Laboratory Studies on Oxytocin for Treatment of Alcohol Use Disorder
Phase: PHASE1
Conditions: Alcoholism, Alcohol Related Disorders
Sponsor: Johns Hopkins University

Date: 06/08/2016 
Principal Investigator: Elise Weerts 
Application Number: IRB00033324 
 
 
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JHM IRB - eForm A – Protocol 
 
Laboratory studies on oxytocin for treatment of alcohol use disorder 
 
 
 
*************************************************************************************************** 
 
Protocol Version 3.3 Dated 06/08/16 
Summary of Updates from Version 3.2 (dated 11/17/15) to Version 3.3 (dated 06/08/16) 
 
 
- 
Adding online screener information  
- 
We are allowing participants to smoke ad lib while on the Bayview CRU.  Nicotine 
patch will still be administered for subjects on the JHH CRU and it will be made 
available on session days. 
- 
We will no longer exclude individuals who meet DSM-V criteria for mild cannabis use 
disorder; moderate and severe cannabis use disorder is still a rule out. 
 
 
 
1. 
Abstract 
This study will lay the necessary groundwork for future comprehensive research to examine the 
utility of the neuropeptide oxytocin (OT) as a potential new medication for the treatment of Alcohol 
use disorder (AUD).  OT modulates a number of key systems involved in addiction processes, 
including dopamine (DA) mesolimbic reward circuitry, and hypothalamic–pituitary–adrenal (HPA) 
axis and corticotrophin-releasing factor (CRF) stress systems, and has low abuse liability[1, 2]. Our 
overarching hypothesis is that OT will attenuate several measures thought to drive compulsive 
alcohol drinking and relapse.  Specifically, we will examine whether OT decreases acute stress 
responses, alleviates alcohol withdrawal symptoms, reduces craving and motivation to drink, and 
decreases alcohol self-administration.  Since interactions with alcohol are an important focus of our 
study, we will enroll non-treatment seeking heavy drinkers with AUD in a double blind, placebo 
controlled inpatient protocol. Subjects will be randomized to receive intranasal OT (40 IU/dose) or 
placebo 3 times daily.  Participants will complete alcohol detoxification; we will measure alcohol 
withdrawal symptoms, craving, and 24-hr urinary free CORT. Participants will then complete 3 
laboratory procedures in fixed order. The Trier Social Stress Test (TSST) which includes public 
speaking and performance of mental arithmetic will be used to examine subjective and 
physiological stress responses. An alcohol motivated responding (AMR) procedure will be used to 
examine subjects’ responding to earn either drinks or money. A cumulative alcohol-dosing (CAD) 
procedure will be used to examine physiological and subjective responses across several blood 
alcohol levels. CORT levels will also be assessed.   
. 
2. 
Objectives (include all primary and secondary objectives) 
 
The primary goal of the study is to provide new information on OT efficacy across a range of 
different measures predictive of alcohol use and misuse, and, if OT shows efficacy, help clarify the 
mechanism of OT action. This research is needed to determine sample sizes for future research and 
will provide important preliminary evidence for the future of OT as a treatment for alcohol drinking 
problems. Towards this goal, we propose four specific aims: 

Date: 06/08/2016 
Principal Investigator: Elise Weerts 
Application Number: IRB00033324 
 
 
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Aim 1: Examine OT effects on severity of alcohol withdrawal symptoms, alcohol craving, and 
CORT during early alcohol abstinence. Hypothesis1a: OT will reduce alcohol withdrawal symptom 
severity, and decrease alcohol craving, compared to placebo. Hypothesis 1b: OT will attenuate the 
elevation in urinary free CORT levels during early withdrawal compared to placebo. 
 
Aim 2: Examine the effects of OT on response to social stress.  
Hypothesis 2: OT will decrease CORT response and psychological responses to TSST, compared to 
placebo.  
 
Aim 3: Examine the effects of OT on motivation to drink.  
Hypothesis 3: OT will decrease alcohol-motivated responding and number of alcohol drinks earned, 
compared to placebo. 
 
Aim 4: Examine the effects of OT on alcohol sensitivity.  
Hypothesis 4a: OT will reduce the positive subjective effects of alcohol, when compared to placebo. 
Hypothesis 4b: OT will attenuate alcohol-induced increases in heart rate, when compared to 
placebo. Hypothesis 4c: OT will not produce significant side effects or adverse interactions with 
alcohol. 
 
Since men and women will be enrolled, we will also explore possible sex differences in OT effects 
(secondary objective), which may have important treatment implications. 
 
3. 
Background (briefly describe pre-clinical and clinical data, current experience with 
procedures, drug or device, and any other relevant information to justify the research) 
 
Stress and alcohol. Stress, generally defined as any stimulus that disrupts the body’s internal 
balance, has long been suggested to be an important contributor to heavy alcohol drinking and 
relapse following a period of abstinence. Current theories suggest that changes in HPA-axis 
reactivity are involved in the behavioral and motivational processes associated with escalation of 
drinking, tolerance, dependence and withdrawal[3]. In rats and monkeys, acute stress enhances 
alcohol preference and reward, and increased alcohol intake is correlated with stress-induced 
increases in cortisol/corticosterone (CORT)[4-6]. In addition, with repeated social stress (e.g., defeat, 
low social rank, and maternal separation), rats and monkeys subsequently show greater alcohol 
intake when compared to non-stressed cohorts[5-7]. CORT increases drug reward by increasing 
mesolimbic DA transmission[8]. Rats self-administer CORT itself at levels similar to those elicited 
by stress, and intracerebroventricular infusions of CORT enhance the reinforcing effects of alcohol 
[9]. During abstinence, rats previously exposed to chronic alcohol vapor escalate voluntary alcohol 
intake, and show persistent alcohol seeking and withdrawal symptoms[10-12]. These effects are 
blocked by a glucocorticoid receptor antagonist[12].  
 
These findings may underlie the association between stress and alcohol consumption observed in 
humans. Large epidemiological studies report a variety of stressors including hazardous and 
demanding work environments, legal issues, family stress and low income are associated with 
increased alcohol consumption and binge drinking[13-16]. People experiencing severe social stress 
following alcoholism treatment have higher rates of relapse compared with people not experiencing 
such stress[17, 18]. Heavy alcohol drinking and AUD are associated with dysregulation of HPA-axis 
activity as shown by episodes of hypercortisolism between drinking bouts and a blunted cortisol 
(CORT) response to stress during early abstinence[19-23]. Blunted CORT response has been 

Date: 06/08/2016 
Principal Investigator: Elise Weerts 
Application Number: IRB00033324 
 
 
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associated with increased anxiety and craving during acute abstinence and subsequent relapse to 
heavy drinking[24-26].  The stress and AUD connection is well recognized by the NIAAA, as 
evidenced by a decade of funding of the Integrative Neuroscience Initiative on Alcoholism stress 
consortium and recent clinical trials of HPA-axis medications for AUD (e.g., arginine vasopressin 
receptor-1 antagonist). We selected OT because of its history of safety, lack of abuse liability and 
known effects on the HPA axis and mesolimbic reward systems.  
 
Oxytocin and stress. In the human brain, OT receptors are primarily localized in thalamic, 
hypothalamic, basal ganglia and brain stem regions. OT neurons project throughout the CNS[27]. 
Initially OT was thought to be primarily involved in sexual behaviors, female parturition and 
lactation. OT is important for a number of adaptive behavioral and physiological processes, such as 
the initiation and maintenance of social-attachment (mother-infant and pair bonding), memory, 
learning, feeding, pain, and stress responses[28]. Studies in laboratory animals have shown that acute 
stress increases release of OT in blood and in hypothalamic and extra-hypothalamic brain regions[29-
32]. The increase in OT appears to be part of the homeostatic regulation of stress responses. Indeed, 
centrally administered OT decreases stress-induced increases in CORT[30, 33, 34] and reduces stress-
induced behaviors in rodent models of anxiety and depression[33-36].  
Investigations in human subjects are in line with the preclinical literature. When administered via 
the intranasal route, OT has an excellent safety profile and produces changes in autonomic arousal 
and mood[37]. OT reduced CORT and psychological responses to social stress, increased positive 
communication during couples conflict discussions and improved recognition and processing of 
positive facial expressions[38-46]. As indicated above, heavy drinking and AUD are associated with 
hypercortisolism during withdrawal, which may increase risk for relapse to heavy drinking[24-26]. 
While the efficacy of OT in attenuating stress responses in normal healthy subjects have been 
shown, its effects on stress responses in persons with an AUD, in whom HPA-axis function is 
impaired, are unknown. The proposed study addresses this knowledge gap by evaluating OT effects 
in heavy drinkers with an AUD undergoing a well-established laboratory social stress procedure. If 
OT can reduce the negative impact of stress in this vulnerable population, this has important 
treatment implications particularly during alcohol withdrawal and early abstinence.  
 
Oxytocin and addiction. There is considerable interest in the role OT may play in neuropsychiatric 
disorders, including substance use disorders[47]. Importantly, the mesolimbic DA and opioid 
systems, which are key substrates involved in drug reward and addiction, interact with the OT 
system during development of tolerance and dependence[1]. Drug tolerance and compulsive drug 
seeking involve associative learning and memory processes, which are also regulated by OT 
systems. Of high significance, recent preclinical data show that OT administration disrupts 
biobehavioral adaptions associated with long-term alcohol exposure [2]. In rats, OT reduces 
development of rapid tolerance to the hypothermic, hypnotic, and myorelaxant effects of alcohol, 
and produces a prolonged decrease in withdrawal symptoms[2, 48-53]. OT decreases alcohol 
preference and produces long-term suppression of alcohol self-administration in rats[54, 55]. The 
potential of OT as an AUD treatment is highlighted by a recent small clinical trial in alcohol 
dependent subjects[56]. All subjects underwent alcohol detoxification with PRN administration of 
the benzodiazepine (BZ) lorazepam and concurrent, randomized intranasal OT or placebo. 
Compared with placebo, OT decreased withdrawal symptoms and amount of lorazepam needed to 
alleviate withdrawal during detoxification[56]. It is unknown whether OT will reduce alcohol 
withdrawal symptoms when administered alone and whether OT alters subjective and reinforcing 
alcohol effects in human subjects.   
 

Date: 06/08/2016 
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There is tremendous need for new medications for treatment of AUD.  The National Institute on 
Alcohol Abuse and Alcoholism (NIAAA) estimates that 1 in 5 adults currently drinks at levels that 
increase risk for alcohol-related problems and 1 in 3 adults will experience lifetime problems with 
alcohol[57]. Only three medications (naltrexone, acamprosate and disulfiram) are approved by the 
Food and Drug Administration for AUD treatment. These drugs have demonstrated clinical 
efficacy, but effect sizes during treatment are generally modest and the majority of patients relapse 
to heavy drinking after medication discontinuation. In addition, the current FDA-approved 
medications do not address the dysfunction of HPA-axis associated with heavy alcohol use and 
dependence. Although naltrexone acutely activates the HPA axis, its primary mechanism for AUD 
treatment is attenuation of alcohol reward and reduction of alcohol craving via blockade of opioid 
receptors[58]. Disulfiram inhibits alcohol metabolism via aldehyde dehydrogenase to produce 
aversive effects if the patient drinks alcohol[59]. Acamprosate decreases the negative reinforcing 
effects of alcohol by normalizing dysregulation of GABAergic and NMDA-mediated glutamatergic 
neurotransmission associated with chronic heavy alcohol use[60]. In contrast, OT treatment may help 
to normalize the HPA-axis and reduce stress-related physiological and subjective responses 
(anxiety, craving) that increase drinking and trigger relapse. Additional benefits of OT may be 
promotion of social behavior and disruption of learned behaviors and neuroadaptive processes 
associated with heavy alcohol use and attenuation of the reinforcing effects of alcohol.  
 
OT has no known abuse liability and an excellent safety profile in clinical research settings[37]. The 
utility and feasibility of intranasal OT as a medication is supported by its success in clinical trials 
for the treatment of behavioral deficits associated with schizophrenia, anxiety, autism, and Prader-
Willi syndrome[61-64]. The rapid delivery and onset of intranasal OT effects allows the possibility of 
its administration as an acute medication under conditions of stress- or cue-induced craving. 
Examination of OT effects under controlled laboratory conditions is the first necessary step in 
developing OT for treatment of AUD, and will address important knowledge gaps. We propose to 
use multiple, well validated laboratory procedures and outcome measures to determine OT efficacy 
across a range of different measures associated with alcohol use and misuse. We will examine 
whether OT alleviates alcohol withdrawal symptoms and craving (Aim 1), alters subjective and 
physiological responses to social stress (Aim 2) and to alcohol intoxication (Aim 4), and reduces the 
motivation to drink after brief abstinence (Aim 3). Our findings will help clarify the mechanism of 
OT action (i.e., anti-stress effects vs. alleviating withdrawal vs. reward). By balancing treatment 
groups for gender, we can evaluate possible gender differences, which may have important 
treatment implications and influence future study designs and use of OT. Importantly, this study 
will establish effect sizes as the basis for future research. For example, if the current study 
demonstrates efficacy of OT on craving and motivation to drink, we would propose an outpatient 
clinical trial in which OT could be self-administered to reduce urges to drink. If OT is efficacious 
for alleviating withdrawal, we would propose an inpatient clinical trial to fully examine its utility in 
a broader sample.  
 
4. 
Study Procedures 
 
a. Study design, including the sequence and timing of study procedures   
(distinguish research procedures from those that are part of routine care). 
 
Subjects: Healthy, non-treatment seeking, 21-50 years old, heavy drinking, male and female 
subjects will be recruited through the media. Minority subjects will be recruited in proportion to 
their representation in the Baltimore metropolitan area. Subjects will complete initial screening for 
eligibility by telephone or online. Subjects who are eligible following the phone screen or online 

Date: 06/08/2016 
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Application Number: IRB00033324 
 
 
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screen will provide informed consent and complete an in-person assessment using a standard battery 
of instruments (see Table 1). The Alcohol Use Disorders Identification Test (AUDIT) and the Mini 
International Neuropsychiatric Interview (M.I.N.I.)[65], Version 7 for DSV-V will be used to assess 
the presence or absence of alcohol or other substance use disorders, and mood and anxiety disorders 
for study eligibility. The pattern and magnitude of drinking will be characterized using the 90-day 
Time Line Follow Back (TLFB) assessment[66]. Subjects must meet DSM-V criteria for AUD, and 
be actively drinking >14 drinks/week for women and >21 drinks/week for men, with at least 2 
heavy drinking days (>4 drinks/day for women, and >5 drinks/day for men) during a consecutive 
30-day period on the 90-day TLFB (inclusion criteria).  In addition to subject self-report of drinking 
on TLFB, levels of phosphatidylethanol (PEth) in blood will be used as a biomarker of recent 
drinking at assessment.  Its formation in blood is specific to ethanol, is highly correlated with 
magnitude of alcohol consumption (g/day) [67], and is detectable for 2 weeks or longer [68]. We will 
use the USDTL (United States Drug Testing Laboratories) threshold of 8ng/mL, to verify alcohol 
drinking. The MINI for Tobacco Use Disorder (TUD) and the Fagerström Test for Nicotine 
Dependence (FTND) [69] will be used to determine presence of TUD and severity of nicotine 
dependence symptoms, respectively. Subjects will undergo a medical history and physical 
examination, administration of the Clinical Institute Withdrawal Assessment Alcohol Revised 
(CIWA-Ar)[70], and standard laboratory tests (complete blood count, comprehensive metabolic 
panel, and urinalysis).  
 
Medical assessment results will be reviewed by Dr. Wand, the study physician, and persons in 
whom study participation is contraindicated will be excluded. Psychological and substance use 
interview results will be reviewed by Dr. McCaul, a licensed psychologist. We typically consent 
and screen 4 persons for each subject who meets study eligibility criteria. Inclusion and exclusion 
criteria are detailed in section 5. It is established that cycle phase can influence HPA-axis reactivity 
to social stress[71, 72]. In females, cycle phase will be determined via menstrual diary.  Ideally, 
women will be scheduled to complete procedures during their luteal phase. We recognize that heavy 
drinking can disrupt cycle regularity, and will therefor confirm cycle phase via progesterone level 
(gold standard), and will include this as a covariate in our analyses.  
 
Subjects will be randomized to treatment groups (OT or placebo), matching for age, gender, and 
nicotine dependence status (as defined by FNDT score) by Johns Hopkins Investigational Drug 
Services (IDS).  The FNDT score determined at assessment will be used to categorize participants 
according to nicotine dependence levels as defined by the instrument (Total Score of 0-2 = No 
Dependence;  3-5 = Moderate Dependence  and 6-9 = Substantial Dependence) and provided to IDS 
for randomization.   
Table 1: Assessment instruments: 
The Alcohol Use Disorders Identification Test (AUDIT) 
MINI for DSM-V 
MINI Tobacco Use Disorder 
Health Checklist 
CIWA-Ar 
90-day Time-line Follow-back  (TLFB) 
Shipley Institute of Living  
REALM (if Shipley below score of 18) 
Fagerström Nicotine Dependence Test 
Spielberger State-Trait Anxiety Inventory (STAI) 

Date: 06/08/2016 
Principal Investigator: Elise Weerts 
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 Beck Depression Inventory (BDI- II) 
Alcohol Dependence Scale (ADS) 
Short Profile of Moods State (POMS)  
Menstrual Cycle Questionnaire (Females only) 
 
Phosphatidylethanol (PEth). A small blood sample will be collected via finger stick for the 
BloodSpot® collection test (US Drug Testing Laboratory, Des Plaines, IL).  We selected dried 
blood spot vs. whole blood assays as it reduces subject risk associated with venipuncture and PEth 
is more stable in dried blood samples than in whole blood[73, 74]. PEth provides a biomarker for 
heavy alcohol consumption due to its high specificity and slow degradation rate [68, 75] Participants 
must have a positive PEth (>8 ng/mL) at assessment for study inclusion. 
 
Design Overview. This study will be completed as a 6-day inpatient protocol on the Johns Hopkins 
Hospital and/or Bayview Clinical Research Units (CRU).  The sequence and timing of study 
procedures is shown below.  Male (accrual n=12) and female (accrual n=12) participants will be 
randomized to receive intranasal OT (40 IU/dose) or placebo three times daily.  During the CRU 
stay, participants will complete self-report assessments of alcohol craving, anxiety and depression; 
nursing staff will administer the CIWA-Ar to evaluate withdrawal symptom severity. Full 
descriptions for OT administration and assessment instruments are below. During the first 3 days, 
participants will undergo alcohol abstinence during which 24-hr urinary free cortisol (UFC) will be 
collected for the first 48 hours. Participants will then complete 3 laboratory procedures in fixed 
order. A urine toxicology screen, a breath alcohol test, and urine pregnancy test (women) are 
completed prior to all procedures. Subjects will be terminated from this protocol if they have 
positive drug toxicology tests (excluding THC) or a positive pregnancy test (females).  On 
procedure days, subjects receive a calorie-controlled breakfast and lunch to control for dietary 
effects on alcohol absorption or stress response.  On day 4, a Trier Social Stress Test (TSST), which 
includes performance of mental arithmetic and public speaking, will be used to examine subjective 
and physiological responses to stress. On day 5, an Alcohol Motivated Responding (AMR) 
procedure, in which subjects respond on the computer to earn either drinks or money and then have 
the opportunity to self-administer earned drinks, will be used to determine OT effects on motivation 
to drink and alcohol self-administration. On day 6, a Cumulative Alcohol Dosing (CAD) procedure 
will be used to examine physiological and subjective responses to fixed-dose alcohol 
administration. The TSST, AMR and CAD laboratory sessions will start at 1 pm, 30 min after the 
mid-day OT or placebo administration since OT reaches peak levels in plasma 30-40 min after 
intranasal administration[76-78]. On day 7, subjects will have a brief intervention for their hazardous 
drinking before discharge.  
 
Subjects who smoke cigarettes or other tobacco products will not be allowed to smoke at any time 
during the JHH CRU stay.  Current smokers on the JHH CRU will be provided with a transdermal 
nicotine patch (21 mg) at admission and each morning to prevent the onset of nicotine withdrawal; 
smokers will be patched throughout their JHH CRU stay. Participants residing on the Bayview CRU 
will be allowed to smoke ad lib in the designated smoking room in the facility. Cigarettes will be 
held at the nursing station to prevent unauthorized smoking in the participant’s bedroom.  They will 
have the option to receive a transdermal patch (21 mg) on the days that they are transported to the 
JHH campus to complete study procedures. 
 
All session procedures (TSST, ARM and CAD) will be completed in our research office (550 
Building). Subjects staying at the JHH CRU will transfer to the Bayview CRU after the TSST for 

Date: 06/08/2016 
Principal Investigator: Elise Weerts 
Application Number: IRB00033324 
 
 
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the remainder of the study.  Subjects will be transported via car service to the 550 Building for 
sessions, then return to the Bayview CRU. The sequence of conditions is: 
. 
Day  
1: 
Admission to Bayview CRU (or JHH CRU)*  
* Subjects will be only be admitted to JHH Bayview if they meet defined parameters 
(see definition below) 
Days 1-6:  
Intranasal self-administration of OT (40IU/dose) or placebo three times daily under 
nursing supervision. 
Completion of daily self-report measures three times daily 
 
Days 1 - 2: 
Monitored alcohol abstinence 
Staff administered CIWA-Ar every four hours while awake* 
24-hr collection of urinary free cortisol 
Practice AMR session procedures 
* symptom triggered benzodiazepine treatment (see below) 
 
Day 4:  
Session 1: Trier social stress test (TSST)  
* JHH CRU participants transfer to the Bayview CRU (after TSST session) for the 
remainder of the study 
Day 5:  
Session 2: Alcohol motivated responding (ARM) procedure  
Day 6:  
Session 3: Cumulative alcohol dosing (CAD) procedure 
Day 7:   
Brief Intervention for heavy drinking and CRU discharge 
 
CRU admission criteria. Since persons at greatest risk for alcohol withdrawal complications will 
have been ruled out prior to study inclusion (e.g., those with prior history of withdrawal-related 
seizures, or serious alcohol withdrawal symptoms based on medical history or current CIWA score 
at the time of assessment see Section 5, Exclusion Criteria), we anticipate that most participants will 
be admitted to the Bayview CRU. Specifically, subjects will be admitted to Bayview CRU if they 
meet ALL of below criteria at assessment: 
 
1) 
No adult seizure history; 
2) 
No serious alcohol withdrawal complications in prior alcohol withdrawal episodes; 
3) 
Some non-drinking days on 90-day TLFB; 
4) 
CIWA-Ar < 9 at time of assessment; 
5) 
Study Physician and Investigator recommendations 
  
Since the JHH CRU and Bayview CRU offer different levels of care, subjects will be placed into 
the appropriate CRU, based on their withdrawal history and pattern of recent drinking.  The 
Bayview CRU is primarily a domiciliary unit with nursing care. The JHH CRU is a licensed 
inpatient facility with full 24-hr medical staff coverage.  Since subjects who do not meet the above 
criteria are at greater risk for complications associated with alcohol withdrawal, they will be 
admitted to the JHH CRU for clinical management of alcohol withdrawal.   
Alcohol abstinence. For the first 24 hours, all subjects will receive an intravenous line with D5 NS 
1000ml with MVI adult Inj 10ml, thiamine Inj 100mg, Folic acid Inj 1mg, Magnesium sulfate Inj 
max of 2g and infused at 84 ml/hour. Subjects will have PRN access to ibuprofen 400mg q 4hours, 
Maalox 30 ml po q 8hours.  If systolic blood pressure is greater than 180 and/or diastolic blood 

Date: 06/08/2016 
Principal Investigator: Elise Weerts 
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pressure greater than 105, atenolol 25 mg bid will be initiated.  For all participants, the Clinical 
Institute Withdrawal Assessment Alcohol Revised (CIWA-Ar)[70], which includes 10-items 
(nausea/vomiting, tremor, paroxysmal sweats, anxiety, agitation, tactile disturbances, auditory 
disturbances and visual disturbances) will be completed every 4 hours during waking hours. This 
well validated clinical tool is administered by a nurse, to assess severity of withdrawal symptoms 
during detoxification, and is the gold standard to direct use of benzodiazepine medication[79, 80]. 
CIWA-Ar scores of 8 points or fewer correspond to mild withdrawal, scores of 9 to 15 points 
correspond to moderate withdrawal, and scores of greater than 15 points correspond to severe 
withdrawal symptoms.  The benzodiazepine lorazepam will be administered as needed using the 
symptom-triggered method[80-82].  Specifically, if CIWA-Ar score is ≥12 the subject is given a 2mg 
dose of lorazepam intravenously (IV), the study physician is notified, and CIWA-Ar scores are then 
repeated 1 hour later. If the score remains ≥10 then another 2 mg dose of lorazepam is given. 
Hourly CIWA-Ar scores and lorazepam treatment are repeated until CIWA-Ar score decreases to 
less than 9 or until a maximum of 4 doses of 2 mg lorazepam are administered; if CIWA is 9 or 
higher after 4 doses, subject will be removed from the study. Subjects will also be removed from the 
protocol for seizures, hallucinations, or disorientation.  At that point in time, the physician on call 
will be contacted who will arrange for transfer to the medical service.  The subject is now 
terminated from the study. Individuals who require benzodiazepine treatment and are successfully 
treated with lorazepam will remain in the study to complete the 3-day abstinence period, and then 
will be discontinued from further participation to avoid potential complications and confounds of 
treatment with benzodiazepines. Discontinued subjects would complete the brief intervention prior 
to early discharge. 
 
Urinary free cortisol measurement. All subjects will provide urine samples for urinary free CORT 
(UFC), as a measure of withdrawal-related stress response. During the CRU stay, all urine voided 
per 24-hrs for the first 48 hours is collected in containers containing boric acid as a preservative as 
in our previous study[19]; an aliquot is frozen (-70°C) for analysis of UFC via Liquid 
Chromatography, Tandem Mass Spectrometry (LC/MS/MS) by Quest Diagnostics Nichols Inst. San 
Juan Capistrano. The coefficient of variance is 5% and 7% for the intra-assay and the inter-assay, 
respectively. 
 
Oxytocin (OT) administration. OT (syntocinon, Novartis) 40 IU/ml, Pharmaworld, Zurich, 
Switzerland) and placebo (generic saline nasal spray, various vendors) will be transferred by JHH 
IDS in identical sterile metered-dose nasal spray bottles (Lukas-Bottles, 6-ml) to deliver 0.1 
mL/spray. Pharmaworld has provided oxytocin for numerous clinical trials in the US, including 
prior studies by Dr. Lee (Co-I).  Syntocinon previously was an FDA-approved product (NDA 
012285) used medically for labor induction, but was discontinued.  It is no longer marketed by 
Novartis.  Oxytocin will be used in these studies under FDA-approval via IND 110,562, which held 
by our collaborator Mary Lee. 
 
Johns Hopkins Hospital Investigational Drug Services will maintain and dispense spray bottles per 
study randomization schedule.  Subjects will self-administer 5 sprays per nostril, 30s apart, of 
placebo or OT (4 IU/spray x 10 sprays = 40IU total dose) 3-times/day under nurse supervision (e.g., 
7 am, 12:30 pm, 7 pm).  
 
Daily self-report measures. The CRU nurses and research staff will insure completion of self-report 
instruments for alcohol craving (visual analog scale, VAS[83]; Alcohol Urges Questionnaire[84]), 
POMS short [85, 86]and medication side effects using a modified version of the SAFTEE[87]. Alcohol 
craving, a new diagnostic criterion for AUD in the DSM-V, is a primary trigger for relapse. 

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Reductions in craving are strongly associated with better treatment outcomes for behavioral 
interventions and AUD medications[88-90]. 
 
Trier Social Stress Test (TSST). On day 4, subjects will complete the TSST. We selected the TSST 
as it is a well-validated procedure for induction of stress responses in the laboratory setting in a safe 
manner without inducing serious mental or physical distress[91]. It stimulates a more robust CORT 
response when compared to other validated stress tests (e.g. guided imagery[92, 93] or Paced Auditory 
Serial Addition Test[94]). The TSST consists of a 5-min public speaking component and a 5-min oral 
mental arithmetic component completed in front of a panel of 2 people (confederates). Subjects are 
told the session will be videotaped and their performance will be rated for speech content, speed and 
accuracy of their mathematical performance when compared to other TSST completers. Mood, 
craving and anxiety self-report measures are completed before, during and after the session.  
 
For the public speaking component, the subject is seated in a chair facing a table. Two chairs to seat 
the test panel are placed at the opposite end of the table. The subject is asked to sit quietly, relax, 
and await instructions for the test protocol.  During this 20-minute waiting period, saliva samples 
are collected for baseline cortisol measurement.  Following baseline sampling, the subject is told to 
listen carefully to the taped instructions for the first task, the job interview.  He/she is told that they 
are interviewing for the position of a hospital administrator and that in a 5-minute speech he/she 
should convince the panel that he/she is the best candidate for the job.  They are told that they must 
maintain eye contact with the panel throughout the interview.  He/she is given 10 minutes to 
mentally prepare for the interview.  The test period begins (Time 0) when a two-member panel 
(confederates) is seated across the table from the subject.  During the session, one of the 
confederates pretends to be filming the subject with a video camera. In actuality, the camera has no 
tape. Following the speech, subjects are given instructions for the mental arithmetic test.  
 
For the mental arithmetic test, the subject is told to repeat a four-digit number after the tester, 
subtract 13 from it, and call out the answer.  The subject continues subtracting and calling out 
answers for 1 min.  A new number is introduced every minute for a total of 5 minutes.  Throughout 
this challenge, the tester distracts the subject by commenting on the speed and accuracy of his/her 
responses and urges the subject to look at the tester at all times. Following all study procedures, 
subjects are debriefed about the speech task.  They are informed that the video camera did not 
contain film, that their performance was not actually being rated. 
 
Salivary CORT will be collected at three times before the TSST (-30, -15 and 0 minutes for 
baseline), immediately after the TSST and every 10 minutes for 120 minutes. Salivary CORT was 
selected to avoid stress of IV placement and blood draws. Unlike serum CORT, salivary CORT is 
unbound to protein and reflects the physiologically relevant fraction. For each sample, subjects 
chew a pad for 1 min, which is then placed into a salivette. Saliva is harvested by centrifugation, 
and stored in a cryotube at -70 until assayed in duplicate (Diagnostic Systems Laboratories; 
Webster, Texas). The intra- and inter-assay coefficients of variation are <5%. The POMS Tension 
and Anxiety (POMS-TA) subscale will be administered before and after the TSST to capture 
perceived stress.  We have extensive experience with the TSST and have used it to examine 
differences in HPA-axis response associated with gender, AUD, family history, and several gene 
variants[19, 71, 95-98].  
 
Alcohol Motivated Responding (AMR). On day 5, subjects will complete the AMR procedure. The 
AMR utilizes a progressive ratio schedule of reinforcement in which the number of required 
responses increases for each successive reinforcer, until the person fails to complete the requirement 

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(breaking point) or the session ends. The maximum response ratio completed that resulted in 
reinforcement provides a quantifiable measure of motivation to drink. A second reinforcer ($1 per 
unit) is included to permit examination of relative rates and distribution of responses between the 
two reinforcers. Using the NIAAA definition of a standard drink unit (SDU, 14 g alcohol), each 
alcohol reinforcer equals 0.5 SDU (7 g alcohol). Alcohol content was standardized to 0.5 SDU to 
ensure equivalency across subjects for amount of alcohol. A maximum of 10 reinforcers (money 
and alcohol) is available. The response ratio requirement begins at 400 and increases by a factor of 
1.2 (400, 480, 576, 692, 830, 995, 1194, 1433, 1720, 2064).  We will administer a priming drink 
(0.5 standard drink of alcohol (liquor type is based on subject preference) immediately before the 
AMR.   This drink volume is sufficient to increase craving or desire to drink in heavy drinkers 
without producing a significant increase in blood alcohol levels or interfering with responding under 
the PR procedure.  Participants will complete self-report measures of alcohol craving and alcohol 
effects following drink completion, and then begin the AMR session.  
 
The AMR session will terminate after 60 min, or after no response occurs for 10 min, whichever 
occurs first. Alcohol is not available for consumption until 60 min elapses. After 60 min, 
participants receive money vouchers and self-administer earned drinks of their preferred liquor 
(vodka or whiskey). Subjects will be allowed up to 90 minutes to finish drinking; Staff will provide 
drinks paced to ensure that subjects cannot exceed 0.5 SDU every 5 min or all earned drinks (5 
SDU maximum) in a 50-minute period. A preferred mixer and snacks is provided.  Using this 
procedure, we have established a baseline in which high levels of responding were maintained. 
Subjects distribute responses to earn about half of available alcohol drinks on average. We targeted 
this distribution to 1) avoid a floor effect in which response cost is too high, and subjects stop 
responding, 2) prevent a ceiling effect in which all 10 drinks are obtained, and 3) allow detection of 
either increases or decreases in drinks during OT treatment.  
 
Cumulative Alcohol Dosing (CAD). On day 6, subjects will complete a CAD procedure in which 1 
placebo and 3 active alcohol drinks are administered at timed intervals to increase BAL 
progressively (0.03-0.1%) Subject doses will be determined using a Computerized Blood Alcohol 
Calculator[99] which adjusts for age, height and gender differences in body water and time spent 
drinking, to target similar BAL in males and females. IDS will prepare each 120 mL drink by 
mixing the appropriate mL of 95% ethanol in a sweet beverage using a w/v metric. The placebo 
drink is blinded by floating 1 mL ethanol on top of the drink and by placing an ethanol-soaked 
wristband around the glass to deliver a strong alcohol odor. Active alcohol drinks are prepared the 
same. Staff monitor subjects and ensure consumption of each drink is paced over 10 min. Subjects 
will complete a computerized subjective report battery at baseline (-30 minutes) and every 30-min. 
The 10-min computerized battery is shown in Table 3. The placebo drink will be administered at 
time 0, followed by active alcohol drinks at 30 min intervals. Breath alcohol levels (BAL) will be 
determined at baseline and 15 min after each drink. Heart rate, skin conductance, skin temperature 
and blood pressure are recorded via a noninvasive monitor. Subjects return to the CRU for 
monitoring, and complete the battery and an Alcohol Hangover Scale[100] every hour for 4 hours 
post session and once the next morning.  We have safely administered alcohol in social and heavy 
drinkers[83, 100-102], and demonstrated reliable alcohol dose-related increases in heart rate and 
subjective effects; these effects are sensitive to AUD medications (naltrexone, acamprosate)[103-106]. 
The CAD was chosen to reduce subject research burden and dropout rates.  
 
Table 3: Computerized battery of subjective report measures for CAD session 

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Drug Effect Visual Analog Scale (VAS) includes the following questions:  "Do you feel ANY effect 
of the drink(s)?," "Do you feel GOOD effects from the drink(s)?," "Do you feel BAD effects of the 
drink(s)?," "Do you LIKE the effects of the drink(s)?," "Do you DISLIKE the effects of the 
drink(s)?" , “Is this the WORST you have ever felt?”,  and “Is this the BEST you have ever felt?”. 
Subjects respond by positioning an arrow on a 100-point line anchored by "not at all" and 
"extremely."  
Tiffany Brief Alcohol Craving Scale is based on a questionnaire developed by Cox, Tiffany and 
Cristen [107] on which subjects rate their alcohol craving. Subjects rate each item on a scale from 0 
(not at all) to 10 (extremely or very strong, depending on the question).  Questions include items 
such as "How badly would you like an alcoholic drink right now?" and "Rate your desire to drink 
alcohol."  
Biphasic Alcohol Effects Scale (BAES) [108] is composed of fourteen items measuring stimulant 
(elated, energized, excited, stimulated, talkative, up, vigorous) and sedative (difficulty 
concentrating, down, heavy head, inactive, sedated, slow thoughts, sluggish) effects of alcohol.  
Items are presented one at a time in alphabetical order.  Subjects rate each item on a scale from 1 
(not at all) to 9 (extremely).  
Subjective High Assessment Scale (SHAS) [109] subjects rate alcohol effects by positioning an arrow 
on a 100-point line ranging from "normal" (0) to "extremely" (100) Subjects are told to assume their 
ratings were "normal" before they received a beverage.  Items are uncomfortable, high, clumsy, 
muddled or confused, slurred speech, dizzy, nauseated, drunk or intoxicated, sleepy, distorted sense 
of time, effects of alcohol or drug, difficulty concentrating, feelings of floating, the worst I've ever 
felt, and the best I've ever felt. 
Alcohol Hangover Scale [100] is composed of ten symptoms (sweaty, loss of appetite, shaky, trouble 
concentrating, racing heart, anxious, alcohol craving, tired, restless and irritable).  Each item is rated 
on an analog scale marked at opposite ends with "not at all" and "most ever."  
Profile of Moods state tension and anxiety (POMS-TA) subscale [85, 110]is composed of a list of 
feelings (tense, shaky, on edge, panicky, uneasy, restless, nervous, anxious, relaxed).  Subjects rate 
each item for how they are feeling on a 4 point scale ranging from 0 (not at all) to 4 (extremely) 
 
Brief Intervention:  Prior to discharge on day 7, participants will receive a brief intervention that 
addresses their heavy drinking and any alcohol-related problems.  The intervention will be delivered 
by one of the Master’s-level research staff or a faculty member (Dr. McCaul, or Dr. Alvanzo).  It 
will follow the NIAAA guidelines from Helping Patients Who Drink Too Much, including 
treatment referral as requested. 
 
b. Study duration and number of study visits required of research participants. 
 
Subjects have a maximum of 6 months to complete the entire study.  We anticipate 2 visits to 
complete the protocol.  This includes an in-person assessment (visit1) and a 6-day inpatient stay 
(visit 2).  Additional 1 or 2 visits may be scheduled if labs at assessment need to be repeated or 
procedures are rescheduled due to study complications. 
 
c.  Blinding, including justification for blinding or not blinding the trial, if applicable. 
 
Alcohol and OT are administered under placebo controlled blind conditions. Blinding is done to 
control for expectancy effects. 

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Justification of why participants will not receive routine care or will have current therapy 
stopped. 
 
N/A.  The subjects are healthy volunteer participants. 
 
c. Justification for inclusion of a placebo or non-treatment group. 
 
Blinding is done to control for expectancy effects for the best test of medication efficacy. 
 
 
d. Definition of treatment failure or participant removal criteria. 
 
Subjects will be terminated from this protocol if they have positive drug toxicology test 
(excluding THC) or a positive pregnancy test (females) at any time during the study.  Subjects 
may also be terminated from this protocol if they do not comply with CRU rules or study 
procedures; they will first be warned of possible dismissal and, if noncompliance persists, will 
be terminated from the protocol. Subject participation may also be terminated based on safety 
issues. 
 
 
Description of what happens to participants receiving therapy when study ends or if a 
participant’s participation in the study ends prematurely. 
 
Subjects terminated prematurely from this protocol will be paid for procedures completed prior 
to termination. We will also attempt to complete the brief intervention interview for participants 
prior to CRU discharge. Subjects who complete the study will receive payment for all 
procedures completed plus the study bonus.   
 
5. 
Inclusion/Exclusion Criteria 
 
a. Inclusion Criteria: 
• 
Healthy 21-50 years old male and female subjects 
• Must meet DSM-V criteria for AUD and not be seeking treatment 
• Actively drinking >14 drinks/week for women and >21 drinks/week for men, with at least 2 
heavy drinking days (>4 drinks/day for women, and >5 drinks/day for men) for a 
consecutive 30-day period in the last 90 days from assessment (Time Line Follow Back, 
TLFB) 
• Positive blood PEth (>8 ng/mL)  
 
b. Exclusion Criteria: 
• Current DSM-V major current mood or anxiety disorder or drug use disorder (excluding 
alcohol and nicotine; excluding mild cannabis use disorder); in or in need of treatment 
• Moderate to severe cannabis use disorder 
• Drug use in last 30 days and/or positive urine toxicology screens (excluding 
marijuana/THC)  
• History of seizure disorder or closed head trauma 

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• History of withdrawal-related seizures or serious alcohol withdrawal symptoms (CIWA 
>12) 
• HIV positive 
• Neuroendocrine disorder 
• Any serious medical condition that would place subject at risk or interfere with study 
participation 
• Liver function tests > 3X times normal at screening 
• Shipley vocabulary score < 18 and REALM score below 19, corresponding to 5th grade 
reading level 
• Prescription medications in last 3 months that could affect CNS or HPA axis function 
• Women who are pregnant, nursing or planning pregnancy cannot participate  
 
6. 
Drugs/ Substances/ Devices 
a. The rationale for choosing the drug and dose or for choosing the device to be used. 
 
Oxytocin/syntonocin:  We chose 40 IU to maximize the likelihood of observing OT effects 
based on evidence of increased cerebrospinal fluid levels after intranasal administration of 
OT[111] and vasopressin (a similar peptide to OT), and prior studies showing efficacy of 40 IU 
OT[38, 42, 112-114]. Doses as high as 320 IU/day OT have been safely administered, without adverse 
events[115, 116].   OT has no known abuse liability and has an excellent safety profile in clinical 
research settings [37]. The utility and feasibility of intranasal OT as a medication is supported by 
its success in clinical trials for the treatment of behavioral deficits associated HRA-axis 
dysfunction including schizophrenia, anxiety, autism, and Prader-Willi syndrome[61-64].   
 
Ethyl Alcohol/Alcohol: Alcoholic beverages are legally sold to adults. The dose of alcohol used 
in the CAD was selected to bring blood ethanol levels to approximately 0.1%was determined 
based on our previous studies and a comprehensive literature on administering alcohol to 
research subjects. This BAC corresponds to about 1 g/kg alcohol.  The drink is prepared by IDS 
using 190 Proof ethanol (95%v/v, 0.775 g/ml Spectrum Chemical); the total alcohol dose is 
divided over three drinks, prepared by mixing the appropriate amount of pure ethanol with a 
sweet beverage.  Using standardized drinking units, 1 (e.g. (One standard drink is equivalent to 
12 ounces of beer, 5 ounces of wine, or 1.5 ounces of 80-proof spirits.), this amount is about 4-5 
drinks for men and about 3-4 drinks for women when consumed in over 2-hour drinking 
episode. This amount is within the limits of the typical drinking episode of participants, and are 
not expected to produce significant adverse events. 
 
After the AMR, subjects may consume up to up to 5 standard drinks (70g ethyl alcohol) of an 
alcoholic beverage of their choice (e.g., beer, wine or liquor) during the alcohol self-
administration session, and drinking is paced. These amounts are within the limits of the typical 
drinking episode of participants and also are sufficiently large to promote alcohol-motivated 
responding.   
 
Use of intranasal OT and alcohol will be under FDA-approval via IND 110,562 (holder Mary 
Lee, MD, Co-I, amendment submitted to FDA 8/4/14). Amendment application is uploaded to 
eIRB protocol. 
 

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Nicotine Patch:  Active nicotine patch (21 mg) is the standard of care for management of 
nicotine withdrawal.   
 
b. Justification and safety information if FDA approved drugs will be administered for non-
FDA approved indications or if doses or routes of administration or participant 
populations are changed. 
 
n/a 
 
c. Justification and safety information if non-FDA approved drugs without an IND will be 
administered. 
 
n/a/ 
 
 
7. 
Study Statistics 
 
a. Primary Outcome variables:  
• Peak scores for CIWA-Ar and Craving Scales for abstinence days 1-3. 
• Total and subscale scores on POMs Short at assessment and during the CRU stay 
• UFC for abstinence days 1-3 
• Peak salivary CORT in the TSST  
• Number of drinks earned in the AMR  
• Peak drug effect VAS scores and peak increase in heart beats per minute (bpm) in the CAD 
 
b. Secondary Outcome variables:  
• Stimulation and sedation subscales of the BAES in the CAD 
• Total score of the SHAS in the CAD 
• Total scores for the tension and anxiety subscale of the POMS  at assessment, during the 
TSST, and during withdrawal 
• Side effects reported on the SAFTEE during the CRU stay 
 
c. Statistical plan including sample size justification and interim data analysis:  
In AUD treatment research, a moderate effect of 30-40% improvement is typical. The primary 
objective of this protocol is to generate estimates of effect size and variance between the OT and 
placebo treatment groups that could be used to calculate sample size for a larger scale, Phase III 
study. We have effect sizes for some of our variables using data drawn from the literature and 
our prior studies. For our power analyses we set type I error (α) = 0.05 where power (1-β) =0.8 
for the specified effect size for each outcome measure between the OT and placebo treatment 
groups (n=12 per group, 24 total). Data from prior small trial[56] showed the OT group  (n=7) 
had 3-fold lower CIWA-Ar scores and a 40% decrease in craving vs. the placebo group (n=4) on 
day 1. In our prior study in AUD subjects (n=25)[117], the mean (SD) peak alcohol craving on 
day 1 of abstinence was 23.4 (7.9). We have power (0.89) to detect a 40% difference in CIWA-
Ar and craving between treatment groups (Aim 1). In a previous study, OT reduced stress-
induced salivary CORT by 30%[38]. Based on our TSST data (n=414), with mean (SD) peak 
salivary CORT of 0.48 (0.46), we will have power (0.8) to detect a 30% difference in CORT 
between treatment groups (Aim 2). In our pilot study (n=9), subjects drank an average of 3.1 
(1.9 SD) drinks, although the 3 drinkers most similar to those in the proposed study drank a 

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mean of 5 drinks (2.7 SD). We have power (>0.8) to detect a 30% difference in drinks between 
groups (Aim 3). In our preliminary data (n=101), mean (SD) was 118 (62.8) for VAS scores and 
+13(6.6) for bpm. We have power >0.8 to detect a 40% reduction in peak VAS and bpm (Aim 
4). Thus, our sample size of 24 subjects should be sufficient to detect differences between 
treatment groups, assuming a moderate effect of OT. 
 
The outcome variables for each Aim are listed above. They are all continuous measures. We 
will first exam the normality by plotting histograms and Shapiro-Wilks tests. The need for 
transformations and/or use of non-parametric analysis will be determined. In each aim, we 
compare the outcomes between two groups (OT vs. Placebo), so the statistical analyses will be 
similar across aims. We will run two-sample t-tests or a non-parametric equivalent method to 
test if the outcomes are different between the OT-treated and placebo-treated groups. 
Randomized treatment groups were matched for age, gender and FNDT score; we will evaluate 
for possible unbalance between the two groups for other baseline measures (e.g., AUD, drinking 
severity).  For each outcome variable, we will construct an ANCOVA model. Potential 
confounding factors (e.g., gender, mean drinks/week) will be added as covariates to the models, 
based on sensitivity analysis. We will also complete exploratory analyses of the effects other 
assessment instruments and alcohol measures (secondary outcome measures) on treatment 
outcomes. 
 
d. Early stopping rules. 
 
Participants with significant alcohol withdrawal symptoms as indicated by a CIWA-Ar score 
>12, will be treated with benzodiazepines. Individuals who require 4 lorazepam doses (2mg) in 
and do not show improvement in symptoms (CIWA= 9 or higher) will be removed from the 
study. Subjects will also be removed from the protocol for seizures, hallucinations, or 
disorientation.  Other individuals in need of benzodiazepine treatment or upon physician 
recommendation will end participation after completion of the 3-day withdrawal phase; subjects 
will be discharged pending approval of a physician on day 4 and will not complete the 
laboratory sessions. Subjects also may be terminated from this protocol if they do not comply 
with CRU rules or study procedures. They will first be warned of possible dismissal and, if 
noncompliance persists, will be terminated from the protocol.   
 
Subjects will also be discontinued from the protocol for positive pregnancy test (females) or 
positive drug toxicology tests (excluding THC). 
 
8. 
Risks 
 
a. Medical risks, listing all procedures, their major and minor risks and expected frequency. 
Subjects will be carefully screened and fully informed of study procedures and risks prior to 
participation in the study. This study involves several separate procedures, each of which entails 
some risk of discomfort or side-effects. These risks are discussed by procedure. Participants will 
receive a thorough description of all potential medical risks in the consent form. 
  
i. 
Assessment procedures: The major disadvantage is the time taken to complete study 
instruments and questionnaires. Our experience with these evaluations indicates they are 
acceptable to patients. This study involves questions about dangerous or illegal behavior, 
psychiatric history, a medical history, and a physical exam. There is a small risk that 

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participants will become upset during the assessment interview. There also is a risk of 
breach of confidentiality if the responses were to be disclosed.  
 
ii. 
Oxytocin Administration:   The use of oxytocin in these studies will be under FDA-approval 
via IND 110,562; this IND is held by Dr. Mary R. Lee, who is a collaborator on the study.  
While many studies have used 24 IU OT[37], we chose the 40 IU dose to maximize the 
likelihood of observing OT effects based on evidence of increases in cerebrospinal fluid 
levels for vasopressin, a similar peptide to oxytocin[112], and use of the 40IU dose in prior 
cognition and stress studies [38, 42, 113], including a recent study by Dr. Lee [114].  It has been 
used in many clinical trials for other medical purposes and only a few people experienced 
any side effects (nasal irritation, runny nose, sleepiness, light-headedness, euphoria, stomach 
pain, anxiousness, or headache). Based on both Dr. Lee’s experience and as cited in the 
literature, we expect the side effects for OT to be minimal.  For example, a recent meta-
analysis of the safety and side effects of intranasal OT drawn from 38 randomized trials 
determined OT produces no reliable side effects, and is not associated with adverse 
outcomes when delivered in 18-40 IU/dose for short-term use in controlled research[37].  In 
addition, doses as high as 320 IU/day OT have been safely administered to human subjects, 
without report of adverse events[115, 116].  
 
iii. 
Blood collection: Blood draw procedures involve minimal risks, such as a slight risk of 
discomfort at the intravenous site. A small amount of bleeding under the skin will produce a 
bruise in about 5% of cases. The risk of temporary clotting of the vein is about 1%. The risk 
of infection or significant blood loss is less than 1 in 1000. In rare cases, fainting could 
occur. For PEth, a small blood sample will be collected via finger stick for the BloodSpot® 
collection test (US Drug Testing Laboratory, Des Plaines, IL).  We selected dried blood spot 
vs. whole blood assays as it reduces subject risk associated with venipuncture and PEth is 
more stable in dried blood samples than in whole blood[73, 74]. 
iv. 
Urine Collection: During the CRU stay, all urine voided during the first 48 hours of the 
CRU stay is collected. There is no risk associated with urine collection, but subjects may 
find this inconvenient. 
 
v. 
Medically supervised alcohol withdrawal and monitored abstinence: Eligible participants 
will undergo monitored alcohol abstinence and alcohol withdrawal on the CRU. There is a 
risk of complications (e.g., elevated BP, seizures) during alcohol detoxification; treatment 
with atenolol and/or lorazepam will be provided if needed, and  as detailed below. To reduce 
risk, applicants with a history of withdrawal-related seizures or other serious alcohol 
withdrawal symptoms will be excluded from participation.  We have been safely using this 
procedure under IRB approval for over 15 years.   
a. Atenolol. Participants that have elevated blood pressure that are above safe limits 
(systolic blood pressure >180 and/or diastolic blood pressure >105) will be given 
atenolol (25 mg BID), which is approved by the Food and Drug Administration for 
treatment of hypertension. The most common symptoms of atenolol include 
dizziness, lightheadedness, tiredness, drowsiness, depression, nausea and diarrhea. 
Less common but more serious side-effects include: shortness of breath, and 
swelling of the hands, feet, ankles or lower legs.   
b. Lorazepam. Participants that experience serious withdrawal symptoms as determined 
by CIWA scores >12 or physician recommendations, will receive 2 mg lorazepam 

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using the system triggered method, and additional monitoring of symptoms.  A 
maximum of 4 doses (2 mg IV) will be administered. Lorazepam has been approved 
by the Food and Drug Administration for treating alcohol withdrawal in this manner.  
The most common side effects of lorazepam are drowsiness, fatigue and ataxia 
(decreased muscle control). Other less common side effects include: confusion, 
depression, headache, hypoactivity, slurred speech, feeling light-headed or dizzy, 
constipation, nausea, incontinence, changes in libido, urinary retention, slower pulse, 
cardiovascular problems, low blood pressure, blurred vision or other visual 
disturbances, blood clots and skin rash.  Participants who receive lorazepam will stay 
in the study to complete alcohol abstinence and withdrawal monitoring only if 
symptoms are controlled (CIWA < 9), but will not complete the laboratory sessions; 
participation will end on day 4 of the CRU stay.  
 
vi. 
Nicotine Patch:  Nicotine dependent subjects will be administered a nicotine patch at the 
time of JHH CRU admission and every morning for the duration of the study.  The nicotine 
patch dose selected for study in this protocol is FDA-approved and has been shown to have 
a low incidence rate of serious side-effects or adverse events in clinical trials with nicotine-
dependent patients. Less than 5% of smokers have to stop using a nicotine replacement 
product because of side effects. Side effects of nicotine patches may include: skin rash at the 
location of the patch; sleep problems when using a 24-hour patch, such as having trouble 
sleeping or having especially vivid dreams. On rare occasions, there have been reports of 
severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; 
swelling of the mouth, face, lips, or tongue); fast or irregular heartbeat; mouth, teeth, or jaw 
problems; pounding in the chest; severe diarrhea, dizziness, nausea, vomiting, or weakness.  
 
vii. 
Trier Social Stress Test (TSST): Subjects will participate in the Trier Social Stress Test as 
part of the experimental protocol. This test includes public speaking and mental arithmetic 
components, which have been shown to elevate a variety of physiological measures, 
including neuroendocrine and autonomic variables. There is a small risk that clinically 
significant symptoms of anxiety or grossly elevated autonomic reactivity may occur. We 
have completed the Trier Stress Test (TSST) in over 400 subjects without inducing serious 
mental or physical distress. This includes completing the TSST in 27 alcohol dependent 
subjects. Participants are monitored throughout the procedure. 
 
viii. 
Alcohol procedures (AMR and CAD): Alcohol may produce mood and behavioral effects 
that are dysphoric and that can result in impairment in performance and judgment and, in 
cases of overdose, ethanol can produce medically serious toxic effects. In the AMR and 
alcohol self-administration session, the maximum dose of alcohol that subjects can self-
administer is five standard drinks over 50 minutes; this dose will produce a blood ethanol 
level of approximately 120mg/dL. In the CAD session, the maximal proposed dose is one 
that produces a blood ethanol level of approximately 100mg/dL. Subjects invited for study 
participation are those who regularly drink doses of ethanol greater than the doses selected 
in this study, reducing the likelihood of adverse events. These are medically safe but 
behaviorally intoxicating levels, associated with impairment of psychomotor and cognitive 
performance and with emotional and behavioral effects that may range from sedation and 
drowsiness to agitation, irritability, depression, and emotional liability. These effects 
dissipate as blood ethanol levels decline. 

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ix. 
IV placement and fluid delivery.  IV placement can cause some pain. There is a slight risk of 
bleeding, bruising, or irritation whenever blood is drawn or IV lines are started. In addition, 
IV fluid can occasionally escape under the skin, causing pain and swelling for a few days. 
When an intravenous product is given, there is always a chance that the needle placed in the 
vein may infiltrate causing temporary swelling, bruising, bleeding and/or discomfort. The 
risk of temporary clotting of the vein is about 1%.  In rare cases, fainting or infection may 
occur. 
 
b. Steps to Minimize Risks.    
i. 
Recruitment and Informed Consent. Participants will be identified through the media. To 
date, we have used newspaper, radio and social media advertisements. All ads and screening 
materials are reviewed and approved by the IRB prior to use. At the initial contact, the 
research assistant will discuss the study purpose and requirements with the participants. This 
information will also be displayed to participants who complete the online screener.  
 
ii. 
Assessment. Prior to the start of the assessment, subjects provide written informed consent 
using a document approved by the Johns Hopkins IRB. The staff member will discuss the 
consent form with the volunteer and answer any questions before they are asked to sign it. 
Volunteers will receive a copy of the signed consent form to keep. The consent form 
describes the experimental procedures and their associated risks. It provides an assurance 
that volunteers may ask and will receive answers to questions, assures volunteers that their 
participation is voluntary and may be terminated by them at any point if they wish, gives the 
conditions for investigator termination of research participation, and provides names and 
numbers to contact in the event of questions or concerns.  
 
Prior to completing any study assessment materials, subjects are breathalyzed and must 
provide a 0mg% reading to participate in the interview. Subjects also must provide a urine 
sample and test negative for illicit drug use (excluding THC). Female participants must also 
test negative in a urine pregnancy test. Subjects with any contraindications are excluded 
from participation. Subjects are permitted to discontinue their participation at any time. 
Subjects are carefully and continually monitored throughout their participation. In case of an 
adverse event, a physician or nurse practitioner is available by beeper for assistance.  
 
iii. 
Insuring protocol comprehension: We exclude potential subjects with a Shipley or REALM 
score below the 5th grade reading level because of concerns about their ability to adequately 
participate in the study procedures. Many of our behavioral/subjective measures are self-
administered and require basic literacy and language skills (e.g., English is not primary 
language). If subjects are not at a 5th grade reading level, they have difficulty responding 
accurately to the study questionnaires.  
 
iv. 
Psychosocial assessments: The risk of distress or personal discomfort elicited during 
assessment is minimized by the use of standardized assessment procedures widely and 
successfully used in research settings. Also, all study staff are trained in nonjudgmental 
interview techniques and crisis intervention procedures. Employees are carefully trained to 
monitor subjects for any adverse effect and to contact an Investigator immediately if such an 
event occurs. If serious psychological concerns (e.g., suicide risk) arise, staff has been 
trained to immediately refer these to study investigators who are licensed psychologists (Dr. 
McCaul) and Psychiatrists (Dr. Alvanzo). In the unlikely event neither of them is available, 
staff will escort the participant to the emergency room. 

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Medically supervised alcohol withdrawal and monitored abstinence: For the first 24 hours, all 
subjects will receive an intravenous line with D5NS with MVI adult Inj 10ml, thiamine Inj 100mg, 
Folic acid Inj 1mg, Magnesium sulfate Inj max of 2g infused at 84 ml/hour. Subjects will have PRN 
access to ibuprofen 400mg q 4hours, Maalox 30 ml po q 8hours. Subjects will be closely monitored 
by nursing and physician staff. Severity of withdrawal will be determined using the Clinical 
Institute Withdrawal Assessment -- Alcohol Revised (CIWA-Ar), a standardized withdrawal 
assessment instrument and determination of vital signs every 4 hrs during waking hours. 
Participants that have elevated blood pressure that are above safe limits, will be given atenolol .We 
will initiate system-triggered lorazepam treatment for alcohol withdrawal symptoms if the 
withdrawal score exceeds the clinical cutoff of CIWA-Ar  > 12 or on the advice of the study 
physician. If the CIWA-Ar score is ≥12 the subject is given a 2mg dose of lorazepam, and CIWA-
Ar scores are then repeated 1 hour later. If the score remains ≥10 then another 2 mg dose of 
lorazepam is given. Hourly CIWA-Ar scores and lorazepam treatment are repeated until CIWA-Ar 
score decreases to less than 9 or until a maximum of 4 doses of 2 mg lorazepam are administered; if 
CIWA is 9 or higher after 4 doses, subject will be removed from the study. Subjects will also be 
removed from the protocol for seizures, hallucinations, or disorientation.  At that point in time, the 
physician on call will be contacted who will arrange for transfer to the medical service.  Individuals 
who require benzodiazepine treatment and are successfully treated with lorazepam will remain in 
the study to complete the 3-day withdrawal period, but will not complete laboratory session in order 
to avoid potential complications and confounds of treatment with benzodiazepines.  
 
To date, we have successfully withdrawn over 98% of our alcohol-dependent subjects without 
medications requiring protocol termination in studies using a similar population. Exclusion of 
subjects with a history of alcohol withdrawal complications, and/or high CIWA-Ar scores is a 
successful strategy to help ensure subject safety in studies of new medications[118-120].   
 
v. 
Oxytocin administration: Oxytocin (40 IU/ml, Syntocinon spray, Novartis) and placebo 
(containing the carrier without the neuropeptide) in identical metered-dose nasal spray 
bottles (Lukas-Bottles, 5-mL, 0.1 mL/actuation) will be obtained from Pharmaworld, Zurich, 
Switzerland.  Oxytocin will be used in these studies under FDA-approval via IND 110,562.  
The IND 110,562 is held by our collaborator Mary Lee. This supplier and formulation has 
been used by Dr. Lee in her prior studies.  Full information sheets of the nasal spray 
formulation are uploaded. Oxytocin and placebo will be dispensed by The Johns Hopkins 
Investigational Drug Services. Throughout the study, subjects will remain on the inpatient 
CRU, and will complete medication side-effects questionnaires. Forms are reviewed by 
nurses and study staff.  
vi. 
Blood collection: Experienced medical personnel using sterile equipment will be performing 
the blood draws, minimizing the risk associated with venipuncture.  
 
vii. 
Trier Social Stress Test: Participants will complete the TSST in our research offices. 
Subjects will be monitored throughout the procedure. If a subject shows clinically 
significant symptoms of anxiety the study physician or nurse practitioner is available by 
beeper for assistance. Subjects are debriefed about the procedure at the end of the study 
participation and prior to CRU discharge. Specifically, they are informed that the video 
camera actually did not contain film, that their performance was not rated, and that the 
interviewers were actually persons associated with the study.  
 

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viii. 
Alcohol Administration Sessions: In conducting alcohol administration procedures in heavy 
drinkers, we will take several important steps to ensure the safety and well-being of subjects 
participating in this protocol. First, we will follow the guidelines of the National Institute on 
Alcohol Abuse and Alcoholism for alcohol administration to persons with an alcohol use 
disorder. Second, we recruit only persons who are not seeking treatment and who are 
volunteering for remuneration. Third, we house subjects on the CRU under observation to 
reduce potential harm during alcohol withdrawal and alcohol intoxication. Fourth, the dose 
of alcohol that will be available during the alcohol motivated responding (AMR) and self-
administration procedure (i.e., 5 standard drinks) and the cumulative alcohol dosing (CAD) 
procedures sessions is well below doses routinely self-administered by the participants and 
drinking will be paced to prevent very rapid ingestion of the available alcohol drinks. Fifth, 
all subjects will participate in a brief intervention at the conclusion of their study 
participation; the intervention provides feedback on their hazardous drinking levels and 
encourages acceptance of treatment referral, as appropriate.  
 
Our laboratory has substantial experience administering ethanol to human subjects under a 
variety of experimental and dosing conditions.  All ethanol doses are administered under 
doctor's orders and prepared by the Johns Hopkins Investigational Drug Service using the 
participant’s preferred alcoholic beverage (e.g., beer, wine or liquor for AMR and self-
administration) or pharmacy-grade ethanol (for CAD). Participants are monitored carefully 
throughout the laboratory sessions; should a subject evidence a medical or behavioral 
adverse effect, a physician will be called immediately and the subject will receive 
appropriate evaluation and treatment. Thus, the careful choice of doses, the medical 
observation and monitoring, and the use of human volunteers who regularly drink doses of 
ethanol comparable to and greater than the ones selected for this study render the likelihood 
of serious adverse ethanol-induced effects unlikely.  
 
ix. 
Confidentiality: Our staff is well trained in the matters of confidentiality. Subject numbers 
will be used to code all data forms for computer entry and storage. Study findings are 
reported using group data only. No information about subjects will be provided to anyone 
outside of the study including family members, third persons or organizations. Experimental 
sessions will take place in the Johns Hopkins 550 Building and the Johns Hopkins Clinical 
Research Unit.  We will obtain a Certificate of Confidentiality for this study from the 
funding agency. 
x. 
IV placement and fluid delivery.  To minimize risks, only experienced medical personnel 
using sterile equipment will be performing IV placements and fluid delivery, and procedures 
are completed on the CRU. 
 
c. Plan for reporting unanticipated problems or study deviations 
 
An adverse event (AE), is defined as any untoward medical occurrence in a subject, not 
necessarily having a causal relationship with the study. A serious adverse event (SAE) is any 
untoward medical occurrence that a) results in death, b) is life- threatening, c) requires inpatient 
hospitalization or prolongation of existing hospitalization, d) results in persistent or significant 
disability/incapacity, or e) is a congenital anomaly/birth defect. 
AE's may be graded as: Mild (no limitation of usual activities), Moderate (some limitation) or 
Severe (inability to carry out usual activities). The relationship of the AE to the study 
procedures is classified as: Not related, Unlikely, Possible, Probable, or Definite.  

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Dr. Wand has responsibility for communication with the IRB and will be responsible for 
distinguishing between an AE and SAE. SAEs that are deemed to be severe and have a high 
probable or definite relationship to study procedures will be reported to the Johns Hopkins 
Medical Institute IRB and NIAAA project officers within 48 hours.  
Annual reports will be submitted to the NIAAA project officer and the IRB summarizing 
protocol deviations, as well as AEs and how they were addressed by the study team.  Dr. Lee 
(holder of the IND) will be responsible for all reports to the FDA per their guidelines and 
regulations. 
d. Legal risks such as the risks that would be associated with breach of confidentiality. 
 
Subject numbers will be used to code all data forms for computer entry and storage. Study 
findings are reported using group data only. No information about subjects will be provided to 
family members, third persons or organizations.  Experimental sessions will take place in the 
Johns Hopkins 550 Building, the Johns Hopkins CRU and the JH Bayview CRU. Our study 
personnel are trained in the protection of human subject confidentiality and are HIPAA trained 
and certified. 
 
e. Financial risks to the participants. 
 
All costs for the CRU stay and study related procedures will be covered by NIH grants. 
 
 
9. 
Benefits 
a. 
Description of the probable benefits for the participant and for society. 
 
This study is conducted for the advancement of science. It is clinically and scientifically 
important to determine the effects of OT on alcohol withdrawal symptoms, stress response, 
alcohol motivation, consumption and sensitivity in heavy drinkers during acute alcohol 
abstinence. These studies will provide new information that is relevant for the development 
of OT as a potential pharmacotherapy for AUD.  
 
At the end of study participation, subjects receive a brief psychosocial intervention for their 
heavy drinking.  Brief psychosocial intervention has been shown to be efficacious in 
reducing alcohol consumption and alcohol-related problems. 
 
10. 
Payment and Remuneration 
a. 
Detail compensation for participants including possible total compensation, proposed bonus, 
and any proposed reductions or penalties for not completing the protocol. 
 
Since participants receive payment depending on which parts of the protocol they participate 
we have divided payments into payment for procedures for study eligibility and procedures 
for study completion. 
 
 
Eligibility Assessment procedures  
Compensation 
($) 
In-person Assessment  
$75 

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extra visit assessment (if needed) 
$25 
Assessment compensation  
$100 
 
Study Protocol Elements for eligible subjects 
Compensation 
($) 
3 Session days ($75 ea) 
$225 
6 overnight CRU ($25 + $15 ea) 
$240 
Bonus for study completion 
$150 
max $ bonus AMR  ($1 per drink) 
$10 
Inpatient procedures compensation  
$625 
Total max study compensation 
$725 
 
 
Subjects who are terminated for noncompliance or who drop out of the study will be paid only the 
amount earned to date for completed procedures, CRU stay or outpatient visits.  They will forfeit 
future possible earnings and bonus payments. To eliminate any financial incentive for early 
termination, subjects who are noncompliant or drop out will not receive payment until the day when 
they were scheduled to complete their study procedures. If subjects are terminated by the 
Investigators for safety reasons, they will be paid the amount earned to date for completed 
procedures, CRU stay or outpatient visits. Additionally, they may be eligible for bonus payments 
prorated for length of study participation. 
 
11. 
Costs 
a. 
Detail costs of study procedure(s) or drug (s) or substance(s) to participants and 
identify who will pay for them. 
 
n/a 
 
12. 
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