Psilocybin-Assisted Therapy for Severe Alcohol Use Disorder: Protocol for a Double-Blind, Randomized, Placebo-Controlled, 7-month Parallel-Group Phase II Superiority Trial
A substantial proportion of patients with alcohol use disorder does not respond to available treatments, which calls for the development of new alternatives. In parallel, psilocybin-assisted therapy for alcohol use disorder has recently yielded promising preliminary results. Building on extant findings, the proposed study aims to determine the feasibility and preliminary clinical efficacy of psilocybin-assisted therapy as a complementary intervention during inpatient rehabilitation for severe alcohol use disorder, and to characterize associated changes in the two key neurocognitive systems identified by dual-process models of addiction. In this double-blind, randomized, placebo-controlled, 7-month parallel-group phase II superiority trial, 62 participants aged 21-64 years will be enrolled to undergo psilocybin-assisted therapy within the context of a 4-week inpatient rehabilitation for severe alcohol use disorder. The experimental group will receive a high dose of psilocybin (30 mg), whereas the control group will receive an active placebo dose of psilocybin, both within the context of a brief standardized psychotherapeutic intervention. The primary clinical outcome is the between-group difference in terms of the change in percentage of heavy drinking days from baseline to four weeks post-hospital discharge, whilst safety and feasibility metrics will also be reported as primary outcomes. Key secondary assessments include between-group differences in terms of changes in 1) drinking behavior parameters up to six months post-hospital discharge, 2) phosphatidyl-ethanol blood concentration, an objective biomarker of alcohol consumption, 3) symptoms of depression, anxiety, trauma, and global functioning, 4) neuroplasticity and key neurocognitive mechanisms associated with addiction, 5) psychological processes and alcohol-related parameters.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
62
Psilocybin-assisted therapy
Placebo-assisted therapy
Brugmann University Hospital
Brussels, Belgium
RECRUITINGPrimary clinical outcome: change in percentage of heavy drinking days
The primary clinical outcome is the difference between the two treatment arms in terms of change from baseline (going back 8 weeks pre-enrolment) to 4 weeks post-hospital discharge (week 1 to 4 post-discharge) in the percentage of heavy drinking days. A heavy drinking day is defined as a day with ≥ 5 standard drinks/60g of alcohol for males, and ≥ 4 standard drinks/48g of alcohol for females. Alcohol consumption will be measured using the Timeline Follow-Back method (Sobell \& Sobell, 1992), a semi-structured interview that provides estimates of the daily quantity, frequency, and pattern of alcohol (and other drugs) use during a set time period. The method has demonstrated adequate to excellent reliability and validity over a wide range of studies and clinical contexts (Carey, 1997; Sobell et al., 1996).
Time frame: Baseline (going back to 8 weeks pre-enrolment) to 4 weeks post-hospital discharge
Feasibility: recruitment and retention rate
Recruitment and retention rate will be recorded and reported. A consort diagram displaying participant retention at each phase of the recruitment, screening and data collection process will be presented. We will report the numbers of individuals provided with participant information sheets who subsequently decided not to participate in the trial, number that underwent screening and number of drop-outs. For full transparency on inclusivity, information on the demographics and reason for exclusion will be reported from the screening dataset.
Time frame: Recruitment rate: at screening and enrolment. Retention rate: at each study visit
Safety: adverse events
Adverse events will be systematically assessed at each study visit and follow-ups. Adverse events summary tables will display the total number of participants reporting an adverse event and the percentage of participants (%) with an adverse event.
Time frame: At each study visit
Percent Heavy Drinking Days
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Alcohol consumption as measured with the Timeline Follow Back Method
Time frame: from pre-hospitalisation (up to 8 weeks pre-hospitalization) to 6 months post-hospital discharge (week 5 to 26 weeks)
Drinks per Day
Alcohol consumption as measured with the Timeline Follow Back Method
Time frame: from pre-hospitalisation (up to 8 weeks pre-hospitalization) to 4 weeks and 6 months post-hospital discharge
Percent Days Abstinent
Alcohol consumption as measured with the Timeline Follow Back Method
Time frame: from pre-hospitalisation (up to 8 weeks pre-hospitalization) to 4 weeks and 6 months post-hospital discharge
EEG-derived auditory long-term potentiation
Index of cortical neuroplasticity
Time frame: Neuroplasticity EEG data will be collected pre-dosing and twice post-dosing (+1 day, +7 days)
EEG-derived alcohol cue reactivity
Time frame: EEG data will be collected pre-dosing and twice post-dosing (+1 day, +7 days)
EEG-derived inhibitory control
Time frame: EEG data will be collected pre-dosing and twice post-dosing (+1 day, +7 days)
Psychological flexibility
The Acceptance and Action Questionnaire II (AAQII; Bond et al., 2011)
Time frame: Baseline, one day prior to psilocybin administration, one week post-psilocybin administration, as well as four weeks, three and six months post-hospital discharge.
Connectedness
The Watts Connectedness Scale (WCS; Watts et al., 2022)
Time frame: Baseline, one day prior to psilocybin administration, one week post-psilocybin administration, as well as four weeks, three and six months post-hospital discharge.
Interoception
The Multidimensional Assessment of Interoceptive Awareness (MAIA; Mehling et al., 2012)
Time frame: Baseline, one day prior to psilocybin administration, one week post-psilocybin administration, as well as four weeks, three and six months post-hospital discharge.
Depressive symptoms
Beck Depression Inventory (BDI; Beck et al., 1961)
Time frame: Baseline, one day prior to psilocybin administration, one week post-psilocybin administration, as well as four weeks, three and six months post-hospital discharge.
Anxiety symptoms
StateTrait Anxiety Inventory - trait subscale (STAI; Spielberger et al., 1983)
Time frame: Baseline, one day prior to psilocybin administration, one week post-psilocybin administration, as well as four weeks, three and six months post-hospital discharge.
Trauma symptoms
International Trauma Questionnaire (ITQ; Cloitre et al., 2018)
Time frame: Baseline, one day prior to psilocybin administration, one week post-psilocybin administration, as well as four weeks, three and six months post-hospital discharge.
Substance use recovery (patient reported outcome measure - PROM)
Substance Use Recovery Evaluator (SURE; Neale et al., 2016)
Time frame: Baseline as well as four weeks, three and six months post-hospital discharge.
Alcohol craving
Penn Alcohol Craving Scale (PACS; Flannery et al., 1999)
Time frame: Baseline, one day prior to psilocybin administration, one week post-psilocybin administration, as well as four weeks, three and six months post-hospital discharge.
Abstinence self-efficacy
Alcohol Abstinence Self-Efficacy Scale (AASE; DiClemente et al., 1994)
Time frame: Baseline, one day prior to psilocybin administration, one week post-psilocybin administration, as well as four weeks, three and six months post-hospital discharge.
Readiness to change
Likert-scale ratings of the participant's perception of 1) the importance of change in drinking; 2) confidence of ability to change; 3) readiness for change; 4) Commitment to the goal of abstinence (Bogenschutz et al., 2022)
Time frame: Baseline, one day prior to psilocybin administration, one week post-psilocybin administration, as well as four weeks, three and six months post-hospital discharge.