Accepted for/Published in: JMIR Research Protocols
Date Submitted: Sep 9, 2025
Open Peer Review Period: Sep 9, 2025 - Nov 4, 2025
Date Accepted: Feb 18, 2026
(closed for review but you can still tweet)
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, remain a major ongoing public health concern in the United States with no approved FDA 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 support the orexin neuropeptide system as a promising therapeutic target for minimizing these disruptive mechanisms. Suvorexant (SUVO), an FDA-approved dual orexin receptor antagonist for insomnia, has previously shown improved sleep, stress, and 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 SUVO 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 SUVO 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 SUVO (20 mg) or treatment as usual (TAU).
Methods:
A total of 40 participants, recruited from a residential treatment facility, will be randomized (1:1) to either 7 days of nightly SUVO (20 mg) or treatment as usual (TAU). Participant’s sleep will be monitored using an activity tracker watch on Nights 4 through 11 and complete a sleep diary each night to confirm bedtimes and wakeup times. Participants in the SUVO group will receive the study medication from Day 5 through Day 11. On Days 5 and 12, participants will be transported to the Center of Neurobehavioral Research on Addiction (CNRA) to complete the study sessions. At both study sessions, participants will complete self-report and safety measures (safety measures for SUVO group only) followed by administration of the stress reactivity test and the EEG assessment.
Results:
The first participant was enrolled in July 2024. At the time of the submission of the manuscript (September 2025), a total of 8 participants have been enrolled in the study towards the planned enrollment of 40 participants.
Conclusions:
Findings from this study will provide critical data on repurposing orexin-based therapy to regulate neurobehavioral mechanisms that are related to vulnerability to resumption of use to inform future medication development for StimUD. Clinical Trial: https://clinicaltrails.gov/study/NCT06444256
Citation
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Copyright
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