This cancer information summary provides an overview of the use of black cohosh as a treatment in breast cancer patients and survivors, generally for the relief of symptoms or side effects. The summary provides a brief history of black cohosh research, the results of laboratory and clinical trials, and possible side effects of black cohosh use.
This summary contains the following key information:
Native to eastern and midwestern North America, black cohosh (Actaea racemosa, also known as Cimicifuga racemosa)  is a member of the buttercup family (Ranunculaceae).[2,3] Black cohosh has many synonyms, including black snakeroot, bugbane, rattleroot, squawroot, and macrotrys or macrotys.[2,3,4] The roots and rhizomes of the black cohosh plant are used for medicinal preparations.
Various types of extracts of black cohosh roots and rhizomes have been studied for their chemical composition and biological activity. Lipophilic extracts have predominantly been used in laboratory studies and only infrequently in clinical trials. The most commonly used clinical preparations of black cohosh (e.g., Remifemin® and BNO 1055) are made from hydrophilic (typically hydroalcoholic) extracts. Lipophilic extracts have in vitro effects on estrogen -regulated genes, whereas hydrophilic extracts generally do not.
Several of the chemical constituents of black cohosh extracts have biological activities that have been demonstrated through in vitro studies and are candidate markers for the observed in vivo and clinical effects. Triterpene glycosides have structures similar to steroids, but no apparent direct binding to the estrogen receptor. One of the most abundant of such glycosides, 23-epi-26-deoxyactein, is specific for black cohosh and is the constituent usually chosen for standardization of commercial products.[2,3] Over 60 different triterpene glycoside analogs have been identified in black cohosh, including two other bioactive types, actein and cimicifugoside.
Other chemical constituents of black cohosh extracts include aromatic acid phenolpropanoids related to caffeic and ferulic acid, along with the black cohosh-specific fukinolic acid. The plant also contains a large variety of guanidine alkaloids, which have been explored chemically but not studied biologically.
Various plants that resemble black cohosh have been mistakenly or intentionally included in some commercial black cohosh products or plants. Such adulteration can be detected by methods such as microscopy, high-performance thin-layer chromatography, high-performance liquid chromatography ultraviolet, and DNA barcoding.
Black cohosh root, rhizome, and associated preparations have gained considerable international market and consumer interest for more than 60 years, particularly gaining U.S. interest within the last 15 years. A market report released by the American Botanical Council stated that black cohosh extract was among the 15 top-selling herbal dietary supplements by the food, drug, and mass-market channel in the United States in 2019, with total sales nearing $30 million. Growth in market demand for black cohosh has led to an increased need for scientific evidence of quality, safety, and efficacy. [4,5,8]
Black cohosh was in use by Native Americans when Europeans arrived in the New World. Among the reported indications for black cohosh in traditional Native American medicine were various female conditions, rheumatism, fever (possibly due to malaria), general malaise, sore throat, childbirth, and snakebite.[1,2] Early European settlers, and subsequently American eclectic physicians, assimilated the use of black cohosh and began exporting the herb to Europe as early as the 18th century.
Europeans have used black cohosh to treat menopausal symptoms for over 50 years. In Germany, the Commission E approved black cohosh as a treatment for dysmenorrhea, menopausal symptoms, heart palpitations, nervousness, irritability, sleep disturbances, tinnitus, vertigo, perspiration, and depression.
Various sources suggested that the recommended dose of crude drug is 40 mg per day.[1,3] At least one trial compared two different doses (39 mg and 127.3 mg)  in women with menopausal symptoms and found equivalent beneficial effects at both doses. The lack of long-term safety studies has led some groups to recommend limiting the use of black cohosh to a maximum of 6 months.[1,5]
Mechanism of Action
Given the apparent clinical effects of black cohosh on menopausal symptoms, early preclinical investigations searched for an anticipated estrogenic activity. These research studies demonstrated differences between lipophilic extracts, which often had evidence of estrogenic activity, and the hydroalcoholic extracts of the type contained in the most commonly used clinical products, which generally lacked such activity.[1,2]
Considering the recent discovery of nitrogenous black cohosh constituents, subsequent hypotheses for the activity of black cohosh involve potential effects on hypothalamic neurotransmitter regulation systems,[1,3] such as those involving the endogenous central opioid system. This hypothesis is supported by the observation that while black cohosh treatment alone has no effect on luteinizing hormone (LH) activity, induction of naloxone blockade of µ-opioid receptors in postmenopausal women treated with Remifemin® leads to the suppression of LH activity.Positron emission tomography imaging in women treated with black cohosh indicated selective µ-opioid receptor availability, with increased availability in regions responsible for emotional and cognitive processing, and pronounced reductions observed in areas associated with the human placebo response. Given such results, and the comparatively high frequency of placebo responsiveness in black cohosh clinical trials, both pharmacologic and placebo effects simultaneously affecting the endogenous opioid system are suggested.
Mechanism of Action, Pharmacokinetics, Pharmacodynamics
Given that the clinically utilized hydrophilic extracts of black cohosh roots and rhizomes are not estrogenic, alternate mechanisms of menopausal symptom relief have been proposed, one of which suggests serotonergic activity by triterpenes to minimize episodes of hot flashes and bone loss.[1,2,3,4] While this finding warrants further investigation, it is currently common practice to standardize the content of commercially available black cohosh supplements to certain triterpene compounds related to actein, such as 23-epi-26-deoxyactein. Likewise, pharmacokinetic (PK) investigations of black cohosh triterpenes are more commonly reported.
The maximum-tolerated dose and PK of 23-epi-26-deoxyactein, the most abundant triterpene found in the plant, has been evaluated in a phase I clinical trial. Single doses of an ethanolic black cohosh extract containing 1.4 mg, 2.8 mg, or 5.6 mg of 23-epi-26-deoxyactein (32 mg, 64 mg, or 128 mg of black cohosh, respectively) were administered to 15 healthy menopausal women.Analysis of the compound in sera indicates a half-life of about 2 hours for all administered dosages (2.1 ± 0.4, 2.7 ± 0.4, and 3.0 ± 1.0 h, respectively). First-order kinetics is also indicated, with maximum concentration and area under the curve increasing proportionately with dosage. It is suggested that 23-epi-26-deoxyactein is excreted intact in bile and degraded in the gastrointestinal tract, as no metabolites of the compound were detected in urine or sera, and only a negligible amount (<0.01%) of the compound was recovered in urine 24 hours after oral administration; specific proof of predominant biliary secretion is needed. In the same study, no alteration in circulating hormone levels (estradiol, follicle-stimulating hormone, luteinizing hormone) were observed in this population relative to baseline (P < .05), nor have changes been observed in similar investigations of systemic hormone levels or those monitoring for estrogenic effects on breast, endometrial, or vaginal tissues.
Although case reports suggested connections between the use of dietary supplements containing black cohosh and liver damage, no evidence of hepatotoxicity—or any other form of serious toxicity—was found in systematic reviews of results from clinical trials of a chemically standardized black cohosh preparation; regardless of dosage administered, no liver function markers were altered.
Reports of hepatic adverse effects include one case of acute liver failure, two cases of hepatitis (without further description), and two cases indicating mild elevation of liver function markers, though many of these patients were taking multiple botanical products simultaneously. An episode of autoimmune hepatitis is questionably related to the use of black cohosh. Although noteworthy, many of these reports are anecdotal in nature. Furthermore, a meta-analysis of randomized, double-blind, controlled clinical trials does not demonstrate evidence of black cohosh causing adverse effects on liver function. Indications of toxicity are reportedly caused by manufacturer contamination or adulteration with other toxic products, thereby necessitating mechanisms of botanical authentication and proper methods of manufacturing the product. The not-infrequent adulteration of black cohosh with Asian Actaea species that contain significantly different phytoconstituents is the most plausible cause of the reported potential adverse hepatic effects.[8,9]
Acute toxicity of black cohosh is also purported to occur through interactions with pharmaceutical agents.[1,10] Though substantial herb -drug interactions can occur in this manner with certain herbs such as St. John's wort, in vivo analysis of black cohosh metabolism is not suggestive of this. Black cohosh supplementation does not significantly alter the expression or activity of metabolic enzymes CYP3A4, CYP1A2, or CYP2E1. While a statistically significant decrease in the CYP2D6 phenotype (approximately 7%; P = .02) has been observed in a human study, the clinical relevancy of this finding is questionable —especially since a very high dose was used for this particular investigation (1,090 mg bid). Studies have yet to verify this effect; however, given that tamoxifen is a selective estrogen receptor modulator and is primarily metabolized by CYP2D6, even mild inhibition of the enzyme by black cohosh may warrant consideration.
Prevention of Breast Cancer/Recurrence
Observational studies of postmenopausal women without a history of breast cancer indicated no significant association between the use of black cohosh and development of the disease when compared with nonuse (hazard ratio = 1.17; 95% confidence interval [CI], 0.75–1.82; adjusted odds ratio [OR], 0.80; 95% CI, 0.63–1.00).
One study suggested a possible protective effect. This case-control trial evaluated whether the use of hormone-related supplements, including black cohosh for the management of menopausal symptoms, was associated with cancer risk or protection. A 53% decreased risk in the incidence of breast cancer was observed among postmenopausal women taking black cohosh compared with nonusers (adjusted OR, 0.47; 95% CI, 0.27–0.82). In subset analyses, ever-use of tamoxifen or raloxifene prior to cancer diagnosis (as a chemopreventive agent, rather than a treatment for cancer) was not a significant confounder in the protective relationship observed between black cohosh use and breast cancer occurrence.
Recurrence -free survival was also evaluated as a primary endpoint measure in a sample of breast cancer patients and survivors (n = 18,861), 1,102 of whom had received a product containing a black cohosh extract (i.e., Remifemin® or Remifemin® plus; R/R+, a 40% isopropanol black cohosh extract, with or without St. John's wort extract, respectively). This retrospective cohort study reported a significantly lower risk of recurrence in R/R+ users compared with nonusers over a mean observation time of 3.6 years. This decrease was observed in patients who also received tamoxifen. These results suggest that R/R+ is not likely to promote breast cancer recurrence or inhibit the therapeutic effect of tamoxifen. No other studies have reported to further explore a potential beneficial effect of black cohosh extracts on breast cancer recurrence.
Effect on Menopausal Symptoms
Several studies have investigated black cohosh in treating women suffering from climacteric complaints, including breast cancer patients and survivors.[2,3] Analyses of the effect of black cohosh preparations on these symptoms in patients with other cancers have not yet been reported.
Breast Cancer Patients
Observational and open-label studies have demonstrated reductions in the number and severity of hot flashes among breast cancer patients undergoing adjuvant endocrine therapy complemented with black cohosh; however, randomized, double-blind, placebo-controlled clinical trials have failed to demonstrate reductions greater than that seen without placebo.
Significant declines in hot flash frequency and severity and in other menopausal symptoms are reported in a review of observational studies of breast cancer patients and survivors taking Remifemin® (20–40 mg/d), with or without tamoxifen or raloxifene.Prospective trials indicated reductions as high as 56% (95% CI = 40%–71%) in hot flash scores (daily frequency times average severity). Self-assessment of menopausal symptoms through the Menopausal Rating Scale (MRS II) has also been evaluated among breast cancer patients on Remifemin® (40 mg/d) plus tamoxifen (10–40 mg/d), indicating significant declines in menopausal symptomology (P < .001) from baseline, and after 1, 3, and 6 months of black cohosh treatment.
Statistically significant reductions in hot flash symptomology have also been observed in open-label administration of another black cohosh product, CR BNO 1055 from Bionorica in Germany (40 mg/d), in breast cancer survivors who received adjuvant therapy with tamoxifen; however, double-blind studies so far have failed to show this to be a specific effect.
Thus far, two randomized, placebo-controlled, double-blind clinical trials have assessed the efficacy of black cohosh use (one trial used black cohosh extract; the other trial used an uncharacterized black cohosh product ) on hot flashes—or related vasomotor symptoms—in breast cancer survivors who received a selective estrogen receptor modulator (SERM). Neither study indicated a significant difference in menopausal symptomology between women taking the supplement (20–40 mg/d), or an identical-appearing placebo, with or without the use of tamoxifen (10–40 mg) or raloxifene (dosage not provided).[2,14]
One randomized clinical study specifically evaluated the preventative effect of Remifemin® on symptoms of menopause syndrome (MPS) in breast cancer patients who received luteinizing hormone-releasing hormone analogs (LHRH-a). Evaluation of MPS was assessed using Kupperman Menopausal Index (KMI) scores. Symptomology increased in both groups throughout the course of study; however, KMI scores of patients on LHRH-a treatment (goserelin, n = 32; leuprorelin, n = 10) with Remifemin® (20 mg/d) were significantly lower than those on adjuvant therapy alone (goserelin, n = 28; leuprorelin, n = 15) at each time point in this 12-week clinical trial (P < .01). Furthermore, 11.9% of participants in the treatment group and 64.29% of participants in the control group received LHRH-a treatment with a SERM or an aromatase inhibitor.
Given these conflicting results in observational and randomized clinical trials, a large placebo effect is presumably at play, especially considering the subjective nature of many of the endpoint measures. Furthermore, the beneficial effect observed through an open-label study left unconfirmed through double-blind studies further obscured the understanding of the true effect of black cohosh in alleviating climacteric symptoms in this patient population; however, given the unlikely negative impact on breast cancer risk or recurrence,[11,13] along with evidence of relative safety, more research is warranted.[1,2,7,10]
The efficacy of black cohosh supplementation on vasomotor symptoms has also been evaluated in noncancer populations; however, these findings to date remain inconsistent.
A meta-analysis of 16 randomized controlled trials investigated the efficacy of monopreparations of black cohosh compared with interventions including placebo, red clover, and fluoxetine in premenopausal and postmenopausal women. No significant difference in hot flash frequency or menopausal symptom scores between the experimental group and control group were detected. While three trials demonstrated a significant reduction in hot flash frequency and menopausal symptom score for hormonal treatment compared with black cohosh, substantial heterogeneity was observed between studies included for review, thus necessitating further investigation in this area.
Similarly, the Herbal Alternatives for Menopause (HALT) study investigated the effect of black cohosh (CimiPure®, 70% ethanol extract standardized to 2.5% triterpene glycosides, 160 mg/d) and an encapsulated multibotanical-containing black cohosh (ProGyne™; black cohosh, 200 mg/d, along with nine other ingredients), both of which failed to show a benefit greater than that of placebo.
Randomized controlled investigations of black cohosh used as monopreparations  or within multibotanical preparations  have yet proven effective in reducing climacteric complaints among women without a history of breast cancer.
Management of Other Conditions
Bone mineral density
The therapeutic effects of black cohosh on bone metabolism have also been investigated as a secondary outcome measure in a randomized, double-blind clinical trial, comparing results to that of conjugated estrogens (CE) and placebo. Daily administration of the black cohosh extract containing commercial product CR BNO 1055 (40 mg/d) demonstrated an effect equipotent to that of CE (0.6 mg) after 3 months of treatment. Analyses of bone turnover markers indicated a significant improvement above placebo values on bone metabolism in both the black cohosh and CE groups (P = .0138, both groups). Unlike other groups, women treated with CR BNO 1055 displayed a significant increase in serum bone-specific alkaline phosphatase levels (P = .0358), indicating increases in bone formation. The effect demonstrated with CE supplementation was comparable, though distinct; compared with placebo, women displayed a significant decrease in bone degradation, as measured by serum levels of the C-terminal breakdown product of bone-specific type-1 collagen (P = .0181). Likewise, while the mechanism of action may be different than that of CE, black cohosh does appear to have an osteoprotective effect in postmenopausal women. Potential benefits on bone metabolism are further supported in an uncontrolled trial by increases in measures of changes in osteocalcin levels in women receiving the supplement.
In general, the hydroalcoholic black cohosh extracts that are widely used as components in commercially available products—and those used in clinical trials —have been very well tolerated, producing rare serious adverse effects, which are likely due to product quality issues (adulteration) rather than black cohosh itself. An overview of the adverse events from a systematic review of the results of several clinical trials, postmarketing surveillance studies, case series, and case reports found only rare serious adverse events that may not have been induced by black cohosh. The most common minor adverse effects noted in these trials were gastrointestinal symptoms (e.g., nausea) and musculoskeletal and connective tissue disorders (e.g., joint pain, rashes).
A small number of studies have explored the potential for black cohosh extracts to interfere with the metabolism or activity of drugs. One group studied the in vivo effect of black cohosh extracts on cytochrome P450 enzymes at doses up to 1,090 mg bid (0.2% triterpene glycosides) and found only weak inhibition of CYP2D6  and no effect on CYP3A4. A single case report suggested a possible effect of a black cohosh extract on reducing the cholesterol -lowering effects of statins.
To assist readers in evaluating the results of human studies of integrative, alternative, and complementary therapies for cancer, the strength of the evidence (i.e., the levels of evidence) associated with each type of treatment is provided whenever possible. To qualify for a level of evidence analysis, a study must:
Separate levels of evidence scores are assigned to qualifying human studies on the basis of statistical strength of the study design and scientific strength of the treatment outcomes (i.e., endpoints) measured. The resulting two scores are then combined to produce an overall score. A level of evidence score cannot be assigned to black cohosh because there has been insufficient clinical research done. For an explanation of the scores and additional information about levels of evidence analysis of CAM treatments for cancer, refer to Levels of Evidence for Human Studies of Integrative, Alternative, and Complementary Therapies
The Committee on Herbal Medicinal Products of the European Medicines Agency describes black cohosh products as a medicine that may be used for the treatment of menopausal symptoms, based on their assessment of the results of around 20 clinical trials involving over 6,000 patients who received black cohosh. However, the lack of demonstration of a clinical benefit significantly greater than that of placebo and the fact that much less research has been performed with cancer patients should lead to extra caution when its use in such patients is being considered .
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Last Revised: 2021-01-08
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