Clinical trial NCT04854551
Conditions: Alcohol Drinking Opioid Use, Unspecified
Sponsor: University of Colorado, Denver
Start date: 2021-05-01; Completion date: 2022-04-18
Enrollment: 13 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This is a double blind study of the effects of opioid antagonism on the brain's reward response. The investigators will recruit participants to undergo two scans, one on active medication and one on placebo. During the scan, the investigators will assess reward.

Detailed description:
The study will employ a crossover design. The study will use the monetary incentive delay task during functional MRI to assess reward. This task presents participants with cues indicating whether they are playing to win $5, win $0, or to avoid losing $5. This task has been well-validated to elicit activation in a key reward response area of the brain called the ventral striatum.

Arms: arm 1: Participants first received placebo capsules each day in a blister pack for 5 days. After a washout period of at least 3 days, they then received naltrexone capsules (matching placebo capsules) at 25mg/day for days 1 and 2 and then 50mg/day for days 3-5 for 5 days. arm 2: Participants first received naltrexone capsules each day in a blister pack for 5 days. Days 1 and 2 were at 25mg/day, and days 3-5 were at 50mg/day. After a washout period of at least 3 days, they then received placebo capsules (matching naltrexone capsules) for 5 days.
Interventions: intervention 1: Naltrexone intervention 2: Placebo
Intervention descriptions: intervention 1: Naltrexone is an opioid antagonist with primary action at the mu opioid receptor. intervention 2: Placebo will be used to control for expectancy effects

Protocol documents:
Prot_SAP_000.pdf: 
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w 
COMIRB Protocol 
COLORADO MULTIPLE INSTITUTIONAL REVIEW BOARD 
CAMPUS BOX F-490    TELEPHONE:  303-724-1055  Fax:  303-724-
0990 
 
 
 
Protocol #: 21-2886 
Project Title: Opioid Modulation and Neural Reward Activation in Healthy Adults 
 
Principal Investigator:  Dr. Joshua Gowin 
Version Date: 10/28/21  
 
  
 
I. Hypotheses and Specific Aims:   
1. 
Evaluate whether mu-opioid receptor blockade via naltrexone alters reward 
activation in the ventral striatum. In a study of 10 healthy, moderate drinking adults, we will use 
a crossover design to examine brain activation during a functional MRI scan during placebo and 
mu-opioid blockade.  
Hypothesis 1. Relative to the placebo scan, participants will show reduced reward-related 
activation in the ventral striatum during the active medication scan. 
2. 
Evaluate whether mu-opioid receptor blockade alters threat activation in the 
amygdala. In the same sample and design from Aim 1, we will use the Emotion Regulation Task to 
assess threat related activation in the amygdala during a functional MRI scan. 
Hypothesis 2. Opioid receptor modulation will not affect threat related activation, consistent with 
naltrexone primarily targeting reward motivation.  
3. 
Examine whether mu-opioid receptor blockade via naltrexone alters valuation of 
alcohol. In the same sample and study design from Aim 1, we will use the Alcohol Purchase Task 
to assess subjective value of an alcoholic beverage in order to link opioid-modulation directly to 
alcohol motivation.  
Hypothesis 3. Relative to the placebo session, participants will be willing to pay less money for an 
alcoholic beverage during the active medication session. 
 
This proposal aims to fill a gap in understanding how endogenous opioid function affects reward 
response in the brain. One of the leading hypotheses is that individuals who drink to maximize 
reward are more likely to benefit from naltrexone treatment, and the current proposal would provide 
evidence for this in a healthy sample. Further, this work could lead to a clinical study of reward-
related brain activation and response to naltrexone treatment in adults with an Alcohol Use 
Disorder. This stands to improve precision medicine approaches to tailor treatments for alcohol use 
disorder. 
 
II. Background and Significance: 
Reward processing contributes to survival for all animals, including humans, since identifying 
sources of sustenance is among the most important information learned during life (Berridge and 
Kringelbach 2008). Dysfunctional reward processing underlies many psychiatric disorders, such as 
depression (Ng, Alloy, and Smith 2019) and substance use disorders (Hyman, Malenka, and 
Nestler 2006), thereby reducing quality of life and leading to premature death. A critical brain 
structure in the reward circuit is the nucleus accumbens. Electrophysiological work in primates 
shows that nucleus accumbens activation occurs when an animal sees a cue that predicts the 
delivery of a favorite food (Schultz, Dayan, and Montague 1997) and functional MRI work in 
humans shows that activation occurs when humans see cues that predict the arrival of money 
(Knutson et al. 2001). While dopamine neurons that originate in the ventral tegmental area and 
terminate in the nucleus accumbens account for a major part of reward signaling (Adamantidis et 
al. 2011), other neurotransmitter systems impinge on these neurons (Heilig et al. 2011). In ongoing 
functional MRI work, we have shown that we can elicit nucleus accumbens activation using 
monetary reward in healthy adults. The nucleus accumbens has a dense population of mu-opioid 


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receptors (Nummenmaa et al. 2018), but their role in human reward processing is poorly 
understood. Determining how modulation of mu-opioid receptor activity affects reward response in 
the nucleus accumbens would improve our understanding of reward circuitry and its effects on 
mental health. 
Neurotransmitter systems that interact with dopamine to encode reward are poorly understood. 
Animal studies show that mu-opioid antagonism blunts dopamine and ventral striatal activity 
(Walters et al. 2005). However, this has not been studied in humans. Psychopathology, such as 
substance use and mood disorders, are associated with altered nucleus accumbens activation to 
reward (Treadway and Zald 2013; Morales et al. 2018) and lower dopamine receptor concentration 
(Volkow et al. 1993). The treatment of such psychopathology is timely and important given the 
impact of the coronavirus (COVID-19) on increased incidence of depression (Salari et al. 2020) and 
substance use problems (Ahmed et al. 2020). Alcohol use remains one of the leading causes of 
death globally (Rehm et al. 2009), accounting for 88,000 annual deaths in the United States alone 
(Centers for Disease Control and Prevention 2004). The opioid system is involved in emotion 
(Nummenmaa and Tuominen 2018) and the mu-opioid receptor is involved in reward processing 
(Nummenmaa et al. 2018) but little is known about how this relates to psychopathology such as 
substance and alcohol use disorders.   
This will be among the first investigations of how mu-opioid antagonism via naltrexone affects 
human monetary reward response. One previous study examined the effect of naltrexone on 
monetary reward response (Nestor et al. 2017), but this study used a monetary reward of less than 
$1. Previous studies have shown that rewards of less than $1 induce low levels of nucleus 
accumbens activation (Knutson et al. 2001). Further, the previous study administered only a single 
dose of naltrexone instead of using a steady-state during imaging (Nestor et al. 2017), so 
medication effects may have been absent for some participants. The study also used multiple study 
sites and scanners, which can increase variance. We will use a single site, a single scanner, a 
steady state of naltrexone during scanning, and a larger reward value of $5 that has been shown to 
induce large activation levels in the nucleus accumbens (Figure 2). 
Our goal is to better understand the neurobiology of reward processing by probing other 
neurotransmitter systems that interact with dopamine to regulate reward. The objective of this 
application is to establish whether healthy adults show reduced reward-related activation in the 
nucleus accumbens when ramped up to steady state dosing with naltrexone. Naltrexone is a mu-
opioid antagonist and one of three medications approved by the Food and Drug Administration for 
the treatment of alcohol use disorder. We will also examine threat processing as a control 
paradigm to establish that opioid modulation primarily affects reward processing. Since diminishing 
reward signaling may reduce incentive to seek alcohol, we will also examine a measure of 
subjective alcohol evaluation. We are prepared to conduct this study based on our expertise in 
psychopharmacology and functional MRI studies of reward and threat processing as well as 
psychiatric disorders. This qualified group of investigators will make certain that our research 
adheres to both neuroscientific theory of reward processing as well as clinical application. 
 
III. Preliminary Studies/Progress Report:   
In a currently ongoing study, we have recruited 45 adults to complete the 
monetary incentive delay task and we have shown a strong main effect of cue type in 
nucleus accumbens activation (F 2,210 = 58.8, p < 0.001), where activation is 
greatest during cues to gain $5 (Figure 1). 
 


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Figure 1. Using the monetary incentive 
delay task, we found a main effect of cue 
on nucleus accumbens activation (F 2,210 = 
58.8, p < 0.001). 
 
IV. Research Methods 
 
A. Outcome Measure(s): There are three outcomes for this study: nucleus accumbens 
activation to monetary reward, amygdala activation to threat, and subjective alcohol 
evaluation. For nucleus accumbens activation, we will use percent signal change in 
response to the cue to earn $5 during the Monetary Incentive Delay task. For the amygdala 
response to threat, we will use the percent signal change in response to negative images 
in the Emotion Regulation task. For the valuation of alcohol, we will use the Alcohol 
Purchase Task to assess the greatest expenditure on drinks (price paid multiplied by 
number of drinks). 
B. Description of Population to be Enrolled:  
a. Recruitment, sample description and inclusion/exclusion criteria. Participants 
will be recruited through advertisements on social media, paper flyering, 
advertising on local list-servs, and by peer recruitment. Our lab has successfully 
attracted over 340 participants to complete our screening measures using these 
methods in the past year. Interested individuals can contact the laboratory via 
email or phone call to arrange a phone screen, where we will assess likely 
eligibility for the study. 
i. Inclusion criteria: A) Between 18 and 35 years of age,  
ii. Exclusion criteria: A) AUDIT Score less than or equal to 14, B) Non-drinker 
C) positive result on urine drug screen or breathalyzer at the start of any 
study visit, D) inability to complete MRI (e.g. presence of ferromagnetic 
objects in body), E) current use of medications that alter the hemodynamic 
response, such as insulin, F) history of trauma resulting in loss of 
consciousness longer than 15 minutes, G) for females, pregnancy, H) 
current (within the last 3 months) use of opioids to avoid acute precipitated 
withdrawal due to opioid receptor antagonism I) treatment for a DSM5 
disorder other than anxiety or depression through therapy J) treatment for 
a DSM5 disorder through medications, K) greater than 10 uses of illicit 
substances in the last year. 
b. Feasibility: We have recruited 45 participants to our laboratory’s studies in the past 
year and conducted 45 MRI scans. To recruit ~10 participants in one year, we 
need to recruit 1 participant per month and conduct 2 scans per month. This is well 
within the capacity of our laboratory operations.  
C. Study Design and Research Methods. After completing an informed consent procedure, 
participants will sign a consent form. They will then complete a psychiatric interview and 
receive 5 capsules. Participants will return five days later for visit 2. On visit 2, they will 
complete a medication side-effect questionnaire. If they report side effects that are more 


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than mild (i.e. if they report moderate or severe side effects), a medical professional (i.e. 
nurse or physician) will follow up to confirm that they are ok to complete the MRI and 
provide care as needed. All participants will complete a breathalyzer and saliva drug test to 
confirm sobriety. Females will be asked to provide a urine sample for a pregnancy test. 
Participants will then complete an MRI and the Alcohol Purchase Task. They will be sent 
home with 5 days’ worth of capsules. They will return after 5 days and repeat the same 
procedures. 
a. Dosing. We will administer doses of naltrexone and placebo. Dosing will be 
double-blind and counter balanced. Participants will receive 5 capsules on their 
first visit to take during the week. They will receive 5 additional capsules to take 
each day of the following week. Naltrexone will be over-encapsulated by the 
Investigational Drug Service at the School of Pharmacy. Matching placebo 
capsules will contain methylcellulose power. Naltrexone will be taken once daily by 
mouth and ramped up by the following schedule: Monday-25mg, Tuesday-25mg, 
Wednesday-50mg, Thursday-50mg, Friday-50mg. A study coordinator blind to the 
contents of the capsules will deliver the capsules to the participant. The 
Investigational Drug Service will maintain blinding and will track dosage, to be 
revealed following study completion. Half of participants will receive placebo during 
week 1 and half will receive placebo during week 2. Remote video monitoring will 
also be used to assess adherence. Participants will receive a text message on 
their mobile phones at 9 am each morning reminding them to take the medication 
and instructing them to upload a video of themselves doing so to a secure data 
repository (REDCap). A study-provided mobile phone will be available for 
participants who do not own a mobile phone or who are not willing to use their 
phone for this purpose (i.e., due to concerns about mobile data cost). The digital 
timestamps of these videos will subsequently be extracted, and their contents 
reviewed, to verify that the participant ingested the medication at the instructed 
time. Other studies of non-treatment-seeking individuals have reported success 
with remote video monitoring (DeWorsop et al. 2016). 
b. MRI. We will conduct a Magnetic Resonance Scan. This will be completed at the 
Brain Imaging Center (BIC) at the University of Colorado Anschutz Medical 
Campus. Scanning will be conducted on a Siemens Skyra 3.0 T MR system that is 
equipped with high performance gradient coils (45mT/m @ 200 T/m/s), a head 
volume RF coil, and a 32-channel phased-array RF neurovascular coil. The 
system has a 70 cm bore opening and a weight capacity of 550 lbs. This will be a 
head-first, supine scan of the brain. Each scan will last one hour. A fMRI run 
sensitive to blood‐oxygenation level‐dependent (BOLD) contrast will be collected 
using T2*‐weighted parameters. For anatomical reference, a high‐resolution, 
magnetization prepared rapid gradient echo (MPRAGE) T1-weighted image will be 
collected during the same session.  
i. 
Monetary Incentive Delay task: The monetary incentive delay task (MID) was 
developed at the National Institute on Alcohol Abuse and Alcoholism (Knutson 
et al. 2001). The task has reliably shown that cues signaling a chance to win 
money recruit activation in the nucleus accumbens, and larger potential gains 
induce greater activity (Knutson et al. 2001). The task is comprised of three 
levels of monetary reward (-$5, +$0, +$5). This task reliably recruits nucleus 
accumbens activation and has a large effect size, with a Cohen’s d > 2.0. In the 
MID task, visual stimuli, such as circles, squares, and triangles, are utilized as 
incentive cues that code the probabilities and magnitudes of outcomes. The first 
box shows the cue types presented, with circles indicating the potential to win 
money (gain cue), triangles indicating the potential to lose money (loss cue), 


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and a square indicating no money will be won or lost (neutral cue). A cue is 
presented for 500 ms, followed by a fixation cross (2,000 to 2,500 ms) and then 
the target square (160 to 260 ms), during which the participant is instructed to 
press a button as quickly as possible to win or avoid losing money. A feedback 
screen (1,650 ms), in which the top number indicated the amount of money won 
or lost during that trial and the bottom number indicates the participant’s total 
amount, is presented at the end of each trial. 
ii. 
Emotion Regulation task: In the emotion regulation task (Waugh et al. 2016), 
we will examine subjects’ ability to change how they are feeling by changing the 
way they think. Participants will be shown a series of pictures from the 
International Affective Picture System that have been validated and grouped by 
rating (e.g. typically induces negative affect) (Lang, Bradley, and Cuthbert 
1997). Some pictures are designed to be neutral, such as pictures of nature 
scenes, and some are designed to evoke strong negative feelings, such as 
disgust or horror. Prior to viewing each picture, the participant will be instructed 
to either “Look” or “Decrease”. When instructed to “Look”, participants are told 
to keep their eyes on the picture and feel any feelings naturally without trying to 
change them. This instruction occurs prior to all 15 neutral pictures and prior to 
15 of the negative pictures.  When instructed to “Decrease” prior to the 
remaining 15 negative pictures, participants are told to keep their eyes on the 
picture and find an aspect of it that is not as bad as it seems at first. After 
viewing each image, participants will be asked how negative they feel. They will 
be shown a five-point Likert scale from one (not at all) to five (extremely 
negative), and they will record their response by pressing one of five buttons on 
a button box attached to their hand. Two sets of pictures will be available so 
that each participant will see a new set of images on each scan. Order of the 
sets will be counterbalanced across participants. 
 
 
iii. 
Social Task: The task, adapted from Jepma et al and Willroth et al, requires 
participants to rate their expected and experienced valence of varying types of 
images (Fig. 3).  Three distinct geometric shapes acted as cues that predicted 
the category of image that the individual would subsequently view (erotic, non-
erotic pleasant, or neutral).  On presentation of the cue, the subject is asked to 
rate the expected valence of the image using a slider device on a scale of 
unpleasant to pleasant (coded as 0 to 100). After rating their expectation, they 
Figure 3: This figure shows 
the presentation of the cues 
for the Social Task used 


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are presented with the image and are required to rate the experienced valence 
of that image using the same slider device.  Subjects rate expected and 
experienced valence of 90 unique images: 30 erotic images, 30 non-erotic 
pleasant images (e.g., scenes of nature, cute animals), and 30 neutral images 
(e.g., forks, furniture).  The same images are presented to each participant, but 
participants are randomly assigned to one of four random orders. The task 
takes place over 2 runs of approximately 8 minutes each. Prior to starting the 
task, participants are given instructions that included 3 practice cue/image pairs 
from each category to introduce them to the task and the relationship between 
each cue and image category. All images were publicly available and/or from 
affective picture sets currently used in research (Lang et al. 2005)(Marchewka 
et al. 2014)(Kurdi et al. 2017).  
c. The Structured Clinical Interview for the Diagnostic (SCID-5) and Statistical 
Manual for Mental Health Disorders 5, research version (First, Williams et al. 2015) 
will be administered to all participants by a psychiatrist or mental health 
professional (e.g. post-doc with clinical background). Diagnoses will be determined 
via a consensus meeting with the study psychiatrist, Dr. Penner. SCID-5 is a semi-
structured interview guide for making diagnoses according to the diagnostic criteria 
published in the American Psychiatric Association’s Diagnostic and Statistical 
Manual for Mental Disorders (DSM). With the release of the fifth edition (DSM-5), 
the SCID for DSM-5 (SCID-5) was published in 2013 and is the latest version 
available. 
d. We will administer questionnaires using Research Electronic Data Capture 
(REDCap), as the University of Colorado is part of the REDCap consortium 
(Patridge and Bardyn 2018). These metrics will establish history of substance use, 
psychopathology such as anxiety and depression levels, and trait levels of 
cognitive reappraisal.  
i. Adult Self Report: (ASR) is used to obtain measures of internalizing and 
externalizing pathology (Rescorla and Achenbach 2004).  
ii. Alcohol Use Disorders Identification Test (Saunders et al. 1993): 
(AUDIT) is a 10-item screening tool developed by the World Health 
Organization (WHO) to assess alcohol consumption, drinking behaviors, 
and alcohol- related problems. This study uses a self-report version of the 
AUDIT. Patients should be encouraged to answer the AUDIT questions in 
terms of standard drinks. A chart illustrating the approximate number of 
standard drinks in different alcohol beverages is on the questionnaire for 
reference. A score of 8 or more is considered to indicate hazardous or 
harmful alcohol use. The AUDIT has been validated across genders and in 
a wide range of racial/ethnic groups and is well suited for use in primary 
care settings. 
iii. Substance Use Risk Profile Scale: (SURPS) (Woicik, Stewart et al. 
2009), measures hopelessness, anxiety sensitivity, impulsivity, and 
sensation-seeking, and has been shown to reliably predict alcohol use. 
iv. Beck Depression Inventory: (BDI) is a 21-item, self-report rating 
inventory that measures characteristic attitudes and symptoms of 
depression (Beck, et al., 1961). The BDI has been developed in different 
forms, including the 13-item short form and the more recent BDI-II by 
Beck, Steer & Brown, 1996.Internal consistency for the BDI ranges from 
.73 to .92 with a mean of .86. (Beck, Steer, & Garbin, 1988). Similar 
reliabilities have been found for the 13-item short form (Groth-Marnat, 
1990). The BDI demonstrates high internal consistency, with alpha 


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coefficients of .86 and .81 for psychiatric and non-psychiatric populations 
respectively (Beck et al., 1988). 
v. The Barratt Impulsiveness Scale: BIS (Patton et al., 1995) is a 
questionnaire designed to assess the personality/behavioral construct of 
impulsiveness. It is the most widely cited instrument for the assessment of 
impulsiveness and has been used to advance our understanding of this 
construct and its relationship to other clinical phenomena for 50 years (for 
review see Stanford et al., 2009). 
vi. Customary Drinking and Drug Use Record (Brown et al. 1998): CDDR 
provides current (past 3 months) and lifetime measures of four alcohol- 
and other drug-related domains: level of involvement, withdrawal 
characteristics, psychological/behavioral dependence symptoms, and 
negative consequences. 
vii. COGA Family History Assessment Module (Vogel-Sprott, Chipperfield, 
and Hart 1985): (COGA FHAM) is semi-structured diagnostic instrument 
intended for clinicians and non-clinicians to assess major DSM-III-R 
psychiatric disorders among relatives of the participant. The following 
psychiatric disorders are ascertained: alcoholism, drug abuse/ 
dependence, depression, mania, schizophrenia, antisocial personality and 
unspecified psychiatric disorder. 
viii. Difficulties in Emotion Regulation Scale (DERS) (Gratz and Roemer 
2004): A measure of subjective emotion ability, as defined by a prominent 
clinically derived model of emotion regulation. The model upon which it is 
based proposes four broad facets of emotion regulation: (a) awareness 
and understanding of emotions; (b) acceptance of emotions; (c) the ability 
to control impulses and behave in accordance with goals in the presence 
of negative affect; and (d) access to emotion regulation strategies that are 
perceived to be effective for feeling better. 
ix. Emotional Regulation Questionnaire: The Emotion Regulation 
Questionnaire (Gross and John 2003) is a 10-question survey that 
assesses trait levels of suppression and reappraisal. Each question has a 
7-point Likert-rated response (1 strongly disagree to 7 strongly agree). 
Emotion regulation assessed via questionnaire has high internal 
consistency (Cronbach’s alpha = 0.80) (Gross and John 2003). The 
reappraisal scale consists of 6 items and the suppression scale consists of 
4 items. An example of reappraisal is, “When I want to feel more positive 
emotion, I change the way I’m thinking about the situation.” An example of 
suppression is, “I control my emotions by not expressing them.” 
x. Friendship, Loneliness, Life Satisfaction, Perceived Rejection from 
the NIH Toolbox Emotion Battery (Salsman et al. 2013): F, L, LS, & PR 
evaluate perceptions that one is alone, lonely, or socially isolated from 
others, perceptions of the availability of friends or companions with whom 
to interact or affiliate, One’s cognitive evaluation of life experiences and 
whether one likes his/her life or not, and Perceptions of being ignored or 
others not listening or responding to requests for help. 
xi. State-Trait Anxiety Inventory: (STAI) is a commonly used measure of 
trait and state anxiety (Spielberger, Gorsuch, Lushene, Vagg, & Jacobs, 
1983). It can be used in clinical settings to diagnose anxiety and to 
distinguish it from depressive syndromes. It also is often used in research 
as an indicator of caregiver distress (e.g., Greene et al., 2017, Ugalde et 
al., 2014). Form Y, its most popular version, has 20 items for assessing 


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trait anxiety and 20 for state anxiety. State anxiety items include: “I am 
tense; I am worried” and “I feel calm; I feel secure.” Trait anxiety items 
include: “I worry too much over something that really doesn’t matter” and “I 
am content; I am a steady person.” All items are rated on a 4-point scale 
(e.g., from “Almost Never” to “Almost Always”). Higher scores indicate 
greater anxiety. The STAI is appropriate for those who have at least a 
sixth-grade reading level. Internal consistency coefficients for the scale 
have ranged from.86 to .95; test-retest reliability coefficients have ranged 
from .65 to .75 over a 2-month interval (Spielberger et al., 1983). Test-
retest coefficients for this measure in the present study ranged from .69 to 
.89. Considerable evidence attests to the construct and concurrent validity 
of the scale (Spielberger, 1989). 
xii. Childhood Trauma Questionnaire: (CTQ) contains 5 subscales, 
emotional abuse, physical abuse, sexual abuse, emotional neglect and 
physical neglect (Bernstein et al. 1998).  
xiii. Marlowe–Crowne Social Desirability Scale: (MC–SDS) is a 33-item self-
report questionnaire that assesses whether or not respondents are 
concerned with social approval. The scale was created by Douglas P. 
Crowne and David Marlowe in 1960 in an effort to measure social 
desirability bias, which is considered one of the most common biases 
affecting survey research (Marlow and Crowne 1961). 
e. We will collect behavioral measures using a laptop during the study visit. 
i. Alcohol Purchase task (APT): (Kaplan et al. 2018): After the scan, we 
will administer this task to determine the amount individuals are willing to 
pay for alcohol. In the alcohol purchase task, participants first read the 
following vignette: “Imagine that you and your friends are at a bar from 9 
p.m. to 2 a.m. to see a band. The following questions ask how many drinks 
you would purchase at various prices. The available drinks are standard 
size beer (12 oz.), wine (5 oz.), shots of hard liquor (1.5 oz.), or mixed 
drinks with one shot of liquor. Assume that you did not drink alcohol before 
you went to the bar and will not go out after.” Participants will then be 
asked “How many drinks would you consume if they were ____ each?” 14 
costs will be listed: $0 (free), $0.25, $0.50, $1.00, $1.50, $2.00, $2.50, 
$3.00, $4.00, $5.00, $6.00, $7.00, $8.00, and $9.00. 
ii. Iowa gambling task: (IGT) is a psychological task thought to simulate 
real-life decision making. It was introduced by Antoine Bechara, Antonio 
Damasio, Hanna Damasio and Steven Anderson, then researchers at the 
University of Iowa (Bechara et al. 1994). We will use the often computer 
based version of the task. The task was originally developed to detect 
problems patients with damage to the ventromedial prefrontal cortex. This 
part of the brain is, among other things, involved in processing risk, fear, 
emotion, and decision making. 
iii. Delay-Discounting Task: (DD) is a measure of temporal discounting, the 
tendency for people to prefer smaller, immediate monetary rewards over 
larger, delayed rewards. Participants complete a series of 5 questions that 
each require choosing between a smaller, immediate reward (e.g., $500 
today) versus a larger, later reward (e.g., $1000 in 25 days). The 5 items 
are divided into three groups according to the size of the larger amount 
(small, medium, or large) (Koffarnus and Bickel 2014). Modeling 
techniques are used to fit the function that relates time to discounting. The 
main dependent measure of interest is the steepness of the discounting 


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curve such that a more steeply declining curve represents a tendency to 
devalue rewards as they become more temporally remote. 
D. Description, Risks and Justification of Procedures and Data Collection Tools: 
a. Justification for Exclusion of Vulnerable Populations: 
Vulnerable populations are routinely excluded from experimental studies with more 
than minimal risk and without an established therapeutic benefit. 
b. Risks/Discomforts and Benefits Ratio  
Benefits: Participation in this study will not provide any known direct benefit. 
Participants will receive psychiatric assessment and will be notified if anything pertinent 
to their health is discovered. The primary benefit of this study will be to others. The 
knowledge gained from this study could help develop treatments and provide 
information about who those treatments will work best on.  
Risks and risk management: Known risks and discomforts associated with study 
procedures and steps to mitigate or minimize the risks are described below.  
 
MRI: There are no known long-term risks of MRI scans. However, people are at risk for 
injury from the MRI magnet if they have certain metal objects in their bodies. These 
include implanted electrical devices such as pacemakers, cochlear implants, delivery 
pumps or brain stimulators. People with implanted metal such as aneurysm clips 
(metal clips on the wall of a large artery), permanent eyeliner, shrapnel fragments or 
some dental implants and prostheses (including metal pins and rods, heart valves) are 
also at risk. Welders and metal workers are also at risk for injury because of possible 
small metal fragments in the eye. Individuals with back problems may have back pain 
or discomfort from lying in the scanner. Individuals with fear of confined spaces may 
become anxious during an MRI. The noise of the MRI machine can be loud enough to 
damage one’s hearing, especially in people who already have hearing loss. 
1. To minimize risk from metal objects, participants will be screened 
for metal in their body using the MRI safety screening 
questionnaire, and individuals who report metal in their bodies will 
be excluded from the study. 
2. Volunteers who are pregnant or planning to become pregnant 
during the study cannot participate. For female participants, a 
urine pregnancy test will be given no more than 24 hours before 
each MRI session. If a pregnancy test is positive or uncertain, she 
may not be in the study. 
3. Participants will be able to communicate with MRI technologist 
during the scan and can ask to be removed from the scanner at 
any time if they become anxious or feel uncomfortable during the 
scan. 
4. The participant will be fitted with earplugs and headphones to 
muffle the sound. 
c. Confidentiality: Medical records will be handled to prevent breach of privacy at a 
level considered sufficient for sensitive health care data. Confidentiality and 
information technology standards will be placed to protect electronic repositories of 
patient data as well as other clinical patient related materials. Research data not 
managed electronically will be stored using codes. No personal identifiers will be 
used. Data will be kept in password-protected computers, either located in access-
controlled areas (servers), or, if transferred onto individual workstations, on 
encrypted media that protect privacy even if storage media are subject to theft. 
Samples will be kept in locked storage in access-controlled areas. Full access to 
data will be provided, under conditions of confidentiality, to individuals or groups 


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conducting quality assurance and appropriate regulatory agencies. With these 
exceptions, only study investigators and their staff will have access to the samples 
and data. When reporting the results of this research in medical journals or at 
scientific meetings, the people who take part will not be named and identified. We 
will not release any information about subject research involvement without the 
subject’s written permission. The Federal Privacy Act protects the confidentiality of 
medical records. However, the Act allows release of some information from a 
subject’s medical record without the subject’s permission; for example, if it is 
required by the FDA, members of Congress, law enforcement officials, or other 
authorized people. 
d. Naltrexone:  
i. Common and Serious Side Effects of Naltrexone 
Nausea, sleepiness, headache, dizziness, vomiting, decreased appetite, painful joints, muscle 
cramps, cold symptoms, trouble sleeping, toothache.  
ii. Serious side effects of naltrexone may include: 
Risk of opioid overdose. Accidental overdose can happen in two ways. Naltrexone blocks the 
effects of opioids, such as heroin or opioid pain medicines. Patients who try to overcome this 
blocking effect by taking large amounts of opioids may experience serious injury, coma, or death. 
After receiving a dose of naltrexone, the blocking effect slowly decreases and completely goes 
away over time. Patients who are taking naltrexone for an OUD can become more sensitive to the 
effects of opioids at the dose used before, or even lower amounts. Using opioids while on 
naltrexone can lead to overdose and death.  
Liver damage or hepatitis is possible. Patients should tell their practitioner about any of the 
following symptoms during treatment: stomach area pain lasting more than a few days, dark urine, 
yellowing of the whites of your eyes, tiredness, Practitioners may need to stop treatment using 
naltrexone if patients develop signs or symptoms of a serious liver problem, Depressed mood, 
Pneumonia, Serious allergic reactions, Skin rash, swelling of face, eyes, mouth, or tongue, trouble 
breathing or wheezing, chest pain, feeling dizzy or faint. 
iii. Minimizing risk 
Remote video monitoring will also be used to assess adherence. Dosing size will be set before 
participants receiving the naltrexone and participants will start on smaller doses (25mg) for two 
days before being raised to the final dosing to allow for adjustment to naltrexone and in case of 
adverse reaction to naltrexone. We will use a questionnaire  to check for adverse reactions and will 
provide care as needed for moderate or severe side effects, such as nausea. 
e. Psychological Tests 
i. During the Standardized Clinical Interview for the DSM-V (SCID) 
participants may discuss negative or traumatic events they have 
experienced. The SCID will be administered by a trained psychiatrist or by 
a member of the team trained by the team psychiatrist. Some of the 
questionnaires may cause emotional distress by asking about traumatic or 
unpleasant events from a person’s life. While most individuals will tolerate 
this discomfort without problems, it is possible that the memories may 
trigger unhappiness. To mitigate the risk, study staff will allow participants 
to take breaks as needed. If serious distress arises, participants will be 
referred to a psychiatrist from the study team. This protocol may identify 
mental health problems, such as depression, suicidality, or substance use 
disorders. Problems with acute danger, such as suicidality will receive 
immediate attention and intervention. Individuals with diagnoses such as 
depression or alcohol use disorder will be given referrals for treatment. 
 


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E. Potential Scientific Problems: One challenge of our study is that we will not directly 
observe naltrexone binding. Directly observing naltrexone’s activity would require PET 
imaging to observe displacement of a tracer that binds to opioid receptors, but we will not 
do that in this study due to cost and time. Thus, even if we observe behavioral or neural 
effects, we will not know if naltrexone is acting at that site. However, since we are using a 
randomized, placebo-controlled design, we can still draw conclusions about naltrexone 
causing the changes even if the changes may be downstream from naltrexone’s direct site 
of action.  
F. Data Analysis Plan: Outcomes will be examined using paired t-tests for two times (active 
medication, placebo). Functional MRI analysis will be conducted with AFNI software (Cox 
1996). Functional images will be time-slice corrected and co-registered with anatomical 
images. Anatomical images will be non-linearly warped to standard space and an identical 
transformation will be applied to the functional image. Functional images will be blurred 
using a 4mm Gaussian kernel and values will be scaled to have a mean intensity of 100. A 
regression algorithm will be applied including six regressors to account for motion. For the 
monetary incentive delay task, regressors of interest include the gain, loss, and neutral 
cue. For the emotion regulation task, regressors of interest include neutral, look, and 
decrease conditions. For the monetary incentive delay task, activation will be extracted 
from the nucleus accumbens for each of the three cues. For the emotion regulation task, 
activation will be extracted from the amygdala for each of the three conditions. As an 
exploratory analysis, we will conduct whole-brain, voxel-wise analysis.  
 
Sample Size and Power Considerations. In terms of evaluating differences in reward 
activation between placebo and mu-opioid antagonism conditions, a study of mice 
estimated a large effect size of mu-opioid antagonism on reward response in the nucleus 
accumbens, with Cohen’s d > 1.0 (Walters et al. 2005). A study of kappa-opioid receptor 
modulation in human reward response measured with functional MRI found a medium to 
large effect size of Cohen’s d = 0.6 (Krystal et al. 2020). We specified significance level 
alpha=.05, two-tailed, and power of 0.8. A sample of 9 adults would provide 80% power to 
detect an effect size of 1.0 or greater as significant. 
 
G.  Summarize Knowledge to be Gained:  We hope to show that reward response is 
diminished when opioid receptors are blocked in humans. We hope to show that opioid 
antagonism has specificity for ventral striatal (e.g. nucleus accumbens) activation for 
rewards. Following this pilot, our goal is to test the effect of naltrexone in adults with an 
alcohol use disorder. A leading theory is that naltrexone will be more effective in patients 
who seek alcohol’s rewarding effects compared to patients who seek relief of negative 
symptoms such as anxiety or withdrawal. This would help develop a precision medicine 
approach to treatment of alcohol use disorder, where clinicians could use reward response 
as a marker to determine the likelihood of naltrexone’s efficacy. We would use this pilot 
data as part of an R01 application to fund the next study.  
 
H. References: 
 
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