 5 (1 week after first drug administration) up to Week 36 | 
| Percent of Participants Achieving WHO Risk Drinking Level Decrease of at Least 2 Levels | For men, WHO low risk drinking (level 1) is defined as >0 grams of alcohol/day (g/d) to 40 g/d; moderate risk (level 2) as >40 g/d to 60 g/d; high risk (level 3) as >60 g/d to 100 g/d; and very high risk (level 4) as >100 g/d. For women, low risk (level 1) is defined as >0 g/d to 20 g/d; moderate risk (level 2) as >20 g/d to 40 g/d; high risk (level 3) as >40 g/d to 60 g/d; and very high risk (level 4) as >60 g/d. Abstinence was defined as no risk (level 0). | From Week 33 Up to Week 36 | 
| Percent of Participants Achieving WHO Risk Drinking Level Decrease of at Least 3 Levels | For men, WHO low risk drinking (level 1) is defined as >0 grams of alcohol/day (g/d) to 40 g/d; moderate risk (level 2) as >40 g/d to 60 g/d; high risk (level 3) as >60 g/d to 100 g/d; and very high risk (level 4) as >100 g/d. For women, low risk (level 1) is defined as >0 g/d to 20 g/d; moderate risk (level 2) as >20 g/d to 40 g/d; high risk (level 3) as >40 g/d to 60 g/d; and very high risk (level 4) as >60 g/d. Abstinence was defined as no risk (level 0). | From Week 5 (1 week after first drug administration) up to Week 36 | 
| Percent of Participants Achieving WHO Risk Drinking Level Decrease of at Least 3 Levels | For men, WHO low risk drinking (level 1) is defined as >0 grams of alcohol/day (g/d) to 40 g/d; moderate risk (level 2) as >40 g/d to 60 g/d; high risk (level 3) as >60 g/d to 100 g/d; and very high risk (level 4) as >100 g/d. For women, low risk (level 1) is defined as >0 g/d to 20 g/d; moderate risk (level 2) as >20 g/d to 40 g/d; high risk (level 3) as >40 g/d to 60 g/d; and very high risk (level 4) as >60 g/d. Abstinence was defined as no risk (level 0). | From Week 33 up to Week 36 |