Effect of Semaglutide on Cannabis Use in Adults With Cannabis Use Disorder

This is a randomized (1:1), double-blind, placebo-controlled clinical study investigating whether semaglutide reduces cannabis use. Participants will receive weekly injections of semaglutide or placebo for 20 weeks, with the primary endpoint assessed at the end of treatment. A follow-up visit will occur at week 46.

A total of 100 participants will be enrolled. Cannabis use and secondary outcomes will be measured at week 0, 6, 12, 20, and 46. Participants will also receive four sessions of supportive therapy.

Randomization and blinding: Injections will be administered by staff who are not involved in any other study procedures to maintain the double-blind setup.

Optional fMRI sub-study: Up to 50 eligible participants will undergo fMRI scans at baseline and week 20. Blood and urine samples will be collected for safety and secondary endpoints.

Inclusion criteria

• Informed oral and written consent.
• Meets the criteria for cannabis use disorder (CUD) according to DSM-5 or ICD-10.
• Currently seeking to cut down or stop cannabis use.
• Positive urine test for cannabinoids.
• Body mass index (BMI) ≥ 23 kg/m².
• Age 18-70 years.
• Recent frequent cannabis use, defined as use on ≥16 days out of the past 28 days.
• Cannabis use (smoked, vaped, edibles) equivalent to THC doses of ≥14 grams in the past 28 days before baseline.
• Ability to comply with study procedures and follow-up.

Exclusion criteria

• Currently meeting non-cannabis/tobacco substance use disorder (ICD-10 or DSM-5).
• Current or past diagnosis of severe psychiatric illness, defined as schizophrenia, bipolar disorder, or other psychoses, within the past five years.
• Suicide attempt or suicidal behavior within the past five years.
• Severe neurological disorders, including previous severe traumatic brain injury, stroke, or intracranial hemorrhage.
• Type 1 diabetes and type 2 diabetes.
• Pregnant or potentially pregnant women: Women of childbearing potential (WOCBP) who are pregnant, breastfeeding, planning to become pregnant within the next eight months (including 20 weeks of treatment plus two months after discontinuation of semaglutide), or not using effective contraception throughout the study period. Effective methods include combined hormonal contraception (oral, intravaginal, transdermal), progestogen-only hormonal contraception (oral, implant, injection), intrauterine device/system (IUD/IUS), bilateral tubal occlusion, partner with vasectomy, or sexual abstinence. WOCBP with a measured serum human chorionic gonadotropin (hCG) level >3 U/L at inclusion will also be excluded.
• Impaired liver function (liver transaminases >3 times the upper reference limit)
• Impaired renal function (eGFR <50 ml/min and/or plasma creatinine >150 µmol/L).
• Impaired pancreatic function (past or current acute or chronic pancreatitis and/or amylase >2 times the upper limit).
• History of medullary thyroid carcinoma (MTC) and/or family history of MTC and/or Multiple Endocrine Neoplasia type 2 (MEN 2).
• Heart disease is defined as decompensated heart failure (NYHA class III or IV), unstable angina pectoris, and/or myocardial infarction within the past 12 months.
• Uncontrolled hypertension (systolic blood pressure >180 mmHg, diastolic blood pressure >110 mmHg).
• Receipt of experimental medication within the past 30 days.
• Use of weight-loss medication within the past 3 months.
• Hypersensitivity to the active substance or any of the excipients.
• For patients undergoing brain scanning only:

Contraindications to MRI scanning (magnetic implants, pacemaker, claustrophobia, etc.).

• Inability to speak and/or understand Danish.
• Other conditions: Any other condition that, in the investigator's opinion, may interfere with participation in the trial.