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Buprenorphine treatment for opioid use disorder (OUD) is highly effective in decreasing opioid use, risk of opioid overdose, and death, but retention is challenging. Buprenorphine does not always eliminate illicit opioid use and craving and does not treat stimulant or other substance co-use, nor common comorbid sleep problems. Tirzepatide, a glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist, may help address substance use and sleep problems. The National Drug Abuse Treatment Clinical Trials Network (CTN) is conducting a 9-site outpatient, intent-to-treat, two-arm, double-blind, randomized controlled trial: Evaluation of Tirzepatide as an Adjunct to Buprenorphine for the treatment of OUD (TAB). The primary objective is to evaluate the effect of tirzepatide, relative to placebo, as an adjunct to buprenorphine on retention and on substance-related and sleep outcomes in adults with OUD. The primary outcome is 6-month buprenorphine treatment retention. The key secondary outcome is proportion of illicit opioid-negative urine samples over the 6-month treatment period. Approximately 310 adults with moderate-severe OUD who recently started buprenorphine will be recruited and randomized 1:1 to tirzepatide or placebo, balancing on site and buprenorphine formulation (transmucosal vs extended-release). Participants will be administered study medication, receive Fitbits to track sleep, and attend weekly research visits through 6 months post-randomization with longer research visits occurring at 1, 3, and 6 months. A follow-up visit at week 30 will collect final safety measures. This paper describes the rationale and study design for TAB, the first randomized trial to test tirzepatide for the treatment of OUD.

Related protocols: CTN-0152

Introduction: Increases in morbidity and mortality associated with stimulant use disorders (StUDs) combined with limited pharmacological research and development highlight the need to explore repurposing existing medications with mechanisms of action relevant to the management of StUDs. This paper presents findings regarding a common set of symptoms common across StUDs, impulsivity and compulsivity, that offer compelling rationale to identify future interventions for evaluation in CTN trials and elsewhere.

Methods: A virtual Task Force meeting held in 2024 by the National Drug Abuse Treatment Clinical Trials Network (CTN) assembled national experts to consider pharmacological and non-pharmacological candidates for repurposing in StUD treatment. Discussion centered on evidence regarding their mechanisms of action, preclinical and clinical evidence in StUD management, and how these interventions could be further researched or applied in clinical practice.

Results: Discussions referenced medications including: suvorexant, GLP-1 agonists, guanfacine, clavulanic acid, cariprazine, cannabidiol and psychedelics. Non-medication therapeutic strategies to consider for managing StUDs include novel neuromodulation techniques (low-intensity focused ultrasound (LIFU), photobiomodulation (tPBM)), which are believed to precisely and deeply penetrate brain tissues, targeting areas responsible for StUDs-related behaviors.

Task Force findings with high enthusiasm for possible consideration as candidate medication options for future research based on novel strategies for StUDs include suvorexant and GLP-1R agonists. Findings with less enthusiasm, but with evidence-based rationale include cariprazine, clavulanic acide, and guanfacine. Findings noted strong rationale for the promise of new neuromodulation therapies; constraints of their time-consuming nature over through multiple sessions across several weeks are challenges.

Discussion: Task Force findings provide guidance for a possible pipeline of candidate therapeutic options for future research on novel strategies for treatment of StUDs. A cross-cutting theme emerged in recognition of heterogeneous behavioral phenotypes presenting challenges to recovery, suggesting that beyond understanding the mechanism of action and efficacy of each therapeutic strategy, it is important to pursue personalized medicine approaches to improve outcomes for StUDs.