Abstract Loss of ovarian 17β-estradiol (E2) in postmenopause is associated with gut dysbiosis, inflammation, and increased risk of cardiometabolic disease and osteoporosis. The risk-benefit profile of hormone replacement therapy is not favorable in postmenopausal women therefore better treatment options are needed. Cannabidiol (CBD), a non-psychotropic phytocannabinoid extracted from hemp, has shown pharmacological activities suggesting it has therapeutic value for postmenopause, which can be modeled in ovariectomized (OVX) mice. We evaluated the efficacy of cannabidiol (25 mg/kg) administered perorally to OVX and sham surgery mice for 18 weeks. Compared to VEH-treated OVX mice, CBD-treated OVX mice had improved oral glucose tolerance, increased energy expenditure,...