Safety evidence for S-equol
Preclinical toxicology
Pure S-equol, 90-day subchronic study: NOAEL 250 mg/kg/day (female rats); acute oral dose of 2,000 mg/kg with no deaths or signs of toxicity (AnandaKumar 2024). For a fermented preparation, the NOAEL corresponds to about 12 mg/kg/day of pure equol (Yee 2008). In reproductive and developmental toxicity studies, the developmental NOAEL corresponds to 13 mg/kg/day of S-equol and the reproductive NOAEL to 6.5 mg/kg/day (Matulka 2009).
Genotoxicity
Three GLP assays, the Ames test, chromosomal aberration in human lymphocytes and rat bone-marrow micronucleus up to 2,000 mg/kg, all negative (pure S-equol, Schwen 2010); a separate set of three assays on a fermented preparation was also negative (Yee 2008).
Uterotrophic effects
No uterotrophic effect at the highest oral doses in rats and cynomolgus monkeys (Schwen 2012), consistent with expectations for a selective ERβ agonist.
Human safety
In Phase I studies, single doses up to 320 mg and repeated doses up to 160 mg twice daily for 14 days produced no significant drug-related adverse events (Jackson 2011). Across randomised trials there were no changes in sex hormones, gonadotropins, thyroid hormones, endometrial thickness or mammography (Aso 2012; Oyama 2012; Tousen 2011); one year of observation of a 98% purified preparation at 10 mg/day showed no significant change in endometrium, cervical smear or mammography (Yoshikata 2018).
Adverse events you should know about
In an 8-week U.S. trial (n=102, Jenks 2012), 47% of subjects reported at least one treatment-emergent adverse event, most commonly bloating (13% in the 10 mg group, 15% in the 20 mg group) and endometrial thickening (13% in the 10 mg group, judged not clinically significant); one case of breast cancer was diagnosed in the 20 mg group and judged unrelated to treatment. There were no clinically significant changes in laboratory values, ECG or vital signs.