MDMA-induced indifference to negative sounds is mediated by the 5-HT2A receptor

MDMA has been consistently shown in experimental studies to enhance emotional empathy, increase feelings of sociability, and promote a positive emotional bias, effects that have been linked to its actions on the serotonergic system. Prior research examining MDMA's prosocial effects has relied almost exclusively on visual emotional stimuli — tasks such as facial emotion recognition, the Reading the Mind in the Eyes test, and the Multifaceted Empathy Test — despite the fact that social communication is inherently multimodal and that auditory cues carry substantial affective information. The neurobiological mechanisms underlying MDMA's social effects remain incompletely characterised, though preliminary evidence has implicated the serotonin 2A (5-HT2A) receptor in MDMA-induced positive mood and emotional excitability. This study aimed to characterise MDMA's effects on the processing of affective auditory stimuli — a dimension previously unexamined — and to evaluate the role of the 5-HT2A receptor in these effects using the selective antagonist ketanserin as a pharmacological probe.

Twenty healthy polysubstance MDMA users (12 male; mean age 21.2 years) participated in a double-blind, placebo-controlled, within-subject 2×2 factorial design. Pre-treatment comprised ketanserin (40 mg, a dose estimated to block approximately 91% of 5-HT2 receptors) or matched placebo, administered approximately 45 minutes prior to treatment with MDMA (75 mg oral) or placebo. The four conditions (placebo/placebo, ketanserin/placebo, placebo/MDMA, ketanserin/MDMA) were completed across separate sessions. The primary outcome was performance on a Processing of Affective Sounds task, in which participants rated the valence and arousal of standardised positive and negative sounds. Secondary outcomes included implicit approach-avoidance biases assessed using Approach-Avoidance Tasks (AATs) for threat, trust, and social stimuli; mood assessed via the Profile of Mood States; and plasma MDMA pharmacokinetics and oxytocin concentrations.

On the affective sounds task, a significant three-way interaction of pre-treatment × treatment × valence was found for arousal ratings (F1,19 = 8.80, p = 0.008, ηp² = 0.32). Under MDMA alone, participants were equally aroused by positive and negative sounds — in contrast to the placebo condition, in which negative sounds produced significantly greater arousal. This equalising effect of MDMA on arousal to negative versus positive sounds was counteracted by ketanserin pre-treatment, implicating the 5-HT2A receptor in MDMA's attenuation of negative-sound arousal. In the approach-avoidance tasks, MDMA produced no significant main effects on threat, trust, or social implicit biases. Ketanserin alone induced divergent effects: an approach tendency in the Trust AAT and avoidance in the Social AAT, independent of emotional stimulus content. MDMA did not significantly alter plasma oxytocin concentrations above placebo, and MDMA pharmacokinetics were consistent with prior literature. Mood scores broadly reflected a positive valence shift under MDMA.

The finding that MDMA induced relative indifference to the arousal-elevating properties of negative sounds — an effect blocked by 5-HT2A antagonism — extends the known prosocial pharmacology of MDMA to the auditory domain and provides a mechanistic basis for this effect. The researchers propose that MDMA attenuates the salience of aversive auditory stimuli rather than globally enhancing positive emotional responding, a distinction with potential relevance to its therapeutic application in PTSD, where hyperarousal to threat-associated auditory cues is a core symptom. The absence of robust MDMA effects on approach-avoidance bias in this study is noted as diverging from some prior findings with visual stimuli, and may reflect the relative insensitivity of the AAT paradigm to MDMA-induced changes in the auditory modality. The unexpected effects of ketanserin alone on social and trust biases are discussed as consistent with 5-HT2A receptor involvement in approach-avoidance regulation independent of drug context.

MDMA induces an attenuation of the heightened arousal normally associated with negative auditory stimuli, and this effect is mediated by the 5-HT2A receptor. These findings extend the characterisation of MDMA's prosocial and emotional effects to the auditory domain and support the role of serotonergic signalling in modulating aversive emotional salience — a mechanism with potential relevance to MDMA-assisted therapy for disorders of threat-related hyperarousal.