Orexin Receptor Antagonists as Modulators of Threat Sensitivity in Individuals With Alcohol Use Disorder

The goal of this double-blind clinical trial is to further explore if, how, and for whom orexin antagonism modifies brain-behavior stress targets in moderate to severe alcohol use disorder (AUD). The main questions it aims to answer are:

• Does an acute dose of suvorexant (SUV) and/or daily use of SUV modify brain-behavior targets of AUD dysfunction?
• Does daily SUV use change alcohol behavior and if so, is this change in behavior linked to brain-behavior change?

Participants will be randomized to a treatment group (SUV or placebo) and protocol arm, electromyography (EMG) only or EMG+functional magnetic resonance imaging (fMRI). Participants will be asked to complete the following:

• Baseline lab visit(s) that include the psychophysiological stress paradigm (EMG only or EMG+fMRI, dependent upon randomization).
• Acute drug challenge where the participant will return to the lab to repeat the stress paradigm following administration of a single dose of either 10mg SUV or placebo.
• Medication trial where participants will be instructed to take 10mg capsules of SUV or placebo orally each night before bedtime for 4-weeks.
• Daily reports of medication adherence, side-effects, sleep, alcohol use, and mood will be collected via smartphones during the 4-week medication trial.
• Post-treatment lab visit(s) where participants will return to the lab at the end of the medication trial and complete the same stress paradigm from baseline (EMG only or EMG+fMRI, dependent upon randomization).

Study Overview

• Status: Completed
• Conditions: Alcohol Use Disorder
• Intervention / Treatment: Other: Placebo; Drug: Suvorexant

• Study Type: Interventional
• Enrollment (Actual): 81
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • Ohio
    • Columbus, Ohio, United States, 43210
      • The Ohio State University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 61 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age 18-65.
• Participant is able to give informed consent.
• Generally medically and physically healthy as confirmed by medical history.
• Meet DSM-5 diagnostic criteria for current moderate or severe AUD.
• Engage in heavy alcohol use defined as drinking equal or greater than 14 standard drinks per week if male and equal or greater than 7 standard drinks per week if female.

Exclusion Criteria:

• Clinically significant medical or neurological condition (e.g., liver disease, narcolepsy, complex sleep behaviors, severe hepatic impairment, COPD, severe obstructive sleep apnea).
• Current cognitive dysfunction (traumatic brain injury, mental retardation, organic mental syndrome, pervasive developmental disorder, or dementia).
• Current use of antihistamines, strong or moderate inhibitors of CYP3A liver enzymes, strong CYP3A inducers, or digoxin.
• Current or past DSM-5 diagnosis of mania, schizophrenia, psychosis, suicidality, major depressive disorder, or obsessive compulsive disorder.
• Current substance use disorder other than alcohol or mild cannabis use disorder.
• Treatment seeking for AUD.
• Recent psychotropic medication use in the past 2 months.
• Currently smokes 5 or more cigarettes (or electronic equivalent) per day.
• BMI equal or greater than 35.
• Engage in night-shift work.
• Lack of fluency in English.
• Presence of ferrous-containing metal in the body.
• Inability to tolerate small, enclosed spaces.
• Deafness in one or both ears.
• Currently pregnant (positive pregnancy test), lactating, or not agreeing to use birth control methods during the duration of the trial.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Control; Individuals will take a placebo pill during the Acute Drug Challenge and daily for 28 days.	Other: Placebo; This study is a double-blind study. Participants will complete an initial screening visit and pre-treatment lab visits (EMG, fMRI). The placebo pill will be identical in appearance to suvorexant but will contain only dextrose. Following the pre-treatment visits, participants will take one pill at the Acute Drug Challenge under medical supervision. Ninety minutes post ingestion participants will complete the EMG paradigm. At the end of the visit participants will be provided a blister pack with 28 pills. Participants will be instructed to take one pill orally about 30 minutes prior to sleep time each night for 28 days. Participants will be provided education about common side effects. Participants will complete daily surveys to monitor side. At the end of the 28 days, participants will complete post-treatment lab visits.
Experimental: Suvorexant Treatment; Individuals will take 10mg of suvorexant (Merck & Co Inc.) during the Acute Drug Challenge and daily for 28 days.	Drug: Suvorexant; This study is a double-blind study. Participants will complete an initial screening visit and pre-treatment lab visits (EMG, fMRI). Suvorexant (SUV) will be placed in opaque capsules with dextrose filler. After the pre-treatment visits participants will take one pill of SUV at the Acute Drug Challenge under medical supervision. Ninety minutes post ingestion participants will complete an EMG. Laboratory assessments will occur during peak concentration, 2 hours post-ingestion. At the end of the visit, participants will be given a blister pack with 28 pills. Participants will be instructed to take one pill orally about 30 minutes prior to sleep time each night for 28 days. Participants will be provided education about common side effects. Participants will complete daily surveys to monitor side effects and potential drug-drug interactions. At the end of the 28 days, participants will complete post-treatment lab visits.; Other Names: Belsomra

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Startle Eyeblink Electromyographic (EMG) Response to Stress With an Acute Dose of Suvorexant	Startle EMG responses were collected during the well-validated No-Predictable-Unpredictable threat paradigm. The task includes within-subjects conditions and raw EMG responses were averaged for each condition. To quantify the difference between threat and no-threat periods, we calculated a standardized residual score for unpredictable threat (U-threat) by saving the variance leftover (i.e., the amount of variability in a dependent variable [DV] that is not explained by an independent variable [IV]) in a simple linear regression, where the no-threat EMG startle average (IV) was entered to predict the U-threat EMG startle average (DV). The U-threat residual score was used as the primary variable. It has a mean of zero and higher scores reflect greater startle reactivity to U-threat. U-threat residual scores were calculated for the baseline session and the acute challenge.	Change from baseline to 2 hours post-ingestion of an acute dose of suvorexant.
Startle Eyeblink Electromyographic (EMG) Response to Stress With Daily Use of Suvorexant.	Startle EMG responses were collected during the well-validated No-Predictable-Unpredictable threat paradigm. The task includes within-subjects conditions and raw EMG responses were averaged for each condition. To quantify the difference between threat and no-threat periods, we calculated a standardized residual score for unpredictable threat (U-threat) by saving the variance leftover (i.e., the amount of variability in a dependent variable [DV] that is not explained by an independent variable [IV]) in a simple linear regression, where the no-threat EMG startle average (IV) was entered to predict the U-threat EMG startle average (DV). The U-threat residual score was used as the primary variable. It has a mean of zero and higher scores reflect greater startle reactivity to U-threat.	Change from baseline to post-treatment, up to 2 months.
Percentage of Heavy Drinking Days During Daily Use of Suvorexant.	Percentage of heavy drinking days (PHDD) was calculated each week for all four weeks of the trial. A heavy drinking day was defined using NIH criteria: 5+ drinks for males and 4+ drinks for females in a single day. We conducted a multilevel mixed model with PHDD from week 1 to 4 as the within-subjects variable and treatment arm as the between subjects variable.	Change from baseline to post-treatment, over the course of 4 weeks.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in Neural Activation During Unpredictable Stress Anticipation Following Daily Use of Suvorexant.	Activation parameter estimates (arbitrary units) were extracted from anatomical bilateral aINS masks for each individual, pre and post treatment. Specifically, activation parameter estimates were extracted from anticipation of unpredictable threat > anticipation of no-threat individual contrast maps for each scanning session. Greater values reflect greater activation in the bilateral insula during the anticipation of unpredictable threat. A repeated measures analysis of variance was used to test the session (time 1 vs. time 2) by treatment arm interaction on bilateral aINS activation during unpredictable threat. Significance was set at p <.05	Change from baseline to post-treatment, up to 2 months.

Collaborators and Investigators

• Sponsor: Ohio State University
• Collaborators: National Institute on Alcohol Abuse and Alcoholism (NIAAA)

Study record dates

Study Major Dates

• Study Start (Actual): November 29, 2022
• Primary Completion (Actual): August 1, 2024
• Study Completion (Actual): August 1, 2024

Study Registration Dates

• First Submitted: December 11, 2022
• First Submitted That Met QC Criteria: December 11, 2022
• First Posted (Actual): December 19, 2022

Study Record Updates

• Last Update Posted (Estimated): October 30, 2025
• Last Update Submitted That Met QC Criteria: October 17, 2025
• Last Verified: October 1, 2025

More Information

Terms related to this study

• Keywords: functional magnetic resonance imaging; electromyography; suvorexant; alcohol use disorder
• Additional Relevant MeSH Terms: Mental Disorders; Substance-Related Disorders; Chemically-Induced Disorders; Alcohol-Related Disorders; Alcoholism; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Hypnotics and Sedatives; Sleep Aids, Pharmaceutical; Orexin Receptor Antagonists; suvorexant
• Other Study ID Numbers: 2022H0265; 1R21AA030097-01A1 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

De-identified data, including fMRI, startle eyeblink, and behavior, from this project will be submitted to the NIAAA Data Archive (NDA) at the subject level along with appropriate supporting documentation to enable efficient use of the data by the research community. We will follow instructions as discussed in the NIAAA Data Archive Data Sharing Terms and Conditions.

We will follow the two-tier procedure described in the guidelines:

1. Raw continuous fMRI recordings will be submitted in standard formats (Matlab mat format, DICOM format and NIFTI format). Experimental condition information will be supplied in text format along with other critical information.
2. Analyzed data (BOLD data, BOLD-startle eyeblink data) associated with a manuscript will be shared as soon as possible, and at the latest, at the time of publication of the manuscript. These data may be accompanied, if applicable, by other data such as behavioral data, supplied in text format.

• IPD Sharing Time Frame: The data, as outlined above, will be submitted to the NIAAA Data Archive biannually per NIAAA requirements throughout the duration of the study.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No