Conditions: Alcohol Drinking
Keywords: Alcohol Drinking Drinkers Alcohol Drinking Naltrexone Alcohol Dependence Alcohol Abuse Alcohol-Related Disorders Ethanol Alcoholism
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 59
Healthy volunteers: no

Brief summary:
The primary purpose of the study is to increase our knowledge of receptor function in the brains of people who are heavy drinkers and taking naltrexone (NTX), a medication that has been approved for the treatment of alcohol dependence. Receptors are special molecules in the brain to which other molecules (neurotransmitters) attach during the normal every-day workings of the brain. Drugs can bind to those receptor molecules as well. Recent evidence suggests that kappa opioid receptors (KOR's) may play an important role in alcohol drinking behavior. This study will try to determine if naltrexone's ability to attach to these receptors is related to its effectiveness. We will use PET (positron emission tomography) for this study. PET is a type of imaging device found in nuclear medicine. It is used for tracking the presence of injected radioactive materials in the body.

Detailed description:

Arms:
arm 1: None

Interventions: intervention 1: Naltrexone
Intervention descriptions: intervention 1: Naltrexone 100 mg titrated over one week

Protocol document:
ICF_002.pdf: 
Study Title: Kappa-PET imaging and naltrexone in alcohol drinking behaviors 
ClinicalTrials.gov Identifier: NCT01625611 
Document Date: 1/10/2018 


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COMPOUND AUTHORIZATION AND CONSENT FOR PARTICIPATION IN A 
RESEARCH PROJECT
YALE UNIVERSITY SCHOOL OF MEDICINE – YALE-NEW HAVEN HOSPITAL
Study Title: Kappa-PET imaging and naltrexone in alcohol drinking behaviors 
Principal Investigator: Suchitra Krishnan-Sarin, Ph.D., Associate Professor of Psychiatry
Funding Source: NIAAA
Invitation to Participate and Description of Project
You are invited to take part in a research study designed to help identify important new targets 
for the development of new pharmacotherapies to treat alcohol dependence.  We are recruiting 
individuals who are heavy drinkers, as well as individuals who are social drinkers for age- and 
gender-matched controls. The primary purpose of the study is to increase our knowledge of 
receptor function in the brains of people who are heavy drinkers and taking naltrexone, a 
medication that has been approved for the treatment of alcohol dependence. Receptors are 
special molecules in the brain to which other molecules (neurotransmitters) attach during the 
normal every-day workings of the brain.  Drugs can bind to those receptor molecules as well.  
Recent evidence suggests that kappa opioid receptors (KOR’s) may play an important role in 
alcohol drinking behavior. This study will try to determine if naltrexone’s ability to attach to 
these receptors is related to its effectiveness.  We will use PET (positron emission tomography) 
for this study.  PET is a type of imaging device found in nuclear medicine. It is used for tracking 
the presence of injected radioactive materials in the body. 
You have been chosen to participate because you report not being a heavy alcohol user and are 
not regularly using street drugs, are you may or may not have a family history of alcohol-related 
problems.  Since this is not a treatment study, you should not participate in this project if you are 
seeking treatment for your drinking.  
In order to decide whether or not you wish to be a part of this research study you should know 
enough about its risks and benefits to make an informed decision. This consent form gives you 
detailed information about the research study. A member of the research team will discuss the 
study with you. This discussion will go over all aspects of our research: the goals, the procedures 
that will be performed, the risks, and the possible benefits. Once you understand the study, you 
will be asked if you wish to participate; if so, you will be asked to sign this form.
Description of Procedures
The study contains three parts: 1) Evaluation: We will obtain informed consent and evaluate 
your eligibility for the study using clinical assessments, a physical exam, and a Magnetic 
Resonance Imaging (MRI) scan. If you are eligible, you will be scheduled for the rest of the 
study; 2) Practice PET: You may or may not participate in a mock (practice) PET (Positron 
Emission Tomography) scan; 3) PET Scan 
1) Evaluation
At the Substance Abuse Center (SAC) in Connecticut Mental Health Center (CMHC) (34 Park
Street, New Haven), we will check whether or not you are eligible to participate in the study.
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This will require two to four hours of your time. You will be asked to not use any drugs while 
you are participating in this study.  If you test positive for any drugs or alcohol, you may not be 
paid for your appointment and may be asked to reschedule.  Females will have a pregnancy test 
and will only be allowed to participate if the result is negative. You will be interviewed and 
asked to fill out questionnaires. Following this, at your convenience, we will schedule you for a 
complete physical examination that will include an electrocardiogram, and blood and urine tests, 
which will require about 1½ hours of your time.  You will also get a psychiatric evaluation to 
confirm your eligibility and may be scheduled to meet with the study physician.  
On a different day, you will be asked to go to the MR center at The Anlyan Center for Medical 
Research & Education at Yale University (TAC, 300 Cedar Street, New Haven) to have an MRI 
scan of your brain. The MRI scan is a routine way to get pictures of the inside of the body. MRI 
scans are painless, do not involve the use of radiation, and are used routinely to diagnose 
neurological problems. You will be asked to lie still on your back, on a comfortable mattress, in 
the MRI scanner for about 20 minutes. Your head will be held still in a cushioned head rest, and 
you will wear earplugs to reduce the level of noise. You will not be able to see out of it, but you 
will be able to hear us and be heard if you wish to say anything. You will hear a drumming noise 
when the camera is taking pictures of your brain. Some people feel mildly anxious in the 
scanner.  If it is too difficult for you to be in the scanner, we can end the scan. However, if you 
cannot complete the MRI scan, you will not be able to continue your participation in the study.
If for some reason more than six months elapses between the MRI scan and PET scan, we will 
ask you to come back and complete a second MRI for a current scan of your brain.
2) Practice PET
You may undergo a mock (dry-run) in the PET scanner.  This means that you will just be walked 
through the steps to get familiar with the process. During the mock PET scan, you will lie in a 
real PET scanner or a replica of the PET scanner, be told when the scanner is being “turned on” 
and when blood samples are “being drawn”. 
3)  PET Scan
You will participate in a PET scan.  You will be asked to arrive at the Yale University PET 
Center (801 Howard Ave, New Haven) for your PET scan by no later than 7:00 am.  We will 
check your vital signs and have you complete some questionnaires.  We will measure your breath 
alcohol level by asking you to blow into a meter. If you arrive with a positive breath alcohol 
level, indicating recent alcohol consumption, then the session will have to be rescheduled. A 
urine drug screen will also be done and if you are female, we will conduct a urine pregnancy test.  
If you test positive for either, you will be discharged from the study.   
Before your PET scan, the research nurse or technologist will help get you settled and check 
your vital signs. A trained nurse or CNMT (Certified Nuclear Medicine Technologist) will place 
an IV line in your arm to inject the radiotracer. The radiotracer is injected as a bolus only (over a 
minute) and the scan is 90 minutes long. You will feel little, if any, pain during this process.  
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An experienced physician will insert an arterial catheter in your wrist area. The arterial catheter 
is about 2 inches long and looks like a regular IV tube, but it is inserted into an artery, not a vein. 
The blood flow in the arteries can tell us about your blood pressure. If an arterial catheter is in 
place, we can measure your blood pressure continuously. The other main reason to put in an 
arterial catheter is to be able to draw blood samples rapidly, repeatedly, and without causing you 
pain.  Here is what happens when an arterial line in placed. First, the skin is cleaned with 
betadine solution (contains iodine) so that it is sterile and protected against infection. Second, the 
insertion area is numbed with a local anesthetic, so that you feel less pain when the catheter is 
inserted. You will probably just feel pressure but may also feel pain.  This pain is usually like the 
pain you feel when an IV is placed and only rarely is it worse. Third, the catheter will be flushed 
regularly during your scan with a salt solution, which prevents clogging of the catheter with a 
blood clot. The arterial line will remain in palce for the whole scanning period. After the catheter 
is removed, local pressure is applied for a minimum of 15 minutes to prevent bleeding under the 
skin. A pressure dressing (coban) and a clear dressing (tegaderm) will then be applied and you 
will be asked to keep it clean and dry, refrain from lifting objects weighing more than 5 pounds, 
and to avoid repetitive movements for 48 hours. You may remove the pressure dressing at 
bedtime and the clear dressing after 48 hours, but do not submerge your hand in water for a full 
72 hours. Strenuous activity is prohibited for at least 48 hours after removal of the arterial 
catheter. After this time, mild physical activity can be resumed.Since the catheter is in for a 
minimal period, there is a low risk of infection.
If for some reason, an arterial catheter cannot be inserted,  after no more than three attempts per 
arm are made,  the scan will be rescheduled for another day. You will still be paid $50 for your 
time. At the rescheduled scan, the physician will try to insert an arterial catheter again and the 
scan will be conducted regardless of whether or not the catheter was inserted.
As part of the PET scanning, you will be asked to lie very still on a table. At the beginning of the 
scan, you are positioned in the scanner and will undergo a “transmission scan” to calibrate the 
PET scanner.  The radiotracer will then be injected into the catheter in your wrist. Following the 
injection, the PET scanner camera will detect the radiotracer present in brain areas. This 
information will be used to create pictures of the receptors in your brain. Each PET scan will 
take about two hours. If you ask, we can stop the scan at any time. However, if you can’t 
complete the PET scan, you may not be able to complete this study. You will be asked to drink 
several glasses of water at the close of the PET scanning session to wash out the radiotracer. 
We will monitor your vital signs throughout the study to see how you are feeling, before, during 
and after scanning.  You will also have several electrocardiograms (ECG's). We will also draw 
blood for routine blood tests to measure levels of substances found naturally in your blood, the 
levels of the radiotracer and its metabolites, and to measure the same chemical in your blood that 
we will measure in your brain. 
After the PET scan, you will be provided with a light meal, discharged and allowed to go back 
home. Depending on the start time of the PET scan, you may be at the PET Center until at least 
the early afternoon. You will be provided with a telephone number you can call anytime after the 
study if you need assistance for problems related to the study procedures.
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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.
Risks and Inconveniences
1)   Magnetic resonance (MR): Magnetic resonance is a technique that uses magnetism and radio 
waves, not x-rays, to take pictures and measure chemicals of various parts of the body.  The 
United States Food and Drug Administration (FDA) has set guidelines for magnet strength 
and exposure to radio waves, and we carefully observe those guidelines.  
You will be watched closely throughout the MR study.  Some people may feel uncomfortable 
or anxious.  If this happens to you, you may ask to stop the study at any time and we will 
take you out of the MR scanner.  On rare occasions, some people might feel dizzy, get an 
upset stomach, have a metallic taste or feel tingling sensations or muscle twitches.  These 
sensations usually go away quickly but please tell the research staff if you have them.  
There are some risks with an MR study for certain people.  If you have a pacemaker or some 
metal objects inside your body, you may not be in this study because the strong magnets in 
the MR scanner might harm you.  Another risk is the possibility of metal objects being pulled 
into the magnet and hitting you.  To reduce this risk we require that all people involved with 
the study remove all metal from their clothing and all metal objects from their pockets.  We 
also ask all people involved with the study to walk through a detector designed to detect 
metal objects.  It is important to know that no metal can be brought into the magnet room at 
any time.  Also, once you are in the magnet, the door to the room will be closed so that no 
one from outside accidentally goes near the magnet.
We want you to read and answer very carefully the questions on the MR Safety 
Questionnaire related to your personal safety.  Take a moment now to be sure that you have 
read the MR Safety Questionnaire and be sure to tell us any information you think might be 
important.  This MR study is for research purposes only and is not in any way a clinical 
examination.  
The scans performed in this study are not designed to find abnormalities.  The primary 
investigator, the lab, the MR technologist, and the Magnetic Resonance Research Center are 
not qualified to interpret the MR scans and are not responsible for providing a diagnostic 
evaluation of the images.  If a worrisome finding is seen on your scan, a radiologist or 
another physician will be asked to review the relevant images.  Based on his or her 
recommendation (if any), the primary investigator or consulting physician will contact you, 
inform you of the finding, and recommend that you seek medical advice as a precautionary 
measure.  The decision for additional examination or treatment would lie solely with you and 
your physician.  The investigators, the consulting physician, the Magnetic Resonance 
Research Center, and Yale University are not responsible for any examination or treatment 
that you receive based on these findings.  The images collected in this study are not a clinical 
MR exam and for that reason, they will not be made available for diagnostic purposes.
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If you become uncomfortable for any reason or at any time, you should inform the MRI   
technician or research assistant immediately.
2)  PET Scan
a) Risks Associated with Use of an Arterial Catheter
Putting in the plastic tube into the artery in the wrist area may cause bruising, and potentially 
infection.  The arterial puncture may also cause spasm or clotting of the artery with a 
temporary decrease in blood flow, this may cause tingling or numbness at the injection site 
and/or in the hand/fingers.  In rare instances blocking of the artery, poor healing, infection, 
hematoma (a solid swelling of blood within the tissues), or inflammation at the catheter 
insertion site may occur. Insertion of arterial catheters for giving drugs or sampling blood 
may be associated with mild-to-moderate pain or bruising at the puncture site. To minimize 
these risks, an experienced physician will insert the arterial line and a trained nurse will 
oversee subject care.
For two days following the placement of the arterial line, you should check your wrist/arm 
daily.  The study team will also be in touch with you daily either via phone, or in person, 
during this two-day period. If you experience any excessive pain, tenderness, swelling, 
redness, drainage, skin color changes, numbness, pins and needles, or decreased strength in 
the arm that had the catheter, you should immediately call the study team (203-464-6015).  
You can also contact the study PI Dr. Krishnan-Sarin (860-575-9895), or the PET center 
physician, Dr, David Matuskey (203-370-1403), or the study physician, Dr. Julia Shi (203-
781-4640).
You may experience a rare allergic reaction to the medicine used to numb your skin prior to 
placement of the arterial catheter. If you have had a bad reaction to lidocaine or other 
anesthetic agents used to numb the skin in the past, please tell us about this experience before 
you go through the arterial line placement. Severe allergic reactions can be life threatening.   
Important: If you have a history of a bleeding disorder or are taking medication to thin your 
blood, you will not be allowed to participate in this study.  You will also be asked to abstain 
from using aspirin and other anti-inflammatory drugs (such as Motrin or Aleve) for 7-10 days 
before arterial line placement and 7-10 days after arterial line removal.
b) Risks Associated with Radiation
This research study involves exposure to radiation from positron emission tomography 
(PET). Please note that this radiation exposure is not necessary for your medical care and is 
for research purposes only. The radiation you will receive in this study is from 
[11C]LY2975050 scan(s) and from transmission scans of your head used to help obtain the 
PET images.
The total amount of radiation you will receive during the PET scan session in this study is 
from 1 injection(s) of the tracer, [11C]LY2795050, and from transmission scans of your head.
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Although each organ will receive a different dose, the amount of radiation exposure you will 
receive from this study is equal to a uniform whole-body exposure of .72 rem, which is the 
equivalent of approximately 2 years of natural environmental exposure. This value is known 
as the “effective dose” and is used to relate the dose received by each organ to a single value. 
This amount of radiation exposure is below the annual limit of 5 rem set by the federal 
government for research subjects. 
The effects of radiation exposure on humans have been studied for over 60 years. In fact, 
these studies are the most extensive ever done of any potentially harmful agent that could 
affect humans. In all these studies, no harmful effect to humans has been observed from the 
levels of radiation you will receive by taking part in this research study. However, scientists 
disagree on whether radiation doses at these levels are harmful. Even though no effects have 
been observed, some scientists believe that radiation can be harmful and may cause cancer 
at any dose- even low doses such as those received during this research.
Please tell your study doctor if you have taken part in other research studies at Yale or other 
places/hospitals that used radiation. This way we can make sure that you will not receive too 
much radiation. You should consider x-rays taken in radiology departments, cardiac 
catheterization, and fluoroscopy as well as nuclear medicine scans in which radioactive 
materials were injected into your body. Before you take part in any future studies that use 
radiation, you should also tell those study doctors about your participation in this study.
If you are pregnant or breast feeding, you may not participate in this research study. We will 
perform urine pregnancy tests prior to your participation on your PET and MRI scan days. 
3)  Risks Associated with Blood Drawing and Urine Collection
Urine samples will be used for drug and pregnancy tests and there is no risk. Drug tests will 
be done at the initial appointment, the PE, and the PET session.
Drawing blood and inserting an intravenous line (IV) into an arm vein are safe and standard 
medical procedures.  Sometimes a bruise will occur at the puncture site and rarely a blood 
clot or infection will occur in the vein.  You should not donate blood for at least 6 weeks 
after the study. Some people feel lightheaded but this effect is temporary.  The total volume 
of blood collected during this study will be about 8 tablespoons (1 tablespoon at the physical 
exam for safety labs and 7 tablespoons at the PET scan).  This amount of blood loss is safe 
for healthy persons.
4)  Risks Associated with Pregnancy and Breastfeeding 
You may not participate in this study if you are currently pregnant, might become pregnant 
during the study, or you are breastfeeding an infant. Acceptable levels of radioactivity are 
lower for pregnant individuals. It is best to avoid radiation exposure to unborn or nursing 
children since they are more sensitive to radiation than adults. You will be tested for 
pregnancy as part of the routine lab tests.  If the test is positive, you will not be included in 
the study.  Before starting the study, we will ask you to avoid becoming pregnant and ask 
you what precautions you plan to take.  If you change your mind about becoming pregnant or 
how you will avoid becoming pregnant, we ask that you to tell us immediately.  You will be 
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given one pregnancy blood test during the initial physical evaluation, and you will also be 
given a urine pregnancy test on the day of the MRI and on the day of the PET scan.
Benefits
There are no direct benefits to you for your participation.  We expect that the results of the study, 
however, will benefit science and others through increasing our knowledge about the use of 
naltrexone as a treatment for alcohol drinking and its efficacy through the use of PET. 
Compensation
You will be paid: 
$50 for the initial interview 
$50 for the physical examination 
$250 for the PET scan 
$50 for each arterial catheter insertion 
$50 for the MRI scan 
Subjects may also earn:
$50 to show up for additional PET scan
$50 for an additional MRI scan
Compensation could total $575 for attending and participating in all appointments.
Appointment
Cash
Check
Intake
$50
Physical Exam  
$50
MRI Scan
$50
PET scan
$250
Arterial Catheter insertion
$50
Repeat Arterial Catheter insertion
$50*
Extra Lab Appointment 
$25**
Standby for PET scan
$50***
*In the case that the first arterial line cannot be placed at the PET scan, you will be paid $50 and 
rescheduled to try again.
**If you are asked to come back in for a repeat lab appointment (bloodwork or EKG), we will 
compensate you $25 in cash for your time.
***You may be asked to come to our office as a standby participant in case the primary 
scheduled participant has a conflict for the PET scan. If the scheduled participant arrives, you 
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will be paid $50 for your time and be asked to come back at a later date to complete your 
scheduled appointment. However, if the scheduled participant does not arrive, you will still be 
paid $50 and will be invited to complete the appointment of the original participant. 
You will receive up to a total of $350.00 in the form of a check after completing the study. This 
check can take 4-6 weeks to process. All other payments will be given in cash.
Subject Obligation
The only way you might be dismissed from the study is if you repeatedly do not show up or lie 
about your alcohol and drug use. We will be monitoring your urine periodically for alcohol and  
other drugs and will also check your breath alcohol level.  If your drug test is positive, the 
session will have to be rescheduled if possible.  
Confidentiality and Privacy
There are two separate statutes which provide the means to protect your confidential information 
related to your health information.  One statute of protection is called HIPAA and the second is 
called a Certificate of Confidentiality (CoC).  
 
A Personal Health Information (PHI) record is routinely created whenever you see a physician or 
go to the hospital or you are seen in an outpatient clinic.  Personal health information is also 
called a medical record.  Your medical record is considered confidential under the privacy 
statutes referred to as HIPAA.  However, there are certain circumstances when medical records 
can be demanded without your written permission.  In some cases, medical records can be 
requested, for example, by an insurance company, the government, or an attorney representing 
another person.  HIPAA allows the court to order such information to be provided to them for 
good reasons.  
When you participate in a research study, your identity as a research participant—and all the 
identifiers that could lead to your identity will be held confidentially.  The investigator cannot be 
forced to release your identifiers to anyone outside of the research team if a Certificate of 
Confidentiality is issued.  Thus, to protect your sensitive information, we have obtained a 
Certificate of Confidentiality (CoC) from the National Institute on Alcohol Abuse and 
Alcoholism (NIAAA) which is part of the National Institutes of Health (NIH). 
The CoC protects the identity of individuals in a study and protects the investigators from being 
forced to tell people that are not connected with this study about your participation in this study, 
even under a subpoena. This protection, however, is not absolute.  The protection offered by the 
CoC does not stop us from voluntarily reporting information about suspected or known sexual, 
physical, or other abuse of a child or older person, or a subject's threats of violence to self or 
others. If any member of the research team is given such information, he or she will make a 
report to the appropriate authorities. Individuals who participate as research subjects (i.e., about 
whom the investigator maintains identifying information) in the specified research project during 
any time the Certificate is in effect are protected permanentlyAlso, because this research is 
sponsored by NIAAA, staff from NIAAA and other DHHS agencies may review records that 
identify you but only for the purposes of audit for quality and accuracy or program evaluation. 
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Even when a CoC is in place, you must still continue to actively protect your own privacy. If you 
voluntarily give your written consent to anyone to receive information about your participation 
in the research or freely volunteer information to anyone other than the study staff that you are a 
research participant in this study, then we may not use the CoC to withhold this information.
Further details about the limitations and protections of your medical records and the information 
you provide as a research participant are provided below.
 
Use and Protection of Collected Medical Record information
Health information about you will be collected if you choose to be part of this research study. 
Health information is protected by law as explained in the Yale University Privacy Notice. If you 
have not received this notice, please request a copy from the investigator. At Yale University, your 
medical record information will only be used or shared as explained and authorized in this consent 
form or when required by law. 
We ask anyone who gets your health information from us to protect your privacy.  However, 
there may be some cases beyond our control where we cannot protect your privacy but we expect 
that those instances will be rare and accidental disclosures.
To participate in this research you must allow the study team to use your health information. If you 
do not want us to use your medical record information, you may not participate in this study. 
Documents that contain your name, such as this consent form signed by you, will be securely 
stored separately from your research data.  All research data will be coded in a way that does not 
identify you by name or initials and will be kept in a secure place that allows only selected study 
personnel to have access to this information. The research data collected will be kept separate 
and distinct from the medical record. 
You should understand that there is a risk that you will be recognized by other patients or staff 
involved in the laboratory or hospital ward and it could be known that you are participating in 
this study. If you find this to be an unacceptable condition you should not sign this consent form.
You have the right to review and copy your health information in your medical record in 
accordance with institutional medical records policies.
Withdrawing Your Authorization to Use and Disclose Your Health Information
 
The use and disclosure of your information has no time limit.  Any research information in your 
research record will be kept indefinitely. If you wish to revoke permission for the use and sharing 
of your health information, you may do so by notifying the study doctor, Dr. Krishnan-Sarin, but 
in doing so; you will no longer be able to participate in this research study.
If you withdraw your permission: 

No new health information identifying you will be gathered after that date.
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
We will no longer use or share medical information about you for this research study, 
except when the law allows us to do so.  

We are unable to take back anything we have already done or any information we have 
already shared with your permission. 

We may continue using and sharing the information obtained prior to your withdrawal if 
it is necessary for the soundness of the overall research. 

We will keep our records of the care that we provided to you as long as the law requires.
MEDICAL RECORD INFORMATION COLLECTED DURING THIS STUDY
The investigator and staff involved with the study will keep your medical record information 
collected for the study strictly confidential. Medical record information covered by HIPAA, 
including your name, initials, and other identifying information will not be released or published 
without your permission unless required by law.  The following medical record information will 
be collected and used for research:  
-
Name
-
Address
-
Telephone number
-
Information from a brief psychiatric examination
-
Emergency contact information
-
Initial telephone screening information
-
Allergies
-
Current and past medications and therapies
-
Information from a physical examination that generally also includes blood pressure
      reading, heart rate, breathing rate and temperature
-
Electrocardiogram
-
Breath Alcohol Tests 
-
Urine Drug Screens
-
Urine Pregnancy Tests if you are female
-
Clinical laboratory Tests
-
Healthcare, Social Functioning, and Addiction Questionnaires/Forms
Information about you and your health which might identify you may be used by or given to: 
• The U.S. Department of Health and Human Services (DHHS) agencies 
• Representatives from Yale University and the Human Investigation Committee, who are 
responsible for insuring research compliance. These individuals are required to keep all 
information confidential. 
Those providers who are participants in the Electronic Medical Record (EMR) system. 
Members of the research team who are participants in the EMR system, including the study 
physicians and study psychologist, will have access to your medical information in the EMR to 
ensure eligibility and safety for research participation.
• Those individuals at Yale who are responsible for the financial oversight of research including 
billings and payments 
• The Principal Investigator and selected members of the research team 
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• Collaborating research groups and research centers where research personnel from this study 
are also involved. 
• Data and Safety Monitoring Boards and others authorized to monitor the conduct of the study 
By signing this form, you authorize the use and/or disclosure of the information described above 
for this research study. The purpose for the uses and disclosures you are authorizing is to ensure 
that the information relating to this research is available to all parties who may need it for 
research purposes. 
All health care providers subject to HIPAA (Health Insurance Portability and Accountability 
Act) are required to protect the privacy of your information. The research staff at the Yale 
School of Medicine and Yale New Haven Hospital is required to comply with HIPAA and to 
ensure the confidentiality of your information. Some of the individuals or agencies listed above 
may not be subject to HIPAA and therefore may not be required to provide the same type of 
confidentiality protection. They could use or disclose your information in ways not mentioned in 
this form. However to better protect your health information agreements are in place with these 
individuals and/or companies that require that they keep your information confidential. 
In Case of Injury
If you develop any mental or physical problems as a direct result of being in this study, we will 
refer you for treatment. You or your insurance carrier will be expected to pay the costs of this 
treatment. No additional financial compensation for injury or lost wages is available. Your legal 
rights are not waived by signing this consent form.
Voluntary Participation and Withdrawal
Participating in this study is voluntary. You are free to choose not to take part in this study.   
Refusing to participate will involve no penalty or loss of benefits to which you are otherwise 
entitled. It will not harm your relationship with your own doctors or with the researchers, 
YNHH, the PET Center, or the Connecticut Mental Health Center.
However, you will not be able to enroll in this research study and will not receive study 
procedures as a study participant if you do not allow use of your information as part of this 
study.
Withdrawing From the Study
If you do become a subject, you are free to stop and withdraw from this study at any time during 
its course. To withdraw from the study, you can call a member of the research team at any time 
and tell them that you no longer want to take part. You will also be paid for your participation up 
until the moment you withdraw from the study.
When you withdraw from the study, no new health information identifying you will be gathered 
after that date.  Information that has already been gathered may still be used and given to others 
until the end of the research study, as necessary to insure the integrity of the study and/or study 
oversight.  
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Withdrawing from the study will involve no penalty or loss of benefits to which you are 
otherwise entitled.  It will not harm your relationship with your own doctors or with the 
researchers, YNHH, the PET Center, or the Connecticut Mental Health Center.
Withdrawing Your Authorization to Use and Disclose Your Health Information
You may withdraw or take away your permission to use and disclose your health information at 
any time. You may withdraw your permission by telling the study staff or by writing to Dr. 
Suchitra Krishnan-Sarin at Yale University, CMHC, 34 Park Street, New Haven, CT 06519.
 If you withdraw your permission, you will not be able to stay in this study.
When you withdraw your permission, no new health information identifying you will be 
gathered after that date.  Information that has already been gathered may still be used and given 
to others until the end of the research study, as necessary to insure the integrity of the study 
and/or study oversight.  
Questions
We have used some technical terms in this form.  Please feel free to ask about anything you don't 
understand and to consider this research and the consent form carefully – as long as you feel is 
necessary – before you make a decision.
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Authorization and Permission
I have read (or someone has read to me) this form and have decided to participate in the project 
described above.  Its general purposes, the particulars of involvement and possible hazards and 
inconveniences have been explained to my satisfaction.  My signature also indicates that I have 
received a copy of this consent form.
By signing this form, I give permission to the researchers to use [and give out] information about 
me for the purposes described in this form.  By refusing to give permission, I understand that I 
will not be able to be in this research. 
Name of Subject:_____________________________
            
Signature:___________________________________
Date:______________________________________
___________________________________________
___________________
Signature of Principal Investigator
Date
                                      or
___________________________________________
___________________
Signature of Person Obtaining Consent
Date
If you have further questions about this project or if you have a research-related problem/injury, 
you may contact the Principal Investigator, Suchitra Krishnan-Sarin, PhD at (203)974-7595 or 
the study physician, Julia Shi, M.D, at (203)781-4640.  If you would like to talk with someone 
other than the researchers to discuss problems, concerns, and questions you may have 
concerning this research, or to discuss your rights as a research subject, you may contact the 
Yale Human Investigation Committee at (203) 785-4688. If after you have signed this form you 
have any questions about your privacy rights, please contact the Yale Privacy Officer at 
203/436-3650.
APPROVED BY THE YALE UNIVERSITY IRB 1/10/2018 VALID THROUGH 1/9/2019

Prot_SAP_000.pdf: 
Study Title: Kappa-PET imaging and naltrexone in alcohol drinking behaviors 
ClinicalTrials.gov Identifier: NCT01625611 
Document Date: 5/6/2019 


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Page 1 of 48
YALE UNIVERSITY
HUMAN INVESTIGATION COMMITTEE
Application to Involve Human Subjects in Biomedical Research
100 FR1
HIC OFFICE USE ONLY
Please refer to the HIC website for application 
instructions and information required to 
complete this application.  The Instructions are 
available at  http://www.yale.edu/hrpp/forms- 
templates/index.html.
Submit the original application and two (2) 
copies of all materials including relevant 
sections of the grant which funds this project 
(if applicable) to the HIC.
DATE STAMPED-RECEIVED
PROTOCOL NUMBER
1011007710
SECTION I: ADMINISTRATIVE INFORMATION
Title of Research Project:
Kappa-PET imaging and naltrexone in alcohol drinking behaviors
Principal Investigator:
Suchitra Krishnan-Sarin, Ph.D.
Yale Academic Appointment:
Associate Professor
Campus Address:
34 Park Street, S-208, New Haven, CT 06519
Campus Phone: 203-974-
7595
Fax: 203-974-7606
Pager:
E-mail: suchitra.krishnan-
sarin@yale.edu
Protocol Correspondent Name & Address (if different than PI):
Dana Cavallo, 34 Park Street, New Haven CT  06519
Campus Phone: 203-974-
7607
Fax: 203-974-
7606
E-mail: dana.cavallo@yale.edu
Faculty Advisor:(required if PI is a student,
resident, fellow or other trainee)
NA
Yale Academic Appointment:
Campus Address:
Campus Phone:
Fax:
Pager:
E-mail:
Does the principal investigator, co-investigator, or any research team member obtaining consent, or any of 
their family members (spouse, child, domestic partner) have an incentive or interest, financial or otherwise, 
that may be viewed as affecting the protection of the human subjects involved in this project, the scientific 
objectivity of the research or its integrity? See Disclosures and Management of Personal Interests in Human 
Research  http://www.yale.edu/hrpp/policies/index.html#COI
Yes
X  No
If yes, list names of the investigator or person obtaining consent:
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Page 2 of 48
SECTION II: GENERAL INFORMATION
1.   Performing Organizations:  Identify the hospital, in-patient or outpatient facility, school or 
other agency that will serve as the location of the research.  Choose all that apply:
a. Internal Location[s] of the Study:
Magnetic Resonance Research Center                    PET Center
(MR-TAC)
YCCI/Church Street Research Unit (CSRU) 
Yale Cancer Center
YCCI/Hospital Research Unit (HRU)
Yale-New Haven Hospital                                      YCCI/Keck Laboratories
Specify Other Yale Location:                                 Cancer Data Repository/Tumor Registry
b. External Location[s]:
APT Foundation, Inc.                                              Haskins Laboratories
Connecticut Mental Health Center
John B. Pierce Laboratory, Inc. 
Veterans Affairs Hospital, West Haven
Other Locations, Specify: CMU
c. Additional Required Documents (check all that apply):
N/A
*YCCI-Scientific and Safety Committee (YCCI-SSC)             Approval Date:
*Pediatric Protocol Review Committee (PPRC)                        Approval Date:
*YCC Protocol Review Committee (YRC-PRC)                      Approval Date:
*Dept. of Veterans Affairs, West Haven VA HSS                     Approval Date:
*Radioactive Drug Research Committee (RDRC)                     Approval Date: 
YNHH-Radiation Safety Committee (YNHH-RSC)                Approval Date: 
Magnetic Resonance Research Center PRC (MRRC-PRC)     Approval Date: 
YSM/YNHH Cancer Data Repository (CaDR)                         Approval Date: 
Dept. of Lab Medicine request for services or specimens form
*Approval from these committees is required before final HIC approval is granted. See instructions 
for documents required for initial submission and approval of the protocol. Allow sufficient time for 
these requests. Check with the oversight body for their time requirements.
2.   Probable Duration of Project: State the expected duration of the project, including all follow-up 
and data analysis activities 5 years
3.   Targeted Enrollment: What is the number of subjects 56 non-treatment-seeking heavy drinkers, 
family history positive and negative and 10 healthy controls
a.targeted for enrollment at Yale for this protocol?  66 participants
If this is a multi-site study, what is the total number of subjects targeted across all sites? 
N/A
b. expected to sign the consent form? 
136
c. expected to complete some or all interventions for this protocol? 66
4.   Research Type/Phase: (Check all that apply)
a. Study Type
Single Center Study
Multi-Center Study
Does the Yale PI serve as the PI of the multi-site study? Yes
No
Coordinating Center/Data Management Other:
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Page 3 of 48
b. Study Phase
N/A
   Pilot
 Phase I
Phase II
Phase III
Phase IV 
Other (Specify)
c. Area of Research: (Check all that apply) Note that these are overlapping definitions and more 
than one category may apply to your research protocol. Definitions for the following can be 
found in the instructions section 4c:
Clinical Research: Patient-Oriented
Clinical Research: Outcomes and 
Clinical Research: Epidemiologic and Behavioral
Health Services 
Translational Research #1 (“Bench-to-Bedside”)
 Interdisciplinary Research
Translational Research #2 (“Bedside-to-Community”)
Community-Based Research
5.   Is this study required to be registered in a public database? Yes
No
If yes, where is it registered?
Clinical Trials.gov registry
Other (Specify)
6. Will this research study utilize clinical care services at Yale New Haven Hospital or YMG?
Yes
No
If yes, might these be billable to the subject, the sponsor, grant or other third party payer? 
Yes
No
If you answered "yes", please register this study in the IDX/GE system at
http://ycci.yale.edu/comply/billing_idxge.html
7. Are there any procedures involved in this protocol that will be performed at YNHH or one of its
affiliated entities?  Yes X No
If Yes, please answer questions a through c and note
instructions below.  If No, proceed to Section III.
a. Does your YNHH privilege delineation currently include the specific procedure that you will 
perform? Yes, use of the IDS pharmacy
b. Will you be using any new equipment or equipment that you have not used in the past for 
this procedure? No
c. Will a novel approach using existing equipment be applied? No
If you answered “no” to question 7a, or "yes" to question 7b or c, please contact the YNHH 
Department of Physician Services (688-2615) for prior approval before commencing with your 
research protocol.
SECTION III: FUNDING, RESEARCH TEAM AND TRAINING
1.   Funding Source: Indicate all of the funding source(s) for this study. Check all boxes that apply.
Provide information regarding the external funding source.  This information should include 
identification of the agency/sponsor, the funding mechanism (grant or contract), and whether 
the award is pending or has been awarded. Provide the M/C# and Agency name (if grant- 
funded). If the funding source associated with a protocol is “pending” at the time of the 
protocol submission to the HIC (as is the case for most NIH submissions), the PI should note 
“Pending” in the appropriate section of the protocol application, provide the M/C# and 
Agency name (if grant-funded) and further note that University (departmental) funds support 
the research (until such time that an award is made).
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Page 4 of 48
PI
Title of Grant
Name of Funding Source
Funding
Funding Mechanism
Suchitra 
Krishnan-Sarin, 
PhD
Kappa-PET 
imaging and 
naltrexone in 
alcohol drinking 
behaviors
NIAAA
 Federal
State
Non Profit 
Industry 
Other For
Profit
 Other
 Grant-
M#1R01AA01998001
Contract# Contract 
Pending 
Investigator/Department
Initiated
Sponsor Initiated
Other Specify:
IRB Review fees are charged for projects funded by Industry or Other For-Profit Sponsors. 
Provide the Name and Address of the Sponsor Representative to whom the invoice should be 
sent.  Note: the PI’s home department will be billed if this information is not provided. 
Send IRB Review Fee Invoice To:
Name:
Company: 
Address:
2
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Approved by the Yale University HIC on March 12, 2012
Department Chair’s Assurance Statement
Do you know of any real or apparent institutional conflict of interest (e.g., Yale ownership of a
NOTE: The HIC will remove from the protocol any personnel who have not completed required training. 
A personnel protocol amendment will need to be submitted when training is completed.
SECTION IV:
PRINCIPAL INVESTIGATOR/FACULTY ADVISOR/ DEPARTMENT CHAIR
AGREEMENT
As the principal investigator of this research project, I certify that:

The information provided in this application is complete and accurate.

I assume full responsibility for the protection of human subjects and the proper conduct of the 
research.

Subject safety will be of paramount concern, and every effort will be made to protect subjects‟
rights and welfare.

The research will be performed according to ethical principles and in compliance with all federal, 
state and local laws, as well as institutional regulations and policies regarding the protection of 
human subjects.

All members of the research team will be kept apprised of research goals.

I will obtain approval for this research study and any subsequent revisions prior to my initiating the 
study or any change and I will obtain continuing approval of this study prior to the expiration date 
of any approval period.

I will report to the HIC any serious injuries and/or other unanticipated problems involving risk to 
participants.

I am in compliance with the requirements set by the University and qualify to serve as the 
principal investigator of this project or have acquired the appropriate approval from the 
Dean‟s Office or Office of the Provost, or the Human Subject Protection Administrator at 
Yale-New Haven Hospital, or have a faculty advisor.

I will identify a qualified successor should I cease my role as principal investigator and facilitate a 
smooth transfer of investigator responsibilities.
PI Name (PRINT) and Signature
Date
As the faculty advisor of this research project, I certify that:

The information provided in this application is complete and accurate.

This project has scientific value and merit and that the student or trainee investigator has the 
necessary resources to complete the project and achieve the aims.

I will train the student investigator in matters of appropriate research compliance, protection of 
human subjects and proper conduct of research.

The research will be performed according to ethical principles and in compliance with all federal, 
state and local laws, as well as institutional regulations and policies regarding the protection of 
human subjects.

The student investigator will obtain approval for this research study and any subsequent revisions 
Prior to initiating the study or revision and will obtain continuing approval prior to the expiration 
of any approval period.

The student investigator will report to the HIC any serious injuries and/or other unanticipated 
problems involving risk to participants.

I am in compliance with the requirements set forth by the University and qualify to serve as 
the faculty advisor of this project.
Advisor Name (PRINT) and Signature
Date
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Page 7 of 48
sponsoring company, patents, licensure) associated with this research project?
Yes (provide a description of that interest in a separate letter addressed to the HIC.) 
No
As Chair, do you have any real or apparent protocol-specific conflict of interest between yourself and 
the sponsor of the research project, or its competitor or any interest in any intervention and/or method 
tested in the project that might compromise this research project?
Yes, and I agree to submit the Protocol-Specific Conflict of Interest Disclosure Form. 
No
I assure the HIC that the principal investigator and all members of the research team are qualified by 
education, training, licensure and/or experience to assume participation in the conduct of this research 
trial. I also assure that the principal investigator has departmental support and sufficient resources to 
conduct this trial appropriately.
Chair Name (PRINT) and Signature
Date
Department
YNHH Human Subjects Protection Administrator Assurance Statement
Required when the study is conducted solely at YNHH by YNHH health care providers.
As Human Subject Protection Administrator (HSPA) for YNHH, I certify that:

I have read a copy of the protocol and approve it being conducted at YNHH.

I agree to submit a Protocol-Specific Conflict of Interest Disclosure Form if I am aware of any real 
or apparent institutional conflict of interest.

The principal investigator of this study is qualified to serve as P.I. and had the support of the hospital 
for this research project.
YNHH HSPA  Name (PRINT) and Signature
Date
For HIC Use Only
Date Approved
Human Investigation Committee Signature
SECTION V: RESEARCH PLAN
1.   Statement of Purpose: State the scientific aim(s) of the study, or the hypotheses to be tested.
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Page 8 of 48
Naltrexone (NTX), a non-specific opioid antagonist that binds dose-dependently to mu, delta, 
and kappa opioid receptors, has been shown to be efficacious in the treatment of alcohol 
dependence [1].  Understanding how NTX reduces drinking is needed to help optimize NTX 
treatment and identify important new targets for the development of new pharmacotherapeutic 
agents  to  treat  alcohol  dependence.  Recent  evidence  suggests  that  kappa  opioid  receptors
(KOR‟s) may play an important, but complex, role in mediating alcohol drinking behavior.  This
proposal brings together a translational team of scientists to examine the in vivo biochemistry of
NTX in heavy drinkers (HD), before and during treatment with NTX, via high resolution PET
imaging of the KOR and relate this to clinical outcomes of NTX efficacy.
Using a laboratory-based human Alcohol Drinking Paradigm (ADP; [2]) that we pioneered, we 
have shown that family history (FH) of alcoholism may moderate (encode the direction of) 
response to NTX [3]. Specifically, pretreatment with a 100 mg/day dose of NTX was associated 
with lower drinking in the ADP in heavy drinkers with a positive FH (FHP), whereas the same 
dose correlated with higher drinking for those with a negative FH (FHN).  What could be the 
underlying biochemistry?  Existing evidence suggests that, at a dose of 50 mg/day, mu-opioid 
receptors are saturated, and therefore unlikely to determine variability in NTX responsivity [4], 
pointing to possible roles for delta and kappa opioid receptors.  At 100 mg/day, NTX should 
antagonize KOR, raising the possibility that the differences we observed in the two cohorts of 
drinkers may be related to differences in KOR.  KOR levels in clinical populations can be 
examined using PET imaging, however, until recently, such an examination was heretofore 
prohibited by the lack of an appropriate tracer.   [11C]LY2795050 (referred to as [11C]-PKAB at 
Yale PET Center) is a selective, high affinity, KOR antagonist tracer with favorable kinetics for 
imaging KOR and drug occupancy in humans [5].  The new tracer has excellent test/retest 
reproducibility and is well-suited to quantitating KOR levels in striatal and extra-striatal regions.
This proposal unites neuroimagers, experts in conducting and analyzing human PET studies with 
behavioral scientists, experts in developing and testing treatments for alcoholism. We will 
conduct the first-ever in vivo PET imaging study of KOR and NTX occupancy in two cohorts of 
HD (18 FHP and 18 FHN) and relate our imaging findings to FH and alterations of drinking 
behavior by NTX in the ADP.  Through this work, we will advance our understanding of (a) the 
degree of involvement of the kappa system in reducing drinking in humans by NTX, (b) the 
contribution of FH to this relationship, and (c) refine the use of a new PET imaging tracer. In so 
doing, we will inform the development of future targeted pharmacotherapies for alcoholism and 
lay the groundwork for other important investigations into the KOR/dynorphin system in vivo.
Primary (P), Secondary (S), and Auxiliary (A) Specific Aims:
P1. Occupancy of KOR by NTX and drinking:  To determine the degree to which occupancy of 
KORs by a 100 mg/day dose of NTX mediates (influences the strength of) responsivity to 
NTX treatment in all heavy drinkers. It is expected that KOR occupancy will significantly 
mediate the relationship between NTX treatment and responsivity. „Responsivity‟,  measured 
via ADP, is the change in number of drinks consumed at the baseline ADP vs. NTX ADP.
P2. Family  History  of  Alcoholism  as  a  moderator:  To  determine  whether  the  relationship 
between NTX responsivity and occupancy of KOR is different in FHP vs. FHN heavy 
drinkers.
P3. To determine if baseline KOR availability differs between heavy drinkers and healthy control 
socialdrinkers
S1. Baseline KOR differences
a.   To determine if baseline levels of KOR differ between FHP and FHN heavy drinkers.
b.   To determine if baseline KOR level is related to either baseline drinking or 
responsivity to NTX.
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S2. Identify and validate a reference region (area devoid of specific binding) for our new KOR
tracer. A reference region would simplify PET analysis.
S3. Optimize the scan duration for clinical populations being imaged with the new 
KOR tracer.
Shorter scans would increase compliance and decrease discomfort to subjects. 
A1.Relationship to other behavioral measures:  To determine if occupancy of KORs 
is related to measures of alcohol craving, stimulation or sedation, assessed in the ADP.
We hypothesize that (1) degree of NTX occupancy of KOR during treatment will be 
correlated with the degree of responsivity to NTX in all heavy drinkers and (2) FHP 
heavy drinkers, who respond positively to NTX, will have lower baseline KOR levels 
when compared with FHN heavy drinkers.
2.   Background: Describe the background information that led to the plan for this 
project. Provide references to support the expectation of obtaining useful scientific 
data.
Alcohol abuse is one of the leading causes of disability in the United States. At present, three 
medications are approved by the FDA for the treatment of alcohol dependence: disulfiram, 
naltrexone, and acamprosate. However, the efficacy of these agents ranges from minimal to 
modest, and they are under-utilized in clinical community settings [6, 7]. There is a pressing 
need for novel medications that are more effective in reducing alcohol use.
Development of new pharmacotherapeutic approaches to treating alcohol dependence should be 
based on our understanding of the behavioral and neurochemical mechanisms mediating alcohol 
drinking, as well the efficacy of agents known to reduce alcohol drinking.  Naltrexone (NTX) is
a non-specific opioid antagonist that has been shown to have minimal-modest efficacy in treating 
alcohol dependence.  Clinical trials indicate that treatment-seeking heavy drinkers who receive 
NTX at a dose of 50 mg/day [1, 8] or 100 mg/day [9], have lower levels of relapse to drinking 
during the treatment period than do those receiving placebo.  Subpopulations of alcohol dependent 
patients may respond better to NTX [10] and family history (FH) of alcoholism is emerging as an 
important predictor of NTX response [3, 11].
Our earlier work, using a laboratory-based alcohol drinking paradigm (ADP) revealed that NTX 
responsivity was altered by the presence  or absence of a FH of alcoholism; specifically NTX 
treatment was associated with lower drinking in those with a positive FH (FHP) and actually 
with higher drinking in those with a negative FH (FHN) [3]. Developing a better pharmacological 
understanding of this differential response could help enhance the efficacy of NTX treatment.  
Naltrexone‟s ability to reduce alcohol drinking is believed to be mediated, in part, through its 
effects on the endogenous opioid system, specifically through dose dependent antagonism of 
mu, delta and kappa opioid receptors. Weerts and colleagues [4] have shown that the most 
commonly used dose of naltrexone, 50 mg/day, results in almost complete occupancy (saturation) 
of mu-opioid sites in the brain with variable, partial occupancy of delta opioid receptor sites.  
This evidence suggests that the differential efficacy of NTX is unlikely to be mediated by mu-
opioid binding but could be related to variability in binding to other (delta or kappa) opioid 
receptor sites.  While some investigations have focused on the delta system [4], to date, no one 
has examined the relationship of kappa opioid receptors (KOR) to alcohol drinking or NTX 
responsivity in human alcoholics.
Emerging evidence suggests an important, but complex, role for the KOR system in alcohol 
drinking.  Dynorphin is the endogenous opioid ligand that binds to both mu and KORs [12].  In 
general, activation of KORs is aversive. Animals will not self-administer dynorphin, 
administration of dynorphin results in conditioned place aversion in animals, and dynorphin 
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Page 10 of 48
activation of KOR results in decreased dopamine release in brain reward areas [13, 14].  The 
potential role of KORs in mediating alcohol drinking behavior has been the focus of several 
studies in animals and humans.  Mice that lack the KOR  drink more alcohol and have greater 
release of dopamine in response to alcohol [15].   Rodents with an increased propensity 
toconsume alcohol have lower dynorphin levels in several brain regions that are involved in the
control of alcohol drinking [16-18]. In humans, the presence of the OPRK1 allele (which 
decreases expression of KOR) is associated with increased risk of alcoholism [19].  The above 
evidence suggests that differences in the status of the KOR system may mediate differences in 
propensity to drink alcohol.  The current proposal will be the first to compare KOR occupancy in 
FHP and FHN drinkers and correlate KOR levels with drinking in the ADP.
The effect of stimulating or inhibiting the KOR opioid system on alcohol drinking appears to 
depend, in part, on the prior history of alcohol exposure.  In alcohol naïve animals, stimulation of 
KOR by agonists decreases alcohol drinking [20], while inhibition of KOR by antagonists 
increases alcohol drinking [21].  Chronic alcohol exposure dysregulates the dynorphin/KOR 
system; specifically, dynorphin levels are enhanced and number of KOR are reduced [22, 23]. 
The aversive effect of dynorphin/KOR activation is decreased in individuals whose 
dynorphin/KOR system has been chronically stimulated, such as those with chronic pain or those 
with a long history of polysubstance abuse, which may reflect a reduced number or binding of
KOR‟s [24,  25].    In  contrast  to  the  above  evidence,  in  alcohol  dependent  animals,  KOR 
antagonists reduce alcohol drinking [26], suggesting that chronic alcohol drinking also alters the 
KOR system.   The above evidence suggests that differences in the KOR system may mediate 
differential responsivity to NTX.
The proposed project would be the first to assess the potential contribution of the KOR system to 
individual differences in naltrexone-mediated changes in alcohol drinking using an established 
ADP in alcohol dependent, heavy drinkers (HD).   Additionally, the current proposal will be the 
first to examine KOR levels and NTX responsivity in FHP and FHN heavy drinkers; this will 
help us understand if the differential responsivity to NTX observed in FHP and FHN drinkers is 
related to KOR occupancy by NTX.
Our project will investigate a provocative finding in alcohol treatment research [3].  Namely, that 
FH of alcoholism may influence (or be a marker of an underlying trait that influences) the 
response of heavy drinkers (HD) to NTX. Simply put, not every HD responds favorably to NTX 
but lower levels of drinking can be achieved and risk of relapse is diminished in some.   It is 
essential for clinical treatment and future drug development to understand how NTX works. 
Preclinical results have implicated kappa in changes in alcohol drinking, but the directionality of 
these changes are complex. We propose that the differential efficacy of naltrexone may be relate 
to differences in occupancy of kappa opioid receptors by naltrexone.  This translational project 
will test this hypothesis.    The results of this project could not only help maximize treatment 
effectiveness of naltrexone but also result in identification of new medication treatment targets 
for more optimal reduction of alcohol drinking.
3.   Research Plan: Provide an orderly scientific description of the study design and research 
procedures as they directly affect the subjects.
A total of 56 HD subjects will be tested; equal numbers of FHP and FHN subjects will be 
recruited. Data from the first year’s subjects (“initial cohort” perhaps specify how many will be used for 
this purpose) will be analyzed prior to scanning the remaining subjects in order to address aims 
S2 and S3 (identification and validation of a reference region; reduction in scan duration) which 
are addressed below in PET methods.
Study design: Because we are interested in investigating the implications of baseline KOR, as 
well as Occupancy of KOR by NTX, we must perform 2 PET scans on each subject; one at 
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baseline and one following 5-11 days of NTX pretreatment. Similarly, because we are interested 
in relating responsivity to occupancy of KOR by NTX we must make two assessments of drinking 
behavior using the ADP; one at baseline the day before or after the first PET scan and one 
following 5-11 days of treatment with NTX.  The post PET scan and post ADP will ideally take 
place on Day 6 or Day 7 of medication, but we will allow up to 11 days of medication for 
scheduling issues and the possibility that the appointments will be within this time frame. All 
eligible participants may or may not complete one mock PET scan and all will receive an 
orientation of the ADP at the Hospital Research Unit (HRU) of Yale New Haven Hospital 
(YNHH). All participants will complete an MRI scan prior to the  first baseline PET scan.  After 
completing the baseline ADP and PET scan, subjects will start NTX. The dose will be given po 
every morning at 10am and tapered up daily.  Participants will take 25 mg on the first day, 50 
mg on the second day, and then 100 mg on each subsequent day. During this 5-11 day outpatient 
treatment period, participants will not be told to alter their drinking behavior.  On the 5th-11th 
day of medication, after they have been stabilized on a 100 mg/day dose, they will complete the 
second ADP and PET scan; this scan will be conducted at peak NTX levels (2-4 hours after oral 
dosing). 
In designing the study, we had to balance various competing interests and we provide 
justifications below:
a.    Lack of Placebo and use of within subjects design: We considered including a placebo control. 
But then in order to control for “order” effects, we would have had to randomize placebo and NTX 
conditions AND allow a significant washout period between medication conditions, especially for 
those receiving NTX first.  This would have led to problems with retention and increased the 
sample size.  We also considered a between subjects design but this would have also increased 
sample size and costs.  Therefore, in order to contain costs and increase feasibility, we decided to 
use a within subjects design examining a change from baseline, and configured the overall duration 
of participation to be as close to a single week as possible.  While our proposed design could still have 
“order” effects we do not believe that it will influence our ability to detect an initial signal.
b.   Use of Mock ADP and PET sessions:  To minimize the possible stress and novelty associated 
with a first PET scan and the ADP sessions, as time and scheduling permits, we will conduct a 
mock PET scan and a walk-through of the ADP procedures prior to the baseline PET and ADP. 
During the mock PET session, the subject will lie in a replica of the PET scanner, be told when the 
scanner is being “turned on” and when blood samples are “being drawn”.  During the mock ADP 
session, participants will be exposed to the HRU rooms in YNHH where the ADP’s are conducted 
and will be walked through the ADP procedures. 
c.   Timing of PET scan: The preliminary PET test/retest data suggest that BPND  for our new 
KOR tracer may be higher in the afternoon (Figure 6).  (Note: This cannot be explained by 
a carryover effect of a high-mass injection of tracer in the morning (test) scan, since that would 
cause BPND  to be lower in the second scan.)  We speculate that this effect could be due to 
diurnal fluctuations in dynorphin level. Regardless, we will control for it by scheduling each 
scan at approximately the same time of day (around mid-day).
d.   Dose, Timing of NTX and PK samples: We will taper subjects up to a NTX maintenance 
dose of 100 mg/day. 100 mg/day is the dose of NTX that has shown efficacy in many recent 
clinical trials [9], and our own preliminary evidence suggests that this dose may produce the 
greatest reduction in drinking in FHP drinkers but increased drinking in FHN drinkers.  We 
considered testing more doses of NTX but we felt that this would not have been justified and 
would have been too costly.  NTX dose will be administered at approximately 10 am each 
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day.   All participants will start with 25 mg/day and be tapered up to 100 mg by day 3 of 
medication. We will obtain 2 blood samples for pharmacokinetic (PK) analysis during the 
post PET scan to confirm that steady state levels of NTX were in effect during these 
procedures.  These PK samples will be tested for NTX and its major active metabolite,
      6(beta)-naltrexol.
e.   Tobacco Use and Smoking breaks:  In our experience, 50% of alcoholics who participate in 
our projects smoke cigarettes or use other tobacco products. In order to avoid nicotine 
withdrawal, on the ADP days, participants will be given smoke breaks until about an hour 
prior to the start of the ADP.  We will not allow them to smoke during the ADP since this 
could not only alter their craving for alcohol but could also pose a potential risk (since 
YNHH is a nonsmoking facility and the participant would have to be walked out for a smoke 
break while intoxicated).   On the PET days, we will allow regular smoke breaks up until 
about two hours prior to PET scans.  It is very unlikely that the smoking on the morning of 
the scans would cause kappa receptors to upregulate.  Since these individuals have been 
smoking and drinking regularly, we expect that any receptor regulation from smoking 
probably  happened  a  long  time  ago.   Further, if  there  is  any  acute  dynorphin  release 
associated with a smoking break, it will occur sufficiently early relative to the start of the 
PET scan to minimize any residual effect of transiently elevated dynorphin on our 
measurements of KOR level (BPND).
Recruitment:
All heavy drinker participants will meet DSM-IV criteria for alcohol abuse or dependence, will 
be drinking 25-70 drinks/week for men and 20-65 drinks per week for women and will report not 
being abstinent more than 3 days per week. All other criteria, designed to protect subjects from 
risks of participation are described in the human subjects section and are similar to those used 
by our group in earlier projects [2, 3, 28].
Participants will be recruited through advertisements in local newspapers, community TV 
channels and postings in community locations (bars, alcohol/coffee shops, grocery stores). We 
have also had success with recruiting participants from postings on Craigslist and social 
networking sites like Facebook as well as our study URL, www.paidalcoholstudy.com, which 
links  subjects  to  confidential  surveys  that  assess  some  preliminary  eligibility  criteria  and
provides preliminary information about the project. Each potential participant‟s eligibility will be
assessed over the phone by the research assistant who will then set them up for the initial intake
appointment. We do not anticipate any problems with recruiting these subjects since their profile 
is similar to that of the participants we have been recruiting for our ongoing projects and we have 
been quite successful in our recruitment efforts.
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We will recruit heavy drinkers who consume between 20-65 drinks per week for women and 25-
70 drinks per week for men. The lower limits reflect alcohol consumption that just exceeds the WHO 
Brief Intervention Study Group guidelines (WHO guidelines) for non-hazardous drinking, which are no 
more than 4 drinks/day 4-5 days per week for men (20 drinks) and no more than 3 drinks/day 5 days per 
week for women (15 drinks). The upper limits were chosen to ensure that we chose subjects whose typical 
drinking quantities would be unlikely to exceed the amount of alcohol that would be available to them for 
possible administration during the laboratory session. These criteria are similar to the ones being used in 
our ongoing work with memantine in HIC # 0602001068. We will also recruit healthy controls to match 
the demographics and background of the heavy drinkers, including family history of alcoholism; these 
controls will be light social drinkers consuming less than or equal to 20 drinks per week for women, and 
less than 25 drinks per week for men in the past 90 days and not meet past or current criteria DSM-IV 
abuse or dependence criteria for the past 5 years.  The remainder of the exclusion criteria will be similar 
to the heavy drinkers.
Justification of Age Criteria and for Excluding Children and Adolescents Under 21 Years of
Age:
We will not use subjects under 21 years of age in this study. First and foremost, this is an alcohol self-
administration study in which we will be offering drinkers an opportunity to consume alcohol, and in the 
State of Connecticut the legal age limit for drinking alcohol is 21. Secondly, subjects below the age of 21 
have probably been drinking alcohol for a shorter duration of time and will have different patterns of drinking 
from older drinkers, which may affect drinking during the self- administration paradigm and confound study 
results. The upper age limit was determined using our pilot data [3] which indicates that the majority of 
the subjects who participated in our ongoing study were in this age range.
Justification for choice of naltrexone dose:
We will use naltrexone in a dose of 100 mg/day. The 100 mg/day dose has shown efficacy in many 
recent clinical trials [9], and our own preliminary evidence suggests that this dose may produce 
greater reduction in drinking in FHP drinkers than the 50 mg dose.
Procedures:
Recruitment, Baseline Assessments, Physical Exam: Each potential participant‟s eligibility will be 
assessed by a research staff member who will then contact them and set them up for the initial intake 
appointment at the Substance Abuse Center in the Connecticut Mental Health Center,
New Haven, CT, where informed consent will be obtained and eligibility will be assessed.  At
this appointment,  DSM-IV criteria (SCID, [41], Family history of alcoholism (FHAM; [42]) and 
drinking over the past 90 days (TLFB; [43, 44]) will be assessed.  Urine will be collected to test for 
drugs and ethylglucuronide, a metabolite of ethyl alcohol that will be used as a biomarker of alcohol 
consumption at baseline and the ADP session. The research assistant will schedule a physical exam 
(including EKG) and routine laboratory work, and hepatic, kidney, and thyroid function tests and 
pregnancy tests for all females. Subject characteristics and medical history will be reviewed by the PI’s 
and the study physician Dr. Julia Shi, medical director of the Central Medical Unit) to ensure that the 
subject meets all the eligibility criteria. If eligible to participate and if they have also consented to 
participate in the genetic study they will have additional blood drawn at this time.  We plan to study the genes 
that might be related to the medication’s effects on drinking behavior. In addition, we may study other genes.  
Since all of the genes cannot be anticipated at this time, we will store the samples to study in the future. 
These samples will only be used for the following purposes: to learn about relationships between genes and 
characteristics of yours that relate to alcohol drinking and to learn about natural variation of genes between 
different groups of individuals. These samples will be de-identified and stored in a -70 freezer until they are 
transported to Dr. Joel Gelernter’s lab. Eligible participants will be scheduled for the study procedures (as 
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described in figure 9) and will be reminded to not use any illicit drugs or other medications throughout the 
duration of the study.
Practice ADP session: All eligible participants will be scheduled to participate in a practice ADP. 
Before participation in the first ADP, participants will be shown  the HRU room where  the 
ADP‟s will be conducted, walked through all the procedures of the ADP, and given information 
on what to bring and not to bring on the day of the ADP. Healthy controls will not complete the ADPs.
Mock PET scan: As time and scheduling permits, we will conduct a mock PET scan prior to the 
baseline PET and ADP. During the mock PET session, the subject will lie in a replica of the PET 
scanner, be told when the scanner is being “turned on” and when blood samples are “being drawn”. 
Medication Administration:  Eligible participants will receive NTX for a five to eleven day period.  
The dose of NTX will be tapered up over the first four days as shown in figure 9 above. Participants 
will come into our clinic on a daily basis to take their medications and provide reports on drinking 
behavior and adverse events. In the event that a participant cannot come to the clinic daily, other 
arrangements will be made, such as giving the participant more than one dose of their medication at 
a time and using a daily phone call as both a reminder to take the medication and as a means to 
monitor adverse events. We will allow this up until the final two doses of medication prior to the 
ADP or PET This arrangement will be determined by the investigator and her staff based on the 
participant’s other obligations and compliance. Healthy controls will not take any medication.
Alcohol Drinking Paradigm:  The procedures for all the alcohol-drinking sessions will be similar. 
Participants will be told not to consume alcohol starting at 5 pm the night before and arrive at the 
Hospital Research Unit (HRU) of Yale New Haven Hospital, New Haven, at 9:00 am.  We will first 
assess breath alcohol levels and conduct urine drug tests.  If the urine drug tests are positive and/or 
breath alcohol levels are 0.05 or greater, then the session will be rescheduled. Participants will be 
given the opportunity to taste and drink two chosen beverages (of which they will choose one for 
the 2 ADPs; see below).  These procedures will make them more comfortable drinking in the HRU 
room and will also help reduce order effects in the current design.
The ADP will be conducted in a private room in the HRU. It will start at 3 pm with the priming dose 
period, which will be followed by three one-hour drinking periods (4-5 pm, 5-6 pm, and 6-7 pm), and 
will conclude at 7 pm.
Exposure to Alcohol Cue
Ten minutes prior to the start of the priming dose (PD) period (i.e., 2:50 pm), the research assistant 
will walk into the participant’s room with the glasses, the alcohol, and the mixers. The research assistant 
will then proceed with the mixing of the priming drink of alcohol in front of the participant. When done, 
he/she will leave the drink on the table, instruct the participant not to consume the priming drink until
they are told to do so and leave the room.
Priming dose (PD) period
The PD of alcohol will be provided at 3 pm to model a “lapse” situation and subjects  will have
5 minutes to drink it. A 40 minute absorption period will follow during which the alcohol
craving (AUQ; [45]), stimulation/sedation (BAES; [46]) and physiological effects (heart rate, 
blood pressure, breath alcohol levels) of this priming dose of alcohol will be monitored every 10 
minutes.
Alcohol self-administration (SA) periods
Following the PD, participants will be exposed to three one-hour SA periods designed to model a 
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“relapse” situation. During each SA period they will be permitted to drink up to four alcoholic drinks 
designed to raise Blood Alcohol Level (BAL) by 0.015 mg% of alcohol, or to receive cash (equivalent 
to the price of each drink that is not consumed). The first SA period will begin at 4 pm, when the 
research assistant will take 4 prepared drinks into the room along with a "tab" sheet worth $12. The 
participant will be informed that these 4 drinks will be available to him/her for the next 60 minutes
 (i.e., until 5 pm). S/he can choose either to drink or to keep the money; each drink will cost $3. For 
example, if the participant chooses to drink only one drink in the next one hour, s/he will earn $9. 
The money will be given to them the next morning before they leave the hospital. The second and
third SA periods will begin at 5 pm and 6 pm, respectively, and will be similar to the SA period. Thus, 
participants can choose to consume up to 12 additional drinks over this 3 hour period or to receive up 
to $36 to take home the next morning.  Number of drinks that each participant consumes during this 
period will serve as the primary outcome for this portion of the experiment.
  Beverage content and mixers
The YNHH Investigational Pharmacy will calculate the alcohol dose for each participant. The PD 
dose will be designed to raise blood alcohol levels to 0.03 mg% and will be based on the formula 
specified by Watson [47] which takes into account gender, weight, and age of the subject. The 
subsequent drinks provided in the SD blocks will raise BAL by 0.015 mg% each, using the same 
formula. The alcohol doses will be delivered to the HRU unit and any unused doses will be returned 
to the pharmacy. Alcoholic beverages administered during this study will consist of 1 part 80 proof 
liquor of the subject's choosing to 3 parts mixer chosen from a selection of equicaloric, non-
caffeinated, non-carbonated drinks. The research assistant will prepare the drinks using the alcohol 
doses prepared by the YNHH pharmacy. Participants would have already chosen their favorite 
alcohol and mixer earlier that day. Specifically, they will be asked to choose two mixed drinks of 
their favorite alcohol and mixer to go with it from a list that will be provided to them at the intake 
appointment. The mixers on this list have been chosen to be equicaloric and to not contain any 
carbonation (which could alter absorption of alcohol). Subjects will be asked to taste both mixed 
drinks on the morning of the baseline ADP and pick the one that they would like to use for both 
ADP’s.
End of alcohol self-administration period and overnight stay in HRU: The alcohol administration 
portion of the study will end at 7:05 pm. Following this, breath alcohol levels and craving will be 
assessed every 30 minutes until the subject's breath alcohol level falls below 0.02. Participants will 
get dinner and will stay in the hospital overnight and will be discharged between 6 and 7 am the next 
day.
Assessments during and after the three choice periods: During the second, third and fourth hour of 
the laboratory session alcohol craving (AUQ; [45]) and stimulation/sedation (BAES; [46]) and breath 
alcohol levels (assessed using Alco-Sensor 3; Intoximeter, St. Louis, MO following rinsing of mouth) 
will be assessed every thirty minutes. The range of assessments, however, is limited to avoid interfering 
with the evaluation of drinking behavior. Changes in craving and stimulation/sedation can then be 
correlated to KOR occupancy.  Breath alcohol levels will be used to confirm that there are no differences 
in alcohol absorption between subjects.
Scheduling of the ADP and PET sessions requires a lot of coordination and requests are made in 
advance. Given the consequences that occur when a participant does not arrive for a scheduled 
appointment, we are asking a secondary participant who is scheduled for a later session to serve as a 
standby participant in case the primary scheduled participant has a conflict for the ADP and/or PET 
scan. If the scheduled participant arrives, we will pay the standby participant $50 for showing up and 
ask them to come back at a later date to complete their scheduled appointments. However, if the 
scheduled participant does not arrive, the standby participant will still be paid $50 and will be invited 
to complete the appointments scheduled for the original participant. 
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In most instances, participants will be scheduled the PET scan the morning after the ADP session; 
however, due to issues that could occur with the PET scanner and chemistry on the morning of the 
scan, participants will need to be rescheduled. In the event that a participant, who is a heavy drinker, 
needs to be rescheduled, they will be asked if they are willing to spend the evening before the 
rescheduled PET scan at the HRU to ensure that they meet the BAC requirements the next morning 
and can complete the PET scan. They will be admitted to the HRU between 3:00 and 4:00 pm and 
be discharged early the next morning to be escorted to the PET Center. The healthy controls will not 
be invited to spend the night at the HRU since they do not meet criteria for heavy drinking.
Follow up appointments: Subjects will participate in a one week follow-up appointment during which 
drinking over the past week will be determined using TLFB techniques and any remaining adverse 
events will be monitored. At this appointment a brief motivational intervention will be provided to 
encourage the subject to address their alcohol problem and an immediate referral to treatment will be 
made if subjects are interested. Even though the subjects participating in this study are not seeking 
treatment for their drinking, we feel that their participation in this project provides us with a “teaching 
moment” to address their drinking behavior. We have found that similar brief advice resulted in 
decreases in alcohol-drinking behavior and increased motivation to quit drinking [48]. As previously 
done, this intervention will be based on the principles of Miller’s Motivational Enhancement Therapy
 (MET) [49]. We will also provide them with the NIAAA brochure, “Rethinking Drinking.”
PET Methods:
Data Acquisition: PET scans will be conducted on the Siemens High Resolution Research 
Tomograph (HRRT), the world‟s highest sensitivity  and resolution  human brain PET scanner, 
with a practical resolution of 2.5-3 mm [50]. The Yale University PET center has conducted 
more than 400 human scans on the HRRT with 20 different tracers.  The excellent spatial resolution 
of the HRRT will be critical in discerning small structures [51].  The HRRT is a list- mode machine 
so we can bin up the dynamic data anyway we choose.   We will create a graduated series 
of time-frames stating with 30 second frames and lengthening to 5 minutes.
Hardware motion correction using the Vicra system (NDI Systems, Waterloo, Ontario) will be 
performed on an event-by-event basis.  Arterial blood samples will be acquired via a continuous 
withdrawal device (PBS-101, Veenstra Instruments, Joure, The Netherlands) for the first 5-10 
minutes of the scan and manually thereafter, and radioactive metabolites identified by HPLC. 
Plasma concentration of free parent tracer over time will be used for subsequent kinetic modeling 
analysis.   Emission images will be reconstructed iteratively with built-in corrections for attenuation, 
normalization, scatter, randoms, deadtime and subject motion [27].
PK samples:  Two PK samples will be collected during the NTX PET session.  Days 5-11 were chosen 
for the NTX PET scan to build some flexibility into scheduling but maximize the likelihood that NTX 
levels would be at equilibrium, which will be confirmed by PK analyses. We will also look (on a 
population basis) for a relationship between occupancy of KOR and NTX (and 6(beta)-naltrexol) 
levels and interaction with FH of alcoholism.
ROI analysis and parametric image generation:  After data reconstruction with all corrections, a 
new summed image (0-10 min) will be registered to the subject's T1-weighted MR image, which will 
be registered to an MR template so that PET and MR images are in the same MNI space. ROI‟s, 
including the 13 examined in the Preliminary data section in Figures 4 and 6 will be taken from a 
template (Anatomical Automatic Labeling (AAL) for SPM2).
Possible to dispense with arterial sampling, 2T model fitting?:  Preliminary results suggest that the 
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cerebellum may be an appropriate reference region. That is, it may be devoid of KOR.  It certainly
 has low specific binding compared to the other regions assayed.   The excellent agreement between 
BPND  estimated by the 2T model and by SRTM certainly suggests that in healthy controls, we can 
assess BPND at baseline with a reference region model using the cerebellum as the reference region.  
If this turns out to be generally true (e.g., in larger samples, in heavy drinkers), then we can justifiably 
dispense with arterial sampling and analyze all data via reference tissue models (such as SRTM and 
SRTM2).   As mentioned in Preliminary PET studies, to validate the absence of KOR in the 
cerebellum, under multiple scan conditions (baseline and NTX) in clinical populations, we will have 
to show that VT of cerebellum does not change between baseline and NTX (i.e., there is no specific 
binding to block).
Possible to shorten scan duration?:
Preliminary results also indicate that we could shorten the scan duration from 2 hrs (used in our 
preliminary scans) to 1 ½ hrs without any loss of accuracy or precision.
Analysis of Initial Cohort: Data from the first 6 FHP and 6 FHN subjects scanned in year one of the 
project (24 scans total) will be analyzed to determine whether or not a reference region exists for 
[11C]LY2795050 ([11C]-PKAB ) and whether or not the scan duration can be shortened without loss 
of precision of the data.  To be sure that a reference tissue model is appropriate in our study, two findings 
are required.  The VT of the putative reference region must be unchanged by blocking and the endpoint, 
BPND, estimated by the reference region method must agree with the BPND calculated using an AIF.  If 
the BPND values from 2T and SRTM continue to show excellent agreement, as applied to both baseline 
and NTX scans, then we may choose to discontinue arterial sampling thereafter and rely solely on a 
reference region model for analysis. After a preliminary analysis of the initial cohort, we will determine 
the acquisition protocol for the remaining 24 subjects.
Modeling of PET data to yield BP in regions of interest and parametric images
1. Standard kinetic modeling approaches: With plasma input function measurements in and, we can 
compare multiple standard methods of estimating our desired endpoints (BPND at baseline and difference 
in BPND from baseline to NTX) to determine the best model or technique [52] that yields the lowest 
variance in the estimates.  Tentatively based on preliminary data, we expect to use the cerebellum as 
the reference region for reference region methods but we will continue to investigate the possibility of 
another (better) reference region.
2. Measuring occupancy does not depend on displacement, time of day:
The two primary imaging endpoints (Bavail and OccupKappa) depend on our ability to measureBPND.  
It is important to note that the half-life of NTX is very long (10.5 hrs in the blood at 100 mg oral dose) 
and subjects would have been on 100 mg for at least 2 days before the NTX scan.  Therefore, we can 
expect that NTX in the brain will be at a nearly constant level prior to and during the NTX-scan. Thus, 
we are not measuring displacement of [11C]LY2795050 ([11C]-PKAB ) but rather, the effect of a 
pre-blocking (i.e., a measurement at a second steady state).  This is an important distinction.  The latter 
does not depend on the displaceability of the tracer (a kinetic issue), and thus, we have not addressed it 
in our preliminary data. To be safe, however, we will scan each subject near mid-day for both baseline 
and NTX scans. Given that the half-life of NTX is 10.5 hours and that it drops ~5% per hour, we will 
maintain the delay from morning oral dose of NTX to time of scan for each subject at 2 hours which 
should coincide with the time of peak NTX concentration in the blood.
Assessments
a)Socio-demographic/General Information: At intake, demographic data, medical history, and 
family psychiatric history will be assessed with interviews and self-report forms that provide 
data on age, race, socioeconomic status, marital status, educational and occupational levels, and 
significant medical history. These are adapted from previous diagnostic and clinical studies at 
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this center.
b)SCID: The Structured Clinical Interview for DSM-IV (SCID) [41] will be used to determine 
psychiatric diagnoses. This interview assesses DSM-IV current and lifetime psychiatric diagnoses 
for anxiety, mood, psychotic, alcohol and substance use, somatoform, and eating disorders.
c)Psychiatric Family History by Interview, the FHAM:  As a source of pedigree information, the 
psychiatric status (including substance abuse/dependence, mood disorder, ASPD, etc.) of all first- 
and second-degree biological relatives will be obtained from each subject (including parents) using
 the family history method (FHAM-Family History Assessment Module) developed by COGA. 
DSM-IV criteria will be used to diagnose all biological family members. The FHAM is a reliable 
method for obtaining family history information and the specificity and sensitivity of the FHAM 
for the diagnosis of substance dependence is quite good [42]. We will administer the FHAM in 
three steps. First, the structure of the family pedigree is drawn and reviewed with the informant. 
Next, psychiatric screening questions are asked about all relatives in the pedigree. Then, based on 
the responses to the screening questions, symptom checklists are completed for each first-degree 
relative, spouse, or other relative well known to the informant.
d)Time-Line Follow-Back Assessment Method: This interview procedure will be used to obtain 
quantity/frequency alcohol consumption data for each day during the 90-day period prior to the 
study, during the outpatient stabilization period, and during the three-month follow-up [38]. 
Subjects are given a blank calendar covering the time interval to be re-constructed and are asked 
to reconstruct retrospectively their drinking behavior over that interval. The process is facilitated 
by establishing anchor points (e.g., holidays, anniversaries, major national events, etc.). It can be 
scored to provide the number of days on which various levels of consumption occurred. The 
time-line method has good test-retest reliability and good validity for verifiable events. It has been 
used in numerous studies to compare pre- to post- treatment drinking.
e) Craving Measures:
Alcohol Urge Questionnaire (AUQ) [45]: The AUQ is an 8 item questionnaire, derived from a 
larger 49 item "Questionnaire of Alcohol Urges," that assesses desire for a drink, expectation of 
positive effect from drinking, and inability to avoid drinking if alcohol was available. The AUQ is 
a reliable and valid scale for the measurement of self-reported alcohol urges, and scores have been 
shown to be strongly related to alcohol dependence severity (as measured by ADS scores) and to 
cognitive preoccupation with alcohol. Its brevity and time frame for ratings (i.e., right now) makes 
it suitable for administration during the alcohol drinking period.
Yale Craving Scale (YCS): We have been collaborating with Linda Bartoshuk to develop this craving 
measure based on psycho physiological scaling methods. In her work on individual differences in the 
ability to taste bitterness, Dr. Bartoshuk and colleagues [35] used magnitude- matching procedures 
[35] in which participants matched the intensity of perceived bitterness to sounds. By doing so, the 
problem of differences in how labels (e.g., very strong) are applied was circumvented by making the 
comparison to a standard that is unrelated to taste. The resulting scale, Labeled Magnitude Scale 
(gLMS) [36], has been extended to measure hedonic ratings for foods, and we have adapted it for
 rating craving for tobacco and alcohol. It is not subject to the ceiling effects that often occur in 
craving research [39]. We have been collecting craving data using this scale in our ongoing 
projects and the findings from this scale have been found to parallel those obtained using the 
Alcohol Urge questionnaire. A significant advantage of this scale is that following completion of 
baseline training to match perceived intensity of craving to the perceived brightness from the sun, 
each assessment timepoint only consists of a single visual analog scale of craving, making it very 
easy to administer.
e)Clinical Institute Withdrawal Assessment for Alcohol-Revised (CIWA-Ar): This is a modified, 
shorter version of the Clinical Institute Withdrawal Scale for Alcohol which is equally efficient 
and reliable as the original scale without a significant loss in accuracy. The CIWA- Ar is a 10 
item scale that contains alcohol withdrawal signs and symptoms that include nausea/vomiting, 
tremor, headache, anxiety, agitation, orientation, sweating, and auditory, visual, and tactile 
disturbances. This tool often guides the clinical management of alcohol [30] withdrawal [29] 
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and is used extensively in research on alcohol withdrawal [31, 32].
f)Intellectual Functioning: In order to obtain an assessment of general intellectual functioning and 
a reference point for other cognitive assessments, we will complete the two-subtest short- form 
of Block Design and Information from the WAIS-III [56]. This combination correlates at .87 
with the Full Scale IQ.
g)Impulsivity and Automatic Motivational Measures:  Change from occasional to compulsive drug use 
may be less dependent on positive reinforcement and more dependent on implicit processes that 
automatically evaluate the motivational significance of the alcohol cue for affect regulation. Such 
processes may include “fast” impulsive responses which automatically orient the individual to 
either approach or avoid the stimulus and “slower,” more reflective processes involving 
conscious deliberation and emotion regulation. We will assess using impulsive responding using 
measures which encompass several clinically relevant core components such as rapidity of 
response, degree of planning, and disregard of future consequences.
Self-Reports:
a)The Behavioral Inhibition System/Behavioral Activation System (BIS/BAS) [57, 58] will 
assess behavioral activation and inhibition, which have been proposed as biological systems 
underlying behavior and affect. This measure has been shown to have good convergent, 
discriminant, and predictive validity in which it measures sensitivity rather than the person’s 
typical experience. The BIS will be used to tap the component of impulsivity related to 
           decreased sensitivity to the negative consequences of behavior.
b)Barratt Impulsiveness Scale (version 11) [59]: This 30 item self-report instrument provides a trait measure 
of impulsiveness and yields four scores: a total score, non-planning activity, cognitive 
   impulsivity, and motor impulsivity. Cronbach alpha coefficients range from .79-.83.
Laboratory Measures:
a)Experiential Discounting Task (EDT) (Reynolds and Schiffbauer, 2004): This delay 
Discounting task exposes participants to choice consequences during test administration. 
The EDT involves multiple blocks of choices, one for each delay. Choices are made between 
A standard amount that is delivered immediately and is certain and a probable amount that is
delayed and uncertain. The EDT is sensitive to various levels of alcohol dosing (i.e., between
0 and 0.8g/kg) (Reynolds et al., 2006).
b)Cued Go-No Go task (Abroms et al., 2006) This task will be used to examine the ability to 
Inhibit prepotent responses.  Subjects are presented with 250 trials over 20 minutes in which a go 
or a no-go target is preceded by a cue; the orientation of which cues the probability that a go or 
no-go target will be displayed.  Dependent measures include: number of failures to inhibit 
responding and speed of responding.  Alcohol has been shown to impair the ability to inhibit 
responses This computerized task assesses a component of impulsivity related to rapid, 
unplanned reactions to stimuli before completing information processing. 
h)Biphasic Alcohol Effects Scale [46]: This 14 item self-report, adjective rating scale will be used to 
Measure the stimulant and sedative effects of alcohol during the priming dose during ADP 2. 
This instrument has been found to be sensitive to memantine and naltrexone's effects on alcohol 
intoxication [63, 61, 64].
j) Ratings of Drinking Behavior During the Alcohol Self-Administration Period: Subjects will
be videotaped during the alcohol self-administration portion. These videotapes will be rated by 
two independent raters who will indicate the onset and offset of each sip of alcohol. Using this 
data, dependent measures will be constructed including time until the first sip and average time 
to consume each drink.
k) Blood Alcohol Levels: Blood samples will be drawn to measure plasma levels of blood alcohol
(BAC) during the priming dose and during the alcohol self-administration paradigm. Blood 
samples will be stored at -4°C and will be analyzed using gas chromatographic techniques at the 
HRU Laboratory.
l) Psychophysiological Measures: These will include heart rate and blood pressure monitored 
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using a Critikon Dinamap while skin temperature will be measured using Yellow Springs 
Instruments 4600 precision thermometer. The cuff of the Dinamap will be on the subject's 
dominant arm while the probe of will be attached to the middle finger of the subject's non- 
dominant arm.  These data will be further used to examine the safety of using the medication 
combination during alcohol self-administration.
l) Cold Pressor Task (Edens & Gil, 1995): To evaluate the ability of participants to deal with a 
physiological stressor and to examine pain thresholds in relation to medication effects and drinking 
behavior.   Subjects will be informed that the experimenters are investigating the body’s physiological 
response to cold water during nicotine withdrawal.  Subjects will be asked to immerse their right arms 
into ice water maintained at 3-4oC.   Subjects are asked to raise their left hand when they begin to feel 
pain (pain threshold) and to remove their hand from the water when they can no longer tolerate the pain 
(pain tolerance).   While their hand is immersed in water subjects are also asked to rate their pain on an 
analog scale of 0-100.
3.   Statistical Considerations: Describe the statistical analyses that support the study design.
Outcomes for this study will be collected using scannable forms (Teleforms). The scanned forms 
will be processed through the Teleforms software and exported to a database on a secure 
computer. Error checking and data validation will occur weekly and any problems will be 
queried and resolved immediately.  Drs. Krishnan-Sarin will receive monthly data quality reports 
to check for completeness and accuracy of key demographic and prognostic variables, as well 
as rates of recruitment, retention, and follow-up.   Statistical tests will be conducted using SAS 
v9.1 and SPSS v16 (or later) and will be performed at 2-tailed alpha level of 0.05
Primary Aim 1. Occupancy of KOR by NTX and drinking. This aim seeks to determine  the  
degree to which occupancy  of  kappa  by  NTX  mediates responsivity to NTX in heavy drinkers. 
Responsivity to NTX is defined as the change in the total number of drinks consumed in the NTX 
ADP versus the baseline ADP. Tests for mediation will be conducted using the regression strategies 
described initially Baron and Kenny [53], and the more recent elaboration by Kraemer et al. [54]. 
The proposed mediator (i.e., the potential mechanism of change), occupancy of KORs, is measured 
as the fractional change in BPND before and after treatment with NTX. The analyses will determine 
whether occupancy is associated with a) NTX treatment, and b) NTX responsivity.
Primary Aim 2.  Family History of Alcoholism as a moderator: This aim seeks to determine 
if the relationship between NTX responsivity and occupancy of KOR is altered by FH status. 
FHP and FHN will be compared on NTX responsivity and occupancy of KOR. Tests for 
moderation will be conducted using the strategies described by Baron and Kenny [53], and the 
elaborated by Kraemer et  al.  [54].  The primary  tests  will  be  whether  there  is  a  significant  
FH  by  dose interaction on NTX response and occupancy of KOR.
Secondary Aim 1. Baseline KOR differences. This aim seeks to determine if baseline levels of 
KOR differ between FHP and FHN heavy drinkers, and are related to either drinking in baseline 
or NTX ADP.  FHP and FHN groups will be compared using chi-square tests for categorical variables, 
and using t-tests or Mann-Whitney tests for continuous variables. All continuous variables 
will be examined for adherence to the normal distribution using normal probability plots 
and Kolmogorov-Smirnov tests. If normality is not satisfied and transformations do not help 
with achieving normality, alternative analytic strategies will be considered such as generalized 
estimating equations or nonparametric methods. The relationship between baseline KOR and 
drinking will be examined via Pearson product-moment correlations.
Secondary Aims 2 and 3. Scan duration and reference region.  We will look for correlations 
between BPND estimates based on 2T model with full AIF and all data vs alternative models and 
data ranges.    Group variances  in  baseline KOR  at  or lower than 2T estimates  will permit 
adoption of simpler models.
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Auxiliary Aim 1.  Kappa and behavioral indicators relevant for alcoholism. This aim will examine 
the correlations between occupancy of KOR and alcohol craving, stimulation and sedation.  A series 
of Spearman rank-order and Pearson correlation analyses will be conducted for this aim.
Power analysis:  The sample size was based on the power calculations for the hypotheses of (a) 
reduced drinking in the NTX 100 condition, and (b) power to detect an interaction by FH. Power 
calculations were generated using G*Power software Version 3.0 [55]. Effect sizes were estimated 
based on the preliminary FH and NTX effects on drinking behavior in the ADP described in 
[6] and in our preliminary studies.  The effect size for the effect of FH is .91. To detect this effect 
size at alpha=.05 with 80% power, a total of 16 participants would be required for each arm. 
Therefore the proposed sample size of n=18 per arm would be sufficient to detect differences in 
drinking between FHP and FHN at the 100 mg dose of naltrexone.
SECTION VI: RESEARCH INVOLVING DRUGS, DEVICES, BIOLOGICS & PLACEBOS
Are there any investigational devices used or investigational procedures performed in a YNHH 
Operating Room?  Yes
No
If Yes, please be aware of the following requirements:
a.  A YNHH OR New Product/Trial Request Form must be completed.  Please contact the OR 
Materials Manager, Chris Baillargeon, at 203-688-8912 for more information on this requirement;
b. Your request must be reviewed and approved by the Operating Room New Technology
Committee before patients may be scheduled; and
c. The notice of approval from the OR New Technology Committee must be submitted to the
HIC for the protocol file.
1.   Identification of Drug, Device or Biologic: What is (are) the name(s) of the drug(s), 
device(s) or biologic(s) being used? Identify whether FDA approval has been granted and 
for what indication(s).
Naltrexone is an FDA approved drug that is used in the treatment of alcoholism and opioid 
addiction.
[C-11]LY2795050 ([C-11]PKAB) PET radiotracer to image kappa opioid receptor,  Production 
of [C-11]LY2795050 ([C-11]PKAB) will be performed with the permission of Yale-New 
Haven Hospital RDRC
All protocols which utilize a drug, device or biologic not approved by, but regulated by, the FDA must 
provide the following information:
Not applicable to this research project
i.   What is the Investigational New Drug (IND) or Investigational Device Exemption (IDE) number
assigned by the FDA?
Production of [C-11]LY2795050 ([C-11]PKAB) will be 
performed with the permission of Yale-New Haven Hospital RDRC
ii.   For IDE‟s: Did the FDA approve this IDE as a Category A (experimental/investigational)  or as a
Category B (non-experimental/investigational)?   Not applicable.
iii.  Who holds the IND or IDE?
The clinical investigation of a drug product that is lawfully marketed in the United States may be 
exempt from the requirements for filing an IND. If there is no IND and an exemption is being sought, 
complete the following:  N/A
i.Is the intention of the investigation to report to the FDA as a well controlled study in support 
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of a new indication for use or to be used to support any other significant change in the labeling for 
the drug?       Yes       No
ii.  If the drug that is undergoing investigation is lawfully marketed as a prescription drug product, is 
the intention of the investigation to support a significant change in the advertising for the product?
Yes
No
iii.  Does the investigation involve a route of administration or dosage level or use in populations or other 
factor that significantly increases the risks (or decreases the acceptability of the risks) associated with the 
use of the drug product?
Yes
No
iv. Will the investigation be conducted in compliance with the requirements for institutional (HIC) 
eview and with the requirements for informed consent of the FDA regulations (21 CFR Part 50 and 21 
CFR Part 56)?      Yes       No
v.   Will the investigation be conducted in compliance with the requirements regarding promotion and 
charging for investigational drugs?
Yes
No
2.   Background Information: Provide a description of previous human use, known risks, and data 
addressing dosage(s), interval(s), route(s) of administration, and any other factors that might influence 
risks. If this is the first time this drug is being administered to humans, include relevant data on animal 
models.
Naltrexone:
Naltrexone, an opioid antagonist, is widely used in the treatment of opioid addiction and more 
recently has been found to be beneficial in the treatment of alcoholism.  Numerous studies have 
found naltrexone use to be safe and rarely associated with toxicity or severe side effects.  The 
most frequent reported side effects are gastrointestinal in nature.  Those include epigastric pain, 
nausea and vomiting.  Other, less frequent side effects include nervousness, dizziness, headaches, 
blurred vision, low energy, fatigue, sleepiness, joint and muscle pain and insomnia.  Hepatotoxicity, 
the most serious potential side effect, has been shown in studies using very high doses of naltrexone 
(1400 to 2100 mg per week).  At the doses used in this study naltrexone has not been reported to 
produce hepatotoxic effects.  However, we will monitor liver function tests prior to the study and 
exclude individuals with evidence of significant hepatocellular injury (AST, ALT >3x normal 
established in pregnant and nursing women, they will be excluded from participation.  Naltrexone 
can also precipitate or exacerbate opiate withdrawal, as a results subjects with abuse or dependence 
on opiates will be excluded from the study on the basis of self-report and urine drug screens.
Since naltrexone is an opiate antagonist, alternative nonopioid methods of analgesia can be used.
In an emergency situation requiring opioids, the amount of opioids necessary for analgesia may be 
greater than usual, and the resulting respiratory depression may be deeper and more prolonged.  As a 
result, a rapidly acting analgesic which minimizes respiratory depression is preferred and the amount 
of the analgesic administration titrated to the needs of the patient in a setting equipped and staffed for 
cardiopulmonary resuscitation.  As a result, subjects will be given a card showing that they may be 
receiving naltrexone.  This card will provide detailed information to medical personnel describing the 
special precautions necessary in the event that the subject should require pain management.  In 
addition, this card will have a code number on it that can be used to identify which medication 
the subject is on.  A phone number of the pharmacy and for the physician on call at the Connecticut 
Mental Health Center will be listed on the card in the event of an emergency in which it is necessary 
to determine whether the subject is on active naltrexone.
[C-11]LY2795050 ([C-11]PKAB)
Dosimetry:
A total of 4 human subjects (2 M, 2 F, 73 ± 16 kg) underwent whole body dynamic PET 
scanning  on  the  Siemens  ECAT  HR+  scanner  following  iv  bolus  injection  of  [11C]PKAB 
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(injected activity = 282 ± 68 MBq).  Subjects were scanned for 150 to 170 min in a sequence of 12 or 
14 passes with 8, 9 or 11 bed positions according to their sizes, covering each subject from top of the 
head to mid-thigh.  Scans were reconstructed and visually inspected for organ activity concentrations 
exceeding background level.  Included organs were liver, kidneys, urinary bladder contents, heart, 
gallbladder, brain, spleen, thyroids, gonads and red marrow (femur).  Regions of interest were drawn on 
these organs and mean activity values computed in order to form time activity curves of activity 
concentration (kBq/cm3).
Within-pass decay correction was removed to reflect actual activity in each organ, and cumulated 
activity (Bq*hr/cm3) computed as trapezoid sums for data from the scan plus physical decay for the 
tail portions after the scan period.  These were multiplied by the organ volumes of a standard 70 kg 
reference mathematical phantom, normalized by subject  mass  /  70  kg  and  then  normalized  to  
injected activity to obtain organ residence times (also called N), (hr).  These were entered into 
Olinda software to obtain absorbed  doses  in  all  organs.     Electron  doses  to  the stomach were 
adjusted to reflect the fact that activity was observed in stomach wall rather than contents.
Absorbed doses derived from the 70 kg reference man 
phantom were expressed as mean ± standard deviation 
across the 4 subjects.  Under RDRC exposure limits as 
specified in CFR 361.1, (For single study, 5 rem per organ 
or 3 rem to selected organs undergoing rapid cell division, 
whichever is less) gallbladder is the dose-limiting organ 
with single study dose of 26 mCi.  Applied to the 55 kg 
adult female phantom (Table 2), gallbladder is still the 
critical organ, with single study dose limit of 23 mCi.
PET Imaging Results –Imaging of KOR Sites
Introduction
The preliminary data in this section represent our initial 
experience with the new PET tracer [11C]LY2795050 ([C-
11]-PKAB) in humans and monkeys.  A number of opioid 
receptor radiotracers are currently available for PET 
imaging in humans: [11C]carfentanil(mu-specific), 
[11C]/[18F]diprenorphine (nonspecific), [11C]buprenorphine 
(nonspecific), [18F]cyclofoxy (mu, kappa), and 
[11C]methylnaltrindole (delta) [33]. None of these existing 
tracers is selective for KOR. So far, the results with 
[11C]LY2795050 ([C-11]-PKAB) suggest that it is taken up 
consistent with the known distribution of KOR [34-36]; It 
also appears to have good contrast to background 
properties, good test/retest reproducibility, and there may 
be a reference region with little to no KOR.
Figure 2. Top row: MRI images of an individual subject. 
Middle row:0-10 min summed PET image. Bottom: 60-120 
min summed PET image.   Left column: axial slice; middle 
column: coronal slice; right column: sagittal slice.   The 
amygdala is bright on all three views at late time.  The 
cingulate cortex is apparent on the coronal image at late time.
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Occupancy of KOR by NTX – or simply “occupancy” - is measured as a percentage change in
BPND from the baseline condition to the drug condition (in our case, a week of NTX treatment).
If we assume that neither the KD nor the fND of the tracer change in an individual between scans, 
then occupancy can be seen to be the fractional change in available
receptors due to the drug.
Total Volume of Distribution, VT, is a related concept to BP.  VT is 
the equilibrium ratio of the concentration of parent tracer in tissue 
to parent tracer in plasma.
b.   In vitro results
Radioligand competition assays were conducted to assess the in 
vitro   binding   affinities   of   LY2795050   to   opioid   receptors.
LY2795050 is a KOR antagonist and displays high binding affinity 
and great selectivity to KOR in vitro (Ki  = 1.37, 87. 3, and 475 
nM, respectively, for kappa, mu, and delta receptors) [38].
c.
Test/retest imaging in humans
Figure 3.   Selected regional time activity curves for 
a single subject; amygdala (AMY, pink, „1‟), cerebellum 
(CER,  blue,  „2‟),   and  caudate  (CAU,  orange,   „3‟). 
Smooth curves through data represent fits of 2T model.
Metabolite-corrected  arterial  plasma samples  were  used
 for input function.
Seven healthy volunteers, age = 26 ± 6 (5 males and 2 females), participated in a test-retest study 
of [11C]LY2795050 ([C-11]-PKAB), an antagonist PET radiotracer for the KOR.  Each subject 
received two bolus injections of up to 20 mCi of radioactivity and mass dose of < 10 µg for each 
injection. The injected activity dose was 13.0 ± 4.6 mCi, specific activity was 0.59 ± 0.22 
mCi/nmol at time of injection, and injection mass was 8.8 ± 1.2 µg across all subjects.  Arterial 
(plasma) input function (AIF) curves were prepared from arterial samples taken during the study. 
Metabolite fraction was applied to yield an input curve for the native tracer only.   BPND 
throughout the brain (calculated two different ways) was used as the study endpoint.   Further
details of our standard image processing methods are given below under „PET methods‟.
d.   Distribution of [11C]LY2795050 ([C-11]-PKAB) in the brain
Figure 2 shows the early- and late-time distributions of [11C]LY2795050 ([C-11]-PKAB) in the 
brain.  The early image is an average of the 0-10 min data (middle row); it reflects initial entry 
into the brain via blood flow. The late image is an average of the 60-120 min data (bottom row) 
and reflects preferential retention of the tracer by brain regions containing specific binding sites 
for the tracer.  Rank order of activity uptake was as follows: amygdala (AMY) > cingulate cortex 
(CIN) > globus pallidus (PAL) ~ putamen (PUT) > temporal cortex (TEM) ~ frontal cortex 
(FRO) > hippocampus (HYP) ~ caudate (CAU) > cerebellum (CER). The distribution of tracer at 
late time agrees with the known distribution of kappa receptors in the brain [34-36].
e.   Time-activity curves: for use with kinetic models
Estimates of kinetic parameters require regional 
tracer concentration values over time.  Automatic 
regions-of-interest (ROI) were applied (see PET 
methods)   to   the   dynamic   emission   images   to
generate time-activity  curves (TACs) in 13 ROI‟s.
The time-activity curves (TAC) were fitted to the 4-
parameter, 2-tissue compartment model (2T) using 
the metabolite-corrected input function.   Examples 
of fitted TACs are shown in Figure 3.   All of the
Figure 4. Regional estimates of BPND  by 2T model (blue 
bars)  and  by  SRTM  (red  bars).    Agreement  between 
models is high and variability across subjects (error bars
are SD = 7 - 8%) is quite good for neuroreceptor tracers.
regions were fit well by the 2T model.  The rapid 
efflux from the cerebellum compared to the other 
regions suggests that the cerebellum has little to no 
specific binding and is therefore a possible reference
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region.  However, the d e f i n i t i v e  i d e n t i f i c a t i o n   of  a  reference  region  must  be  
based  on displacement experiments.
f. Regional distribution of desired endpoint: KOR at baseline (BPND)
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Figure 7.  Correlation between estimates 
of BPND using either a full 120 min dataset 
(X-axis) or only 90 minutes (Y-axis) of TAC 
data.
We  computed  BPND   in  each  ROI  two 
ways. One method requires the use of AIF 
and the other does not.   From the fits of 
the TAC data via 2T model with AIF, we 
calculated BPND  as the relative difference 
in volumes of distribution between the 
target ROI and the putative reference 
region, in this case, cerebellum: (VT(ROI)
– VT  (CER)) / VT(CER).   BPND  was also
computed using the Simplified Reference
Tissue 
Model 
(SRTM) 
using 
the 
cerebellum as the reference region. The 
regional distribution of BPND based on 2T 
and SRTM is shown in Figure 4.  Figure 4 
shows that the methods are in close 
agreement and the variability, by region, 
across the cohort is small.
                         a.                                                  b.
Figure 5 a. Effect of pre-block with unlabeled  KOR antagonist 
drug.   Baseline TACs for cerebellum (CER), caudate (CAU), and 
frontal cortex (FRO)   (solid circles, open circles, diamond, all in 
red).  Curves after pre-block (blue) all show reduced specific 
binding and are nearly indistinguishable from CER at baseline.  
Curves are from one animal and are normalized to injected activity 
dose.   b. BPND  is reduced dose-dependently according to dose of 
specific KOR antagonist in both CAU and FRO region.
g.   Pre-blocking of [11C]LY2795050 ([C-11]-PKAB): can we 
detect drug occupancy at kappa sites?
We can verify that uptake and retention of [11C]LY2795050
([C-11]-PKAB) is due to specific binding to KOR by looking 
at pre- blocking studies with well-characterized (unlabeled) 
drugs. Pre- blocking studies were performed in 3 rhesus 
monkeys.   The experiments were similar to what is 
being proposed herein to measure occupancy of KOR by 
NTX.  In the preliminary studies, rhesus monkeys were 
given iv, 1mg/kg naloxone, a non-selective KOR  antagonist,  
or  varying  doses  of  LY2456302,  a  selective kappa  
antagonist  developed  by  an  industry  partner.  Example 
results for the blocking studies are shown in two parts of 
Figure 5. Figure 5a: At baseline, regions such as CAU and 
FRO appear to have more uptake than CER. Under 
pre-block with the specific KOR antagonist, TACs for
Figure 6.  Percent change in BPND from test to retest 
scans for  both  2T (blue bars)  and  SRTM  
(red  bars)  models. Each region is based on the average 
of 7 subjects. Test/retest variability is actually slightly 
better for SRTM estimates than for 2T.
two target regions  (CAU and  FRO) are nearly identical to the putative reference region 
(CER) in the unblocked case because they reflect only (the same) non- displaceable binding. The 
data from these two experiments on the same animal have been normalized by injected activity.   
The behavior of the regions shown is typical.  These data are suggestive, but not definitive 
proof that CER is a valid reference region (See ”SRTM vs. 2T”,immediately below for 
criteria).  Further evidence of specific binding in CAU and FRO is shown
in 5b.  BPND declines in a dose-dependent manner as the specific KOR antagonist dose is 
increased from low to high.
h.   SRTM vs 2T: Can we use a reference region model?
A reference region model such as SRTM has a number of practical advantages, if its use is 
appropriate.  Its use obviates the need for arterial sampling, thus decreasing the risk to the patient and 
simplifying the PET experiment.  Figure 4 shows that estimation of BPND via SRTM and 2T is in 
good agreement and that use of the reference region method would be justified.  In this case, CER was 
used as the reference region.  The correlation based on all regionsover all subjects was BPND 
(SRTM) = 1.01*BPND(2T), R2 = 0.98,
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which confirms near-perfect agreement.  Note: this agreement between the 2T and SRTM does 
not validate the CER as a true reference region.  It indicates a valuable fact: the two estimates of 
BPND are consistent (they might both be biased for different reasons).  For many purposes, 
consistency may be sufficient to argue for adoption of
the SRTM or other reference method. For the reference 
region to be validated (i.e., shown to be devoid of 
specific binding), we must also show that VT of the 
region does not change in the presence of a pre- 
blocking drug such as NTX.
i.
Percent change between „test‟ and „retest‟
scans: How small an effect can we detect?
Small test/retest variability is essential for us to be able 
to  detect  small  diferences  between  conditions.    For 
each subject, the test-retest variability was measured by 
computing the ratio of the difference between binding 
potentials to their means:
100*(BPND(TEST) - BPND(RETEST))
[ ½ ( BPND(TEST) + BPND(RETEST) ) ].
The mean test-retest variability indices were 8.2% (2T)
and   7.2%   (SRTM)   indicating   that   BPND     values
increased during the retest scan (conducted in the 
afternoon of the same day) compared to the test scan, 
across all regions. Figure 6 shows the test/retest 
comparison as an average value over subjects for all 
regions.
Figure  8.  Top  row:  MRI images  (axial,  coronal,  sagittal)  of  individual
subject. Middle row: Corresponding BPND images estimated using SRTM 
Bottom: Corresponding BPND images estimated using SRTM2. They are 
slightly less noisy than SRTM, as would be expected.
j. 90 min vs 120 min results: Can we shorten the scan?
A 1 ½ hr PET scan is slightly less burdensome for the subject than a 2 hr scan and given the 
fairly rapid kinetics of the tracer, it seems worth considering the shorter scan.   Therefore, we 
compared results of BPND estimates from the SRTM model using the full 120 min worth of scan 
data and using only 90 minutes of data.  The answers were nearly identical.  The correlation plot 
between the two families of estimates is shown in Figure 7.   We conclude from this exercise that 
we need only to scan for 90 minutes in each scan session.  A shorter scan time could improve 
subject compliance.
k.   BPND images
One advantage of having a kinetically well-behaved tracer, such as [11C]-LY2795050 ([C-11]- 
PKAB), with sufficient signal to noise in the TACs for each pixel, is that we can produce pixel- 
by-pixel parametric images of BPND.  Figure 8 shows BPND (created with two variants of the 
SRTM model) for one of the subjects in our test/retest cohort.  The middle row in the figure 
presents three canonical views of the BPND estimated by SRTM; the bottom row repeats the same 
views of BPND images estimated via SRTM2 which imposes a constraint that the apparent efflux
rate parameter, k2‟ be the same at each voxel.   The constraint has the effect of reducing the
variance in the image which may further aid our ability to detect slight differences between
patient populations or conditions.  The images show that there is discernible specific binding of 
tracer in cortical areas and maximal specific binding in the amygdala and cingulate cortex.
Summary: As we have shown above, we have developed and validated a specific KOR ligand 
that has high specificity and sensitivity and that can be combined with our established ADP to 
evaluate the hypotheses that are central to the current proposal.
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3.   Source: a) Identify the source of the drug, device or biologic to be used.
All study medications (naltrexone) will be purchased from appropriate vendors through 
the Investigational Pharmacy of YNHH.
Production of [C-11]LY2795050 ([C-11]PKAB) will be performed with the permission of Yale-New
Haven Hospital RDRC
b) Is the drug or device provided free of charge?
Yes
No
If yes, by whom?
4.   Preparation and Use: Describe the method of preparation, storage, stability information, and for 
parenteral products, method of sterilization and method of testing sterility and pyrogenicity.
The starting material for the production of [C-11]PKAB / [C-11]LY2795050 will be provided by 
Eli Lilly and company. Manufacturing of [C-11]LY2795050 ([C-11]PKAB) will be carried out at 
the Yale PET Center.
[11C]Carbon dioxide is produced by bombardment of a target containing a mixture of nitrogen and
0.5 – 1% oxygen with accelerated protons.  [11C]CO2 is then converted to [11C]HCN using an 
automated chemistry device from GE Medical Systems.  Reaction of [11C]HCN with the iodo
precursor LY2806578 under Pd(0)-catalyzed conditions provides the radiolabeled benzonitrile 
intermediate [C-11]LY2893110, which is hydrolyzed under basic conditions and in the presence of 
hydrogen peroxide to produce the radioactive drug product [C-11]LY2795050 ([C-11]PKAB).
The product is purified by semi-preparative HPLC and formulated with a mixture of ethanol and 
saline (final ethanol concentration less than 10%).  The final product solution is filtered through a
0.22 um membrane filter for terminal sterilization before its release for dispensing and IV
administration.
The carbon-11 labeled drug product [C-11]LY2795050 ([C-11]PKAB) has a radioactive half-life 
of 20 min and has been demonstrated to be stable for at least 65 min after preparation and 
formulation.  An expiration time of 60 min post-formulation will be assigned to the drug product.
For each batch of the radioactive drug product [C-11]LY2795050 ([C-11]PKAB) that will be used 
for human study, pyrogen and sterility tests will be performed.  Pyrogen testing will be conducted 
in house at the Yale PET Center using FDA-approved method.  Sterility test will be performed by 
the Yale Microbiology Laboratory.
The radioactive drug product [C-11]LY2795050 ([C-11]PKAB) will be produced according to the 
local Drug Master File and to local quality control procedures in effect at the Yale PET Center. 
Production of [C-11]LY2795050 ([C-11]PKAB) will be performed with the permission of Yale- 
New Haven Hospital RDRC
5.   Use of Placebo:
Not applicable to this research project
Provide a justification which addresses the following:
a.   Describe the safety and efficacy of other available therapies (if any).
This is not a treatment trial or a treatment seeking population of heavy drinkers
b.   State the maximum total length of time a participant may receive placebo while on the study.
No placebo
c.   Address the greatest potential harm that may come to a participant as a result of not receiving 
effective therapy (immediate or delayed onset.)
Not a treatment seeking population
d.   Describe the procedures that are in place to safeguard participants receiving placebo.
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Not a treatment seeking population
6.   Use of Controlled Substances:
Will this research project involve the use of controlled substances in human subjects?
Yes
No  See instructions to view controlled substance listings.
If yes, is the use of the controlled substance considered:
Therapeutic: The use of the controlled substance, within the context of the research, has the 
potential to benefit the research participant.
Non Therapeutic: Note, the use of a controlled substance in a non therapeutic research study 
involving human subjects may require that the investigator obtain a Laboratory Research License. 
Examples include controlled substances used for basic imaging, observation or biochemical studies 
or other non-therapeutic purposes. See Instructions for further information.
7.   Continuation of Drug Therapy After Study Closure
Not applicable to this project
Are subjects provided the opportunity to continue to receive the study drug(s) after the study has 
ended?
Yes
No
If yes, describe the conditions under which continued access to study drug(s) may apply as well as 
conditions for termination of such access.
SECTION VII: HUMAN SUBJECTS
1.   Recruitment Procedures: Describe how potential subjects will be identified, contacted and 
recruited.
56 heavy drinkers, drinking on at least 4 days per week (20-45 weekly standard drinks for women 
and 25-70 for men), an equal number of family history positive and family history negative (as 
specified by the FHAM) will be recruited for the study. All subjects will be 21-65 years of age, 
physically healthy non-treatment-seeking heavy drinkers. Volunteers will be recruited through 
advertisements in local newspapers, postings in community locations (bars, coffee shops, grocery 
stores) and advertisements on free community TV channels. Additionally, 25 healthy controls who 
report drinking socially will be recruited to match the demographics and background of the heavy 
drinkers, including family history of alcoholism; these controls will be light social drinkers 
consuming less than or equal to 20 drinks per week for women, and less than 25 drinks per week 
for men in the past 90 days and not meet past or current criteria DSM-IV abuse or dependence 
criteria, for the past 5 years.  The remainder of the exclusion criteria will be similar to the heavy 
drinkers.
1. Indicate recruitment methods below.  Attach copies of any recruitment materials that will be used.
Flyers
Internet/Web Postings
Radio
Posters
Mass E-mail Solicitation
Telephone
Letter
Departmental/Center Website
Television
Medical Record Review
Departmental/Center Research Boards
Newspaper
Departmental/Center Newsletters
Web-Based Clinical Trial Registries
Other (describe):
Clinicaltrials.gov Registry (do not send materials to HIC)
2. Assessment of Current Health Provider Relationship for HIPAA Consideration: 
Does the Investigator or any member of the research team have a direct existing clinical 
relationship with any potential subject?
Yes, some of the subjects If yes, describe the nature of this relationship.
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No
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3. Subject Population Provide a detailed description of the targeted involvement of human subjects 
for this research project.
56 healthy heavy drinkers who are not currently seeking treatment for their drinking behavior, 
between 21-65 years of age, family history positive or family history negative. Also, 10 
healthy controls between 21-65 years of age matched on demographics including family 
history of alcoholism. 
4.   Inclusion/Exclusion Criteria: What are the criteria used to determine subject inclusion or 
exclusion? How will eligibility be determined, and by whom?
Inclusion criteria: 
Ages 21-65
Able to read English at 6th grade level or higher and to complete study evaluations
Meet DSM-IV criteria for alcohol abuse or dependence (assessed using the 
SCID)
Family history criteria (assessed using the FHAM; see Assessment section)
Family history positive subjects: At least one first-degree relative 
with alcoholism as determined by the FHAM
Family history negative subjects:  No first degree relative with alcoholism and no 2nd 
degree relative with alcoholism unless the participant cannot answer details about the 2nd 
degree family member’s drinking consequences on the FHAM.
   Average weekly alcohol consumption of standard drinks of at least 25-70 drinks for men 
and 20-65 drinks for women
   No more than 3 days abstinence/week in order to maximize the likelihood that subjects will 
choose to drink during the laboratory sessions
Exclusion criteria:
   Individuals who are seeking alcohol treatment or have been in alcohol treatment within the 
past 6 months
DSM-IV dependence criteria for other substances, other than nicotine in the past year
Positive for opiates, cocaine, benzodiazepines, or barbiturates at more than one appointment
Quantitative marijuana levels going up from PE to MR appointment
Regular use of psychoactive drugs including anxiolytics and antidepressants
Psychotic or otherwise severely psychiatrically disabled
Medical conditions that would contraindicate the consumption of alcohol
Medical conditions that would contraindicate the use of naltrexone such as hepatic 
dysfunction
   Any history of neurological trauma or disease, seizures, head injury, brain tumor, delirium, 
or hallucinations, or hepatic, cardiovascular, metabolic, endocrine, or gastrointestinal 
disease
   Subjects who at any intake appointment have a Clinical Institute Withdrawal Assessment 
Scale score of 8 or greater, or who report any history of significant or repeated alcohol 
withdrawals will be excluded from the study and referred for standard alcohol 
detoxification. This is to reduce the likelihood that subjects enrolled in the study will 
experience withdrawal symptomatology if they reduce their drinking.
   Women who are pregnant, nursing, or refuse to use a reliable method of birth control; urine 
pregnancy tests will be completed at intake and prior to administration of alcohol
   Subjects who report disliking spirits will be excluded because hard liquor will be provided 
during the alcohol administration components of the study.
   Subjects who have taken any investigational drug within 3 weeks immediately preceding 
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admission to the treatment period
   Subjects who report any use during the 30 days prior to randomization of the following:
anxiolytics, beta blockers, central nervous system stimulants, hypnotics, non-therapeutic
cause excessive sedation.
Subjects who have donated blood within the past six weeks
Subjects with a history of a bleeding disorder or are currently taking anticoagulants (such as 
Coumadin, Heparin, Pradaxa, Xarelto).
Additionally, subjects who meet the following imaging exclusion criteria will not be included in 
this study:
Subjects who suffer from claustrophobia.
Subjects with MRI-incompatible implants and other contraindications for MRI, such as 
pace-maker, artificial joints, non-removable body piercings, tattoos larger than 1 cm in 
diameter, claustrophobia, etc.
   Subjects who have received a diagnostic or therapeutic radiopharmaceutical within 7 days 
prior to participation in this study.
   Participation in other research studies involving ionizing radiation within one year of the 
PET scans that would causes the subject to exceed the yearly dose limits for normal 
volunteers.
   Subjects with history of IV drug use which would prevent venous access for PET tracer 
injection.
Severe motor problems that prevent the subject from lying still for PET and MR imaging. 
Subjects who complain of chronic pain (e.g., as the result of rheumatoid arthritis)
4.a. Will email or telephone correspondence be used to screen potential subjects for eligibility 
prior to the potential subject coming to the research office?
Yes
No
4.b. If yes, will identifiable health information be collected during this screening process and 
retained by the research team?
Yes
No
5.   Subject Classifications: Check off all classifications of subjects that will be invited to enroll in 
the research project. Will subjects, who may require additional safeguards or other
considerations, be enrolled in the study? If so, identify the population of subjects requiring special 
safeguards and provide a justification for their involvement.
Children
Healthy
Fetal material, placenta, or dead fetus
Non-English Speaking
Prisoners
Economically disadvantaged persons
Decisionally Impaired
Employees
Pregnant women and/or fetuses
Students
Females of childbearing potential
5.a. Is this research proposal designed to enroll children who are wards of the state as potential 
subjects?
Yes
No (If yes, see Instructions section VII #4 for further requirements)
SECTION VIII: CONSENT/ ASSENT PROCEDURES
1.Consent Personnel: List the names of all members of the research team who will be obtaining 
consent/assent.  Nicholas Franco, Dana Cavallo, Tricia Dahl, Thomas Liss, Suchitra Krishnan- 
Sarin, Evan Morris, Alissa Goldberg.
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2.   Process of Consent/Assent: Describe the setting and conditions under which consent/assent will
be obtained, including parental permission or surrogate permission and the steps taken to ensure
subjects‟ independent decision-making.
At the start of the intake session, all subjects will receive an explanation of the study including its
risks, benefits, and procedures, and will be given an opportunity to withdraw from the study. 
Following the resolution of any questions, the subject will be asked to sign the consent form, if 
he/she agrees to participate.
3.   Evaluation of Subject(s) Capacity to Provide Informed Consent/Assent: Indicate how the personnel 
obtaining consent will  assess the potential subject‟s ability and capacity to consent to the research being 
proposed.
Subjects with limited decision making capacity will not be enrolled in this study.
4.   Documentation of Consent/Assent: Specify the documents that will be used during the 
consent/assent process. Copies of all documents should be appended to the protocol, in the same 
format that they will be given to subjects.
Adult consent form
5.   Non-English Speaking Subjects: Explain provisions in place to ensure comprehension for 
research involving non-English speaking subjects. Translated copies of all consent materials must 
be submitted for approval prior to use.
Due to the intensity and complexity of the design of this study we will enroll only English 
speaking subjects.
6.   Waiver of Consent: Will you request either a waiver of consent, or a waiver of signed consent, for 
this study? If so, please address the following:
This section is not applicable to this research project
Waiver of consent: (No consent form from subjects will be obtained.)
a.         Does the research pose greater than minimal risk to subjects?      Yes       No 
b.         Will the waiver adversely affect subjects‟ rights and welfare?      Yes       No 
c.         Why would the research be impracticable to conduct without the waiver?
d.
Where appropriate, how will pertinent information be returned to, or shared with subjects 
at a later date?
Waiver of signed consent: (Verbal consent from subjects will be obtained.)
This section is not applicable to this research project
a.         Would the signed consent form be the only record linking the subject and the research?
Yes
No
b.         Does a breach of confidentiality constitute the principal risk to subjects?      Yes       No
OR
c.         Does the research pose greater than minimal risk?      Yes       No AND
d.
Does the research include any activities that would require signed consent in a non- 
research context?
Yes
No
7.  Required HIPAA Authorization: If the research involves the creation, use or disclosure of 
protected health information (PHI), separate subject authorization is required under the HIPAA 
Privacy Rule. Indicate which of the following forms are being provided:
Compound Consent and Authorization form
HIPAA Research Authorization Form
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8.   Request for waiver of HIPAA authorization: (When requesting a waiver of HIPAA 
Authorization for either the entire study, or for recruitment purposes only)
Choose one: For entire study:
For recruitment purposes only:
X
Describe why it would be impracticable to obtain the subject‟s authorization for use/disclosure of
this data - Data is collected over the phone and through survey monkey so it wouldn‟t be
practical to obtain authorization to use this data.
i.   If requesting a waiver of signed authorization, describe why it would be impracticable
to obtain the subject‟s signed authorization for use/disclosure of this data;
By signing this protocol application, the investigator assures that the protected 
health information for which a Waiver of Authorization has been requested will not 
be reused or disclosed to any person or entity other than those listed in this 
application, except as required by law, for authorized oversight of this research 
study, or as specifically approved for use in another study by an IRB.
Researchers are reminded that unauthorized disclosures of PHI to individuals outside of the Yale 
HIPAA-Covered entity must be accounted for in the “accounting for disclosures log”, by subject 
name, purpose, date, recipients, and a description of information provided.  Logs are to be 
forwarded to the Deputy HIPAA Privacy Officer.
SECTION IX: PROTECTION OF RESEARCH SUBJECTS
1.   Risks: Describe the reasonably foreseeable risks, including risks to subject privacy, discomforts, 
or inconveniences associated with subjects participating in the research.
The major potential risks in this study are related to naltrexone, administration of alcohol, the 
blood draw during the physical exam and alcohol drinking period, and the PET and MRI scans.
1. MRI:
MR carries a risk for subjects who are claustrophobia or have pacemakers, metal pieces, 
aneurysm clips, large colored tattoos, or any other contraindications for MR.  Magnetic 
resonance (MR) is a technique that uses magnetism and radio waves, not x-rays, to take pictures 
and measure chemicals of various parts of the body.  The United States Food and Drug 
Administration (FDA) has set guidelines for magnet strength and exposure to radio waves, and 
we carefully observe those guidelines.
2. Risks Associated with Radiation:
The Yale-New Haven Hospital Radiation Safety Committee (RSC) will review the use of 
radiation in this research study, and no subjects will be enrolled until RSC approval is obtained. 
This research study involves exposure to radiation from [C-11]PKAB PET scanning. This 
radiation exposure is not necessary for medical care and is for research purposes only. The total 
amount of radiation an individual subject will receive in this study is from 2 injections with a
total of ≤ 40 mCi from [C-11]PKAB plus transmission scans of the brain.
Although each organ will receive a different dose, the amount of radiation exposure subjects will
receive from this study is equal to an effective dose of 1.44 rem for a total of  ≤ 40 mCi of [C-
11]PKAB in 2 injections (approx. 20 mCi each). That is, a total of 1.44 rem for 2 PET scans is the
amount of radiation exposure that a subject will receive from the study.  This calculated value is 
used to relate the dose received by each organ to a single value.
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The amount of radiation subjects will receive in this study is below the dose guidelines established 
by the FDA and monitored by the Yale-New Haven Hospital Radiation Safety Committee for 
research subjects. This guideline sets an effective dose limit of 5 rem per year.
3. Alcohol:
A number of medical conditions could potentially be worsened by acute alcohol administration 
(e.g., liver disease, cardiac abnormality, pancreatitis, diabetes, neurological problems, and 
gastrointestinal disorders). As a result, subjects with medical problems as revealed by physical 
exam and laboratory findings will be excluded from the study.  Alcohol may also cause nausea in 
high doses; however, nausea is not expected at the dose being used in this sample of heavy 
drinkers. Subjects will not be drinking to levels more than they typically consume in their own 
drinking context and with the exception of the priming dose, they determine the amount of 
alcohol consumed.
Another area of potential risk to subjects under the influence of alcohol involves their safety 
during the experimental procedures. Although impairment of gross motor coordination in heavy 
drinkers is rare at the alcohol dose used in this study, all subjects will be under the supervision of 
the experimenters to prevent possible accidents such as falls. Subjects will not leave the 
laboratory during the self-administration procedure. By staying in the YCCI or CNRU overnight, 
the possibility that the subject might leave the session and continue to drink alcohol thereby 
placing themselves at risk for accidents is prevented.
Alcohol is a reinforcing agent, which may cause changes in behavior including repetitive or 
excessive alcohol consumption. Because of this, the administration of alcohol to alcoholics in 
treatment could potentially impede the progress of their recovery. In addition, the administration 
of alcohol to sober alcoholics living in the community presents a possible risk of relapse. As a 
result, we will be recruiting non-abstinent non-treatment seeking alcoholics in keeping with the 
National Advisory Council on Alcohol Abuse and Alcoholism's (1989) recommended guidelines 
on ethyl alcohol administration. At completion of the study, we will make a serious and 
concerted effort to link the subject with treatment for their alcohol problems. This will be done 
by giving the subject objective feedback about the fact that their drinking exceeds standards for 
avoiding hazardous drinking, providing a brief one session motivational intervention for their 
drinking, and by arranging for alcohol treatment services if they are interested. In our previous 
and ongoing work, several participants quit drinking and many others reduced their drinking in 
the three months following this intervention.
4. Naltrexone:
Naltrexone has been shown to have an effect on the embryo in the rat and the rabbit when given 
in doses approximately 140 times the human therapeutic dose.  Naltrexone, an opioid antagonist, 
is widely used in the treatment of opioid addiction and more recently has been found to be 
beneficial in the treatment of alcoholism.  Numerous studies have found naltrexone use to be safe 
and rarely associated with toxicity or severe side effects.  The most frequent reported side effects 
are gastrointestinal in nature.  Those include epigastric pain, nausea and vomiting.  Other, less 
frequent side effects include nervousness, dizziness, headaches, blurred vision, low energy, 
fatigue, sleepiness, joint and muscle pain and insomnia.  Hepatotoxicity, the most serious 
potential side effect, has been shown in studies using very high doses of naltrexone (1400 to
2100 mg per week).  At the doses used in this study naltrexone has not been reported to produce 
hepatotoxic effects.  However, we will monitor liver function tests prior to the study and exclude 
individuals with evidence of significant hepatocellular injury (AST, ALT >3x normal established 
in pregnant and nursing women, they will be excluded from participation.  Naltrexone can also
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precipitate or exacerbate opiate withdrawal, as a results subjects with abuse or 
dependence on opiates will be excluded from the study on the basis of self-report and 
urine drug screens.
Since naltrexone is an opiate antagonist, alternative nonopioid methods of analgesia can 
be used. In an emergency situation requiring opioids, the amount of opioids necessary 
for analgesia may be greater than usual, and the resulting respiratory depression may be 
deeper and more prolonged.  As a result, a rapidly acting analgesic which minimizes 
respiratory depression is preferred and the amount of the analgesic administration 
titrated to the needs of the patient in a setting equipped and staffed for cardiopulmonary 
resuscitation.  As a result, subjects will be given a card showing that they may be 
receiving naltrexone.  This card will provide detailed information to medical personnel 
describing the special precautions necessary in the event that the subject should require 
pain management.  In addition, this card will have a code number on it that can be used 
to identify which medication the subject is on.  A phone number of the pharmacy and for 
the physician on call at the Connecticut Mental Health Center will be listed on the card 
in the event of an emergency in which it is necessary to determine whether the subject is 
on active naltrexone.
5. Interactions of Naltrexone and Alcohol:
There are no known risks to contraindicate the administration of alcohol to subjects on 
naltrexone. It has been shown that pharmacokinetics properties of naltrexone and ethanol 
are not altered on simultaneous administration of both agents.
6.  Risks Associated with Blood Drawing and IV line Insertion:
Drawing blood and inserting an intravenous line (IV) into an arm vein are safe and 
standard medical procedures. Sometimes a bruise will occur at the puncture site and 
rarely a blood clot or infection will occur in the vein. Certain individuals may feel light-
headed during venipuncture. The volume of blood collected during this study, include 
screening laboratories, will be approximately 19 tablespoons. This is not expected to 
have any serious negative effects on a study participant.
Subjects will have approximately 30 cc of blood drawn at the intake appointment to 
determine liver and kidney functioning and for genetics testing and a total of 60 cc of 
blood during the 2 ADPs. 180 cc will be taken at the PET scans and an additional 15cc 
in PK samples will be drawn during the NTX PET scan.  Therefore, the total amount of 
blood drawn during the study ( 30+60+180+15= 285cc) is within the HIC guidelines of 
450 cc within eight research weeks and the blood loss poses minimal risk in healthy 
subjects. We will advise subjects against donating blood for six weeks following study 
participation.
7. Risks Associated with Use of an Arterial Catheter:
On the PET scan day, a radial arterial catheter will be inserted. Arterial sampling may be 
associated with mild-to-moderate pain or bruising at the puncture site. In rare instances 
blocking of the artery, poor healing, hematoma, inflammation, or infection at the catheter 
insertion site may occur. Certain individuals may feel light-headed during arterial catheter 
placement. If for some reason, an arterial catheter cannot be inserted, after no more than 
three attempts per arm by a trained staff member, per the Yale University Positron 
Emission Tomography Center, the scan will be rescheduled for another day and the 
participant will still be paid $50 for his/her time. At the rescheduled scan, the physician 
will try to insert an arterial catheter again and the scan will be conducted regardless of 
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whether or not the catheter was inserted.
For two days following the placement of the arterial line, participants will be instructed to 
check their wrist/arm daily.  The study team will also be in touch with them daily either via 
phone, or in person, during this two-day period. If they experience any excessive pain, 
tenderness, swelling, redness, drainage, skin color changes, numbness, pins and needles, or 
decreased strength in the arm that had the catheter, they are instructed call the study team 
immediately (203-464-6015).  They can also contact the study PI Dr. Krishnan-Sarin (860-
575-9895), the PET center physician, Dr, David Matuskey (203-370-1403), or the study 
physician, Dr. Julia Shi (203-781-4640).
8.  Alcohol Withdrawal:
We will not ask participants to alter their drinking behavior during their participation in the 
study.  However, there is always the possibility that some participants may reduce or stop 
drinking during the outpatient period while on the study medication.  Therefore, we will 
inform that that some individuals who reduce or stop their drinking can experience alcohol 
withdrawal symptoms such as mild agitation, anxiety, restlessness, tremor, loss of appetite 
and difficulty sleeping or even more severe (but rare) symptoms like extreme restlessness, 
nervousness, disorientation, confusion, hallucinations (hearing and seeing things that are 
not there) and seizures, but these are extremely rare.  We will monitor them daily during 
their visits to our clinic and will also inform them that if they experience worsening of 
withdrawal symptoms (CIWA > 8) we may have to hospitalize them and give them 
medications that are typically used to treat and manage withdrawal including 
benzodiazepines, such as chlordiazepoxide (librium), and other medications such as 
carbamazepine (tegretol).
9. Rating Scales and Questionnaires:
These are all noninvasive and should add no risk. The major disadvantages are the time 
taken to complete them, and possible breach of confidentiality. Our past experience with 
these measures indicates that they are acceptable to subjects. Careful efforts aimed at 
maintaining confidentiality will be made.
10.  Laboratory Tasks:  The computer tasks (, EDT and Cued Go-No-Go) as well as the cold 
water task can produce some uneasiness at the time of the task.  The hand kept in the very 
cold water can be uncomfortable. However, once the task is over, there is very little anxiety 
that carries over, thus posing minimal risk.  Moreover, the participants will have total 
control over the task and can stop performing it if he/she gets too uncomfortable.  There is 
the possibility that the desire to drink may occur in participants during the task, which may 
linger after the end of the task. 
2.   Minimizing Risks: Describe the manner in which the above-mentioned risks will be 
minimized.
1) Naltrexone:
Effective screening will exclude all subjects who would be at greater risk for complications 
because of medical, neurological or psychiatric illnesses.  Individuals currently dependent 
on other drugs will be screened out.  Subjects who are using opiates will be excluded to 
avoid any possibility of the subjects experiencing naltrexone precipitated opiate 
withdrawal. The risk of hepatotoxicity will be minimized by excluding subjects with a 
history of cirrhosis or significantly elevated liver enzyme tests. Subjects will be issued 
medcards which allow health professionals to find out more about Naltrexone by calling 
the CMHC pharmacy. Subjects will also be constantly monitored for troublesome side 
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effects during the course of the outpatient and inpatient periods.
Given the uncertain effects of naltrexone during pregnancy, the following precautions will 
be taken for women:  1) urine pregnancy tests will be performed at intake, and pregnant or 
nursing women will be excluded from participation, and encouraged to seek advice about 
the risk of heavy drinking, encouraged to seek treatment and if interested referred to other 
cessation programs; 2) women must agree to use a reliable method of birth control while 
they are in the study and to alert the principal investigator if she departs from her birth 
control plans or if, in spite of adherence to these plans, she thinks she might be pregnant.
2)  Alcohol Challenges:
The alcohol challenges will be conducted by personnel experienced in alcohol challenge 
research. As described above, all subjects will be under supervision to prevent possible 
accidents. At the end of the challenge session all subjects will be kept in the HRU where 
they will stay overnight to prevent the possibility that they would continue drinking after 
the session and place themselves at risk of accidents. Although we have never had a 
subject chose to leave a session early, should a subject insist on leaving the research 
setting prematurely, we will provide transportation back to their residence. This 
contingency is explicitly addressed in the consent form. Clearly, subjects are free to 
discontinue the experiment at any time.  However, ifa subject chose to discontinue 
participation after alcohol has been administered we will require them to stay in the HRU 
until their blood alcohol level is below 0.04 and they will then be provided with a ride 
home. Furthermore, at the Principal Investigator’s discretion, a participant will be 
discontinued if he/she does not drink any of the choice drinks at ADP 1. This absence of 
drinking creates a floor effect and does not allow for evaluation of change in drinking 
behavior at ADP 2 after taking study medication. Given the cost of the scan and the 
hospital visit, it does not seem reasonable to continue participants whose data will not be 
meaningful. Participants will be told that the study doctor may discontinue his/her 
participation if they think you are not responding well to the medication.
3)  Research Records:
Right to privacy for participation in this research will be protected through anonymous coding 
of data and proper storage of research records. Access will be limited to the PI and her 
designates involved in the study. A certificate of confidentiality has been obtained from 
NIAAA. Safeguards include screening by experienced professionals in order to ensure that 
the inclusion
and exclusion criteria are met before patients are entered in the study, including physical 
exam and laboratory tests.
4)  Risks Associated with Blood Drawing:
The risks of bruising, clotting, and infection will be minimized by having venipuncture 
performed by trained and experienced personnel under sterile conditions. To avoid injury due 
to fainting, the antecubital vein catheter will be inserted when the subjects are recumbent. The 
blood draws during PET scanning sessions will be obtained from the already inserted 
catheter, to minimize discomfort.
5)  Risks Associated with Use of an Arterial Catheter:
Risks of radial artery cannulation are minimized by having the procedure performed by an 
experienced physician. Pain is minimized by local anesthesia. Bleeding is prevented by 
local pressure applied for a minimum of 15 minutes after catheter removal. Subjects will 
have their hand and finger blood supply examined after arterial cannulation and again 
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following catheter removal. Also, subjects will be asked to abstain from aspirin and other 
NSAIDs for 7-10 days prior to arterial line insertion and 7-10 days following arterial line 
removal.  Subjects will be provided a 24 hour emergency physician telephone number to 
call if they encounter pain, discoloration, numbness, tingling, coolness, hematoma, 
inflammation, or any other unusual symptoms in the wrist or hand, or fever, chills or 
drainage from the vascular puncture sites, following the procedure. Nurses will provide 
the subjects an instruction sheet documenting problems to watch for and procedures to 
follow should such problems occur. Infection is avoided by adequate cleansing of the skin 
prior to intravascular line insertion.
6)  Risks Associated with Radiation:
The dose of radiation will be submitted for approval to the Yale-New Haven Hospital 
Radiation Safety Committee (Y-NHH RSC). All scans will be done in the presence of 
medical supervision and trained nursing staff in an institution specifically designed to 
support imaging studies. In the event of serious medical complications, the PET scan 
facilities have immediate access to or consultation with specialized medical units at the 
Yale-New Haven Hospital.  Preparation of radiopharmaceuticals and performance of PET 
scans will be by radiochemists, physicians, and technologists of the Department of 
Diagnostic Radiology, Yale University School of Medicine. These professionals are 
qualified by training and experience in the safe use and handling of radiopharmaceuticals. 
Subjects will be asked about their previous radiation exposure and those who have had 
research exposure within the past year will be excluded if their cumulative annual exposure 
(including the present study) exceeds FDA limits.   The information on the previous 
radiation exposure of study subjects will be notified to the study doctor.
No PET studies will be performed on pregnant or potentially pregnant women, as 
confirmed by pregnancy testing during evaluation and on each scan day before initiation 
of any scan procedures. If subjects are breastfeeding they will not be able to participate in 
this research study.
7) MRI:
Magnetic resonance imaging (MRI) scans (3 T) will be collected in each subject to co-
register PET and MRI for image analysis. Within four weeks of the PET study, an MRI 
will be acquired at the Yale University MRI Center. In the event that the PET does not 
occur within six months of the MRI, subjects will be asked to perform a repeat MRI. 
Subjects will be taken through a ferromagnetic metal detector before entering the scan 
room. The acquisition sequence is a 3D fast spoiled grass (FSPGR) MR pulse sequence 
with an IR prep of 300 ms. (TE= 3.3 ms, flip angle=17 degrees;   slice thickness= 1.2 mm) 
optimized for delineating gray matter/white matter/CSF boundaries.   The small voxel size 
(0.93 X 1.2 X 0.93 mm) provides high-resolution volumetric images. MR images provide a 
matching anatomical atlas for creating individualized region-of-interest templates for each 
subject.
To minimize risks, each subject will fill out the Yale Magnetic Resonance Research Center 
MRI Safety Questionnaire before the study. Only subjects who fulfill the criteria by this 
questionnaire will be eligible for the study. In addition, subjects will remove all metal 
(watch, hair pins, jewelry) and change into scrubs immediately prior to the study and pass 
through the metal detector in the MRRC before entering the MRI room.
Subjects will be watched closely throughout the MR study.  Some people may feel 
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uncomfortable or anxious.  If this happens, the subject may ask to stop the study at any 
time and we will take them out of the MR scanner.  On rare occasions, some people might 
feel dizzy, get an upset stomach, have a metallic taste or feel tingling sensations or muscle 
twitches.  These sensations usually go away quickly but we will ask subjects to tell the 
research staff if they have them.
There are some risks with an MR study for certain people.  If subjects have a pacemaker or 
some metal objects inside their body, they may not be in this study because the strong 
magnets in the MR scanner might harm them.  Another risk is the possibility of metal 
objects being pulled into the magnet and hitting a subject.  To reduce this risk we require 
that all people involved with the study remove all metal from their clothing and all metal 
objects from their pockets.  We also ask all people involved with the study to walk through 
a detector designed to detect metal objects.  It is important to know that no metal can be 
brought into the magnet room at any time.  Also, once subjects are in the magnet, the door 
to the room will be closed so that no one from outside accidentally goes near the magnet.  If 
the subject has any metallic prostheses/implants they will be excluded from the study.
This MR study is for research purposes only and is not in any way a clinical examination.  
The scans performed in this study are not designed to find abnormalities.  The primary 
investigator, the lab, the MR technologist, and the Magnetic Resonance Research Center are 
not qualified to interpret the MR scans and are not responsible for providing a diagnostic 
evaluation of the images.  If a worrisome finding is seen on a subject’s scan, a radiologist or 
another physician will be asked to review the relevant images.  Based on his or her 
recommendation (if any), the primary investigator or consulting physician will contact the 
subject, inform them of the finding, and recommend that they seek medical advice as a 
precautionary measure.  The decision for additional examination or treatment would lie 
solely with the subject and their physician.  The investigators, the consulting physician, the 
Magnetic Resonance Research Center, and Yale University are not responsible for any 
examination or treatment that a subject receives based on these findings.  The images 
collected in this study are not a clinical MR exam and for that reason, they will not be made 
available for diagnostic purposes.
3.   Data and Safety Monitoring Plan: Replace with new HIC text for data safety and monitoring
plan form hrpp website, document: 420FR1DSMPTemplate.pdf (use text for moderate risk 
studies) Include an appropriate Data and Safety Monitoring Plan (DSMP) based on the 
investigator‟s risk assessment stated below. (Note: the HIC will make the final determination of 
the risk to subjects.) For more information, see the Instructions, page 24.
a.   What is the investigator‟s assessment of the overall risk level for subjects participating 
in this study?
This protocol is a moderate risk protocol and therefore requires a data safety and 
monitoring plan.
b.   If children are involved, what is the investigator‟s assessment of the overall risk level
for the children participating in this study? NA
c.Data and Safety Monitoring Plan:
1. Personnel responsible for the safety review and its frequency:
The principal investigator will be responsible for monitoring the data, assuring protocol
compliance, and conducting the safety reviews at the specified frequency which must be 
conducted at a minimum of every 6 months (including when reapproval of the protocol is 
sought). During the review process, the principal investigator (monitor) will evaluate 
whether the study should continue unchanged, require modification/amendment, continue 
or close to enrollment. Either the principal investigator, or the Yale HIC have the authority 
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to stop or suspend the study or require modifications.
2. The risks associated with the current study are deemed moderate for the 
following reasons: (choose those that apply)
1. We do not view the risks associated with the Naltrexone as minimal.
2. We do not view the risks associated with the combined use of Naltrexone and alcohol as 
minimal.
3. Given the now established safety and validity of the current Naltrexone in our 
prior work, we do not view the proposed studies as high risk.
4. Given our experience with the combined co-administration Naltrexone and alcohol, we do not 
view the proposed studies as high risk.
Although we have assessed the proposed study as one of moderate risk, the potential 
exists for anticipated and/or unanticipated adverse events, serious or otherwise, to occur 
since it is not possible to predict with certainty the absolute risk in any given individual 
or in advance of first-hand experience with the proposed study methods. Therefore, we 
provide a plan for monitoring the data and safety of the proposed study as follows:
3. Attribution of Adverse Events:
Adverse events will be monitored for each subject participating in the study and
attributed to the study procedures / design by the principal investigator, Suchitra Krishnan-Sarin, 
PhD, according to the following categories:
a.) Definite: Adverse event is clearly related to investigational procedures(s)/agent(s). 
b.) Probable: Adverse event is likely related to investigational procedures(s)/agent(s). 
c.) Possible: Adverse event may be related to investigational procedures(s)/agent(s). 
d.) Unlikely: Adverse event is likely not to be related to the investigational 
procedures(s)/agent(s).
e.) Unrelated: Adverse event is clearly not related to investigational 
procedures(s)/agent(s).
4. Plan for Grading Adverse Events:
The following scale will be used in grading the severity of adverse events noted during
the study:
1. Mild adverse event
2. Moderate adverse event
3. Severe
5. Plan for Determining Seriousness of Adverse Events: 
Serious Adverse Events:
In addition to grading the adverse event, the PI will determine whether the adverse event 
meets the criteria for a Serious Adverse Event (SAE). An adverse event is considered 
serious if it:
1. is life-threatening
2. results in in-patient hospitalization or prolongation of existing hospitalization
3. results in persistent or significant disability or incapacity
4. results in a congenital anomaly or birth defect OR
5. results in death
6. based upon appropriate medical judgment, may jeopardize the subject‟s health
and may require medical or surgical intervention to prevent one of the other
outcomes listed in this definition, or
7. adversely affects the risk/benefit ratio of the study
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An adverse event may be graded as severe but still not meet the criteria for a Serious 
Adverse Event. Similarly, an adverse event may be graded as moderate but still meet the 
criteria for an SAE. It is important for the PI to consider the grade of the event as well as 
its “seriousness” when determining whether reporting to the HIC or HSC is necessary.
6. Plan for reporting serious AND unanticipated AND related adverse events, 
anticipated adverse events occurring at a greater frequency than expected, and 
other unanticipated problems involving risks to subjects or others to the HIC or 
HSC.
The investigator will report the following types of adverse events to the HIC or HSC: a)
serious AND unanticipated AND possibly, probably or definitely related events; b) 
anticipated adverse events occurring with a greater frequency than expected; and c) other 
unanticipated problems involving risks to subjects or others.
These adverse events or unanticipated problems involving risks to subjects or others will 
be reported to the HIC or HSC within 48 hours of it becoming known to the investigator, 
using the appropriate forms found on the website.
7. Plan for reporting adverse events to co-investigators on the study, as appropriate 
the protocol’s research monitor(s), e.g., industrial sponsor, Yale Center for Clinical 
Investigation Research Subject Advocates (RSAs), Cancer Center's Quality 
Assurance, Compliance and Safety Committee (QUACS) Protocol Review 
Committee (PRC), DSMBs, study sponsors, funding and regulatory agencies, and 
regulatory and decision-making bodies.
For the current study, the following individuals, funding, and/or regulatory
agencies will be notified (choose those that apply):
X All Co-Investigators listed on the protocol.
X Yale Center for Clinical Investigation
X Yale New-Haven Hospital Radiation Safety Committee (Y-NHH-RSC)
□ Quality Assurance and Compliance and Safety Committee (QUACS)
□ National Institutes of Health
□ Food and Drug Administration (Physician-Sponsored IND # 
)
□ Medical Research Foundation (Grant 
)
The principal investigator, Suchitra Krishnan-Sarin, PhD, will conduct a review of all adverse 
events upon completion of every study subject. The principal investigator will evaluate
the frequency and severity of the adverse events and determine if modifications to the 
protocol or consent form are required.
d. For multi-site studies for which the Yale PI serves as the lead investigator: NA
i.   How will adverse events and unanticipated problems involving 
risks to subjects or others be reported, reviewed and managed?
ii.   What provisions are in place for management of interim 
results?
iii.  What will the multi-site process be for protocol 
modifications?
4.
Confidentiality & Security of Data:
a.
What protected health information about subjects will be collected and used for the 
research? Name, address, telephone number, email address SS #, and birth date will be 
collected from subjects
b.
 How will the research data be collected, recorded and stored? Research will be 
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collected in a private room by a research assistant, recorded in binders, and stored in a 
locked, secure location. 
c. How will the digital data be stored?  X Secure Server
d.
What methods and procedures will be used to safeguard the confidentiality and 
security of the identifiable study data and the storage media indicated above during the 
subject participation in the study?
Identifiable research data, including recruitment and screening information and code keys, 
are stored on a secure database located on the internal PET Center Network.  The PET 
network is protected by a Cisco PIX firewall operated by ITS.  All research data are 
backed up nightly to a Dell PV-136T library with 4 IBM Ultrium-TD2 tape drives using 
the backup software Legato Networker 7.3 from EMC. Human subjects enrolled in the 
study are assigned a subject-specific random identifier.   Subject identifiers and the means 
to link the subject names and codes with the research data are stored in separate locations 
within the database.  The software of the database limits the ability to connect the random 
identifier to the actual subject identification information to those members of the research 
team who have direct contact with the research subjects, such as physicians,  research 
nurses, and technologists. Access to the database is password protected and each research 
team member is required to have a unique ID and password to gain access to the database.  
Authorized users employ their netid, and authentication is performed using Yale‟s central 
authentication server.  Users always access research data through the random identifier only.  Direct 
identifiers belonging to subjects who withdraw from the study will be stripped from the 
key.
e.
What mechanisms are in place to ensure the proper use and continued protection of 
these data after the subject participation in the study has ceased?
Procedures to ensure confidentiality follow the regulations and policies of Yale School of
Medicine.  The security measures in 4d will continue to be in place to protect study data.
f.
What will be done with the data when the research is completed? Are there plans to 
destroy the identifiable data? If yes, describe how, by whom and when identifiers will 
be destroyed. If no, describe how the data and/or identifiers will be secured.
Study data will be archived in a secure storage facility, data will not be destroyed.
g.
Who will have access to the protected health information? (such as the research 
sponsor, the investigator, the research staff, all research monitors, FDA, QUACS, SSC, 
etc.)
The PI, study personnel and the Department of Psychiatry Business Office
h.   Which external or internal individuals or agencies (such as the study sponsor, FDA, 
QUACS, SSC, etc.) will have access to the study data?
Internal: Principal investigators and their respective research teams, YCCI Hospital 
Research Unit, CMU, PET and MRI centers, Y-NHH Radiation Safety Committee (RSC) 
and Yale University RSC.
i.
If appropriate, has a Certificate of Confidentiality been 
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obtained? A certificate has been obtained from NIAAA
j
Are there any mandatory reporting requirements? (Incidents of child abuse, elderly 
abuse, communicable diseases, etc.)
Child abuse, elder abuse and intent to harm self or others.
5.
Potential Benefits: Identify any benefits that may be reasonably expected to result from 
the research, either to the subject(s) or to society at large. (Payment of subjects is not 
considered a benefit in this context of the risk benefit assessment.)
This study will not directly benefit the participants. The results of this laboratory-based 
drinking paradigm with high resolution PET imaging before and after naltrexone treatment 
will shed new light on the actions of NTX and the dynorphin/KOR system in alcohol 
drinking behavior. An additional benefit to subjects is that they will be offered feedback 
about their drinking and active referral to treatment for their alcohol problems should they 
so desire. Most alcohol abusers have impairments in their psychosocial functioning as a 
result of their drinking and can benefit from treatment. The proposed study may be a 
conduit for some to receive treatment and for others to reduce their drinking on their own. 
Although the direct benefit is not great for subjects, given the potential benefit to 
developing effective treatments for alcoholism, the risk-benefit ratio appears favorable.
SECTION X: RESEARCH ALTERNATIVES AND ECONOMIC CONSIDERATIONS
1.
Alternatives: What other alternatives are available to the study subjects outside of the 
research?
NA-This is not a treatment study. However, participants will be provided with a 
motivational interview upon completion of the inpatient and outpatient portions of this 
study to provide feedback on their drinking. If they request a referral for treatment to cut 
back or quit drinking at this time, we will provide them with referral options.
2.
Payments for Participation (Economic Considerations): Describe any payments that 
will be made to subjects, the amount and schedule of payments, and the conditions for 
receiving this compensation.
Heavy Drinkers: Because this study may not have direct benefits to the individual 
participant, subjects will be offered payment for their participation. Subjects will have the 
opportunity to receive $50 for the initial interview, $50 for the physical examination, $250 
for the first PET scan, $450 for the second PET scan and $50 for the MRI. Subjects will 
also receive $150 for participating in the first drinking paradigm, $10 per day (up to 11 
days) for transportation to our clinic for daily medication dose, $170 for taking medication 
on all days, $250 for participating in the second lab drinking paradigm, and $30 for 
completing a one week follow up.  In addition, all subjects will have the opportunity to 
earn an extra $36 (depending on their drink consumption) during each of the ADP sessions 
and $30 for computer assessments at each of the ADP sessions. Additionally, in the case 
that the first arterial line cannot be placed at the first PET scan, participants will be paid 
$50 and rescheduled. In the event that a participant is asked to come back in for a repeat 
lab appointment (bloodwork or EKG) he/she will be paid $25. In the event that the 
participant serves as a standby for ADP/PET 1, he/she will be paid $50. In the event that 
a participant needs a repeat MRI, he/she will be paid $50. In the event that a participant 
needs to complete an extra overnight visit on the evening prior to a rescheduled PET 
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scan, he/she will be paid $100. That is a possible total of $2017, for attending and 
participating in all appointments.
An additional benefit to subjects is that they will be offered feedback about their drinking 
and active referral to treatment for their alcohol problems should they so desire. Most 
alcohol abusers have impairments in their psychosocial functioning as a result of their 
drinking and can benefit from treatment. The proposed study may be a conduit for some to 
receive treatment and for others to reduce their drinking on their own.
This progressively increasing payment structure was developed in order to motivate 
subjects to complete all phases of the study, since obtaining complete data in this within-
subject crossover study is the key to achieving the goals of the project.  We are trying to 
avoid early drop out by using increasing incentives for completion of the entire study.
Healthy controls:  Healthy controls will be paid $50 for the initial interview, $50 for the 
physical examination, $250 for the PET scan, and $50 for the MRI. Additionally, in the 
case that the first arterial line cannot be placed at the PET scan, participants will be paid 
$50 and rescheduled. In the event that a participant is asked to come back in for a repeat 
lab appointment (bloodwork or EKG) he/she will be paid $25. In the event that the 
participant serves as a standby for a PET scan, he/she will be paid $50. In the event that 
a participant needs a repeat MRI, he/she will be paid $50. That is a possible total of $575 
for attending and participating in all appointments.
3.
Costs for Participation (Economic Considerations): Clearly describe the subject‟s costs 
associated with participation in the research, and the interventions or procedures of the 
study that will be provided at no cost to subjects.
The subject will incur no costs to participate in this research and will receive a full 
physical exam at no cost.
4.   In Case of Injury: This section is required for any research involving more than minimal 
risk. a.  Will medical treatment be available if research-related injury occurs? Yes, but 
injury is unlikely
b.  Where and from whom may treatment be obtained? Treatment may be provided by 
Yale- New Haven Hospital or any health care provider chosen by the study subjects.
c.  Are there any limits to the treatment being provided? Limits to treatment may be 
imposed by the insurance carrier of the study subjects.
d.  Who will pay for this treatment? The study participant or their insurance carrier will 
be expected to pay for the cost of the treatment. No additional financial compensation 
for injury or lost wages is available.
e.   How will the medical treatment be accessed by subjects? The study team will provide 
assistance to the subjects in accessing medical treatment through referrals, or the study 
subjects may choose to access treatment on their own.
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ICF_001.pdf: 
Study Title: Kappa-PET imaging and naltrexone in alcohol drinking behaviors 
ClinicalTrials.gov Identifier: NCT01625611 
Document Date: 1/10/2018 


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COMPOUND AUTHORIZATION AND CONSENT FOR PARTICIPATION IN A 
RESEARCH PROJECT
YALE UNIVERSITY SCHOOL OF MEDICINE – YALE-NEW HAVEN HOSPITAL
Study Title: Kappa-PET imaging and naltrexone in alcohol drinking behaviors 
Principal Investigator: Suchitra Krishnan-Sarin, Ph.D., Associate Professor of Psychiatry
Funding Source: NIAAA
Invitation to Participate and Description of Project
You are invited to take part in a research study designed to help identify important new targets 
for the development of new pharmacotherapies to treat alcohol dependence.  The primary 
purpose of the study is to increase our knowledge of receptor function in the brains of people 
who are heavy drinkers and taking naltrexone, a medication that has been approved for the 
treatment of alcohol dependence. Receptors are special molecules in the brain to which other 
molecules (neurotransmitters) attach during the normal every-day workings of the brain.  Drugs 
can bind to those receptor molecules as well.  Recent evidence suggests that kappa opioid 
receptors (KOR’s) may play an important role in alcohol drinking behavior. This study will try to 
determine if naltrexone’s ability to attach to these receptors is related to its effectiveness.  We 
will use PET (positron emission tomography) for this study.  PET is a type of imaging device 
found in nuclear medicine. It is used for tracking the presence of injected radioactive materials in 
the body. 
You have been chosen to participate because you report being a heavy alcohol user, are currently 
using alcohol, not regularly using other street drugs, are not seeking treatment for your alcohol 
use, and you may or may not have a family history of alcohol-related problems.  Since this is not 
a treatment study, you should not participate in this project if you are seeking treatment for your 
drinking.  
In addition, in this project we would also like to study genes that might be related to your 
drinking behavior.  All cells in the body contain genes.  Blood contains genes.  Genes provide 
instructions for processes (such as binding of molecules) in the body and for traits such as eye 
color.  Everyone's genes are a little different.  Information about these differences among people 
may help researchers understand how best to use drugs to treat disease.   
In order to decide whether or not you wish to be a part of this research study you should know 
enough about its risks and benefits to make an informed decision. This consent form gives you 
detailed information about the research study. A member of the research team will discuss the 
study with you. This discussion will go over all aspects of our research: the goals, the procedures 
that will be performed, the risks, and the possible benefits. Once you understand the study, you 
will be asked if you wish to participate; if so, you will be asked to sign this form.
Description of Procedures
The study contains seven parts: 1) Evaluation: We will obtain informed consent and evaluate 
your eligibility for the study using clinical assessments, a physical exam, and a Magnetic 
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Resonance Imaging (MRI) scan. If you are eligible, you will be scheduled for the rest of the 
study;  2) Practice PET: You may or may not  participate in a mock (practice) PET (Positron 
Emission Tomography) scan; 3) First PET Scan; 4) First Alcohol Drinking Session: Baseline 
ADP and overnight stay at the Hospital Research Unit (HRU) of Yale Center for Clinical 
Investigation (YCCI) at Yale New Haven Hospital; 5) Medication period: After baseline PET 
scan and ADP are complete, the medication period begins (5-11 days depending on scheduling); 
6) Second Alcohol Drinking Session: Second ADP and stay overnight at YNHH; 7) Second PET 
Scan. 
1) Evaluation
At the Substance Abuse Center (SAC) in Connecticut Mental Health Center (CMHC) (34 Park 
Street, New Haven), we will check whether or not you are eligible to participate in the study. 
This will require two to four hours of your time. You will be asked to not use any drugs while 
you are participating in this study.  If you test positive for any drugs or alcohol, you may not be 
paid for your appointment and may be asked to reschedule.  Females will have a pregnancy test 
and will only be allowed to participate if the result is negative. You will be interviewed and 
asked to fill out questionnaires. Following this, at your convenience, we will schedule you for a 
complete physical examination that will include an electrocardiogram, and blood and urine tests, 
which will require about 1½ hours of your time.  You will also get a psychiatric evaluation to 
confirm your eligibility and may be scheduled to meet with the study physician.  During the 
physical exam, if you have agreed to participate in the genetic portion of this study, we will also 
draw blood for genetic testing. We plan to study the genes that might be related to the 
medication’s effects on drinking behavior. In addition, we may study other genes.  Since all of 
the genes cannot be anticipated at this time, we will store the samples to study in the future. 
These samples will only be used for the following purposes: to learn about relationships between 
genes and characteristics of yours that relate to alcohol drinking and to learn about natural 
variation of genes between different groups of individuals.
If you choose to participate in this study, you do not have to participate in the genetics portion of 
this study. Please indicate below whether you wish to participate in the genetic (DNA) portion of 
this study.
                  Yes, I will participate in the genetics portion:____________
                  No, I do not want to participate in the genetics portion:______________ 
On a different day, you will be asked to go to the MR center at The Anlyan Center for Medical 
Research & Education at Yale University (TAC, 300 Cedar Street, New Haven) to have an MRI 
scan of your brain. The MRI scan is a routine way to get pictures of the inside of the body. MRI 
scans are painless, do not involve the use of radiation, and are used routinely to diagnose 
neurological problems. You will be asked to lie still on your back, on a comfortable mattress, in 
the MRI scanner for about 20 minutes. Your head will be held still in a cushioned head rest, and 
you will wear earplugs to reduce the level of noise. You will not be able to see out of it, but you 
will be able to hear us and be heard if you wish to say anything. You will hear a drumming noise 
when the camera is taking pictures of your brain. Some people feel mildly anxious in the 
scanner.  If it is too difficult for you to be in the scanner, we can end the scan. However, if you 
cannot complete the MRI scan, you will not be able to continue your participation in the study.
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On the day of your MRI or at one of your previous appointments, we will walk you over to 
YNHH to show you the HRU, the layout of the rooms, and walk you through the ADP 
procedures.  You will also be given a list of what to bring and not to bring when you come for 
your overnight stays.
If for some reason more than six months elapses between the MRI scan and PET scan, we will 
ask you to come back and complete a second MRI for a current scan of your brain..
2) Practice PET
You may undergo a mock (dry-run) in the PET scanner.  This means that you will just be walked 
through the steps to get familiar with the process. During the mock PET scan, you will lie in a 
real PET scanner or a replica of the PET scanner, be told when the scanner is being “turned on” 
and when blood samples are “being drawn”. 
3) First PET Scan
You will participate in your first (baseline) PET scan.  You will be asked to arrive at the Yale 
University PET Center (801 Howard Ave, New Haven) for your PET scan by no later than 7:00 
am.  We will check your vital signs and have you complete some questionnaires.  We will 
measure your breath alcohol level by asking you to blow into a meter. If you arrive with a 
positive breath alcohol level, indicating recent alcohol consumption, then the session will have to 
be rescheduled. A urine drug screen will also be done and if you are female, we will conduct a 
urine pregnancy test.  If you test positive for either, you will be discharged from the study 
Before your PET scan, the research nurse or technologist will help get you settled and check 
your vital signs. A trained nurse or CNMT (Certified Nuclear Medicine Technologist) will place 
an IV line in your arm to inject the radiotracer. The radiotracer is injected as a bolus only (over a 
minute) and the scan is 90 minutes long. You will feel little, if any, pain during this process.  
An experienced physician will insert an arterial catheter in your wrist area. The arterial catheter 
is about 2 inches long and looks like a regular IV tube, but it is inserted into an artery, not a vein. 
The blood flow in the arteries can tell us about your blood pressure. If an arterial catheter is in 
place, we can measure your blood pressure continuously. The other main reason to put in an 
arterial catheter is to be able to draw blood samples rapidly, repeatedly, and without causing you 
pain.  Here is what happens when an arterial line in placed. First, the skin is cleaned with 
betadine solution (contains iodine) so that it is sterile and protected against infection. Second, the 
insertion area is numbed with a local anesthetic, so that you feel less pain when the catheter is 
inserted. You will probably just feel pressure but may also feel pain.  This pain is usually like the 
pain you feel when an IV is placed and only rarely is it worse. Third, the catheter will be flushed 
regularly during your scan with a salt solution, which prevents clogging of the catheter with a 
blood clot. The arterial line will remain in place for the whole scanning period. After the catheter 
is removed, local pressure is applied for a minimum of 15 minutes to prevent bleeding under the 
skin. A pressure dressing (coban) and a clear dressing (tegaderm) will then be applied and you 
will be asked to keep it clean and dry, refrain from lifting objects weighing more than 5 pounds, 
and to avoid repetitive movements for 48 hours. You may remove the pressure dressing at 
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bedtime and the clear dressing after 48 hours, but do not submerge your hand in water for a full 
72 hours. Strenuous activity is prohibited for at least 48 hours after removal of the arterial 
catheter. After this time, mild physical activity can be resumed. Since the catheter is in for a 
minimal period, there is a low risk of infection.
If for some reason, an arterial catheter cannot be inserted, after no more than three attempts per 
arm are made, the scan will be rescheduled for another day. You will still be paid $50 for your 
time. At the rescheduled scan, the physician will try to insert an arterial catheter again and the 
scan will be conducted regardless of whether or not the catheter was inserted.
As part of the PET scanning, you will be asked to lie very still on a table. At the beginning of the 
scan, you are positioned in the scanner and will undergo a “transmission scan” to calibrate the 
PET scanner.  The radiotracer will then be injected into the catheter in your wrist. Following the 
injection, the PET scanner camera will detect the radiotracer present in brain areas. This 
information will be used to create pictures of the receptors in your brain. Each PET scan will 
take about two hours. If you ask, we can stop the scan at any time. However, if you can’t 
complete the PET scan, you may not be able to complete this study. You will be asked to drink 
several glasses of water at the close of the PET scanning session to wash out the radiotracer. 
We will monitor your vital signs throughout the study to see how you are feeling, before, during 
and after scanning.  You will also have several electrocardiograms (ECG's). We will also draw 
blood for routine blood tests to measure levels of substances found naturally in your blood, the 
levels of the radiotracer and its metabolites, and to measure the same chemical in your blood that 
we will measure in your brain. 
After the PET scan, you will be provided with a light meal, discharged and allowed to go back 
home. Depending on the start time of the PET scan, you may be at the PET Center until at least 
the early afternoon. You will be provided with a telephone number you can call any time after 
the study if you need assistance for problems related to the study procedures.
4) First Alcohol Drinking Session
On the day before or after your PET scan, you will participate in your first ADP.   We will ask 
you to arrive at the Hospital Research Unit (HRU) (20 York Street, New Haven) by 9:00am.  We 
ask that you not consume any alcohol after 5 pm on the evening prior to each ADP.  When you 
arrive at the HRU, we will monitor your breath alcohol level by asking you to blow into a meter.  
If you arrive with a positive breath alcohol level and your breath alcohol level is above 0.05 
and/or is increasing, indicating recent alcohol consumption, then the session will have to be 
rescheduled.  If your breath alcohol level is less than 0.05 and is decreasing, we will have to wait 
until it comes down to 0 before conducting any assessments. If your breath alcohol level is above 
0.05 and the session has to be rescheduled, we will have to keep you at the HRU and advise you 
to not drive until it comes down to 0.02; alternatively, we could provide you with transportation.  
We will also collect a urine sample to screen for the use of drugs (e.g., cocaine, opiates, 
marijuana, benzodiazepines); this test will have to be negative for you to continue in the ADP.  If 
you test positive for marijuana, we will ask you to discontinue use until you complete the study 
and we will get quantitative levels at your next 2 appointments to ensure that the levels are going 
down. If the levels increase, you will not be able to continue in this study. 
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Once you are settled in your room, you will be presented with a sample of two of your preferred 
drink choices to taste. You will be asked to take a sip of each drink; swish it around in your 
mouth and then spit it out. You will then choose your favorite drink to be used during the alcohol 
drinking session later that day. We will get your height and weight, take measurements of heart 
rate and blood pressure, and have you complete some assessments and computer tasks between 
10:00 and 12:30. You will also complete a task to measure how your body responds to cold water, 
during which you will be asked to place your hand in a bucket of ice-cold water for as long as you 
can.  You will be provided with lunch at 12:30 pm.  If you are a smoker, you will be provided 
with a “smoke-break" which you will be escorted out and allowed to smoke up to 2 cigarettes. 
Non-smokers will also be given the option of taking ‘breaks’ at predetermined intervals. When 
you are not completing assessments, you will be able to relax and watch TV.
Later that same day, you will participate in the ADP.  A video camera will be recording this 
session to monitor your drinking behavior.  Prior to the start of this session, you will be asked to 
complete some questionnaires and rating scales.  We will put an IV catheter in your arm to avoid 
having to stick you more than once for the blood collections.  These blood samples will be 
analyzed for naturally occurring chemicals that your body produces regularly. A cuff will be 
placed on your arm to monitor heartbeat and blood pressure.   
You will be provided with your first drink at 3:00 pm. The alcohol content of this drink will vary 
according to your weight and will be equivalent to one typical mixed drink. You will be asked to 
drink it in 5 minutes.  You will be monitored for the next 55 minutes and complete assessments.  
Following this, at 4:00 p.m., you will be presented with four drinks, each of which we consider 
to be worth $3, for a total of $12.  During the next 50 minutes, you can either choose to drink or 
keep the monetary value of the drinks ($3 per drink that you do not drink).  If you choose the 
money, it will be given to you after the session is completed.  At 4:50 p.m. the old drinks will be 
removed and at 5 pm you will be presented with four fresh, new drinks, each worth $3.  These 
will be available to you for the next 50 minutes.  Again, you can choose to drink them or keep 
the money. The drinks will be removed at 5:50 pm and at 6 pm you will be presented with four 
fresh new drinks, which will be available to you for the next 50 minutes.  The drinks will be 
removed at 6:50 pm at which time the session is over.  You will be given dinner and allowed to 
retire for the night.  Breath alcohol levels will be monitored periodically after completion of the 
laboratory session until they decrease to a level of 0.02.   We will take measurements of heart 
rate and blood pressure throughout your stay.  You will then spend the night in the HRU.
The next morning, we will check your vital signs and you will be asked to complete some 
assessments.  You will then be given breakfast. You will either receive your first dose of study 
medication, naltrexone, before you are discharged from the HRU or you will be asked to walk 
over to the PET Center for your first scan and receive your medication there or you will start 
medication on a future day, depending on scheduling and availability. 
In the event that your PET scan needs to be rescheduled due to technical issues, we will 
reschedule your PET scan to a later date and ask you to stay overnight at the HRU the evening 
prior to ensure that you arrive at the PET Center on time with a negative BAC. We will admit 
you between 3 and 4 pm and you will spend the night with no other study obligations. 
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5) Medication Period
You will come to our clinic at CMHC every day to receive your naltrexone and be monitored for 
any side effects.  In the event that this may be challenging due to your work schedule or other 
obligations, we will discuss alternative options, such as meeting you in a local hospital or 
providing you with additional doses to take home accompanied by a phone call reminder to take 
your medication and to ask you about side effects. You will take medication over the next 5-11 
days, depending on scanner availability and scheduling conflicts. The dose of medication will 
slowly be tapered up to 100 mg, beginning at 25mg. If you are experiencing excessive side 
effects, you may be scheduled to meet with the study physician and may be asked to discontinue 
your participation.  You do not need to change your drinking behavior while participating in this 
study. We will give you a medical card indicating that you are taking naltrexone.  Any doctor 
may find out what dose of naltrexone you are getting by calling the Yale-New Haven 
Investigational pharmacy (203-688-2978).   You should carry this phone number with you in 
case of an emergency.  
 
6) Second Alcohol Drinking Session
You will come in for your second ADP session and 24-hour overnight stay at the HRU after at 
least 5 days of medication, depending on scheduling.  You will follow the same procedure as in 
the first ADP.   
7) Second PET Scan
You will participate in a second PET scan, very similar to the first.  This scan will ideally be 
scheduled the day after the second ADP session, but depending on scanner availability, it may be 
scheduled the day prior to the ADP session. Either way, you will arrive at the PET Center at 
7:00am, be injected with a radiotracer and be scanned. If the first arterial line cannot be placed 
for any reason, the scan will still be completed. You will remain at the PET Center for one-hour 
after completion of the scan for observation and then discharged to home. Again, plan to be at 
the PET Center until early afternoon or later. 
When you have completed all parts of the study, you will be scheduled for a 1-week follow up 
appointment.  We will record any remaining adverse events that you may have as well as your 
current drinking behavior.  A clinical psychologist will talk to you about your drinking behavior 
and if you are interested, will provide you with treatment referrals. You will also be interviewed 
and asked to complete some questionnaires. This appointment should last approximately one 
hour. 
A follow-up appointment will be conducted with all participants, even those who do not 
complete the entire study.  You will be told of any significant new findings that are developed 
during the course of your participation in this study that may affect your willingness to continue 
to participate.
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.
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Risks and Inconveniences
1)   Magnetic resonance (MR): Magnetic resonance is a technique that uses magnetism and radio 
waves, not x-rays, to take pictures and measure chemicals of various parts of the body.  The 
United States Food and Drug Administration (FDA) has set guidelines for magnet strength 
and exposure to radio waves, and we carefully observe those guidelines.  
You will be watched closely throughout the MR study.  Some people may feel uncomfortable 
or anxious.  If this happens to you, you may ask to stop the study at any time and we will 
take you out of the MR scanner.  On rare occasions, some people might feel dizzy, get an 
upset stomach, have a metallic taste or feel tingling sensations or muscle twitches.  These 
sensations usually go away quickly but please tell the research staff if you have them.  
There are some risks with an MR study for certain people.  If you have a pacemaker or some 
metal objects inside your body, you may not be in this study because the strong magnets in 
the MR scanner might harm you.  Another risk is the possibility of metal objects being pulled 
into the magnet and hitting you.  To reduce this risk, we require that all people involved with 
the study remove all metal from their clothing and all metal objects from their pockets.  We 
also ask all people involved with the study to walk through a detector designed to detect 
metal objects.  It is important to know that no metal can be brought into the magnet room at 
any time.  Also, once you are in the magnet, the door to the room will be closed so that no 
one from outside accidentally goes near the magnet.
We want you to read and answer very carefully the questions on the MR Safety 
Questionnaire related to your personal safety.  Take a moment now to be sure that you have 
read the MR Safety Questionnaire and be sure to tell us any information you think might be 
important.  This MR study is for research purposes only and is not in any way a clinical 
examination.  
The scans performed in this study are not designed to find abnormalities.  The primary 
investigator, the lab, the MR technologist, and the Magnetic Resonance Research Center are 
not qualified to interpret the MR scans and are not responsible for providing a diagnostic 
evaluation of the images.  If a worrisome finding is seen on your scan, a radiologist or 
another physician will be asked to review the relevant images.  Based on his or her 
recommendation (if any), the primary investigator or consulting physician will contact you, 
inform you of the finding, and recommend that you seek medical advice as a precautionary 
measure.  The decision for additional examination or treatment would lie solely with you and 
your physician.  The investigators, the consulting physician, the Magnetic Resonance 
Research Center, and Yale University are not responsible for any examination or treatment 
that you receive based on these findings.  The images collected in this study are not a clinical 
MR exam and for that reason, they will not be made available for diagnostic purposes.
If you become uncomfortable for any reason or at any time, you should inform the MRI   
technician or research assistant immediately.
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2)  PET Scans
a) Risks Associated with Use of an Arterial Catheter
Putting in the plastic tube into the artery in the wrist area may cause bruising, and potentially 
infection.  The arterial puncture may also cause spasm or clotting of the artery with a 
temporary decrease in blood flow, this may cause tingling or numbness at the injection site 
and/or in the hand/fingers.  In rare instances blocking of the artery, poor healing, infection, 
hematoma (a solid swelling of blood within the tissues), or inflammation at the catheter 
insertion site may occur. Insertion of arterial catheters for giving drugs or sampling blood 
may be associated with mild-to-moderate pain or bruising at the puncture site. To minimize 
these risks, an experienced physician will insert the arterial line and a trained nurse will 
oversee subject care.
For two days following the placement of the arterial line, you should check your wrist/arm 
daily.  The study team will also be in touch with you daily either via phone, or in person, 
during this two-day period. If you experience any excessive pain, tenderness, swelling, 
redness, drainage, skin color changes, numbness, pins and needles, or decreased strength in 
the arm that had the catheter, you should immediately call the study team (203-464-6015).  
You can also contact the study PI Dr. Krishnan-Sarin (860-575-9895), or the PET center 
physician, Dr, David Matuskey (203-370-1403), or the study physician, Dr. Julia Shi (203-
781-4640).
You may experience a rare allergic reaction to the medicine used to numb your skin prior to 
placement of the arterial catheter. If you have had a bad reaction to lidocaine or other 
anesthetic agents used to numb the skin in the past, please tell us about this experience before 
you go through the arterial line placement. Severe allergic reactions can be life threatening.  
Important: If you have a history of a bleeding disorder or are taking medication to thin your 
blood, you will not be allowed to participate in this study. You will also be asked to abstain 
from using aspirin and other anti-inflammatory drugs (such as Motrin or Aleve) for 7-10 days 
before arterial line placement and 7-10 days after arterial line removal.
b) Risks Associated with Radiation
This research study involves exposure to radiation from positron emission tomography 
(PET). Please note that this radiation exposure is not necessary for your medical care and is 
for research purposes only. The radiation you will receive in this study is from 
[11C]LY2975050 scan(s) and from transmission scans of your head used to help obtain the 
PET images.
The total amount of radiation you will receive during the 2 PET scan sessions in this study is 
from 2 injection(s) of the tracer, [11C]LY2795050, and from transmission scans of your head.
Although each organ will receive a different dose, the amount of radiation exposure you will 
receive from this study is equal to a uniform whole-body exposure of 1.44 rem, which is the 
equivalent of approximately 4 years of natural environmental exposure. This value is known 
as the “effective dose” and is used to relate the dose received by each organ to a single value. 
This amount of radiation exposure is below the annual limit of 5 rem set by the federal 
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government for research subjects. 
The effects of radiation exposure on humans have been studied for over 60 years. In fact, 
these studies are the most extensive ever done of any potentially harmful agent that could 
affect humans. In all these studies, no harmful effect to humans has been observed from the 
levels of radiation you will receive by taking part in this research study. However, scientists 
disagree on whether radiation doses at these levels are harmful. Even though no effects have 
been observed, some scientists believe that radiation can be harmful and may cause cancer 
at any dose- even low doses such as those received during this research.
Please tell your study doctor if you have taken part in other research studies at Yale or other 
places/hospitals that used radiation. This way we can make sure that you will not receive too 
much radiation. You should consider x-rays taken in radiology departments, cardiac 
catheterization, and fluoroscopy as well as nuclear medicine scans in which radioactive 
materials were injected into your body. Before you take part in any future studies that use 
radiation, you should also tell those study doctors about your participation in this study.
If you are pregnant or breast feeding, you may not participate in this research study. We will 
perform urine pregnancy tests prior to your participation on your PET and MRI scan days. 
3)  Risks Associated with Alcohol
A number of medical conditions could potentially be worsened by acute alcohol 
administration (e.g., liver disease, cardiac abnormality, pancreatitis, diabetes, neurological 
problems, and gastrointestinal disorders). As a result, if you have any of these medical 
problems, you should not participate in this study. Alcohol may also cause nausea in high 
doses; however, nausea is not expected at the dose being used in this study.  In order to 
ensure that you do not fall and hurt yourself after consuming alcohol, we will ask you to stay 
in the HRU overnight after the drinking session. Alcohol is a reinforcing agent, which may 
cause changes in behavior including repetitive or excessive alcohol consumption. We do not 
endorse drinking alcohol in the quantities used in this research study.
4)  Risks Associated with Naltrexone
Naltrexone, an opioid antagonist, is widely used in the treatment of opioid addiction and 
more recently has been found to be beneficial in the treatment of alcoholism.  Numerous 
studies have found naltrexone use to be safe and rarely associated with toxicity or severe side 
effects.  The most frequently reported side effects are gastrointestinal in nature.  Those 
include stomach pain, nausea and vomiting.  Other, less frequent side effects include 
dizziness, nervousness, headaches, blurred vision, low energy, fatigue, sleepiness, joint and 
muscle pain and insomnia.  Liver toxicity, the most serious potential side effect, has been 
shown in studies using very high doses of naltrexone (1400 to 2100 mg per week). At the 
doses used in this study naltrexone has not been reported to produce damaging effects on the 
liver.  If you use opiates (like heroin, morphine, codeine or Tylenol # 3) on a regular basis 
you should not participate in this study since naltrexone can also cause or worsen withdrawal 
from opiates.   During your participation in this study we will monitor you daily for side 
effects from naltrexone.  If while participating in this study you require emergency surgery or 
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are involved in a situation where you might need an opioid anesthetic, your doctor should be 
aware that you are on naltrexone.
5)  Risks Associated with Interactions of Naltrexone and Alcohol
There are no known risks to contraindicate the administration of alcohol to subjects on 
naltrexone. 
6)  Risks Associated with Blood Drawing and Urine Collection
Urine samples will be used for drug and pregnancy tests and there is no risk. Drug tests will 
be done at the initial appointment, the PE, the 2 ADP sessions, the 2 PET sessions, and Day 4 
of medication.
Drawing blood and inserting an intravenous line (IV) into an arm vein are safe and standard 
medical procedures.  Sometimes a bruise will occur at the puncture site and rarely a blood 
clot or infection will occur in the vein.  You should not donate blood for at least 6 weeks 
after the study. Some people feel lightheaded but this effect is temporary.  The total volume 
of blood collected during this study will be about 19 tablespoons.  This amount of blood loss 
is safe for healthy persons.
Here are the amounts of blood to be drawn during different parts of the study:
Screening procedures at start of week…
1 tablespoon
First ADP session …
2 tablespoons 
Two PET scans… 
13 tablespoons
      Second ADP session…       
2 tablespoons 
Genetics portion…
1 tablespoon  
7)  Risks Associated with Pregnancy and Breastfeeding 
You may not participate in this study if you are currently pregnant, might become pregnant 
during the study, or you are breastfeeding an infant. Alcohol drinking is harmful to an unborn 
child and acceptable levels of radioactivity are lower for pregnant individuals. It is best to 
avoid radiation exposure to unborn or nursing children since they are more sensitive to 
radiation than adults. You will be tested for pregnancy as part of the routine lab tests.  If the 
test is positive, you will not be included in the study.  Before starting the study, we will ask 
you to avoid becoming pregnant and ask you what precautions you plan to take.  If you 
change your mind about becoming pregnant or how you will avoid becoming pregnant, we 
ask that you to tell us immediately.  You will be given one pregnancy blood test during the 
initial physical evaluation, and you will also be given a urine pregnancy test on the day of the 
MRI and on the day of each PET scan.
8)  Risks Associated with Alcohol Withdrawal
We are not going to ask you to alter your drinking behavior while you are participating in 
this study.  However, you should know that some individuals who reduce or stop their 
drinking can experience alcohol withdrawal symptoms such as mild agitation, anxiety, 
restlessness, tremor, loss of appetite and difficulty sleeping or even more severe (but rare) 
symptoms like extreme restlessness, nervousness, disorientation, confusion, hallucinations 
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(hearing and seeing things that are not there) and seizures, but these are extremely rare.  We 
will monitor you very closely for withdrawal symptoms during your daily visits to our clinic.  
If you experience worsening of withdrawal symptoms, you may have to be hospitalized and 
will be given medications that are typically used to treat and manage withdrawal.  These 
medications include benzodiazepines, such as chlordiazepoxide (librium), and other 
medications such as carbamazepine (tegretol). 
9)  Risks Associated with Taking Blood Samples for Genetic Testing 
The blood samples obtained from you for the purpose of genetic testing will be stored in the 
laboratory of a co-investigator on this project, Dr. Joel Gelernter.  Genetic testing will only 
be conducted for research purposes and the results will only be available to investigators on 
this study.   Variation in some genes is known to be directly related to risk for certain 
illnesses and drug dependence. Other genes we will be studying may be shown at some point 
in the future to be related to illness. Since the results of these genetic tests may allow 
prediction of risk of illness in some cases, only scientists working on this research project 
will know the results. We will not make any of our laboratory results available to you, nor 
will we add them to your medical record. (If you want to know your risk for genetic diseases, 
we will refer you to a genetics counselor.)
The genetics blood samples obtained from you will also be stored indefinitely and will be 
used only for research purposes.  If after you provide the sample, you decide that you want to 
withdraw from this portion of the study you are certainly free to do as specified in the 
“Voluntary Participation” section below.  
There is a federal law called the Genetic Information Nondiscrimination Act (GINA). In 
general, this law makes it illegal for health insurance companies, group health plans, and 
most employers to discriminate against you based on your genetic information. However, it 
does not protect you against discrimination by companies that sell life insurance, disability 
insurance, or long-term care insurance.
10) Risks Associated with Completing Laboratory Tasks
The computer and cold water tasks can produce some uneasiness at the time of the task.  
However, once the task is over, there is very little anxiety that carries over, thus posing 
minimal risk.  Moreover, you will have total control over these tasks and can stop performing 
any of them if you get too uncomfortable.
Benefits
There are no direct benefits to you for your participation.  We expect that the results of the study, 
however, will benefit science and others through increasing our knowledge about the use of 
naltrexone as a treatment for alcohol drinking and its efficacy through the use of PET. 
Compensation
You will be paid 
$50 for the initial interview 
$50 for the physical examination 
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$250 for the first PET scan 
$50 for each arterial catheter insertion 
$50 for the MRI scan 
$150 for participating in the first drinking paradigm 
$170 for taking medication (up to 11 days)
$10 per day for transportation to our clinic to take medication - (up to $110)
$250 for participating in the second lab drinking paradigm 
$450 for the second PET scan
$30 for completing a one week follow-up
Appointment
Cash
Check
Intake
$50
Physical Exam  
$50
MRI Scan
$50
PET scan #1
$250
Arterial Catheter insertion- Scan 1
$50
Overnight (ADP) #1
$150
Medication (5-11 days)
$170
Transportation (medication appts) 
Up to $110
Overnight (ADP) #2
$250
Computer assessments- ADP 1 and ADP 2
Up to $30
PET Scan #2
$450
Arterial Catheter insertion- Scan 2
$50
1 Week Follow Up
$30
You will receive up to a total of $1370.00 in the form of a check  if you complete the study. This 
check can take 4-6 weeks to process. You will receive up to a total of $180 in cash for 
completing the intake, physical exam, MRI, and follow-up. 
Subjects may also earn these payments in cash:
$50 if the first arterial line cannot be placed at the first PET scan and you need to be rescheduled
$36 (depending on your drink consumption) during the first alcohol-drinking period
$36 (depending on your drink consumption) during the second alcohol-drinking period
Up to $30 for computer assessments at ADP sessions
$50 to show up for additional ADP/PET scan as a standby participant in case the primary 
scheduled participant has a conflict for the ADP and/or PET scan. (if the scheduled participant 
arrives, you will be paid asked to come back at a later date to complete your scheduled 
appointments).
$50 for an additional MRI scan
$100 to spend an additional overnight at HRU if PET is rescheduled
$25 if you are asked to come back for a repeat lab appointment (bloodwork or EKG)
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You may be responsible for paying taxes on payments you receive to the IRS for your participation 
in this study, since payments over $600 are usually reported on Form 990 to the IRS. However, your 
confidentiality will be protected by the Certificate of Confidentiality (described below). The business 
office will not identify or link a payment to any research study and will neither confirm nor deny any 
details whatsoever about your participation.
Treatment Alternatives
This is not a treatment study.  You should not participate in this study if you want to stop 
drinking.  If you are currently interested in changing your drinking behavior, we will provide you 
with a treatment referral and you will not be eligible to participate in this study.
Subject Obligation
We ask that you do not use any medicines except the study medications or participate in any 
other research study without discussing this with us first while you are in our study. Please let us 
know if you use any other medications or drugs during this time, since we may need to 
reschedule your study sessions. The ways in which you might be dismissed from the study are  if 
you repeatedly do not show up, lie about your alcohol and drug use, or don't take your study 
medication.  The Principal Investigator may decide to discontinue your participation in the study 
based on data collected at the first overnight appointment. In that case, the initial PET scan and 
all other appointments will be cancelled. Although your participation will be discontinued at this 
point, you will receive payment for all completed appointments. 
We will be monitoring your urine periodically for use of alcohol and other drugs and will also 
check your breath alcohol level.  If your breath alcohol level is positive, you will have to wait 
until it drops to 0.02 before we can allow you to leave or we can arrange for an alternate form of 
transportation for you.  Similarly, if your drug tests are positive, the sessions will have to be 
rescheduled if possible.  
Confidentiality and Privacy
There are two separate statutes which provide the means to protect your confidential information 
related to your health information.  One statute of protection is called HIPAA and the second is 
called a Certificate of Confidentiality (CoC).  
 
A Personal Health Information (PHI) record is routinely created whenever you see a physician or 
go to the hospital or you are seen in an outpatient clinic.  Personal health information is also 
called a medical record.  Your medical record is considered confidential under the privacy 
statutes referred to as HIPAA.  However, there are certain circumstances when medical records 
can be demanded without your written permission.  In some cases, medical records can be 
requested, for example, by an insurance company, the government, or an attorney representing 
another person.  HIPAA allows the court to order such information to be provided to them for 
good reasons.  
When you participate in a research study, your identity as a research participant—and all the 
identifiers that could lead to your identity will be held confidentially.  The investigator cannot be 
forced to release your identifiers to anyone outside of the research team if a Certificate of 
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Confidentiality is issued.  Thus, to protect your sensitive information, we have obtained a 
Certificate of Confidentiality (CoC) from the National Institute on Alcohol Abuse and 
Alcoholism (NIAAA) which is part of the National Institutes of Health (NIH). 
The CoC protects the identity of individuals in a study and protects the investigators from being 
forced to tell people that are not connected with this study about your participation in this study, 
even under a subpoena. This protection, however, is not absolute.  The protection offered by the 
CoC does not stop us from voluntarily reporting information about suspected or known sexual, 
physical, or other abuse of a child or older person, or a subject's threats of violence to self or 
others. If any member of the research team is given such information, he or she will make a 
report to the appropriate authorities. Individuals who participate as research subjects (i.e., about 
whom the investigator maintains identifying information) in the specified research project during 
any time the Certificate is in effect are protected permanently.. Also, because this research is 
sponsored by NIAAA, staff from NIAAA and other DHHS agencies may review records that 
identify you but only for the purposes of audit for quality and accuracy or program evaluation. 
Even when a CoC is in place, you must still continue to actively protect your own privacy. If you 
voluntarily give your written consent to anyone to receive information about your participation 
in the research or freely volunteer information to anyone other than the study staff that you are a 
research participant in this study, then we may not use the CoC to withhold this information.
Further details about the limitations and protections of your medical records and the information 
you provide as a research participant are provided below.
 
Use and Protection of Collected Medical Record information
Health information about you will be collected if you choose to be part of this research study. 
Health information is protected by law as explained in the Yale University Privacy Notice. If you 
have not received this notice, please request a copy from the investigator. At Yale University, your 
medical record information will only be used or shared as explained and authorized in this consent 
form or when required by law. 
We ask anyone who gets your health information from us to protect your privacy.  However, 
there may be some cases beyond our control where we cannot protect your privacy but we expect 
that those instances will be rare and accidental disclosures.
To participate in this research you must allow the study team to use your health information. If you 
do not want us to use your medical record information, you may not participate in this study. 
Documents that contain your name, such as this consent form signed by you, will be securely 
stored separately from your research data.  All research data will be coded in a way that does not 
identify you by name or initials and will be kept in a secure place that allows only selected study 
personnel to have access to this information. The research data collected will be kept separate 
and distinct from the medical record. 
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The blood samples obtained from you for the genetics study will be stored indefinitely and will 
be used only for research purposes.  Information from these samples will only be made available 
to the investigative team working on this project.  
You should understand that there is a risk that you will be recognized by other patients or staff 
involved in the laboratory or hospital ward and it could be known that you are participating in 
this study. If you find this to be an unacceptable condition you should not sign this consent form.
You have the right to review and copy your health information in your medical record in 
accordance with institutional medical records policies.
Withdrawing Your Authorization to Use and Disclose Your Health Information
 The use and disclosure of your information has no time limit.  Any research information in your 
research record will be kept indefinitely. If you wish to revoke permission for the use and sharing 
of your health information, you may do so by notifying the study doctor, Dr. Krishnan-Sarin, but 
in doing so; you will no longer be able to participate in this research study.
If you withdraw your permission: 

No new health information identifying you will be gathered after that date.

We will no longer use or share medical information about you for this research study, 
except when the law allows us to do so.  

We are unable to take back anything we have already done or any information we have 
already shared with your permission. 

We may continue using and sharing the information obtained prior to your withdrawal if 
it is necessary for the soundness of the overall research. 

We will keep our records of the care that we provided to you as long as the law requires.
MEDICAL RECORD INFORMATION COLLECTED DURING THIS STUDY
The investigator and staff involved with the study will keep your medical record information 
collected for the study strictly confidential. Medical record information covered by HIPAA, 
including your name, initials, and other identifying information will not be released or published 
without your permission unless required by law.  The following medical record information will 
be collected and used for research:  
-
Name
-
Address
-
Telephone number
-
Information from a brief psychiatric examination
-
Emergency contact information
-
Initial telephone screening information
-
Allergies
-
Current and past medications and therapies
-
Information from a physical examination that generally also includes blood pressure
      reading, heart rate, breathing rate and temperature
-
Electrocardiogram
-
Breath Alcohol Tests 
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-
Urine Drug Screens
-
Urine Pregnancy Tests if you are female
-
Clinical laboratory Tests
-
Healthcare, Social Functioning, and Addiction Questionnaires/Forms
Information about you and your health which might identify you may be used by or given to: 
• The U.S. Department of Health and Human Services (DHHS) agencies 
• Representatives from Yale University and the Human Investigation Committee, who are 
responsible for insuring research compliance. These individuals are required to keep all 
information confidential. 
Those providers who are participants in the Electronic Medical Record (EMR) system. 
Members of the research team who are participants in the EMR system, including the study 
physicians and study psychologist, will have access to your medical information in the EMR to 
ensure eligibility and safety for research participation.
• Those individuals at Yale who are responsible for the financial oversight of research including 
billings and payments 
• The Principal Investigator and selected members of the research team 
• Collaborating research groups and research centers where research personnel from this study 
are also involved. 
• Data and Safety Monitoring Boards and others authorized to monitor the conduct of the study 
By signing this form, you authorize the use and/or disclosure of the information described above 
for this research study. The purpose for the uses and disclosures you are authorizing is to ensure 
that the information relating to this research is available to all parties who may need it for 
research purposes. 
All health care providers subject to HIPAA (Health Insurance Portability and Accountability 
Act) are required to protect the privacy of your information. The research staff at the Yale 
School of Medicine and Yale New Haven Hospital is required to comply with HIPAA and to 
ensure the confidentiality of your information. Some of the individuals or agencies listed above 
may not be subject to HIPAA and therefore may not be required to provide the same type of 
confidentiality protection. They could use or disclose your information in ways not mentioned in 
this form. However, to better protect your health information agreements are in place with these 
individuals and/or companies that require that they keep your information confidential. 
To protect your confidentiality, the videotapes of the drinking sessions will be identified by code 
number and erased within a period of 24 months after completion of the study. 
In Case of Injury
If you develop any mental or physical problems as a direct result of being in this component of 
the study, we will refer you for treatment. You or your insurance carrier will be expected to pay 
the costs of this treatment. No additional financial compensation for injury or lost wages is 
available. Your legal rights are not waived by signing this consent form.
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Voluntary Participation and Withdrawal
Participating in this study is voluntary. You are free to choose not to take part in this study.   
Refusing to participate will involve no penalty or loss of benefits to which you are otherwise 
entitled. It will not harm your relationship with your own doctors or with the researchers, 
YNHH, the PET Center, or the Connecticut Mental Health Center.
However, you will not be able to enroll in this research study and will not receive study 
procedures as a study participant if you do not allow use of your information as part of this 
study.
Withdrawing From the Study
If you do become a subject, you are free to stop and withdraw from this study at any time during 
its course. To withdraw from the study, you can call a member of the research team at any time 
and tell them that you no longer want to take part. You will also be paid for your participation up 
until the moment you withdraw from the study.
When you withdraw from the study, no new health information identifying you will be gathered 
after that date.  Information that has already been gathered may still be used and given to others 
until the end of the research study, as necessary to insure the integrity of the study and/or study 
oversight.  
Withdrawing from the study will involve no penalty or loss of benefits to which you are 
otherwise entitled.  It will not harm your relationship with your own doctors or with the 
researchers, YNHH, the PET Center, or the Connecticut Mental Health Center.
Withdrawing Your Authorization to Use and Disclose Your Health Information
You may withdraw or take away your permission to use and disclose your health information at 
any time. You may withdraw your permission by telling the study staff or by writing to Dr. 
Suchitra Krishnan-Sarin at Yale University, CMHC, 34 Park Street, Room S-208, New Haven, 
CT 06519.
If you withdraw your permission, you will not be able to stay in this study.
When you withdraw your permission, no new health information identifying you will be 
gathered after that date.  Information that has already been gathered may still be used and given 
to others until the end of the research study, as necessary to insure the integrity of the study 
and/or study oversight.  
Participation in the genetics portion of this study is also completely voluntary.  You are free 
to decline to participate in the genetics portion and still participate in the rest of the study. 
If you choose to withdraw from the genetic portion of this study, you can request that we 
either destroy all records in our research files connecting your name with your DNA 
sample, so that it would only be studied anonymously from that point forward.  
Alternatively, if you so request, we will also destroy your sample used for DNA testing.  
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You must follow up this request with a written request, mailed to: Suchitra Krishnan-
Sarin, PhD, 34 Park Street, Room S-208, New Haven, CT  06519. 
Questions
We have used some technical terms in this form.  Please feel free to ask about anything you don't 
understand and to consider this research and the consent form carefully – as long as you feel is 
necessary – before you make a decision.
Authorization and Permission
I have read (or someone has read to me) this form and have decided to participate in the project 
described above.  Its general purposes, the particulars of involvement and possible hazards and 
inconveniences have been explained to my satisfaction.  My signature also indicates that I have 
received a copy of this consent form.
By signing this form, I give permission to the researchers to use [and give out] information about 
me for the purposes described in this form.  By refusing to give permission, I understand that I 
will not be able to be in this research. 
Name of Subject:_____________________________
            
Signature:___________________________________
Date:______________________________________
___________________________________________
___________________
Signature of Principal Investigator
Date
                                      or
___________________________________________
___________________
Signature of Person Obtaining Consent
Date
If you have further questions about this project or if you have a research-related problem/injury, 
you may contact the Principal Investigator, Suchitra Krishnan-Sarin, PhD at (203)974-7595 or 
the study physician, Julia Shi, M.D, at (203)781-4640.  If you would like to talk with someone 
other than the researchers to discuss problems, concerns, and questions you may have concerning 
this research, or to discuss your rights as a research subject, you may contact the Yale Human 
Investigation Committee at (203) 785-4688. If after you have signed this form you have any 
questions about your privacy rights, please contact the Yale Privacy Officer at 203/436-3650.
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CONSENT TO FILMING OR VIDEO-TAPING 
FOR RESEARCH PURPOSES 
I agree that videotape or motion pictures may be taken of me under the direction of Suchitra 
Krishnan-Sarin, Ph.D. as part of the study entitled “Kappa-PET imaging and naltrexone in 
alcohol drinking behaviors” under the following conditions: 
These films will be erased within a period of 24 months after completion of the study. 
It is specifically understood that, after filming, video cassettes will be identified by code number 
only to protect my confidentiality.. 
It is specifically understood that only those persons involved in this research project will view 
these videotapes or films and that my confidentiality will otherwise be maintained. 
Signature ________________________________________________________________ 
Date _________________________ 
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