An ethanolic extract of black cohosh causes hematological changes but not estrogenic effects in female rodents

Abstract

Black cohosh rhizome (Actaea racemosa) is used as a remedy for pain and gynecological ailments; modern preparations are commonly sold as ethanolic extracts available as dietary supplements. Black cohosh was nominated to the National Toxicology Program (NTP) for toxicity testing due to its widespread use and lack of safety data. Several commercially available black cohosh extracts (BCE) were characterized by the NTP, and one with chemical composition closest to formulations available to consumers was used for all studies. Female B6C3F1/N mice and Wistar Han rats were given 0, 15 (rats only), 62.5 (mice only), 125, 250, 500, or 1000 mg/kg/day BCE by gavage for 90 days starting at weaning. BCE induced dose-dependent hematological changes consistent with a non-regenerative macrocytic anemia and increased frequencies of peripheral micronucleated red blood cells (RBC) in both species. Effects were more severe in mice, which had decreased RBC counts in all treatment groups and increased micronucleated RBC at doses above 125 mg/kg. Dose-dependent thymus and liver toxicity was observed in rats but not mice. No biologically significant effects were observed in other organs. Puberty was delayed 2.9 days at the highest treatment dose in rats; a similar magnitude delay in mice occurred in the 125 and 250 mg/kg groups but not at the higher doses. An additional uterotrophic assay conducted in mice exposed for 3 days to 0.001, 0.01, 0.1, 1, 10, 100 and 500 mg/kg found no estrogenic or anti-estrogenic activity. These are the first studies to observe adverse effects of BCE in rodents.

A Black Cohosh Extract Causes Hematologic and Biochemical Changes Consistent with a Functional Cobalamin Deficiency in Female B6C3F1/N Mice

“…In addition, BCE preparations are variable natural mixtures of compounds and it is not known which of these compounds are active. The mice in the current study were dosed relatively high at 1000 mg/kg; however, hematological effects were observed as low as 62.5 mg/kg (low-dose group) in the subchronic study (Mercado-Feliciano et al 2012). In addition, similar CBC changes were observed in the NTP subchronic rat BCE study (Mercado-Feliciano et al 2012).…”

“…The mice in the current study were dosed relatively high at 1000 mg/kg; however, hematological effects were observed as low as 62.5 mg/kg (low-dose group) in the subchronic study (Mercado-Feliciano et al 2012). In addition, similar CBC changes were observed in the NTP subchronic rat BCE study (Mercado-Feliciano et al 2012). The typical recommended daily dose of BCE for humans is 40 mg daily, which is approximately 0.5mg/kg for a 70kg person.…”

“…Because homocysteine does not differentiate between a folate or cobalamin deficiency, the possibility of a concurrent functional deficiency of folate cannot be ruled out. In humans, increased levels of homocysteine and MMA are also associated with renal failure; however, creatinine levels were unchanged in the treated mice and, in the previous BCE subchronic study, no renal histologic lesions were observed (Mercado-Feliciano et al 2012). …”

“…Because black cohosh is almost exclusively used by women, a 90-day (subchronic) study was conducted on female mice and rats only (i.e., not males) using a black cohosh extract (BCE) to evaluate general toxicity in addition to select developmental reproductive endpoints. Results of the mouse subchronic toxicity study revealed a dose-dependent decrease in red blood cell (RBC) count, hemoglobin concentration, and hematocrit with no change in the reticulocyte count and an increase in the mean corpuscular volume (MCV) (Mercado-Feliciano et al 2012). Similar changes were observed in the rats.…”

A Cycloartane Glycoside Derived from Actaea racemosa L. Modulates GABAA Receptors and Induces Pronounced Sedation in Mice

“…Understanding its molecular mechanism(s) of action is, however, a conditio sine qua non for considering potential beneficial and unwanted side effects. The initially suggested estrogenic activity of lipophilic components, such as triterpenoids, was disproved by later studies (Gaube et al, 2007;Mercado-Feliciano et al, 2012;Hajirahimkhan et al, 2013). There, however, is evidence that A. racemosa L. preparations interact with distinct neurotransmitter systems in the central nervous system, including m-opioid receptors (Rhyu et al, 2006;Reame et al, 2008), serotonin (5-HT) receptors (subtypes 5-HT 1A , 5-HT 1D , and 5-HT 7 ) (Burdette et al, 2003), and dopamine subtype 2 receptors (Jarry et al, 2003).…”