The purpose of this study is to evaluate semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA), in combination with cognitive behavioral therapy (CBT) for the treatment of cocaine use disorder (CUD). This project is part of the NIH Helping to End Addiction Long-term (HEAL) initiative (https://heal.nih.gov/).

The United States is facing a resurgence in cocaine use and cocaine-related mortality. Despite the significant public health burden, there are no FDA-approved pharmacotherapies for CUD, and existing behavioral interventions, such as cognitive behavioral therapy (CBT), demonstrate only modest efficacy when used alone. Identifying pharmacological agents that can enhance the effectiveness of behavioral treatments remains a critical public health priority.

One particularly promising class of medications for CUD is glucagon-like peptide-1 receptor agonists (GLP-1RA). These agents are widely used to treat type 2 diabetes and obesity due to their ability to regulate blood glucose and support metabolic health. Importantly, GLP-1 receptors are expressed in brain regions involved in reward processing and hedonic behavior. Consistent with this, animal studies have shown that GLP-1RAs reduce the rewarding and reinforcing effects of various addictive substances, including cocaine. If similar effects are observed in humans, GLP-1RAs may improve treatment outcomes by directly reducing the motivational salience of cocaine and its cues, and/or by enhancing responsiveness to behavioral therapies such as CBT.

The primary objective of this trial is to provide proof-of-concept evidence for the use of a GLP-1RA semaglutide as a treatment for CUD. The study hypothesizes that semaglutide will modulate three key reward-related target mechanisms underlying cocaine use: (1) motivational relevance of cocaine cues, assessed via event-related potentials (ERPs); (2) cocaine valuation, measured by behavioral economic demand for cocaine; and (3) subjective experience of craving. These mechanisms will be evaluated using a multimodal approach - neurophysiological, behavioral, and self-report- within a framework of a randomized clinical trial. In addition to assessing changes in the proposed target mechanisms, the study will evaluate the impact of semaglutide on cocaine use.

This project addresses the urgent need to explore novel pharmacological targets using an experimental therapeutics framework and has the potential to accelerate the development of effective treatments for CUD. If successful, the findings will support a fully powered efficacy trial.

Study data will be submitted to a HEAL Initiative-approved repository within the HEAL Data Ecosystem (NIDA Data Share), in accordance with NIH and HEAL initiative data-sharing requirements. Persistent identifiers, seeded with essential project metadata, will be generated. These identifiers with associated project metadata will be made publicly available. The data will be available at the time of publication or at the end of the project period. The data submission and release timeframes will be specified by the funding agency and policies, as described on NIH's data sharing webpage. Study data will be available to the research community for the duration required by NIDA's retention policies.

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.