A Phase II randomized clinical trial will test whether adding semaglutide to standard opioid addiction treatment can increase abstinence and reduce cravings in 200 patients with treatment-resistant opioid use disorder.
200-patient Phase II RCTFirst randomized, placebo-controlled trial testing semaglutide for opioid abstinence in outpatient addiction treatment patients
What the researchers found
This is a clinical trial protocol — no results are reported yet. The study design is:
- Phase II randomized, double-blind, placebo-controlled trial
- 200 participants with treatment-refractory OUD (100 on buprenorphine, 100 on methadone)
- Intervention: semaglutide (GLP-1 RA) vs. placebo added to existing MOUD
- Primary outcomes: probability of opioid abstinence, craving measures, days of drug use
- Assessment: urine toxicology screens and self-report across 19 weeks (12 treatment weeks + washout + follow-up)
- Registered: ClinicalTrials.gov NCT06548490
Why it matters
The opioid crisis has killed hundreds of thousands of people, and existing treatments for opioid addiction — while helpful — have high relapse rates, especially in treatment-resistant cases. If semaglutide can reduce opioid cravings through GLP-1 receptor pathways in the brain's reward system, it would represent an entirely new class of addiction medication — one that doesn't act on opioid receptors and could complement existing treatments.
How the study worked
Randomized, double-blind, placebo-controlled clinical trial. Participants are 200 adults enrolled in outpatient medication for opioid use disorder (MOUD) programs — split evenly between buprenorphine and methadone patients. After screening (week 1), participants receive 12 weeks of semaglutide or placebo (weeks 2-13), followed by a washout visit (week 14) and final follow-up (week 19). Outcomes assessed via urine drug screens and self-report measures.
What this study cannot tell us
This is a protocol paper — no results are available. The study is Phase II with 200 participants, which may not be large enough to detect modest effect sizes. The 12-week treatment duration is relatively short for evaluating sustained abstinence. The preprint (Research Square) has not been peer-reviewed. Generalizability may be limited to outpatient MOUD populations.
How to read the evidence
This is a clinical trial protocol — it describes the study design but reports no results. The trial design (randomized, double-blind, placebo-controlled) is rigorous, and results when published will provide strong evidence.
When this study was published
Published as a preprint in 2025, with the trial registered in August 2024. Results are expected after the trial completes enrollment and follow-up.
The bigger picture
The potential of GLP-1 drugs for addiction is one of the most exciting emerging areas in neuropharmacology. GLP-1 receptors are expressed in brain reward circuits, and animal studies have shown that GLP-1 agonists reduce consumption of alcohol, nicotine, and opioids. Epidemiological data from patients taking GLP-1 drugs for diabetes have also suggested lower rates of substance use. This trial represents the critical step of rigorous human testing of this hypothesis.
Questions still open
- Does semaglutide reduce opioid cravings through the same brain reward pathways that mediate its effects on food intake?
- Will the anti-craving effects persist during the washout period after semaglutide is discontinued?
- Could GLP-1 drugs eventually become a standard add-on to methadone or buprenorphine programs for treatment-resistant patients?
Common questions
Why might a weight loss drug help with opioid addiction?
What does 'treatment-refractory' opioid use disorder mean?
Read the original research
Efficacy of the GLP-1 receptor agonist, semaglutide, in abstinence from illicit and nonprescribed opioids in an outpatient population with treatment-refractory OUD: A randomized, double-blind, placebo-controlled clinical trial protocol.
Research square
Citation
Freet, Christopher S; Shuler, Kirsten; Kawasaki, Sarah; Weintraub, Eric; Greenblatt, Aaron; Kladney, Mat; Nunes, Edward; Foster, Katrina L; Kong, Lan; Raja-Khan, Nazia; Cleveland, H Harrington; Grigson, Patricia S; Bunce, Scott C; Brick, Timothy R; Nyland, Jennifer E. (2025). Efficacy of the GLP-1 receptor agonist, semaglutide, in abstinence from illicit and nonprescribed opioids in an outpatient population with treatment-refractory OUD: A randomized, double-blind, placebo-controlled clinical trial protocol.. Research square. https://doi.org/10.21203/rs.3.rs-6666196/v1