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

Supplementary Material


Screening Procedures

Interested individuals were telephone screened prior to an in-person visit. Inclusion criteria required participants to be in good health, between 18 and 35 years old, fluent in English, and right-handed (for the fMRI scan). Participants were excluded for major self-reported mental and physical illness (e.g., hepatic illness), depressive symptoms (>9 on the PHQ; Spitzer, Kroenke, & Williams, 1999), excessive alcohol use, medication aside from birth control, a positive urine pregnancy or drug test ((Opiates, Tetrahydracannabinol (THC), Cocaine, Amphetamines (AMP), Methamphetamines (mAMP)) both at the time of screening and before drug administration, a BMI greater than 35, and non-removable metal in the body or claustrophobia (for the fMRI scan). The study physician (CA) provided final approval of participants.

Pre-session Message Collection

Prior to the experimental session, participants nominated 8 close others. Participants nominated friends (63%; e.g., best friends, roommates), family members (29%; e.g., parents, siblings, grandparents), and romantic partners (8%). The experimenters then contacted the close others via email to help create the social warmth task. Emails explained that the experimenters were interested in exploring reactions to messages from friends, family members, and strangers and requested that the close other respond with 12 brief (1-2 sentences) messages addressed to the participant. Example messages were provided to guide the close others in their writing. Close others were asked not to tell the participant what the experimenters had emailed them to keep the participant unaware of the study goals. During a manipulation check, participants reported 100% compliance with this request. Average ratings of closeness (on a 1-not at all close to me, to 10-extremely close to me, scale) suggested the selected individuals were indeed close (M = 8.285, SD = .893). Once 5 close others had responded to the original email request, personalized social warmth tasks were made for each participant for presentation in the fMRI scanner.

Experimental Session

Neuroimaging Measures

In addition to the Social and Physical Warmth tasks, participants completed a modified version of a picture viewing task (Aron, Fisher, Mashek, Strong, & Brown, 2005) during which time they viewed images of people they know and people they do not know. In between blocks of images, participants completed mental serial subtraction. Results from this task are reported separately.

Self-report Measures

Physical Symptoms

Physical symptoms commonly experienced when taking naltrexone (Ray, Chin, & Miotto, 2010) were assessed before and after drug administration. Specifically, participants reported on headaches, dizziness/faintness, stomach discomfort, nausea, and tiredness/fatigue on a 0 (no symptoms) to 4 (very severe symptoms) scale. The highest reported value for any physical symptom, in either condition, was a 2. In addition, to assess the subjective experience of physical symptoms, participants were also asked, "overall, how distressing do you find these symptoms?" on a 1 (not distressing at all) to 7 (very distressing) scale.

Whole Brain Analyses

In addition to ROI analyses, neural activity across the whole brain was examined as a manipulation check, confirmation of the ROI analyses, and a replication attempt of our previous neuroimaging study using the same tasks (Inagaki & Eisenberger, 2013). Activity to the primary contrasts of interest from the social warmth task (messages from close others > messages from strangers) and physical warmth task (warm > neutral and warm > cool) were examined in the placebo group. Results were interrogated using a False Discovery Rate (FDR) of 0.05 with a cluster size threshold of 16 voxels to correct for multiple comparisons. Coordinates are reported in Montreal Neurological Institute (MNI) format.


Study Drug Blind and Physical Symptoms

Participants were not able to guess which drug they had been given above chance levels (50%) in either the placebo (X2 (1) = 2.489, p = .115) or naltrexone condition (X2 (1) = 1.766, p = .184). In addition, physical symptoms were greater for those in the naltrexone condition (M = .425, SD = .357) than placebo condition (M = .210, SD = .293, t(78) = 2.942, p = .001) post-drug administration. The same pattern emerged for distress of the symptoms such that distress from the symptoms was greater in the naltrexone (vs. placebo) condition (t(78) = 2.014, p = .024). Feelings of social connection to the social and physical warmth task remain unchanged when controlling for physical symptoms or distress of the symptoms.

Neural Activity to Social Warmth Task-whole brain corrected

Replicating our previous results with the social warmth task and as confirmation of the ROI analyses, there was extensive activity in the ventral striatum (VS) and middle-insula (MI). In addition, there was greater activity in regions of the social cognition network (temporal pole, dorsomedial prefrontal cortex; Mitchell, Macrae, & Banaji, 2004), regions implicated in affiliative responding (dorsal, mid, and posterior cingulate cortex, ventral tegmental area, septohypothalamic regions; Moll et al., 2012), and the cerebellum to messages from close others as compared to messages from strangers. For a full list of activations, see Supplementary Table 1.

Neural Activity to Physical Warmth Task-whole brain corrected

In a replication of our previous results and previous studies on the neural response to warm, cutaneous stimuli (Becerra et al., 1999; Davis et al., 1998; Olausson et al., 2005; Rolls et al., 2008), holding a warm (vs. neutral) object lead to increased activity in the left and right MI and the caudate (extending into the VS; see Supplementary Table 3 for a full list of activations). Thus, warmth increased activity in the VS and MI, consistent with the notion that warmth might contribute to social connection. No regions showed greater activity to the warm than cool pack at the current threshold.


Results from analyses corrected at the whole brain align with the ROI results reported in the parent manuscript to confirm that the social and physical warmth tasks lead to increased activity in the VS and MI in the placebo condition. Of note, neural activity to reading messages from close others (vs. strangers) resulted in a large activation with peaks in the cerebellum, regions of the social cognition network, and regions previously implicated in affiliative responding. Though traditionally associated with motor movement, the cerebellum may, in the current context where participants read messages from close others, reflect reading and interpreting the messages (Buckner, 2013). Indeed, in a meta-analysis of the role of the cerebellum in social cognition, cerebellum activity is high when the level of abstraction is also high (Van Overwalle, Baetens, Marien, & Vandekerckhove, 2014). An intriguing additional possibility, based on recent findings in mice, is that cerebellum activity in response to the messages from close others reflects social reward (Carta, Chen, Schott, Dorizan, & Khodakhah, 2019).


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