Protocol published for a randomized semaglutide trial in opioid use disorder

Researchers have published the design of a randomized, double-blind, placebo-controlled clinical trial that will test whether semaglutide, the GLP-1 receptor agonist used in Ozempic and Wegovy, can help outpatients with opioid use disorder (OUD) stop using illicit and non-prescribed opioids. The protocol appeared October 30, 2025, in Addiction Science & Clinical Practice and is registered on ClinicalTrials.gov as NCT06548490, first listed August 12, 2024.^[1]

The trial will enroll 200 people already being treated for OUD in outpatient programs — 100 on buprenorphine and 100 on methadone — who continue to use non-prescribed opioids despite that treatment. Participants will be randomly assigned to receive semaglutide or a placebo alongside their existing medication. The study runs 19 weeks: a screening visit in week 1, 12 treatment visits from weeks 2 through 13, a washout visit in week 14, and a final follow-up visit in week 19. Researchers will measure abstinence from illicit and non-prescribed opioids using urine toxicology screens along with self-reported craving and days of drug use.^[1]

In the United States, only three medications are approved for OUD: buprenorphine, methadone, and naltrexone. While these treatments work better than no treatment or behavioral therapy alone, many patients still relapse or drop out of care, and continued opioid use raises the risk of overdose. Other approaches used elsewhere, such as slow-release oral morphine or injectable opioid agonist treatment available in parts of Canada and Europe, are barred in the U.S. under the Controlled Substances Act. That gap has driven interest in non-opioid options like GLP-1 receptor agonists.^[1]

The rationale draws on how GLP-1 works in the brain. GLP-1 is a hormone made in the gut that reduces food intake, and it is also produced in a brainstem region called the nucleus of the solitary tract, which sends signals to areas involved in reward, including the ventral tegmental area and nucleus accumbens. Earlier controlled trials have tested GLP-1 drugs for other addictions. A study of exenatide in people with alcohol dependence showed reduced brain reactivity to alcohol cues on imaging, but did not significantly reduce heavy drinking days overall, except in a subgroup with higher body mass. A separate trial of semaglutide in alcohol use disorder found reductions in alcohol consumed during a lab task, fewer drinks per drinking day, and less craving.^[1] No controlled trial has yet tested a GLP-1 drug for opioid abstinence in an outpatient population, according to the protocol authors, though observational research has suggested these drugs may lower craving in people with OUD in residential settings.^[1]

Why it matters for patients

This is a study design, not a result — no data on whether semaglutide helps with opioid abstinence exist yet from this trial. For the roughly one in three patients on standard OUD medications who continue using illicit opioids, an add-on treatment that reduces craving could matter, but its effectiveness and safety in this context are unproven. People currently on buprenorphine or methadone should know that any future use of semaglutide for OUD would be an experimental addition, not a replacement for approved medications, and this protocol does not change current treatment guidelines.^[1]

What happens next

The trial was registered on ClinicalTrials.gov on August 12, 2024, and the protocol was published October 30, 2025. The authors describe this as a phase II study intended to establish feasibility for a larger phase III trial. No results, completion date, or estimated enrollment timeline are given in this protocol publication.^[1]