Abstract

Introduction: Cocaine use disorder (CUD) is a significant public health concern in the USA, with considerable prevalence and mortality and no FDA-approved pharmacotherapies. Recent advances in addiction science emphasise the need for novel, mechanism-based treatments. Glucagon-like peptide-1 receptor agonists, such as semaglutide, have shown promise in modulating reward-related behaviours and may offer therapeutic benefits for CUD. The authors present a study protocol evaluating semaglutide, as an adjunct to cognitive behavioural therapy (CBT), as a novel approach for treating CUD.

Methods and analysis: This is a randomised, double-blind, placebo-controlled trial enrolling 75 treatment-seeking adults with CUD. Participants will be randomised 1:1 to receive either once-weekly semaglutide (0.25 to 1.0 mg) or placebo injections over 14 weeks, alongside weekly individual CBT. Primary outcomes include changes in neurophysiological reactivity to drug-related and non-drug-related motivationally relevant cues (late positive potential), behavioural economics (cocaine demand), craving (Cocaine Craving Questionnaire), and cocaine use (self-report, urine drug screens). Exploratory aims assess associations between mechanistic changes and cocaine use, consumption of other substances (tobacco, alcohol, and cannabis), and dose-response relationships. Data will be analysed using Bayesian statistical methods using an intention-to-treat approach.

Ethics and dissemination: The study has been approved by the UTHealth Committee for the Protection of Human Subjects (HSC-MS-25-0412) and is registered on ClinicalTrials.gov (NCT07227948). All participants will provide written informed consent. Findings will be disseminated through peer-reviewed publications and scientific conferences.

Study at a Glance

Study Snapshot

Study Facts

What Researchers Actually Did

The UTHealth Center for Neurobehavioral Research on Addiction team designed a 14-week randomized, double-blind, placebo-controlled trial enrolling 75 treatment-seeking adults who meet DSM-5 criteria for cocaine use disorder, require a BMI of at least 25 kg/m², and confirm recent cocaine use with at least one positive urine drug screen at intake. Participants are allocated 1:1 via urn randomization — stratified on baseline cocaine use severity, sex, and concurrent use of tobacco, alcohol, or cannabis — to receive either once-weekly subcutaneous semaglutide (Ozempic) or volume-matched sterile saline placebo. Semaglutide is titrated from 0.25 mg/week (weeks 1-4) to 0.5 mg/week (weeks 5-8) to 1.0 mg/week (weeks 9-14), stopping short of the 2.4 mg weight-management dose. All participants simultaneously receive weekly one-hour individual cognitive behavioral therapy. Blinding is maintained through participant blindfolding during each injection, administered by a dedicated unblinded study nurse not involved in data collection.

The primary mechanistic outcomes, assessed at baseline, week 5, week 9, and end-of-treatment (week 15), include: (1) late positive potential amplitude measured by 64-channel EEG during a passive image-viewing paradigm contrasting cocaine-related, pleasant, unpleasant, and neutral stimuli; (2) cocaine demand indices derived from the hypothetical Cocaine Purchasing Task, fitted to an exponentiated demand model; and (3) Cocaine Craving Questionnaire scores. The primary clinical outcome is the proportion of cocaine-negative urine drug screens during the final two weeks of treatment. All analyses follow Bayesian intention-to-treat principles, with a posterior probability exceeding 0.70 in favor of semaglutide set as the go/no-go threshold for advancing to a larger confirmatory trial.

Key Findings: Primary Outcomes

• Hypothesis 1a (LPP): Semaglutide, compared to placebo, is hypothesized to attenuate event-related potential (LPP) reactivity specific to cocaine-related stimuli at end-of-treatment (week 15). The primary outcome is the LPP relative amplitude difference between non-drug pleasant images and cocaine images.
• Hypothesis 1b (Cocaine Demand): Semaglutide is hypothesized to reduce motivation to purchase and consume cocaine as measured by Cocaine Purchasing Task demand indices (Q₀, essential value, O_max, P_max, breakpoint) at week 15.
• Hypothesis 1c (Craving): Semaglutide is hypothesized to reduce Cocaine Craving Questionnaire scores at week 15.
• Hypothesis 2 (Cocaine Use): Semaglutide is hypothesized to increase the proportion of cocaine-negative urine drug screens during weeks 13-14. The authors specify that a minimum absolute difference of 10 percentage points favoring semaglutide would constitute a clinically meaningful effect, referenced against a baseline transition rate of 20.9% in 13 RCTs of pharmacological CUD interventions.
• Statistical threshold: A Bayesian posterior probability greater than 0.70 that an effect exists favoring semaglutide constitutes the predefined go signal for a larger confirmatory trial.

Key Findings: Secondary Outcomes and Exploratory Aims

As prespecified in the protocol, the following secondary and exploratory analyses are planned:

• Secondary outcome (treatment response): Proportion of participants achieving at least 3 cocaine-negative urine drug screens out of 4 samples collected during weeks 13-14, analyzed as a dichotomous variable.
• Exploratory Aim 3 (Mechanistic mediation): Association between longitudinal changes in LPP, cocaine demand, and craving (modeled at weeks 5, 9, and 15) and cocaine use outcomes at weeks 13-14, using generalized linear mixed models with participant-level random effects.
• Exploratory Aim 4 (Polysubstance effects): Effects of semaglutide on frequency of tobacco, alcohol, and cannabis use (Timeline Followback self-report), plus subjective effects assessed by validated questionnaires for each substance. Food craving will be assessed with the Food-Craving Inventory and the Reward-based Eating Drive scale.
• Exploratory Aim 5 (Dose-response): Longitudinal models will evaluate primary outcomes as a function of time and semaglutide dose as a time-varying covariate across the three dose phases, to inform dosing strategy for future trials.

No subgroup efficacy analyses by demographic or clinical characteristics are prespecified for the primary aims, consistent with the sample size and proof-of-concept framing of the trial.

Adverse Events and Safety Profile

No trial-derived adverse event data are available, as this is a protocol publication. The safety monitoring plan is detailed and includes:

• Vital signs and body weight at every visit; fingerstick blood glucose prior to each dose
• Twice-weekly urine drug screens and twice-weekly clinic visits throughout treatment
• Columbia Suicide Severity Rating Scale and Patient Health Questionnaire-9 at each treatment visit
• Adverse event and serious adverse event reporting to the IRB, NIDA, and the FDA for events deemed serious
• Prespecified medication discontinuation criteria: suspected pancreatitis, excessive weight loss, pregnancy or intent to become pregnant, suicidal thoughts or behavior, or any safety concern at investigator discretion
• An independent Data Safety and Monitoring Board (two physicians, one psychologist, one biostatistician) conducting annual reviews with provision for emergency sessions

The known class-effect safety profile of semaglutide includes gastrointestinal symptoms (nausea, vomiting, diarrhea, constipation, abdominal cramps), with the package insert warnings encompassing acute pancreatitis, diabetic retinopathy complications, hypoglycemia risk with concomitant insulin secretagogue or insulin, acute kidney injury from volume depletion, severe gastrointestinal adverse reactions, hypersensitivity reactions, acute gallbladder disease, and pulmonary aspiration under general anesthesia or deep sedation. Multiple exclusion criteria directly address these risks.

Statistical Approach and Rigor

The analysis plan is methodologically sophisticated. All primary and secondary analyses use Bayesian generalized linear models (GLMs), with multilevel extensions for repeated-measure outcomes. Rather than frequentist p-value thresholds, inference centers on posterior probability distributions, and a posterior probability greater than 0.70 favoring semaglutide is the prespecified go/no-go decision rule, consistent with thresholds used in prior substance use disorder medication trials cited by the authors. Weakly informative neutral priors are specified (normal with mean 0, SD ≈100 for continuous outcomes; normal with mean 0, SD 0.56 in log-form for discrete outcomes), which the authors describe as producing conservative, regularized estimates. Missing data are handled via joint modeling robust to MCAR and MAR missingness, with pattern-mixture modeling for non-ignorable dropout. Software is specified (R 4.2.1, Stan 2.30, rstanarm, brms). Power calculations are based on 1,000 Monte Carlo simulations calibrated to effect sizes drawn from referenced prior studies in CUD treatment. Urn randomization stratified on three variables limits chance imbalance on prognostic factors.

One candid methodological note: because this is explicitly a proof-of-concept trial, the go/no-go posterior probability threshold of 0.70 is lower than the 0.95 (or 95% credible interval excluding null) that would be required for definitive inference. The authors acknowledge this directly, framing it as appropriate for the phase IIa purpose of detecting a signal rather than confirming efficacy. The sample size of 75 is powered for this threshold, not for definitive between-group conclusions.

Clinical Takeaway

For the busy clinician, the operational fact is this: there remains no FDA-approved medication for cocaine use disorder as of this writing, and cocaine-related overdose deaths have risen more than fourfold over the past eight years. This trial protocol does not provide new efficacy data, but it establishes a rigorous, well-funded infrastructure to test whether semaglutide’s demonstrated capacity to modulate reward signaling in preclinical cocaine models and its epidemiological association with reduced stimulant use disorder risk in a VA database population translates into a meaningful clinical signal. The 1.0 mg target dose, the mechanistic outcome battery (EEG, behavioral economics, craving), and the Bayesian analytic framework are defensible design choices. Results are not expected until 2029. Until then, prescribing semaglutide off-label for cocaine use disorder is not supported by clinical trial evidence.