Glutide for Ending Methamphetamine - Project Summary/Abstract Methamphetamine use and toxicity has increased substantially over the past decade, with deaths attributed to methamphetamine toxicity, largely consisting of cardiovascular complications, increasing 9-fold from 2012- 2021. There remains no FDA-approved medication to treat methamphetamine use disorder (MeUD), notwithstanding decades of efforts. Moreover, most experts now feel that a combination of agents will be required to effectively treat MeUD, addressing multiple neurotransmitter systems simultaneously. While many agents that have shown promise are anti-depressant medications, GLP-1 agents have significant potential promise and an entirely distinct mechanism of action. GLP-1 agonists, and semaglutide in particular, have demonstrated a marked ability to reduce craving for people with substance use disorders. Craving is a major component of MeUD and reducing this component may have a significant impact on methamphetamine use. Some concerns exist in the use of GLP-1 agonists in this population, most notably the weight loss induced by GLP-1 agonists, given the fact that some people with MeUD are significantly underweight. However, this weight loss may be a benefit for the substantial proportion of people with MeUD whose methamphetamine use is at least partially driven by weight loss or weight control benefits. Abstention from methamphetamine use is associated with substantial weight gain, which may be prevented by GLP-1 agonist treatment. We propose a two-phase study of semaglutide for MeUD. In the first phase, we will conduct an open-label single-arm Phase IIa trial of semaglutide for MeUD. If the eligible:enrollment ratio, medication adherence, and willingness to continue therapy meet prespecified levels, and there is evidence of reduced methamphetamine use, we will proceed to a Phase IIb placebo-controlled randomized trial of semaglutide versus placebo to determine the efficacy of this medication in achieving a clinically-meaningful reduction in methamphetamine use. These studies will be done under FDA IND, in order to allow for potential future studies that could lead to a new indication for semaglutide as the first medication approved for MeUD.
