Efficacy of Semaglutide versus Placebo in Reducing Cannabis Consumption in Adults with Cannabis Use Disorder: A Randomized, Double-Blind, Placebo-Controlled Trial

The primary objective is to evaluate the efficacy of semaglutide 2.4 mg administered via subcutaneous injection in reducing total cannabis consumption in adults diagnosed with cannabis use disorder. This investigation compares the therapeutic effect of the active substance against a placebo.

The sponsor did not provide information regarding the total number of participants. The study population consists of male and female adults, aged 18 to 70 years, diagnosed with Cannabis Use Disorder according to DSM-5 or ICD-10 criteria. Eligible participants must have a body mass index of at least 23 kg/m² and demonstrate recent frequent cannabis use, defined as use on 16 or more days within the previous 28 days. Inclusion requires a positive urine test for cannabinoids and a history of cannabis consumption, including smoking, vaping, or edibles, equivalent to THC doses of 14 grams or more in the 28 days preceding baseline. Participants must be actively seeking to reduce or cease cannabis consumption.

This phase 4, randomized, double-blind, placebo-controlled trial is designed to evaluate the efficacy of semaglutide in reducing cannabis consumption in adults diagnosed with cannabis use disorder. Participants are assigned to receive either escalating doses of semaglutide via subcutaneous injection or a placebo consisting of sodium chloride solution. The study protocol begins with a screening visit to assess eligibility based on criteria such as body mass index, age, and recent cannabis use frequency. Following baseline assessments, the treatment period lasts for 20 weeks. During this time, the primary objective is to measure the reduction in total cannabis intake. Secondary endpoints include assessments of THC concentrations, sleep quality, and various clinical scales. The study involvement concludes with an end-of-study visit after the 20-week treatment duration. The total duration of the trial, including recruitment, is estimated to span from March 2026 to March 2028.

The experimental treatment consists of semaglutide, provided as a solution for injection in a pre-filled pen. The investigation utilizes various strengths, including 0.25 mg, 0.5 mg, 1 mg, 1.7 mg, and 2.4 mg, to be administered via subcutaneous injection at a dose of 2.4 mg.

The control group receives a placebo consisting of sodium chloride, formulated as a solution for infusion. This substance is administered via subcutaneous injection at a volume of 0.5 ml.

The primary efficacy endpoint is the reduction in total cannabis intake in grams over the preceding 28 days, assessed using the Timeline Follow-Back (TLFB) method after 20 weeks of treatment and adjusted for baseline. Secondary endpoints evaluated through Week 20 include changes in cannabis-free days via self-reported TLFB and changes in total THC consumption measured in standard units using the Enhanced Cannabis Timeline Follow-Back (EC-TLFB).

Clinical assessments include changes in various validated scales: Cannabis Use Disorder Identification Test – Revised (CUDIT-R), Marijuana Problem Scale (MPS), Marijuana Craving Questionnaire – Short Form (MCQ-SF), Patient Health Questionnaire-9 (PHQ-9), Pittsburgh Sleep Quality Index (PSQI), Alcohol Use Disorders Identification Test (AUDIT), Drug Use Disorders Identification Test (DUDIT/DUDIT-ED), Fagerström Test for Nicotine Dependence, and World Health Organization Quality of Life – BREF (WHOQOL-BREF).

Biological and physiological parameters measured from baseline to Week 20 include:

• Plasma and urine concentrations of Δ9-THC and its metabolites, such as THC-COOH.
• Blood cotinine levels.
• HbA1c.
• Blood pressure and pulse.
• Body weight percent change and waist circumference.
• Mean daily cigarette consumption.
• fMRI cue reactivity and resting-state fMRI connectivity.