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Intermittent MDMA Attenuates Ovariectomy-induced Bone Loss via a Gut Microbiota-Bone Axis
Xiayun Wan1, Akifumi Eguchi2, Rumi Murayama1,3
1Chiba University Center for Forensic Mental Health, Chiba, Japan.
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-κB 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 β-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.
Insights
Repeated, intermittent 3,4-Methylenedioxymethamphetamine (MDMA) use in mice increased bone mineral density (BMD) and altered gut bacteria. This suggests MDMA may protect against bone loss by influencing the gut microbiota-bone axis.
Area of Science:
- Pharmacology
- Microbiology
- Bone Biology
Background:
- Low bone mineral density (BMD) is prevalent in psychiatric disorders.
- 3,4-Methylenedioxymethamphetamine (MDMA) affects gut serotonergic signaling and microbiota.
- The impact of MDMA on bone metabolism is largely unexplored.
Purpose of the Study:
- To investigate whether repeated, intermittent MDMA administration attenuates bone mineral density (BMD) loss in ovariectomized (OVX) mice.
- To explore the association between MDMA, gut microbiota, and bone remodeling markers.
Main Methods:
- Ovariectomized (OVX) mice received MDMA (10 mg/kg) or vehicle three times weekly for six weeks.
- Bone mineral density (BMD) was assessed.
- Untargeted plasma metabolomics and fecal gut microbiota profiling were performed.
Main Results:
- MDMA significantly increased whole-body and femoral BMD compared to vehicle.
- MDMA shifted bone remodeling markers towards an antiresorptive profile (decreased RANKL, increased osteoprotegerin).
- Gut microbiota analysis revealed reduced Clostridia and enriched Bacilli, with decreased plasma β-D-allose.
Conclusions:
- Intermittent MDMA administration may mitigate OVX-induced BMD loss.
- These effects are potentially mediated by remodeling of the gut microbiota-bone axis.
- Further research is needed to identify specific microbial and metabolic mediators.
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