Conditions: Alcohol Use Disorder
Keywords: Alcohol use disorder Oxytocin, intranasal Alcohol tolerance Alcohol intake Alcohol treatment Alcohol, intravenous
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 6
Healthy volunteers: yes

Brief summary:
This pilot study is intended to demonstrate feasibility and acquire preliminary data. If successful, this data could support a future project studying the effect of oxytocin on tolerance and alcohol seeking in humans.

Detailed description:
This pilot study is designed to demonstrate feasibility and provide preliminary data supporting use of intranasal oxytocin in treatment of alcohol use disorders. Specifically, experiments are planned to test the ability of oxytocin to reverse tolerance and alcohol seeking in humans by employing state-of-the-art computer-assisted intravenous alcohol administration. Two separate experiments will be run. In the first, tolerance will be assessed using sensitive tests of subjective response and cognitive function during an intravenous infusion that maintains a steady breath and therefore brain exposure to alcohol. In the second, an intravenous alcohol self-administration paradigm that requires increasing effort for each additional infusion will be used to assess change in motivation for alcohol. Demonstrating that oxytocin (compared to placebo) worsens test performances in alcohol-dependent individuals and/or reduces the compulsive drive to self-administer alcohol would be strong evidence for its potential to treat alcohol use disorders.

Arms:
arm 1: Repeated subjective and cognitive tests during a 4 hour session that includes a baseline period, an oxytocin or placebo delivery, absorption and testing period, and a 2 hour alcohol clamp. Oxytocin or placebo were delivered intranasally in two sessions, scheduled 3-4 weeks apart, double blind. arm 2: Progressive work alcohol exposure, 2 sessions (intranasal oxytocin or placebo), double blind.

Note this Arm was not completed (see Overall Status for explanation of study termination)

Interventions: intervention 1: Intranasal oxytocin intervention 2: Intranasal placebo
Intervention descriptions: intervention 1: Initial dose 40 IU in 1 ml; 2 booster doses of 24 IU in 0.6 mls each, spaced about 1 hour apart intervention 2: Initial volume 1 ml; 2 booster volumes of 0.6 mls each, spaced about 1 hour apart

Protocol document:
Prot_SAP_000.pdf: 
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Does Oxytocin Alter Tolerance to Alcohol or Motivation for Alcohol in 
Heavy Drinking Human Subjects: 
 Testing a Novel Anti-Addiction Mechanism  
 
 
 
 
Martin Plawecki, M.D., Ph.D., 550 N University Blvd. UH5505 
Indianapolis, IN 46202 
 
 
 
Co-I: Ann Kosobud, Ph.D., Associate Professor, Dept. Neurology, IUSOM 
Co-I: Sean O’Connor, M.D., Professor, Dept. Psychiatry, IUSOM 
 
 
 
Support Provided by: 
Hanlon Trust  
 
Advisor (non-interacting): Cort A. Pedersen, MD 
Advisor (non-interacting): Carolina Haas-Koffler, PharmD  
 
 
 
 
 
NCT05312008 
 


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Table of Contents: 
 
Study Schema 
1.0 
Background & Rationale 
2.0 
Objective(s) 
2.1 
Primary Objective 
2.2 
Secondary Objective 
2.3 
Tertiary/Exploratory/Correlative Objectives 
3.0 
Outcome Measures 
3.1 
Primary Outcome Measures 
3.2 
Secondary Outcome Measures 
3.3 
Tertiary/ Exploratory/ Correlative Outcome Measures 
4.0 
Eligibility Criteria 
4.1 
Inclusion Criteria 
4.2 
Exclusion Criteria 
5.0 
Study Design 
6.0 
Enrollment/Randomization 
7.0 
Study Procedures 
8.0 
Study Calendar 
9.0 
Reportable Events 
10.0 
Data Safety Monitoring 
11.0 
Study Withdrawal/Discontinuation 
12.0 
Statistical Considerations 
13.0 
Data Management 
14.0 
Privacy/Confidentiality Issues 
15.0 
Follow-up and Record Retention 
16.0 
Appendix 
 


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 1.0  Background & Rationale 
 
Alcohol use disorder (AUD; formerly termed alcohol dependence or addiction), is a chronic disorder that 
includes 1) compulsivity in and lack of control over alcohol seeking and consumption, 2) the development of 
tolerance, and eventually 3) the emergence of withdrawal (including physical and affective symptoms when 
alcohol is restricted). It is among the most common and costly mental health problems1-4. FDA-approved 
medications for alcohol dependence have had only modest efficacy and have been minimally used5,6. AUD is 
theorized to progress through three overlapping stages: binge-intoxication, preoccupation-anticipation, and 
withdrawal-negative affect7. Binge-intoxication is thought to consist of frequent ingestion of alcohol to achieve 
a pleasurable, inebriated state. Because of chemical adaptations in the brain with repeated alcohol exposure 
(neuroadaptations), achieving intoxication requires ingestion of steadily increasing amounts of alcohol, a 
process referred to as tolerance formation. While associated changes in activity of some brain neurotransmitter 
systems have been found, the precise mechanisms of alcohol tolerance formation remain poorly understood8,9.  
During the preoccupation-anticipation stage, drinking is increasingly driven by compulsion rather than 
pleasure.  Sustained, heavy drinking leads to increasing tolerance, and eventually physiologic alcohol 
dependence. At this stage, cessation of drinking produces unpleasant, potentially fatal, withdrawal symptoms 
because the neurochemical balance in the alcohol-adapted brain is abruptly disrupted.  In the withdrawal-
negative affect stage, avoiding the discomfort of withdrawal, rather than seeking pleasurable inebriation, may 
become the primary motivation to continue heavy drinking10,11. 
 
Oxytocin (OT) is a small protein that is both a neurotransmitter in the brain and a hormone released into the 
blood from the pituitary gland. Because numerous studies in animals and, more recently, in humans have 
found a wide variety of prosocial effects of OT that are exerted in the brain, it has become known in the popular 
culture as the “love” hormone12-14. In humans, nasal OT administration has been shown in some studies to 
increase interpersonal trust and cooperation as well as accurate interpretation of social cues such as facial 
expressions15-17.  
 
However, animal research has also suggested some potentially clinically useful effects of OT on alcohol use 
and abuse.  Numerous preclinical studies have shown that OT treatment: 1) prevents tolerance formation to 
repeated doses of alcohol non-dependent animals; 2) blocks withdrawal seizures in alcohol-dependent 
animals, and 3) in a recent study, results in decreased motivation for alcohol in alcohol-dependent animals18-24.  
For example, when non-dependent mice are given an impairing dose of alcohol on successive days, they 
adapt and steadily improve on daily tests of balance and coordination conducted after each alcohol dose. 
However, when OT is given before each alcohol dose, the development of tolerance is inhibited and balance 
and coordination improves more slowly on daily tests18. Treatment with the GABA-antagonist picrotoxin 
triggers withdrawal seizures in alcohol-dependent mice, an effect reduced by OT administration23. More 
recently, OT administration reduced motivation for alcohol and alcohol self-administration in alcohol dependent 
rats but not non-dependent animals24. 
 
In alcohol-dependent, heavy drinking individuals, studied on a research unit, Dr. Pedersen and colleagues 
recently discovered that twice-daily OT treatment (given in a nasal spray that results in significant brain 
delivery) potently and rapidly blocked alcohol withdrawal as judged by a decreased need for lorazepam 
intervention25. This, to the knowledge of the investigators, is the only journal publication on OT treatment of 
human AUD.  Dr. Pedersen and colleagues have also recently completed a National Institute of Alcohol Abuse 
and Alcoholism (NIAAA) funded, randomized, placebo-controlled clinical trial; preliminary analysis found that 
12 weeks of twice-daily intranasal administration of OT significantly decreased heavy-drinking days (5 standard 
drinks/day for men and 4 for women; a standard drink contains the same amount of alcohol as a 12 oz. beer) in 
heavy-drinking individuals. Other non-treatment examinations of the human response to OT in the context of 
an alcohol exposure or an AUD is limited, yet informative. While no effect of OT on the subjective response to 
alcohol was identified in light or social drinkers26, 27, OT was reported to benefit baseline interoceptive accuracy 


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in heavy drinkers27. In contrast, when examined in veterans with comorbid post-traumatic stress disorder and 
AUD, OT was found to only marginally reduce stress reactivity (a core non-tolerance feature of the later stage 
of withdrawal-negative affect), and did not reduce self-reported craving28. Similarly, OT was not found to 
reduce emotional reactivity during a conflict task in couples with substance misuse29. These human studies, in 
conjunction with our own, suggest that: OT acts upon chronic tolerance, would be most effective in heavy 
drinkers, and its assessment should include subjective response to alcohol and craving, as well as objective 
measures of cognition and behavior. 
 
Based on OT effects in rodents, and the available human literature, we hypothesize that OT may exert 
therapeutic effects by rapidly reversing alcohol-induced neuroadaptations in the brain. This putative reduction 
of tolerance would represent a unique approach to treatment that could revolutionize clinical AUD care. If 
clinicians could reduce or eliminate tolerance, it would mitigate one of the key drivers of relapse. Furthermore, 
the availability of a treatment that reduces acute withdrawal and risk of relapse would provide a continuum of 
medical care that is now lacking.  The proposed project will directly test whether OT reverses tolerance and 
associated alcohol seeking in humans by employing state-of-the-art computer-assisted intravenous alcohol 
administration.  Two separate experiments will be run, one of which combines a standardized breath and 
therefore brain alcohol exposure with sensitive tests of subjective response and cognitive function.  The 
second is  an alcohol self-administration paradigm, assessing objective change in motivation for alcohol. 
Demonstrating that OT (compared to placebo, PL) worsens test performances in alcohol-dependent individuals 
and/or reduces the compulsive drive to self-administer alcohol would be strong evidence for its potential AUD 
treatment utility.  
 
2.0  Objective(s) 
 
The goal of this project is to provide evidence supporting the hypothesis that intranasal OT treatment blocks or 
reduces tolerance to alcohol and motivation for alcohol in heavy drinking individuals. Evidence supporting 
either outcome would indicate that OT has a potentially novel therapeutic effect and would then be used in a 
subsequent, larger study of the effect. Such an outcome would open new fields of investigation into a potential 
role for OT in AUD treatment, notably the prevention of relapse and support of abstinence. This could have 
profound effect on treatment approaches for AUDs.  The project will examine whether OT reverses tolerance 
and associated alcohol seeking in humans.  Tolerance to and motivation for alcohol will be assessed with 
sensitive tests of subjective response and cognitive function tested prior to, at the beginning, and at the end of 
an intravenous alcohol BrAC clamp (a standardized brain alcohol exposure).  Alcohol seeking will be tested 
using a progressive ratio alcohol self-administration paradigm, assessing objective change in motivation for 
alcohol. 
 
2.1 
Primary Objective:  
Aim 1: Demonstrate that OT alters alcohol tolerance.  This will be assessed using a within-subjects design 
comparing OT and PL infusion sessions.  Cognitive, motor and subjective responses will be tested prior to, at 
the beginning, and at the end of a steady-state alcohol clamp. 
 
2.2 
Secondary Objective: 
Aim 2:  Demonstrate that OT decreases motivation for alcohol.  Motivation for alcohol will be measured directly 
when participants will be able to earn standardized alcohol exposures by performing a button pressing task on 
a progressive ratio scale in the active versus control condition. Motivation will also be assessed by measures 
given during the clamp (and its respective baseline and control assessments) including an alcohol purchase 
task (APT) that assesses the value of alcohol from a behavioral economics perspective and measures of 
subjective perception and craving for alcohol.   
 
3.0  
Outcome Measures/Endpoints 
 


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3.1 Primary Outcome Measures:  
 
Aim 1: OT will alter alcohol tolerance.  Compared to their performance under PL and respective baseline 
assessment, participants given intranasal OT will show, in one or more of the following, greater alcohol-related 
perturbation of the subjective response to alcohol, the Stroop test, and Stop Signal task performance. 
 
3.2  
Primary Outcome Measures:  
 
Aim 2:  OT will reduce motivation for alcohol.  Participants will display lower motivation for alcohol under OT 
compared to PL, reflected by one of more of the following: During alcohol self-administration, less cumulative 
work for alcohol on the progressive ratio task, and reduced overall alcohol exposure as reflected by the breath 
alcohol concentration (BrAC) curve during alcohol self-administration; During the BrAC clamp, altered APT 
derived behavioral economic indices and/or reduced subjective craving for alcohol.  
  
 
4.0  Eligibility Criteria 
 
4.1 
Inclusion Criteria 
 
• 
Overtly healthy men and women aged 21 – 60. 
• 
Heavy alcohol drinkers [greater than 14 (men) or 7 (women) drinks per week, and at least 5 binges per 
month, with a binge defined as 5 (men) or 4 (women) drinks on the same occasion30], unless determined 
by PI that drinking history meets study objectives. 
• 
Able to understand/complete questionnaires and procedures in English. 
• 
Have venous access sufficient to allow blood sampling. 
 
4.2 
Exclusion Criteria 
 
• 
Latex allergy (due to oxytocin/latex cross-reactivity). 
• 
Nasal condition that compromises delivery and/or absorption of intra-nasal oxytocin 
• 
Pregnant or breast-feeding women. 
• 
Desire to be treated for any substance use disorder or court ordered to not drink alcohol 
• 
Medical disorders or other conditions such as alcohol withdrawal seizures or delirium tremens that may 
influence study outcome or participant safety. 
• 
Positive urine drug screen for amphetamines/ methamphetamines, barbiturates, benzodiazapines, 
cocaine, opiates, or phencyclidine if determined by the PI to adversely affect participant safety or data 
integrity. 
• 
Medications (past 30 days) that could influence participant safety or data integrity (e.g. antidepressants, 
antipsychotics, benzodiazepines, etc.) as determined by the PI. 
• 
DSM 5 Disorders (non-AUD) or current/history of neurological disease of cerebral origin, or head injury 
with > 20 min loss of consciousness, if determined by the PI to affect participant safety or data integrity. 
• 
Positive BrAC reading at beginning of the experimental session. 
• 
Actively suicidal (for example, any current suicidal intent, including a plan) or are at serious suicidal risk, 
by clinical judgment of the PI. 
• 
Any condition for which the PI and investigative team determine it is unsafe or not prudent to enroll a 
participant. 
 
5.0  Study Design 
 
Overview: This project employs a double-blind, within-subject design.  Each participant will be randomly 
assigned to either the clamp or self-administration condition, and be studied twice, once with intranasal 
administration of OT and once with intranasal PL.  At least 3 weeks will elapse between each participant’s tests 
to ensure that residual effects of OT administration have dissipated.  
 


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6.0 
Enrollment/Randomization 
 
Participants will be randomized to study session order (OT-PL or PL-OT) at time of scheduling, using a 
procedure that ensures an equal number of participants in each group.  Stratification of other potentially key 
risk or analytical variables, such as sex and age distribution, will be periodically monitored and individual 
subject order assignment may be adjusted to achieve balance.  Neither subjects nor technicians will know 
which session is PL, and which is OT. 
 
 
7.0 
Study Procedures 
 
Recruitment and Screening 
 
We expect to recruit most of the participants for this study from our database of subjects who have completed 
a past experiment and have consented to be contacted for additional studies.  Some participants may learn 
about the study from print, electronic advertising, or word of mouth, and then contact our phone line or visit the 
study website.  Participants who meet basic criteria will be invited for an interview.  Participants who have not 
previously completed an interview in our lab will complete a full interview.  Participants who have interview data 
on record may be asked to update some interview information as needed for participant safety or data integrity.  
Updates may be done by phone, online, or in person.  Interview measures may include some or all of the 
following measures, at the discretion of the principal investigator: 
 
Self-Report Measures: 
• 
The Alcohol Use Disorders Identification Test (AUDIT) 
• 
The Urgent Premeditation, Perseverance, Sensation Seeking and Positive Urgency (UPPS-P) Impulsive 
Behaviors Scale measures impulsivity traits, including urgency. 
• 
Self-Rating of Effect of Alcohol assessing retrospective sensitivity to the subjective response to alcohol 
(SRE). 
• 
Short Inventory of Problems – Revised (SIP-r) 
• 
Medical History (including menstrual phase for women) 
• 
Nicotine History Measure 
• 
Penn Alcohol Craving Scale (PACS) 
 
Interviews: 
• 
Brief medical history (including menstrual phase for women) 
• 
The Semi-Structured Assessment for the Genetics of Alcoholism – IV (SSAGA-IV), Alcohol 
• 
The Semi-Structured Assessment for the Genetics of Alcoholism – IV (SSAGA-IV), Family History of 
Alcoholism 
 
Diary Measures:  
• 
Timeline Follow-back (TLFB) modified to assess for one-month recall of alcohol use 
 
Screening tools:  
• 
Clinical Institute Withdrawal Assessment for Alcohol Scale (CIWA) 
• 
Generalized Anxiety Disorder Assessment (GAD-2, GAD-7).  Anxiety symptoms over the last 2 weeks are 
queried in a 2 item scale which expands to 5 additional items if the first 2 are endorsed. 
• 
Patient Health Questionnaire (PHQ-2 and PHQ-9).  Depressive symptoms over the last 2 weeks are 
queried in a 2 item scale which expands to 7 additional items if the first 2 are endorsed. 
• 
Urine pregnancy and drug screen (UPS, UDS, the latter including EtG urine screen at discretion of PI) 
• 
Breath Alcohol Concentration (BrAC) Measurement 
• 
Liver function assessment (standard liver panel)  
 
Participants: We plan to recruit up to 30 subjects in order to complete study of 10-15 heavy drinking 
participants (minimum 5 each in the clamp and self-administration arms).  Approximately equal numbers of 
men and women will be recruited.  


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Payment:  Participation fees are paid in cash at the end of each study visit, by email using an Amazon gift 
card, or by mail using a visa card or check.  For the interview, participants will receive $15 if they complete the 
online portion only, and $25 if they complete both the online and in person portions, or complete the full 
interview in person.   Subjects who completed and were paid for the interview for another study, and who 
provide only minimal updates to their information, will not be paid an additional interview fee.  For the IV 
alcohol infusion sessions, the experimental day lasts about 11 hours; session 1 pays $130, and session 2 pays 
$200.  In addition, subjects will be reimbursed for parking, bus pass or up to $10 for taxi/ride sharing. Thus a 
subject can receive up to $365 for participation.  Payments are calculated to reimburse subjects at a rate of 
about $15/hour if they complete all sessions; session 2 pays more than session 1 because of the increased 
value of the subject's participation. If an infusion session is terminated early, participants will be paid $15 per 
hour, calculated in 20 min increments, for time they are at the Clinical Research Center, up to the total 
promised for the study day.  
 
Method:  We will assess the effects of OT on alcohol tolerance in heavy drinking participants using the 
computer-assisted alcohol infusion system (CAIS; Figure 1) developed30- 32 and maintained at Indiana 
University with the support of the Indiana Alcohol Research Center. Individual characteristics (height, weight, 
age and sex) are used to compute physiologically-based pharmacokinetic models of the distribution and 
elimination of alcohol 41-42, which in combination with model-based control techniques, allows for the precise 
control of breath, and therefore arterial and brain, alcohol concentrations 43. CAIS IV alcohol techniques span a 
broad range of applications, from the assessment of initial sensitivity and tolerance using the alcohol clamp31-37 
to the assessment of alcohol self-administration 39-40.  The need for controlled IV alcohol administration is 
illustrated in Figure 2 - Top, which shows the wide variation in alcohol exposure within and across individuals 
resulting from oral challenge paradigms.  In contrast, (Figure 2 – Bottom) shows data from an alcohol clamp, 
 
 
 
Figure 1. Schematic of CAIS system, including computer specifications, software, and accessories.  The 
CAIS system consists of PC-based software interfacing with iv infusion pumps.  Prior to infusion, the 
participant’s age, height, weight, and gender are entered into the software, which transforms those 
measurements into parameters of a physiologically-based pharmacokinetic (PBPK) model of alcohol 
distribution and elimination. Infusate and breath alcohol concentration measurements provide feedback to 
adjust the PBPK model for each participant. Computation of the infusion rate profile is based on the 
updated model to achieve virtually identical clamp then incremental exposures to alcohol across 
participants. The subject and the infusion rate profile are monitored at all times by a technician. 


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the first developed and most common IV alcohol paradigm.  Breath alcohol concentration (BrAC) is raised to a 
target level, usually within 15-20 minutes, that can then be maintained (“clamped”) at or near the target for 
whatever duration is necessary for a specific study.   Recently, CAIS-based alcohol self-administration 
paradigms have been developed that provide the participants with control over individual alcohol increments 
that are virtually identical within and across participants.  The overall alcohol exposure differs due to the 
participant’s choice of timing and number of increments (see Figure 3, Alcohol Self-Administration phase). 
CAIS IV techniques allow investigators to study the higher BrAC typical of heavy drinkers safely, both due to 
the reduced variability of each incremental exposure and because BrAC immediately descends upon 
termination of the infusion; after oral intake, the BrAC continues to rise until absorption is complete.  In 
addition, IV alcohol infusion reduces expectancy effects (arising from sight, odor, taste and the physical act of 
drinking), without affecting the subjective effects associated with intoxication46.  In the present study, half of the 
subjects will be tested using a BrAC clamp to assess performance on a battery of perceptive, cognitive and 
behavioral tests, and half of the subjects will be tested in a self- administration session for a direct measure of 
motivation for alcohol and self-selected BrAC, consistent with our prior work.   
  
Study day procedures:  Upon arrival at the Indiana Clinical Research Center (ICRC), participants will be re-
screened for drug use, pregnancy (if applicable), and BrAC.  Participants are asked to abstain from alcohol 
after 8:00 pm the night before each session and must have a BrAC of zero at the beginning of an infusion.  We 
will record the participant’s recent drinking using a TLFB.  Car keys will be held for safekeeping. Using sterile 
technique, an indwelling catheter will be placed in a vein of one arm.  For the clamp, only a single pump is 
needed to deliver alcohol.  For self-administration, the catheter will be connected to the two infusion pumps, 
one of which is used to deliver saline as the alternative reward; the second delivers ethanol infusate prepared 
by IU Health Investigational Drug Services (IDS) by mixing sterile half-normal saline with 95% sterile ethanol to 
create an approximately 6.0% (v/V) solution.  Infusate concentration is checked using a refractometer prior to 
the start of the session and the result incorporated into the infusion profile determination.  After the catheter is 
placed, a standardized 550 calorie breakfast is served. Testing will be performed in one of the lab’s 5’x7’ 
Industrial Acoustic Corporation® sound-dampened chambers or in a private room in the ICRC. Testing location 
will be identical across sessions for each subject. When testing is done in the lab chambers, a closed-loop 
intercom system enables the participant to talk to the technician at any time without manual effort. When 
testing is done in a private room in the CRC, technicians will be located behind a curtain and immediately 
available to the subject whenever needed. 
 
Figure 2.  
 
Top. Individual BrAC trajectories in ingestion. 
Alcohol ingestion yields variable trajectories of 
BrAC. Exposure trajectories after ingestion of a 
dosage normalized by total body water to 
produce a peak BrAC of 80 mg/dL under 
standardized conditions for 44 participants is 
displayed44,45. 
 
 
Bottom. BrAC clamping trajectories. BrAC 
clamping experiment conducted in 50 young 
adults with the goal of raising BrAC to 60 
mg/dl in 10 minutes, then maintaining it for 3 
hours. The result minimizes the variability in 
BrAC trajectories across participants44.45.  


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Session procedures:  Alcohol Clamp (Figure 3). Clamp sessions begin with a baseline battery lasting 
approximately 30 min and consisting of the Stop Signal Task (a motor impulsivity task that has demonstrated 
sensitivity to alcohol exposure); a subjective perceptions assessment, including craving; a side effects 
questionnaire; the Alcohol Purchase Task (a cognitive test providing measures of behavioral economics, 
revised for use during iv infusion); and the Stroop Test of mental concentration (accuracy and speed stating 
the color of a series of words printed in colors different from the colors they actually name). The battery is 
repeated after an initial dose of OT or PL, and at the beginning and end of a 2 h clamp, with booster doses of 
OT or PL 20 min prior to each of the clamp batteries.  The dosing schedule of oxytocin relative to testing is 
derived from studies suggesting onset of effects in approximately 30 minutes and a duration of approximately 
60 minutes48-51. The first dose of OT or PL will consist of 10 intranasal puffs [insufflations] alternating every 30 
seconds between nostrils, delivering in total 40 IU of OT in 1 ml of solution or 1 ml of PL solution. A 20-30 min 
drug absorption period follows the first dose; booster doses of 24 IU of OT will be given 20 min prior to each of 
the remaining 2 test batteries.   During the intervals between test batteries, the participant will be free to rest, 
read, or use an electronic device for entertainment. 
 
 
 
Figure 3: Alcohol Clamp.  Diagram of the experimental session showing test batteries (orange boxes), OT and PL 
administrations (green boxes), alcohol clamp (grey box) and example subject breath alcohol concentrations (colored 
lines). Experimental timeline:  Min 0-30: Baseline battery.  Min 30-35: Intranasal OT or PL administered.  Min 35-60: 
Pause for drug absorption.  Min 60-90: OT/PL battery.  Min 90-105:  OT/PL booster dose at the beginning of a 15 min 
alcohol infusion ramp (4 mg/dL/min) to bring BrAC to 60 mg/dL.  Min 110-140:  Alcohol+OT or Alcohol+PL battery 
assessing initial response to alcohol during BrAC clamp at 60 mg/dL.  Min 180-182.5: Booster dose of OT or PL.  Min 
200-230: Alcohol+OT or Alcohol+PL battery assessing adapted response to alcohol during BrAC clamp at 60 mg/dL.     


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Session procedures:  Self-administration (Figure 4). During the 150 min alcohol self-administration session, the 
participant initiates each work-set by choosing between 1 of 2 rewards, either alcohol or water. Work-sets 
consist of trials of the Constant Attention Task, or CAT (Figure 5), developed by our laboratory and with 
demonstrated sensitivity to pharmacogenomics and sex effects38, 39.  Successive rewards require an increasing 
number of successful CAT trials. The work schedules required to obtain water or alcohol are identical, but 
progress is tracked separately and not communicated to the participants. Throughout any workset, participants 
are free to wait, work ad-lib, pause, or cease working. The available rewards are a standardized increment in 
BrAC (alcohol, labeled “A”) or an infusion of saline (water, labeled “W”), each delivered over 2.5 min. Reward 
delivery begins immediately after the last correct CAT trial required for the work-set is performed. Alcohol 
reward increments raise the participant’s BrAC by 10.0 mg/dL in 2.5 min before declining at a steady rate of -
0.8 mg/dl/min, until the next alcohol reward is delivered or as long as pharmacokinetically possible. CAIS 
continuously estimates the future time course of BrAC and prohibits infusion that would yield a BrAC exceeding 
the predetermined, ecologically valid safety limit (180 mg/dL in this heavy alcohol drinking sample).  The first 
dose of OT or PL will be administered 30 min before the start of the self-administration phase, and consist of 
10 intranasal puffs [insufflations] alternating every 30 seconds between nostrils, delivering in total 40 IU of OT 
in 1 ml of solution or 1 ml of PL solution. Booster doses of 24 IU of OT will be given approximately hourly after 
the initial dose.    Participants will complete the subjective perceptions assessment and side effects 
questionnaire prior to the first OT/PL administration, immediately before the start of alcohol self-administration, 
and at 20 min intervals throughout the session, timed with alcohol reward increments when possible. Except 
for ad-libitum bathroom breaks, participants remain in the chamber or room for the duration of the experiment; 
technician interaction is limited to occasional BrAC samples, data collection, and verbal checks to assure 
subject comfort at the beginning/end of each intervention.  
 
 
Figure 4:  Alcohol Self-Administration session:  Diagram of the experimental test session showing timing of OT/PL 
administration relative to the alcohol self-administration phase.  The array of lines during the alcohol self-
administration phase, derived from subject data from a past experiment, reflects a range of possible behavior, limited 
by the 180 mg/dL safety limit and the increasing demands of the progressive work schedule. 


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Recovery/Discharge procedures: Alcohol clamp sessions.  Upon completion of the alcohol clamp, participants 
will stay in an inpatient room until they can be safely discharged with a BrAC <35mg/dL. They are served lunch 
from the ICRC kitchen.  Subjects will be told that they should expect to stay at the CRC until 7:00 pm, although 
they will be dismissed earlier if their BrAC is below 35 mg/dL.  Participants with a BrAC > 35 mg/dL at 7:00 pm 
will be compensated at the rate of $15/hour in 20-minute increments for the time stayed past 7:00 pm.  
Participants staying past 5:00 pm will be offered dinner. 
 
Recovery/Discharge procedures, Alcohol self-administration sessions.  Subjects participating in the self-
administration sessions will be required to stay until at least 7:00 pm and until BrAC < 35 mg/dL, whichever is 
later.  Participants are served lunch from the ICRC kitchen; they will also be given dinner at about 5:30 pm. 
Participants with a BrAC of 35 mg/dl or below but who show signs of intoxication and/or self-report any 
concerns regarding their safe passage home at the time of discharge will be provided transport home via car 
service. Participants with a BrAC > 35 mg/dL at 7:00 pm will be compensated at the rate of $15/hour in 20-
minute increments for the time stayed past 7:00 pm in a payment made at the second session.  Any 
participants who must stay past 7:00 pm for the first session will be informed that they have to stay until the 
same time for the second session (in order to reduce discharge-motivated drinking behavior during the second 
session compared to the first).  However, for the second session, participants will only actually be required to 
stay past 7:00 pm if their BrAC remains at or above 35 mg/dL or if a concern regarding their ability to be safely 
discharged exists.  At the discretion of the PI, subjects may be discharged before 7:00 pm if their BrAC is at or 
below 35 mg/dL and an early discharge would not jeopardize subject safety or study objectives. 
 
8.0 
Study Calendar 
 
  
Screening 
Study Day 
 
Interventions 
Phone 
Interview 
Before 
session 
Baseline 
Block 
OT/PL 
Block 
Alcohol 
Clamp 
Alcohol Self-
administration 
Phone Screen 
X 
Liver Function panel 
X 
Medical History 
X 
UPPS-P Impulsive Behaviors Scale  
X 
Generalized Anxiety Disorder 
Assessment (GAD-7) 
X 
Patient Health Questionnaire for 
depressive symptoms (PHQ-9) 
X 
 
Figure 5:  The CAT task.  Subjects initiate the task by pressing down on one of two buttons, labeled 
“A” (alcohol) or “W” (Water).  Holding the button down results in a screen graphic showing the 
choice button (“A” in this example) surrounded by a yellow circle.   When the yellow changes to blue, 
the subject must release as quickly as possible.  On release, the circle returns to white and the subject 
must indicate whether they thought they were successful.  The screen graphic then shows green for 
successful release, and red for an unsuccessful (too slow) release.  The task adapts by increasing the 
release time window required after errors, and decreasing it after successes.  Thus, the percent of 
successful trials remains constant across subjects and is not affected by basal reaction time, practice, 
fatigue, or intoxication. 


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Alcohol Use Disorders Identification 
Test (AUDIT) 
X 
Semi-structured Assessment for the 
Genetics of Alcoholism (SSAGA); 
Alcohol and Family History modules 
X 
Self-Rating of Effects of Alcohol  
(SRE). 
X 
Short Inventory of Problems – 
Revised (SIP-r) 
X 
Clinical Institute Withdrawal 
Assessment for Alcohol Scale (CIWA) 
 
X 
 
 
 
 
 
Nicotine History (NHF) 
X 
Penn Alcohol Craving Scale (PACS) 
 
X 
 
 
 
 
 
Timeline Followback (TLFB) recall of 
alcohol and drug use 
X 
X 
Urine Pregnancy Screen (UPS) 
X 
X 
Urine Drug Screen (UDS) 
X 
X 
Breath Alcohol Concentration (BrAC) 
X 
X 
X 
X 
Alcohol Purchase Task (APT) 
X 
X 
X 
X 
Stop Signal Response Task 
X 
X 
X 
Stroop Test 
X 
X 
X 
Subjective Perceptions Assessment  
X 
X 
X 
X 
Side-Effects Questionnaire 
 
 
 
X 
X 
X 
X 
 
9.0 
Reportable Events 
 
Serious adverse events resulting in any physical harm associated with testing will be reported to the IRB as 
required by applicable policies and guidance.  Minor, and expected, adverse events (e.g. nausea, infusate 
infiltration, discomfort associated with infusion, nasal irritation) will be reported to the Alcohol Studies DSMB 
meeting at least annually. Side effects attributable to the interventions will be reported in any manuscripts or 
scientific reports based upon the collected data and entered into any mandated database.  
 
10.0 
Data Safety Monitoring 
 
The Data Safety and Monitoring Board (DSMB) that monitors virtually all the alcohol studies at IUSM will 
review this study at least annually. This board is comprised of all IU faculty engaged in IV alcohol research, 
and chaired by Dr. Laura Tormoehlen, who is independent of the sponsor and investigators.  The following will 
be monitored as part of the Data Safety Monitoring Plan (DSMP): data quality, recruitment, accrual, retention, 
outcome and adverse event data, assessment of scientific reports or therapeutic development, results of 
related studies that may impact participant safety, and procedures designed to protect the privacy of 
participants. 
 
11.0 
Study Withdrawal/Discontinuation 
 
The participant may withdraw from the study at any time for any reason. The PI may choose to terminate any 
subject’s participation at any time if it is deemed that s/he cannot participate or cooperate in testing procedures 
safely or if a subject’s behavior jeopardizes integrity of the collected data.  Partial days will be compensated at 
a rate of $15/hour, including time to recover to a BrAC < 35 mg/dL.  Payment will be calculated in 20 min 
increments.   
 
12.0 
Statistical Considerations 
 
The primary goal of the study is to generate data that would be supportive of a large, properly powered study 
of the effects of OT on tolerance and/or motivation for alcohol. For this exploratory study, we anticipate 
examining within-subject effects of OT compared to PL using paired t-tests, accommodating baseline 
assessments as appropriate for the specific measures.  


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Aim 1 Hypothesis Testing Plan 
Hypothesis 1:  Tolerance to alcohol will be altered by OT, such that participants exhibit greater effects of 
alcohol when tested with OT compared to PL and each with respect to its own baseline assessment.  
Specifically, we predict the following differences in one or more of the following measures: 
 
Stop Signal Response Task:   
Participants will have more rapid reaction times under PL compared to OT. 
Subjective Perceptions of Alcohol and Craving 
Participants will report weaker subjective effects of alcohol and higher craving under PL compared to OT. 
Stroop Test 
Participants will have shorter response times and fewer errors under PL compared to OT.  
 
 
Aim 2 Hypothesis Testing Plan 
Hypothesis 2:  OT will reduce motivation for alcohol as demonstrated by changes in one or more of the 
following measures: 
 
Alcohol Purchase Task 
Participants will display alteration in behavioral economic indices derived from the Alcohol Purchase task under 
OT compared to PL (for example, a reduction in intensity, greater elasticity, lower breakpoint, lower total 
outcome, etc.).  
Subjective Perceptions of Alcohol and Craving 
Participants will report weaker subjective effects of alcohol and higher craving under PL compared to OT.  
Alcohol Self-Administration 
Participants will demonstrate reduced cumulative work for alcohol rewards and less overall alcohol exposure 
under OT compared to PL. 
 
 
Missing Data 
 
Missing data may occur intermittently or due to attrition. Due to the within-subjects design, participants 
completing only one of two experimental sessions will be excluded from final analyses.  
 
Power Analyses 
 
 
While OT is a commonly used agent in human studies, this is a novel investigation of the effect of OT 
on laboratory measures of alcohol tolerance and motivation for alcohol. Consequently, no directly relevant 
preliminary data exists upon which to base proper power analyses – collection of such data is the primary 
objective of this investigation. However, our previous alcohol self-administration work showed effect sizes from 
0.49 to 1.31 according to the phenotype of interest. Effect size estimates attributable to an alcohol clamp vary 
considerably in the literature depending on the participant population, exposure, and outcome of interest. For 
example, we and our colleagues have identified effect size for the differences in alcohol elimination rate in 
participants stratified by sex is moderate (f2=0.07). We recently identified an alcohol effect on P300 amplitude 
in response to the stop signal using the clamp (f2 = 0.57). At baseline, we have also documented both large 
and small sex differences in subjective responses in both general (large effect of f2 = 0.35) and specifically as 
a function of abstinence (small effect of f2 = 0.034).  
 
 
13.0 
Statistical Data Management 
 
Primary data will be collected via paper, electronic forms, and computer software output and stored 
electronically on a department server. The storage location is backed up automatically daily.  Other data 
sources include pathology lab data that will be stored in separate electronic files and merged with the primary 
data as needed.  The following data quality control methods will be used: single entry with random checks of 


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accuracy, range checks, testing of database by study team prior to moving to data analysis, and regular, 
periodic extraction and cleaning of data. 
 
14.0 
Privacy/Confidentiality Issues 
Procedures for protecting privacy interest in the study include advising the participant to ensure his/her privacy 
during the phone screen and interview if performed electronically, and conducting all further recruiting and 
testing from or on the Indiana CTSI Clinical Research Center, in a private room during regular hours of 
operation.  Research data is stored either in a lockable file cabinet in a locked and secured area, or on 
password protected network file servers. 
 
15.0 
Follow-up and Record Retention 
 
We expect project completion no later than December 2022.  The identifiable project participant files will be 
destroyed at the conclusion of data analysis.  The records will be kept for 7 years after completion of the study.  
The databases will be kept on a secure server in password-protected files.  The database files will be over-
written with null data at the completion of the retention interval.   
 
16.0 
Appendix 
 
The following materials are included: 
 
1. The Urgent Premeditation, Perseverance, Sensation Seeking and Positive Urgency Impulsive 
Behaviors Scale (UPPS-P) 
2. Generalized Anxiety Disorder Assessment (GAD-2 and GAD-7) 
3. Patient Health Questionnaire for depressive symptoms (PHQ-2 and PHQ-9) 
4. Alcohol Use Disorders Identification Test (AUDIT) 
5. Semi-structured Assessment for the Genetics of Alcoholism -IV (SSAGA-IV) – Alcohol module 
6. Semi-structured Assessment for the Genetics of Alcoholism -IV (SSAGA-IV) – Family History module 
7. Self-Rating of Effect of Alcohol (SRE). 
8. Short Inventory of Problems – Revised (SIP-r) 
9. Clinical Institute Withdrawal Assessment for Alcohol Scale (CIWA) 
10. Nicotine History Form (NHF) 
11. Penn Alcohol Craving Scale (PACS) 
12. Timeline Followback (TLFB) recall of alcohol and drug use 
13. Alcohol Purchase Task (APT)  
14. Subjective Perceptions Assessment (Squizzer) – Hanlon  
15. Side-Effects Questionnaire 
16. Adverse Events Reporting Form 
17. Intranasal Administration Training Guidelines 
 
 
 
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