Semaglutide for the Treatment of Cannabis Use Disorder

• semaglutide (Drug): All participants will receive open-label semaglutide for 8 weeks. Semaglutide will be self-administered as a once-weekly subcutaneous injection according to standard clinical titration procedures to maximize tolerability and minimize gastrointestinal side effects. Subjects may receive their first injection during an in-person study visit, during which study staff will provide instruction on proper injection technique and answer any questions. Participants will initiate treatment at 0.25 mg weekly for Weeks 1-4 and increase to 0.5 mg weekly for Weeks 5-8, consistent with FDA-approved dosing recommendations. Importantly, the study is not designed to promote weight loss, and weight-related outcomes are monitored solely for safety.

Primary outcomes

• Cannabis cue-reactivity [Baseline (pre-intervention), 8 weeks]: Investigators will measure brain reactivity to smoking vs. neutral images. A whole-brain fixed-effects general linear model (GLM) will be run using image regressors (cannabis, neutral images) and motion confound regressors. The 2-gamma hemodynamic response function will be convolved with square waves defined by the onset-offset of each image presentation. Beta maps comparing smoking with neutral images will be created for each subject. Multiple comparisons will be FDR corrected. Additionally, beta weights for the cannabis image > neutral image contrasts will be extracted from the anterior insula, dACC, DLPFC, and amygdala across all voxels within each ROI.
• Resting state connectivity [Baseline (pre-intervention), 8 weeks]: To evaluate connectivity between the insula and dorsal anterior cingulate cortex (dACC; ROIs) investigators will use techniques comparable to published work and preliminary data. Given the investigator's focus on large scale networks, static connectivity patterns of the DMN, SN, and FPN will be compared between visits as a secondary exploratory analysis. These methods will overlap with prior work where ICA was used to evaluate resting networks. The investigators will also determine if the change in coupling at rest relates to the change in brain reactivity to cannabis cues using a linear regression.

Sex: All, ages: 18 Years to 60 Years

Inclusion Criteria:

* Adults aged 18-60 years, inclusive;
* Use cannabis daily or near daily and have been using cannabis consistently for at least the past year, by self-report;
* Diagnosed with moderate to severe DSM-5 cannabis use disorder
* Access to a mobile device to complete daily surveys
* Desire to quit or reduce cannabis consumption
* Be able to read, speak, and understand the English language. English can be a second language provided that the subject understands all the questions used in the assessment measures.

Exclusion Criteria:

* Active psychosis, active suicidality (current suicidal ideation with specific plan or intent) or homicidality, suicide attempt or psychiatric hospitalization in the past year, or any psychiatric condition that may impair ability to provide informed consent.
* Any current or lifetime diagnosis of eating disorders including anorexia, bulimia, or binge eating;
* Any current substance use disorder other than cannabis or mild alcohol use disorder;
* BMI <21 kg/m2;
* MRI contraindications (including presence of metallic foreign bodies such as cardiac pacemakers, perfusion pumps, aneurysm clips, metallic tattoos anywhere on the body, tattoos near the eye);
* Current or lifetime diagnosis of Type 1 or Type 2 diabetes;
* Personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2;
* Use of any GLP-1 agonist medications in the prior 3 months;
* Anticipating use of any other GLP-1 agonist medications during the trial;
* Current hypoglycemia as indicated by a blood sugar level of <71 mg/dL measured at baseline visit;
* Untreated cholelithiasis or gallbladder disease;
* History of acute myocardial infarction, cerebrovascular accident (stroke), unstable angina, or congestive heart failure in the last year;
* Systolic blood pressure persistently above 160mmHg or diastolic blood pressure persistently above 100mmHg during screening;
* History of inflammatory bowel disease, bariatric surgery, pancreatitis, diabetic gastroparesis, or non-arteritic anterior ischemic optic neuropathy;
* Liver function test greater than 3 times upper normal limit at baseline;
* Renal impairment as indicated by eGFR of <30;
* History of hypersensitivity or allergy to semaglutide;
* Pregnant or breastfeeding;
* Currently taking GLP-1 agonists or other weight loss drugs;
* Anticipated to participate in a concurrent drug trial;
* Anticipating to undergo elective surgeries or procedure requiring general anesthesia during duration of the study;
* Any other reason or clinical condition that the investigators judge may interfere with study participation and/or be unsafe for a participant.

• Jodi Gilman, PhD, Principal investigator, Massachusetts General Hospital