Intermittent MDMA Attenuates Ovariectomy-induced Bone Loss via a Gut Microbiota–Bone Axis

Objective: 3,4-Methylenedioxymethamphetamine (MDMA) is widely used recreationally but also modulates serotonergic signaling in the gut, potentially influencing the microbiota. Because low bone mineral density (BMD) is common in depression and other psychiatric disorders, we tested whether repeated, intermittent MDMA attenuates BMD loss in ovariectomized (OVX) mice. Methods: OVX mice received MDMA (10 mg/kg) three times per week for six weeks. BMD was measured, and untargeted metabolomics of plasma samples along with gut microbiota profiling of fecal samples were performed. Results: Compared with vehicle, MDMA increased whole-body and femoral BMD and shifted circulating bone-remodeling markers toward an antiresorptive profile—lower receptor activator of nuclear factor-B ligand (RANKL) and higher osteoprotegerin. Gut microbiota profiling and untargeted metabolomics showed reduced Clostridia and enrichment of Bacilli, along with a marked decrease in plasma -D-allose, a metabolite linked to Lactobacillus johnsonii. Conclusion: These findings suggest that intermittent MDMA may mitigate OVX-induced BMD loss in association with remodeling of a gut microbiota–bone axis. Future studies should define causal microbial and metabolic mediators and evaluate generalizability across additional bone-loss models.