Commentary on Qeadan <i>et al</i> .: Leveraging opportunities to expand the substance use disorder treatment arsenal

While awaiting randomized controlled trial results, analyses of electronic heath record data can further our understanding of the effectiveness glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonists for substance use disorders without medication treatment options, such as cannabis and stimulant use disorders. Many efficacious behavioral and medication treatments exist for substance use disorders (SUDs), but these treatments often have important limitations. Behavioral options that include cognitive–behavioral therapy and contingency management can effectively treat a variety of SUDs [1, 2], but these interventions are limited by their expense, availability of trained clinicians and the motivation and time commitment required of those seeking treatment [3, 4]. SUD medications are similarly impacted by access, cost and motivational barriers [3], with further structural barriers in some countries [5, 6] resulting from unique concerns about the potential for misuse or diversion of highly effective opioid agonist treatments [7]. Along with these limitations, many individuals with SUD may not benefit from a specific treatment, highlighting the need for ongoing medication and behavioral therapy development. Qeadan et al. [8] provide intriguing evidence that glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonists are linked to reduced incidence of alcohol intoxication and opioid overdose in individuals with alcohol use disorder or opioid use disorder, respectively. Using electronic health record (EHR) data from a US sample, they found a 50% reduction in the incidence of medical visits for alcohol intoxication and a 40% reduction in the incidence of opioid overdose. When combined with animal evidence [9] and emerging but more mixed evidence from human experimental and observational studies [10-12], Qeadan et al.’s [8] methodological perspective strengthens the case for double-blind, randomized controlled trials (RCTs) to evaluate the effectiveness of these medications for SUD. Indeed, the diverse sets of methodologies and samples that support effectiveness of GIP and GLP-1 receptor agonists further increase the case for RCTs, and addictions research needs these diverse methodological perspectives to truly understand the causes and develop treatments for SUD. Medication treatment options for alcohol, nicotine/tobacco and opioid use disorders or dependence may be limited for reasons noted above, but at least such options exist. This is not the case for stimulant and cannabis use disorders, where no approved medications are available [13-15]. Thus, a clear direction for future research is to test the efficacy of GIP and GLP-1 receptor agonists for treatment of psychostimulant and cannabis use disorders. While the ultimate standard will be the effectiveness of these medications in double-blind RCTs, researchers should also consider using available administrative data such as Qeadan et al. [8] to evaluate outcomes for stimulant and cannabis use disorders. Together with animal studies and re-analysis of existing human study data, rapid evaluation of EHR data can motivate and inform design of RCTs that will ultimately determine utility of these medications for cannabis, stimulant and other SUDs. In addition to evaluations of GLP-1 and GIP-1 agonists for stimulant and cannabis use disorders using EHR data, administrative data sets offer a rich opportunity to evaluate other medications for reuse as treatments for SUDs. In the past, only very perceptive clinicians and researchers could identify promising medications for repurposing to treat SUD, but with exponential increases in computing power and newer machine-learning and artificial intelligence methods, opportunities exist for large-scale exploratory investigations that identify promising medication candidates for later hypothesis-driven evaluation. Ultimately, caution is needed when approaching use of GIP and GLP-1 receptor agonists for SUD, as Leggio et al. [16] have highlighted. Regulatory approval is a necessary step before any use of these medications for SUD [16], but in the meantime use of existing data to investigate their utility for stimulant and cannabis use treatment and exploration of large data for other potential therapies for SUD should move forward to advance the scope of treatment options for SUD. Ty S. Schepis: Conceptualization; funding acquisition; writing - original draft. This article was funded by the US Department of Health and Human Services, the National Institutes of Health, and the National Institute on Drug Abuse (R01DA043691). T.S.S. receives research support from the US National Institute on Drug Abuse, the US Substance Abuse and Mental Health Services Administration and the US Food and Drug Administration.