Clinical trial NCT03216954
Conditions: Alcohol Use Disorder
Sponsor: William Stoops
Start date: 2017-09-15; Completion date: 2020-04-23
Enrollment: 14 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This study will evaluate the behavioral effects of alcohol during placebo and n-acetylcysteine maintenance using sophisticated human laboratory methods.

Detailed description:

Arms: arm 1: Subjects will receive oral placebo capsules two times daily. arm 2: Subjects will receive 0.6 g oral n-acetylcysteine two times daily. arm 3: Subjects will receive 1.2 g oral n-acetylcysteine two times daily.
Interventions: intervention 1: Alcohol intervention 2: Placebos intervention 3: N-acetyl cysteine
Intervention descriptions: intervention 1: During each arm, subjects will receive doses of alcohol, designed to raise BALs to 0.015 and 0.03 g/dl. intervention 2: Subjects will receive placebo capsules intervention 3: Subjects will receive n-acetyl cysteine capsules

Protocol documents:
ICF_001.pdf: 
Official Title: A Human Laboratory Study of n-Acetylcysteine for Alcohol Use Disorder   
NCT Number: NCT03216954 
Date of Document: 3 March 2020 
 


 
 
 
 
 
 
 
 
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CONSENT TO PARTICIPATE 
IN A RESEARCH STUDY 
University of Kentucky Medical Center  
 
TITLE OF STUDY: 
Behavioral Effects of Drugs: Inpatient (34) (Alcohol and N-Acetylcysteine)  
 
INVESTIGATOR INFORMATION: 
William W. Stoops, Ph.D.  
 
(859) 257-5388 
Lon R. Hays, MD, M.B.A.  
 
(859) 323-6021 x 79015 
Abner O. Rayapati, M.D.   
 
(859) 257-9175 
 
WHY ARE YOU BEING INVITED TO TAKE PART IN THIS RESEARCH? 
You are being invited to take part in a research study about the effects of drugs on behavior. You 
are being asked to participate because you are 21-55 years old with a recent history of alcohol use. 
You are also being asked to participate because you have expressed interest in participating in this 
study, you passed the medical screen, and it is unlikely that you will react badly to the laboratory 
setting or to the drugs you will take. You must be at least 21 years of age to participate in this 
research study and you will be asked to provide legal proof of age. If you volunteer to take part in this 
study you will be one of about 25 people to do so over the next two years at the University of 
Kentucky.  
WHO IS DOING THE STUDY? 
This study is being conducted under the scientific and administrative supervision of William W. 
Stoops, Ph.D., Department of Behavioral Sciences at the University of Kentucky College of Medicine 
and the medical supervision of Lon R. Hays, MD, M.B.A. and Abner O. Rayapati, M.D., Department of 
Psychiatry, at the University of Kentucky College of Medicine. There may be other people on the 
research team assisting at different times. 
WHAT IS THE PURPOSE OF THIS STUDY? 
This medication development experiment is testing the effects of placebo (a blank, no drug) or n-
acetylcysteine (a medication used to treat acetaminophen overdose) on the subjective, cognitive and 
physiological effects of alcohol. We are also interested in determining whether n-acetylcysteine 
impacts whether you like alcohol and want to choose to drink it. The purpose of this research is to 
gather information on how safe n-acetylcysteine and ethanol are. The results of this study will be 
shared with the sponsor providing financial support for the study (the National Institute on Alcohol 
Abuse and Alcoholism), the Food and Drug Administration and other federal agencies, if required.  
You should understand that this is a research project, not a treatment program. The procedures of 
the study are designed to provide scientific information in a way that is relatively safe and comfortable 
for you, but not to provide benefits. If you are seeking treatment, do not agree to participate in 
the study. This study will not help you stop using alcohol. The investigators can arrange for 
referral to an appropriate treatment program if you so desire.  
ARE THERE REASONS WHY YOU SHOULD NOT TAKE PART IN THIS STUDY? 
You should not participate if you have a history of serious physical disease, current physical 
disease, impaired cardiovascular functioning like heart attack or stroke, high blood pressure, chronic 
obstructive pulmonary disease, history of epilepsy or seizure, diabetes, current or past histories of 
serious psychiatric disorder. You should not participate if you have a history of other significant 
medical problems. 
IRB Approval
3/3/2020
IRB # 42362
IRB2


 
 
 
 
 
 
 
 
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You should not participate if you are seeking treatment for your drug or alcohol use, are currently in 
treatment for your drug or alcohol use, or are currently in successful remission from your drug or 
alcohol use. If you have ever been addicted to drugs or alcohol, you should discuss this with the 
research staff before agreeing to participate. 
If you are a female, you should not participate if you are pregnant or plan on becoming pregnant 
during your participation in this experiment. You must be using an effective form of birth control (e.g. 
birth control pills, surgically sterilized, IUD, cervical cap with a spermicide, condoms, or abstinence), 
and you must be willing to take a pregnancy test before being accepted into the research study. You 
will also be required to take a pregnancy test prior to each experimental session. Should one of these 
tests show that you are pregnant, your participation will be terminated immediately. If you are female, 
you should not participate if you are lactating or breast feeding a baby. 
WHERE IS THE STUDY GOING TO TAKE PLACE AND HOW LONG WILL IT LAST? 
The research procedures will be conducted at the University of Kentucky Laboratory of Human 
Behavioral Pharmacology (LHBP) and at the Inpatient Unit of the Clinical Services Core (CSC) at the 
University of Kentucky Medical Center. Your participation in this study will last approximately one 
month as outlined in Table 1 below.  
 
Day 
Table 1: Overall Participation Timeline 
0 
Practice Session at the LHBP. The timeline of this session matches that of  
experimental sessions, except no alcohol will administered, nor will you stay overnight 
at the CSC. You will be provided with doses to take at 7:00 PM and 7:00 AM through 
Day 5. Doses will be provided in a Wisepill® device that will monitor when you take the 
doses.  
1-5 
Placebo or n-acetylcysteine maintenance. On day 1, you will take your oral dose of 
placebo or n-acetylcysteine at approximately 7:00 AM. You will then take doses to take 
at 7:00 PM and 7:00 AM through Day 5. 
5 
Experimental Session 1 at the CSC inpatient unit. The Experimental Session timeline is 
outlined in Table 2. You will stay on the inpatient unit overnight after completing this 
session. 
6-12 
Discharge from the CSC on the morning of Day 6, followed by a 7 day washout period 
in which you do not take placebo or n-acetylcysteine. 
13-17 
Placebo or n-acetylcysteine maintenance. Details are the same as Days 1-5 above. 
17 
Experimental Session 2 at the CSC inpatient unit. Details are the same as those for Day 
5 above.  
18-24 
Discharge from the CSC on the morning of Day 18, followed by a 7 day washout period 
in which you do not take placebo or n-acetylcysteine. 
25-29 
Placebo or n-acetylcysteine maintenance. Details are the same as Days 1-5 above. 
29 
Experimental Session 3 at the CSC inpatient unit. Details are the same as those for Day 
5 above. 
30 
Study is completed after discharge from the CSC on the morning of Day 30.  
 
Over the course of your approximately month-long participation, you will be asked to complete 4 
total sessions as outlined in Table 1 above. They will consist of 1 practice session at the LHBP and 3 
experimental sessions at the CSC. Experimental sessions will be completed after a period of 
maintenance on placebo or n-acetylcysteine. Each of these sessions will last about 5 hours, but you 
will be required to stay at the CSC overnight after completing each experimental session as outlined 
in Table 2 below.  
 
 
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Approximate 
Time 
Table 2: Experimental Session Timeline 
2:00-3:00 
PM 
Arrival at the LHBP. If you drove to the LHBP, your car keys will be collected. Urine 
sample collected and analyzed for drugs for all and pregnancy for females. Breath 
alcohol level, field sobriety test, vital signs assessment, self-reported times of 
maintenance dosing, questionnaires about drug and alcohol use completed. You will 
need to abstain from alcohol for at least 12 hours prior to your arrival at the LHBP. 
3:00-3:30 
PM 
Transport to, admission and acclimation to the CSC. You will receive a light snack. 
3:30-4:15 
PM 
Baseline subjective, physiological and cognitive-behavioral measures completed. 
4:15-5:30 
PM 
Sampling phase. During this time you will sample a dose of alcohol. Subjective and 
physiological measures will be completed at 10, 20 and 30 minutes after this sample 
dose. Cognitive-behavioral measures will be completed 30 minutes after this sample 
dose.  
5:30-6:30 
PM 
Choice Phase 1. During this time, you will be able to choose between drinking 4 alcohol 
doses and $3.00. That is, for each alcohol dose you choose not to drink, you will earn 
$3.00 that will be added to your study payment. Subjective and physiological measures 
completed every 30 minutes during this time.  
6:30-7:30 
PM 
Choice Phase 2. During this time, you will be able to choose between drinking 4 alcohol 
doses and $3.00. That is, for each alcohol dose you choose not to drink, you will earn 
$3.00 that will be added to your study payment. Subjective and physiological measures 
completed every 30 minutes during this time. 
7:30-7:45 
PM 
Side Effects Rating Scale completed. Session ends. You will then receive dinner. 
7:45-11:00 
PM 
During this time you may engage in recreational activities. 
11:00 PM 
Lights out. 
7:00 
AM 
(the 
next 
day) 
At this time, you will receive breakfast.  
7:30-8:00 
AM 
Sobriety test and breath alcohol level measured. 
8:00 AM 
After passing the sobriety test and having a breath alcohol level of 0.000, you will be 
discharged from the CSC and returned to the LHBP to receive payment and your car 
keys. You may depart for your home after returning to the LHBP and being paid.  
 
During your time on the CSC you must agree to follow the general rules of the CSC and share in 
the routine responsibilities of keeping the unit and yourself neat, clean and orderly. You will be 
provided a detailed list of the CSC rules before being admitted as an inpatient. You should 
understand that during the time that you spend on the CSC that you will not be allowed to leave the 
unit unsupervised, nor will you be allowed to have visitors.  You will be allowed to make telephone 
calls. 
You should also understand that upon arrival to the LHBP on experimental session days, the 
LHBP staff will take your car keys and will return them when you are released from the hospital the 
following morning. Should you leave the hospital prior to that time, you will need to arrange 
transportation (e.g., have a friend pick you up, arrange a taxi). You must agree to follow the 
investigator's advice about caution and refrain from operating dangerous machinery if you leave the 
hospital. Your car keys will be returned the morning following the experimental session upon 
successful completion of a field sobriety test. 
 
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WHAT WILL YOU BE ASKED TO DO? 
Before participating in this research study, it will be necessary for you to have a physical and 
psychiatric examination. During the time you participate, you must agree to participate as an 
outpatient at the LHBP for 1 practice session and an inpatient at the CSC for 3 experimental sessions 
over approximately 1 month. During the time you participate, you should refrain from using any illicit 
substances. Also, please refrain from drinking alcohol 12 hours prior to coming to the laboratory and 
consuming food or caffeine 4 hours prior to a session. The first session will be a “practice” session to 
make you familiar with the various tasks and procedures of the experiment. The remaining 
experimental sessions will occur as outlined in the tables above. Sessions will last approximately 5 
hours each, but you will be asked to stay as an inpatient at the CSC overnight until you are no longer 
affected by any of the alcohol you consume. During the sessions we will collect data concerning your 
physiological status and your subjective status. That is, we will record your heart rate, blood pressure, 
and temperature. We will also repeatedly ask you to answer various questionnaires about how you 
feel and about what kind of drug effect you feel. Finally, you will also have the opportunity to choose 
to consume alcohol during two 1 hour blocks as outlined in Table 2 above. The scheduled tasks pose 
no hazard or risk to you. You must agree to complete these forms and to do the tasks to the best of 
your ability and at the scheduled times. At the end of sessions, you will be paid the $40 for completing 
the session and whatever money you earned for choosing to not consume alcoholic beverages in the 
two choice phases described in Table 2 above. The morning after each session, you will be 
discharged from the CSC, provided that you meet appropriate release criteria (i.e., pass a sobriety 
test and have a breath alcohol level of 0.000). 
During the active treatment phase (i.e., drug maintenance periods of the study), you will be given 
a device called a Wisepill® that will contain medications for you to take and that will monitor when you 
take the medication. We ask that you take the medication at the specified time (i.e., 7:00 AM and 7:00 
PM) and that you return the device to us undamaged and in good working condition. We ask that you 
take that medication at the time specified, as well, returning at intervals noted in Table 1 for additional 
medication. 
During your participation, you should not use any illicit drug. There will be urine checks and 
breathalyzers prior to each experimental session. These urine and breath checks will be conducted at 
the LHBP and CSC. If a urine screen or breathalyzer shows that you used other drugs or you have 
them in your possession, you may be dropped from the study. If you are dropped from the study 
because you used other drugs, or had them in your possession, you will lose a substantial portion of 
the money you might have earned. 
Daily experimental procedures. On your first session, you will complete a practice session. This 
practice session is to familiarize you with the experimental routine. Every other session will be an 
experimental session. If you smoke tobacco cigarettes, you should understand that you will not be 
allowed to smoke during the experimental session which will last approximately 5 hours. We have 
included a table above to help you better understand the study protocol. 
Drugs and Drug Administration.  During the experiment you will be given doses of commonly 
prescribed drugs or recreational drugs. Drugs will be administered by mouth.  The drugs tested will be 
placebo (a blank, no drug), an acetaminophen overdose treating medication (n-acetylcystine 
[Acetadote®]) and alcohol.  
The prescription drugs will be administered in doses approved by the Food and Drug 
Administration (FDA). These drugs will be administered alone and in combination.   
 
WHAT ARE THE POSSIBLE RISKS OR DISCOMFORTS? 
The physiological measures, cognitive-behavioral tasks and subjective-effects questionnaires 
present no risks exceeding those of everyday experience. The primary risks to participation are those 
specifically related to the ingestion of the study drugs. The drugs under study occasionally produces 
side effects and these are outlined in the tables below. We will monitor for these side effects during 
experimental sessions at CSC. If you feel you are experiencing any of these side effects, you should 
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tell the nursing staff or physician. In addition to the risks listed below, you may experience a 
previously unknown risk or side effect. 
 
Possible Risk or  
Side Effect of Alcohol 
How often has it 
occurred? 
How serious is it? 
Can it be corrected? 
Drowsiness, slurred speech, 
headache, gastrointestinal 
upset, breathing difficulties, 
distorted vision and hearing, 
impaired judgment and 
decreased perception and 
coordination 
These are likely 
to or will occur. 
Somewhat serious 
These side effects are 
likely to decrease over time 
as the medications clear 
from your system. 
Blackouts (memory lapses, 
where the drinker cannot 
remember events that 
occurred while under the 
influence), anemia, 
unconsciousness and 
coma 
These are 
extremely 
uncommon. 
Very Serious 
No. 
 
Possible Risk or  
Side 
Effect 
of 
n-
acetylcysteine 
How often has it 
occurred? 
How serious is it? 
Can it be corrected? 
Nausea, vomiting, diarrhea, 
constipation, rash, fever, 
headache, drowsiness, 
reduced blood pressure 
These are likely 
to or will occur. 
Somewhat serious 
These side effects are 
likely to decrease over time 
as the medications clear 
from your system. 
Liver damage 
This is extremely 
uncommon. 
Very Serious 
This may go away with 
treatment. 
 
WILL YOU BENEFIT FROM TAKING PART IN THIS STUDY? 
Understand that you are not a patient receiving medical treatment and that you will not receive any 
direct benefits from this study. However, the knowledge gained will contribute to a better 
understanding of alcohol effects and may result in improved therapeutic treatments. If you are 
seeking treatment, please notify the investigator now and he will make the necessary referral. 
DO YOU HAVE TO TAKE PART IN THE STUDY? 
If you decide to take part in the study, it should be because you really want to volunteer. You will 
not lose any benefits or rights you would normally have if you choose not to volunteer. You can stop 
at any time during the study and still keep the benefits and rights you had before volunteering.  
IF YOU DON’T WANT TO TAKE PART IN THE STUDY, ARE THERE OTHER CHOICES? 
If you do not want to be in the study, there are no other choices except not to take part in the study. 
WHAT WILL IT COST YOU TO PARTICIPATE? 
Participating in this research study will not cost you anything. The clinical laboratory tests, physical 
examination and psychiatric screen described above will be paid by a grant from the National Institute 
on Alcohol Abuse and Alcoholism (NIAAA). The University of Kentucky may not be allowed to bill your 
insurance company, Medicare or Medicaid for the medical procedures done strictly for research. 
Therefore, these costs will be paid by the sponsor (the NIAAA). 
 
 
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WHO WILL SEE THE INFORMATION THAT YOU GIVE? 
Every effort will be made to maintain the confidentiality of your study records. The data from the 
study may be published; however, you will not be identified by name. Your identity will remain 
confidential, unless you give prior written approval or unless it meets our disclosure criteria (i.e., 
about communicable diseases, abuse of a child or elderly person or that you intend to harm yourself 
or others). Your name, address, and social security number will be listed on the receipt for payment 
that you receive, as required by the Internal Revenue Service; but no information about your 
participation in this research project will be released. We will be collecting your social security number 
for payment purposes. You cannot participate in this research if you withhold your social security 
number. A certificate of confidentiality has been obtained from the Department of Health and Human 
Services (DHHS). This certificate protects the investigators from being forced to release any research 
data that identifies you, even under a court order or subpoena. This protection, however, is not 
absolute. The investigators will report certain communicable diseases, abuse of a child or elderly 
person or that you intend to harm yourself or others to the appropriate authorities. Also, because this 
research is regulated by the National Institute of Health (NIH), the Food and Drug Administration 
(FDA) and The University of Kentucky, staff from these and other DHHS agencies may review 
records that identify you. However, it is the policy of these agencies and of these investigators that 
every attempt will be made to resist demands to release information that identifies you. When results 
of this study are published, your name will not be used. 
CAN YOUR TAKING PART IN THE STUDY END EARLY? 
You can discontinue your participation in this study at any time. If you choose to withdraw from the 
study, you will be required to remain in the facility until the investigators are satisfied that you are no 
longer affected by the drug. During this time, you will be free to spend your time engaged in activities 
that are not part of the study. You should understand that you must remain in the facility in order to 
protect yourself and others from the effects of the drug and that your judgment while you are affected 
by the drug may be impaired sufficiently to necessitate that you remain in the facility.  
You should understand, however, that if you decide to withdraw from the study early you will not 
receive any of the completion allowance described below. You will receive the $40 per session 
completion allowance for each of the experimental sessions you completed.  
You should understand the principal investigator on this project, William W. Stoops, Ph.D., can 
terminate your participation for the following reasons: 1) failure to adhere to patients rules for CSC, 2) 
if you verbally or physically assault another volunteer, patient, or staff member on the CSC, 3) if your 
behavior is disruptive to other ongoing studies that are conducted on the CSC, 4) if your behavior is 
disruptive to the other volunteers, patients, research staff, or medical staff on the CSC, 5) failure to 
comply with the alcohol, drug, and food restrictions, 6) failure to comply with the pregnancy 
restrictions, 7) failure to take the doses as prescribed or complete a scheduled experimental session, 
8) failure to perform the behavioral tasks to the best of your ability, 9) if you leave the hospital against 
the advice of the principal investigator or the medical doctors. If you are terminated for any of these 
reasons, it will be deemed that you did not complete all of your scheduled experimental sessions and 
you will not receive the completion allowance described below. 
You should also understand that the medical doctors on this project, Lon R. Hays, MD, M.B.A. 
and Abner O. Rayapati, M.D., can terminate your participation if they do not feel that it is medically 
safe for you to continue. If your participation is terminated for medical reasons, you will receive the 
$40/session completion allowance for each of the experimental sessions you completed. 
If you choose to withdraw from the study early, the data collected until that point will remain in the 
study database and may not be removed. The individuals conducting the study may need to withdraw 
you from the study and the study intervention and/or medication will no longer be provided by the 
investigator and may not be accessible commercially. This may occur if you are not able to follow the 
directions they give you, if they find that your being in the study is more risk than benefit to you, or if the 
agency funding the study decides to stop the study early for a variety of scientific reasons. It is not 
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expected that withdrawing from the study will lead to risks in your health and welfare, but investigators 
may request follow up appointments if you withdraw.  
ARE YOU PARTICIPATING OR CAN YOU PARTICIPATE IN ANOTHER RESEARCH STUDY AT 
THE SAME TIME AS PARTICIPATING IN THIS ONE? 
You may not take part in this study if you are currently involved in another research study. It is 
important to let the investigator/your doctor know if you are in another research study. You should 
also discuss with the investigator before you agree to participate in another research study while you 
are enrolled in this study. 
WHAT HAPPENS IF YOU GET SICK OR HURT DURING THE STUDY? 
If you believe you are hurt or if you get sick because of something that is due to the study, you 
should call Lon R. Hays, M.D., M.B.A. at (859) 323-6021 x 79015 or Abner O. Rayapati, M.D. at (859) 
257-9175 immediately. You can also call 911 in the case of an emergency. Dr. Hays or Dr. Rayapati 
will determine what type of treatment, if any, is best for you at that time. The medical costs related to 
your care and treatment because of research related harm will be your responsibility.  
It is important for you to understand that the University of Kentucky does not have funds set 
aside to pay for the cost of any care or treatment that might be necessary because you get hurt or 
sick while taking part in this study. Also, the University of Kentucky will not pay for any wages you 
may lose if you are harmed by this study.  
The medical costs related to your care and treatment because of research related harm will be 
your responsibility.  
You do not give up your legal rights by signing this form. 
WILL YOU RECEIVE ANY REWARDS FOR TAKING PART IN THIS STUDY? 
You will be paid for your participation in this experiment. You will earn payments for attending 
visits, making certain selections during experimental sessions, and taking medications as directed.  
Specifically, you will earn $40 for each practice and experimental session that you finish. This will be 
paid to you upon completing that session. If you complete the entire study (i.e., complete 1 practice 
session and 3 experimental sessions over approximately one month), you will earn an additional $40 
per session bonus at the end of the study. You can also earn money based on how you choose 
alcohol (or not) during experimental sessions. During each experimental session, as outlined in Table 
2 above, you will have the opportunity to choose between 8 alcohol doses and money. For each 
alcohol dose you do not choose, $3.00 will be added to your session completion payment. So, if you 
do not choose to drink any of the alcohol during an experimental session, you can earn an additional 
$24. Thus, the maximum amount of money you can earn from completing practice and experimental 
sessions is $392 ($160 [session completion payment] +$160 [study completion bonus] +$72 [total 
amount available if you do not choose alcohol doses during any experimental sessions]).  
You will earn $10 for coming to pick up your study doses at the outset of each maintenance 
period as outlined in Table 1. You will also earn money if you take the doses given to you as 
prescribed. Specifically, on the first day of maintenance that you take your doses at 7:00 AM and 7:00 
PM, as verified by the Wisepill®, you will earn $5 for that day. For each consecutive day that you take 
doses as prescribed, that payment will increase by $2 (e.g., you will earn $7 on the second day in a 
row that you take your doses at 7:00 AM and 7:00 PM as verified by the Wisepill®). 
If you complete the entire study, attending each visit as scheduled and taking each dose as 
directed, you can earn up to approximately $707.  
You should understand that if you make more than a total of $600 by participating in research 
projects, the University of Kentucky will report your earnings to the appropriate state and federal 
government agencies (i.e., Internal Revenue Service [IRS]). You should further understand that it is 
your responsibility to determine how these earnings might affect your personal financial situation. 
WHAT IF I HAVE QUESTIONS, SUGGESTIONS, CONCERNS, OR COMPLAINTS? 
Before you decide whether to accept this invitation to take part in this research study, please ask 
any questions that might come to mind now. Later, if you have questions about the study, you can 
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contact the investigator, William W. Stoops, Ph.D., at (859) 257-5388. If you have questions about 
your rights as a volunteer in this research study, contact the staff in the Office of Research Integrity at 
the University of Kentucky at (859) 257-9428 or toll free at 1-866-400-9428. We will give you a copy 
of this consent form to take with you. 
WHAT IF NEW INFORMATION IS LEARNED DURING THE STUDY THAT MIGHT AFFECT MY 
DECISION TO PARTICIPATE? 
If the investigators on this project, William W. Stoops, Ph.D., Lon R. Hays, MD, M.B.A. and Abner 
O. Rayapati, M.D., learn of new information in regards to this study, and it might change your 
willingness to stay in this study, the information will be provided to you. You may be asked to sign a 
new informed consent form if the information is provided to you after you have joined the study. If you 
choose not to continue, you will not lose any of your earnings. That is, you will receive the completion 
allowance for each of the experimental sessions you completed. 
 
Contacting Research Subjects for Future Studies 
 
Do you give your permission to be contacted in the future by Dr. Stoops or his staff regarding your 
willingness to participate in future research studies about how to prevent, detect, or treat substance 
use disorders?  
 
 Yes 
 
 No 
 
_________Initials 
 
WHAT ELSE DO YOU NEED TO KNOW? 
This research is supported by a grant from the National Institute on Alcohol Abuse and Alcoholism 
(NIAAA 
[R21 
AA 
026129]). 
A 
description 
of 
this 
clinical 
trial 
will 
be 
available 
on 
http://www.ClinicalTrials.gov, as required by U.S. Law. This Web site will not include information that 
can identify you. At most, the Web site will include a summary of the results. You can search this 
Web site at any time. 
There is a possibility that the data/specimens/blood collected from you may be shared with other 
investigators in the future. If that is the case the data/specimen/blood will not contain information that 
can identify you unless you give your consent/authorization or the UK Institutional Review Board (IRB) 
approves the research. The IRB is a committee that reviews ethical issues, according to federal, state 
and local regulations on research with human subjects, to make sure the study complies with these 
before approval of a research study is issued. 
AUTHORIZATION TO USE OR DISCLOSE YOUR IDENTIFIABLE HEALTH INFORMATION  
 
The privacy law, HIPAA (Health Insurance Portability and Accountability Act), requires researchers to 
protect your health information. This form describes how researchers may use your information. 
Please read it carefully.  
 
Your health information will be used and/or released (disclosed) for the following research study: 
Behavioral Effects of Drugs (Inpatient) (34). 
 
You allow William W. Stoops, Ph.D. and his research staff at the University of Kentucky to create, 
access, use, and release your health information for the purposes listed below.  
 
 
 
Your health information that may be used and released includes: 
 
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• 
Demographic 
information 
(for 
example, 
information 
about 
your 
race, 
gender, 
socioeconomic status, and age) 
• 
Results of physical examinations  
• 
Results of psychiatric screening tests 
• 
Results of questionnaires and study procedures 
• 
Results of blood tests and urine screens 
• 
Medical history 
 
Your health information will be used for: 
 
• 
A study coordinated by William W. Stoops, Ph.D. examining the effects of stimulant drugs. 
Your protected health information is necessary to conduct this line of research, as well as to meet 
legal, institutional, and accreditation requirements. 
 
The Researchers may use and share your health information with: 
 
• 
The University of Kentucky’s Institutional Review Board/Office of Research Integrity, 
• 
University of Kentucky Medical Center, Investigational Drug Service, Center for Clinical 
and Translational Sciences, Clinical Services Core, and Clinical Research Organization  
• 
The National Institute on Alcohol Abuse and Alcoholism, 
• 
The Food and Drug Administration 
 
The researchers agree to only share your health information with the people listed in this document.  
Should your health information be released to anyone that is not regulated by the privacy law, your 
health information may be shared with others without your permission; however, the use of your 
health information would still be regulated by applicable federal and state laws.  
You will not be allowed to participate in the research study if you do not sign this form. If you decide 
not to sign the form, it will not affect your: 
• 
Current or future healthcare at the University of Kentucky 
• 
Current or future payments to the University of Kentucky  
• 
Ability to enroll in any health plans (if applicable) 
• 
Eligibility for benefits (if applicable) 
 
After signing the form, you can change your mind and NOT let the researcher(s) release or use 
your health information (revoke the Authorization). If your revoke the authorization: 
 
• 
You will send a written letter to: William W. Stoops, Ph.D. 465 E. High Street, Suite 204B, 
Lexington, KY 40507 to inform him of your decision. 
• 
Researchers may use and release your health information already collected for this research 
study. 
• 
Your protected health information may still be used and released should you have a bad 
reaction (adverse event). 
• 
You will not be allowed to participate in the study. 
 
If you have not already received a copy of the Privacy Notice, you may request one. If you 
have any questions or concerns about your privacy rights, you should contact the University 
of Kentucky’s Privacy Officer at: (859) 323-9817. 
 
42362


 
 
 
 
 
 
 
 
Subject's Initials _________ 
Witness' Initials _________ 
Date _________  10 
You are the subject or are authorized to act on behalf of the subject. You have read this 
information, and you will receive a copy of this form after it is signed. 
 
 
_________________________________  
 
 
 
_____________     
Signature of research subject or *research                 Date 
subject’s legal representative 
 
_________________________________  
 
 
 
_____________ 
 
Printed name of research subject or  
 
 
 
 
 
Representative’s relationship  
*research subject’s legal representative  
 
 
 
 
to research subject 
 
*(If, applicable) Please explain Representative’s relationship to subject and include a description of 
Representative’s authority to act on behalf of subject: 
 
__________________________________________  
 
 
 
 
_____________ 
Name of person obtaining informed consent/HIPAA authorization      Date 
  
 
_________________________________________ 
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42362

Prot_SAP_002.pdf: 
Behavioral Effects of Drugs: Inpatient (34) (Alcohol and N-Acetylcysteine) (PI: William W. Stoops, Ph.D.) 
1 
Official Title: A Human Laboratory Study of n-Acetylcysteine for Alcohol Use Disorder   
NCT Number: NCT03216954 
Date of Document: 15 December 2020 


Behavioral Effects of Drugs: Inpatient (34) (Alcohol and N-Acetylcysteine) (PI: William W. Stoops, Ph.D.) 
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1. BACKGROUND 
Alcohol (ALC) use disorder (AUD) is an unrelenting public health concern. Approximately 17 million 
Americans meet criteria for AUD, with 85,000 deaths directly attributable to ALC each year, resulting in an 
annual economic burden of about $250 billion. Several medications have been approved for treating AUD 
(i.e., disulfiram, naltrexone, acamprosate), but these pharmacotherapies are not widely used, nor are they 
universally effective or appropriate to use in all AUD patients due to contraindications. To address the 
continued need to improve AUD treatment, identifying novel AUD pharmacotherapies is an NIAAA priority.  
A wealth of data indicates that ALC use produces profound changes in the brain glutamate system. 
Preclinical studies show that chronic or binge-like ALC administration decreases extracellular glutamate 
levels, which are then increased during ALC withdrawal. These elevated glutamate levels observed during 
ALC withdrawal can be reduced with further ALC administration, driving a cycle of heavy ALC use and 
withdrawal periods that characterize AUD. The changes in glutamate homeostasis that occur during the 
cycle of chronic ALC intoxication and withdrawal have been attributed to altered glutamate transport (e.g., 
changes in cystine-glutamate exchanger [xCT] and glial glutamate transporter [GLT-1] expression and 
function). Normalization of extracellular glutamate levels through administration of compounds like 
ceftriaxone or n-acetylcysteine (NAC), which increase expression of the xCT and GLT-1, attenuates 
maladaptive brain changes produced by ALC, as well as ALC self-administration and behavioral 
sensitization in preclinical models. 
These preclinical data provide a strong scientific premise for the hypothesis that normalization of 
extracellular 
glutamate 
levels 
(i.e., 
restoration 
of 
glutamate 
homeostasis) 
is 
a 
promising 
pharmacotherapeutic approach for AUD, yet this research area remains unexamined in prospective clinical 
studies. Because ceftriaxone must be administered intravenously and can result in serious side effects 
(e.g., C. Difficile infection), as well as antibiotic resistance, it is not feasible for testing as an AUD treatment 
in clinical research. NAC can be administered orally and has a low incidence of side effects making it an 
ideal lead compound to be evaluated as a potential medication for treating AUD. Although we are not 
aware of any clinical studies that have prospectively tested NAC for AUD, there is clinical evidence, 
including data from our laboratory, supporting its utility in treating other substance use disorders linked to 
disrupted glutamate homeostasis.  
The overarching goal of this application is to demonstrate that restoration of glutamate homeostasis with 
NAC is a viable strategy for treating AUD. This goal will be achieved through the conduct of a rigorous 
human laboratory study designed to accomplish three specific aims.  
The first aim is to demonstrate that maintenance on NAC reduces the pharmacodynamic effects 
of ALC that contribute to its abuse. A within-subjects study will be conducted in which non-treatment-
seeking subjects with AUD (N=25) will be maintained on placebo and two doses of NAC (1.2 and 2.4 
g/day). Two active doses will be tested in order to identify which dose is most effective and should be 
advanced to a clinical trial. Order of maintenance conditions will be randomly determined for each subject. 
After being maintained on each dose condition for 4 days, the reinforcing and subjective effects of ALC, 
including ALC craving, will be determined. Self-reported ALC use in the natural environment during 
maintenance will also be assessed. This reverse-engineered human laboratory approach has good 
predictive validity for clinical pharmacotherapy efficacy. After completing a session, subjects will undergo a 
1-week washout and begin maintenance on the next condition, repeating this cycle until all conditions have 
been completed.  
The second aim is to demonstrate the safety and tolerability of NAC when combined with ALC. 
Physiological responses (e.g., heart rate) and breath alcohol levels will be measured throughout each 
experimental session. Adverse events will also be assessed across each maintenance period in order to 
demonstrate that NAC can safely be administered to subjects with AUD.  
A third, exploratory, aim is to evaluate potential mechanisms contributing to the influence of 
NAC on the pharmacodynamic effects of ALC. To this end, a number of validated trait measures (e.g., 
the Zuckerman-Kuhlman Personality Questionnaire, the Barratt Impulsivity Scale) and cognitive-behavioral 
tasks (e.g., Go/Stop Task, Alcohol Delay Discounting Task) will be completed. Outcomes from these 
measures will be correlated with pharmacodynamic and safety/tolerability outcomes.  
The research proposed here will directly translate findings from preclinical research and provide the 
initial prospective clinical evidence that restoration of glutamate homeostasis with NAC has promise for 
treating AUD. This study will also provide basic science information about the glutamatergic mechanisms 


Behavioral Effects of Drugs: Inpatient (34) (Alcohol and N-Acetylcysteine) (PI: William W. Stoops, Ph.D.) 
3 
underlying the pharmacodynamic effects of ALC in humans. Overall, the proposed research seeks to 
expand the scope of current AUD treatment research by focusing on glutamate homeostasis, which has 
strong preclinical evidence supporting its critical role in AUD but remains unstudied in clinical research.  
2. OBJECTIVES 
A within-subject, double-blind, NAC placebo-controlled human laboratory experiment will be conducted 
to demonstrate that maintenance on NAC attenuates the pharmacodynamic effects of ALC that contribute 
to its use (Drobes et al., 2003; Hendershot et al., 2016; O’Malley et al., 2002). ALC use in the natural 
environment, as well as the safety and tolerability of combining NAC with ALC, will also be evaluated.  
3. STUDY DESIGN 
This study will use a rigorous within-subject, double-blind, NAC placebo-controlled human laboratory 
design with subjects receiving all NAC doses in a randomized order (i.e., NAC is a within subject factor). 
4. STUDY POPULATION 
Up to 150 individuals will be screened to participate in this study. We intend to enroll 25 (17 male and 8 
female) completers into the study. Screening procedures will be conducted under our lab’s screening 
protocol (03-0509). Inclusion and exclusion criteria are outlined below.  
Inclusion/Exclusion Criteria 
The following criteria must be met for an individual to participate in the study: 1) able to speak/read 
English; 2) not seeking treatment at the time of the study; 3) female or male between the ages of 21 and 55 
years; 4) one binge drinking episode (5+/4+ standard alcoholic drinks per drinking session for men and 
women, respectively) in the past 30 days; 5) recent ALC use verified by ethyl glucuronide positive urine, as 
well as fulfillment of DSM-5 diagnostic criteria for AUD; 6) other than the diagnosis for AUD at the time of 
the interview, subjects must be otherwise healthy; 7) ECG, read by cardiologist, within normal limits; 8) 
body mass index of 19-35; 9) females using an effective form of birth control and not pregnant or breast 
feeding; 10) judged by the medical staff to be psychiatrically and physically healthy; 11) able to abstain 
from ALC for 12 hours prior to session; and 12) no contraindications/allergies to NAC or ALC. Potential 
research subjects who are seeking treatment for substance abuse/dependence will be excluded from 
research participation, and will be referred to an appropriate treatment program.  
Other than the diagnoses for AUD at the time of the interview, subjects must be healthy. Screening 
procedures for all subjects will include a medical-history questionnaire, drug-use questionnaire, physical 
examination, laboratory chemistries (e.g., blood chemistry screen including liver and kidney function tests, 
hemogram with differential, urinalysis), electrocardiogram (ECG) and a mini-mental status examination. All 
subjects must have a Body Mass Index (BMI) of 19-35. Dr. Rayapati must consider blood-chemistry, 
complete blood count and urinalysis values that are not within the normal range clinically insignificant. Dr. 
John Gurley, a cardiologist, or an authorized colleague, will review the results of the ECG. The ECG must 
be considered to be within normal limits in the opinion of Dr. Gurley for a potential subject to be enrolled. 
Any potential subject with a history of serious physical disease, current physical disease (e.g., impaired 
cardiovascular functioning, histories of seizure, head trauma, or CNS tumors) or current or past histories of 
psychiatric disorder, other than AUD or tobacco use disorder, will be excluded from research participation. 
Female subjects must be using an effective form of birth control (e.g., birth control pills, surgical 
sterilization, IUD, cervical cap with a spermicide or abstinence) in order to participate and must not be 
pregnant. A urine pregnancy test will be conducted prior to each session to ensure female subjects do not 
continue in the study if pregnant. All study subjects will be judged by the medical staff to be psychiatrically 
and physically healthy and without contraindications/allergies to NAC or ALC. 
5. SUBJECT RECRUITMENT METHODS AND PRIVACY 
 Subjects are recruited primarily through formal advertisement (i.e., regular newspaper advertisements 
placed generally in free newspapers), local flyers posted in public areas (e.g., bars, restaurants, stores) 
and by word-of-mouth. These advertisements are approved under our screening protocol (IRB # 03-0509). 
Subjects make initial contact by phone with one of our recruiters who have completed the research training 
and HIPAA compliance web-based modules. If the subject self-discloses information that would make 
him/her potentially eligible for the study, they will be invited to a screening appointment. Screening is 
completed by one of our research assistants at the UK Laboratory of Human Behavioral Pharmacology 
(LHBP). Study investigators may interact with subjects in this setting and appropriate cautions are in place 
to ensure privacy during the intake process.  
 


Behavioral Effects of Drugs: Inpatient (34) (Alcohol and N-Acetylcysteine) (PI: William W. Stoops, Ph.D.) 
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6. INFORMED CONSENT PROCESS 
All potential subjects that are identified using the subject recruitment methods noted above will provide 
informed consent prior to participating in the protocol. Subjects that meet the eligibility criteria noted above 
will come to the LHBP and will undergo a field sobriety test and provide an expired air sample that will be 
tested for the presence of alcohol. If the subject passes the field sobriety test (walk and turn, one-leg 
balance [timed], finger-to-nose and backwards-counting tasks) and the expired air sample is negative, he 
or she will then be given a copy of the approved informed consent document to read and sign. After 
reading the consent document, the PI or one of the Co-Is on this protocol will address any questions the 
subject may have in order to assess the subject’s understanding of the protocol. After this, the subject will 
receive a copy of the informed consent document and will sign a form indicating that they have received a 
copy of the form they read and signed.  
7. RESEARCH PROCEDURES 
Subjects that meet the inclusion criteria will participate as outpatients at the LHBP and as inpatients at 
the Clinical Services Core (CSC) unit of the University of Kentucky Medical Center. 
Twenty-five (≈8 women) non-treatment-seeking subjects with AUD will complete the study. Subjects, 
recruited from the community, will earn $40/session and a $40/session completion bonus if they finish the 
protocol. To maximize medication adherence, a contingency management approach will be used wherein 
subjects will receive a monetary bonus each day that medications are administered per protocol as verified 
by Wisepill®. Payments will start at $5 and increase by $2 each consecutive day of dosing adherence. 
The study protocol will use previously developed methods that have predictive validity for AUD 
treatment efficacy (Drobes et al., 2003; Hendershot et al., 2016; O’Malley et al., 2002). More specifically, 
the sensitivity of this clinical laboratory approach was established with a medication already known to be 
effective for AUD (i.e., naltrexone; see above). After screening, subjects will complete the protocol as 
outlined in Table 1. After completing the protocol, all subjects will be offered referral to a treatment program 
per the NIAAA National Advisory Council guidelines (National Council on Alcohol, 1988; Sinha et al., 1999). 
 
Day 
Table 1: Protocol Schedule 
0 
Practice Session at the Laboratory of Human Behavioral Pharmacology (LHBP). Matches 
Experimental Session, except no ALC administered, nor is there an overnight stay at the CSC. 
Subjects will receive NAC doses for take-home administration.  
1-5 
NAC (0, 0.6 or 1.2 g/dose; dose order randomly assigned) administered at 0700 and 1900h. 
5 
Experimental Session 1 at Inpatient Clinical Services Core (CSC) unit.  
6-12 
Washout. 
13-17 
NAC (0, 0.6 or 1.2 g/dose; dose order randomly assigned) administered at 0700 and 1900h. 
17 
Experimental Session 2 at Inpatient CSC unit. 
18-24 
Washout. 
25-29 
NAC (0, 0.6 or 1.2 g/dose; dose order randomly assigned) administered at 0700 and 1900h. 
29 
Experimental Session 3 at Inpatient CSC unit.  
30 
Subject discharged from study. 
 
Subjects will be instructed to maintain their standard diet, ALC and cigarette intake throughout 
participation, with the exception that they will be asked to abstain from ALC for at least 12h prior to a 
session. All subjects will provide urine and expired-breath samples prior to experimental sessions. The 
presence of drugs of abuse in the urine or positive BALs upon arrival for experimental sessions will result in 
rescheduling of the session. Repeated occurrences will result in study dismissal. Subjects will not be 
allowed to smoke tobacco cigarettes during experimental sessions, consistent with previous work (O’Malley 
et al., 2002).  
NAC Maintenance Conditions. After completing screening, a subject will be randomized to a NAC dose 
order condition using a random number generator. Completing subjects will experience all dose conditions. 
A pharmacist in the Investigational Drug Service will maintain the randomization key to preserve the double 
blind. NAC doses will be prepared with commercially available drug placed into opaque capsules. 
Cornstarch will be used as filler. Placebo capsules will contain only cornstarch, but will be visually identical 
to capsules that contain NAC. Placebo capsules will also be washed in a NAC slurry to control for the 


Behavioral Effects of Drugs: Inpatient (34) (Alcohol and N-Acetylcysteine) (PI: William W. Stoops, Ph.D.) 
5 
distinct smell of NAC as has been done in previous research (Kevin M. Gray, M.D., Personal 
Communication). Subjects will receive practice taking the study capsules during the practice session. 
Subjects will be provided two placebo capsules during this session and instructed on how to correctly 
administer those capsules. Subjects will be told that these capsules are placebos, but that placebo and 
NAC capsules will look visually identical. 
Total daily doses are 0, 1.2 and 2.4 g/day (i.e., 0, 0.6g and 1.2 g administered two times daily at 0700 
and 1900h; Table 1). One of the doses reduced ALC use in one study (i.e., 1.2 g/day; Squeglia et al., 2016) 
and the other dose reduced elevated brain glutamate levels in another (i.e., 2.4 g/day; Schmaal et al., 
2012). Testing two doses in this study will inform dose selection when NAC is advanced to a clinical trial. 
The dosing regimen and maintenance period were chosen based on previous studies (Amen et al., 2011; 
LaRowe et al., 2013; Squeglia et al., 2016).  
Medication adherence will be assessed with the Wisepill® digital monitoring system. This device uses 
mobile phone and Internet technologies to provide real-time and comprehensive medication management. 
When the subject opens the device, it sends a signal to the server with a time-stamped confirmation. The 
Wisepill® digital monitoring system is currently being used successfully in other studies conducted in our 
laboratory. Subjects will receive the Wisepill® device packed with the appropriate doses in the practice 
session and in the afternoon of Days 13 and 25 of participation (see Table 1). They will receive $10 for 
coming to pick up doses.  
Apparatus. After 4 full days of maintenance (i.e., on the 5th day of maintenance in each condition), 
subjects will be admitted to the CSC for an overnight stay while they participate in each of the three 
experimental sessions (see Table 2). Subjects will be tested in individual rooms on the CSC in order to 
eliminate the effects of social factors on the behavioral and physiological effects of ALC (e.g., Kirkpatrick 
and de Wit, 2013). Subjects will complete the subjective-effects questionnaires on a computer, which 
automates the collection of behavioral data, increasing the efficiency and accuracy of data collection and 
management. The TLFB and trait questionnaires (see below) will be administered using pen and paper and 
double verified by study staff. 
Time 
Table 2: Experimental Session Activities 
1400-1500h 
Arrival at LHBP. If the subject drove to the LHBP, the subject’s car keys will be collected. 
Urinalysis (including pregnancy test for females), Breath alcohol level (BAL), field 
sobriety test, vital signs assessment, self-reported times of maintenance dosing, TLFB 
completed. 
1500-1530h 
Admission and acclimation to the CSC. Subject provided a light standardized snack. 
1530-1615h 
Baseline subjective, physiological and cognitive-behavioral measures. 
1615-1730h 
ALC Sampling. Subjective and physiological measures completed at 10, 20 and 30 
minutes after dosing. Cognitive-behavioral measures completed 30 minutes after dosing.  
1730-1830h 
Choice Block 1. Subjects can consume ALC (up to 4 drinks total) or receive an 
alternative reinforcer. Subjective and physiological measures completed every 30 
minutes.  
1830-1930h 
Choice Block 2. Details the same as noted for the 1640-1740h period.  
1930-1975h 
Udvalg for Kliniske UndersØgelser (UKU) Side Effects Rating Scale. Subject provided a 
standardized dinner. 
1975-2300h 
Recreational activities (i.e., movies, magazines, and books). 
2300h 
Lights out. 
0700h 
Subject provided a standardized breakfast.  
0730-0800h 
BAL sample and field sobriety test. 
0800h 
Discharged from CSC and car keys returned.  
 
Session Activities. On experimental session days, subjects will arrive at the LHBP at the University of 
Kentucky at 1400h. Upon arrival to the LHBP, the LHBP staff will take the subject’s car keys and will return 
them when the subject is released from the hospital the following morning. Should the subject leave the 
hospital prior to that time, the LHBP staff or subject will arrange transportation (e.g., arrange a taxi). The 
car keys will be returned the morning following the experimental session upon successful completion of a 
field sobriety test. 


Behavioral Effects of Drugs: Inpatient (34) (Alcohol and N-Acetylcysteine) (PI: William W. Stoops, Ph.D.) 
6 
Urine and expired breath samples will be obtained for drug and ALC testing. A field sobriety test will be 
completed. Time of maintenance dosing will be confirmed by self-report and Wisepill® log. If subjects miss 
more than 3 doses or take doses more than 2 hours outside their scheduled window on 3 occasions within 
a single dose condition, they will be coached on adherence and that dose condition will be repeated. If this 
non-adherence occurs again during any other dose condition (or during the repeat condition), the subject 
will be dropped from the study. Subjects will report their ALC consumption during each 4-day maintenance 
block using the TLFB (Sobell et al., 1992). Subjects will be then admitted to the CSC at 1500h for their 
overnight stay and provided a light snack upon admission.  
ALC Self-Administration Procedures. The reinforcing effects of ALC, alone and during maintenance on 
NAC will be assessed using a sophisticated clinical laboratory approach that has predictive validity for AUD 
pharmacotherapy efficacy (Drobes et al., 2003; Hendershot et al., 2016; O’Malley et al., 2002). The primary 
outcome measure for this procedure is Number of Drinks Chosen. Testing under this procedure involves 
two phases: 1) Sampling and 2) Self-Administration. 
Sampling Phase. Subjects will complete a Sampling Phase at 1600h during experimental sessions to 
acquaint them with ALC effects. During each Sampling Phase, subjects will receive a single administration 
of 95% ALC mixed with non-alcoholic mixer (e.g., lemon lime soda, tonic water) (designed to raise BALs to 
0.03 g/dl), to be consumed over 5 minutes. 
Self-Administration Phase. After sampling the ALC dose, subjects will complete the Self-Administration 
Phase. During each Self-Administration Phase, subjects will complete 2 1-h choice blocks in which they will 
be provided with a tray containing 4 drinks, with each drink prepared with 95% ALC mixed with non-
alcoholic mixer (e.g., lemon lime soda, tonic water) (designed to raise BALs 0.015 g/dl/drink) and a “tab” 
detailing the cost of each drink, based on the cost of a drink purchased in a local bar (i.e., $3.00). Subjects 
will be instructed to consume as many drinks on the tray as they want during the 1-h choice block. Subjects 
may instead choose to receive the corresponding dollar amount for the drinks that they do not consume. At 
the end of the first choice block, the drink tray will be replaced with a second tray of 4 drinks for the second 
choice block. Subjects can thus consume a maximum of 8 drinks or earn maximum of $24, but may choose 
freely between these two options. Including money as an alternative reinforcer provides an incentive for not 
drinking ALC, which models the natural ecology. Any money earned will be added to that subject’s $40 
payment for attending the session. 
Subjective-Effects Questionnaires. Five standardized subjective-effects questionnaires that measure 
various aspects of mood and ALC effects (Ray et al., 2009; Roche et al., 2016) will be completed as 
outlined in Table 2: 1) ALC Urge Questionnaire to measure craving (Bohn et al., 1995); 2) Subjective High 
Assessment Scale (Schuckit, 1984); 3) Biphasic ALC Effects Scale (Martin et al., 1993); 4) Profile of Mood 
States (Schacham, 1983) and 5) Drug Effects Questionnaire (Johanson and Uhlenhuth, 1980).  
Safety and Tolerability Measures. Physiological measures (i.e., BAL measurements, heart rate and 
blood pressure) will be recorded upon arrival at the LHBP, before ALC administration and throughout the 
session at the intervals noted in Table 2 using digital monitors. ALC will not be administered if a subject’s 
heart rate is ≥100 bpm, systolic pressure is ≥150 mmHg or diastolic pressure is ≥100 mmHg. A subject will 
be excluded from further participation if he/she exhibits hypersensitivity (i.e., heart rate > 130 bpm, systolic 
pressure > 180 mmHg, diastolic pressure > 120 mmHg) during maintenance on NAC and/or to the effects 
of ALC. The UKU Side Effects Rating Scale will be completed at the end of sessions (Lingjaerde et al., 
1987). 
Trait Questionnaires and Cognitive Behavioral Tasks. To explore potential mechanisms of NAC effects, 
subjects will complete a battery of trait measures at screening that assess various aspects of personality, 
including the Zuckerman-Kuhlman Personality Questionnaire, the Barratt Impulsiveness Scale and the 
Snaith-Hamilton Pleasure Sale (Patton et al., 1995; Snaith et al., 1995; Zuckerman and Kuhlman, 2000). 
As outlined in Table 2, subjects will also complete the Commodity Purchase Task, n-back Task, the 
Go/Stop Task and Money and Alcohol and Money Delay Discounting Tasks. These specific tasks measure 
several key facets of alcohol-related decision-making and impulsivity (MacKillop, 2016; Reynolds et al., 
2008) and, along with the self-administration and subjective effects outcomes described above, model key 
stages of the addiction cycle (Litten et al., 2016b; MacKillop, 2016). 
Commodity Purchase Tasks (Appendix A). Commodity tasks will be used to assess economic demand 
for alcohol and soda (Amlung et al., 2015; Bruner and Johnson, 2014; Murphy and MacKillop, 2006; 
Strickland and Stoops, 2017). In these task subjects are asked to indicate the hypothetical number of items 


Behavioral Effects of Drugs: Inpatient (34) (Alcohol and N-Acetylcysteine) (PI: William W. Stoops, Ph.D.) 
7 
(e.g., one alcoholic drink) they would purchase at a range of monetary increments (e.g., $0.00 [free] to 
$15/drink). All choices are hypothetical and will not be purchased or administered. Data from the 
commodity purchase task will be analyzed using economic demand equations previously applied to 
purchase task data (e.g., Strickland et al., 2016). Primary outcomes of this task include elasticity of 
demand (α) and intensity of demand (Q0). 
n-Back (Appendix B). The n-Back task will be used to measure working memory and working memory 
capacity (Jaeggi et al. 2010). In this task, subjects are presented with a sequence of numbers and asked to 
indicate when the current stimulus matches the one from “n” steps earlier. Two settings will be used in this 
study, the 1-back and the 2-back (i.e., matching 1 and 2 stimuli back, respectively). The primary outcome 
of this task is the percentage of correct responses. 
Go/Stop Task (Appendix C). A cued go/stop task will be used as a measure of response-inhibition 
(Miller et al., 1991). In this task, subjects must respond to target stimuli and withhold responses to non-
target stimuli. During this task, go stimuli (e.g., a horizontal rectangle) will be followed by go target stimuli 
(i.e., a green horizontal rectangle) 80% of the time and followed by no-go stimuli (i.e., a blue horizontal 
rectangle) 20% of the time. Conversely, no-go stimuli (e.g., a vertical rectangle) will be followed by no-go 
target stimuli (i.e., a blue vertical rectangle) 80% of the time and go target stimuli (i.e., a green vertical 
rectangle) 20% of the time. 
Hypothetical Delay Discounting (Appendix D). A 5-trial adjusting delay discounting task will be used to 
rapidly assess discounting rates for various commodities (Koffarnus and Bickel, 2014). In this task, 
subjects making a series of 5 choices between an immediately available, smaller reinforcer and a larger 
reinforcer at various delays. Versions of this task with monetary (e.g., $1000 delayed versus $500 now) 
and alcohol (e.g., $1000 of alcohol delayed versus $500 of alcohol now) commodities will be used. 
Subjects will be told that all choices are hypothetical. The primary outcome of this task is the discounting 
rate (k). Previous research has demonstrated that this measure provides rapid and accurate discounting 
rates across a range of commodities (Cox and Dallery, 2016; Koffarnus and Bickel, 2014; Strickland et al., 
2017). 
Data Analysis 
Data will be analyzed as raw scores. Statistical significance refers to p < .05. Number of Drinks Chosen 
on the ALC self-administration procedure will be analyzed with a one-factor, repeated-measure ANOVA 
with NAC dose (0, 1.2 and 2.4 g/day) as the factor. A significant attenuation (i.e., decreased ALC self-
administration) will be inferred if the main effect of NAC attains statistical significance in the ANOVA. 
Tukey’s HSD post-hoc test will be used to make appropriate pair-wise comparisons between means if the 
ANOVA outcome attains statistical significance. Data from the subjective-effects questionnaires and 
safety/tolerability measures following administration of the sampling dose will be calculated as peak effect 
(i.e., the maximum score observed after ALC sampling). These data will be analyzed in the same fashion 
as ALC self-administration data. The influence of relevant biological (e.g., age) and behavioral variables 
(e.g., cigarette smoking, weekly ALC use) will be determined in initial correlation analyses and included as 
covariates in analyses should they be significantly associated with outcomes. Outcomes from trait 
questionnaires and cognitive behavioral tasks will also be correlated with self-administration, subjective 
effect and physiological data to explore the mechanisms by which NAC attenuates the effects of ALC.  
Power and Sample Size Considerations. We used the results of a prior meta-analysis of human 
laboratory studies of ALC self-administration and craving to determine an appropriate sample size for the 
present experiment (Hendershot et al., 2016). That meta-analysis demonstrated that naltrexone 
maintenance decreased the quantity of ALC consumed and self-reported craving relative to placebo with 
an average estimated effect size (i.e., Cohen’s f) of approximately 0.27. Considering the overall design and 
use of three NAC doses, enrolling 25 subjects will provide sufficient power (power = 0.80, a = 0.05, 
G*Power) to detect a medium effect size (f) of approximately 0.26 for attenuation of the effects of ALC as a 
function of NAC dose. 
8. RESOURCES 
This study will take place at University of Kentucky Laboratory of Human Behavioral Pharmacology 
(LHBP) and the Clinical Services Core (CSC) unit. Study visits will only be conducted on weekdays, but 
subjects will be provided with emergency contact information should they experience problems/AEs/SAEs 
on weekends. The LHBP and CSC are well equipped to conduct the necessary physiological monitoring 
and behavioral assessments. Dr. Rayapati is a psychiatrist who has worked extensively with individuals 


Behavioral Effects of Drugs: Inpatient (34) (Alcohol and N-Acetylcysteine) (PI: William W. Stoops, Ph.D.) 
8 
with substance use disorders in both the clinical and research setting and he is the responsible medical 
investigator for this study. Dr. Hays is an adult psychiatrist who has worked extensively with individuals with 
substance use disorders, especially alcohol use disorder, in both the clinical and research setting and he is 
the back up medical investigator for this study. They will be available to attend to medical problems as well 
as any psychological or psychiatric issues that may arise. Drs. Stoops will provide scientific oversight for 
the study and have safely completed numerous human behavioral pharmacology studies. Overall, the 
study team and resources described above are well equipped to protect subjects and successfully 
implement, carry out and complete this study protocol. 
9. POTENTIAL RISKS 
The behavioral and physiological assessment procedures employed in this study are benign. The risks 
to the study subjects are those related to the ingestion of the drugs under study. All of the drugs to be 
administered in the proposed research have been administered safely to human subjects under controlled 
laboratory conditions. The relative safety, as well as the contraindications and possible side effects of 
these compounds are well known and documented. We, and others, have administered all the drugs and 
doses in prior studies without serious side effects. However, the administration of any drug involves some 
risks simply because individuals differ in their reactions to drugs. The main risk is that subjects will 
experience side effects that may be unpleasant.  
Common side effects of ALC include drowsiness, slurred speech, headache, gastrointestinal upset, 
breathing difficulties, distorted vision and hearing, impaired judgment and decreased perception and 
coordination. More serious side effects following the chronic, unsupervised administration of much higher 
doses of ALC have occurred and include blackouts (memory lapses, where the drinker cannot remember 
events that occurred while under the influence), anemia, unconsciousness and coma. These side effects 
may be more frequent and larger in magnitude when testing the ALC with NAC.  
Common side effects of NAC include nausea, vomiting, diarrhea and constipation. Less common side 
effects include rashes, fever, headache, drowsiness, low blood pressure and liver damage.  
There is also the risk that others may see a subject’s Protected Health Information (PHI). PHI is 
considered individually identifiable health information transmitted or maintained in any form (e.g., 
electronic means, on paper, or through oral communication) that relates to the past, present, or future 
physical or mental health conditions of an individual that may be used or disclosed. The following PHI will 
be collected as part of this project: names (e.g., individual, employer, relatives, etc.), address, telephone 
number, Social Security number, dates (e.g., birth, admission, discharge), medical record numbers, 
driver’s license numbers, mental and physical health history, drug use history, results from mental and 
physical health screening, results from personality questionnaires and data from experimental measures. 
The doses to be administered in the present experiment were chosen to minimize, if not eliminate, the 
chance of these side effects occurring since these side effects are related to dose. Thus, it is unlikely that 
subjects will experience side effects during the experimental protocol. All work proposed here will be 
conducted at the LHBP, under medical supervision. Side effects of the drugs are temporary, usually 
dissipating in less than 24 hours. The principal investigator on this project, Dr. Stoops, has had extensive 
experience for over 17 years administering therapeutic and supratherapeutic doses of drugs to subjects in 
an outpatient and inpatient setting and has never observed untoward effects. Dr. Stoops will train all staff 
on this project. 
To avoid potential drug interactions, subjects taking any prescribed medication chronically, except 
birth control or as described in the inclusion/exclusion criteria above, will be excluded. The medical 
personnel on this protocol will determine if it is safe for a potential subject to discontinue taking their 
medication during their participation. 
There is some theoretical risk that subjects might choose to seek out sources of drugs they received 
experimentally and liked. However, this risk is minimal since all drugs are administered under blind 
conditions and in a setting that is not conducive to the development of dependence. 
10. SAFETY PRECAUTIONS 
Subjects are carefully screened (history and physical exam, routine labs such as CBC, complete 
metabolic panel and urinalysis, ECG and psychiatric assessment) to exclude those with potential increased 
risk of adverse effects, such as personal or family histories of heart disease, histories of seizure or head 
injury associated with more than a brief loss of consciousness, hypertension, psychosis, etc. During 
sessions subjects remain under careful medical observation and are monitored continuously by on-site 


Behavioral Effects of Drugs: Inpatient (34) (Alcohol and N-Acetylcysteine) (PI: William W. Stoops, Ph.D.) 
9 
medical staff. Vital signs will be collected throughout the dosing period. Staff is familiar with the acceptable 
physiological parameters for these studies. In addition, Dr. Stoops has substantial experience 
administering medications to human subjects under a variety of dosing conditions. Lastly, female subjects 
are also given pregnancy tests prior to each session to ensure that we do not administer active 
medications to a pregnant woman.  
Legal risks including loss of confidentiality: All intake documentation that contains personal 
information is handled separately from the actual data collected during the study. All information of a 
personal nature (intake assessments, medical test results) is kept locked either on password-protected 
computers or in secure filing cabinets all behind locked doors and accessible only to key personnel 
involved in the research. A Certificate of Confidentiality has been obtained from NIAAA.  
11. BENEFIT vs. RISK 
The degree of risk to which individual study subjects are exposed as a consequence of their research 
participation is slight. In contrast, the potential and probable benefits to be derived by society in general and 
by patients as a group appear to be considerable. The major benefits of this study are clinical and scientific 
ones related to the knowledge gained about putative medications for AUD. The data from this project will 
contribute to a better understanding of alcohol abuse and will ultimately contribute to the development of 
improved prevention, control and treatment procedures. Individual study subjects are expected to benefit 
personally from the medical and psychiatric evaluations and from referrals for medical and psychiatric 
treatment that are provided whenever appropriate. Overall, the risk/benefit ratio appears favorable and the 
conduct of this research seems well justified. 
12. AVAILABLE ALTERNATIVE TREATMENTS  
There are no available alternative treatments as this is not a treatment study. If subjects express the 
desire for treatment they will be given referrals for treatment and not be allowed to participate in this study. 
13. RESEARCH MATERIALS, RECORDS AND PRIVACY 
Urine and blood samples will be collected at screening prior to a subject’s participation in the 
experimental protocol under another IRB approved protocol (Number 03-0509). These urine samples will be 
tested for the presence of a full range of drugs of abuse. Blood samples will be used for the laboratory 
chemistries. Females will also be given a pregnancy test at the time of screening (via the urine sample). 
Urine drug and pregnancy tests will be conducted prior to the conduct of each experimental session. Other 
data obtained from the subjects will involve subjective effects based on questionnaires, various computer-
based tasks and non-intrusive staff observations and ratings. The consent form states that subject’s 
confidentiality will be protected.  
14. CONFIDENTIALITY 
Identifying information will be stored in a separate, locked area from all other de-identified data and 
codes linking the two will be kept under lock and key or on password protected computers. Incidental 
materials containing subject identifiers will be shredded or incinerated. Identification and access of identified 
data/specimens will be available only to study investigators when it is detrimental to subject safety or the 
conduct of the research protocol. For example, if a subject has an adverse event, we will want to obtain a 
quantitative drug screen to identify whether there may have been illicit drug use while in the study versus a 
true adverse event related to the study procedures. In the future, data/specimens may be shared with non-
UK affiliations in a HIPAA compliant manner.  
15. PAYMENT 
Twenty-five (≈8 women) non-treatment-seeking subjects with AUD will complete the study. Subjects, 
recruited from the community, will earn $40/session and a $40/session completion bonus if they finish the 
protocol. Subjects may also make up to $24/session during the ALC self-administration phase if they do not 
choose to drink any of the alcohol available. To maximize medication adherence, a contingency 
management approach will be used wherein subjects will receive a monetary bonus each day that 
medications are administered per protocol as verified by Wisepill®. Payments will start at $5 and increase 
by $2 each consecutive day of dosing adherence. Subjects will receive the Wisepill® device packed with 
the appropriate doses in the mornings of Day 1, 13 and 25 of participation (see Table 1). They will receive 
$10 for coming to pick up doses. The total possible earnings during the course of the trial are $707 if every 
appointment is kept/dose is taken as scheduled and no alcohol is chosen during the self-administration 
phase. We believe that this strategy is a relatively inexpensive investment that, if successful, will ensure 
the power and scientific integrity of a future large-scale clinical trial.  


Behavioral Effects of Drugs: Inpatient (34) (Alcohol and N-Acetylcysteine) (PI: William W. Stoops, Ph.D.) 
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16. COSTS TO SUBJECTS 
There will be no cost to the subject for participating. Costs for the screening procedures (i.e., medical 
history questionnaire, physical examination including laboratory chemistries (blood chemistry screen, 
complete blood count, urinalysis) and a psychiatric examination will be paid by the Laboratory of Human 
Behavioral Pharmacology. 
17. DATA AND SAFETY MONITORING 
Data Monitoring Plan. Data will be collected using a computerized data collection and management 
system. This system automates the collection of the subjective-effect and physiological data, which 
ensures the accuracy and completeness of data collection. The data are stored in a unique file on the hard 
drive of the computer and are printed after all the tasks are completed. Paper-and-pencil task data are 
verified by staff and double-entered into excel spreadsheets after each session. In all instances, the data 
files do not contain the name of the subject; but instead, a unique four-digit number identifies each subject. 
A computer file linking the unique number with the subject’s name will be kept on a stand-alone, password-
protected computer. Data files for experimental tasks and physiological measures from each experimental 
session will be manipulated and combined into a single electronic spreadsheet for each subject by the PI. 
Data for all subjects will then be combined into a single electronic spreadsheet and separated by 
experimental measure for statistical analysis using SPSS (IBM Corporation, Armonk, NY). 
The primary outcome for this study will be Number of Drinks during ALC self-administration. Secondary 
outcome measures will include craving, BALs, physiological and subjective response to ALC, self-reported 
ALC use in the natural environment during maintenance, as well as performance on cognitive-behavioral 
tasks, and the Udvalg for Kliniske UndersØgelser (UKU) Side Effects Rating Scale. 
As noted above, the majority of data are collected using an automated computer system, which 
increases the accuracy and completeness of data collection and ensures the validity and integrity of the 
data. Hand written questionnaires and tasks are double-entered and verified by staff prior to analysis. The 
initial data manipulation described above will be conducted twice and compared. The quality of 
manipulated data and data analyses will be monitored by random inspection by the PI and/or Co-
Investigators. 
Safety Monitoring Plan. Potential subjects will provide information regarding their ALC and drug use 
history and undergo an extensive physical and psychiatric health screening to determine their eligibility and 
safety of their participation. Potential subjects must meet DSM-5 criteria for AUD and must present with a 
urine sample positive for ethyl glucoronide at the time of screening. Any potential subject with a history of 
clinically significant physical disease, current physical disease (e.g., impaired cardiovascular functioning, 
histories of seizure, head trauma or CNS tumors), or current or past histories of psychiatric disorder, other 
than AUD or tobacco use disorder, will be excluded from research participation. Females must be using an 
effective form of birth control in order to participate and must not be pregnant. Methods for monitoring AEs 
will include observations by the medical and research staff, spontaneous report by the subjects, regular 
measurement of cardiovascular indices and use of the UKU Side Effects Rating Scale and subjective-
effects questionnaires. Subjects will not receive study drug if they have any signs or symptoms that may 
contraindicate its administration (e.g., heart rate and blood pressure outside of predetermined range). 
All AEs occurring during the course of the study will be collected, documented and reported to the PI. 
The occurrence of AEs will be assessed daily for the duration of participation and during the follow-up visits 
at 2 and 4 weeks following discharge. Each week a study investigator will review the AE forms from the 
previous week for events that were reported as new or continuing. The study investigators will follow all 
AEs to the point of a satisfactory resolution. Subjects may be withdrawn from the study if the medically 
responsible investigator determines it is the best decision in order to protect the safety of the subject. All 
AEs will be assessed to determine if they meet criteria for a serious AE. 
Serious AEs, as defined by the FDA, will be systematically evaluated daily for the duration of 
participation and during the follow-up visits at 2 and 4 weeks following discharge. Any serious AE, whether 
or not related to the study drug, will be reported to the IRB, NIAAA, and the FDA. The initial serious AE 
report will be followed by submission of a completed serious AE report to all three institutions. 
In the event that a subject either withdraws from the study or the investigator decides to discontinue a 
subject due to a serious AE, the subject will have appropriate follow-up medical monitoring. Monitoring will 
continue until the problem requiring hospitalization has resolved or stabilized with no further change 
expected, is clearly unrelated to the study medications, or results in death. Outcome of serious AEs will be 


Behavioral Effects of Drugs: Inpatient (34) (Alcohol and N-Acetylcysteine) (PI: William W. Stoops, Ph.D.) 
11 
periodically reported to NIAAA. A summary of the serious AEs that occurred during the previous year will 
be included in the annual progress report to NIAAA. 
18. SUBJECT COMPLAINTS 
Subjects may at any time ask study personnel questions about the study procedures or make 
complaints. All staff will be aware to notify Drs. Stoops, Rush, Lile, Hays, or Rayapati about any subject 
concern or complaint as it arises. Subjects will be allowed the opportunity to discuss any concerns or 
questions with an investigator promptly, in person and in confidence. It should be noted, however, that 
subjects will be told that some concerns and complaints will not be kept private such as an adverse event, 
protocol deviation or threat to the safety of subjects or integrity of the research study. In these cases, all 
information will be made available to the Principal Investigator in order to determine any further course of 
action. Dr. Hays or Rayapati will also communicate with the nursing or laboratory staff on at least a weekly 
basis in order to discuss any concerns regarding particular subjects or with respect to the conduct of the 
study. 
19. RESEARCH INVOLVING NON-ENGLISH SPEAKING SUBJECTS OR SUBJECTS FROM A 
FOREIGN CULTURE Not Applicable.  
20. HIV/AIDS RESEARCH POLICY Not applicable. 
21. PI SPONSORED FDA-Regulated Research Not applicable. 


Behavioral Effects of Drugs: Inpatient (34) (Alcohol and N-Acetylcysteine) (PI: William W. Stoops, Ph.D.) 
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Appendix A 
 
Commodity Purchase Task 
 
Example Instructions for Subjects 
 
This is a series of questions designed to assess choices for alcohol across changes in price. This 
information is entirely for research purposes. All questions about purchasing are completely hypothetical 
(pretend). 
 
Imagine a TYPICAL DAY during which you drink alcohol. The following questions ask how much alcohol 
you would consume if it cost various amounts of money. The alcohol is your preferred brand and type (e.g., 
beer, wine, liquor). Assume that each drink is a standard drink (i.e., 12 oz. beer, 5 oz. wine, 1.5 oz. shot 
alone or in mixed drink). Assume that you have the same income that you have now and NO ACCESS to 
any alcohol products than those offered at these prices. In addition, assume that you would consume all 
the alcohol you purchase on that day; that is you cannot save or stockpile any for a later date. 
 
Example Questions for Subjects (for the Alcohol Purchase Task) 
 
 
 
Price/Drink 
# Drinks Purchased 
Free 
 
$0.02 
 
$0.05 
 
$0.13 
 
$0.25 
 
$0.50 
 
$1.00 
 
$2.00 
 
$3.00 
 
$4.00 
 
$5.00 
 
$6.00 
 
$7.00 
 
$8.00 
 
$9.00 
 
$10.00 
 
$11.00 
 
$12.00 
 
$13.00 
 
$14.00 
 
$15.00 
 
 
 


Behavioral Effects of Drugs: Inpatient (34) (Alcohol and N-Acetylcysteine) (PI: William W. Stoops, Ph.D.) 
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Appendix B  
 
n-Back Trial Diagram (Figure from Borgwardt et al. 2012) 
 
 
 
 
 
 
 
 
 


Behavioral Effects of Drugs: Inpatient (34) (Alcohol and N-Acetylcysteine) (PI: William W. Stoops, Ph.D.) 
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APPENDIX C 
 
Traditional Cued Go/No-go Task 
 
Cued RT 
 
Set-up 
• 
Select Cued RT Task – FB 
• 
Press space bar to begin task 
 
Instructions to Participant: 
This is a reaction time task that I would like you to perform. While you are performing the task you 
sit in front of the computer screen just as you are doing. You place your index finger on the green 
dot (?) key. 
 
Presented on the screen will be rectangular boxes that are standing upright or lying flat. The boxes 
are empty when they first appear on the screen. If the box turns green then you are to press the 
green dot (?) button as quickly as possible. If the box turns blue then no response is required. 
 
Now, before the box appears, you will see a plus sign in the middle of the screen. It serves as a 
fixation point so that you know where to focus your attention on the computer screen. After the plus 
sign disappears, a box will appear on the screen. Again, if the box turns green, respond as quickly 
as possible by pressing the green dot (?) key. If the box turns blue then no response is required.  
 
To help you respond quickly, the computer will display how fast you are pressing the key when the 
green target appears. Once you respond to a green target, the screen will show the amount of time 
it took for you to make a response. So lower numbers are better. If you accidentally respond to a 
blue target, the screen will say “Incorrect Response.” 
 
*** There are four 30-second breaks programmed into the task 


Behavioral Effects of Drugs: Inpatient (34) (Alcohol and N-Acetylcysteine) (PI: William W. Stoops, Ph.D.) 
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Appendix D 
 
5-Trial Adjusting Delay Discounting Task (Table from Koffarnus and Bickel 2014) 
 
The below table describes the outcomes for the 5-trial task. For each of the 5 choices (i.e., No.), the 
subject is asked if the would prefer the immediate or delayed reinforcer. The delay to the delayed choice is 
systematically increased or decreased based on previous trial choice (i.e., Delay Choice; increases if delay 
is chosen, decreases if immediate is chosen). The primary outcome is k as labeled in the table below.