The Effects of Orexin Receptor Antagonism During Early Withdrawal in Stimulant Use Disorder: Protocol for a Proof-of-Concept Study

Abstract Background Stimulant use disorders (StimUDs), including cocaine and methamphetamine use disorders, remain a major public health concern in the United States with no US Food and Drug Administration (FDA)–approved pharmacological treatments. The early recovery period following stimulant use is marked by sleep disturbances, heightened stress reactivity, and dysregulated reward processing, contributing to high rates of resumption of use. Evidence from animal and human studies supports the orexin neuropeptide system as a promising therapeutic target for minimizing these disruptive mechanisms. Suvorexant, an FDA-approved dual orexin receptor antagonist for insomnia, has previously been shown to improve sleep, reduce stress, and attenuate craving in the first-in-human study with non–treatment-seeking individuals with cocaine use disorder. Objective The primary objective of this randomized open-label clinical trial is to evaluate the effects of suvorexant on sleep, stress, reward processing, and craving during early abstinence in treatment-seeking individuals with StimUD. This proof-of-concept trial represents the first mechanistic evaluation of suvorexant in a residential sample of individuals with StimUD. Methods A total of 40 participants, recruited from a residential treatment facility, will be randomized (1:1) to either 7 days of nightly suvorexant (10 mg) or treatment as usual. Participants’ sleep will be monitored using an activity tracker watch, and they will complete a sleep diary each night to confirm bedtimes and wake-up times. Participants in the suvorexant group will receive the study medication for 7 nights. On premedication and postmedication study days, participants will be transported to the Center for Neurobehavioral Research on Addiction to complete the study sessions. At both study sessions, participants will complete self-report and safety measures (safety measures for the suvorexant group only) followed by administration of a stress reactivity test and an electroencephalographic assessment. Results The study was funded in January 2025 and is currently ongoing. We began enrollment of the first participant prior to funding in July 2024. At the time of manuscript submission (September 2025), a total of 8 participants had been enrolled in the study toward the planned enrollment of 40 participants. This study is expected to conclude in January 2027. Conclusions Findings from this study will provide initial evidence for the mechanisms involved in suvorexant for StimUD, with the long-term goal of repurposing orexin-based therapy to regulate neurobehavioral mechanisms and inform future medication development for StimUD.