Understanding How Trait Negative Emotionality (NEM) Influences Social Connectedness and Responses to ± 3,4-Methylenedioxymethamphetamine (MDMA)

Negative Emotionality (NEM), a tendency toward intense negative emotions and heightened reactivity, was examined in 30 healthy volunteers in a double-blind, placebo-controlled study. NEM did not predict baseline friendliness or changes in social connectedness after a closeness-building procedure. Higher NEM showed a trend toward greater MDMA-induced peak friendliness change. In an exploratory model, NEM predicted MDMA-induced oxytocin release after accounting for sex. These preliminary findings suggest that individual differences in personality and sex may shape drug response, with implications for patient selection and dose optimization in MDMA-assisted therapy for conditions linked to elevated NEM.

Study at a glance

Abstract

Negative Emotionality (NEM) is a trait measure that reflects a tendency toward experiencing intense negative emotions and heightened reactivity to perceived threats or stressors, contributing to challenges with social integration and interpersonal relationships. This secondary analysis in healthy volunteers (N = 30) employed a within-subject, double-blind, placebo-controlled design to investigate whether trait NEM influences feelings of social connectedness after a closeness-building procedure, as well as subjective and neurobiological responses to ±3,4-methylenedioxymethamphetamine (MDMA). Results indicated that NEM was not associated with baseline ratings of friendliness or changes in social connectedness after a closeness-building procedure. Higher NEM showed a trend-level association with greater MDMA-induced peak friendliness change (p = .056). In an exploratory model including sex and NEM × Sex interaction, NEM predicted MDMA-induced oxytocin release after accounting for sex (p = .049). Although the small sample size and non-clinical population render these findings preliminary, they highlight the importance of considering individual differences in personality that may shape drug response. They also point to the need for accounting for sex differences in drug-related research, particularly when evaluating the efficacy and underlying mechanisms of drug-assisted clinical interventions. As MDMA-assisted therapy advances through clinical trials for psychiatric conditions associated with elevated NEM, understanding which populations exhibit the strongest neurobiological responses has direct implications for patient selection, dose optimization, and addressing treatment heterogeneity. Future research should assess these interactions within clinical populations, where the functional impact of NEM is more pronounced.