Inclusion Criteria:
* Ability to provide informed consent before any study-related activity, willing to comply with all study procedures, and be available for the duration of the study.
* Meet Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM 5) diagnostic criteria for CUD and report recent cocaine use (verified by at least one positive urine drug screen (UDS) for the cocaine metabolite benzoylecgonine (BE), during intake).
* Have body mass index (BMI) of ≥25 kg/m2
* Agree (if the participant is female and of child-bearing potential) to use effective contraceptive methods, unless the participant's male partner(s) is surgically sterile (underwent vasectomy). Acceptable contraceptives include oral contraceptives, contraceptive sponge, patch, double barrier (diaphragm/spermicidal or condom/spermicidal), intrauterine contraceptive system, etonogestrel implant, medroxyprogesterone acetate contraceptive injection, complete abstinence from sexual intercourse, and/or hormonal vaginal ring. Contraceptive measures sold for emergency use after unprotected sex are not acceptable methods for routine use. Women of child-bearing potential must provide negative urine pregnancy test prior to randomization. Note: A woman is considered fertile (of childbearing potential) following menarche and until becoming postmenopausal unless permanently sterile. Women in the following categories are not considered a woman of childbearing potential: premenarcheal, premenopausal female with one of the following: documented hysterectomy, documented bilateral salpingectomy, documented bilateral oophorectomy. Postmenopausal female is defined as no menses for 12 months without an alternative medical cause. Females on HRT and whose menopausal status is in doubt will be required to use one of the nonhormonal highly effective contraception methods if they wish to continue their hormone replacement therapy (HRT) during the trial.
* Have a medical and psychiatric history and a brief physical examination demonstrating no clinically significant contraindications for study participation, in the judgment of the Study Physician and the Principal Investigator.
* Be able to provide the names of at least 2 persons who can consistently locate their whereabouts.
Exclusion Criteria:
Medical Exclusions
* Personal or first-degree relative(s) history of medullary thyroid carcinoma (MTC) or multiple endocrine neoplasia syndrome type 2 (MEN 2).
* History or presence of chronic pancreatitis or recent acute pancreatitis.
* Type 1 or type 2 diabetes mellitus (previously diagnosed or indicated by HbA1C ≥48 mol/mol (6.5%) as measured at screening).
* Severe gastrointestinal disease (i.e., severe gastroparesis).
* History of malignant neoplasms within the past 5 years prior to screening. Basal and squamous cell skin cancer and any carcinoma in-situ are allowed.
* History of severe cardiovascular disease.
* History of retinopathy.
* Systolic blood pressure (SBP) \>180 mmHg and/or diastolic blood pressure (DBP) \>105 mmHg)
* End stage renal disease (ESRD, previously diagnosed or indicated by estimated glomerular filtration rate (eGFR) value of eGFR \< 15 ml/min/1.73 m2 at screening).
* Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥3 times the upper limit of normal range at screening.
* Known or suspected hypersensitivity to semaglutide, excipients, or related products.
* History of seizure or elevated risk of seizure.
* Women who are currently pregnant, or plan to become pregnant, or lactating, or of childbearing potential and are not using medically accepted forms of contraception
* Have any medical illness or condition which in the opinion of the PI and/or the Study Physician would preclude safe and/or successful completion of the study.
* Any foreseeable procedure requiring general anesthesia or deep sedation.
Psychiatric/Substance Use Exclusions
* Current ≥ moderate substance use disorder aside from alcohol, nicotine, or marijuana, or a Substance Use Disorder (SUD) requiring medical detoxification (e.g., alcohol, opioid, benzodiazepine)
* Current or recent suicidal ideation.
* Homicidal ideation that requires immediate attention.
* Have any psychiatric illness or condition which in the opinion of the PI and/or the Study Physician would preclude safe and/or successful completion of the study.
Weight-Related Exclusions
* Gained/lost ≥4.5 kg (10 lb.) over the past 6 months (prior to screening).
* Uncontrolled thyroid disease at screening
Medication-Related Exclusions
* Currently using sincalide, sulfonylureas, insulin and insulin products, or medication used for weight management (i.e., orlistat, naltrexone-bupropion, liraglutide, semaglutide, tirzepatide, phentermine, topiramate, benzphetamine, diethylpropion, phendimetrazine).
* Any otherwise not specified concomitant medication that could compromise participant safety or treatment in the opinion of the Study Physician and/or the PIs.
General Exclusions
* Current, anticipated, or pending enrollment in another addiction treatment program and/or research study that could potentially affect participant safety and/or the study data/design as determined by the Principal Investigator and/or Study Physician.
* Not planning to live in the area for the duration of the trial.
* Surgery scheduled for the duration of the trial, except for minor surgical procedures, in the opinion of the PI and/or the Study Physician.
* Unable to communicate (read, write, and speak) fluently in English.
