Black Cohosh (PDQ®): Integrative, alternative, and complementary therapies - Health Professional Information [NCI]

Overview

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:

• The roots and rhizomes of black cohosh are used for various medicinal purposes ranging from gynecologic to other disorders.
• Black cohosh was first used by American Indian or Alaska Native people; it is now commonly used in Europe.
• Black cohosh is frequently studied as a complementary therapy for breast cancer patients and survivors to reduce vasomotor symptoms associated with treatment-induced menopause.
• Purported estrogenic actions of black cohosh are refuted by current, up-to-date laboratory and clinical studies of commercially available hydroalcoholic extracts; suggestions of serotonergic activity are well supported.
• Recent findings show that black cohosh contains a large variety of constituents that are chemically related to central nervous system –active molecules, which have not been studied in detail yet.
• Commercially available hydroalcoholic extracts of black cohosh have been well tolerated, with very rare serious adverse effects reported.
• Observational and open-label studies indicate benefits of black cohosh on climacteric symptoms in cancer and noncancer populations, though gold-standard clinical investigations fail to confirm this effect.
• Given both the evidence and variability of previous findings, including the lack of demonstration of a clinical benefit against placebo and underexplored constituents, further preclinical and clinical studies of black cohosh are warranted.

General Information

Native to eastern and midwestern North America, black cohosh (Actaea racemosa, also known as Cimicifuga racemosa) [1] 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.[3] The most commonly used clinical preparations of black cohosh (e.g., Remifemin® and BNO 1055) are made from hydrophilic (typically hydroalcoholic) extracts.[4] Lipophilic extracts have in vitro effects on estrogen -regulated genes, whereas hydrophilic extracts generally do not.[3]

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,[4] but no apparent direct binding to the estrogen receptor.[3] 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] At least 40 different triterpene glycoside analogues have been identified in black cohosh (A. racemosa), including actein and cimicifugoside congeners.[2,3]

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.[5] 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.[2]

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.[6] 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.[7] Growth in market demand for black cohosh has led to an increased need for scientific evidence of quality, safety, and efficacy. [4,5,8]

Companies distribute black cohosh as a dietary supplement. In the United States, dietary supplements are regulated as foods, not drugs. Therefore, premarket evaluation and approval of such supplements by the U.S. Food and Drug Administration (FDA) are not required unless specific disease prevention or treatment claims are made. The FDA can remove dietary supplements from the market that are deemed unsafe. Because dietary supplements are not formally reviewed for manufacturing consistency, ingredients may vary considerably from lot to lot and there is no guarantee that ingredients claimed on product labels are present (or are present in the specified amounts). The FDA has not approved the use of black cohosh as a treatment for cancer or any other medical condition.

References:

1. European Union Herbal Monograph on Cimicifuga racemosa (L.) Nutt., rhizoma. London, United Kingdom: Committee on Herbal Medicinal Products, 2018. Available online. Last accessed February 16, 2022.
2. Predny ML, De Angelis P, Chamberlain JL: Black cohosh (Actaea racemosa): an annotated bibliography. U.S. Department of Agriculture Forest Service, Southern Research Station, 2006. General Technical Report SRS 97.
3. Fabricant DS, Krause EC, Farnsworth NR: Black cohosh. In: Coates PM, Blackman MR, Cragg GM: Encyclopedia of Dietary Supplements. 2^nd ed. CRC Press, 2015, pp 60-74.
4. Qiu F, McAlpine JB, Krause EC, et al.: Pharmacognosy of black cohosh: the phytochemical and biological profile of a major botanical dietary supplement. Prog Chem Org Nat Prod 99: 1-68, 2014.
5. Gafner S: Black Cohosh Laboratory Guidance Document. ABC-AHP-NCNPR Botanical Adulterants Program, 2015.
6. Foster S: Exploring the peripatetic maze of black cohosh adulteration: a review of the nomenclature, distribution, chemistry, market status, analytical methods, and safety. HerbalGram (98): 32-51, 2013. Available online. Last accessed February 16, 2022.
7. Smith T, May G, Eckl V, et al.: US sales of herbal supplements increase by 8.6% in 2019. HerbalGram (127): 54-69, 2020. Available online. Last accessed February 16, 2022.
8. Gafner S: Botanical adulterants bulletin on adulteration of actaea racemosa. Black Cohosh - Botanical Adulterants Bulletin 1-5, 2016.

History

Black cohosh was in use by American Indian or Alaska Native people when Europeans arrived in the New World.[1] Among the reported indications for black cohosh in traditional American Indian or Alaska Native 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.[1]

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.[1]

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) [4] 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]

References:

1. Predny ML, De Angelis P, Chamberlain JL: Black cohosh (Actaea racemosa): an annotated bibliography. U.S. Department of Agriculture Forest Service, Southern Research Station, 2006. General Technical Report SRS 97.
2. Qiu F, McAlpine JB, Krause EC, et al.: Pharmacognosy of black cohosh: the phytochemical and biological profile of a major botanical dietary supplement. Prog Chem Org Nat Prod 99: 1-68, 2014.
3. Fabricant DS, Krause EC, Farnsworth NR: Black cohosh. In: Coates PM, Blackman MR, Cragg GM: Encyclopedia of Dietary Supplements. 2^nd ed. CRC Press, 2015, pp 60-74.
4. Liske E, Hänggi W, Henneicke-von Zepelin HH, et al.: Physiological investigation of a unique extract of black cohosh (Cimicifugae racemosae rhizoma): a 6-month clinical study demonstrates no systemic estrogenic effect. J Womens Health Gend Based Med 11 (2): 163-74, 2002.
5. Cimicifugae Rhizoma. Amsterdam, The Netherlands: European Medicines Agency, 2018. Available online. Last accessed February 16, 2022.

Laboratory / Animal / Preclinical Studies

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,[1] 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,[2] 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.[4] 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.[4]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.[4] 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.

References:

1. Fabricant DS, Krause EC, Farnsworth NR: Black cohosh. In: Coates PM, Blackman MR, Cragg GM: Encyclopedia of Dietary Supplements. 2^nd ed. CRC Press, 2015, pp 60-74.
2. Qiu F, McAlpine JB, Krause EC, et al.: Pharmacognosy of black cohosh: the phytochemical and biological profile of a major botanical dietary supplement. Prog Chem Org Nat Prod 99: 1-68, 2014.
3. Fritz H, Seely D, McGowan J, et al.: Black cohosh and breast cancer: a systematic review. Integr Cancer Ther 13 (1): 12-29, 2014.
4. Reame NE, Lukacs JL, Padmanabhan V, et al.: Black cohosh has central opioid activity in postmenopausal women: evidence from naloxone blockade and positron emission tomography neuroimaging. Menopause 15 (5): 832-40, 2008 Sep-Oct.

Human / Clinical Studies

Mechanism of Action, Pharmacokinetics, Pharmacodynamics

Given that the clinically utilized hydrophilic extracts of black cohosh roots and rhizomes are not estrogenic, alternative 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,[5] 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.[1]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.[1] In the same study, no alteration in circulating hormone levels (estradiol, follicle-stimulating hormone, luteinizing hormone) was observed in this population relative to baseline (P < .05), changes have not been observed in similar investigations of systemic hormone levels or those monitoring for estrogenic effects on breast, endometrial, or vaginal tissues.[2]

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.[1]

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.[6] An episode of autoimmune hepatitis is questionably related to the use of black cohosh. Although noteworthy, many of these reports are anecdotal in nature.[6] Furthermore, a meta-analysis of randomized, double-blind, controlled clinical trials does not demonstrate evidence of black cohosh causing adverse effects on liver function.[7] Indications of toxicity are reportedly caused by manufacturer contamination or adulteration with other toxic products,[1] 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 does not suggest this interaction. Black cohosh supplementation does not significantly alter the expression or activity of metabolic enzymes CYP3A4, CYP1A2, or CYP2E1.[10] 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 [10]—especially since a very high dose was used for this particular investigation (1,090 mg bid). Studies have yet to verify this effect;[2] 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.[2]

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).[2]

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.[11] 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.[11]

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,[12] respectively).[13] 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.[13] 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.[13] 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 with placebo.[2]

Significant declines in hot flash frequency and severity and 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.[2]Prospective trials indicated reductions as high as 56% (95% CI = 40%–71%) in hot flash scores (daily frequency times average severity).[2] 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.[2]

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.[2]

Thus far, two randomized, placebo-controlled, double-blind clinical trials have assessed the efficacy of black cohosh use (one trial used black cohosh extract;[14] the other trial used an uncharacterized black cohosh product [15]) 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).[3] Some patients received LHRH-a treatment in addition to an aromatase inhibitor or SERM, though no significant difference in use was found between the treatment group and the control group.[3] 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® (40 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).

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.[2] 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]

Noncancer Patients

The efficacy of black cohosh supplementation on vasomotor symptoms has also been evaluated in noncancer populations; however, these findings to date remain inconsistent.

At least two meta-analyses have addressed questions about the specific effect of black cohosh supplements versus placebo. The first meta-analysis [16] compared the effect of oral black cohosh monopreparations with that of the control group. Subjects in the control group were given red clover, fluoxetine, or placebo. In three studies with placebo-control groups, there was no significant difference in hot flash frequency between the black cohosh group and the placebo group. The second meta-analysis included six different randomized controlled trials that investigated the efficacy of a single formulation of black cohosh (isopropanolic black cohosh extract [iCR]) in reducing climacteric symptomology (neurovegetative and psychological menopausal symptoms) in perimenopausal and postmenopausal women.[17] Patients who received iCR displayed significant reductions in climacteric symptoms when compared with patients who received the placebo. One study used a black cohosh/St. John's wort combination therapy, and the other five studies used iCR alone. This meta-analysis also found that women treated with higher doses of black cohosh monotherapy demonstrated the greatest improvement in climacteric symptomology.[17]

A comprehensive review of clinical trials that studied the use of black cohosh in noncancer menopausal and/or aging women was published in 2014. The review demonstrated that the overall heterogeneity of clinical evidence was due to major variation in exact intervention materials and clinical endpoints.[12,18] Variability in study results are possibly because of differences in extract preparation methods, potentially affecting the concentration of alkaloid constituents, which have not been previously studied in in vitro and clinical research. Other factors that contributed to the heterogeneity included doses administered and study group characteristics.

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),[19] both of which failed to show a benefit greater than that of placebo.[20]

Randomized controlled investigations of black cohosh used as monopreparations [16] or within multibotanical preparations [20] 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.[21] 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).[21] 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.[21] Potential benefits on bone metabolism are further supported in an uncontrolled trial by increases in osteocalcin levels in women receiving the supplement.[22]

References:

1. van Breemen RB, Liang W, Banuvar S, et al.: Pharmacokinetics of 23-epi-26-deoxyactein in women after oral administration of a standardized extract of black cohosh. Clin Pharmacol Ther 87 (2): 219-25, 2010.
2. Fritz H, Seely D, McGowan J, et al.: Black cohosh and breast cancer: a systematic review. Integr Cancer Ther 13 (1): 12-29, 2014.
3. Wang C, Huang Q, Liang CL, et al.: Effect of cimicifuga racemosa on menopausal syndrome caused by LHRH-a in breast cancer. J Ethnopharmacol 238: 111840, 2019.
4. Wuttke W, Gorkow C, Seidlová-Wuttke D: Effects of black cohosh (Cimicifuga racemosa) on bone turnover, vaginal mucosa, and various blood parameters in postmenopausal women: a double-blind, placebo-controlled, and conjugated estrogens-controlled study. Menopause 13 (2): 185-96, 2006 Mar-Apr.
5. Gafner S: Black Cohosh Laboratory Guidance Document. ABC-AHP-NCNPR Botanical Adulterants Program, 2015.
6. Cohen SM, O'Connor AM, Hart J, et al.: Autoimmune hepatitis associated with the use of black cohosh: a case study. Menopause 11 (5): 575-7, 2004 Sep-Oct.
7. Naser B, Schnitker J, Minkin MJ, et al.: Suspected black cohosh hepatotoxicity: no evidence by meta-analysis of randomized controlled clinical trials for isopropanolic black cohosh extract. Menopause 18 (4): 366-75, 2011.
8. Foster S: Exploring the peripatetic maze of black cohosh adulteration: a review of the nomenclature, distribution, chemistry, market status, analytical methods, and safety. HerbalGram (98): 32-51, 2013. Available online. Last accessed February 16, 2022.
9. Gafner S: Botanical adulterants bulletin on adulteration of actaea racemosa. Black Cohosh - Botanical Adulterants Bulletin 1-5, 2016.
10. Gurley B, Hubbard MA, Williams DK, et al.: Assessing the clinical significance of botanical supplementation on human cytochrome P450 3A activity: comparison of a milk thistle and black cohosh product to rifampin and clarithromycin. J Clin Pharmacol 46 (2): 201-13, 2006.
11. Rebbeck TR, Troxel AB, Norman S, et al.: A retrospective case-control study of the use of hormone-related supplements and association with breast cancer. Int J Cancer 120 (7): 1523-8, 2007.
12. Qiu F, McAlpine JB, Krause EC, et al.: Pharmacognosy of black cohosh: the phytochemical and biological profile of a major botanical dietary supplement. Prog Chem Org Nat Prod 99: 1-68, 2014.
13. Henneicke-von Zepelin HH, Meden H, Kostev K, et al.: Isopropanolic black cohosh extract and recurrence-free survival after breast cancer. Int J Clin Pharmacol Ther 45 (3): 143-54, 2007.
14. Pockaj BA, Gallagher JG, Loprinzi CL, et al.: Phase III double-blind, randomized, placebo-controlled crossover trial of black cohosh in the management of hot flashes: NCCTG Trial N01CC1. J Clin Oncol 24 (18): 2836-41, 2006.
15. Jacobson JS, Troxel AB, Evans J, et al.: Randomized trial of black cohosh for the treatment of hot flashes among women with a history of breast cancer. J Clin Oncol 19 (10): 2739-45, 2001.
16. Leach MJ, Moore V: Black cohosh (Cimicifuga spp.) for menopausal symptoms. Cochrane Database Syst Rev (9): CD007244, 2012.
17. Castelo-Branco C, Gambacciani M, Cano A, et al.: Review & meta-analysis: isopropanolic black cohosh extract iCR for menopausal symptoms - an update on the evidence. Climacteric 24 (2): 109-119, 2021.
18. Geller SE, Shulman LP, van Breemen RB, et al.: Safety and efficacy of black cohosh and red clover for the management of vasomotor symptoms: a randomized controlled trial. Menopause 16 (6): 1156-66, 2009 Nov-Dec.
19. NIH-Funded HALT Study Finds Black Cohosh Ineffective for Treating Menopausal Symptoms. Morrisville, NC: Relias Media, 2007. Available online. Last accessed February 16, 2022.
20. Reed SD, Newton KM, LaCroix AZ, et al.: Vaginal, endometrial, and reproductive hormone findings: randomized, placebo-controlled trial of black cohosh, multibotanical herbs, and dietary soy for vasomotor symptoms: the Herbal Alternatives for Menopause (HALT) Study. Menopause 15 (1): 51-8, 2008 Jan-Feb.
21. Wuttke W, Seidlová-Wuttke D, Gorkow C: The Cimicifuga preparation BNO 1055 vs. conjugated estrogens in a double-blind placebo-controlled study: effects on menopause symptoms and bone markers. Maturitas 44 (Suppl 1): S67-77, 2003.
22. Raus K, Brucker C, Gorkow C, et al.: First-time proof of endometrial safety of the special black cohosh extract (Actaea or Cimicifuga racemosa extract) CR BNO 1055. Menopause 13 (4): 678-91, 2006 Jul-Aug.

Adverse Effects

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.[1] 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).[1]

Herb-Drug Interactions

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 [2] and no effect on CYP3A4.[3] A single case report suggested a possible effect of a black cohosh extract on reducing the cholesterol -lowering effects of statins.[4]

References:

1. Borrelli F, Ernst E: Black cohosh (Cimicifuga racemosa): a systematic review of adverse events. Am J Obstet Gynecol 199 (5): 455-66, 2008.
2. Gurley BJ, Gardner SF, Hubbard MA, et al.: In vivo effects of goldenseal, kava kava, black cohosh, and valerian on human cytochrome P450 1A2, 2D6, 2E1, and 3A4/5 phenotypes. Clin Pharmacol Ther 77 (5): 415-26, 2005.
3. Gurley BJ, Swain A, Hubbard MA, et al.: Clinical assessment of CYP2D6-mediated herb-drug interactions in humans: effects of milk thistle, black cohosh, goldenseal, kava kava, St. John's wort, and Echinacea. Mol Nutr Food Res 52 (7): 755-63, 2008.
4. Asher GN, Corbett AH, Hawke RL: Common Herbal Dietary Supplement-Drug Interactions. Am Fam Physician 96 (2): 101-107, 2017.

Summary of the Evidence for Black Cohosh

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:

• Be published in a peer-reviewed scientific journal and include sufficient parameters about the quality and reproducibility of the investigated material derived from black cohosh.
• Report on therapeutic outcome or outcomes, such as tumor response, improvement in survival, or measured improvement in quality of life.
• Describe clinical findings in sufficient detail for a meaningful evaluation to be made.

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. For an explanation of the scores and additional information about levels of evidence analysis of CAM treatments for cancer, see 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.[1] 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 .

References:

1. Cimicifugae Rhizoma. Amsterdam, The Netherlands: European Medicines Agency, 2018. Available online. Last accessed February 16, 2022.

Changes to This Summary (06 / 07 / 2022)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Human/Clinical Studies

Added text about the results of a meta-analysis that compared the effect of oral black cohosh monopreparations with that of the control group. Subjects in the control group were given red clover, fluoxetine, or placebo. Also added text about the results of a second meta-analysis that included six different randomized controlled trials and investigated the efficacy of a single formulation of black cohosh in reducing climacteric symptomology in perimenopausal and postmenopausal women (cited Castelo-Branco et al. as reference 17).

Added text to state that a comprehensive review of clinical trials that studied the use of black cohosh in noncancer menopausal and/or aging women was published in 2014. The review demonstrated that the overall heterogeneity of clinical evidence was due to major variation in exact intervention materials and clinical endpoints (cited Geller et a. as reference18). Variability in study results are possibly because of differences in extract preparation methods, potentially affecting the concentration of alkaloid constituents, which have not been previously studied in in vitro and clinical research. Other factors that contributed to the heterogeneity included doses administered and study group characteristics.

Renamed Table 1 title from Clinical Studies of Black Cohosh to Clinical Studies of Black Cohosh in Patients With Cancer.

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About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the use of black cohosh in people with cancer.. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

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PDQ® Integrative, Alternative, and Complementary Therapies Editorial Board. PDQ Black Cohosh. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/about-cancer/treatment/cam/hp/black-cohosh-pdq. Accessed <MM/DD/YYYY>.

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Last Revised: 2022-06-07