Orexin Receptor Antagonists as Modulators of Threat Sensitivity in Individuals With Alcohol Use Disorder
Phase: EARLY_PHASE1
Conditions: Alcohol Use Disorder
Sponsor: Ohio State University

01/17/2024 
Orexin Receptor Antagonists as Modulators of Threat Sensitivity in Individuals 
With Alcohol Use Disorder 
Protocol ID: 2022H0265 
NCT05656534 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Orexin Receptor Antagonists as Modulators of Threat Sensitivity in individuals 
with Alcohol Use Disorder 
Principal Investigator: 
Stephanie Gorka, PhD 
Assistant Professor 
The Ohio State University 
Department of Psychiatry & Behavioral Health  
 
 
Co-Investigators: 
K. Luan Phan, M.D. 
Professor and Chair 
The Ohio State University  
Department of Psychiatry & Behavioral Health  
 
 
Stacey Culp, PhD 
Assistant Professor 
The Ohio State University 
Center for Biostatistics 
 
 
Study Location:  
 
Department of Psychiatry 
Institute for Behavioral Medicine Research 
 
Clinical Research Center 
 
The Ohio State University  
Center for Cognitive and Behavioral Brain Imaging 
 
 
Version: #9 
Date:1/17/2024 
 
 

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TABLE OF CONTENTS 
Page 
Table of Contents……………………………………………………………………………….2 
List of Abbreviations…………………………………………………………………………….3 
1.0 
Project Summary/Abstract……………………………………………………………..4 
2.0 
Background/Scientific Rationale………………………………………………………5 
3.0 
Objectives/Aims…………………………………………………………………………6 
4.0 
Eligibility………………………………………………………………………………… 6 
4.1 Inclusion Criteria…………………………………………………………………… 6 
4.2 Exclusion Criteria………………………………………………………………….. 7 
4.3 Excluded or Vulnerable Populations……………………………………………. 8 
5.0 
Subject Enrollment…………………………………………………………………….. 8 
6.0 
Study Design and Procedures………………………………………………………. 10 
7.0 
Expected Risks/Benefits………………………………………………………………18 
8.0 
Data Collection and Management Procedures……………………………………. 21 
9.0 
Data Analysis…………………………………………………………………………. 22 
10.0 Quality Control and Quality Assurance…………………………………………….. 22 
11.0 Data and Safety Monitoring……………………………………………................... 23 
12.0 Statistical Considerations……………………………………………...................... 24 
13.0 Regulatory Requirements……………………………………………...................... 24 
13.1 Informed Consent……………………………………………....................... 25 
13.2 Subject Confidentiality……………………………………………................ 25 
13.3 Unanticipated Problems…………………………………………….............. 26 
14.0 References……………………………………………............................................ 26 
Appendices……………………………………………....................................................... 30 

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LIST OF ABBREVIATIONS  
 
AE 
 
 
Adverse Event 
aINS   
 
Anterior insula 
AUD  
 
Alcohol Use Disorder 
BOLD  
 
Blood Oxygen Level Dependent 
BMI 
 
 
Body Mass Index 
CITI 
 
 
Citi.gov Human subjects training 
CRC  
 
Clinical Research Center 
dACC  
 
Dorsal anterior cingulate cortex 
DSM  
 
Diagnostic and Statistical Manual of Mental Disorders 
EEG  
 
Electroencephalography 
EMG  
 
Electromyography 
FDA  
 
Food and Drug Administration 
fMRI   
 
Functional Magnetic Resonance Imaging 
HIPAA 
 
Health Insurance Portability and Accountability Act 
IDS 
 
 
Investigational Drug Services 
IRB 
 
 
Institutional Review Board 
ISI 
 
 
Interstimulus Interval  
MRI 
 
 
Magnetic Resonance Imaging 
N- 
 
 
No 
NPU           
 
No-Predictable-Unpredictable  
NIH 
 
 
National Institutes of Health 
ORX  
 
Orexin  
P- 
 
 
Predictable  
PBO  
 
Placebo 
PHI 
 
 
Protected Health Information 
PI 
 
 
Principal Investigator 
SAE  
 
Serious Adverse Event 
SCID  
 
Structured Clinical Interview for DSM-5 
SUV  
 
Suvorexant 
U- 
 
 
Unpredictable  
U-Threat 
 
Uncertain Threat 
 
 
 
 

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1.0 
PROJECT SUMMARY/ABSTRACT 
Alcohol use disorder (AUD) affects millions and is one of the leading causes of 
preventable death worldwide. In the US, pharmacotherapy for AUD is under-utilized; 
related to the fact that there are only three FDA-approved drugs to treat patients with 
AUD. These medications work well for some but have small to moderate effect sizes on 
drinking outcomes. The development of more efficacious pharmacotherapies for AUD is 
a top public health priority. A recent emphasis in psychiatric medication development is 
the use of reliable human laboratory measures of AUD dysfunction to test promising 
compounds to directly inform and power large-scale mechanistic clinical trials. PI Gorka 
and Co-I Phan have developed an assay of stress reactivity that is robustly related to 
drinking behavior and AUD. This assay reflects a negative reinforcement model of AUD 
and is reliably captured in the lab using complimentary objective psychophysiological (i.e., 
startle eyeblink potentiation) and functional neuroimaging measures. Using this model, 
we have uncovered that suvorexant (SUV) – a dual receptor antagonist of the orexin 
system, FDA-approved for insomnia – acutely modifies our AUD target in healthy adults, 
while sparing changes in other markers of stress reactivity. Compelling animal and human 
evidence together suggest that the orexin system is critically involved in stress-related 
alcohol use. The overarching goal of this study is to systematically advance this line of 
work to uncover if, how, and for whom orexin antagonism modifies brain-behavior stress 
targets of AUD to inform and power future large scale clinical trials. The study is a targeted 
double-blind, between-subjects, randomized clinical trial design with repeat lab 
assessment. A total of eighty subjects with AUD will complete our psychophysiological 
stress paradigm at baseline. They will return to the lab days later to repeat the protocol 
following administration of a single dose of either 10mg SUV or placebo (40 
subjects/arm). Participants are then instructed to take daily 10mg capsules of SUV or 
placebo for the next 4-weeks before returning for a post-treatment lab assessment. Daily 
reports of medication adherence, side-effects, sleep, alcohol use, and mood will be 
collected via smartphones.  
 
This multimodal design allows for a well-controlled test of whether an acute dose of SUV 
(Aim 1) and/or daily use of SUV (Aim 2) modifies brain-behavior targets of AUD 
dysfunction, particularly within individuals with high objective baseline stress reactivity. 
We will also examine whether daily SUV changes alcohol behavior, and whether this 
change in behavior is linked to brain-behavior change (Aim 3). Findings from this study 
will provide critical new knowledge regarding if and how orexin antagonism can be 
leveraged to treat AUD. The findings will also be used to inform and power a large-scale 
mechanistic clinical trial of SUV for AUD. 
 

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2.0 
BACKGROUND/SCIENTIFIC RATIONALE  
Alcohol use disorder (AUD) is a serious public health issue and a leading cause of 
preventable death worldwide1. In the US, there is a paucity of pharmacotherapies for 
AUD, related to the fact that there are only three FDA approved drugs used to treat 
patients2-3. These medications work well for some but have small to moderate effect sizes 
with ~50-60% relapsing within 12 weeks of treatment4-5. The development of more 
efficacious pharmacotherapies for AUD is urgently needed and a top public health 
priority6-7; though ushering compounds through the clinical testing process and into the 
AUD clinic has been a well-documented challenge.  
A recent emphasis in medication development is the use of valid and reliable 
human laboratory measures of AUD pathophysiology to test promising compounds to 
inform and power targeted clinical trials7-9. The ultimate goal is to more quickly identify 
compounds deserving of clinical testing and accelerate the pace of mechanistic drug 
discovery. PI Gorka and Co-I Phan have developed a reliable assay of stress reactivity 
that is robustly associated with drinking behavior and AUD10. We have shown that greater 
brain (i.e., anterior insula [aINS] and dorsal anterior cingulate cortex [dACC]) and 
behavioral (i.e., startle eyeblink) reactivity to threats that are uncertain (U-threat) is 
associated with greater frequency of drinking, changes in drinking over time, and onset 
of AUD11. Individuals with AUD reliably exhibit greater brain-behavior reactivity to U-threat 
compared with controls, and magnitude of reactivity correlates with AUD severity11-14. 
These findings have been replicated by other labs and coincide with studies showing 
alcohol intoxication selectively and effectively dampens reactivity to U-threat (but not 
predictable threat; P-threat)15-18. We have therefore developed a negative reinforcement 
model of AUD that is reliably captured in the lab using objective, complimentary 
psychophysiological and neuroimaging measures. This paradigm is now being 
incorporated into several ‘Fast-Fail’ proof-of-concept medication trials. 
Novel preclinical research indicates that the hypocretin/orexin (ORX) hypothalamic 
neuropeptide system plays a pivotal role in alcohol abuse. In rodents, antagonism of ORX 
receptors prevents alcohol-seeking behavior and binge-like alcohol drinking, while 
preserving motivation for natural rewards19-22. ORX receptor antagonism also robustly 
reduces behavioral and psychophysiological stress reactivity to threat and 
pharmacological challenge23-24. ORX antagonism may therefore be an effective strategy 
for disrupting the negative reinforcement cycle of addiction. Remarkably, using a within-
subjects, placebo-controlled design our prelim data indicates an acute dose of suvorexant 
(SUV) – an FDA-approved dual ORX receptor antagonist for insomnia – robustly reduces 
behavioral reactivity to U-threat in adults, while sparing changes in other 
psychophysiological markers of threat sensitivity less relevant to AUD. ORX antagonism 
selectively engages the U-threat target, providing compelling evidence it is a promising 
pharmacological treatment for individuals with AUD and high U-threat reactivity, who 
frequently engage in stress-related alcohol use22, 25-28. 
No prior study has measured stress-related ORX target engagement in humans to 
uncover how ORX antagonism can be leveraged to treat AUD. The overarching goal of 
the current study is to advance ORX translation to the AUD clinic using a proof-of-concept 

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double-blind, between-subjects, randomized clinical trial design with repeat lab 
assessment.  
All subjects will complete three lab visits of psychophysiological data collection. A 
subset of 20 subjects per arm (40 total) will also complete our stress task during 
simultaneous startle and functional magnetic resonance imaging (fMRI), pre- and 
posttreatment. This design allows us to address if, how, and for whom ORX antagonism 
modifies brain-behavior stress targets to inform and power future large scale mechanistic 
clinical trials. 
 
3.0 
Objectives/Aims 
 
Aim 1. Does an acute dose of suvorexant decrease reactivity to U-threat? H1: 
Relative to placebo, SUV will acutely dampen psychophysiological reactivity to U-threat, 
but not P-threat. 
Aim 2. Does daily use of suvorexant decrease reactivity to U-threat? H2a: 4-weeks 
of SUV will result in greater reductions in psychophysiological reactivity to U-threat 
compared with placebo, and these changes will be specific to U-threat. H2b: SUV-related 
change in U-threat reactivity will be greatest amongst those with higher baseline U-threat 
reactivity. Exploratory: Daily SUV will similarly result in decreases in aINS and dACC 
reactivity and connectivity during U-threat relative to placebo, and brain change will 
correlate with startle change. 
Aim 3. Does daily use of suvorexant change alcohol behavior, and is this change 
linked to brain-behavior U-threat change? H3a: Daily SUV will result in greater 
reductions in proportion of heavy drinking days (PHDD) and drinks per drinking day 
(DPDD). H3b: SUV-related changes in PHDD and DPDD will be greatest in those with 
higher U-threat reactivity. H3c: In all subjects, changes in alcohol behavior will correlate 
with changes in brain-behavioral U-threat reactivity. 
 
Study duration. Participants will complete a Screening Session and three to five in-
person laboratory sessions (dependent upon randomization) over the course of 1.5 – 2 
months. 
 
4.0 
Eligibility 
 
4.1 Inclusion Criteria 
 
Adults 18-65 years old will be enrolled in this study. Participants will be required to 
be generally medically and neurologically healthy. They will also be required to 
meet current DSM-5 diagnosis of moderate to severe AUD and engage in heavy 
alcohol use defined as drinking ≥14 standard drinks per week if male, and ≥7 
standard drinks per week if female. 
 
4.2 Exclusion Criteria 
 

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Exclusion criteria for all subjects will be: (a) clinically significant medical or 
neurologic condition or neurocognitive dysfunction that would affect function, 
and/or task performance, and/or interfere with the study protocol, and/or be 
contraindicated for suvorexant (SUV), including narcolepsy, complex sleep 
behaviors, severe hepatic impairment, and compromised respiratory function such 
as COPD, and severe obstructive sleep apnea; (b) current or past major DSM-5 
psychiatric disorder including mania, schizophrenia, psychosis, suicidality (as 
defined by a score of 5 or higher on the Beck’s Scale for Suicidal Ideation - Lifetime 
[SSI]), major depressive disorder (MDD), or obsessive-compulsive disorder 
(OCD); (c) current substance use disorder for any substance, except for mild 
cannabis use disorder; (d) treatment seeking for AUD due to the study design and 
experimental nature of SUV; (e) currently pregnant (positive pregnancy test), 
lactating, or not agreeing to use birth control methods during the duration of the 
trial (women); (f) recent (in the past 2 months) use of any psychoactive 
medications; (g) current antihistamines use; (h) current use of strong or moderate 
inhibitors of CYP3A liver enzymes; (i) current use of strong CYP3A inducers; (j) 
current use of digoxin; (k) night shift work; (l) smoke 5 or more cigarettes (or 
electronic equivalent) per day and are thus susceptible to acute nicotine withdrawal 
during lab visits; (m) obesity as defined by a body-mass index (BMI) greater than 
35, as calculated from weight and height self-report; (n) lack of fluency in English; 
(o) acute alcohol withdrawal the day of the lab sessions, defined as a score >8 on 
the Clinical Institute Withdrawal Assessment of Alcohol Scale Revised (CIWA-
Ar)29; (p) unwilling/unable to sign the informed consent document; (q) under 18 
years old or over 65 years old at the time of enrollment; (r) history of traumatic 
brain injury (as defined by The American Congress of Rehabilitation as a 
traumatically induced physiological disruption of brain function - i.e., the head 
being struck, the head striking an object, and/or the brain undergoing an 
acceleration/deceleration movement, such as whiplash - without direct external 
trauma to the head), as manifested by at least one of the following: any loss of 
consciousness; any loss of memory for events immediately before or after the 
injury; any alteration in mental status at the time of the incident; or focal 
neurological deficits that may or may not be transient. 
 
Additional exclusion criteria for all participants pertaining to the fMRI scan include: 
a) presence of ferrous-containing metals within the body (e.g., aneurysm clips, 
shrapnel/retained particles) or b) inability to tolerate small, enclosed spaces 
without anxiety (e.g., claustrophobia). 
 
Acute alcohol intoxication, verified via breath test, will disqualify immediate 
participation for lab tasks; though subjects may be able to re-schedule the visit for 
a later date. Upon arrival to the lab sessions, individuals will provide a urine sample 
for drug screen and complete a corresponding detailed Timeline Follow-back 
(TLFB)30 of their substance use. If individuals test positive for recreational 
substance use and self-report use within the past 24-hours their lab visit will be re-
scheduled for a later date. 

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4.3 Excluded or Vulnerable Populations 
 
No individuals will be allowed to participate in the study if they are < 18 years of 
age or > 65 years of age. This study will exclude children (<18 years of age).  
 
This age range was chosen to minimize the potential for adverse medication side-
effects. Limiting the sample to adults younger than 65 also reduces potential 
heterogeneity in brain structure and function, and psychophysiological stress 
reactivity, which could confound data interpretation in the current sample size. 
 
Individuals younger than age 18 will be excluded because suvorexant is not FDA-
approved for use in children. 
 
The study will also exclude individuals who are pregnant, nursing, or are trying to 
get pregnant to ensure safety of the fetus/child during procedures. This study will 
exclude prisoners. 
 
 
5.0 
Subject Enrollment 
 
• 
We propose to recruit from multiple sources with the intent to enroll a 
community sample.    
• 
Participants will be recruited via print advertisements across the central 
Ohio area, word-of-mouth referrals (including through the OSU emergency 
department (ED)), and internet and social media postings (e.g., craigslist, 
Facebook, Snapchat, Instagram), and through OSU websites (such as 
Study Search) and electronic newsletters.  
• 
We expect to recruit up to 120 participants in 2 years. 
• 
Advertisements will include a QR code that when scanned will direct 
interested individuals to the study’s online Recruitment Survey on REDCap. 
If the individual chooses, they will complete the online survey that assesses 
for initial eligibility criteria. 
• 
The study staff will determine potential participants’ eligibility for the 
research. 
• 
If an individual meets this initial eligibility criteria on the survey, trained 
clinical research staff or investigators will call the individual and complete a 
phone screen to further assess eligibility for the research study. Data from 
participants not eligible for the study based on the initial phone screen will 
be destroyed once they are determined to be ineligible. 
• 
In collaboration with Dr. Michael Lyons, Professor of Emergency Medicine 
at the OSU Wexner Medical Center, we propose to also recruit from the 
OSU ED. IRB approved and trained research specialists, employed by Dr. 
Lyons, who work in the OSU ED will assist in recruitment procedures by 
conducting the phone screen verbally in-person with interested participants. 

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The research specialists are a part of an established research initiative and 
are specifically trained to enroll individuals in the ED into IRB approved 
research studies. Thus, phone screening individuals in the ED is a part of 
the research specialists’ routine job responsibilities. 
• 
As outlined in the phone screen, the OSU ED research specialists will read 
a brief description of the study and if the individual is interested, the phone 
screen will be completed. Study staff will not access medical records at any 
point during the recruitment process. 
• 
Following the completion of the phone screen, potentially eligible individuals 
will be scheduled for a Screening Session. Participants will be given the 
choice to complete the Screening Session online or in-person to 
accommodate potential limited access to the internet. 
• 
During the Screening Session, participants will provide informed consent. 
Specifically, once the procedures are explained to them in detail, subjects 
will be given ample time to read the consent form, formulate questions and 
ponder the responses. Subjects will have time between initial contact and 
the scheduled testing to discuss participation with people of their choice; 
the initial laboratory session date will be scheduled for their convenience. 
We will emphasize to subjects the voluntary nature of their participation in 
the study. Subjects will also be told that they are free to drop out of the study 
at any time for any reason.  
o Online Screening Sessions: Consent will be collected via 
REDCap software. The authenticity requirements involve 
Remote Signing, Username & Password. During the phone 
screen, if participants are found to be eligible, they will establish 
a password with study staff. The study staff will enter the 
passcode in the participant’s REDCap record.  Participants are 
sent a link to sign the consent form in REDCap via email, which 
does not include the password.  Participants are then asked for 
the password which is cross referenced with the password 
already on file in the REDCap project. The completed consent 
form will be downloaded and stored in the PI’s laboratory in a 
locked cabinet and locked office. A copy of the signed consent is 
emailed to the participant by REDCap. 
o In-person Screening Sessions: Consent will be collected via 
REDCap software. The authenticity requirements involve in-
person signing.  Participants can provide ID, insurance card, 
name and date of birth, etc. for study staff to verify their identity. 
The completed consent form will be downloaded and stored in 
the PI’s laboratory in a locked cabinet and locked office. A copy 
will be given to participants.  
• 
At the Screening Session a clinically trained study staff member will perform 
the Structured Clinical Interview for DSM-5 (SCID-5)31 and administer a 
small battery of questionnaires. MD level physician will review his/her 
medical and neurological history. Initial eligibility for the research will be 

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documented in the research record. Final determination of subject eligibility 
will be made by the PI or the PI in consultation with research staff. 
• 
Following the Screening Session, eligible participants will be randomized to 
a treatment group (i.e., SUV or placebo) and protocol arm (i.e., EMG/EEG 
only or EMG/EEG + fMRI). Treatment group randomization will be double-
blinded. 
• 
Research study staff will monitor the participants throughout the course of 
the research to ensure that they still meet eligibility criteria, and their 
continuing eligibility will be documented by the research staff. This will 
include ensuring abstinence from alcohol at both laboratory visits. It will also 
ensure that no participant is pregnant at either session.  
• 
Upon enrollment into the study, participants will be required to agree and 
consent to not operating heavy machinery, including driving a vehicle, for at 
least 24-hours after the Acute Drug Challenge visit due to day-time drug 
administration. 
• 
Participants will also be instructed that they will be required to fast for at 
least 2-hours prior to the Acute Drug Challenge visit to avoid interactions 
between food and SUV metabolism. The Acute Drug Challenge visit will 
therefore begin at approximately 9-10am.  
• 
Following the Acute Drug Challenge visit, participants will be instructed to 
take either SUV or placebo, dependent upon their randomized treatment 
group, once daily before bed for 4 weeks. Participants will complete daily 
online clinical assessments. The PI and study staff will monitor potential 
side effects and drug adherence throughout the duration of the 4 weeks. 
• 
Participants will return to the lab at the end of the 4 weeks and complete a 
third EMG/EEG, and second fMRI (dependent upon randomization). 
• 
Participants will be debriefed and provided AUD treatment referrals as 
appropriate at the end of their study participation.  
 
• Termination Criteria:  Participants may be terminated for any of the following: (a) 
completion of study; (b) participant request to exit or withdraw consent; (c) development 
of suicidal or homicidal ideation requiring hospitalization; (d) development of a systemic, 
medical, neurologic or psychiatric illness requiring treatment that would exclude 
participation; (e) clinical deterioration (see below); (f) non-compliance with study 
protocol requirements including refusing to consent to not driving for at least 24-hours 
after Lab Visit 2 (Acute Drug Challenge) due to day-time drug administration; (g) 
significant worsening of AUD symptoms that would require treatment; and (h) a positive 
pregnancy test. If alcohol tests are positive, participants will be given the option to 
reschedule. If breath tests are again positive, participation will be terminated.  
 
6.0 
Study Design and Procedures 
Participants. The sample size for the present study is 80 adults, ages 18-65 years old. 
However, to account for potential screen-fails, participants requesting to drop out of the 
study, and the PI withdrawing participants due to meeting termination criteria, approval 
for 120 participants is requested. Exclusion criteria are listed above. We will recruit 

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individuals who meet DSM-5 criteria for moderate or severe AUD. As noted above, we 
will not include individuals who meet DSM-5 diagnostic criteria for current or lifetime MDD, 
OCD, bipolar disorder, or psychotic disorder. All other lifetime psychiatric diagnoses will 
be assessed and examined as potential covariates in analyses. Individuals younger than 
age 18 will be excluded because suvorexant is not FDA-approved for use in children. 
Individuals older than 65 will be excluded to minimize the potential for adverse medication 
side-effects and prescription drug interactions. Limiting the sample to adults younger than 
65 also reduces potential heterogeneity in brain structure and function, and 
psychophysiological stress reactivity, which could confound data interpretation in the 
current sample size. 
 
Recruitment. Adults will be recruited via print advertisements, word-of-mouth referrals 
(including through the OSU ED), and internet postings (e.g., craigslist, social media sites). 
We expect to recruit all participants within 2 years, consistent with our prior 
psychophysiological and pharmacological challenge studies.  
 
Entry Assessments. Inclusion/exclusion criteria. Potential participants will be 
screened using structured questionnaires (see Table 1 and Table 2). Exclusionary criteria 
will be those that would interfere with interpretation of brain and/or behavioral findings or 
increase risk of side effects/adverse events - see above for a complete list.  After consent, 
if interested participants meet eligibility criteria, and are able to provide consent, they will 
be enrolled in the study. 
 
Figure 1. 
 
Study Overview. The study is a double-blind, between-subjects, randomized clinical trial 
with a multi-session lab paradigm (see Figure 1). Participants will first complete an initial 
Screening Session where they will complete an assessment of study eligibility (described 
above), a clinical interview, and questionnaires. If participants are found to be eligible, 
they will be randomized to a treatment group (SUV or placebo) and protocol arm 
(BEHAVIOR or BRAINS Group). Those in the BEHAVIOR Group will complete   
electromyography (EMG)/electroencephalography (EEG) only and those in the BRAINS 
Group will complete EMG/EEG + fMRI. 
 

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Therefore, participants have a chance of being randomized to four different groups (20 
participants/group): 1) BEHAVIOR - SUV; 2) BEHAVIOR - Placebo; 3) BRAINS - SUV; 
and 4) BRAINS - Placebo. 
 
BEHAVIOR Group Overview: 
Following the Screening Session, participants randomized to the BEHAVIOR 
group will come in-person to Lab Visit 1 where they will complete the 
psychophysiological stress paradigm and Alcohol Cue Reactivity EEG task. Days 
later, they will return to the lab for Visit 2 (Acute Drug Challenge) and repeat the 
protocol during their first dose of medication (placebo or 10mg SUV). Next, they 
will be instructed to take a 10mg dose of SUV (or placebo) each night before bed 
for 4-weeks. Daily online assessments of medication compliance, side-effects, 
alcohol use, mood, and sleep will be collected. During the final week of the protocol 
subjects will return for Lab Visit 3 to repeat the paradigm (dose taken night prior, 
as prescribed). 
 
BRAINS Group Overview: 
Following the Screening Session, participants randomized to BRAINS Group will 
complete the same procedures as above with the exception of completing two 
additional fMRI visits pre- and post-treatment. Therefore, participants will 
complete: Lab Visit 1 (EMG/EEG), Lab Visit 2 (fMRI), Lab Visit 3 (Acute Drug 
Challenge), four weeks of SUV (or placebo) administration with daily online 
assessments, Lab Visit 4 (EMG/EEG), and Lab Visit 5 (fMRI). 
 
 
Screening. During the Screening Session, participants will complete an assessment of 
study eligibility, the Structured Clinical Interview for DSM-5 (SCID-5)31 with trained study 
staff, and a short battery of self-report questionnaires (see Table 1 and Table 2). 
Participants will be given the choice to complete the Screening Session online or in-
person to accommodate potential limited access to the internet.  
 
Measures of Alcohol and Other Substance Use: (1) Alcohol Use Disorders 
Identification Test (AUDIT)32, (2) Timeline Follow-back (TLFB)30; (3) The 
Obsessive Compulsive Drinking Scale (OCDS)33, (4) The Drinker Inventory of 
Consequences (Dr-InC)34, (5) the CIWA-Ar29, (6) Drinking Motives Questionnaire-
Revised (DMQ-R)35, (7) Drug Abuse Screening Test (DAST)36, (8) Cannabis Use 
Disorder Identification Test (CUDIT)37, and (9) the Fagerstrom Test for Nicotine 
Dependence (FTND)38. 
 
Measures of Psychiatric Symptoms and Personality: (1) Beck Depression 
Inventory (BDI-II)39, (2) Beck Anxiety Inventory (BAI)40, (3) Generalized Anxiety 
Disorder Questionnaire (GAD-7)41, (4) Beck Hopelessness Scale42, (5) Snaith-
Hamilton Pleasure Scale (SHAPS)43, (6) PTSD Checklist-Civilian Version (PCL-
5)44, (7) Life Events Checklist for DSM-5 (LEC-5)45, (8) The Personality Inventory 

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for DSM-5 (PID-5)46, and (9) Beck’s Scale for Suicidal Ideation Lifetime (SSI)47, 
(10) The Depression, Anxiety and Stress Scale (DASS-21)48, (11) The Inventory 
of Depression and Anxiety Symptoms (IDAS-II)49, (12) Childhood Trauma 
Questionnaire (CTQ)50, (13) Anxiety Sensitivity Index (ASI), (14) Highly Sensitive 
Person Questionnaire (HSP). 
 
Other Measures: (1) Pittsburg Sleep Quality Index (PSQI)51, (2) Health 
Questionnaire, (3) Demographic Questionnaire, (4) Intolerance of Uncertainty 
(IUS)52, (5) Contact Information Form, (6) Emotion Regulation Questionnaire 
(ERQ)53, (7) Psychiatric Treatment History Form (clinician administered), (8) 
Medication History form (clinician administered); (9) Exclusionary Medication 
Checklist; (10) BMI Questionnaire. 
 
 
Identifying and Monitoring Drug-Drug Interactions. The study physician will review 
the participant’s self-report Health Questionnaire, self-report Exclusionary Medication 
Checklist, and clinician administered Medication History form prior to randomization in 
order to assess exclusionary criteria and identify potential drug-drug interactions. PI and 
the study physician will utilize Lexicomp to check drug-drug interactions and only 
interactions of minor severity will be allowed. Those found to have potential moderate or 
severe drug-drug interactions will be withdrawn from the study, consistent with study 
exclusionary criteria. Potential drug-drug interactions will continually be monitored 
throughout the duration of the study.  
 
 
Randomization, Blinding, and Dosing. A computerized stratified block randomization 
will assign subjects to a treatment group and protocol arm. The randomization will be 
stratified by biological sex. The research team and participants will be blind to medication 
assignment. The PI will have the ability to unblind if needed. OSU Investigational Drug 
Services (IDS) staff and CRC medical staff will be unblinded. 
 
Participants will receive either placebo or suvorexant (Belsomra®; 10mg; Merck & Co). 
This dose was chosen because it is the lowest clinical dose for sleep and arousal-related 
outcomes. We used 10mg in our pilot project and found significant change in reactivity to 
U-threat without adverse reactions (Protocol#: 2020H0285).  
 
 
Laboratory Tasks. Participants will complete a startle response to threat task at the 
EMG/EEG, fMRI, and Acute Drug Challenge Visits (described below). The same 
paradigm will be administered during the EMG/EEG and Acute Drug Challenge Visit. The 
fMRI task is analogous to the original design; however, shock is administered to the left 
foot to minimize potential scanner interference and individual shock levels are re-
calibrated. During the tasks, we will collect psychophysiological measures including 
startle eyeblink potentiation. At the EMG/EEG visit a second task, Alcohol Cue 
Reactivity71 will be completed. These tasks are well-established, validated paradigms, 

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previously used in our laboratory for the past several years in both healthy and adults with 
AUD.  
 
EMG/EEG Lab Visits. Task 1: Startle response 
to 
threat. 
Consistent 
with 
prior 
studies54,55, 
participants will first complete a brief habituation task 
to prevent early exaggerated startle responding, 
during which a series of acoustic startle probes will be 
administered. For the threat task itself, a brief, mild 
electric shock will be used to elicit aversive 
responding. Importantly, the current shock equipment 
and shock protocol has previously been used in our 
laboratory. Prior to the task, shock electrodes will be 
placed on the participants’ left wrist, followed by a shock work-up procedure in which they 
will receive increasing levels of shock intensity (max. = 5 mA) until they reach a level that 
they describe as feeling “highly annoying but not painful.” Shock level will be determined 
ideographically to ensure equality in perceived shock aversiveness. The task itself 
includes three within-subjects conditions – no shock (N), predictable shock (P), and 
unpredictable shock (U). Text at the bottom of the screen informs participants of the 
current condition. Conditions last 145-s, during which a 4-s visual countdown (CD) is 
presented six times. The interstimulus intervals (ISIs) range from 15 to 21-s during which 
only the text of the condition is on the screen. No shocks are delivered during the N 
condition. A shock is delivered every time the CD reaches 1 during the P condition. 
Shocks are delivered at random during the U condition. Startle probes are administered 
during both the CD and ISI. Each condition is presented two times in a randomized order. 
Participants receive 24 shocks (12 in P; 12 in U) and 60 startle probes (20/condition). This 
task will be conducted during all three EMG visits, including the Acute Drug Challenge 
Visit. 
 
Startle Data Collection and Processing. Via Presentation software (Albany, CA), 
acoustic startle probes that are 40-ms duration, 103-dB bursts of white noise will be 
presented. Electric shocks will last 400-ms. Startle will be recorded using the PI’s BioSemi 
Active Two system (BioSemi, Amsterdam, The Netherlands) and data collected and 
processed (e.g., filtering, rectification, smoothing, scoring blinks) according to published 
guidelines, as reported in the PI’s publications56-58. Startle is processed using the PI’s 
interactive ‘batch’ program in BrainVision Analyzer 2 (Brain Products). Consistent with 
the PI’s work, and published recommendations59, we will calculate standardized residual 
scores for the two forms of threat anticipation - U-threat and P-threat. This method has 
been shown to most accurately quantify the difference between threat and no-threat 
reactivity. Blinks will be scored as missing if the baseline period was contaminated with 
noise, movement artifact, or if a spontaneous or voluntary blink began before minimal 
onset latency. For each task, mean blink magnitude scores for each condition (N, P, U) 
will be calculated and used in primary analyses. 
EMG/EEG Visits. Task 2: Alcohol Cue Reactivity. Participants will complete a 
modified Alcohol Cue Reactivity Task71. The task consists of four conditions: alcoholic 

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beverages, non-alcoholic beverages, pixilated control images, and fixation (rest) periods. 
Each of the 4 conditions consists of 22 stimuli each presented four times. Stimuli are 
presented sequentially in a pseudo-randomized order each for about 1 second with a 
1250 ms inter-stimulus interval. Alcohol and non-alcohol beverage stimuli were previously 
standardized to ascertain adequate identification, and comparable valence, arousal, and 
visual characteristics between the two conditions71. Throughout the task, participants will 
be instructed to indicate their mood and the valence of the different stimuli. 
Psychophysiology Data Collection and Processing. During the Alcohol Cue 
Reactivity task we will record continuous electroencephalography (EEG) readings using 
a 32 channel ActiveTwo BioSemi system (BioSemi, Amsterdam, Netherlands).The data 
is recorded off the scalp, non-invasively, while participants are wearing a stretch lycra 
EEG cap. The EEG signal will be pre-amplified at the electrode to improve the signal-to-
noise ratio. The data will be digitized at 24-bit resolution with a Least Significant Bit (LSB) 
value of 31.25nV and a sampling rate of 1024Hz, using a low-pass fifth order sinc filter 
with a -3dB cutoff point at 204.8Hz. Off-line analysis will be performed using Brain Vision 
Analyzer software (Brain Products), using conventional preprocessing steps. Data will be 
re-referenced to the average of the two mastoids and high-pass (0.1Hz) and low-pass 
(30Hz) filtered. Data will be segmented around event markers that correspond to the 
administration of task stimuli. Baseline correction for each trial will be performed and brain 
activity averages will be computed for each condition, for each task.  
 
fMRI Data Collection. All scanning will be performed at the OSU Center for 
Cognitive and Behavioral Brain Imaging (CCBBI), using a Siemens 3T Prisma MR 
scanner with Total Imaging Matrix (TIM) system and a phase-array head coil for parallel 
imaging to minimize signal loss and image distortion. Prior to entering the fMRI scan, 
female participants will complete a urine pregnancy test. Each session will begin with an 
MP-RAGE high-resolution structural imaging of the whole brain (TI =950 ms; TR = 1950 
ms; TE = 4.44 ms; flip angle 12o; 176 sagittal slices; 256 x 256 matrix size with spatial 
resolution as 1x1x1mm^3, slice partial Fourier of 6/8). fMRI signal measures will be 
acquired using a T2*-weighted Echo-Planar Imaging sequence with BOLD contrast to 
measure task-related effects, optimized to reduce susceptibility artifact in the ventral 
frontal cortex and medial temporal lobe (TR = 2000 ms; TE = 25 ms; flip angle =70o; 64 
x 64 in-plane resolution; and 1906 Hz/pixel bandwidth). Thirty-five 3 mm axial slices will 
be acquired to cover the cerebrum and most of the cerebellum with no gap. Slices will be 
tilted about 20o clockwise along the AC-PC plane to obtain better signal in the 
orbitofrontal cortex. These parameters are used to 
minimize signal dropout, image distortion and 
susceptibility artifacts. Head movement is minimized 
through instruction, eye-tracking, and foam padding 
within the head coil. Participants will complete 2 tasks 
and spend 45 minutes in the bore of the magnet. 
fMRI Lab Visits - Task 1: Startle response 
to threat. Stress reactivity will be probed using an 
fMRI version of the NPU threat paradigm, developed 

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and implemented by the PI60. The fMRI task is analogous to the original NPU design; 
however, shock is administered to the left foot to avoid scanner interference. Individual 
shock levels are re-calibrated.  
The task uses threat-of-mild-electric-shock to elicit stress in two contexts: threat of 
a predictable electric shock (fear) and threat of an unpredictable electric shock 
(anticipatory anxiety). Shock level is determined ideographically using a pre-task shock 
work-up in which participants receive increasing levels of shock intensity (max 5mA) until 
they reach a level they describe as “highly annoying but not painful.” The task includes 
three within-subjects conditions: no-threat (N), predictable threat (P), and unpredictable 
threat (U). Text at the bottom of the screen informs participants of the current task 
condition. Each condition includes a countdown (CD) that ranges 3-8s (M=5s). During N, 
no shocks are delivered. During P, a shock is delivered when the CD reaches “1”. During 
U, shocks are delivered at random. Following each CD there is a fixation for 5-7s (M= 6s). 
N, P and U CDs are presented in blocks of 5 and each condition/block is administered in 
a randomized order 5 times over two runs for a total task time of 10 mins. Participants 
receive 20 shocks (10 in P, 10 in U) during each run. Electric shocks will last 400-ms. The 
rate of “Shock at 1” during the P condition is 60% to prevent an excessive number of total 
shocks during the task, consistent with the NPU version used by Grillon and colleagues61. 
Acoustic white noise startle probes that are 103bd, 40-ms duration will be administered 
via headphones during the NPU threat paradigm. Startle data is collected from two 
peripheral electrodes placed under the participant's left eye and recorded using Brain 
Vision Recorder software. Our data from two studies indicate that despite being shocked, 
participants are able to remain still and total motion is minimal (n=237; M 
translation=.03±.02mm and rotation=.02±.01degrees). PI Gorka’s lab is currently 
recording simultaneous fMRI+startle in another IRB approved study (Protocol#:  
2021H0039). After the task, self-report ratings of the threat, consistent with above, will be 
assessed. 
During the NPU task, BOLD is the index of stress reactivity. The BOLD contrasts 
of interest will capture activation during threat anticipation: U-threat anticipation > No-
threat anticipation and P-threat anticipation > No-threat anticipation. At the end of the 
task, participants rate how intense, arousing, and anxiety provoking the conditions and 
shocks were. Of note, our prelim data from two separate studies indicate that despite 
being shocked, participants are able to remain still and total motion is minimal (n=237; M 
age=19.3; M translation=.03±.02mm and rotation=.02±.01degree across runs). 
 
fMRI Lab Visits - Task 2: The Resting State Task (RST). For this task 
participants will view a fixation cross on a blank background for approximately 10 minutes. 
Participants will be instructed to keep their eyes open and focused on the cross, and to 
try not to think of anything in particular. 
 
fMRI Data Processing. Data preprocessing will involve well-tested, routine 
procedures used in our lab. Conventional steps (e.g., realignment, normalization, 
smoothing) will be executed using Statistical Parametric Mapping software (SPM8; 
Wellcome Trust Center for Neuroimaging, London). Strict quality control procedures will 
be in place to evaluate head motion (e.g., excluding subjects with >1.5 mm movement in 
any direction) and ensure proper normalization. Motion parameters will be included in all 

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first-level models as regressors of no interest. Statistical analyses will use the modified 
General Linear Model (GLM) in combination with a temporal convolution for block-related 
analyses in a random effects model. Statistical inference will use random field theory to 
account for non-independent observations within a smooth map. We will implement 2 
complementary approaches to test regional activation: 1) hypothesis-driven region-of-
interest (ROI)-based analysis of BOLD percent signal change (PCS) created from 
anatomy-based landmarks using small-volume correction (p<.05, FWE-corrected); and 
2) whole-brain activation search at a threshold of p<.05 (FWE-corrected). 
 
Suvorexant Accountability and Compliance. The compound pharmacy will prepare the 
study capsules and supply them to OSU Investigational Drug Services (IDS). Appropriate 
storage temperature of suvorexant will be maintained by IDS. IDS staff will maintain 
records of distribution to each subject. These records will include dates, quantities, batch, 
expiration dates, and unique code numbers assigned to the product and study subjects. 
Prior to distribution, the IDS will prepare each subject’s study medication in blister 
packaging. Each blister is clearly marked with the date the capsule will be ingested. 
 
Administration of Drug or Placebo (Acute Drug Challenge).  
Overview. Following the initial EMG/EEG or fMRI visit (dependent upon 
randomization) participants will return to the lab for the Acute Drug Challenge Visit. 
Participants will first arrive to the Clinical Research Center (CRC) for drug or placebo 
administration. After 2-hours, participants will then be escorted to the PI’s laboratory for 
the EMG assessment. After the assessment, participants will return to the CRC for further 
monitoring and discharge to assure that vital signs (heart rate, oximetry, blood pressure) 
are within normal limits and/or do not require immediate medical attention and that the 
participant can maintain wakefulness as demonstrated by a score of 7 or less on the 
Karolinska Sleepiness Scale (KSS)62 (1=“Very alert”; 5=“Neither alert nor sleepy”; 7= 
“Sleepy, but no difficulty remaining awake; 9=“Very sleepy, fighting sleep”). Participants 
will consent to not operating a vehicle for at least 24 hours after the Acute Drug Challenge 
Visit. A taxi voucher or Uber reservation will be provided by study staff for transportation 
home if participants do not have a means to transportation.  
Placebo and suvorexant (i.e., Belsomra®; 10mg; Merck & Co., Inc.) will be obtained 
from the compound pharmacy and will be placed in opaque capsules with dextrose filler 
for each session. Placebo capsules will be identical in appearance but will contain only 
dextrose. All capsules will be administered to subjects in double-blind conditions at the 
CRC under medical supervision.  
Administration Timing. Peak plasma concentration for suvorexant is 2 hours post-
ingestion. Therefore, participants will receive the drug (or placebo) at the CRC upon 
arrival. After 1.5 hours (90 minutes post ingestion), participants will be escorted to the 
laboratory for EMG/EEG testing. Laboratory assessments will occur during peak 
concentration, ~2 hours post-ingestion.    
Self-Report Assessments During Acute Drug Challenge. Throughout the Acute 
Drug Challenge Visit standardized questionnaires will be used to assess mood states and 
subjective drug effects: (1) Karolinska Sleepiness Scale (KSS)62; (2) Anxiety Visual 
Analog Scales (VAS)63; and (3) Drug Effects Questionnaire (DEQ)64; and Profile of Mood 

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States (POMS)65. The KSS, VAS and DEQ will be collected immediately before capsule 
ingestion (Time 0), and approximately 30, 60, 90, 120, 150, 180, and 210, and 240 
minutes afterwards. The POMS will be completed immediately prior to capsule ingestion 
(Time 0), and approximately 60 minutes, 120 minutes, and 240 minutes afterwards. 
Vitals Signs Measurements During Acute Drug Challenge.  Physiologic measures 
will be collected throughout the study visit: (1) Blood Oxygen (O2) Saturation; (2) Heart 
Rate and (3) Blood Pressure will be taken before capsule ingestion (Time 0), and 
approximately 30, 60, 90, 120, 150, 180, and 210, and 240 minutes afterwards. 
Measurements will be performed at the CRC or in the PI’s lab using portable blood 
pressure and finger oximeter. Measurements will be obtained using a finger oximeter and 
portable blood pressure cuff. Any participant who experiences excessive drowsiness, 
allergy symptoms, and/or adverse drug reactions will be assessed by the CRC and study 
physician and immediately withdrawn from the study as a safety measure. 
 
Drug Trial and Monitoring. At the end of the acute challenge, subjects will be provided 
the rest of their prescription (SUV or placebo) in blister packaging, prepared by OSU IDS. 
The blister packaging will be labeled with each date of the protocol. Subjects will be 
directed to ingest one pill each night, as they get into bed (~30 mins prior to sleep time) 
to mitigate drowsiness, consistent with SUV’s prescription.  
Each morning for the 4-week medication trial period, subjects will be asked to 
complete a brief clinical assessment, sent directly to subjects’ smartphones at 8:30am. 
The survey will capture: medication adherence (yes/no); timing of pill ingestion; time spent 
in bed and asleep; medication side-effects; number and timing of alcoholic beverages; 
alcohol craving; illicit substance use; mood; and new medication usage to monitor 
potential drug-drug interactions. If the survey is not completed, a reminder will be sent to 
the participant every 30 minutes for 150 minutes (5 total reminders). Responses will be 
collected, password-protected, and encrypted locally on smartphones. 
Subjects who endorse medication side effects other than nighttime drowsiness will be 
contacted by the study physician for a review of symptoms and safety. Additionally, if 
subjects endorse taking new medications, the study physician will review the information 
and contact the subject if further information is needed. The study physician and PI will 
utilize Lexicomp to check drug-drug interactions and only interactions of minor severity 
will be allowed. Those found to have moderate or severe interactions will be withdrawn 
from the study, consistent with study exclusionary criteria. 
 Subjects will also be contacted if medication compliance falls below 80% or above 
120%. At the final lab visit, subjects will be asked to bring their blister pack with them to 
verify compliance using the pill count method. Thus, medication compliance is tracked 
using both daily self-report, pictures, and objective pill count. 
 
Post-Treatment Lab Visits. During the final days of the trial, subjects will return to the 
lab to repeat the lab protocol. Individuals enrolled in the BRAINS Group will come in for 
a separate visit to repeat the fMRI. At study conclusion, subjects will be debriefed and 
provided a list of AUD treatment referrals and resources. 
 

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Self-report Data Processing. All measures will be double entered, checked for 
discrepancies, and cleaned. Analyses will assume that ‘missingness’ occurred at random, 
with data imputed when necessary.  
 
7.0 Expected Risks/Benefits 
 
There will be no direct benefit to participants for participation in this study, other than they 
will be compensated for their time for participation in this study. The study will be used to 
further our knowledge on the potential utility of suvorexant for the treatment of AUD. 
 
 
 
Diagnostic/Assessment Procedures: The diagnostic interview and questionnaires are 
time consuming and may be boring to some individuals. These are, however, necessary 
in order to determine eligibility for the study and test hypotheses. In addition, questions 
about alcohol/drug use, abuse/trauma history, and questions related to history of suicidal 
and/or homicidal behavior may be considered sensitive by some participants. The 
collection of such data poses a potential risk of loss of confidentiality around sensitive 
information such as psychiatric status and history of substance abuse. Participants will 
also be informed in the consent document that confidentiality will be limited in cases 
where the participant reveals intentions to harm themselves or others, and the 
investigator feels that the proper authorities may need to be notified in order to prevent 
the occurrence of harm to the participant, or others. Interviews will be conducted by 
experienced mental health workers who will maintain confidentiality and all data from 
interviews and questionnaires will be numbered so as to conceal the identity of the 
participant.  
 
Tasks: Some subjects may feel anxiety in response to the acoustic startle probes during 
the startle task. The experience of mild, electrical stimulation during the threat task elicits 
temporary mild anxiety by design. Any distress experienced while participating in the 
study is unlikely to persist beyond completion of study procedures. It should be noted that 
neither the acoustic startle probes nor the electrical stimulation to be used in the study 
present greater than minimal risk. The startle probe is a 40ms, 103dB burst of white noise 
– 10,000 times lower than Occupational Safety and Health Administration guidelines for 
maximum daily acoustic energy exposure for adults. Moreover, studies have used more 
intense acoustic stimuli with infants with no adverse effects. The electrical stimulation 
lasts only 400ms, and the maximum stimulation level is 5 mA. This is in the ampere range 
used by physical therapists and chiropractors, but of a much shorter duration. This level 
of stimulation presents no risk of physical injury. The PI and/or Co-I will be available during 
all tasks in order to evaluate and recommend treatment for the emergence of any 
anxiety/panic attack or elevated levels of anxiety. 
 
Magnetic Resonance Imaging: Magnetic resonance imaging is non-invasive, widely 
used, and safe. The potential risks such as static magnetic field, radio-frequency field, 
magnetic field gradients, and acoustic noise are rarely dangerous or life threatening. 
Additional minor and/or rare risks include: (a) discomfort or anxiety from being in the 
confined space of the MRI scanner; (b) fast imaging sequences, such as those employed 

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in this study, have the potential to induce peripheral nerve stimulation (PNS). PNS can 
be described as a light touching sensation on the skin surface and may cause mild 
discomfort, but is not harmful to the subject; (c) risks of hearing damage due to loud 
noises produced by the scanner; (d) risk that the magnetic resonance image will reveal a 
minor or significant lesion in the brain, e. g. a tumor, previously unknown to the subject, 
and requiring additional follow-up; (e) risk of injury from objects accelerated by the strong 
magnetic field of the magnet, striking the subject; or metallic substances on the skin or 
foreign bodies implanted deliberately or accidentally in the subject that acquire kinetic or 
thermal energy from the magnetic or radiofrequency emissions of the MRI, causing tissue 
injury to the subject; (f) sometimes, subjects report a temporary, slight dizziness or light-
headedness when they come out of the scanner; (g) potential risk for pregnant women: 
According to the NIMH Council Workgroup on MRI Research and Practices (September, 
2005), “there is no known risk of MR brain scanning of a pregnant woman to the 
developing fetus for scanning at 4T or less, and no known mechanism of potential risks 
under normal operating procedures.” Nevertheless, subjects should be warned about 
potential risks not yet discovered. 
 
Discovery and disclosure of incidental finding or abnormality on MRI scans: During the 
formal consent process, all subjects will be informed about the potential risks of 
discovering an incidental finding or abnormality on their MRI scan. The Center for 
Cognitive and Behavioral Brain Imaging is a research center. It is NOT a Clinical MRI 
facility in a hospital. There are no neuroradiologists at the Center for Cognitive and 
Behavioral Brain Imaging, therefore the staff are unable to make any medical comments 
the scans. However, all structural scans obtained in normal research subjects are sent to 
a neuroradiologist for review. In addition, participants are given the structural images on 
a CD.  In the event the neuroradiologist detects an abnormality, the Center staff will 
forward his findings to the participant primary care physician (PCP) within one month of 
the scan. The participant and PCP will receive information that the neuroradiologist has 
found some abnormalities that could be potentially significant. This will be communicated 
by a letter. The neuroradiologist will be available to consult with the PCP if it is necessary. 
Any costs associated with seeing the primary care physician will be participant 
responsibility. If participants cannot designate a primary care physician in the MRI 
Screening Form, they cannot participate in the study. Normal scan results will be available 
one month after the study and will not be communicated to a primary care physician. 
 
Suvorexant-Related Risks: Suvorexant is a Drug Enforcement Administration (DEA) 
schedule IV-controlled substance in the United States because it is considered to have 
abuse liability similar to other approved sleep medications (e.g., zolpidem). Preclinical 
self-administration studies in rats and monkeys indicate suvorexant does not have 
positive reinforcing effects65. In previous clinical trials there has been no evidence of 
physical dependence with the prolonged use66. There is also no evidence of withdrawal 
or “discontinuation syndrome” following abrupt discontinuation66.  
Suvorexant is associated with some potential adverse side-effects including: 
sleepiness or drowsiness, headache, nausea, dizziness, diarrhea, dry mouth, and 
abnormal dreams. Next day drowsiness is considered the most common side-effect. All 

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other side-effects have an incidence between 1-10%. Rare but potentially serious side 
effects include: worsening of depression and increase of suicidal ideation, complex sleep 
behavior and sleep paralysis, and temporary weakness in legs. Taking a CNS depressant 
(e.g., benzodiazepines, opioids, some antidepressants and anxiolytics, other sleeping 
medication) increase the risk of side effects and should not be taken at the same time as 
suvorexant. Suvorexant should not be taken with grapefruit juice, as this may significantly 
increase the levels of medication in the blood. Suvorexant should not be taken unless 
individuals are able to stay in bed for a full night (at least 7 hours) before they must be 
active again. Individuals should also not drive, operate heavy machinery, or do other 
activities that require clear thinking immediately after taking suvorexant. 
Co-I, Dr. Phan, M.D., is a Board-certified psychiatrist and physician, and will be 
available during the Acute Drug Challenge and Drug Trial in order to evaluate and/or 
recommend further evaluation and treatment for the emergence of any adverse 
events/side effects. Participants taking psychoactive/psychotropic medications or 
medications that would interact with suvorexant will be excluded. Pregnant participants 
will be excluded from participation because there is insufficient data to assure safety of 
the fetus during suvorexant exposure. As well, female participants who are not using 
acceptable methods of contraceptives or abstinence will be excluded. In addition, nursing 
mothers will be excluded from the study because the extent to which suvorexant is 
concentrated and excreted in human breast milk is unknown. Participants will be fully 
debriefed following the study. During debriefing, any questions participants may have will 
be answered.  
 
Drug-Alcohol Interactions: To date, there have been at least three human laboratory 
studies that have directly investigated the pharmacokinetic (PK) and pharmacodynamic 
(PD) interactions between ethanol and orexin antagonists67-69. All three studies used the 
highest possible dose of orexin-based medication to robustly probe for the potential for 
ethanol interactions (e.g., 40mg of suvorexant). All three studies confirmed that 
coadministration with ethanol does not alter the PK of orexin therapeutics, apart from 
potentially prolonging time to reach maximum plasma concentration (tmax) by about 75 
mins. There is no effect of orexin therapeutics on the ethanol concentration versus time 
profile. With regard to PD, co-administration produced additive impairment on measures 
of sustained attention/vigilance, balance, and working memory. There was no evidence 
of supra-additive effects. High doses of orexin antagonism alone, and in combination with 
ethanol, were well tolerated with no severe or serious AEs reported and no observed 
effects on clinical laboratory or cardiac variables. Mild to moderate treatment emergent 
adverse events (TEAEs) reported following co-administration included headache, fatigue, 
and sudden onset of sleep. There was no impact of co-administration on positive or 
negative mood. All three studies concluded that concomitant use of alcohol and orexin-
based antagonists should be avoided due to the potential for additive psychomotor 
effects; though there are no serious concerns regarding safety and tolerability like with 
other sleep medications such as hypnotics. Participants will be informed of these risks 
during informed consent and at the Acute Drug Challenge Visit. 
 
8.0 Data Collection and Management Procedures 

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• 
Sources of material from human subjects include: (a) written informed consent, (b) 
telephone screen form, (c) diagnostic interview, (d) self-report questionnaires, (e) 
urine drug screen, (f) urine pregnancy test (women only), (g) startle eyeblink data, 
(h) fMRI data, and (i) EEG data. 
• 
Each subject is given a unique number and there is a password-protected master 
key database separate from study data linking the subject with the code only 
accessible to research team members. This file is a password-protected master 
key database, which links the participant with unique participant codes; it is stored 
on the password-protected server, and kept separate from study data. The 
information in this file could be used to indirectly identify participants. The record 
linking participants to the research codes will be destroyed 6 years after completion 
of the study, thereby anonymizing the data. 
• 
All research materials from participants will be labeled with the unique participant 
code (not participant name).  
• 
Paper forms with the participant code will be kept in a locked cabinet where only 
IRB approved key research personnel will have access.  
• 
Data collected during the tasks and fMRI for each participant will be saved with a 
research identifier number only and stored in computer files without reference to 
any personally identifiable information. These files will be stored on the lab server. 
These measurements will be obtained solely for the purposes of research.  All 
research materials will be maintained in strict confidentiality. 
• 
To protect against, or minimize risk associated with participants using smart 
phones in an unsafe way (attempting to respond to smart phone survey questions 
while driving a car), participants will be trained to delay responding to the smart 
phone beeps when it is unsafe (e.g., when driving) or potentially embarrassing 
(e.g., during a religious service or at the movies). Data collection will be encrypted 
to prevent access of personally identifiable data should telephones be lost or 
stolen. The data will be stored on the device itself and can only be accessed by a 
password system. This means that no one, even the research participant, can see 
or review entered data.  
• 
When daily clinical assessments are completed, the data will be transferred from 
the software platform and maintained on secure servers within Center for Human 
Resource Research (CHRR). CHRR maintains a secure data storage 
infrastructure. The procedures and infrastructure meet the stringent data protection 
requirements of the U.S. Census Bureau and the Bureau of Labor Statistics.  
• 
Only IRB approved key research personnel have access to the data. If any member 
of the research study leaves, his or her access to the network and all files will be 
removed immediately, thereby terminating access to this file and other files 
associated with the study.  
 
9.0 Data Analysis 
• Startle Data Collection, Processing and Statistical Analysis: Stimuli will be 
administered using Presentation software (Albany, CA) and data collected using 

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Biosemi Actiview 2 system. Acoustic startle probes will be 40-ms duration, 103-dB 
bursts of white noise with near-instantaneous rise time presented binaurally 
through headphones. For the threat task, electric shocks will last 400-ms. Startle 
responses will be recorded and data collected and processed (e.g., filtering, 
rectification, smoothing, scoring blinks) according to published guidelines. The 
startle data will be processed using an interactive ‘batch’ program that the PI 
developed in BrainVision Analyzer (BrainProducts). The PI’s data indicate that 
~7% of blinks are “missing” and thus, we will administer a large number of startle 
probes (72) to ensure that missing responses do not bias analyses. Consistent 
with prior studies, we will create startle potentiation scores for U and P, which 
account for individual differences in baseline reactivity by subtracting responses 
during the N condition. All variables will be checked for inter- and intra-measure 
consistency, and frequency distributions will be examined for outliers. Data 
transformations will be employed as necessary.   
• 
EEG Data Collection, Processing and Statistical Analysis: During the Alcohol Cue 
Reactivity task we will record continuous electroencephalography (EEG) readings 
using a 32 channel ActiveTwo BioSemi system (BioSemi, Amsterdam, 
Netherlands).The data is recorded off the scalp, non-invasively, while participants 
are wearing a stretch lycra EEG cap. The EEG signal will be pre-amplified at the 
electrode to improve the signal-to-noise ratio. The data will be digitized at 24-bit 
resolution with a Least Significant Bit (LSB) value of 31.25nV and a sampling rate 
of 1024Hz, using a low-pass fifth order sinc filter with a -3dB cutoff point at 
204.8Hz. Off-line analysis will be performed using Brain Vision Analyzer software 
(Brain Products), using conventional preprocessing steps. Data will be re-
referenced to the average of the two mastoids and high-pass (0.1Hz) and low-pass 
(30Hz) filtered. Data will be segmented around event markers that correspond to 
the administration of task stimuli. Baseline correction for each trial will be 
performed and brain activity averages will be computed for each condition, for each 
task.  
• fMRI Data Collection, Processing and Statistical Analysis: All MR scanning will be 
performed on a 3.0 Tesla GE Discovery MR750 System (Milwaukee, WI) using a 
state-of-art 8-channel radiofrequency coil and updated software (Discovery 20.0, 
Neuro-optimized gradients), optimized to reduced susceptibility artifact in the 
ventral frontal cortex and medial temporal lobe. A high-resolution T1 scan (Bravo 
3D IR-prepped fast SPGR: Axial 22 x 22cm FOV, 1mm slice thickness, 13⁰ flip, TI 
= 450 ms, matrix = 256 x 256 matrix, 186 slices, NEX=0.75, 25kHz rBW, minimum 
TR/TE [~8-9ms/3-4ms]) will provide precise anatomical localization. Participants 
will be instructed on tasks and will be acclimated in an MRI simulator. Whole-brain 
fMRI BOLD-related signal measures will be acquired using a T2*-weighted echo-
planar imaging sequence with BOLD contrast (gradient-echo axial EPI with 22 x 
22cm FOV, 3 mm slice thickness, 0 gap, TR=2s, TE=minFull [~25ms], 90⁰ flip, 250 
kHz rBW, Parallel imaging (ASSET) =ON, Number of Slices: 43+ (optimal for 
normal coverage), 64 x 64 matrix) to measure task-related effects and designed to 
minimize susceptibility artifact (signal loss). 

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• Functional data will be processed and analyzed using conventional methods 
(GLM, event-related design, random effects) with Statistical Parametric Mapping 
(SPM8; 
Wellcome 
Department 
of 
Cognitive 
Neurology, 
London; 
www.fil.ion.ucl.ac.uk/spm). 
Analysis 
will 
implement 
two 
complementary 
approaches: 1) a hypothesis-driven, anatomically focused region of interest (ROI)-
based analysis; and 2) exploratory whole-brain voxel-wise analysis.  
• The Data Analysis Plan for each aim is presented in the “Statistical Considerations” 
section.  
 
10.0 Quality Control and Quality Assurance 
• 
Please see bullet below for description on how startle and fMRI data is 
evaluated for adherence with the protocol.  As noted above, all self-report data 
will be double entered, checked for discrepancies, and cleaned. Analyses will 
assume that ‘missingness’ occurred at random, with data imputed when 
necessary. Type 1 error rates will be adjusted using Bonferroni corrections. 
• 
The PI of the study and her research staff are responsible for the monitoring of 
the research and the evaluation of the data quality. After each session data is 
transferred to the lab storage drive. The data is closely reviewed to ensure its 
quality and that nothing is missing.  
• 
Both startle and fMRI data are processed using automated scripts; however, 
the PI and study staff examine each blink file by hand to ensure acceptability 
and high-quality data.  
 
11.0 Data and Safety Monitoring 
 
• 
We have developed a formal data safety and monitoring plan to ensure the 
ongoing safety of participants (as well as the integrity of the study). The plan 
involves weekly meetings that will be used to communicate any concerns or issues 
with safety, confidentiality, or progress. 
• 
Suicidal Ideation: The PI is a clinician and has extensive experience in the 
assessment of acutely depressed and anxious patient volunteers at screening and 
in the context of lab assessments. The PI routinely evaluates for suicidal ideation, 
behavior and risk, and will consult with and closely oversee the clinical monitoring 
and suicide assessment during the study. If suicidality is endorsed by a participant 
at any point during the assessment or experimental portion of the study, 
appropriate steps will be taken. Specifically, the PI or trained study staff member 
will a) obtain a more detailed assessment of intent, plan and method, including 
using the gold-standard, empirically-validated Columbia Suicide Severity Rating 
Scale (CSSRS)70; b) discuss the situation with the participant, the participant’s 
emergency contact, and/or members of the mentorship team as warranted; c) 
consult with the PI and/or CO-Is; and d) make an appropriate treatment referral for 
the participant. If the PI believes that the participant is in imminent danger, they 
will call 911 or will walk the participant over to the emergency room at the Ohio 
State University hospital, only 1 block away.  

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• 
Once enrolled, participants who show deterioration between assessment and the 
lab tasks (e.g., increased anxiety, depression, mania, psychosis, or suicidality) 
may be removed from the study and referred to our outpatient psychiatry clinic or 
emergency psychiatric evaluation, if necessary. Participants who are deemed to 
be at high risk during either the assessment or experimental session may need to 
be psychiatrically hospitalized. If the CSSRS indicates suicidal thinking or if 
suicidal behavior is present, or if there is any concern about current suicide risk, 
the PI will evaluate suicide risk and decide what level of care is sufficient. The PI 
will then facilitate follow-up visit, Emergency Room/emergency department visit or 
inpatient admission if necessary.  
• 
Weekly meetings of the research staff of this study will be conducted that will 
include review of accrual, consenting procedures, protocol adherence, adverse 
events, and quality control of all data obtained from the study in the previous week. 
All changes in protocol design will be reviewed by the IRB before such changes in 
protocol design take place.  
• 
All AEs occurring during the course of the study will be reported to the PI. Serious 
adverse events (SAEs) will be reported by the PI to the IRB within 5 business days 
of the PI (or her team’s) knowledge of the SAE. Moderate adverse events (AEs) 
that are unexpected and indicate that the research is associated with a greater risk 
of harm to participants or others than previously known will be reported to the IRB 
within 15 business days of the PI’s (or her team’s) knowledge of the event. All mild 
AEs and moderate AEs that are expected or are not associated with a greater risk 
of harm to participants or others than previously known will be reported to the IRB 
at the scheduled Continuing Review. 
  
12.0 Statistical Considerations 
13.0 Aim 1. Does a single dose of SUV decrease reactivity to U-threat? Hypothesis 
1: Relative to PBO, SUV will acutely dampen startle reactivity to U-threat, but not P-
threat. We will conduct a multilevel mixed model with startle magnitude as the 
dependent variable. Startle to U-threat and P-threat will be included as a within-
subjects factor, to test for specific changes in U-threat. Time (baseline vs. acute 
challenge) and treatment arm (SUV vs. PBO) will be included as within-subjects and 
between-subjects factors, respectively, and we expect a time x treatment arm x task 
condition interaction on startle. Models will include a random effect for participant.  
14.0 Aim 2. Does daily use of SUV decrease reactivity to U-threat? Hypothesis 2a: 
4-weeks of SUV will result in greater reductions in reactivity to U-threat compared 
with PBO, and these changes will be specific to U-threat. Hypothesis 2b: SUV-
related change in U-threat reactivity will be greatest amongst those with higher 
baseline U-threat reactivity. Exploratory Analysis: SUV will similarly result in 
decreases in aINS and dACC reactivity and connectivity during U-threat relative to 
PBO, and brain change will correlate with startle change. For H2a, we will conduct a 
multilevel mixed model that is nearly identical to the model described for H1. 
However, the time variable will be modeled as baseline vs. post-treatment. For H2b, 

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we will include baseline startle to U-threat as a predictor in our model and test for a 
baseline startle by treatment arm interaction. Lastly, for our exploratory fMRI 
analyses, we will first extract activation and functional connectivity parameter 
estimates from anatomical aINS and dACC during U-threat (and P-threat) > No-threat 
contrast maps. fMRI variables will be tested as dependent variables in the model 
used for H2a. Magnitude of brain change will be directly correlated with magnitude of 
startle change.  
15.0 Aim 3. Does daily use of SUV change alcohol behavior, and is this change 
linked to brain-behavior U-threat change? Hypothesis 3a: Daily SUV will result 
in greater reductions in PHDD and DPDD compared with PBO. Hypothesis 3b: SUV-
related changes in PHDD and DPDD will be greatest in those with higher U-threat 
reactivity. Hypothesis 3c: In all subjects, changes in brain-behavioral U-threat 
reactivity will correlate with changes in drinking behavior. For H3a, linear mixed 
models will be used to assess the impact of treatment arm (SUV vs. PBO) on 
changes in drinking behavior over the 4-week follow-up period (daily reports). If the 
assumptions of linear models are violated due to skewed residual errors, we will 
explore the use of Poisson and negative binomial generalized linear mixed models 
to model drinking behavior. For H3b, baseline startle potentiation to U-threat (and in 
secondary models, aINS, dACC, and BNST parameter estimates) will be entered as 
a covariate/predictor and we will test for a baseline startle to U-threat by treatment 
arm interaction on drinking behavior outcomes. Lastly, the hypothesis for H3c will be 
tested using a linear mixed model that includes magnitude of U-threat and P-threat 
reactivity (startle and brain, separate models), time, and treatment arm as predictors 
and PHDD and DPDD as the outcomes. We expect a startle by time interaction such 
that regardless of treatment arm, a change in U-threat reactivity will correspond to a 
change in drinking behavior.  
Sample Size. Our key hypothesis testing involves treatment arm by session 
interactions on startle eyeblink potentiation. Assuming a medium to large effect size, 
which is supported by our preliminary data, a sample size of 40 individuals per treatment 
group would conservatively yield 91% power (a total sample size of 80 individuals). To 
account for potential screen-fails, participants requesting to drop out of the study, and the 
PI withdrawing participants due to meeting termination criteria, approval for 120 
participants is requested. 
 
 
13.0 Regulatory Requirements 
13.1 Informed Consent 
• During the initial assessment, the nature of the research project will be 
described to participants. A written summary, in lay terms, of the research 
project will be provided to the participants in the written informed consent 
document that the participants will review. The consent document will inform 

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the participants of the voluntary nature of the study procedures, the purpose 
of the study, the procedures to be followed, the duration of the study, the 
risks associated with suvorexant, the risks associated with startle and fMRI 
procedures such as exposure to loud noise bursts, as well as the potential 
benefits to the community at large.  Women will agree that they are not 
pregnant, nursing, or planning to become pregnant. Participants will be 
informed that a urine sample for a pregnancy/toxicology screen and a 
breathalyzer will be obtained at both sessions. Written informed consent will 
be obtained by the PI or designated research staff and the participant will 
receive a copy of the signed consent form. Participants will be informed that 
they can discontinue participation at any time without penalty.   
• Each member of the research team will complete the HIPAA and CITI 
human subjects trainings and will be trained in the research protocol and 
will have reviewed the informed consent document and assent forms 
themselves.   
• The informed consent document will be stored in a separate locked file 
cabinet from any other research files in a locked office.  Only research staff 
on this specific research study will have access to the informed consent 
documents.   
13.2 Subject Confidentiality  
• All data from subjects will be marked with a research identifier number only 
and kept in locked cabinets. No data will have subject names on them, 
except for consent forms, which will be stored separately from other 
questionnaires in a locked file cabinet. Paper records will be kept in locked 
file drawers in a locked room, to which only authorized research personnel 
have access. Confidentiality of subject’s records is assured by assigning 
each subject a research identifier number/code, and such data, as well as 
fMRI and startle data, are stored in computer files (except for a single 
tracking file) without reference to name, or any other type of personally 
identifiable information. Data that may be reported in scientific journals will 
not include any information that identifies any person as a subject in this 
study. 
• Location and storage of computer files, which will store the startle/fMRI 
data: These files will be stored on the lab server.  
 
• Single tracking file: This file is a password-protected master key database, 
which links the participant with unique participant codes; it is stored on the 
password-protected server, described above, and kept separate from study 
data. The information in this file could be used to indirectly identify 
participants. Only research study personnel directly involved with the 
project (e.g., the PI, her research assistants and the project manager) will 
have access to this file. If any member of the research study leaves, his or 
her access to the network will be removed immediately, thereby terminating 
access to this file and other files associated with the study. The record 

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linking participants to the research codes will be destroyed 6 years after 
study completion, thereby anonymizing the data. 
• Limits of Confidentiality on Clinical Information: Confidentiality is limited, 
however, when a danger to self or others is present. If the subject is 
discovered to be acutely homicidal or suicidal during the evaluation period, 
the subject will be evaluated for hospitalization in a mental health facility 
(either voluntarily or involuntarily as necessary). If, for whatever reason, the 
subject is not hospitalized when it is determined that he/she is either 
homicidal or suicidal (e.g., we receive a phone call from the subject or 
another person) the police may be alerted to bring the subject to a 
psychiatric emergency room. 
• Confidentiality of Drug Tests Prior to Scans or Assessment: 
The results of the urine drug and pregnancy screens will remain 
confidential. The only individuals who will have knowledge of the results of 
these tests are research staff directly working on the project.  
• The only PHI we are collecting in this study include the participants name 
and contact information (phone number, email address, home address).  
The reasons that we are collecting this information include: the participants 
name for the informed consent document, phone number and email address 
to schedule lab appointments. 
 
13.3 Unanticipated Problems 
• Any unanticipated problems (its occurrence, frequency or severity is new or 
greater than previously known or as expected based on subject 
characteristics, including natural progression of disease). They are always 
unanticipated by definition and will be reported to the IRB within 5 business 
days of the PI’s (or her team’s) knowledge of the event.     

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Appendices. 
Table 1. Administration of Questionnaires for BEHAVIOR Group. 
Interviews and Questionnaires 
Screening 
Session 
Lab Visit 1: 
Pre-Tx 
(EMG #1) 
Lab Visit 2: Acute 
Drug Challenge 
(EMG #2) 
Daily Clinical 
Assessments 
1-Month 
Follow-up 
Lab Visit 3: 
Post-Tx  
(EMG #3) 
SCID-5 Diagnostic Interview  
x 
 
 
 
 
 
C-SSRS* 
x 
 
 
 
 
 
Contact Information Form 
x 
 
 
 
 
 
NIAAA GUID Information 
x 
 
 
 
 
 
Health Questionnaire 
x 
 
 
 
 
 
BMI Questionnaire 
x 
 
 
 
 
 
Exclusionary Medication Checklist 
x 
 
 
 
 
 
Medication History Questionnaire 
(clinician administered) 
x 
 
 
 
 
 
Psychiatric Treatment History 
Form (clinician administered) 
x 
 
 
 
 
 
Demographic Information Form 
x 
 
 
 
 
 
BDI-II 
x 
 
 
 
x 
 
BAI 
x 
 
 
 
x 
 
SSI (timeframe: lifetime) 
x 
 
 
 
 
 
IUS 
x 
 
 
 
x 
 
GAD 
x 
 
 
 
x 
 
ASI 
x 
 
 
 
x 
 
BHS  
x 
 
 
 
 
 
PID-5 
x 
 
 
 
 
 
DASS-21 
x 
 
 
 
x 
 
SHAPS 
x 
 
 
 
 
 

                                      
 
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PSQI 
x 
 
 
 
x 
 
IDAS-II 
x 
 
 
 
x 
 
ERQ 
x 
 
 
 
 
 
CTQ-SF 
x 
 
 
 
 
 
PCL-5 
x 
 
 
 
 
 
LEC-5 
x 
 
 
 
 
 
AUDIT 
x 
 
 
 
x 
 
Dr-InC 
x 
 
 
 
x 
 
DMQ-R 
x 
 
 
 
x 
 
OCDS 
x 
 
 
 
x 
 
DAST 
x 
 
 
 
x 
 
FTND 
x 
 
 
 
x 
 
CUDIT 
x 
 
 
 
x 
 
TLFB (timeframe: past 3-months) 
 
x 
 
 
 
 
TLFB (timeframe: since Lab Visit 1) 
 
 
 
 
 
x 
CIWA-Ar – Clinician Administered 
 
x 
x 
 
 
x 
KSS 
 
 
 
x (9 times) 
 
 
 
VAS 
 
 
 
x (9 times) 
 
 
 
DEQ 
 
 
x (9 times) 
 
 
 
POMS  
 
 
x (4 times) 
 
 
 
Daily Clinical Assessment Form 
 
 
 
x 
 
 
*CSSRS will be completed as necessary based upon participant reports of suicidal ideation. 
 
 
 
 

                                      
 
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Table 2. Administration of Questionnaires for BRAINS Group. 
Interviews and Questionnaires 
Screening 
Session 
Lab Visit 1: 
Pre-Tx 
(EMG #1) 
Lab Visit 2: 
Pre-Tx  
(fMRI #1) 
Lab Visit 3: 
Acute Drug 
Challenge 
(EMG #2) 
Daily Clinical 
Assessments  
1-Month 
Follow-up 
Lab Visit 4: 
Post-Tx 
(EMG #3) 
Lab Visit 5: 
Post-Tx  
(fMRI #2) 
 
SCID-5 Diagnostic Interview  
x 
 
 
 
 
 
 
 
C-SSRS* 
x 
 
 
 
 
 
 
 
Contact Information Form 
x 
 
 
 
 
 
 
 
NIAAA GUID Information 
x 
 
 
 
 
 
 
 
Health Questionnaire 
x 
 
 
 
 
 
 
 
BMI Questionnaire 
x 
 
 
 
 
 
 
 
Exclusionary Medication Checklist 
x 
 
 
 
 
 
 
 
Medication History Questionnaire 
(clinician administered) 
x 
 
 
 
 
 
 
 
Psychiatric Treatment History Form 
(clinician administered) 
x 
 
 
 
 
 
 
 
Demographic Information Form 
x 
 
 
 
 
 
 
 
BDI-II 
x 
 
 
 
 
x 
 
 
BAI 
x 
 
 
 
 
x 
 
 
SSI (timeframe: lifetime) 
x 
 
 
 
 
 
 
 
IUS 
x 
 
 
 
 
x 
 
 
GAD 
x 
 
 
 
 
x 
 
 
ASI 
x 
 
 
 
 
x 
 
 
HSP 
x 
 
 
 
 
x 
 
 
BHS  
x 
 
 
 
 
 
 
 
PID-5 
x 
 
 
 
 
 
 
 
DASS-21 
x 
 
 
 
 
x 
 
 
SHAPS 
x 
 
 
 
 
 
 
 

                                      
 
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PSQI 
x 
 
 
 
 
x 
 
 
IDAS-II 
x 
 
 
 
 
x 
 
 
ERQ 
x 
 
 
 
 
 
 
 
CTQ-SF 
x 
 
 
 
 
 
 
 
PCL-5 
x 
 
 
 
 
 
 
 
LEC-5 
x 
 
 
 
 
 
 
 
AUDIT 
x 
 
 
 
 
x 
 
 
Dr-InC 
x 
 
 
 
 
x 
 
 
DMQ-R 
x 
 
 
 
 
x 
 
 
OCDS 
x 
 
 
 
 
x 
 
 
DAST 
x 
 
 
 
 
x 
 
 
FTND 
x 
 
 
 
 
x 
 
 
CUDIT 
x 
 
 
 
 
x 
 
 
TLFB (timeframe: past 3-months) 
 
x 
 
 
 
 
 
 
TLFB (timeframe: since Lab Visit 1) 
 
 
 
 
 
 
x 
 
CIWA-Ar – Clinician Administered 
 
x 
x 
x 
 
 
x 
x 
MRI Screening Form 
 
 
x 
 
 
 
 
x 
KSS 
 
 
 
 
x (9 times) 
 
 
 
 
VAS 
 
 
 
 
x (9 times) 
 
 
 
 
DEQ 
 
 
 
x (9 times) 
 
 
 
x 
POMS  
 
 
 
x (4 times) 
 
 
 
 
Daily Clinical Assessment Form 
 
 
 
 
x 
 
 
 
*CSSRS will be completed as necessary based upon participant reports of suicidal ideation.