Evaluation of Cannabidiol and Naltrexone on Cue-Induced Alcohol Craving in Alcohol Dependence: A Randomized, Double-Blind, Placebo-Controlled Trial

The primary objective of this study is to evaluate the effect of either 800mg or 1200mg oral **Cannabidiol** (CBD) in addition to a background treatment with 50mg oral **Naltrexone** on the reduction of alcohol craving in patients with **alcohol dependence**, compared to the effects of a placebo in addition to standard treatment with 50mg oral Naltrexone. This is clinically relevant as it aims to determine the potential efficacy of CBD as an adjunctive treatment in reducing alcohol craving, which is a significant challenge in managing alcohol dependence.

Secondary objectives include:

• Investigation of the effects of CBD on changes in alcohol craving, quality of life, depressive symptoms, and state and trait anxiety.
• Assessment of patient-reported outcomes, including subjective burden and benefit of treatment, and effects on alcohol craving, perceived stress, mood, anxiety, well-being, daily functioning, and confidence in abstinence.
• Evaluation of CBD plasma levels to detect effects on CBD blood plasma levels.
• Measurement of time to relapse to alcohol, cumulative alcohol use, and percent heavy drinking days.
• Analysis of average weekly alcohol consumption and maximum weekly craving via smartphone-based e-diary during follow-up.
• Safety assessment through the evaluation of adverse events and serious adverse events.
• Examination of changes in neural brain activation assessed by the blood oxygenated level dependent (BOLD) response during various stimuli and functional connectivity during resting state.

The clinical trial focuses on individuals diagnosed with **alcohol dependence** as per the ICD10 criteria. The study population includes both male and female participants, aged between 18 and 70 years. Participants are required to report alcohol craving as a symptom of their condition. The trial involves a vulnerable population, and all participants must have the ability to comprehend the nature and implications of the clinical trial. Written informed consent is mandatory prior to enrollment. Additionally, participants must agree to random assignment and, for those with childbearing potential, adhere to a highly effective birth control method until one month after the last investigational medicinal product administration, with a negative pregnancy test at enrollment. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled** study to evaluate the effects of **cannabidiol** in combination with **naltrexone** on cue-induced alcohol craving in individuals with **alcohol dependence**. The trial will involve the administration of either 800 mg or 1200 mg of oral cannabidiol alongside a standard treatment of 50 mg oral naltrexone, compared to a placebo with the same naltrexone regimen. The primary objective is to assess the reduction in alcohol craving, measured by the Obsessive Compulsive Drinking Scale (OCDS-G), from baseline to the end of treatment. The trial is expected to commence on June 15, 2025, and conclude by June 30, 2028.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (18-70 years), diagnosis of alcohol dependence according to ICD10, and the ability to provide informed consent. The study will include multiple follow-up visits: visit 2 (day -2) for baseline assessments, visit 3 (day 1) for initial treatment administration, visit 4 (day 7), visit 5 (day 14) marking the end of treatment, and subsequent visits 6 (day 28), 7 (day 42), 8 (day 105), and 9 (day 196) for long-term follow-up assessments. The end-of-study visit will occur at visit 9, where final evaluations will be conducted.

The expected duration of participant involvement is approximately 196 days, with the active treatment phase lasting 14 days. Conditions that may lead to early termination from the study include withdrawal of consent, adverse events, or non-compliance with study protocols. Secondary endpoints will evaluate changes in quality of life, depressive symptoms, anxiety, and other patient-reported outcomes across the study visits. The trial will also monitor **CBD** plasma levels and assess neural brain activation in response to alcohol cues for specific participants. The study is categorized as a Phase 4 trial, focusing on the therapeutic effects of a novel product in a non-low intervention setting.

The clinical trial involves the administration of **Cannabidiol Capsules** as the experimental medication. These capsules are formulated as hard capsules and contain the active substance **cannabidiol**, which is of chemical origin. The dosage of cannabidiol administered in the trial is either 800 mg or 1200 mg per day, delivered orally. The maximum daily dose is set at 1200 mg, with a total maximum dose of 16.8 grams over the treatment period. The treatment duration is limited to 14 days. The administration of the capsules is conducted in conjunction with a background treatment of 50 mg oral **Naltrexone**. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol.

In addition to the experimental treatment, the study employs **Cannabidiol Placebo Capsules** as a comparator. These placebo capsules are designed to mimic the appearance of the cannabidiol capsules but do not contain any active substance. The placebo is administered in the same manner as the experimental treatment, ensuring the study remains double-blind. The placebo is also given alongside the standard treatment of 50 mg oral Naltrexone. The use of a placebo control allows for the assessment of the true efficacy of cannabidiol in reducing alcohol craving in individuals with alcohol dependence.

Efficacy in the clinical trial titled "ICONICplus - Randomized, double-blind, placebo-controlled trial to investigate the Effects of Cannabidiol plus Naltrexone on Cue-Induced Alcohol Craving in Alcohol Dependence" will be assessed using both primary and secondary endpoints. The primary endpoint is the difference in alcohol craving, measured by the Obsessive Compulsive Drinking Scale (OCDS-G), between baseline (visit 2, day -2) and the end of treatment (visit 5, day 14). This scale is a validated tool for assessing craving levels in individuals with alcohol dependence.

Secondary endpoints include various measures to provide a comprehensive evaluation of efficacy. These include the difference from baseline of OCDS-G craving scores at multiple timepoints: visits 4 (day 7), 6 (day 28), 7 (day 42), 8 (day 105), and 9 (day 196). Additionally, changes in Quality of Life (WHO-QOL-BREF scores), depressive symptoms (BDI-II scores), and state and trait anxiety (STAI scores) will be assessed at specified visits. Patient-reported outcomes will be collected at visits 3 (day 1), 4 (day 7), 5 (day 14), 6 (day 28), 7 (day 42), 8 (day 105), and 9 (day 196).

Further assessments include **CBD** plasma levels at visits 3 (day 1) and 5 (day 14) for patients at the CIMH site, and measures of time to relapse, cumulative alcohol use, and percent heavy drinking days at visits 5, 6, 7, 8, and 9. Average weekly alcohol consumption and maximum weekly craving will be assessed every 7th day during the follow-up period, starting after visit 5 and continuing until visit 9, for patients who agree to use the study-specific app. Additionally, differences in neural brain activation during various stimuli presentations and fMRI paradigms will be evaluated from baseline to visit 5 for patients at the CIMH site.