Clinical trial NCT03610633
Conditions: Alcohol Use Disorder
Sponsor: Medical University of South Carolina
Start date: 2016-03-01; Completion date: 2018-09-01
Enrollment: 11 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Individuals with alcohol use disorder (AUD) will complete one functional Magnetic Resonance Imaging (fMRI) scanning visit. Prior to the scan, individuals will receive a nasal spray of either 24 international units (IU) of oxytocin (OT), or placebo (PBO). During the scan, they will perform the Montreal Imaging Stress Task (MIST), a social stress task. Subjective craving and anxiety data will be collected.

Detailed description:
Participants: Twenty-four individuals with AUD will be recruited through the Clinical Intake and Assessment (CIA) Core of the Alcohol Research Center (ARC). Screening and basic assessments will be conducted by the CIA Core to determine eligibility and suitability for participation in this pilot project. Each individual will sign an Institutional Review Board (IRB)-approved informed consent form.

Study Visit Assessments: The Drinking Motives Questionnaire Revised will be used to assess motivation for drinking across four subscales: (1) coping motives; (2) social motives; (3) conformity motives; and (4) enhancement motives. The Form 90 will be used to assess daily alcohol consumption in the 90 days prior to the study visit and the time from last drink . A modification of the Within Session Rating Scale will be used to assess craving and mood.

Study Visit Procedures: Participants will be asked to arrive at the Addiction Sciences Division on the study visit day. Female participants will have their urine tested for pregnancy. Females who test positive for pregnancy will be excluded. All participants will be tested for drugs of abuse and alcohol. Patients testing positive for drugs, with the exception of marijuana, will be excluded; patients testing positive for alcohol may be re-scheduled. Participants will be asked about substance use in the last 90 days and will fill out the Drinking Motives Questionnaire. Subjects who have not had a research physical exam within the last 30 days will have a physical completed. They will then be escorted to the scanner at 30 Bee Street.

The study will use a double-blind placebo controlled design. Intranasal OT (n=12) or PBO (n=12) sprays will be administered at 11:30 am, approximately 45 min prior to the scanning session. This dose and timing of OT administration were selected based on the literature.

MIST Procedure: The study will use a block design of three, 6-min runs separated by 2-min of rest for feedback, for a total of 24 min. During each run, participants will be exposed to 40-sec blocks of three different conditions (rest, control, and experimental). Prior to the task, participants will are shown images of what the screen will look like during each condition. The participants will be instructed to relax during the rest condition and focus on the screen. During the control condition, the participants will be asked to answer math problems as accurately as possible but will also be told that their responses will not be recorded. During the experimental condition, the participants will be asked to perform the math task as quickly and accurately as possible. A performance bar located on the screen will allow them to see their performance as compared to an "average" person. The participants will be told that the average person would answer about 85% of the problems correctly; however, the program limits the participants' performance rate to between 35-45%. A time limit will be enforced throughout the experimental condition. After each run, the participants will be given negative feedback from the investigator.

Blood Oxygen Level Dependent (BOLD)-fMRI Procedure: Data will be acquired on a Siemens Trio 3T scanner in MUSC's Center for Biomedical Imaging. For co-registration and normalization of functional images, a high resolution T1-weighted Magnetization-Prepared Rapid Acquisition with Gradient Echo (MPRAGE) anatomical image will be acquired with the following parameters: Time of Repetition (TR)= 2100 ms, Echo Time (TE)= 4.18 ms, flip angle= 12°, field of view= 256 mm, slice thickness= 1.0 mm. The scanning planes will be oriented parallel to the anterior commissure-posterior commissure line. Participants will be asked to relax and keep their eyes opened and fixed on a cross-hair for 6 min while resting state data are collected. Participants will then complete the MIST. T2\*-weighted gradient-echo planar images (EPI) will be acquired with the following parameters: TR= 2000 ms, TE= 27 ms, flip angle= 76º, matrix 64 x 64, field of view= 23 cm, slice thickness= 3.7 mm with no gap, with 36 slices to cover the entire brain.

Arms: arm 1: Participants will receive 24 IU of oxytocin prior to completing fMRI scanning procedures. arm 2: Participants will receive placebo (saline solution) prior to completing fMRI scanning procedures.
Interventions: intervention 1: Oxytocin intervention 2: Placebo
Intervention descriptions: intervention 1: The neuropeptide oxytocin (OT) increases social approach, trust, and reduces anxiety to social stress. intervention 2: Saline solution.

Protocol documents:
Prot_SAP_000.pdf: 
Impact of Neurobiological Substrates of Social Stress in 
Individuals with Alcohol Use Disorder 
NCT03610633 
Version Date: January 4, 2018 


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Page 1 
 
Impact of Oxytocin on Neurobiologic Substrates of Social Stress in Individuals with Alcohol Use 
Disorder 
 
 
Social stress is an important factor in the motivation to use and abuse alcohol, and social avoidance is a 
symptom of alcohol dependence [1, 2]. Social avoidance also impedes effective treatment particularly in group 
settings that are a commonly employed treatment modality. Data from human neuroimaging studies suggest 
that functional connectivity between the prefrontal cortex and limbic brain regions is important for maintaining 
affective and behavioral responses to social stimuli while results from clinical and preclinical studies suggest 
that chronic alcohol exposure produces alterations in corticolimbic brain regions that may underlie compulsive 
drug seeking behavior and relapse [3-6]. Therefore, therapeutic interventions that increase corticolimbic 
connectivity may be effective at ameliorating reactivity to social stress and reducing craving in alcohol 
dependent individuals. The neuropeptide oxytocin (OT) increases social approach, trust, and reduces anxiety 
to social stress [7-9]. Data from recent studies show that OT administration restored corticolimbic connectivity 
in individuals with social anxiety disorder and decreased withdrawal symptoms in alcohol dependent 
individuals[10, 11]. In addition, OT attenuated drug craving and anxiety in marijuana-dependent individuals 
exposed to a social stress task [12]. In this project, we propose a double-blind placebo controlled pilot study to 
compare the impact of OT versus placebo on corticolimbic connectivity in alcohol dependent subjects. Blood 
oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) will be used to measure 
corticolimbic connectivity at rest and during the Montreal Imaging Stress Task (MIST)[13]. Subjective craving 
and anxiety data will also be collected. Prior to the scanning session, participants will receive either intranasal 
OT (24 IU) or a placebo (PBO) spray.  
 
Aim 1: Determine the impact of OT on corticolimbic connectivity in alcohol dependent individuals 
exposed to social stress. Psychophysiologic interaction (PPI) analysis using the amygdala as the seed 
region will be used to assess significant task (stress condition > control condition) x seed interactions. 
Hypothesis 1A: The OT group will exhibit greater functional connectivity between the amygdala and prefrontal 
cortical regions (orbitofrontal and anterior cingulate cortices) than the PBO group.  Hypothesis 1B: The OT 
group will report lower subjective anxiety and craving in response to the MIST than the PBO group. 
 
Aim 2: To determine the impact of OT on resting-state functional connectivity in alcohol dependent 
individuals. Hypothesis 2A: OT will modulate resting-state functional connectivity among sub-networks 
implicated in reward and motivation (nucleus accumbens, and orbitofrontal cortex), memory and learning 
(amygdala and hippocampus), and cognitive control (prefrontal cortex and anterior cingulate cortex).  
 
 
Preliminary Data: Evidence for Corticolimbic 
Uncoupling During Social Stress in Individuals 
with SUDs 
We examined corticolimbic coupling during the 
MIST in cocaine-dependent (DSM-4) (n=13) and 
healthy 
control 
(n=15) 
subjects 
using 
a 
psychophysiological 
interaction (PPI) 
analysis.  
Using the left amygdala as the seed region, 
significant task x seed interactions were found in 
both groups (Figure 1A). In the cocaine-dependent group, the left amygdala exhibited significantly greater 
functional connectivity with the posterior cingulate cortex during stress. In the control group, the left amygdala 
exhibited significantly greater functional connectivity with the orbitofrontal cortex during stress. The MIST 
produced a significantly greater increase in anxiety in cocaine-dependent individuals than healthy controls 
(Figure 1B).  These data provide support and lend feasibility to employing these imaging and stress task 
procedures in this proposed pilot project. 
 
Approach:  
Participants: Twenty-four individuals with AUD will be recruited through the Clinical Intake and 
Assessment (CIA) Core of the ARC. Screening and basic assessments will be conducted by the CIA Core to 
determine eligibility and suitability for participation in this pilot project.  Each individual will sign an IRB-
z = 2
CD
L
z = 30
HC
2.8
3.2
3.6
4.0
A
Figure 1. (A) Areas exhibiting significant functional connectivity with the left amygdala during the
MIST in cocaine-dependent (CD) individuals, posterior cingulate cortex, (MNI; ± 2, - 54, 30) and
healthy controls (HC), orbitofrontal cortex (MNI; ± 40, 58, 2). Z statistic images were thresholded
using clusters determined by Z>2.3 and a corrected cluster significance of p=0.05 (B) Peak anxiety to
the MIST. Values are group means (+) se * Denotes significant difference from HC (p<0.05)
B
0
1
2
3
4
5
6
7
HC
CD
Anxiety
*
A


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approved informed consent form. Inclusion criteria include: 1) male or female, any race or ethnicity; ages 21-
40, 2) able to comprehend English and function at an intellectual level sufficient to provide informed consent 
and complete the assessments, 3) meet DSM-5 criteria for current alcohol use disorder and reports drinking on 
average, at least 20 standard alcoholic drinks per week for at least the past three months, 5) not engaged in 
and does not want treatment for alcohol related problems, 6) lives within a 50 mile radius of the ARC,  and 7) 
able to maintain abstinence from alcohol for the two days prior to the study visit.  Exclusion criteria include: 1) 
meet DSM-5 criteria for any other psychoactive substance use disorder, 2) psychoactive substance use 
(except marijuana and nicotine) within the last 30 days, 3) meet DSM-5 criteria for current major depression, 
panic disorder, obsessive-compulsive disorder, post-traumatic stress syndrome, bipolar affective disorder, 
schizophrenia, dissociate disorders, eating disorders, and any other psychotic disorder or organic mental 
disorder, 4) women who are pregnant or breastfeeding, 5) current suicidal ideation or homicidal ideation, 6) 
taking psychoactive medications or medications known to affect alcohol intake, 8) history of/or current 
cardiovascular, renal, GI, neurological or endocrine diseases, 9) history of alcohol related illness, 10) SGPT 
(ALT) or SGOT (AST) levels greater than 2.5 times normal at screening, 11) charges pending for a violent 
crime, 12) an unstable living situation, 13) presence of ferrous metal in the body, 14) claustrophobia or morbid 
obesity, and 15) history of head injury with >2 minutes of unconsciousness. 
Study Visit Assessments: The Drinking Motives Questionnaire Revised will be used to assess 
motivation for drinking across four subscales: (1) coping motives; (2) social motives; (3) conformity motives; 
and (4) enhancement motives [14]. The Form 90 will be used to assess daily alcohol consumption in the 90 
days prior to the study visit and the time from last drink [15] . A modification of the Within Session Rating Scale 
will be used to assess craving and mood [16]. The Childhood Trauma Questionnaire (CTQ) will be used to 
assess trauma prior to age 18 [24]. To determine MRI safety, the Metal Screening Questionnaire (MSQ) 
 
will be filled out by each participant and reviewed by study staff. To assess potential alcohol withdrawal 
symptoms, the Clinical Institute Withdrawal Assessment of Alcohol Scale, Revised (CIWA-Ar) will be 
administered [30]. 
Study Visit Procedures: Participants will be asked to arrive at the Addiction Sciences Division on the 
study visit day. Female participants will have their urine tested for pregnancy. Females who test positive for 
pregnancy will be excluded. All participants will be tested for drugs of abuse and alcohol. Patients testing 
positive for drugs, with the exception of marijuana, will be excluded; patients testing positive for alcohol may be  
re-scheduled. Participants who have not had a physical exam in the Addiction Sciences Division within the lat 
30 days will have and H&P. Participants will be asked about substance use in the last 90 days and will fill out 
the Drinking Motives Questionnaire, the CTQ, and the MSQ. They will then be escorted to the scanner at 30 
Bee Street. 
The study will use a double-blind placebo controlled design. Intranasal OT (n=12) or PBO 
(n=12) sprays will be administered at 11:30 am, approximately 45 min prior to the scanning session.  
This dose and timing of OT administration were selected based on the literature [17, 18].  MIST 
Procedure:  The study will use a block design of three, 6-min runs separated by 2-min of rest for 
feedback, for a total of 24 min. During each run, participants will be exposed to 40-sec blocks of three 
different conditions (rest, control, and experimental).  Prior to the task, participants will are shown 
images of what the screen will look like during each condition. The participants will be instructed to 
relax during the rest condition and focus on the screen. During the control condition, the participants will 
be asked to answer math problems as accurately as possible but will also be told that their responses 
will not be recorded.  During the experimental condition, the participants will be asked to perform the 
math task as quickly and accurately as possible.  A performance bar located on the screen will allow 
them to see their performance as compared to an “average” person.  The participants will be told that 
the average person would answer about 85% of the problems correctly; however, the program limits the 
participants’ performance rate to between 35-45%.  A time limit will be enforced throughout the 
experimental condition. After each run, the participants will be given negative feedback from the 
investigator. BOLD-fMRI Procedure:  Data will be acquired on a Siemens Trio 3T scanner in MUSC’s 
Center for Biomedical Imaging. For co-registration and normalization of functional images, a high 
resolution T1-weighted MPRAGE anatomical image will be acquired with the following parameters: TR= 
2100 ms, TE= 4.18 ms, flip angle= 12°, field of view= 256 mm, slice thickness= 1.0 mm. The scanning 
planes will be oriented parallel to the anterior commissure–posterior commissure line. Participants will 
be asked to relax and keep their eyes opened and fixed on a cross-hair for 6 min while resting state 
data are collected. Participants will then complete the MIST. T2*-weighted gradient-echo planar images 
(EPI) will be acquired with the following parameters: TR= 2000 ms, TE= 27 ms, flip angle= 76º, matrix 
64 x 64, field of view= 23 cm, slice thickness= 3.7 mm with no gap, with 36 slices to cover the entire 


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brain. Implicit Facial Affect Recognition Task: The amygdala response to emotional faces that are 
presented outside the focus of attention (i.e. implicit tasks) is significantly greater than that observed 
during overt (explicit) presentation of the same stimuli [25]. Emotional adult faces will be selected from 
a variety of sources are standardized in size and enclosed in the same oval surround [26].  Dr. Joseph 
(MUSC) has developed a corpus of faces for a recent project (National Institute of Mental Health, R21 
MH086958-01, “A comparative developmental connectivity study of face processing”) that will be used 
for the present project. The faces will depict male and female Caucasian, Asian and African Americans 
expressing three different categories of emotion; fear, anger, and happiness. Neutral faces will also be 
presented (Figure 5). Because the participants will also be from different ethnic categories, it is 
important to include a mixture of races.  In a block design, participants will view a series of faces (for 
27.5 sec) within a block and report on the gender of those faces at the end of the block (for 5 sec). 
Each block will present 56 faces that depict the same emotion and same gender so there will be 6 
pseudorandomly ordered task blocks (3 emotions x 2 genders) and 7 rest blocks (27.5 sec each) that 
present a crosshair to be fixated. In each task block, each emotional face will be presented for 33 
msec. followed by a neutral face mask (from a different individual) for 167 msec. followed by a blank 
screen for 291 msec. At the end of the block participants will report the gender using two buttons on a 
response pad. Assignment of face sets to sessions will be counterbalanced across subjects. 
 
 
Payment to Participants: Participants will receive $100 for completing the scanning visit. 
 
Data Analyses MIST: Post-acquisition preprocessing and statistical analysis of all of imaging data will be 
performed using FEAT (FMRI Expert Analysis Tool) Version 5.98, part of FSL (FMRIB's Software Library). 
Data will be preprocessed using scripting tools from FMRI Expert Analysis Tool (FEAT). Functional 
connectivity will be measured using a PPI seed-based approach [19]. A customized square wave-form 
representing the task and the duration of each condition will be convolved with a double-gamma hemodynamic 
response function. A mask of the seed region will be made using a 12-mm diameter sphere located in the 
center of the amygdala using the MNI coordinates (x, y, z = ±22, 0, -22).  For each participant, the mean 
corrected and high pass filtered time series of the BOLD signal in the amygdala will be extracted and used in a 
single subject whole brain PPI analysis.  The PPI model will include (1) the task vector; (2) the time series of 
the BOLD signal in the amygdala; (3) a term representing the positive task x seed interaction; and (4) a term 
representing the negative task x seed interaction. The first level analysis will generate contrast images of the 
parameter estimates for each of the four regressors. Since the hypotheses explore increases in corticolimbic 
connectivity, the group analysis will focus on the positive interaction term. The contrast images of the 
parameter estimates of the positive interaction term will be entered into a 2nd level random effects analysis. 
Unpaired t-tests will be used to test for group differences. All group level results will be thresholded at Z> 2.3 
using a corrected cluster threshold of p= 0.05. A linear mixed effects model containing all serially measured 
time points will be used to assess the effects of OT versus placebo on alcohol craving and anxiety Implicit 
Facial Affect Recognition Task: : Following preprocessing (described above), within-task data from individual 
participants will be analyzed with a fixed-effects general linear model (GLM), with each emotion (described 
below) modeled as a box-car function convolved with a double-gamma hemodynamic response function. The 
response period at the end of each block will also be modeled as a separate variable to remove effects of 
explicit decision making and response selection. The GLM procedure is repeated for each voxel with six 
movement parameters (3 rotation values in radian and 3 translation values in millimeter) included as covariates 
to control for the influence of head motion on the data. Following first-level analysis, subject-specific contrasts 
will be entered into second-level, random-effects analyses. Since the hypotheses associated with Specific Aim 
2 explore amygdala activity, we will use a region of interest approach (ROI).  The BOLD signal from the left 
amygdala will be extracted using an anatomical mask generated by a 12-mm diameter sphere located in the 
center of the left amygdala using the MNI coordinates (x, y, z = -22, 0, -22). The percent signal change 
between the fearful and neutral conditions (contrast of interest) will be calculated for each participant. Separate 
random-effects one-way analysis of variance tests (ANOVA) will be used to test for the following group 
differences (AUD-PBO vs. AUD-OT). Since human neuroimaging studies have found that other brain regions 
play a role in implicit emotional processing, including the right amygdala and insula [27,28], secondary 
analyses will also include these regions. In addition, OT may impact amygdala responding to happy faces [29] 
therefore group differences in amygdala responding in the happy-neutral contrast may be explored in future 


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analyses. For multiple comparisons that are not part of the hypothesis a priori, the Bonferroni correction will be 
used. In addition, contrasts of other pertinent baseline characteristics will be performed between groups.  If the 
groups differ significantly on any of these baseline characteristics, the corresponding variables will be used as 
covariates in the above analyses.  The statistical analyses will be conducted using SAS 9.3 software (SAS 
Institute Inc., Cary, NC, USA). 
 
 
 
PROTECTION OF HUMAN SUBJECTS 
1. RISKS TO THE SUBJECTS 
1.1 Human Subject Involvement and Characteristics 
 
Admission into the study is open to men and women and to all racial and ethnic groups, age 21-40 with 
alcohol use disorder. Participants will be recruited through the Medical University of South Carolina’s (MUSC) 
Addictions Research Center (ARC) Assessment Core. Inclusion/exclusion criteria are listed below: 
General Inclusion/Exclusion Criteria 
Inclusion Criteria 
1. Age 21-40.  
2. Subjects must be able to provide informed consent and function at an intellectual level sufficient to 
allow accurate completion of all assessment instruments. 
3. Meets the DSM-5 criteria for current alcohol use disorder. 
4. Reports drinking on average, at least 20 standard alcoholic drinks per week for at least the past three 
months. 
5. Currently not engaged in, and does not want treatment for, alcohol related problems. 
6. Lives within 50 miles of the study site. 
7. Subjects must consent to random assignment. 
8. Able to maintain abstinence for two days (without the aid of detoxification medications) as determined 
by self-report and breathalyzer measurements Subjects must also have a negative breathalyzer urine 
drug screen at the study visit. 
9. Subjects must consent to the study visit which includes an outpatient admission to the Addiction 
Sciences Division and completing one functional magnetic resonance imaging (fMRI) scanning session. 
Exclusion Criteria 
1. Currently meets DSM-5 criteria for any other psychoactive substance use disorder. 
2. Is determined 
3. Any psychoactive substance use (except marijuana and nicotine) within the last 30 days by self-report 
and urine drug screen. For marijuana, no use within the last seven days by verbal report and negative 
(or decreasing) urine THC levels. 
4. Meets DSM-5 criteria for current major depression, panic disorder, obsessive-compulsive disorder, 
post-traumatic stress syndrome, bipolar affective disorder, schizophrenia, dissociate disorders, eating 
disorders, and any other psychotic disorder or organic mental disorder.   
5. Has current suicidal ideation or homicidal ideation. 
6. Has the need for maintenance or acute treatment with any psychoactive medication including anti-
seizure medications and medications for ADHD. 
7. Is currently taking medication known to affect alcohol intake (e.g., disulfiram, naltrexone, acamprosate, 
topiramate). 
8. Has clinically significant medical problems such as cardiovascular, renal, GI, neurological (e.g. seizure 
disorder) or endocrine problems that would impair participation or limit medication ingestion. 
9. Has past history of alcohol related medical illness such as gastrointestinal bleeding, pancreatitis, peptic 
ulcer, hepatic cirrhosis or alcoholic hepatitis.  
10. Has hepatocellular disease indicated by elevations of SGPT (ALT) or SGOT (AST) greater than 2.5 
times normal at screening. 
11. Females of childbearing potential who are pregnant (by urine HCG), nursing, or who are not using a 
reliable form of birth control. 


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12. Has current charges pending for a violent crime (not including DUI related offenses). 
13. Does not have a stable living situation. 
14. Presence of ferrous metal in the body, as evidence by metal screening and self-report. 
15. Severe claustrophobia or morbid obesity that preclude placement in the MRI scanner. 
16. History of head injury with >2 minutes of unconsciousness. 
 
1.2 Sources of Materials 
 
Research materials obtained from indiviudual subjects includes structured clinical interviews, 
questionnaires, blood samples, urine drug screens, urine pregnancy tests, breathalyzer tests, structural and 
functional MRI scans.  
1.3 Potential Risks  
 
Risks associated with the assessment include the possibility that subjects might be upset by questions 
related to their substance use and psychiatric history. Risks associated with venipuncture may be mild pain 
and possible bruising. Under certain conditions, participants may experience psychological discomfort from a 
positive pregnancy test. There are very few potential risks from fMRI itself. There is no exposure to ionizing 
radiation and the machine and scanning sequences and gradients are approved by the FDA for routine clinical 
use. Individuals who are claustrophobic might experience anxiety during the scanning procedures. However, 
we will pre-select individuals who, in general, do not have this problem. A patient may experience some loud 
noises during the scanning procedure and there is a mild risk of hearing damage if patients are not given 
hearing protection. Participants may experience psychological discomfort from undergoing the scanning 
procedure, such as boredom and fatigue.  Ferrous objects in the body that are undetected could move during 
scans. This could lead to tissue damage and hemorrhage. The MIST is designed to induce a stress response, 
and therefore subjects are likely to experience some psychological discomfort. In addition, individuals could 
experience alcohol craving, therefore alcohol use after the study visit is a potential risk. Adverse effects 
associated with systemic oxytocin use in pregnancy include seizures, mental disturbances, unexpected 
bleeding or contraction of the uterus.  However, several studies have been conducted in men and women who 
are not pregnant with intranasal doses between 20 and 60 IU, and no side effects have been reported [20, 21]. 
A review by MacDonald and colleagues (2011) also found no adverse outcomes associated with oxytocin 
dosages of 18-40 IU for short term use in controlled research settings [22]. To date, our research group has 
adminsted intranasal oxytocin to over 170 individuals with substance use disorders and healthy controls with 
no side effects. These risks are outlined in the informed consent documents.   
2. ADEQUACY OF PROTECTION AGAINST RISKS 
2.1 Recruitment and Informed Consent 
 
Patients will primarily be recruited through the MUSC ARC Assessment Core through the use of 
advertisements (internet, newspaper, radio and TV). Medical records will NOT be reviewed to identify potential 
study subjects.  The study PI, a Co-I, or other qualified study staff will obtain informed consent. The informed 
consent (IC) form includes a detailed description of the study procedures, along with statements regarding 
participants’ rights to withdraw from the procedure at any time without consequences. The IC form will 
specifically review the potential for psychological distresss, risks associated with MRI and oxytocin that may 
occur as a result of study participation. The IC will also inform individuals that the scanner is located on-
campus at a research facility and not at a clinical facility, therefore immediate emergency medical services may 
not be available. The IC form will be explained to individuals using language that is easy-to-understand and 
individuals will be instructed to read the form carefully prior to signing it. The IC form will include emergency 
contact information for the PI. Any questions pertaing to the study or consent will be answered. Potential 
participants will not be required to make a decision to participate at this initial contact, though that possibility 
will be available. If individuals wish to discuss study participation with their family and/or significant others, they 
will be encouraged to do so. Consent will be documented by the signature of the participant on the informed 
consent agreement, accompanied by the signature of the individual obtaining the consent. 
2.2 Protections Against Risks 
 
Dr. Joseph and an on-call physician will be be available by pager/cell telephone during the entire study for 
any questions or emergencies that may arise. Our past research experience suggests that data collection 
using many of these same assessments and questionnaires can be conducted without undue psychological 
distress. Efforts will be made to protect the confidential nature of the information collected; however, this 


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cannot be guaranteed (e.g., subpoena). This experience includes substantial research with individuals with 
SUDs, healthy controls and work on large-scale studies asking questions about similar topics. At the 
conclusion of the study visit, each participant will be debriefed and provided with full disclosure about the 
deception of the MIST. Subjects will be told that the computer makes adjustments to keep the number of 
correct responses to less than 50% and therefore a good score on the task is impossible. If appropriate, the 
psychiatrist will personally evaluate the subject. Should any craving or anxiety induced during the experimental 
manipulation fail to subside within 3-4 hours, a study psychiatrist will be available to arrange either 
hospitalization through the MUSC CDAP or make an appropriate referral. These protective procedures are in 
place for all of our on-going research studies of stress reactivity in individuals with SUDs.  
 
All sessions will be conducted under the supervision of experienced personnel. The research team and all 
of the study staff will have succesfully completed the Miami Collaborative IRB Training Initiative (CITI) course 
and its associated tests in research ethics. To ensure confidentiality, each participant will be assigned a unique 
identification number and all information will be collected under that number. Identification numbers linked with 
names will be retained separately from the data files and locked in a different cabinet. Only the investigator will 
have access to the master lists of codes. No names or personal identifiers will be included in the data files. 
Files will be stored in the Clinical Neurosciences Division, in an office that is locked when not in use. Structural 
and functional neuroimaging data will be stored on a secure password protected server maintained by the 
MUSC Center for Biomedical Imaging (CBI). Only the PI and Co-I’s will have access to files on the server. 
Care will be taken to prevent disclosure of pregnancy tests or any other lab results to anyone other than the 
study participant.  
 
 
All of the study staff will be required to complete the CBI MRI safety training class. The course is taught by 
an AART (American Registry of Radiologic Technologists) registered technician. The staff will be trained about 
safety in the MRI environment, and how to screen oneself and others. The staff will also have knowledge of 
safety procedures for entering the scanner facility, safely removing participants from the scanner, when and 
how to quench the magnet and basic emergency procedures including emergency contact information.  
Standard operating procedures for emergency situations are located on-site. The technician and the PI are 
authorized to operate the equipment and will be present throughout the scanning sessions.  Although there are 
no known risks of MRI scanning to a developing fetus at 3.0 T, the possibility that risks could be discovered in 
the future cannot be ignored. Urine pregnancy tests will be used to exclude pregnant women from study 
participation. A careful metal screening history will be taken from each subject to assess the possibility of metal 
devices/implants and will be reviewed by the PI, MRI technician and/or clinical staff who have had extensive 
training and experience with MRI safety. If the screening yields information that raises a question of safety, the 
subject will be asked to provide the appropriate documentation (i.e. film) before they are allowed to participate. 
In addition, participants will be asked to empty their pockets and will be screened with a hand-held 
ferromagnetic-detector wand.  Subjects will wear earplugs and sound-dampening headphones to decrease the 
intensity of the scanner noise. Prior exposure to pictures of the scanner, getting into the scanner and seeing 
others in the scanner often reduces psychological discomfort or identifies people for whom scanning is not 
appropriate.  If abnormalities in the brain images are found, the subjects will be referred to an appropriate 
clinical care provider.   
 
Subjects will be informed about the potential symptoms of alcohol withdrawal and advised to call for 
medical assistance if they experience severe symptoms. The CIWA-Ar will be administered prior to procedures 
on the study visit day [23]. 
 
Subjects will be taught about the potential side effects of oxytocin. Pregnancy tests will be performed at the 
screening visit and again at the study visit. The pregnancy test will occur before the participants receive the 
intranasal spray. Urine pregnancy tests are routinely used in all of our clinical research studies. In the event 
that a pregnancy test is positive, the results will be disclosed to the participant by the PI or Co-I and if 
necessary the participant will be given an appropriate referral for counseling. Oxytocin administration will occur 
in a fully staffed clinical environment with emergency medications (i.e., IM diphenhydramine, alprazolam) and 
equipment available as needed. All subjects will be informed at the onset that they may terminate study 
participation at any time without reprocussions. 
3. POTENTIAL BENEFITS OF THE PROPOSED RESEARCH TO THE SUBJECT AND OTHERS  
 
There are no guarantees of specific benefits to individual study participants. However, potential benefits 
include a detailed psychiatric and substance use assessment and referral for treatment if requested. In 
addition, subjects may benefit from the realization that, through their study participation, they are helping to 


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advance our state of knowledge regarding the neurobiologic factors that underscore stress induced alcohol 
craving and relapse. An investigation of oxytocin’s effects on subjective anxiety and alcohol craving in may 
provide important information that can guide treatment individuals with alcohol use disorder. While the benefits 
to the individual patient are minimal, the minimal risks are reasonable in relation to the benefits to be gained 
from the investigation.  
4. IMPORTANCE OF THE KNOWLEDGE TO BE GAINED 
 
This study may provide important information that can improve treatment for future patients with alcohol 
use disorder. The minimal risks of the investigation are considered reasonable in relation to the expected 
knowledge to be gained. 
5. DATA AND SAFETY MONITORING PLAN (DSMP) 
5.1 Summary of the Protocol 
 
The primary objective of this proposal is to identifying the neurobiologic substrates of social stress in 
individuals with alcohol use disorder. Individuals with alcohol use disorder will receive either intranasal oxytocin 
(24 IU) or a placebo spray prior to participating in a single fMRI scanning session.  During the scanning 
session participants will complete the Montreal Imaging Stress Task, a Facial Affect Recogntion Task,  and a 
resting state scan.  The primary outcomes of interest are (1) corticolimbic functional connectivity at rest; (2) 
corticolimbic functional connectivity during the MIST and (3) subjective anxiety and craving responses to the 
MIST. 
5.2 Trial Management  
 
The study will be managed from the Addiction Sciences Division within the Department of Psychiatry and 
Behavioral Sciences at the Medical University of South Carolina.  The target population is described above in 
the inclusion/exclusion criteria. 
5.3 Data Management and Analysis 
 
Data will be entered by a research assistant directly into a computer using standard database software 
using REDCap.  Neuroimaging data will be stored and analyzed on the CBI’s password protected server.  
5.4 Quality Assurance 
 
Quarterly data audits, overseen by the PI will be conducted.  Confidentiality protections are outlined above. 
5.5 Regulatory Issues 
 
Dr. Moran-Santa Maria was issued an IND from the FDA for the use of (IND 122,040). An FDA 
amendments has been submitted to transfer her IND to another investigator. Potential conflicts of interest will 
be reported using NIH guidelines outlined in “Issuance of the Final Rule - Responsibility of Applicants for 
Promoting Objectivity in Research for which Public Health Service Funding is Sought and Responsible 
Prospective Contractors” for disclosure. All unexpected Adverse Events (AEs) will be reported to the MUSC 
Committee on Human Research and NIDA within 48-business hours. Serious Adverse Events (SAEs) will be 
reported within 24-business hours.  Follow-up of all unexpected and serious AEs will also be reported to these 
agencies. All AEs will be reviewed weekly by the PI, bi-annually by the Data Safety and Monitoring Board 
(DSMB) and yearly by the IRB. Any significant actions taken by the local IRB and protocol changes will be 
relayed to NIAAA. AEs and SAEs occurring during the course of the project will be collected, documented, and 
reported in accordance with the protocol and IRB reporting requirements. All research staff involved with AE 
reporting will receive general and protocol specific AE/SAE training including identification, assessment, 
evaluation, documentation, and reporting. The research assistant, study coordinator, or the PI will identify any 
potential AEs and SAEs during the course of the study. This information will be provided to the study physician, 
who will be responsible for AE/SAE assessment and evaluation including a determination of seriousness and 
study relatedness.  
5.6 Definition of AE and SAE 
 
An Adverse Event (AE) is defined as any unwanted change, physically, psychologically or behaviorally, that 
occurs in a study participant during the course of the study that may or may not be related to study 
participation.  A Serious Adverse Event (SAE) is defined as an adverse event that has one of the following 
outcomes: 


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• 
Results in death 
• 
Is life-threatening 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability/incapacity 
• 
Is a congenital anomaly/birth defect  
• 
Requires intervention to prevent one of the above outcomes 
5.7 Documentation and Reporting 
 
AEs/SAEs will be documented and reported as per protocol and IRB requirements.  Research staff will 
identify AEs and obtain all available information to assess severity, seriousness, study relatedness, 
expectedness, outcome and the need for change or discontinuation in the study intervention.  Adverse events 
will be documented on AE Logs and AE Case Report Forms (CRFs).  Additional relevant AE information if 
available will be documented in a progress note in the research record as appropriate to allow monitoring and 
evaluating of the AE.  All AEs will be reported to the IRB online as soon as possible, but no later than 10 
working days after the investigator first learns of the event.  The MUSC IRB AE reporting requirements are as 
follows:  All deaths that occur during the study or 30 days post termination from the study are required to be 
reported as adverse events even if they are expected or unrelated.  Other adverse events are reportable to the 
MUSC IRB if the AE is unexpected AND related or possibly related AND serious or more prevalent than 
expected.  All three criteria must be met for an AE to be reported to the MUSC IRB.  The IRB definition of 
unexpected is that the AE is not identified in nature, severity or frequency in the current protocol, informed 
consent, investigator brochure or with other current risk information.  The definition of related is that there is a 
reasonable possibility that the adverse event may have been caused by the drug, device or intervention.  
Reportable AEs are reviewed by the IRB Chair and reported to the IRB Board at the next meeting. If the AE 
meets the definition for serious, appropriate SAE protocol specific reporting forms will be completed and 
disseminated to the appropriate persons and within the designated timeframes as indicated above.  For each 
AE/SAE recorded, the research staff will follow the AE/SAE until resolution, stabilization or until the participant 
is no longer in the study as stated in the protocol. When a reportable SAE is identified, the research staff will 
notify the MUSC IRB within 24-hours and complete the AE report form in conjunction with the PI. If complete 
information is not available when the initial 24-hour SAE report is disseminated, follow-up information will be 
gathered to enable a complete assessment and outcome of the event.  This information may include hospital 
discharge records, autopsy reports, clinic records, etc.  The research staff will attach copies of source 
documents to the SAE report for review by the PI and study clinician.  These source documents will be 
forwarded to the NIH program officer as appropriate within 2-weeks of the initial SAE report.  In addition, the PI 
will provide a signed, dated SAE summary report, which will be sent to the designated NIH Institutional Medical 
Safety Officer within two weeks of the initial SAE report. 
 
The MUSC IRB meets monthly and is located on-campus at 165 Cannon Street, Rm. 501, Charleston SC, 
29425. Communication with the IRB will be through email, memos, official IRB forms, and online reporting. 
 
5.8 Trial Safety 
 
The potential benefits, risks and methods to minimize risks are outlined above. Protocols for reporting AEs 
and SAEs are outlined above.  All unexpected AEs and SAEs will be monitored until resolved.  A detailed 
summary of all AEs will be prepared weekly by the research staff.  Study procedures will follow the FDA’s 
Good Clinical Practice Guidelines (www.fda.gov/oc/gcp). Any outside requests for information or any breaches 
in confidentiality will be reported to the PI.  All requests by participant’s physicians and other medical providers 
will be referred directly to the PI and the study clinician. 
5.9 Trial Efficacy 
 
This is not an intervention trial.  An interim analysis is not planned at the time. 
5.10 DSM Plan Administration 
 
Dr. Joseph will be responsible for monitoring the study. She will examine (monthly) the outcomes database 
and CBI server for missing data.  Dr. Joseph will work with the ARC statistician to monitor unexpected 
distributions, responses and outliers.  A DSM report will be filed with the IRB on a yearly basis, unless greater 
than expected problems occur.  The report will include participant characteristics, retention and disposition of 


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study participants, quality assurance issues and reports of AEs, significant/unexpected AEs and serious AEs. 
We will report outcomes at the end of the study. 
5.11 DSM Board   
 
If directed by NIAAA program staff, we will create a Data Safety and Monitoring Board to monitor both the 
rate and severity of AEs.  This panel will include three clinicians with expertise in alcohol use disorder and a 
statistician.   
5.12 Risk Benefit Ratio 
 
While the benefits to the individual participant are minimal, the minimal risks are reasonable in relation to 
the benefits to be gained from the investigation. Potential risks of concern are loss of confidentiality, and 
adverse events to oxytocin. The assessments and questionnaires are non-invasive and have inherently 
minimal risks. The potential risks of MRI are minimal. As discussed above, our research team has extensive 
experience with these study populations, psychiatric assessments, fMRI, oxytocin administration, the MIST and 
will attempt to minimize these risks. Knowledge gained by the proposed study would help fill an important void 
in our understanding neurobiologic substrates of social stress in individuals with alcohol use disorder.  
6. CLINICALTRIALS.GOV REQUIREMENTS 
 
In accordance with Public Law 110-85, this project will be registered at the ClinicalTrials.gov Protocol 
Registration System Information Website prior to study initiation. 
 
 
 
 
 
 
 
 
 
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