Clinical and Mechanistic Effects of Psilocybin in Alcohol Addicted Patients

Primary Outcomes

• Changes in Time-Line Follow-Back every day from baseline until 6 months after the intervention (primary endpoint: 4 weeks after administration, follow-up period 6 months)

  measures changes of the alcohol use behavior over time.The Time-Line Follow-Back questionnaire assesses the standard glasses of alcohol consumed in a day. The minimum is no alcohol consumption, with the maximum being an open end. Less alcohol consumption will be the better outcome, whereas more alcohol consumption will be a worse outcome. The primary efficacy value will be alcohol use (average of daily standard units of alcohol use between visit 3 and visit 6) between psilocybin administration and visit 6 (four weeks after psilocybin administration)

• Relapse using Time-Line Follow-Back Relapse will be compared between the placebo and psilocybin group in the time period four weeks after visit 3

  Re-instatement of alcohol drinking behaviour \> 1 standard drink will be defined as relapse.

Secondary Outcomes

• Brain The MRI will be completed at baseline (visit 2, approx. 5 days prior), approx. 90 minutes after the administration of the investigational medicinal product (IMP), and following IMP-administration (approx. 4 weeks later).

  Changes in resting-state fMRI, cue-reactivity task fMRI, autobiographic memory task fMRI and DTI. MRI data will be analysed using general lineal models (GLMs) and psychophysiological interaction models. For these analyses, the generally established methods of controlling for multiple comparisons will be applied.

• Empathy five days before IMP-administration, one day post and approx. 4 weeks post intervention

  Changes in empathy assessed with the Multifaceted Empathy Task

• Blood sample: Neural profile analysis At baseline, approx. five days before intervention

  To investigate the in vitro neuronal profile of psilocybin in alcohol dependent individuals blood cells before psilocybin administration will be differentiated into cortical neurons.

• Blood sample: Epigenetic analysis At baseline (approx. five day before intervention), one day after the IMP-administration, and approx. 4 weeks after the IMP-administration

  Genome-wide genetic analyses will be conducted to investigate association between gene variants and treatment outcomes. Genome-wide changes in epigenetic markers of treatment response will be analysed before and after psilocybin administration

• Blood sample: Markers of alcohol use This will be analysed at screening visit and approx. 4 weeks after the IMP-administration.

  Ethylglucuronid, aspartate aminotransferase (AST), alanine aminotransferase (ALT) and gamma-glutamyltransferase (GGT) will be analysed from blood samples (except for Ethylglucuronid which will be analysed in urine samples) as objective markers of alcohol use. Additionally, cortisol will be analysed.

• Alcohol Self-Efficacy Scale The questionnaire will be completed at screening (visit 1, approx. 14 days prior), baseline (visit 2, approx. 5 days prior), and post IMP administration (1, approx. 14, approx. 28 days post-treatment and follow-ups)

  The Alcohol Self-Efficacy scale measures an individual's confidence in their ability to resist drinking alcohol in high-risk situations. It consists of 20 items and uses a 5-point Likert scale, with 0 representing "not at all confident" and 4 representing "extremely confident." The minimum score possible is 20, and the maximum score is 100. Higher scores indicate greater self-efficacy or confidence in one's ability to resist drinking in high-risk situations, while lower scores indicate lower levels of self-efficacy. The scale can be used to assess an individual's readiness to change their drinking behavior and to identify areas where additional support or intervention may be necessary.

• Penn Alcohol Craving Scale The questionnaire will be completed at screening (visit 1, approx. 14 days prior), baseline (visit 2, approx. 5 days prior), directly before IMP administration, and post IMP administration (1, approx. 14, approx. 28 days post-treatment and follow-ups)

  The Penn Alcohol Craving Scale is a tool used to assess the intensity of an individual's craving for alcohol. It consists of 5 items, each rated on a 7-point Likert scale ranging from 0 (not at all) to 6 (extremely). The minimum score possible is 0, and the maximum score is 30. Higher scores on the Penn Alcohol Craving Scale indicate more intense alcohol cravings, while lower scores indicate lower levels of craving. The scale can be used to monitor the effectiveness of treatments aimed at reducing alcohol craving, as well as to identify triggers for alcohol use and to assess an individual's readiness to change their drinking behavior.

• Snaith-Hamilton-Pleasure Scale (SHAPS) The questionnaire will be completed at baseline (visit 2, approx. 5 days prior), and following IMP administration (1, approx. 14, approx. 28 days post-treatment and follow-ups).]

  The Snaith-Hamilton-Pleasure Scale (SHAPS) is a tool used to measure an individual's capacity to experience pleasure in daily life. It consists of 14 items and uses a 4-point Likert scale, with 1 representing "strongly disagree" and 4 representing "strongly agree." The minimum score possible is 14, and the maximum score is 56. Higher scores on the SHAPS indicate greater capacity for pleasure, while lower scores may suggest anhedonia, which is a reduced ability to experience pleasure. The scale can be used to assess an individual's emotional well-being and screen for depressive symptoms or other mood disorders. Additionally, the scale may be used to monitor the effectiveness of treatment interventions aimed at improving an individual's ability to experience pleasure in daily life.

• Number of Heavy Drinking Days (HDDs) 4 weeks after administration, and at 6 month follow-up

  HDD was defined as a day with alcohol consumption of five or more standard units for a man and four or more standard units for a woman

• Time to Relapse 4 weeks after administration, and at 6 month follow-up

  The Time to Relapse is the amount of self-reported abstinent days post administration until relapse occurs (relapse is defined as \> 1 standard drink).

• Emotion-Regulation Questionnaire (ERQ) The questionnaire will be completed at baseline (approx. 5 days prior), and following IMP administration (1, approx. 14, approx. 28 days post-treatment and follow-ups)

  The ERQ is a self-report tool measuring an individual's tendency to regulate their emotions in two ways: reappraisal and suppression. The scale range for each subscale is as follows: for the reappraisal subscale, the minimum score is 6 and the maximum score is 42; for the suppression subscale, the minimum score is 4 and the maximum score is 28. Higher scores on the reappraisal subscale indicate a greater tendency to regulate emotions by reinterpreting them in a more positive light, while higher scores on the suppression subscale indicate a greater tendency to inhibit the expression of emotions. Lower scores on either subscale suggest a weaker tendency to use that emotion regulation strategy.

• Savoring Believes Inventory (SBI) The questionnaire will be completed at baseline (visit 2, approx. 5 days prior), and following IMP administration (1, approx. 14, approx. 28 days post-treatment and follow-ups).]

  The SBI is a self-report tool assessing an individual's beliefs towards savoring positive experiences. It consists of 21 items and uses a 4-point Likert scale, with 1 representing "strongly disagree" and 5 representing "strongly agree." The minimum score possible is 24, and the maximum score is 120. Higher scores on the SBI indicate a greater tendency to savor positive experiences, while lower scores suggest a weaker tendency to engage in savoring behaviors.

• Temporary Experience of Pleasure Scale (TEPS) The questionnaire will be completed at baseline (visit 2, approx. 5 days prior), and following IMP administration (1, approx. 14, approx. 28 days post-treatment and follow-ups).]

  The TEPS is a self-report tool measuring an individual's capacity to experience pleasure in response to natural rewards. The minimum score possible is 18, and the maximum score is 108. The TEPS assesses two dimensions of pleasure: anticipatory pleasure and consummatory pleasure. Higher scores on the TEPS indicate a greater capacity to experience pleasure in response to natural rewards, while lower scores suggest a reduced ability to experience pleasure. The scale can be used to assess an individual's emotional well-being and to screen for anhedonia, which is a reduced ability to experience pleasure. Additionally, the scale may be used to monitor the effectiveness of treatment interventions aimed at improving an individual's capacity to experience pleasure. The TEPS has been used in research to investigate the relationship between pleasure and various psychological outcomes, such as depression, substance use disorders, and personality traits.

• Quality of Life Scale (QOL) It will be completed at baseline (approx. 5 days prior), and following IMP administration (1, approx. 14, approx. 28 days post-treatment and follow-ups)

  The QOL is a self-report tool measuring an individual's subjective evaluation of their overall quality of life. The scale measures multiple domains related to quality of life, including physical health, psychological well-being, social relationships, and environmental factors. The scale range for each subscale is as follows: for physical health, the minimum score is 4 and the maximum score is 28; for psychological well-being, the minimum score is 5 and the maximum score is 35; for social relationships, the minimum score is 3 and the maximum score is 21; for environmental factors, the minimum score is 4 and the maximum score is 28. The total score for the QOL ranges from 32 to 168. Higher scores on the QOL indicate a better quality of life, while lower scores suggest a poorer quality of life.

• Positive and Negative Affect Schedule (PANAS) The questionnaire will be completed at baseline (visit 2, approx. 5 days prior), and following IMP administration (1, approx. 14, approx. 28 days post-treatment and follow-ups).

  PANAS is a questionnaire for measuring positive and negative affect. It consists of two 10-item scales, one measuring positive affect (PA) and one measuring negative affect (NA). Each item is rated on a 5-point scale, ranging from "very slightly or not at all" to "extremely". The scores for the PA and NA scales can be summed separately, with higher scores indicating higher levels of positive or negative affect, respectively. The minimum score for the Positive Affect (PA) scale is 10 (when all 10 items are rated as "very slightly or not at all"). The maximum score for the PA scale is 50 (when all 10 items are rated as "extremely"). The minimum score for the Negative Affect (NA) scale is 10 (when all 10 items are rated as "very slightly or not at all"). The maximum score for the NA scale is 50 (when all 10 items are rated as "extremely").

• Stundentagebuch, STEPP/STEPT The questionnaire will be completed at baseline (visit 2, approx. 5 days prior), and following IMP administration (1, approx. 14, approx. 28 days post-treatment and follow-ups).

  The Stundenbogen are short standardized questionnaires for formative evaluation of psychological counseling. Both questionnaires include 12 items which have to be answered by the patient or client or by the psychotherapist or counselor after a psychotherapy or counseling session. Items are constructed complementarily for therapists and patients and refer to (1) the motivational clarification and development of the patient, (2) the active help for problem-solving by the patient and (3) the therapeutic support experienced by the patient (patient questionnaire) versus that perceived by the therapist (therapist questionnaire). Higher scores over time would indicate a better outcome.

• Hopelessness-Scale (HS-scale) The questionnaire will be completed at baseline (visit 2, approx. 5 days prior), and following IMP administration (1, approx. 14, approx. 28 days post-treatment and follow-ups).

  The HS-scale is a self-report tool used to measure an individual's level of hopelessness, pessimism, and negative expectations about the future. It consists of 20 items and uses a true-false response format. The scale range for the HS-scale is from 0 to 20, with higher scores indicating greater levels of hopelessness. The HS-scale can be used to assess an individual's level of hopelessness and to identify areas where additional support or intervention may be necessary. It is commonly used in clinical and research settings to study the relationship between hopelessness and various psychological outcomes, such as depression, suicidal ideation, and anxiety. The scale may also be used to monitor the effectiveness of treatment interventions aimed at reducing hopelessness and improving mental health outcomes.

• Frankfurt Self-Concept Scale (FSKN) The questionnaire will be completed at baseline (visit 2, approx. 5 days prior), and following IMP administration (1, approx. 14, approx. 28 days post-treatment and follow-ups).

  The Frankfurt Self-Concept Scale (FSKN) is a self-report tool assessing an individual's self-concept or self-image. The FSKN measures multiple dimensions of self-concept, including social self-concept, competence self-concept, and affective self-concept. The FSKN assesses an individual's self-concept and identifies areas where additional support or intervention may be necessary. It is commonly used in clinical and research settings to study the relationship between self-concept and various psychological outcomes, such as self-esteem, anxiety, and depression. The scale may also be used to monitor the effectiveness of treatment interventions aimed at improving self-concept and overall well-being. Higher scores indicating a more positive self-concept.

• Beck Depression Inventory (BDI) The questionnaire will be completed at baseline (visit 2, approx. 5 days prior), and following IMP administration (1, approx. 14, approx. 28 days post-treatment and follow-ups).

  The BDI measures the severity of depression. It consists of 21 items that assess a range of symptoms associated with depression, such as sadness, guilt, worthlessness, and loss of pleasure. Each item is scored on a four-point scale ranging from 0 to 3, with higher scores indicating greater severity of depression. The scale ranges from "0" indicating the absence of the symptom to "3" indicating the most severe form of the symptoms. The total score on the BDI ranges from 0 to 63, with higher scores indicating greater levels of depression.

• Hamilton Anxiety Scale (HAMA) The questionnaire will be completed at baseline (visit 2, approx. 5 days prior), and following IMP administration (1, approx. 14, approx. 28 days post-treatment and follow-ups).]

  The Hamilton Anxiety Scale (HAMA) is a questionnaire for assessing the severity of anxiety symptoms. It consists of 14 items that measure both psychic anxiety (e.g., tension, fear, insomnia) and somatic anxiety (e.g., palpitations, sweating, headaches). Each item is scored on a five-point scale ranging from 0 to 4, with higher scores indicating greater severity of anxiety. On this scale, a score of "0" indicates the absence of the symptom, while a score of "1" indicates mild, "2" moderate, "3" severe, and "4" very severe symptoms. The total score on the HAMA ranges from 0 to 56, with higher scores indicating greater levels of anxiety.

• The Stress Questionnaire (CQ) The questionnaire will be completed at baseline (visit 2, approx. 5 days prior), and following IMP administration (1, approx. 14, approx. 28 days post-treatment and follow-ups).]

  The CQ is 7-item self-report scale that measures potential stressors, the burden it elicits and the progress done regarding this issue. It is adapted from the Stress \& Coping Inventory. The questionnaire is used to measure a person's level of stress and their ability to manage and cope with it.

• Drinker Inventory of Consequences (DrInc) The questionnaire will be completed at screening (visit 1, approx. 14 days prior to the IMP-administration), and following IMP administration (approx. 28 days post-treatment and follow-ups)

  The "Drinker Inventory of Consequences (DrInc)" is a self-report inventory that measures the negative consequences associated with alcohol use. It consists of 50 items that assess 5 domains of consequences: physical, interpersonal, intrapersonal, impulse control, and social responsibility. The items ask about the frequency and severity of negative consequences experienced due to alcohol use. The DrInc uses a Likert scale, where participants rate the frequency and severity of the negative consequences they experienced due to alcohol use. The response options for each item range from 0 (never) to 4 (almost always), with some items having additional response options. The total score is the sum of all 50 items, with higher scores indicating more severe negative consequences related to alcohol use. The possible score on the DrInc scale ranges from 0 (no negative consequences) to 200 (highest score on all 50 items).

• Symptom Checklist (SCL-90-R) The questionnaire will be completed at screening (visit 1, approx. 14 days prior to the IMP-administration), and following IMP administration (approx. 28 days post-treatment and follow-ups)

  The "Symptom Checklist (SCL-90-R)" is a self-report inventory that assesses a broad range of psychological symptoms and psychological distress. It consists of 90 items that evaluate 9 domains of symptoms: somatization, obsessive-compulsive, interpersonal sensitivity, depression, anxiety, hostility, phobic anxiety, paranoid ideation, and psychoticism. The questions use a Likert scale, where participants rate the severity of symptoms they have experienced in the past week. The response options range from 0 (not at all) to 4 (extremely), with higher scores indicating more severe psychological distress.