Methamphetamine use disorder is a major public health concern in Australia and globally. GLP-1 medications such as semaglutide (e.g. Ozempic) are approved for diabetes and medication, and may potentially affect craving for other substances apart from food. We do not know if this will help people who use methamphetamine ('ice') to reduce their use. This study will treat people who use methamphetamine with weekly injections of semaglutide. It will provide data on if this is a potentially safe and practical treatment for this group of people.

Methamphetamine use disorder is a major public health concern in Australia and globally, associated with high morbidity and limited treatment options. People with methamphetamine use disorder frequently face social marginalisation, psychiatric comorbidity, housing instability, and criminal justice involvement, contributing to poor treatment access and outcomes. At present, no pharmacotherapies have been approved for the treatment of methamphetamine use disorder. While several agents have demonstrated preliminary promise-including mirtazapine, which has shown consistent findings across trials-none have yet established sufficient efficacy to achieve regulatory approval. Ongoing registrational trials, such as those evaluating extended-release naltrexone combined with bupropion, and mirtazapine, may clarify the potential role of these agents in clinical practice.

Glucagon-like peptide-1 (GLP-1) receptor agonists, including semaglutide, are approved for diabetes and obesity and have central effects on reward pathways relevant to addiction. Preclinical studies show GLP-1 agonists reduce stimulant-related dopamine signalling and drug-seeking behaviour. Observational studies in humans suggest semaglutide may reduce risk of alcohol use disorder, hospitalisations related to substance use, and overdose, and a recent randomised controlled trial demonstrated reductions in cravings, and use of, alcohol and tobacco. However, no trials have yet evaluated semaglutide in methamphetamine use disorder. This pilot study will be the first to assess its feasibility, safety, and preliminary efficacy for methamphetamine use disorder.

Inclusion Criteria:

1. Has provided voluntary, written informed consent;
2. Aged 18 years or older;
3. Diagnosed with moderate to severe methamphetamine use disorder (DSM-5 criteria);
4. Self-reported methamphetamine use on at least 14 of past 28 days and a positive oral fluid drug screen for amphetamine/methamphetamine;
5. Willing and able to comply with study procedures and follow-up visits;
6. People of child-bearing potential must agree to use effective contraception during treatment and during the 60 days after treatment end.

Exclusion Criteria:

1. Uncontrolled medical or psychiatric conditions that may interfere with participation;
2. Body mass index less than 22 kg/m2;
3. Confirmed diagnosis of diabetes mellitus (either known history of diabetes; concomitant treatment with insulin, metformin, sulfonylureas, thiazolidinediones, SGLT2 inhibitor, DPP4 inhibitor; or HbA1c >6.5 at screening);
4. Currently taking a GLP-1 receptor agonist;
5. Known hypersensitivity or contraindications to GLP-1 receptor agonists as per product information;
6. Current enrolment in another interventional trial;
7. Lactating, pregnant or at risk of pregnancy not willing to avoid pregnancy
8. History of pancreatitis;
9. History of medullary thyroid cancer;
10. Current admission to a residential rehabilitation program or inpatient program or planned admission during the study period, which would interfere with participation in study visits or procedures;
11. Currently experiencing psychosis or current active suicidality
12. Any condition or circumstance that, in the opinion of the investigator, would compromise the participant's ability to comply with the study procedures, complete protocol requirements, or provide reliable data.