Naltrexone Alters Responses to Social and Physical Warmth: Implications for Social Bonding

Tristen K. Inagaki; Laura I. Hazlett; Carmen Andreescu


Soc Cogn Affect Neurosci. 2019;14(5):471-479. 

In This Article

Materials and Method


Recruitment took place via flyers and a posting to a research registry. A total of 82 participants were deemed eligible and were then randomized to naltrexone or placebo by an individual unassociated with the study. Two participants did not complete the study (see the CONSORT flow diagram as Supplementary Figure 1), leaving a final sample of 80 participants (M age = 22.39, s.d. = 3.362) who were randomly assigned to naltrexone (n = 40, 21 females) or placebo (n = 40, 27 females). For information about screening, see Supplementary Materials. The University of Pittsburgh's Investigational Drug Service compounded study drugs and the PI's (T.K.I.) lab dispensed drugs. Participants were compensated $90 for completing the study.

Supplementary Figure 1.

CONSORT Flow Diagram

The study was registered on the U.S. National Institutes of Health Clinical Trials registry as NCT02818036. Procedures were performed between September 2016 and June 2018 following approval from the University of Pittsburgh's Human Research Protection Office (including written consent).

Overview of Experimental Session

Details regarding the study procedures are reported elsewhere (Inagaki et al., unpublished data) and in the Supplementary Materials, but none of the data or tasks reported here have previously been reported. During the experimental session, participants were randomly assigned to 50 mg of oral naltrexone or placebo. Approximately 60 min following drug administration, when naltrexone shows peak effects (Lee et al., 1988), participants completed three tasks in the fMRI scanner in the following order: social warmth task, picture task (see Supplementary Materials) and physical warmth task. Finally, post-scan self-reports were collected. Physical symptoms and the distress from any symptoms are reported under Supplementary Materials.

Neuroimaging Measures

Social warmth task. For the social warmth task, experimenters collected messages from each of our participants' close others in order to create personalized tasks. For pre-scan message collection procedures, see Supplementary Materials. Participants were told that the experimenters had asked their friends and family members to provide 12 messages each and that they would be reading the messages in the scanner (close other condition). In addition, participants read randomly selected messages from a previous participant's friends and family members (stranger condition). No specific instructions were given as to what to think about while reading. Blocks began with a 2-s cue explaining whom the messages were from [e.g. The following messages are from Ed (example close other cue); the following messages are from a previous participant (stranger cue)] followed by three messages, either from a single close other or a stranger, presented for 5 s each. Blocks were separated by 6 s of fixation crosshair, and close other and stranger blocks were randomized. Presented were 40 sets of messages (20 close other; 20 stranger) over 2 functional runs. Examples of messages from close others in the current study include the following: 'I really appreciate the way you love and support me; our connection is one of the most beautiful things in my life.'; 'You are endlessly funny and bring joy to everyone around you.'; 'I love that I can always call on you to experience new things with.'; 'You light up my entire world.'

Physical warmth task. For the physical warmth task, participants held warm and cool therapeutic packs and a neutral, room temperature object (ball) ostensibly for a product evaluation task (Kang et al., 2010). Blocks began with a 3-s cue indicating which object would be presented. The experimenter then placed one of the three objects in the participant's left hand where they held the item for 10.5 s. Each block was separated by 7 s during which time no stimulation was delivered. Each of the three objects was presented 10 times over 2 functional runs, no object was presented twice in a row and the order of presentation was randomized for each participant.

Post-scan Self-report Measures

Social warmth task. After exiting the scanner, participants re-read the messages they had read in the scanner and rated their feelings of social connection on a 1 (not at all) to 7 (very) scale using the same measure used in our previous study on the effect of naltrexone on feelings of social connection to the same task (Inagaki et al., 2015; i.e. 'When you were reading the last set of messages: how connected/touched/warm did you feel?'). Ratings to the three items were combined to create our measure of feelings of connection (α for close others = 0.823; α for strangers = 0.874). Ratings for two participants were not included in final analyses (Supplementary Figure 1).

Physical warmth task. For the physical warmth task, participants rated the thermal intensity (how warm/cool did the item feel?) and their feelings of social connection to the three objects on a 1 (not at all) to 7 (very) scale (When you were holding the warm pack/cool pack/ball, how connected/touched/warm did you feel when holding this item?; α for combined three-item measure = 0.693–0.881). In addition, to enhance the cover story that the aim of the task was to evaluate commercial products, participants were asked how likely they would be to recommend the product to a friend. Ratings to the physical warmth task were missing from one participant in the naltrexone condition.

fMRI data acquisition. Participants were scanned at the MR Research Center at the University of Pittsburgh on a Siemens 3 T MAGNETOM Prisma MRI Scanner. A magnetization-prepared rapid gradient echo scan (MPRAGE; TR/TE = 5000/2.97 ms, flip angle = 4°, 256 × 256 matrix, 177 sagittal slices, FOV = 258; 1 mm thick) was acquired prior to functional scans to aid in data registration. Participants then completed two runs of the social warmth task (7 min, 53 s each), one run of the picture task (reported separately) and two runs of the physical warmth task (5 min, 25 s each), (T2*-weighted gradient-echo covering 60 axial slices, TR/TE = 1000/28 ms; flip angle = 55°; 112 × 112 matrix; FOV = 220 mm; 2 mm thick).

Statistical Analyses

Neuroimaging data. Imaging data were pre-processed in SPM8 (Wellcome Department of Imaging Neuroscience, London) using the DARTEL procedure. After motion correction, images were realigned to the MPRAGE, warped into Montreal Neurological Institute (MNI) space and smoothed with a 5-mm Gaussian kernel full-width, half-maximum. Contrasts for the main comparisons of interest were computed (social warmth task: messages from close others > strangers; physical warmth task: warm > cool; warm > neutral; cool > neutral) at the first level and then brought to the group level of analysis. Three participants were removed from imaging analyses (Supplementary Figure 1), leaving a final imaging sample of 77 (placebo n = 37, naltrexone n = 40).

Group level results were examined in two ways. To confirm the regions-of-interest (ROI) analyses described below and to replicate our previous findings using similar social and physical warmth tasks (Inagaki and Eisenberger, 2013), whole-brain analyses were run. Whole-brain results are reported under Supplementary Materials.

The main aim of the current study is to assess the effect of naltrexone on neural activity to both social and physical warmth. As such, an a priori, independently defined structural mask of the only two regions to show similar activity to social and physical warmth in our previous work (Inagaki and Eisenberger, 2013) was created. Specifically, anatomical masks of the VS (Inagaki and Eisenberger, 2012; Inagaki et al., 2016c) and MI were created with the MarsBar Toolbox (Brett et al., 2002). Due to directional hypotheses and convention, ROI analyses are thresholded at P < .05, one-tailed.

Post-scan self-report data. Self-report data were analyzed in SPSS v.25. To assess changes in feelings of social connection to the social and physical warmth tasks as a function of naltrexone, self-reports were submitted to repeated measures analysis of variance with drug (naltrexone vs placebo) as a between-subjects factor and social target (messages from close others vs strangers) or temperature (warm vs cool) as within-subjects factors. For ease of interpretation and to remain consistent with the way the physical warmth task has been analyzed and reported on previously (Inagaki et al., 2015), difference scores were calculated, subtracting mean ratings to the neutral object from mean ratings to each of the other temperature conditions (warm and cool). Significant interactions were further evaluated with independent samples t-tests to assess differences between drug conditions.

Associations between feelings of social connection and neural activity. Correlational analyses assessed associations between feelings of social connection and VS and MI activity to the social and physical warmth tasks. 95% confidence intervals (CI) were estimated using the bias corrected and accelerated percentile bootstrap method with 1000 random samples with replacement.

Shared neural activity: social and physical warmth. Previous research suggests that social and physical warmth share neurobiological mechanisms (Inagaki and Eisenberger, 2013; Inagaki et al., 2015). To examine this possibility, we ran conjunction analyses on the whole brain in the placebo group and the naltrexone group separately. Specifically, we tested the primary contrasts from social warmth (messages from close others > strangers) and physical warmth (warm > neutral) against the conjunction null that identifies neural regions active during both tasks (Nichols et al., 2005). We expected to see similarities in the VS and MI to the two tasks during placebo but not during naltrexone. Conjunction analyses were thresholded at a false discovery rate (FDR) of <0.05 with a cluster size threshold of 16 voxels.