MAJOR CHEMICAL CONSTITUENTS

Numerous triterpene glycosides (e.g., actein, cimicifugoside, cimigoside, 23-epi-26 deoxyactein, cimiracemoside A); aromatic acids (e.g., ferulic acid, isoferulic acid, acyl caffeic acid, fukinolic acid, salicylic acid); tannins, volatile oils, resin, phytosterols, starch, and sucrose. More recent studies suggest that black cohosh, contrary to prior alleged identification of isoflavones in the plant, does not contain isoflavones (e.g., biochanin A, formononetin). Kaempferol has been found in extracts of the leaf. The salicylic acid is in such as low concentration as to be unlikely to cause any allergic reactions in those sensitive to this agent. A unique bitter principle also has been identified.

PRINCIPAL USES

TRADITIONAL AND HISTORICAL USES

Black cohosh is an indigenous North American herb that was used widely by eastern Native American tribes including the Cherokee, Iroquois, Penobscot, and MicMac for gynecologic complaints and pain, including rheumatic pain, and also in the treatment of hives, constipation, colds, coughs, fatigue, sore throat, and snakebite. It appears in the botanical literature as early as the 1680s, and it was described by von Linne in 1749 as an herb primarily for female debility and pain relief, but also as a diaphoretic, stomachic, expectorant, cardiac tonic, and uterine tonic. Black cohosh was largely popularized by the Eclectics, who called it Macrotys, and who used it extensively for women’s “muscular pains, uterine pains

Black Cohosh (Actaea racemosa).

(Photo by Martin Wall.)

with tenderness, false pains, irregular pains, rheumatism of the uterus, dysmenorrhea.” They also recognized its value as a superb sedative. It was considered to have particular affinities for the uterus, heart, and circulatory system, supposedly improving (cardiac) contractile force; however, this indication has not been widely studied nor borne out by limited scientific evaluation of the plant. It was considered a reliable herb to aid in birth and relieve pain afterward, given in small doses before, during, and after labor. Its effects for the treatment of all manner of musculoskeletal and neuralgic pains were widely reputed. Listed in the USP from 1820 until 1920, it was and continues to be one of the most popular herbal medicines sold in Western nations.

CLINICAL INDICATIONS

Black cohosh is the most widely sold and used herb in western nations for the treatment of perimenopausal neurovegetative complaints. It is commonly used for such by herbal practitioners and research has largely centered on its use for these purposes. Herbal practitioners also use black cohosh as a reliable anti-inflammatory, antispasmodic, and analgesic for all manner of neuromuscular complaints, for premenstrual headache, as well as for treating spasmodic or paroxysmal coughs. Plant Profile Black Cohosh Table 2 lists the uses of this herb by contemporary herbalists and naturopathic physicians.

TABLE 2 Common Uses of Black Cohosh in Modern Herbal Practice

TABLE 1 Black Cohosh for Gynecologic and Obstetric Problems: Eclectic Medical Uses

IN VITRO, ANIMAL, AND CLINICAL DATA

Black cohosh has been used widely to treat menopausal complaints in Europe for over 50 years. However, in spite of numerous studies, few that are without methodologic flaws have emerged to solidly demonstrate efficacy. Two reviews of human studies on the effectiveness of black cohosh for alleviating menopausal symptoms concluded that it is safe and effective, with pronounced effects on the central nervous system. In a study of hot flashes caused by tamoxifen in breast cancer survivors, it was found to reduce the number and severity of hot flashes (almost half the patients in the intervention group were free of hot flushes, whereas severe flashes were reported by 24.4% of the intervention group and 73.9% of the usual-care group), with assessment at 2-month intervals over 1 year. Yet other studies have found no benefit in the treatment of these symptoms. A 6-month randomized, double-blind, controlled study (by the manufacturer of the extract) showed efficacy, tolerability, and lack of systemic estrogenic effect (no change in vaginal cytology or relevant hormone levels) with two dose levels of black cohosh.

The data on estrogenic effects of black cohosh are very contradictory, demonstrating everything along the spectrum from positive estrogenic effects to no effects to antiestrogenic effects; selective estrogen receptor modulation to no estrogen receptor binding whatsoever. Although on balance, it does not appear that there is estrogenic activity associated with use of this herb, it is prudent for women with a history of estrogen-sensitive cancer to avoid use of this herb.

In vitro and in vivo evidence from animal trials has clearly demonstrated anti-inflammatory effects with black cohosh extract, supporting its traditional use as an herb for the treatment of rheumatism and rheumatoid arthritis.

Osteoprotective effects have been demonstrated with black cohosh in postmenopausal women. In a double-blind study of 62 postmenopausal women, the effects of a Cimicifuga racemosa extract on markers of bone metabolism, hormones, sex hormone–binding globulin (SHBG), lipometabolism, vaginal maturity, and routine laboratory parameters were compared with those of conjugated estrogens (CE) and placebo over 12 weeks. Markers of bone turnover, estradiol, follicle-stimulating hormone (FSH), leuteinizing hormone (LH), sex hormone binding globulin (SHBG), triglycerides, total cholesterol, high-density cholesterol, low-density cholesterol, and routine clinical chemistry parameters were determined from blood samples. Vaginal “maturity index” was determined from vaginal smears. The analyses of bone turnover markers indicated beneficial effects with stimulated osteoblast activity with mild estrogen-like activity on vaginal tissue with the black cohosh extract. Although these findings are preliminary, this represents an area of possible new and interesting research on this herb.

MECHANISMS OF ACTION

There is considerable interest in understanding the mechanisms of black cohosh. Nonetheless, in spite of its popularity, its mechanisms have not been elucidated. Studies on estrogenic activity have been contradictory. In spite of initial studies suggesting estrogenic effects, many recent studies demonstrate lack of systemic estrogenic effects and even antiestrogenic effects, with no changes in LH, FSH, prolactin, and SHBG, and no changes in endometrial or vaginal proliferation. SERM activity has also been postulated, however, some studies also demonstrate lack of binding to estrogen receptors. Recent in vitro and animal research suggests possible serotinergic effects, and receptor binding assays suggest a possible dopaminergic mechanism of action.

RATINGS

PREPARATIONS USED CLINICALLY

DOSAGE

SAFETY INFORMATION: HERB–DRUG INTERACTIONS, TOXICITY, AND CONTRAINDICATIONS

Taking a serious and concerted look at the relative safety of black cohosh products for the treatment of menopausal symptoms, particularly for women in whom HRT is contraindicated, Low Dog et al. conducted a careful review of published and unpublished safety data extending well over 100 years. Analysis of more recent adverse events systems databases yields records demonstrating a high level of safety. The FDA Special Nutrition Adverse Events Monitoring System (SN/AEMS), shows only nine adverse reports reported prior to October 20, 1998; of these, only one—headaches and elevated blood pressure—was caused by black cohosh as a solo agent. The WHO Collaborating Center also maintains a database of adverse events reports, with summary clinical reports and some medical detail. As of July 31, 2000, a total of only 35 adverse events relating to all forms of black cohosh constituents and root products had been reported. Of these, the events were mostly related to general symptoms, “suggesting a good tolerability of Cimicifuga preparations.”

More recently, concerns have arisen because of the report of a small number of hepatic complications associated with black cohosh use. Two cases of hepatitis and two cases of liver failure have been reported in women taking black cohosh extracts. One case was autoimmune hepatitis in a woman taking black cohosh for 3 weeks along with several prescription drugs. The second was a case of hepatitis after 1 week of black cohosh ingestion. The cases of liver failure were acute and occurred after 3 and 5 months of black cohosh administration. None of the cases was causally linked to black cohosh. In a systematic review of clinical trials, published case reports and pharmacovigilance reporting center data, Huntley and Ernst concluded that black cohosh is generally safe. If products are taken for a limited amount of time and in the recommended dosage range, the risk of adverse events is slight and the events are rare and usually mild and transient, with gastrointestinal upset and rashes being the most common events reported. When higher doses than those recommended are used, dizziness, headaches, nausea, and vomiting may be seen. Discontinuation of the herb resolves the symptoms. The European Medicines Agency (EMEA) recently assessed the case reports of hepatotoxicity associated with ingestion of C. racemosa root extracts (EMEA/HMPC/88766/2006) and concluded that the cases reported in the literature as well as the pharmacovigilance reports are mostly poorly documented and that these adverse events should be interpreted with caution. Although a recent animal study did show hepatocellular toxicity at high concentrations of herb, and minimal hapatocellular mitochondrial changes even at lower doses, the authors conclude that toxic concentrations seen in this study are likely not able to be reached in humans treated with the recommended doses. They conclude that ethanolic black cohosh extract is associated with hepatic mitochondrial toxicity both in vivo in rats and in vitro using cell cultures and isolated rat liver mitochondria, but that this toxicity is not clinically relevant for most patients but may become important in patients with underlying risk factors.

There are no expected herb–drug interactions, and even in combination with HRT, minimal side effects have been observed. No mutagenicity (Ames test) has been found and the herb has a very low toxicity risk based on animal toxicity studies. One case of nocturnal seizures was reported in a 45-year-old woman taking a combination of black cohosh, chaste tree, and evening primrose oil for menstrual irregularity. Her sister had also been taking this combination for duration of 1 to 2 years with no reported side effects. The woman’s seizures abated upon discontinuation of the herb, no other pathology was identified, and the seizures were not directly attributed to the herbs in combination or singly. The limited number of other adverse events that have reported (a thorough review of which is provided by Low Dog et al.) suggest that these may be owing to the use of the herb in combination with other herbal products or dietary supplements, or other ingredients in such combinations.

For short-term use, black cohosh clearly has a high safety profile. Long-term use of the herb, however, as a treatment for menopausal complaints, has been and continues to be debated because of concern over risk of estrogenic effects and cancer. The German Commission E Monographs rends a limited duration of 6 months for black cohosh use with no specific rationale provided for this caution. Bone states that “Black cohosh may be taken long term within the recommended dose, although the Commission E recommends not more than 6 months, perhaps because controlled studies over longer periods are lacking.” According to Blumenthal, Professor Hans Schilcher, vice president of the Commission E, explains that the limitation is based not upon concerns about the safety of long-term black cohosh use, and in fact, the German Commission E had considered approval the herb for use over an unlimited duration without safety concerns, but based the more conservative recommendation on the “desire to ensure that women return to their health-care provider for periodic examinations at six month intervals.” This follows prescription recommendations similar to those for HRT prescription in Germany, which are given for this same reason and seem a prudent standard of practice.

Preclinical human, animal, and in vitro studies have given mixed results on the estrogenic activity of black cohosh, although recent 6- and 12-month human clinical trials have indicated a lack of estrogenic effects. Questions persist regarding the estrogenic effects of black cohosh and safety for use in women with a history of or risk of uterine and breast cancer. Effects on vaginal epithelium have been variable and remain inconclusive. Because no trial has been conducted for a duration greater than 6 months, and it may take this long to see marked proliferation, lack of demonstration of cell proliferation in shorter trials is not a conclusive finding. Although reduction of LH has been demonstrated in animal studies (ovariectomized rodents), human clinical trials have consistently failed to show an effect on FSH and LH levels, leading to the current belief that black cohosh’s mechanism of action is nonestrogenic. Further, black cohosh has shown antiproliferative activity in vitro on breast cancer cells under conditions testing for estrogenic activity and actually enhanced the antiestrogenic effects of tamoxifen in a trial combining the two agents. It appears, by all data available at this time, that this herb does not increase or predispose to breast cancer risk and is not contraindicated in such cases. Reviews examining the estrogenic effects of black cohosh have indicated that data from in vitro studies are mixed but leans toward lack of estrogenic activity or estrogenicity.

It appears that black cohosh is safe and possibly effective for some of the neurovegetative and psychological effects of menopause, as well as for numerous other complaints, particularly musculoskeletal and gynecologic pain. It also appears that the efficacy of this plant is not caused by direct estrogenic effects, and the herb has a significantly greater safety profile than HRT, especially for women who cannot use HRT because of cancer risk. A common pattern is for women to use black cohosh preparations for 1 to 2 years for the treatment of menopausal symptoms, then to discontinue use after this duration or with improvement of symptoms. It would appear that such use at this duration is beneficial with minimal risk compared with conventional hormonal preparations, and can be confidently used in the care and treatment of menopausal women; however, because of lack of long-term clinical studies, long-term safety is not conclusive. Clearly all women at risk for medical conditions should be re-evaluated by their primary care provider at regular interval, and patients should be queried for use of black cohosh and other herbs. Short-term use of black cohosh for acute conditions and within recommended doses appears to be a safe practice.

The safety of long term use of black cohosh cannot be established based on either traditional use, which was typically short-term, or on current research and literature. However, according to Low Dog et al., “practitioners should be reassured that Cimicifuga appears to be a safe option for women who wish to take it for relief of menopausal symptoms.”

No drug or supplement interactions have been reported for black cohosh. Reviews of clinical trials and other safety data have indicated that black cohosh is generally safe. Although black cohosh does not appear to have any estrogenic activity, until further evidence is available, the herb should be avoided by those with estrogen-dependent cancers. Risk of hepatotoxicity from black cohosh use, particularly if of limited duration and within recommended dosage ranges, appears to be extremely minimal; however, patients with prior history of hepatic problems should avoid the use of black cohosh. Any patients taking black cohosh who experience any of the following signs or symptoms of possible hepatic injury should discontinue use of the herb immediately, and consult their physician: fatigue, appetite loss, yellow discoloration of the skin and/or eyes, severe epigastric pain with nausea and vomiting, and dark urine.

USE AND SAFETY IN PREGNANCY AND LACTATION

Limited scientific literature is available on the safety of black cohosh during pregnancy and lactation, although it is traditionally used to ease labor. Black cohosh is generally contraindicated by most contemporary authors for use during pregnancy and lactation. The American Herbal Products Botanical Safety Handbook takes a slightly more liberal position and assigns black cohosh a pregnancy Class 2b rating, herbs not to be used during pregnancy unless otherwise directed by an expert qualified in the use of the described substance, and a lactation Class 2c rating, herbs not to be used while nursing unless otherwise directed by an expert qualified in the use of the described substance.

Contraindication of black cohosh during pregnancy appears to be based largely on historical records of this herb’s ability to affect uterine activity, with reports of its use both as a uterine stimulant (emmenagogue) and uterine relaxant by the Eclectic physicians. Numerous published Eclectics (Cook, Ellingwood, Felter, Howe, King, and others) regularly used black cohosh during pregnancy for the treatment of threatened miscarriage and premature labor, and for relaxation of a rigid os uteri during labor, suggesting its action as a uterine antispasmodic. Although this was not necessarily the first choice of treatment (Viburnum prunifolium being specifically indicated for threatened miscarriage), it was clearly used often and with comfort during pregnancy. In a seeming contradiction, however, it was also used as a partus preparator, an herb used in the last weeks of pregnancy to prepare the uterus for labor, as well as an herb to stimulate labor and effect an expedient delivery. It was considered a gentle and safe alternative to ergot at the time and still used in the form of ergonovine. Black cohosh was considered specifically able to effect regular and effective uterine contractions while eliminating irregular or nonproductive pain in labor. It was also used for postpartum uterine pain and the treatment of uterine subinvolution.

It is black cohosh’s reputation as an herb for initiating labor that has led to modern contraindications regarding its use during pregnancy. However, it appears that this may be an exaggerated concern that fails to take into account several factors, including the facts that the herb was equally used to relieve uterine contractions, its effects appear to be dose-dependent (with lower doses specifically leading to antispasmodic activity and significantly higher doses leading to increased uterine tone), Eclectic physicians used it to induce labor in significantly higher doses than herbalists and midwives presently use it clinically, and although it was frequently written about as a single herb, it was often combined with other herbs, such as Caulophyllum thalictroides (blue cohosh) or Gossypium herbaceum (cotton root), both known uterine contractants used to stimulate or enhance uterine contractions. It was considered only a very weak oxytocic, capable of inducing labor and abortion only in large doses. Reports on black cohosh from Eclectic physicians suggest very few adverse events associated with its use in pregnancy and birth, in spite of widespread use. One report among the Eclectics of “free use” during pregnancy correlated it with “premonitions of abortion” (allegedly threatened uterine contractions), but the author noted that this was the exception. Ellingwood, in 1919, mentioned six cases of the use of black cohosh during labor followed by severe uterine hemorrhage at birth.

Another confounding factor in the literature that appears to have contributed to the modern case against using black cohosh as a uterine antispasmodic during pregnancy is the fact that, as was the case with the Eclectics, the herb continues to be combined with blue cohosh, which has known cardiac glycosides and has been associated with several case reports of neonatal complications, including a case of myocardial infarction in a newborn whose mother took a combination of blue and black cohosh as a partus preparator during the last weeks of her pregnancy.

Black cohosh continues to be used by midwives for the prevention and treatment of threatened miscarriage when there are uterine contractions. It is also used as a partus preparator and an aid in difficult labors to impart uterine relaxation, effective rhythmic uterine contractions when there is dysfunctional labor, and to relax a rigid cervical os. Few clinical trials have been done on the uses of black cohosh outside of menopause, but Upton reports on a case series by Görlich published in 1962 involving the use of black cohosh in 258 women with various gynecologic and obstetric complaints. Among the case series are 18 cases of morning sickness successfully treated with black cohosh (only two requiring antiemetic medications) and successful prevention of miscarriage in six women with threatened miscarriage and a prior history of miscarriage. Considering the thousands of case reports cited by the Eclectics for use of this herb during pregnancy, it appears that further research is warranted for the application of this herb for threatened miscarriage and difficulties in labor for women who prefer an alternative to pharmaceutical drugs; and there may be some margin of safety when used appropriately, as suggested by the Botanical Safety Handbook, under the guidance of a qualified practitioner. Self-medication with this herb is not recommended, and neither the safety of this herb for the mother and fetus, nor safe dosing strategies for its use during pregnancy have been established.

Very little information is available on the safety of this herb for breastfeeding babies and its effects on milk production. Limited ethnobotanical evidence points to its postpartum use by the Iroquois to promote milk flow. A NAPRALERT search conducted by McKenna et al. yielded no records of adverse effects on lactation, and the same authors report that there is no evidence from human or animal studies regarding the transmission of constituents of black cohosh into breast milk. Further, McKenna et al. cite no reports of negative effects on the neonate associated with use of the herb during labor or the early postpartum period. The German Commission E Monographs do not contraindicate the use of this herb during lactation, and the herb does not appear to affect prolactin levels, although the herb’s effects on prolactin have not been tested in lactating women.

Given concerns over estrogenicity and hepatotoxicity—however unlikely these are to be an actual problem with use—it is prudent avoid this herb for any more than short-duration acute use during labor to relieve pain and spasmodic uterine contractions associated with dysfunctional labor.