Given previous findings from animal studies and small-scale studies in humans, variation in the mu-opioid receptor gene (OPRM1) has been proposed as a strong biological candidate for moderating sensitivity to social rejection. Using a substantially larger sample (N = 490) than previous studies, a prospective genotyping strategy, and preregistered analysis plans, we tested the hypotheses that OPRM1 variation measured by the functional A118G polymorphism (rs1799971) moderates (a) dispositional sensitivity to rejection and feelings of distress following social exclusion and (b) decision making involving social cognition. In three experimental tasks commonly used to assess altruism, reciprocity, and trust in humans, we found no evidence in favor of the hypotheses; nine main tests were preregistered, and all of them yielded small and statistically insignificant estimates. In secondary analyses, we used Bayesian inference and estimation to quantify support for our findings. Taken together, our results strongly suggest that the link between OPRM1 A118G variation and social-rejection sensitivity is weaker than previously thought.

Objectives: Childhood maltreatment (CM), widely held as a risk factor for substance use disorders (SUDs), is commonly assessed using the Childhood Trauma Questionnaire (CTQ). Retrospective self-reports are, however, potentially subject to bias. We used a unique patient sample with prospectively documented CM to examine the performance of the CTQ and how this is affected by the presence of SUD.

Methods: Analysis was based on a total of 104 individuals. Subjects with prospectively recorded CM were identified from a specialized childhood trauma unit in Linköping, Sweden (n = 55; 31 with SUD, 61% females; 24 without SUD, 71% females). Clinical controls had SUD but no CM (n = 25, 48% females). Healthy controls had neither SUD nor CM (n = 24, 54% females). We analyzed the agreement between retrospective CTQ scores and prospectively documented CM by κ analysis and assessed the performance of the CTQ to identify CM exposure using receiver operating characteristic (ROC) analysis.

Results: Agreement between prospectively and retrospectively recorded CM exposure was poor for sexual abuse (36.6%, Cohen κ = 0.32, P = 0.008) and physical abuse (67.3%, κ = 0.35, P = 0.007). Overall CTQ performance was fair (ROC: area under the ROC curve = 0.78, optimal cutoff = 36.5, sensitivity = 0.65, specificity = 0.75). However, performance was excellent in the absence of SUD (area under the ROC curve = 0.93, cutoff = 32.0, sensitivity = 0.88, specificity = 0.88), but poor in participants with lifetime SUD (area under the ROC curve = 0.62, cutoff = 42.0, sensitivity = 0.60, specificity = 0.36).

Conclusions: These data support the CTQ as a tool to assess CM exposure but suggest that it may be less useful in patients with SUD.

Insula responses to drug cues are correlated with cravings, and lesions in this area reduce nicotine seeking. Here, we investigated the potential efficacy of repetitive transcranial magnetic stimulation (rTMS) targeting the insula in alcohol addiction. Treatment-seeking alcohol-dependent patients (Diagnostic and Statistical Manual of Mental Disorder, Fourth Edition; N = 56) participated in this double-blind, sham-controlled, randomized trial. Participants received 10 Hz rTMS or sham using an H8 coil, 5 days a week for 3 weeks. Stimulation targeted insular cortex and overlaying regions bilaterally, while excluding anterior prefrontal areas. Craving and self-reported as well as biomarker-based drinking measures were collected at baseline, during treatment, and through 12 weeks. Resting-state magnetic resonance imaging (rsMRI) data were collected before and after treatment. Task-based MRI was used to probe brain correlates of reward processing, affective responses, and alcohol following completion of treatment. A marked overall decrease in craving and drinking measures was observed during treatment, but did not differ between rTMS or sham stimulation. Both groups equally increased their alcohol use following completion of treatment and through the 12-week follow-up. Analysis using seeds in the insula identified differences in resting-state connectivity between active and sham groups at completion of treatment, potentially indicating an ability of treatment to modify insula function. However, while each task robustly replicated brain responses established in the literature, no effects of rTMS were found. Collectively, this study does not support efficacy of rTMS targeting the insula in alcohol addiction.