Intermittent MDMA Attenuates Ovariectomy-induced Bone Loss via a 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.