Neurobehavioral Mechanisms of Psilocybin-assisted Treatment for AUD

DRUG

Psilocybin

One 25 mg capsule and one 5 mg capsule (30 mg total) administered once orally

OTHER

Inactive Placebo

Two matching placebo capsules administered once orally

BEHAVIORAL

Supportive therapy sessions

Participants will receive four supportive therapy sessions of manual-based treatment from two Center for Psychedelic Medicine (CPM) clinicians. The lead clinician will be a licensed physician, clinical psychologist, or nurse practitioner who will be primarily responsible for the content of the intervention. The second therapist will have at least a master's degree or be pursuing a master's or doctoral degree in a related clinical field.

Percent change in the alcohol cue-induced Blood-oxygen-level dependent (BOLD) signal in the lateral prefrontal cortex (PFC)

Time frame: Baseline, Day 2

Percentage change in the BOLD signal is the difference in fMRI signal between the baseline condition (B) and the alcohol cue-induced task condition (T); percent signal change = (T-B)/B×100%. A positive value of the percentage change in BOLD signal indicates up-regulation of BOLD signal.

Percent change in the alcohol cue-induced BOLD signal change in the caudate

Time frame: Baseline, Day 2

Percentage change in the BOLD signal is the difference in fMRI signal between the baseline condition (B) and the alcohol cue-induced task condition (T); percent signal change = (T-B)/B×100%. A positive value of the percentage change in BOLD signal indicates up-regulation of BOLD signal.

Percent change in alcohol cue-induced BOLD signal change in the ventromedial PFC (vmPFC)

Time frame: Baseline, Day 2

Percentage change in the BOLD signal is the difference in fMRI signal between the baseline condition (B) and the alcohol cue-induced task condition (T); percent signal change = (T-B)/B×100%. A positive value of the percentage change in BOLD signal indicates up-regulation of BOLD signal.

Percent change in alcohol cue-induced BOLD signal change in the inferior frontal gyrus (IFG)

Time frame: Baseline, Day 2

Percentage change in the BOLD signal is the difference in fMRI signal between the baseline condition (B) and the alcohol cue-induced task condition (T); percent signal change = (T-B)/B×100%. A positive value of the percentage change in BOLD signal indicates up-regulation of BOLD signal.

Percent change in alcohol cue-induced BOLD signal change in the insula

Time frame: Baseline, Day 2

Percentage change in the BOLD signal is the difference in fMRI signal between the baseline condition (B) and the alcohol cue-induced task condition (T); percent signal change = (T-B)/B×100%. A positive value of the percentage change in BOLD signal indicates up-regulation of BOLD signal.

Percent change in negative affective cue-induced BOLD signal change in the dorsomedial PFC (dmPFC)

Time frame: Baseline, Day 2

Percentage change in the BOLD signal is the difference in fMRI signal between the baseline condition (B) and the alcohol cue-induced task condition (T); percent signal change = (T-B)/B×100%. A positive value of the percentage change in BOLD signal indicates up-regulation of BOLD signal.

Percent change in negative affective cue-induced BOLD signal change in the supramarginal gyrus

Time frame: Baseline, Day 2

Percentage change in the BOLD signal is the difference in fMRI signal between the baseline condition (B) and the negative affective cue-induced task condition (T); percent signal change = (T-B)/B×100%. A positive value of the percentage change in BOLD signal indicates up-regulation of BOLD signal.

Percent change in negative affective cue-induced BOLD signal change in the amygdala

Time frame: Baseline, Day 2

Percentage change in the BOLD signal is the difference in fMRI signal between the baseline condition (B) and the negative affective cue-induced task condition (T); percent signal change = (T-B)/B×100%. A positive value of the percentage change in BOLD signal indicates up-regulation of BOLD signal.

Percent change in negative affective cue-induced BOLD signal change in the insula

Time frame: Baseline, Day 2

Percentage change in the BOLD signal is the difference in fMRI signal between the baseline condition (B) and the negative affective cue-induced task condition (T); percent signal change = (T-B)/B×100%. A positive value of the percentage change in BOLD signal indicates up-regulation of BOLD signal.

Percent change in alcohol cue-induced functional connectivity in prespecified regions of interest (ROI)

Time frame: Baseline, Day 2

ROI include the ventral striatum, lateral PFC (dlPFC and IFG), and caudate with target clusters in the PFC, ACC, and sensorimotor cortex (S1 and M1).

Percent change in negative affective cue-induced functional connectivity in prespecified regions of interest (ROI)

Time frame: Baseline, Week 4

ROI include the ventral striatal and amygdala with target clusters in temporal and occipital regions relative to placebo.

Percent change in the frequency of failed response inhibition

Time frame: Baseline, Week 4

A Go/NoGo task will be used as an objective measure of response inhibition. This task includes alcohol, non-alcohol, and neutral stimuli. The Go/No-go task requires participants to respond by pressing a button when they see a "go" signal, and not respond when they see the "no-go" signal. The key behaviour measured with this experiment is the participants' ability to withhold a response on No-go trials and the frequency of their failed responses.

Change in discounting rate (log(k))

Time frame: Baseline, Week 4

The discounting rate is derived from the Delay Discounting Task. Delay discounting tasks provide a measure of the temporal window and examine the devaluation of awards as a function of the delay to the receipt. The task includes 80 items requiring a choice between a delayed reward of $100 and smaller immediate rewards (ranging from $10 to $99, at delays ranging from one to 365 days. Discounting rates will be measured and pre-post differences will be assessed. Higher k values indicate higher impulsive decision-making.

Change in participant-level reference points

Time frame: IP Administration (Day 0), Week 24

A Foraging Task will be used as an objective measure of cognitive flexibility. The task involves making "stay" or "go" decisions to harvest apples from stylized "trees" that have hidden initial rewards. Within each block, trees have a mean initial reward rate. Subjects decide to either harvest the tree ("stay") or search for a new one ("go"), incurring an S second delay penalty for searching. Harvesting reveals the reward, which depletes by a fixed amount, plus a small error term. After a 1-second inter-trial interval, the tree reappears for another "stay" or "go" choice. Rewards on each sequential trial are computed. Rewards are computed dynamically, with optimal strategies varying based on the delay penalty. The optimal reference point is calculated using the marginal value theorem, while the empirical reference point is the participant's cutoff for searching.

Percentage of no heavy drinking days

Time frame: Baseline, Week 24

Outcome will be measured using the Timeline Followback (TLFB) interview-based assessment. The TLFB derives subjects' retrospective daily estimates of alcohol consumption patterns. Using a calendar as a visual aid, special events, and other memory cues, subjects are guided through the process of recalling and reporting daily drinking estimates.

Change in phosphatidyl ethanol (PEth) blood levels

Time frame: Baseline, Week 12

Change in carbohydrate-deficient transferrin (CDT) blood levels

Time frame: Baseline, Week 12

Change in the Drinker Inventory of Consequences questionnaire (DrInC-2R) total score

Time frame: Baseline, Week 24

DrInC-2R is a validated self-report questionnaire consisted of 50 questions to measure adverse consequences of alcohol abuse in five areas: Interpersonal, Physical, Social, Impulsive, and Intrapersonal as well as frequency of these consequences (answers given on frequency scale grade from 0-3: 0 - never, 1 - once or a few times, 2 - once or twice a week 3 - daily or almost daily). Higher scores indicate greater levels of alcohol-related problems.

Change in PSQI global score

Time frame: Baseline, Week 24

Sleep quality is measured by the Pittsburgh Sleep Quality Index (PSQI) . The PSQI is a 19-item, self-rated questionnaire designed to measure sleep quality and disturbance over the past month in clinical populations. The 19 items are grouped into 7 components, including (1) sleep duration, (2) sleep disturbance, (3) sleep latency, (4) daytime dysfunction due to sleepiness, (5) sleep efficiency, (6) overall sleep quality, and (7) sleep medication use. Each of the sleep components yields a score ranging from 0 to 3, with 3 indicating the greatest dysfunction. Adding up the average scores of the seven factors gives a global PSQI score from 0 to 21, with 0-4 indicating "good" sleep and 5-21 indicating "poor" sleep.

Change in patient's self-assessed health-related quality of life (by the SF-36 Questionnaire)

Time frame: Baseline, Week 24

The Short Form Health Survey (SF-36) is a validated 36 item self-report Quality of Life Questionnaire that measures eight multi-item dimensions of health: physical functioning, social functioning, role limitations due to physical problems, role limitations due to emotional problems, mental health, energy/vitality, pain, and general health perception. Scores range from 0 - 100. Lower scores = more disability, higher scores = less disability

Change in Alcohol craving score

Time frame: Baseline, Week 24

The alcohol cravings score will be assessed using the Penn Alcohol Craving Scale (PACS). The PACS consists of 5 questions with sub-scales ranging from 0 (never) to 6 (nearly all of the time). Scores greater than 20 were considered to meet diagnostic criteria for craving for a diagnosis of Alcohol Use Disorder.

Change in negative affect score

Time frame: Baseline, Week 24

Negative affect will be assessed using the negative affect scale of the Positive and Negative Affect Schedule (PANAS) which is a 10-item measure of negative emotions on a scale of 1 ("very slightly or not at all) to 5 ("extremely"). Total scores can range from 10 - 50, with higher scores representing higher levels of NA and reflect a dimension of general distress summarizing a variety of negative states such as anger, guilt, or anxiety.

Change in impulsivity score (Barratt impulsivity scale by the subscales and by the total score)

Time frame: Baseline, Week 24

Impulsivity will be assessed using the Barratt impulsivity scale (BIS-11), a validated self-report questionnaire composed of 30 items describing common impulsive or non-impulsive (for reverse scored items) behaviors and preferences. Items are scored on a 4-point scale: Rarely/Never = 1, Occasionally = 2, Often = 3, Almost Always/Always = 4. Total score is assessed. The total scores can range from 30 to 120. The higher total score corresponds to the more impulsive behavior

What is a clinical trial?

A clinical trial is a research study that tests new medical treatments, drugs, devices, or procedures to determine their safety and effectiveness. Trials are carefully designed and monitored to protect participants while advancing medical knowledge.

Is it safe to participate?

Clinical trials follow strict safety guidelines and ethical standards. Trials must be reviewed and approved, and participants are closely monitored by medical professionals throughout the study. You can withdraw at any time if you choose.

Will I be compensated?

Many clinical trials offer compensation for your time, travel expenses, and inconvenience. The specific compensation varies by study and will be discussed during the screening process. All study-related medical care is typically provided at no cost to participants.

Will I receive a placebo instead of treatment?

When effective treatment exists, participants typically receive either the standard treatment plus the study intervention, or the standard treatment plus placebo. You would not be denied effective care. Placebos are primarily used when no proven treatment is available, or in addition to standard care. Your trial consent form will clearly explain what treatments you may receive.

Can I leave a trial if I change my mind?

Absolutely. Participation in clinical trials is completely voluntary. You have the right to withdraw from the study at any time, for any reason, without penalty or loss of benefits to which you are otherwise entitled.

How long does a clinical trial last?

Trial duration varies widely depending on the study design and purpose. Some trials last just a few weeks, while others may continue for months or years. The study coordinator will provide specific timeline information during your screening call.