Abstract
The purpose of this article is to assess recent data supporting the safety and efficacy of black cohosh products for the mitigation of menopause-related symptoms. Searches of the published literature in Napralert, Cochrane Library and PubMed databases were performed from 2003 to 2006. Information from drug regulatory agencies from five different countries was obtained to evaluate safety. While there are a few contradictory studies, the majority of the clinical trials indicate that extracts of black cohosh (Actaea racemosa L.) improve menopause-related symptoms. However, to date, at least 50 cases of possible hepatotoxicity have been reported. Although previous safety reviews suggest that black cohosh is well tolerated, the increasing numbers of these case reports indicates that further preclinical toxicological evaluations of black cohosh are urgently needed. At this time, it appears prudent to advise menopausal women with underlying liver disease, autoimmune diseases or those taking medications that may impact liver function not to use products containing black cohosh.
Menopause & its global impact
Demographic data indicates that the elderly comprise the fastest-growing segment of the world population and that women make up the majority of the aging population in all countries [1]. By the year 2030, it is estimated that there will be more than 60 million postmenopausal women in the USA and 1.2 billion postmenopausal women worldwide [1–3]. In light of 21st century demographic changes, it is increasingly important to expand our understanding of this important transition during a women's life and search for alternative, safe treatments for the symptoms and conditions associated with menopause.
Menopause is defined as the cessation of menstruation due to a depletion of follicular stores and is retrospectively determined after 12 months of amenorrhea during the midlife period [2,4]. The menopause transition begins with a depletion of ovarian reserves, is followed by menstrual irregularities during perimenopause and culminates in the cessation of menstruation and loss of reproductive capacity in the postmenopausal female [2,4]. Between 55 and 75% of these women will experience vasomotor symptoms (hot flashes) or other symptoms such as depression, mood swings, sleep disorders, vaginal dryness and joint pain [5]. Approximately 25–30% of women will seek treatment from their healthcare provider for the symptoms of menopause, and for many, hormone replacement therapy (HRT) will be recommended as the first-line treatment for menopausal symptoms [5,6].
Numerous studies have demonstrated the acute and chronic benefits of HRT, including the relief of menopausal symptoms, such as hot flashes and insomnia, as well as possible reductions in the risk of osteoporosis [5,8]. However, a significant number of women never seek treatment, or will refuse/discontinue HRT due to the perceived risks of the therapy, medical contraindications or a general reluctance to use ‘unnatural’ exogenous hormones [9]. As a consequence, women worldwide are actively seeking alternative approaches, including botanical therapies such as black cohosh, to manage their menopausal symptoms.
Black cohosh, known scientifically as Actaea racemosa (syn. Cimicifuga racemosa [L.] Nutt., Ranunculaceae), is a coarse, perennial woodland herb with large compound leaves and a thick, knotted rhizome (root) system [3,10–14]. The plant is native to North America, with a distribution from southern Canada to Georgia. There are numerous vernacular (common) names for this plant, including black snakeroot, black root, bugbane, rattle root, rattle top, rattle squawroot and and rattleweed [10,11]. Historically, black cohosh rhizomes were routinely used as a medicine by the Native American Indians (Penobscot, Winnebago and Dakota) for the treatment of coughs, colds, constipation, fatigue and rheumatism, as well as to increase breast milk production. In 1832, a tincture of black cohosh rhizome was used for the treatment of pain and inflammation associated with endometriosis, rheumatism, neuralgia and dysmenorrhea [3]. More recently, extracts of black cohosh have been marketed worldwide for the management of menopausal symptoms.
The purpose of this review is to evaluate new data for the safety and efficacy black cohosh reported between 2003 and 2006, and to discuss the future for black cohosh products. Extensive reviews of the clinical trials and other data published prior to 2003 are available [3,10–14]. Searches of the scientific and medical literature pertaining to the safety and efficacy of black cohosh using the Cochrane, Napralert, PubMed, and Sci Finder databases, in addition to library searches of the foreign literature from January 2003 to April 2006, were performed and the data reviewed. In addition, case reports and other information were obtained from drug regulatory agencies from Australia, Germany, Sweden, Switzerland and the UK, as well as the National Institutes of Health (Bethseda, MD, USA) to help assess safety.
New clinical studies for black cohosh
Prior to 2003, there were at least 25 published reports detailing observational and case studies, as well as clinical trials of black cohosh for the treatment of various gynecological ailments and for the management of climacteric symptoms such as anxiety, hot flushes, profuse sweating, insomnia and vaginal atrophy [3,10,11]. Analyses of these clinical studies have been addressed in previous reviews [3,10–14]. In the period of 2003–2005, at least nine clinical studies assessing the efficacy of black cohosh products in various menopausal populations were published [15–23]. An overview of the studies and the details of the products used in the majority of these new clinical trials, Remifemin® (REM) (Enzymatic Therapy, Inc., WI, USA) and Klimadynon® (Bionorcia AG, Newmarkt, Germany)/Menofem® (Pharmaton SA, Bioggio, Switzerland) are described in Table 1. A randomized, comparison-controlled, prospective clinical trial assessed the efficacy of an isopropanolic aqueous extract of black cohosh (REM) on climacteric complaints in comparison with low-dose transdermal estradiol (T-E2) in 64 postmenopausal women (n = 32 in each group) [17]. Patients were randomly allocated to receive either 40 mg of REM extract daily or 25 μg T-E2 every 7 days, plus dihydrogesterone 10 mg/day for the last 12 days of the 3-month estradiol treatment. Outcomes measured included vasomotor symptoms using the Green scale (a visual analog scale designed to measure quality of life and the daily number and severity of hot flushes), as well as anxiety and depression using the Symptom Rating Test. Gonadotropins (follicle-stimulating hormone [FSH], luetinizing hormone [LH], prolactin [PRL], 17 β-estradiol [E2] and cortisol, lipid profile (total cholesterol high-density lipoprotein [HDL]/low-density lipoprotein [LDL]-cholesterol, triglycerides), liver function (alanine aminotransferase and aspartate aminotransferase) and endometrial thickness were also measured. Both treatments significantly reduced the number of hot flushes/day (p <0.001) and the Green score for vasomotor symptoms (p <0.001), starting at the first month of therapy. This effect was maintained throughout the remainder of the 3-month treatment period, without any significant difference between the two treatments. In addition, anxiety and depression (all p <0.001), were significantly reduced following 3 months of both REM and low-dose T-E2 treatment. Total cholesterol was unchanged by REM treatment, but was significantly (p <0.033) reduced by 3 months of low-dose T-E2 treatment. A slight, but significant increase in HDL-cholesterol (p <0.04) was found only in women treated with REM, while LDL-cholesterol levels were significantly reduced by 3 months of both REM (p <0.003) and low-dose T-E2 (p <0.002). Trig-lycerides were not affected by either treatment, and aminotransferase levels remained in the normal range during therapy. FSH, LH and cortisol were not significantly affected after the 3-month treatment, while PRL (p <0.005) and 17 β-E2 (p <0.001) were increased slightly only by low-dose T-E2. Endometrial thickness was not affected by treatment with REM or low-dose T-E2. The study concluded that 40 mg/day of REM extract is an alternative to low-dose T-E2 in the management of menopausal symptoms [17]. The major concern with this study is the lack of a placebo arm.
Overview of the recent clinical trials and product information for black cohosh extracts for the treatment of menopausal symptoms.
CE: Conjugated estrogens; CR: Cimicifugae racemosae; HPLC: High pressure liquid chromatography; MRS: Menopause rating scale; T-E2: Transdermal estradiol; v/v: Volume/volume.
A randomized, multicenter, double-blind, placebo-controlled clinical trial assessed the efficacy and tolerability of REM extract in the treatment of menopausal symptoms in 304 menopausal women (average age 53 years) recruited at 24 centers [18]. The patients were randomly allocated to receive 40 mg REM (one tablet twice daily) or matching placebo for 12 weeks. The primary outcome measured was the change from baseline in the Menopause Rating Scale (MRS) I; while secondary measures included changes in its subscores and safety variables such as liver enzymes. Clinical evaluations were performed prior to treatment and at 4 and 12 weeks.
The results of this study show that treatment with the REM extract was more effective than placebo (p <0.001). The effect size was 0.03–0.05 MRS units, which was similar to recent HRT study results (0.036 MRS units). Women who had entered more recently into menopause benefited more than those in the later stages. The hot flush MRS subscore improved the most with REM as compared with placebo. In terms of adverse events, 32.7% of the patients in the REM group reported a total of 71 adverse events, as compared with 31.1% in the placebo group reporting 67 adverse events. The differences were not statistically significant and no serious adverse events were reported. No changes in liver enzymes were observed. The study was performed in accordance with the current quality standards for clinical trials and the outcomes were statistically significant [18].
Another multicenter, randomized, placebo-controlled, double-blind, parallel-group study was conducted to assess the safety and efficacy of the black cohosh extract Cimicifuga racemosa 99 (Cr 99; 60% ethanol extract, corresponding to 29–55 mg of drug, mean 42 mg) in 122 menopausal women (intention-to-treat population) with three or more hot flashes a day [15]. The women were treated with one Cr 99 capsule or matching placebo for 12 weeks. Two main outcome measures were the weekly weighted score of hot flashes and Kupperman Index. Secondary efficacy variables included the MRS, FSH serum levels and karyopyknotic index. Routine safety laboratory parameters and adverse events were also documented. The primary efficacy analysis showed that Cr 99 extract was not superior to placebo. The weekly weighed score of hot flashes decreased by 37% for Cr 99 and 30% for placebo. The results in the Kupperman index were a 26% reduction for Cr 99 and a 17% reduction for placebo. Subgroup analysis of patients with a Kupperman Index greater than or equal to 20 showed that treatment with Cr 99 was superior to placebo (p <0.018). A decrease of 47 and 21% was observed in the black cohosh and placebo group, respectively. The weekly weighted scores of hot flashes (p <0.052) and the MRS (p <0.009) showed similar results. Prevalence and intensity of the adverse events did not differ in the two treatment groups. The results of this study showed no treatment effect for CR-99 in the intention-to-treat population as a whole, but did show a benefit in patients with menopausal disorders of at least moderate intensity (Kupperman index ≥20). No differences were observed in the secondary outcomes or adverse event rate between groups (20% in Cr 99 and 23% in placebo) [15]. This study demonstrates the importance of including a placebo arm in the trial, and indicates that there may be some differences between black cohosh products in terms of efficacy.
The therapeutic effects of the black cohosh extract Cimicifuga racemosa BNO 1055 (CR BNO 1055) (Klimadynon/Menofem) were assessed for menopausal symptoms, bone metabolism and endometrial thickness, and compared with those of conjugated estrogens (CE) and placebo [23]. A total of 62 peri- and postmenopausal women (aged 40–60 years) were included in the double-blind, randomized, placebo- and CE-controlled study, and treated either with CR BNO 1055 (daily dose corresponding to 40 mg herbal drug, n = 20), 0.6 mg CE (n = 22), or matching placebo (n = 20), for 3 months. Menopausal symptoms were assessed using the MRS (ten symptoms) and a diary. Levels of CrossLaps (marker of bone degradation) were determined by Elecsys® system (Roche, Basel, Switzerland) and bone-specific alkaline phosphatase (marker of bone formation) by an enzymatic assay. Endometrial thickness was measured via transvaginal ultrasound and vaginal cytology was also studied. The primary efficacy criterion was the change from baseline to end point in the MRS. Change from baseline was also analyzed for the secondary variables. Analysis of the results of the study showed that the total scores in all ten MRS items were similar for the black cohosh product and CE, and showed a trend toward superiority to placebo (p = 0.0506). CR BNO 1055 had no effect on endometrial thickness, which was significantly increased by treatment with CE. Vaginal superficial cells were increased after treatment with CE (p = 0.0001), and were increased after treatment with CR BNO 1055, but this was not statistically significant as compared with placebo (p = 0.0542). Bone turnover after 12 weeks was reduced in both the black cohosh arm and the CE arm (p <0.05). While this was one of the better clinical trials for black cohosh, the study still suffered from a number of problems. A total of 97 patients were initially randomized with one of the inclusion criteria being last menstrual bleeding at least 6 months ago. However, 35 patients were eventually excluded from the final analyzes due to masked ovulary or unovulatory cycles and BMI greater than 30. In addition, the baseline characteristics of the patients are noted as being comparable in all treatment groups but no data are given. Furthermore, the black cohosh extract and placebo were not described adequately and the study was short (12-week treatment period). Finally, while it is true that CR BNO 1055 gave similar results to low dose CE (0.6 mg/day), with the exception of bone turnover, none of these results were significantly better than placebo, including the data for CE [23].
Two clinical studies published in 2005 reported on the safety and efficacy of black cohosh extracts in combination with other botanicals such as soy (Glycine max) and St. John's wort (Hypericum perforatum) [20,21]. A 12-week multicenter randomized double-blind, placebo-controlled study was performed to investigate the efficacy of a combination of soy isoflavones and black cohosh for the management of menopausal symptoms in perimenopausal women [21]. In this study, 124 women experiencing at least five vasomotor symptoms every 24 h were randomized to receive either the combination soy/black cohosh-containing supplement (n = 60) or placebo (n = 64) daily for 12 weeks. The modified Kupperman index and Green climacteric scale were used to assess outcomes prior to the start of the study and at weeks 6 and 12. The results show that at weeks 6 and 12, all scores in both groups had decreased compared with baseline; however, there was no statistical difference between the treated and placebo groups [21]. This study suffers from numerous flaws, such as the lack of adequate description of the black cohosh extract used in the product. In addition, although soy products are purported to reduce hot flashes, recent reviews of the clinical trials for soy show that there is currently insufficient data to support these claims [12]. In the current study, 1500 mg of evening primrose oil was also included in the supplement, and there are no data supporting its use for the treatment of menopausal symptoms. Furthermore, olive oil was used in the placebo capsules. Olive oil is not without biological activities, including anti-inflammatory and antioxidant activities, which make it far from inert and a poor choice for placebo. Thus, this study suffers from a poor product choice and lack of sufficient description of the product itself.
The second combination product consisted of black cohosh and St. John's wort extracts [20]. St. John's wort is well known for antidepressant activity that has been evaluated in numerous clinical trials. In this double-blind, randomized, placebo-control study 301 (294 completed; 97.7%) women experiencing menopausal symptoms with psychological symptoms were treated with ethanol extract of St. John's wort and isopropanol extract of black cohosh (Remifemin Plus) or a matched placebo for 16 weeks. The patients were treated with the product or matching placebo at 2 × 2 tablets/day for 8 weeks and the 2 × 1 tablet/day for another 8 weeks. Climacteric complaints were evaluated by means of the MRS mean score, and psychological complaints were evaluated using the Hamilton Depression Rating Scale sum score. The results of this investigation demonstrate a decrease in the mean (± standard deviation) of the MRS score by 50% (0.46 ± 0.13 to 0.23 ± 0.13) in the treatment group and 19.6% (0.46 ± 0.14 to 0.37 ± 0.15) in the placebo group. The Hamilton Depression Rating Scale total score was decreased by 41.8% in the treatment group (18.9 ± 2.2 to 11.0 ± 3.8 points) compared with 12.7% in the placebo group (18.9 ± 2.1 to 16.5 ± 4.3). The treatment was significantly (p <0.001) superior to placebo in both measures. There were no relevant group differences regarding adverse events, laboratory values or tolerability. The study concluded that a fixed combination of black cohosh and St. John's wort was superior to placebo in alleviating menopausal symptoms, including psychological sequalae [20]. This study appears to have a sound rationale for the product combination and the clinical methodology was performed according to the Guidelines on Good Clinical Practice.
Uncontrolled trials
Although results from uncontrolled trials are very limited by the high rate of placebo response, some of the investigations did provide statistical analysis of the data. In one uncontrolled study published in 2005, the subjective symptoms of menopause were investigated in 2016 Hungarian women, treated with an isopropanol extract of black cohosh (REM) [22]. The inclusion criteria were age 40–65 years, a Kupperman index of 20 or higher, and refusal or contraindication for estrogen therapy. The women took two REM tablets (40 mg of extract) daily on an empty stomach for 12 weeks. The severity of the symptoms was evaluated at the start of the study and at the end of 4, 8, and 12 weeks of treatment. The decrease in the Kupperman index was the greatest during the first 4 weeks of treatment. The average decrease in Kupperman index after 12 weeks of therapy was 17.64 points (p <0.001). Based on the weighted symptom scores, the most favorable changes were found in hot flashes (−6.31 points), sweating (−2.86 points), insomnia (−2.27 points), and anxiety (−2.00 points) (p <0.001 in each case). Thus, the results of this uncontrolled study support those of the randomized, controlled clinical trials suggesting that an isopropanol extract of black cohosh (REM) is effective for the management of menopausal symptoms [22].
Clinical trials involving breast cancer patients
Hot flashes cause significant morbidity in post-menopausal women, but also in women with breast cancer who have had a hysterectomy or are being treated with antiestrogens [24]. Tamoxifen, an estrogen antagonist, is used as adjuvant therapy for the treatment of breast cancer in women after total or segmental mastectomy and breast irradiation, in the treatment of women with advanced or metastatic disease, and as a preventative for women at high risk for breast cancer [24]. However, hot flushes are a well-known side effect of tamoxifen, and since HRT is not acceptable for these patients, alternative treatments are being actively sought. Since black cohosh does not appear to be estrogenic and does not stimulate the proliferation of breast cancer cells, it is a possible treatment for breast cancer survivors taking tamoxifen [25]. In 2003–2004, two clinical trials assessed the safety and efficacy of black cohosh products in women with a history of breast cancer [16,19]. The studies used either REM or CR BNO 1055 (Klimadynon/Menofem) products in conjunction with tamoxifen or raloxifene.
In 2004, one pilot study was published that assessed the efficacy of black cohosh in menopausal women, including those with breast cancer [19]. Women who reported significant hot flashes (≥14/week) were treated with a black cohosh extract (REM). The first week was a no-treatment baseline period, and then the women were treated with one tablet of REM (20 mg extract) daily for 4 weeks. Hot-flash data were collected by daily questionnaires during baseline and treatment weeks. Adverse effects were recorded. A total of 21 women completed the study, and the mean age was 56 years (range: 38–80 years). A total of 13 patients had a history of breast cancer, and six patients had been treated with tamoxifen or raloxifene as part of their breast cancer treatment. Patients reported an average of 8.3 hot flashes per day during the baseline week. The reduction in mean daily hot-flash frequency was 50% (95% confidence interval [CI]: 34–65%), while weekly hot flash scores were reduced 56% (95% CI: 40–71%) after 4 weeks of treatment. Overall, patients reported less trouble with sleeping, less fatigue and a reduction in abnormal sweating. No patient stopped therapy due to adverse effects [19]. While the authors concluded that the black cohosh extract was effective, the major issue was a lack or placebo or comparator drug.
A 2003 clinical trial assessed the effects of CR BNO 1055 in young premenopausal breast cancer survivors with hot flushes due to tamoxifen administration [16]. The study involved 136 breast cancer survivors aged 35–52 years. After treatment with segmental or total mastectomy, radiation therapy and adjuvant chemotherapy, participants were randomly assigned to receive tamoxifen 20 mg/day orally (n = 46) or tamoxifen (20 mg/day) and CR BNO 1055 (40 mg/day, n = 90) in an open-label study. Duration of treatment was 5 years for tamoxifen, according to international standards for adjuvant therapies, and 12 months for CR BNO 1055. Follow-up included clinical assessment every 2 months; the primary end point was to record the number and intensity of hot flushes. As compared with the usual-care group, those assigned to the tamoxifen/black cohosh group had a reduction in the number and severity of hot flushes. Almost half of the patients in the black cohosh group were free of hot flushes, while severe hot flushes were reported by 24.4% of patients in the intervention group and 73.9% of the usual-care group (p <0.01). The study concluded that combined administration of tamoxifen plus CR BNO 1055 for a period of 12 months reduced the number and severity of hot flushes. This study lasted for 12 months, with a large patient population and reports a statistical difference in both the number and severity of hot flashes [16]. Two caveats to this study are the lack of an adequate description of the data analysis and the reliance on subjective assessment of hot flashes by the patients.
Safety of black cohosh extracts
Estrogenic effects
It was previously thought that black cohosh extracts may reduce the symptoms of menopause through a mechanism that involves estrogen. However, reviews of the evidence from numerous in vitro and in vivo studies, including one clinical trial, do not support this hypothesis and an estrogenic mechanism of action for black cohosh does not appear plausible [12,25].
Adverse events
Safety data from previously published postmarketing surveillance studies, clinical trials and reviews have generally found very few serious adverse events associated with the ingestion of black cohosh products [12,25]. However, since 2003, a number of adverse events reports have been published causing concern about the safety profile of black cohosh [26,101].
Asthenia
One case of a woman with severe asthenia and very high blood levels of creatine phosphokinase and lactate dehydrogenase was published in 2006 [26]. The patient was using a black cohosh-containing dietary supplement for the management of menopausal hot flashes. After discontinuation of the product, the patient showed a progressive normalization of biochemical parameters and improvement of clinical symptoms. Factors suggesting an association between black cohosh and the observed myopathy included the temporal relationship between use of herbal product and asthenia and the absence of other identified causative factors. Re-challenge with the product was not performed for obvious ethical reasons and the potential for serious relapse. This is the only report of black cohosh-associated asthenia that has been published.
Hepatotoxicity
Since 2002, at least 50 cases of hepatotoxicity associated with the administration of black cohosh extracts, have been reported to various drug regulatory agencies throughout the world, including acute hepatitis and fulmanent hepatic failure [101]. Only a handful of these cases have been published [27–31]. In a report by Whiting and colleagues, a woman was taking a black cohosh product for 2 weeks and then developed symptoms of jaundice, with an elevated bilirubin and aminotranferase levels [27]. Histological examination confirmed severe hepatitis and multiacinar dropout. The patient eventually progressed into fulminant liver failure, but was fortunate enough to receive a liver transplant [27]. In the second published case, Lontos and colleagues reported a causal relationship between the ingestion of a product containing black cohosh and acute hepatic failure [28]. The patient was taking a product that, in addition to black cohosh, also contained ground ivy, which is known to contain pulegone, a hepatotoxin. In the third report, a case of autoimmune hepatitis (AIH) was reported in a 57-year-old woman [29]. The subject had used black cohosh for 3 weeks prior to the incident and other causes had been ruled out. Unfortunately, the product that was used during the incident was of unknown brand or dose.
Thus, a direct connection between hepatotoxicity in this case and black cohosh cannot be easily made. In 2005, Levitsky and colleagues reported a case of fulminant liver failure in a 50-year-old Caucasian female [31]. The provisional diagnosis was AIH and the patient was treated with steroids, but the patient eventually progressed into fulminant liver failure and underwent orthotopic liver transplantation [31].
In 2006, the Australian Therapeutic Goods Administration (TGA) ruled that herbal medicines sold in Australia containing black cohosh should be labeled with the following statement: “Warning: Black cohosh may harm the liver in some individuals. Use under the supervision of a healthcare professional” [101]. New Australian products containing black cohosh must comply with this requirement from the time of manufacture. Existing products will have a 12-month phase-in period to allow adequate time to comply with the new labeling requirements. This decision was published on February 9, 2006 on the Australian TGA website [101]. The TGA based this decision on a review of 47 cases of liver injury in women around the world, including nine Australian cases (according to the TGA that total has risen now to 11 cases from February 2006, for a global total of at least 50 cases). The TGA review indicated that although many cases were poorly documented and confounded by multiple ingredients, by multiple medications, or by other medical conditions, “there is sufficient evidence of a causal association between black cohosh and serious hepatitis” [101].
The sheer numbers of case reports of hepatotoxicity that are currently associated with black cohosh ingestion are disturbing [3]. Black cohosh has been used in over 5800 patients in human studies and clinical trials with a low incidence of adverse events, and no reports of alterations in liver enzymes or hepatotoxic effects. Unfortunately, the details of many of the individual case reports are inadequately described and these reports have come under severe criticism for a lack of verification of the plant materials used, insufficient exclusion of other causes of hepatotoxicity and the lack of a plausible mechanism [30]. The lack of important details in many of the case reports has made it extremely difficult to assess a direct association of black cohosh with the adverse hepatotoxic events. However, the number of case reports of hepatotoxicity continues to grow and the similarities between some of the cases, particularly with reference to AIH, suggests that there is cause for concern for specific patient populations.
AIH has an estimated prevalence of 17 cases/100,000 people, and in some cases, may be triggered by chemical or nutritional components [32,33]. Drug-induced AIH is suspected in cases where other pathologies such as active liver disease or viral hepatitis, as well as alcohol or drug abuse, have been ruled out [29,31]. In the Cohen and colleagues report, the International Autoimmune Hepatitis Group diagnostic score was 18, indicating ‘definite’ AIH [31]. The woman also developed a strongly positive antinuclear antibody titer, and the liver biopsy revealed features of both autoimmune and drug-induced hepatitis [31]. None of her other medications were implicated as triggers for AIH. The women also responded rapidly to steroid therapy, another indication that an autoimmune response was involved. Further research is urgently needed to determine the mechanisms of black cohosh-induced hepatotoxicity and AIH.
Conclusion
Black cohosh has been used historically as a herbal remedy and is currently advocated as an alternative therapy for menopausal symptoms. A review of the recently published randomized clinical trials suggests that treatment with a standardized black cohosh extract may be of some benefit for the management of menopausal symptoms, and further indicates that 40 mg of a black cohosh extract/day is sufficient for symptom reduction. Women using black cohosh products at the recommended dose should discontinue use of these production if no reduction in symptoms is observed within 4–6 weeks and seek other therapeutic options.
Executive summary
By the year 2030, it is estimated that there will be more than 60 million postmenopausal women in the USA and 1.2 billion postmenopausal women worldwide.
Women are actively seeking alternative approaches, including botanical therapies such as black cohosh (Actaea racemosa), to manage their menopausal symptoms.
Extracts of black cohosh have been marketed worldwide for the management of menopausal symptoms.
Prior to 2003, there were at least 25 published studies supporting the use of black cohosh for the treatment of various gynecological ailments and for the management of symptoms such as anxiety, hot flushes, profuse sweating, insomnia and vaginal atrophy.
Since 2003, nine clinical studies have been published, with all but one supporting the use of black cohosh to manage menopausal symptoms.
In one pilot study, treatment of breast cancer survivors with a black cohosh product reduced the mean daily hot flash frequency by 50% and patients reported less trouble with sleeping, less fatigue and a reduction in abnormal sweating.
In another study of women with hot flashes due to tamoxifen administration, comparisons of the usual-care group with the tamoxifen/black cohosh group showed a reduction in the number and severity of hot flushes in those patients treated with black cohosh.
Since 2003, more than 50 cases of hepatotoxicity are purported to have been associated with the ingestion of black cohosh.
Many of the case reports of hepatotoxicity are complicated by other medications, poor case description and other disease states that may contribute to the liver toxicity.
However, there is sufficient evidence of a causal association between black cohosh and some cases of serious hepatitis.
It appears prudent to advise menopausal women with underlying liver disease, autoimmune diseases, or those taking medications that may impact liver function not to use products containing black cohosh until this issue has been scientifically investigated.
Black cohosh products appear to be effective for the treatment of vasomotor symptoms related to menopause; however, the increasing adverse-event profile may put into question its risk:benefit ratio.
Preclinical assessment of black cohosh is now urgently needed.
On a serious note, the number of purported cases of autoimmune or drug-induced hepatotoxicity associated with the ingestion of black cohosh has escalated to more than 50 worldwide. While many of the cases were poorly described and the occurrence appears to be rare considering the millions of doses of black cohosh sold/year, there are now a sufficient number of cases to cause concern. Reports of hepatotoxicity due to black cohosh ingestion should be thoroughly investigated and preclinical toxicological studies are needed to try to address this serious issue. In the meantime, it appears prudent to advise menopausal women with underlying liver disease, autoimmune diseases, or taking medications that may impact liver function not to use products containing black cohosh until this issue has been scientifically investigated.
Future perspective
Currently, the future of black cohosh may be in question due to the increasing number of cases of hepatotoxicity. Since black cohosh appears to be one of the only herbal supplements, to date, that may have some efficacy for menopause, it is critical that preclinical testing be performed to identify any safety issues that need to be addressed. If these investigations are not performed over the next 5 years and the number of hepatotoxic events associated with the ingestion of black cohosh continues to increase, it will only be a matter of time before the drug regulatory agencies call for warnings or possible withdrawal of these products from the market, as occurred with kava products.
Footnotes
Acknowledgement
This publication was made possible by grant number AT 02381 from the National Center for Complementary and Alternative Medicine, National Institute of Health. The contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Center for Complementary and Alternative Medicine or National Institute of Health.