Initially, the presumed mechanism of black cohosh involved the activation of estrogen receptors. However, both in vitro and in vivo studies on black cohosh extracts yielded no evidence of estrogenic activity. Instead, it appears that black cohosh binds to receptors in the central nervous system responsible for functions like thermoregulation, mood, and sleep (e.g., mu-opioid,[1] serotonin, dopamine, c-aminobutyric acid). This mode of action clarifies why black cohosh does not influence estrogen levels, breast tissue density or proliferation, endometrial thickness, or vaginal cytology.[2][3]
Additionally, black cohosh showed anti-estrogenic properties in breast cancer studies. This anti-estrogenic effect was observed in vitro as a reduction in the growth of estrogen-responsive breast cancer cells.[4]
Another in vitro study found a potential nonestrogenic thermoregulatory mechanism of black cohosh, which may modulate the immune system by promoting nitric oxide (NO) production in cells treated with interferon gamma (INF-gamma).[2]