An fMRI Study of Opioid-related Changes in Neural Activity
Phase: NA
Conditions: Social Acceptance
Sponsor: Tristen Inagaki

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Study Protocol with SAP 
 
 
 
 
 
 
Official Title: An fMRI Study of Opioid-related Changes in Neural Activity 
  
 
 
 
ClinicalTrials.gov ID (NCT number): NCT02818036 
 
 
 
 
Protocol Date: 8/13/15 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Scientific Background 
 
Having and maintaining close social bonds is so fundamental to health, well-being, and normal 
functioning that bonding has been referred to as a basic need, much like the need for food and 
water (Baumeister & Leary, 1995). In fact, being deprived of care and support early in life 
results in severe cognitive, social, developmental, and health consequences throughout 
development (Bowlby, 1988; Gunnar, 2001; House, Landis, & Umberson, 1988; Holt-Lundstad, 
Smith, & Layton, 2010; Tottenham & Sheridan, 2010). However, although humans require close 
social bonds to survive and thrive (Bowlby, 1988; Taylor, 2010; Uchino, 2004) few have 
explored the experience of social connection—the positive, contented feelings associated with 
being close to others—or how individuals come to feel connected to those they love the most. 
Furthermore, little is known about the neurochemical mechanisms that help support social bonds, 
especially in humans. 
 
According to the brain opioid theory of social attachment, endogenous opioids, specifically µ-
opioids, are thought to mediate the pleasant feelings stemming from social bonding and 
affiliation (Panksepp, 1998). More specifically, opioids have been proposed to underlie the 
affiliative, interpersonal feelings (e.g. warmth, affection) that come from social connection 
(Depue and Morrone-Strupinsky, 2005; Panksepp, 1998). Furthermore, the theory states that 
experiences of social loss or separation lead to reduced opioid activity thus leading to feelings of 
disconnection and separation distress. Although few studies have examined the role of opioids in 
human attachment relationships, data from animal models support the theory that opioids are 
involved in social bonding (e.g., Burkett et al, 2011; Kalin et al, 1988; Kalin et al, 1995; Keverne 
et al, 1989; Moles et al., 2004; Panksepp et al., 1980; Shayit et al., 2003; Schino & Troisi, 1992; 
Trezza et al, 2011).  
 
Only a handful of studies have explored the effects of opioids on perceptions of social rewards 
and social attachment experiences in humans. With regard to the effect of opioids on social 
rewards, morphine (vs. naltrexone) leads to higher attractiveness ratings for the most attractive 
faces presented, suggesting that opioids can enhance ‘liking’ toward certain stimuli (Chelnokova 
et al., 2014). One early study (described in Depue and Morrone-Strupinsky, 2005 but not 
published on its own), examined the role of opioids in social attachment processes. Here, female 
participants were administered naltrexone (25mg) and placebo (separated by a 4-day period) and 
were asked to rate their feelings of connection in response to watching two separate movie clips: 
an affiliative movie clip of a couple giving birth to their first child and a neutral film clip of a 
nature scene. In line with the brain opioid theory of social attachment, naltrexone (vs. placebo) 
reduced the increases in warm, affectionate feelings to watching the affiliative clip (compared to 
the neutral clip) among those high in trait affiliation. Similarly, Schweiger and colleagues (2014) 
have recently shown that a 25mg dose of naltrexone (vs. placebo) reduced affiliative feelings 
(cozy, comforting, liked, secure) after an economic trust game. Furthermore, we have recently 
shown that naltrexone (vs. placebo) reduces feelings of connection both in the lab and out in the 
real world (Inagaki, Ray, Irwin, Way, & Eisenberger, 2016). Together, these results suggest that 
opioids may subserve feelings of connection. 
 
Though not directly manipulating opioids, neuroimaging findings on close social bonds show 
that opioid-rich neural regions activate to cues of close others. Thus, reading loving messages 

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(vs. neutral messages) from close friends and family members activates the ventral striatum 
(VS), ventral tegmental area (VTA), pregenual (pACC) and dorsal anterior cingulate cortex 
(dACC); orbitofrontal cortex (OFC), and insula (Inagaki & Eisenberger, 2013), all regions 
known to be high in µ-opioid receptors (Cross, Hille, & Slater, 1987; Jones et al., 1999; 
Panskepp & Bishop, 1981; Vanderschuren, Stein, Wiegant, & Van Ree, 1995; Willoch et al., 
1999; Wise & Herkenham, 1982; Zubieta et al., 2001). Similarly, the VS, OFC, and VTA are 
more active when viewing images of close others (vs. strangers or acquaintances) such as one’s 
own baby or romantic partner (Acevedo, Aron, Fisher, & Brown, 2012; Bartels & Zeki, 2004; 
Strathearn, Li, Fonagy, & Montague, 2008). Though not tested yet, it is possible that opioid 
antagonism may reduce activity in these affiliation-related neural regions. 
 
Together, emerging evidence from humans and animals point to the possibility that µ-opioids 
contribute to the experience of bonding and connecting with others, but few have explored the 
role of opioids in social bonding in humans. As such, the current study aims to test the brain 
opioid theory of social attachment to better understand the role of opioids in maintaining close 
social bonds.  
 
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Study Objectives 
 
This study will examine the role of opioids on social connection processes and more specifically, 
will explore the effect of blocking opioids on feelings of social connection and connection-
related neural activity.  
 
Study Design & Methods 
 
Overview: To assess the role of opioids in the experience of connecting with others, an opioid 
antagonist, naltrexone, will be administered in a randomized, double-blinded, placebo controlled 
design. Participants will attend a baseline session where they will complete trait measures in 
order to obtain baseline measures in feelings of connection. Participants will then be scheduled 
for an fMRI scan where they will be randomly assigned to a drug condition (naltrexone or 
placebo). During the scan, participants will complete a number of tasks designed to elicit feelings 
of social connection. After the scan, participants will complete self-report measures in order to 
assess the effect of opioid antagonism on perceptions of their social relationships.  
 
Timeline and anticipated duration of study procedures: 
1. 
Telephone Screening (15 minutes) 
2. 
In-person visit #1 (Sennott Square): review and sign consent form, baseline 
questionnaires (60 minutes) 
3. 
In-person visit #2 (Neuroscience Imaging Center): Experimental Session at fMRI scanner 
(3 hours) 
3a. 
Assignment to study drug, wait for peak effects (60 minutes) 
3b. 
fMRI scan (60 minutes) 
3c. 
post scan assessments and video recording (60 minutes) 
 
Total time: 4 hours 
 
IN-PERSON BASELINE VISIT #1: 
Participants will review the consent form and be allowed to ask clarifications before giving 
consent to participate. Participants will then answer questions about their perceptions of their 

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social relationships, feelings over the past 24 hours, general health and health-related behaviors, 
and demographics. In addition, participants will be asked to complete a number of personality 
measures to establish a baseline for social interactions and feelings about relationships. 
 
IN-PERSON VISIT #2: 
On the day of the study, participants will arrive at the Magnetic Resonance Research Center 
(MRRC) where they will complete a urine drug test to test for the presence of opiates and other 
drugs, a urine pregnancy test (if female) and complete a baseline physical symptoms checklist. A 
positive urine test for either drugs or pregnancy will result in the withdrawal of the participant 
from the study.  
 
To ensure safety for an MRI scan, participants will undergo a two-step safety screening 
procedure with the MRI technician. First, a written screening form is completed during a face-to-
face interview with the participant and the technologist. Once the participant has passed the 
written screening, then visual screening is performed by the technologist to identify and 
eliminate any contraindicated objects on the participant’s body or clothing. Participants will then 
be randomly assigned to receive either 50mg of oral naltrexone or placebo.  
 
Details on drug randomization and study drug blind methods: (1) Randomization: An individual 
unassociated with the main study will randomly assign participants to drug A or drug B on the 
day of the scheduled scanning session by using a block randomization method. This will ensure 
that there are equal numbers of men and women assigned to each drug condition. This individual 
will not have access to any of the data or any information about the participant except for their 
gender and age. It will be necessary for the person in charge of randomization to know the 
gender and age of the participant so that they may keep the two conditions balanced. (2) Study 
Drug Blind: The PI (Tristen Inagaki), study coordinator, any trained research assistant’s, and the 
participants will all be blinded during the study, thereby maintaining the double-blind. Only the 
study physician, Dr. Carmen Andreescu, and the individual who performs the randomization will 
be unblinded. The PI will be told which drug is A and which is B at the end of data collection. 
Finally, the drug and placebo will be packaged into identical capsules so that the pills look 
identical to the experimenters.  
 
fMRI SCAN: 
Approximately 60 minutes after taking the study drug, when naltrexone is known to show peak 
effects (Lee et al, 1988), participants will complete an fMRI scan. During this time they will be 
asked to either lie still inside the bore of the magnet while brain scans are acquired or be asked to 
perform the following tasks inside the MRI machine: 
 
Messages task: Participants will read a variety of messages from friends and family members, 
and from strangers. Messages will be presented in a block design with 3 messages presented per 
block, separated by 6-second rest periods. Participants will read both positive and neutral 
messages from close others and as further control conditions, positive and neutral messages from 
strangers. 
 
Picture task: Prior to attending their experimental session, participants will provide the study 
coordinator with 2 images of 2 different people with whom they feel close. Once in the scanner, 

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participants will view images of their close others as well as gender, race, and age-matched 
strangers as a control condition. In between blocks of pictures, participants will complete mental 
arithmetic.  
 
POST SCAN ASSESSMENTS: 
Outside of the scanner, participants will rate their feelings of connection (e.g. “How connected 
did reading the messages make you feel?”, “How warm did reading the messages make you 
feel?”, “How touched did reading the messages make you feel?”) to reading each set of 
messages. They will also complete the same physical symptoms checklist that they completed 
prior to taking the study drug and their perceptions of their close other from the picture task.  
 
Eligibility Criteria  
Inclusion criteria require participants to be in good health, between the ages of 18 and 35, fluent 
in English, be willing to provide digital photographs of their close others (for the picture scanner 
task) and identify 6-8 friends and family members who might be willing to be contacted in 
regards to the current research study (for the messages scanner task). In addition, participants 
must be right-handed and free of metal (for the fMRI scan).  
  
Participants will be excluded for the following: 
Self-reported current or past diagnoses of physical or mental illness. 
Score on the Patient Health Questionnaire (depressive symptoms) above a 9  
Positive urine drug test (for THC, Opiates, Cocaine, AMP, and mAMP) 
Positive urine pregnancy test 
Use of any prescription medication, except for birth control 
Use of any over-the-counter medications on the day of the fMRI session and 24 hours after the 
fMRI session 
Self-reported problems with liver functioning, including hepatitis or liver failure 
Difficulty swallowing or taking pills 
 
fMRI specific exclusions: 
BMI greater than 35 or weight greater than 400 lbs (the weight limit of the fMRI scanner) 
Claustrophia 
Nonremovable metal in the body 
 
Statistical Considerations 
 
Primary outcomes: Neural activity and self-reported feelings of connection in response to the 
messages task and the picture-viewing task. 
 
Neuroimaging outcome: The imaging data will be analyzed using SPM8 (Wellcome Department 
of Cognitive Neurology, Institute of Neurology, London, UK). Images for each participant will 
be realigned to correct for head motion, normalized into a standard stereotactic space, and 
smoothed with an 8mm Gaussian kernel, full width at half maximum, to increase signal-to-noise 
ratio. The imaging tasks are all block designs and therefore we will use a boxcar function 
convolved with a canonical hemodynamic response function. For each participant, each block 

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type will be modeled separately (e.g. viewing images of a close other will be modeled separately 
from viewing images of a stranger). After the task is modeled for each participant, planned 
comparisons will be computed as linear contrasts to investigate neural activity separately during 
each of the conditions compared to baseline (fixation crosshairs) and each condition compared to 
its respective control condition (e.g. images of close other vs. images of stranger). Random 
effects analyses of the group will be computed using the contrast images generated for each 
participant.  
 
To assess between-group differences in the effect of naltrexone vs. placebo on neural responses 
to the different tasks, we will conduct two kinds of analyses for each task. First, based on a priori 
hypotheses regarding the effect of naltrexone on affiliation-related neural responses, we will 
conduct region-of-interest (ROI) analyses, using structurally-defined ROIs, to examine between-
group differences in neural activity in these pre-specified neural regions (p<.05, corrected). For 
the task where participants read messages from their loved ones, ROIs of the VS and mid-insula, 
have been created (with the PickAtlas toolbox) using the automated anatomical atlas (AAL; 
Tzourio-Mazoyer et al., 2002), and will be examined to see if average neural activity in these 
regions differs between naltrexone and placebo participants in response to the messages. 
Similarly, for the picture-viewing task, ROIs of the left and right VS will be analyzed in the 
same way (these have also been structurally defined previously; Inagaki et al., 2015). Second, to 
more fully investigate the specific neural regions that are differentially activated as a function of 
naltrexone (beyond the predicted ROIs), we will conduct whole-brain between-group analyses to 
see which neural regions differ in activity among participants exposed to naltrexone vs. placebo 
(p<.001, 10 voxels). 
 
Feelings of social connection: To assess between-group differences in the effect of naltrexone vs. 
placebo on self-reported feelings of connection in response to the scanner tasks, we will conduct 
independent samples t-tests.  
 
Results for primary outcomes 
 
Effect of Naltrexone on Neural Activity to Messages task: To examine the effect of naltrexone 
on neural activity to the social warmth task, analyses were constrained to the a-priori defined VS 
and MI mask. VS and MI activity was greater to messages from close others than strangers (left 
t(76)=6.138, p<.001; right t(76)=4.493, p<.001). Naltrexone, however, reduced VS and MI 
activity to the social warmth task as compared to placebo (left t(75)=1.859, p=.034; right 
t(75)=2.198, p=.016).  
 
Effect of Naltrexone on Feelings of Social Connection to Messages task: The effect of drug on 
feelings of social connection to the messages task was in the expected direction, but did not 
reach statistical significance (p>.10).