2026 ECNP Congress

PS04-4014

Rewiring reward circuits in binge-eating disorder with combined MDMA and semaglutide therapy

Vlera Fonda — A. Pospisilik, K. Timper, T. Gruber · Helmholtz Munich, Institute of Translational Metabolism Research- ITMR, Oberschleißheim, Germany

2026 ECNP Congress

Binge-eating disorder (BED) affects 2–3% of the general population and is highly prevalent among individuals with obesity [1], and is increasingly understood as involving maladaptive reward learning and compulsive habits. Glucagon-like peptide-1 receptor (GLP1R) agonists such as semaglutide reduce binge frequency [2], but primarily through increased satiety during ongoing treatment, potentially leaving the underlying reward circuitry unchanged. In rodents, a single dose of 3,4-methylenedioxymethamphetamine (MDMA) reopens an oxytocin-dependent critical period for social reward learning that normally closes after adolescence, with the reopened window persisting for approximately two weeks [3], [4]. In humans, MDMA robustly increases plasma oxytocin and prosocial behaviours in healthy controls, but this response is blunted in patients with hypothalamic damage affecting oxytocin-producing neurons [5], confirming that MDMA’s effects depend on a conserved oxytocin mechanism across species. Since oxytocin and GLP1 receptor systems converge in forebrain reward circuits, we asked whether a single dose of MDMA combined with semaglutide, delivered during social experience, can exploit this transient plastic window to produce lasting reductions in binge-like eating in mice. Using a conditioned place preference (CPP) assay contrasting high-fat diet (HFD) with social interaction in male C57BL/6J mice (n = 5-7 per group), we tested whether MDMA shifts reward preference toward social interaction. MDMA increased the variability of preference scores with a subset of animals shifting toward the social chamber, an effect that was absent when hypothalamic oxytocin (OXT) neurons were inhibited via the designer receptor hM4Di, suggesting the involvement of OXT neurons in MDMA-driven reward revaluation. Qualitative c-Fos mapping showed increased neuronal activation in the lateral septum (LS) after MDMA, and this activation was attenuated when OXT neurons were inhibited, linking the behavioural effect to oxytocin-dependent recruitment of the LS. In a binge-like HFD paradigm, co-administration of MDMA and semaglutide produced a trend toward longer-term reduction of binge size two weeks after drug washout in a pilot cohort (n = 4 per group; fully powered replication ongoing), whereas vehicle-treated and semaglutide-only groups reverted back to baseline intake levels. Spatial transcriptomics (10x Visium HD) of the LS combined with pseudobulk differential expression analysis (DESeq2) identified a Glp1r-positive neuronal population in which the addition of MDMA to semaglutide selectively altered expression of genes involved in synaptic remodeling and neuropeptide signalling, highlighting candidate molecular mechanisms that may contribute to the persistence of the behavioural effect after drug washout. Together, these preliminary findings suggest that a single combined exposure to MDMA and semaglutide can produce a reduction in binge-like eating that persists beyond the treatment window and was not observed with semaglutide alone. The lateral septum emerges as a candidate region where oxytocin and GLP1R signalling converge to sustain this effect. Rather than continuous pharmacotherapy that suppresses symptoms during dosing, brief interventions that transiently reopen the brain’s capacity for plasticity may offer a conceptually different approach to treating BED, with potential relevance to other compulsive disorders involving dysregulated reward learning and habit formation.

References

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  2. J. Richards et al., “Successful treatment of binge eating disorder with the GLP-1 agonist semaglutide: A retrospective cohort study,” Obes. Pillars, vol. 7, p. 100080, Sep. 2023, doi: 10.1016/J.OBPILL.2023.100080.
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