OVERVIEW

CASE REPORTS

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Black Cohosh – Generic

DRUG CLASS

Herbal and Dietary Supplements

SUMMARY INFORMATION

Fact Sheet at National Center for Complementary and Integrative Health, NIH

Fact Sheet at Office of Dietary Supplements, NIH

CHEMICAL FORMULA AND STRUCTURE

CITED REFERENCES

1.

Lontos S, Jones RM, Angus PW, Gow PJ. Acute liver failure associated with the use of herbal preparations containing black cohosh. Med J Aust. 2003;179:390–1. [PubMed: 14503910]

2.

Lynch CR, Folkers ME, Hutson WR. Fulminant hepatic failure associated with the use of black cohosh: a case report. Liver Transpl. 2006;12:989–92. [PubMed: 16721764]

3.

Pierard S, Coche JC, Lanthier P, Dekoninck X, Lanthier N, Rahier J, Geubel AP. Severe hepatitis associated with the use of black cohosh: a report of two cases and an advice for caution. Eur J Gastroenterol Hepatol 2009; 21: 941-5. (Modified from case 2.) [PubMed: 19404202]

ANNOTATED BIBLIOGRAPHY

References updated: 04 November 2020

• Zimmerman HJ. Unconventional drugs. Miscellaneous drugs and diagnostic chemicals. In, Zimmerman, HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott,1999: pp. 731-4.

  (Expert review of hepatotoxicity published in 1999; black cohosh is not discussed).
• Seeff L, Stickel F, Navarro VJ. Hepatotoxicity of herbals and dietary supplements. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, pp. 631-58.

  (Review of hepatotoxicity of herbal and dietary supplements [HDS]; black cohosh is mentioned as having been linked to cases of acute hepatitis, acute liver failure and autoimmune hepatitis, the mechanism of injury being unknown and the actual relationship to black cohosh being controversial).
• Black cohosh. In, PDR for Herbal Medicines. 4th ed. Montvale, New Jersey: Thomson Healthcare Inc. 2007: pp. 95-100.

  (Compilation of short monographs on herbal medications and dietary supplements).
• Lieberman S. A review of the effectiveness of Cimicifuga racemosa (black cohosh) for the symptoms of menopause. J Womens Health. 1998;7:525–9. [PubMed: 9650153]

  (History of the development of black cohosh and series of open label and controlled trials showing its efficacy in decreasing symptoms of menopause).
• American College of Obstetricians and Gynecologists Committee on Practice Bulletins–Gynecology. Clinical management guidelines for obstetrician-gynecologists: use of botanicals for management of menopausal symptoms. Obstet Gynecol. 2001;97:1–11. [PubMed: 11501568]

  (Review of evidence of benefit of various botanicals for menopausal symptoms: “Black cohosh may be helpful in the short-term treatment of women with vasomotor symptoms”).
• Whiting PW, Clouston A, Kerlin P. Black cohosh and other herbal remedies associated with acute hepatitis. Med J Aust. 2002;177:440–3. [PubMed: 12381254]

  (6 cases of severe hepatitis in patients taking herbal medications, including 1 on black cohosh alone and 5 taking multiple herbals including skullcap [n=3], valerian [n=2], chaparral [n=1] and greater celandine [n=1] for 1-14 weeks, presenting with jaundice [bilirubin 9.9-62.7 mg/dL, ALT 1293-3764 U/L, Alk P 80-219 U/L], the 1 on black cohosh alone requiring emergency liver transplantation, the other 5 resolving in 7-25 weeks, 3 treated with prednisone for prolonged cholestasis).
• Vitetta L, Thomsen M, Sali A. Black cohosh and other herbal remedies associated with acute hepatitis. Med J Aust. 2003;178:411–2. [PubMed: 12697018]

  (Letter in response to Whiting [2002] suggesting that hepatitis may have been due to a contaminant and without verification, the link to black cohosh cannot be made).
• Thomsen M, Schmidt M. Hepatotoxicity from Cimicifuga racemosa? Recent Australian case report not sufficiently substantiated. J Altern Complement Med. 2003;9(3):337–40. [PubMed: 12816621]

  (Authors argue that case series of Whiting [2002] lacked essential information such as analytic verification of components and was weakened by insufficient exclusion of other causes, implausible mechanism of injury, overrating of dangers of herbals and lack of previous reports of hepatotoxicity in multiple prospective studies).
• Lontos S, Jones RM, Angus PW, Gow PJ. Acute liver failure associated with the use of herbal preparations containing black cohosh. Med J Aust. 2003;179:390–1. [PubMed: 14503910]

  (52 year old woman developed jaundice 3 months after starting an herbal mixture including black cohosh [bilirubin 21.5 mg/dL, ALT 1380 U/L, Alk P 230 U/L, INR 3.0], with progressive hepatic failure and liver transplantation 1 month later: Case 1).
• Pittler MH, Ernest E. Systematic review: hepatotoxic events associated with herbal medicinal products. Aliment Pharmacol Ther. 2003;18:451–71. [PubMed: 12950418]

  (Systematic review of published cases of hepatotoxicity due to herbal medications listing 52 case reports or case series, most common agents being celandine [3], chaparral [3], germander [8], Jin Bu Huan [3], kava [1], Ma Huang [3], pennyroyal [1], skullcap [2], Chinese herbs [9], valerian [1]).
• Estes JD, Stolpman D, Olyaei A, Corless CL, Ham JM, Schwartz JM, Orloff SL. High prevalence of potentially hepatotoxic herbal supplement use in patients with fulminant hepatic failure. Arch Surg. 2003;138:852–8. [PubMed: 12912743]

  (Among 20 patients undergoing liver transplantation for acute liver failure during 2001-2, 10 were potentially caused by herbals; none were attributed to black cohosh).
• Thomsen M, Vitetta L, Sali A, Schmidt M. Acute liver failure associated with the use of herbal preparations containing black cohosh. Med J Aust. 2004;180:598–9. [PubMed: 15175000]

  (Authors challenge the relationship between black cohosh and liver injury [Lontos 2003] on the basis that the herbal mixture also contained group ivy which has pulegone and that black cohosh has “a very good safety record”).
• Cumming FJ, Kelly L. Acute liver failure associated with the use of herbal preparations containing black cohosh. Med J Aust. 2004;180:599–600. Author reply. [PubMed: 15175000]

  (Reply to letter [Thomsen 2004] by the Office of Complementary Medicines indicating that the herbal product was analyzed and pulegone levels were below the level of detection).
• Cohen SM, O’Connor AM, Hart J, Merel NH, Te HS. Autoimmune hepatitis associated with the use of black cohosh: a case study. Menopause. 2004;11:575–7. [PubMed: 15356412]

  (57 year old woman developed fatigue 3 weeks after starting black cohosh for hot flashes [bilirubin normal, ALT 1220 U/L, Alk P minor elevations], with ANA 1:640 and liver biopsy suggesting autoimmune hepatitis, resolving with prednisone therapy and relapsing with stopping [bilirubin 9.2 mg/dL, ALT 1694 U/L]).
• National Center for Complementary and Integrative Health, NIH. Workshop on safety of black cohosh in clinical studies. November 22, 2004. Available at: http://nccih​.nih.gov​/news/events/blackcohosh​/blackcohosh_mtngsumm.pdf.

  (Workshop on black cohosh and its association with liver injury including two case reports from Australia: 47 year old woman developed acute liver failure 3 weeks after starting black cohosh for menopausal symptoms [bilirubin 32 mg/dL, ALK 1276 U/L, Alk P 153 U/L, INR 5.0], leading to emergency liver transplant and explant showing massive necrosis [Whiting 2002]; 52 year old woman developed acute liver failure presenting 1 month after taking a 3 month course of black cohosh [bilirubin 20 mg/dL, ALT 1380 U/L, Alk P 230 U/L, INR 3.0], undergoing liver transplant and explant showing massive necrosis).
• Australian Therapeutic Goods Administration Statement. New labelling requirements and consumer information for medicines containing Black cohosh(Cimicifuga racemosa). 2006. Available at: http://www​.tga.gov.au​/safety/alerts-medicine-black-cohosh-070529.htm.

  (Labeling requirements for black cohosh from the Therapeutic Goods Administration of Australia: “Warning: Black cohosh may harm the liver in some individuals”).
• Huntley A. The safety of black cohosh(Actaea racemosa, Cimicifuga racemosa). Expert Opin Drug Saf. 2004;3:615–23. [PubMed: 15500420]

  (Review of experimental animal and human studies of black cohosh focusing upon mechanism of action, clinical efficacy and adverse events; in human trials few adverse events were reported and no liver side effects were encountered; in spontaneous reporting systems worldwide there have been 8 reports of liver and biliary adverse events).
• Levitsky J, Alli TA, Wisecarver J, Sorrell MF. Fulminant liver failure associated with the use of black cohosh. Dig Dis Sci. 2005;50:538–9. [PubMed: 15810638]

  (50 year old woman developed jaundice 5 months after starting black cohosh [500 mg daily] for menopausal symptoms [bilirubin 7.6 g/dL, ALT 1474 U/L, Alk P 232 U/L, INR 2.5], with subsequent worsening despite prednisone therapy leading to liver transplantation 5 weeks after first presentation).
• Low Dog T. Menopause: a review of botanical dietary supplements. Am J Med. 2005;118 Suppl 12B:98–108. [PubMed: 16414334]

  (Systematic review of 19 controlled trials found evidence that black cohosh is beneficial for relief of menopause related symptoms, but recommendations are tempered by methodologic problems with the published trials, questions about its mechanism of action, and 4 recent reports of severe liver injury suspected to be due to black cohosh).
• Lynch CR, Folkers ME, Hutson WR. Fulminant hepatic failure associated with the use of black cohosh: a case report. Liver Transpl. 2006;12:989–92. [PubMed: 16721764]

  (54 year old woman developed fatigue 6 months after starting black cohosh [1 g daily] and jaundice in next 2 months [bilirubin 2.4 mg/dL, ALT 1003 U/L, Alk P 266 U/L, INR 1.4], with subsequent worsening leading to liver transplantation; explant showed shrunken liver with marked centrilobular necrosis and regenerative nodules: Case 2).
• Dugoua JJ, Seely D, Perri D, Koren G, Mills E. Safety and efficacy of black cohosh (Cimicifuga racemosa) during pregnancy and lactation. Can J Clin Pharmacol. 2006;13:e257–e261. [PubMed: 17085773]

  (Systematic review of literature on efficacy and safety of black cohosh during pregnancy concluded that it should be used with caution; no mention of hepatotoxicity).
• Nisbet BC, O’Connor RE. Black cohosh-induced hepatitis. Del Med J. 2007;79:441–4. [PubMed: 18203607]

  (50 year old woman developed abdominal pain 2 weeks after starting black cohosh [40 mg/day] for menopausal symptoms [bilirubin 1.1 mg/dL, ALT 691 U/L, Alk P 117 U/L], with rapid resolution on stopping).
• Newton KM, Reed SD, LaCroix AZ, Grothaus LC, Erlich K, Guiltinan J. Treatment of vasomotor symptoms of menopause with black cohosh, multibotanicals, soy, hormone therapy, or placebo. Ann Intern Med. 2006;145:869–79. [PubMed: 17179056]

  (Controlled trial of black cohosh [160 mg/day], vs a multibotanical with black cohosh, vs a multibotanical with dietary soy, vs estrogen vs placebo in 351 women with vasomotor symptoms attributed to menopause found no difference between herbals and placebo in improving symptoms or in rates of adverse events; no hepatotoxicity or ALT results reported).
• Briese V, Stammwitz U, Friede M, Henneicke-von Sapelin HH. Black cohosh with or without St. John’s wort for symptom-specific climacteric treatment–results of a large-scale, controlled, observational study. Maturitas. 2007;57:405–14. [PubMed: 17590291]

  (Open label observation study of 6141 women receiving either black cohosh alone or combined with St. John’s wort for menopausal symptoms showed similar improvements with either treatment; only 2.2% developed adverse events and there were no case of liver dysfunction reported, but laboratory data were not collected).
• Gori L, Firenzuoli F. Is black cohosh a hepatotoxic medicinal herb? Forsch Komplementmed. 2007;14:109–10. [PubMed: 17464162]

  (The European Medicines Agency [EMEA] announced that 42 cases of liver injury attributed to black cohosh have been reported; however, authors argue that many cases were poorly documented and the possibility of contamination and other comorbidities raise issue of whether black cohosh was the cause; concluding that black cohosh hepatotoxicity is probably rare).
• Herbal Medicinal Products Committee, European Medicines Agency. Assessment of case reports connected to herbal medicinal products containing Cimicifugae racemosae rhizoma (black cohosh, root). 2007. Available at: http://www​.ema.europa​.eu/docs/en_GB/document_library​/Herbal_-​_HMPC_assessment_report​/2010/02/WC500074167.pdf.

  (Assessment of reported cases of black cohosh hepatotoxicity by the Committee on Herbal Medicinal Products of the European Medicines Agency using the RUCAM scoring system, concluded that most cases were inadequately documented and only 3 could be considered possible and 2 probable).
• Seeff LB. Herbal hepatotoxicity. Clin Liver Dis. 2007;11:577–96. [PubMed: 17723921]

  (Review of HDS associated hepatotoxicity, with review of the literature including 4 reports of hepatic injury due to black cohosh).
• Dunbar K, Solga AF. Black cohosh, safety, and public awareness. Liver International. 2007;27:1017–8. [PubMed: 17696943]

  (41 year old woman developed fatigue 2 weeks after starting black cohosh and developed progressive jaundice, ascites and hepatic encephalopathy leading to transfer to a transplant center [bilirubin 13.1 mg/dL, ALT 393 U/L, INR 2.0], undergoing liver transplant 2.5 months after onset).
• Walji R, Boon H, Guns E, Oneschuk D, Younus J. Black cohosh (Cimicifuga racemosa [L.] Nutt.): safety and efficacy for cancer patients. Support Care Cancer. 2007;15:913–21. [PubMed: 17602247]

  (Systematic review of literature of safety and efficacy of black cohosh in patients with cancer concluded that evidence for benefit as well as for liver toxicity was “inconclusive”).
• Teschke R. Questions regarding causality in presumed black cohosh hepatotoxicity. Del Med J. 2008;80:233–4. [PubMed: 18714667]

  (Letter in response to Nisbet [2006] suggesting that symptoms predated time of starting black cohosh and that other diagnoses were not adequately excluded; reply by authors stating that symptoms arose soon after starting black cohosh and that other diagnoses were either excluded or highly unlikely).
• Joy D, Joy J, Duane P. Black cohosh: a cause of abnormal postmenopausal liver function tests. Climacteric. 2008;11:84–8. [PubMed: 18202968]

  (Two cases: 50 year old woman developed headaches and mild AST [53-70 U/L] and GGT [213-571 U/L] elevations on black cohosh, which resolved on stopping; 51 year old woman developed abdominal pain and liver test abnormalities [bilirubin normal, ALT 722 U/L, Alk P 226 U/L] after taking black cohosh for 2 months, values normalizing within 2 weeks of stopping).
• Chow EC, Teo M, Ring JA, Chen JW. Liver failure associated with the use of black cohosh for menopausal symptoms. Med J Aust. 2008;188:420–2. [PubMed: 18393750]

  (51 year old woman developed fatigue followed by jaundice 3 years after starting intermittent doses of black cohosh [20 mg daily], [bilirubin 6.2 mg/dL, ALT 1230 U/L, Alk P 191 U/L, INR 1.8], with progressive liver failure leading to liver transplantation; explant showed massive necrosis and collapse).
• Borrelli F, Ernst E. Black cohosh (Cimicifuga racemosa) for menopausal symptoms: a systematic review of its efficacy. Pharmacol Res. 2008;58:8–14. [PubMed: 18585461]

  (Systematic review of six randomized placebo controlled trials of black cohosh in women with menopausal symptoms found no consistency in support of beneficial effects, but that such an effect could not be excluded; no discussion of adverse events).
• Mahady GB, Low Dog T, Barrett ML, Chavez ML, Gardiner P, Ko R, Marles RJ, et al. United States Pharmacopeia review of the black cohosh case reports of hepatotoxicity. Menopause. 2008;15:628–38. [PubMed: 18340277]

  (Expert committee review of case reports of hepatotoxicity related to black cohosh from all possible sources found 30 separate reports, but on analysis none were considered “certain” or even “probable”, which, nevertheless, led to recommendation that black cohosh be labeled with a cautionary statement regarding liver injury).
• García-Cortés M, Borraz Y, Lucena MI, Peláez G, Salmerón J, Diago M, Martínez-Sierra MC, et al. Rev Esp Enferm Dig. 2008;100:688–95. [Liver injury induced by “natural remedies”: an analysis of cases submitted to the Spanish Liver Toxicity Registry] Spanish. [PubMed: 19159172]

  (Among 521 cases of drug induced liver injury submitted to Spanish registry, 13 [2%] were due to herbals, none were attributed to black cohosh).
• Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, Yang H, Rochon J., Drug Induced Liver Injury Network (DILIN). Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology. 2008;135:1924–34. [PMC free article: PMC3654244] [PubMed: 18955056]

  (Among 300 cases of drug induced liver disease in the US collected between 2004 and 2008, 9% of cases were attributed to herbal medications or dietary supplements, but none were attributed to black cohosh).
• Pierard S, Coche JC, Lanthier P, Dekoninck X, Lanthier N, Rahier J, Geubel AP. Severe hepatitis associated with the use of black cohosh: a report of two cases and an advice for caution. Eur J Gastroenterol Hepatol. 2009;21:941–5. [PubMed: 19404202]

  (Two cases with histological features of chronic hepatitis during black cohosh therapy for menopausal symptoms: 62 year old woman developed abdominal pain 3 months after starting black cohosh [bilirubin normal, ALT 322 U/L, GGT 320 U/L, ANA 1:320], with resolution upon stopping [transient worsening when given prednisolone and azathioprine]; 58 year old woman developed fatigue sometime after starting black cohosh for menopausal symptoms [bilirubin normal, ALT 318 U/L, GGT 95 U/L], with persistence of abnormalities on continuing and rapid improvement upon stopping black cohosh: Case 3).
• Naser B, Liske E., Teschke R. Liver failure associated with the use of black cohosh for menopausal symptoms. Med J Aust. 2009;190:99–100. [PubMed: 19278034]

  (Two letters in response to Chow [2008] raising the issue of alcohol as a cause of the liver injury and the possibility of other causes such as herpes simplex, adenovirus and Wilson disease; reply by authors stating that these etiologies were unlikely).
• Teschke R. A U.S. review determined that black cohosh products should be labeled with a cautionary statement. Menopause. 2009;16:214–author reply 214-5. [PubMed: 19131847]

  (Letter in response to Mahady [2008] questioning the use of the Naranjo rather than the RUCAM scale in assessing causality in cases of black cohosh hepatotoxicity; authors reply stating that the causality assessment was done by expert consensus opinion and the Naranjo scale was used only as an aid).
• Teschke R, Schwarzenboeck A. Suspected hepatotoxicity by Cimicifugae racemosae rhizoma (black cohosh, root): critical analysis and structured causality assessment. Phytomedicine. 2009;16:72–84. [PubMed: 19010650]

  (Among 42 reports of severe hepatotoxicity received by the European Medicine Agency, only 4 were considered as possible or probable; application of RUCAM to these 4 cases by the author yielded scores in the “excluded” range [-1 to -3], largely because of other possible diagnoses [autoimmune hepatitis, herpes] and other drugs used).
• Teschke R, Bahre R, Fuchs J, Wolff A. Black cohosh hepatotoxicity: quantitative causality evaluation in nine suspected cases. Menopause. 2009;16:956–65. [PubMed: 19339903]

  (Analysis of 9 cases of suspected black cohosh hepatotoxicity using RUCAM suggested that none could be considered even possibly related, largely because of competing diagnoses, other medications being taken and lack of information on course and outcome).
• Navarro VJ. Herbal and dietary supplement hepatotoxicity. Semin Liver Dis. 2009;29:373–82. [PubMed: 19826971]

  (Review of the problems of causality assessment in herbal and dietary supplement [HDS] associated liver disease, including the variable clinical presentations, the complexity and lack of information on their components, absence of controlled trials demonstrating safety and efficacy, the possibility of contamination or incorrect labeling and frequent underreporting of herbal use by patients. Black cohosh is discussed as a potential cause of severe acute hepatitis).
• Vannacci A, Lapi F, Gallo E, Vietri M, Toti M, Menniti-Ippolito F, Raschetti R, et al. A case of hepatitis associated with long-term use of Cimicifuga racemosa. Altern Ther Health Med. 2009;15:62–3. [PubMed: 19472866]

  (37 year old woman developed jaundice 6-8 months after starting black cohosh for menopausal symptoms [bilirubin 1.5 mg/dL, ALT 20 times ULN, GGT slightly increased], with persistent ALT abnormalities until use of the herbal was admitted, resolution occurring within 1 month of stopping).
• Guzman G, Kallwitz ER, Wojewoda C, Chennuri R, Berkes J, Layden TJ, Cotler SJ. Liver injury with features mimicking autoimmune hepatitis following the use of black cohosh. Case Rep Med. 2009;2009:918156. [PMC free article: PMC2814377] [PubMed: 20130783]

  (Two women, ages 42 and 53, developed fatigue 6 and 8 months after starting black cohosh for menopausal symptoms [bilirubin 3.1 and 2.0 mg/dL, ALT 1457 and 443 U/L, Alk P 94 and 188 U/L, ANA 1:20-1:40], biopsy showing changes suggestive of chronic hepatitis and both responding to corticosteroids).
• Mahady G, Low Dog T, Sarma DN, Giancaspro GI. Suspected black cohosh hepatotoxicity—causality assessment versus safety signal. Maturitas. 2009;64:139–40. [PubMed: 19781876]

  (Letter in response to Teschke [2009] mentioning that there have been 82 reports of hepatotoxicity attributed to black cohosh and that a product warning is warranted).
• Betz JM, Anderson L, Avigan MI, Barnes J, Farnsworth NR, Gerden B, Henderson L, et al. Black Cohosh: considerations of safety and benefit. Nutrition Today. 2009;44:155–62.

  (Summary of a 2007 NIH workshop on the safety of black cohosh and making recommendations for future research and analysis).
• Jacobsson I, Jönsson AK, Gerdén B, Hägg S. Spontaneously reported adverse reactions in association with complementary and alternative medicine substances in Sweden. Pharmacoepidemiol Drug Saf. 2009;18:1039–47. [PubMed: 19650152]

  (Review of 778 spontaneous adverse event reports of herbals to the Swedish Registry includes 38 [5%] related to black cohosh, including 3 related to enzyme elevations and 3 various hepatic reactions).
• Barnes J. Black cohosh (black snakeroot, Cimicifuga racemosa (L.) Nutt., Actaea racemosa L.). J Prim Health Care. 2010;2:79–80. [PubMed: 20690409]

  (Review mentions that a systematic review conducted in 2007 of 6 controlled trials of black cohosh extracts in 1112 women found evidence of efficacy to be "uncertain" and several spontaneous reports of hepatotoxicity have been published).
• Reuben A, Koch DG, Lee WM., Acute Liver Failure Study Group. Drug-induced acute liver failure: results of a U.S. multicenter, prospective study. Hepatology. 2010;52:2065–76. [PMC free article: PMC3992250] [PubMed: 20949552]

  (Among 1198 patients with acute liver failure enrolled in a US prospective study between 1998 and 2007, 133 [11%] were attributed to drug induced liver injury of which 12 [9%] were due to herbals, 1 to black cohosh).
• Teschke R. Black cohosh and suspected hepatotoxicity: inconsistencies, confounding variables, and prospective use of a diagnostic causality algorithm. A critical review. Menopause. 2010;17:426–40. [PubMed: 20216279]

  (Author performed a reanalysis of 69 cases of suspected liver injury from black cohosh using RUCAM and concluded that 27 were excluded, 21 unlikely, 8 unrelated, 12 unassessable, and only 1 possibly related).
• Mahady G, Low Dog T, Sarma ND, Giancaspro GI, Griffiths J. The causal relationship between the use of black cohosh-containing products and hepatotoxicity. Menopause. 2010;17:1088–9. [PubMed: 20827114]

  (Letter in response to Teschke [2010] arguing that the modified RUCAM he used made most cases unassessable and that several groups have agreed that black cohosh has a "signal of safety concern"; author replies addressing the need of an improved causality instrument).
• Painter D, Perwaiz S, Murty M. Black cohosh products and liver toxicity: update. Can Adverse Reaction Newsl. 2010;20:1–2.

  (Among 4 cases of suspected black cohosh hepatotoxicity reported to Health Canada, analysis of retrieved samples showed that none contained authentic black cohosh, but had phytochemical profiles consistent with presence of other related herbal species).
• Firenzuoli F, Gori L, Roberti di Sarsina P. Black Cohosh Hepatic Safety: Follow-Up of 107 patients consuming a special Cimicifuga racemosa rhizome herbal extract and review of literature. Evid Based Complement Alternat Med. 2011;2011:821392. [PMC free article: PMC3110476] [PubMed: 21660145]

  (Among 107 women treated with black cohosh extract for at least one year, none had clinical or biochemical evidence of liver injury).
• Jiang B, Ma C, Motley T, Kronenberg F, Kennelly EJ. Phytochemical fingerprinting to thwart black cohosh adulteration: a 15 Actaea species analysis. Phytochem Anal. 2011;22:339–51. [PubMed: 21337649]

  (Analysis of 15 Actaea species by HPLC and LC-MS methods showed a characteristic pattern of polyphenols and triterpene glycosides in Actaea racemosa extracts; a specific marker compound [cimifugin] was found in most other species, but not racemosa [black cohosh]).
• Naser B, Schnitker J, Minkin MJ, de Arriba SG, Nolte KU, Osmers R. Suspected black cohosh hepatotoxicity: no evidence by meta-analysis of randomized controlled clinical trials for isopropanolic black cohosh extract. Menopause. 2011;18:366–75. [PubMed: 21228727]

  (Metaanalysis of 5 randomized controlled trials of black cohosh [Remifemin] found no significant changes in mean ALT, AST or GGT levels among black cohosh and placebo recipients; among 7 patients who developed significant rises in liver tests during therapy, none were judged to be related to black cohosh therapy).
• Teschke R, Schmidt-Taenzer W, Wolff A. Spontaneous reports of assumed herbal hepatotoxicity by black cohosh: is the liver-unspecific Naranjo scale precise enough to ascertain causality? Pharmacoepidemiol Drug Saf. 2011;20:567–82. [PubMed: 21702069]

  (2 cases of suspected black cohosh hepatotoxicity were evaluated by the RUCAM and Naranjo causality scales: scores ranged from -2 to +2 by RUCAM [none even possible] and -1 to +2 by Naranjo [6 possible]).
• Teschke R, Schwarzenboeck A, Schmidt-Taenzer W, Wolff A, Hennermann KH. Herb induced liver injury presumably caused by black cohosh: a survey of initially purported cases and herbal quality specifications. Ann Hepatol. 2011;10:249–59. [PubMed: 21677326]

  (Review of problems of causality assessment in cases of liver injury attributed to herbal medications focusing upon black cohosh).
• Mahady G, Low Dog T, Sarma ND, Griffiths J, Giancaspro GI. Response to Teschke et al. Pharmacoepidemiol Drug Saf. 2012;21:339–40. [PubMed: 22407603]

  (Letter in response to Teschke [2011] arguing that the calculation of RUCAM scores was based upon the author's modifications of the scoring system that resulted in all cases being unlikely or excluded).
• Wang YJ, Dou J, Cross KP, Valerio LG Jr. Computational analysis for hepatic safety signals of constituents present in botanical extracts widely used by women in the United States for treatment of menopausal symptoms. Regul Toxicol Pharmacol. 2011;59:111–24. [PubMed: 20920542]

  (Computer analyses of chemical structures of compounds found in botanicals used to treat menopausal symptoms identified several predicted to cause hepatic injury, including protocatechuic acid in black cohosh).
• Teschke R, Wolff A, Frenzel C, Schulze J, Eickhoff A. Herbal hepatotoxicity: a tabular compilation of reported cases. Liver Int. 2012;32:1543–56. [PubMed: 22928722]

  (A systematic compilation of all publications on the hepatotoxicity of specific herbals identified 185 publications on 60 different herbs, herbal drugs and supplements, but neither black cohosh or Cimicifuga racemosa are listed).
• Bunchorntavakul C, Reddy KR. Review article: herbal and dietary supplement hepatotoxicity. Aliment Pharmacol Ther. 2013;37:3–17. [PubMed: 23121117]

  (Systematic review of the literature on HDS associated hepatotoxicity mentions that black cohosh has been implicated in causing liver injury in at least 6 publications).
• Björnsson ES, Bergmann OM, Björnsson HK, Kvaran RB, Olafsson S. Incidence, presentation and outcomes in patients with drug-induced liver injury in the general population of Iceland. Gastroenterology. 2013;144:1419–25. [PubMed: 23419359]

  (In a population based study of drug induced liver injury from Iceland, 96 cases were identified over a 2 year period [2010-12], including 15 attributed to herbals or dietary supplements, but none specifically to black cohosh).
• Navarro VJ, Seeff LB. Liver injury induced by herbal complementary and alternative medicine. Clin Liver Dis. 2013;17:715–35. [PubMed: 24099027]

  (Review of herbal hepatotoxicity including discussion of black cohosh, which has been linked to liver injury ranging from asymptomatic increases in ALT levels to acute liver failure and hepatitis with autoimmune features).
• Abdualmjid RJ, Sergi C. Hepatotoxic botanicals - an evidence-based systematic review. J Pharm Pharm Sci. 2013;16:376–404. [PubMed: 24021288]

  (Extensive review of the hepatotoxicity of botanicals mentions the main active constituents of black cohosh are terpene glycosides and discusses 3 case reports of serious liver injury from its use).
• Lim TY, Considine A, Quaglia A, Shawcross DL. Subacute liver failure secondary to black cohosh leading to liver transplantation. BMJ Case Rep. 2013;2013:cr2013009325. pii. [PMC free article: PMC3736182] [PubMed: 23833086]

  (60 year old woman developed jaundice 2 weeks after starting black cohosh for menopausal symptoms [bilirubin 27.7 mg/dL, AST 2385 U/L, Alk P 151 U/L, INR 1.57], with progressive worsening requiring liver transplantation 3 weeks later).
• Enbom ET, Le MD, Oesterich L, Rutgers J, French SW. Mechanism of hepatotoxicity due to black cohosh (Cimicifuga racemosa): Histological, immunohistochemical and electron microscopy analysis of two liver biopsies with clinical correlation. Exp Mol Pathol. 2014;96:279–83. [PubMed: 24657312]

  (Two women, ages 65 and 55 years, developed jaundice while taking black cohosh preparations for an unknown period [peak bilirubin 6.6 and 5.4 mg/dL, ALT 92 and 2061 U/L, Alk P 368 and 156 U/L], resolving within 3 months of stopping).
• Cimicifuga: liver transplantation. Prescrire Int. 2013;22:73. [PubMed: 23593697]

  (Brief report that the UK Drug Regulatory Agency has received 36 spontaneous reports of hepatic injury due to black cohosh and one instance of severe hepatitis requiring liver transplantation).
• Teschke R, Schulze J, Schwarzenboeck A, Eickhoff A, Frenzel C. Herbal hepatotoxicity: suspected cases assessed for alternative causes. Eur J Gastroenterol Hepatol. 2013;25:1093–8. [PubMed: 23510966]

  (Review of 23 case series of herb induced liver disease found alternative possible diagnoses for 278 of 573 cases including 58 of 94 cases [62%] attributed to black cohosh).
• Masada-Atsumi S, Kumeta Y, Takahashi Y, Hakamatsuka T, Goda Y. Evaluation of the botanical origin of black cohosh products by genetic and chemical analyses. Biol Pharm Bull. 2014;37:454–60. [PubMed: 24583864]

  (Testing of commercial black cohost products from the US and Europe by DNA fingerprinting found that half were derived from Cimicifuga dahurica rather than C. racemosa and liquid chromatography followed by tandem mass spectroscopy showed that one third of products were contaminated with plant species other than C. racemosa).
• Muqeet Adnan M, Khan M, Hashmi S, Hamza M, Abdul Mujeeb S, Amer S. Black cohosh and liver toxicity: is there a relationship? Case Rep Gastrointest Med. 2014;2014:860614. [PMC free article: PMC4100270] [PubMed: 25093128]

  (44 year old woman developed jaundice one month after starting black cohosh for menopausal symptoms [bilirubin 20 mg/dL, ALT 215 U/L, Alk P 201 U/L, INR 1.2], resolving within 3 months of stopping the herbal product).
• Navarro VJ, Barnhart H, Bonkovsky HL, Davern T, Fontana RJ, Grant L, Reddy KR, et al. Liver injury from herbals and dietary supplements in the U.S. Drug-Induced Liver Injury Network. Hepatology. 2014;60:1399–408. [PMC free article: PMC4293199] [PubMed: 25043597]

  (Among 85 cases of HDS associated liver injury [not due to anabolic steroids] enrolled in a US prospective study between 2004 and 2013, one was attributed to a product containing black cohosh: remifemin).
• Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al. United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN Prospective Study. Gastroenterology. 2015;148:1340–52.e7. [PMC free article: PMC4446235] [PubMed: 25754159]

  (Among 899 cases of drug induced liver injury enrolled in a prospective database between 2004 and 2012, HDS were implicated in 145 [16%], one of which was attributed to Remifemin, a product advertised as helpful for menopausal symptoms that contains black cohosh [Navarro et al. Hepatology 2014]).
• Ulbricht C, Windsor RC. An evidence-based systematic review of black cohosh(Cimicifuga racemosa, Actaea racemosa) by the Natural Standard Research Collaboration. J Diet Suppl. 2015;12:265–358. [PubMed: 25153652]

  (A 357 page “evidence-based” review of the safety and efficacy of black cohosh states: “Case reports have indicated that in certain individuals, hepatic failure is possible”).
• Tanmahasamut P, Vichinsartvichai P, Rattanachaiyanont M, Techatraisak K, Dangrat C, Sardod P. Cimicifuga racemosa extract for relieving menopausal symptoms: a randomized controlled trial. Climacteric. 2015;18:79–85. [PubMed: 24941138]

  (Among 54 women with menopausal symptoms treated with black cohosh [40 mg daily] or placebo for 12 weeks, symptoms improved in both groups to a similar extent, there were no serious adverse events, and serum mean ALT and AST levels did not change appreciably).
• García-Cortés M, Robles-Díaz M, Ortega-Alonso A, Medina-Caliz I, Andrade RJ. Hepatotoxicity by dietary supplements: A tabular listing and clinical characteristics. Int J Mol Sci. 2016;17:537. [PMC free article: PMC4848993] [PubMed: 27070596]

  (Listing of published cases of liver injury from HDS products, does not list publications on black cohosh or Cimicifuga species).
• Brown AC. An overview of herb and dietary supplement efficacy, safety and government regulations in the United States with suggested improvements. Part 1 of 5 series. Food Chem Toxicol 2017; 107(Pt A): 449-71. [PubMed: 27818322]

  (Summary of the US regulations on safety and efficacy of herbal and dietary supplements).
• Brown AC. Liver toxicity related to herbs and dietary supplements: Online table of case reports. Part 2 of 5 series. Food Chem Toxicol 2017; 107(Pt A): 472-501. [PubMed: 27402097]

  (Description of an online compendium of cases of liver toxicity attributed to HDS products, lists 16 publications implicating black cohosh [Actaea racemose] in liver injury, including hepatitis, hepatic failure and deaths).
• Franco DL, Kale S, Lam-Himlin DM, Harrison ME. Black cohosh hepatotoxicity with autoimmune hepatitis presentation. Case Rep Gastroenterol. 2017;11:23–28. [PMC free article: PMC5301124] [PubMed: 28203134]

  (69 year old woman developed abdominal pain followed by dark urine and jaundice 3 weeks after starting black cohosh [150 mg daily] for menopausal symptoms [bilirubin 6.3 mg/dL, ALT 2385 U/L, Alk P 296 U/L, INR 1.0, ANA and SMA positive], with rapid improvement on stopping the herbal product and initiation of prednisone and azathioprine which were stopped 3 and 6 months later, with normal liver tests thereafter).
• Svedlund E, Larsson M, Hägerkvist R. Spontaneously reported adverse reactions for herbal medicinal products and natural remedies in Sweden 2007-15: report from the Medical Products Agency. Drugs Real World Outcomes. 2017;4:119–25. [PMC free article: PMC5457307] [PubMed: 28353157]

  (A total of 116 spontaneous reports of adverse reactions to herbal products were received by a Swedish registry between 2007 and 2015, including 15 related to black cohosh, 5 of which were considered “severe” and all 5 were related to liver injury; details were not provided).
• Guo Y, Yin T, Wang X, Zhang F, Pan G, Lv H, Wang X, et al. Traditional uses, phytochemistry, pharmacology and toxicology of the genus Cimicifuga: A review. J Ethnopharmacol. 2017;209:264–82. [PubMed: 28826891]

  (Extensive review of the botanical characteristics, traditional medical uses, phytochemistry, quality control and potential mechanisms of action of the genus Cimicifuga which includes at least 28 species, that are widely distributed, C. racemose in the Americans and C. dahurica, foetida and hercleifolia in Asia, the bioactive components are believed to be the triterpene glycosides which constitute 2-6% of the herbal extracts isolated largely from dried rhizomes; mentions that hepatotoxicity is a possible adverse event associated with its use).
• Gao L, Zheng T, Xue W, Wang Y, Deng Y, Zuo H, Sun A. Efficacy and safety evaluation of Cimicifuga foetida extract in menopausal women. Climacteric. 2018;21:69–74. [PubMed: 29198157]

  (Among 96 postmenopausal women treated with either one of two fixed combinations of estrogen and progesterone or with C. foetida extract daily for 24 months, improvements in menopausal symptoms were similar across groups and there were no serious adverse events and no differences in serum ALT levels in the three groups during treatment).
• Hoban CL, Byard RW, Musgrave IF. Analysis of spontaneous adverse drug reactions to echinacea, valerian, black cohosh and ginkgo in Australia from 2000 to 2015. J Integr Med. 2019;17:338–43. [PubMed: 31113761]

  (Among spontaneous adverse drug events reported to the Australian Therapeutic Goods Administration between 2000 and 2015, 35 were attributed to black cohosh, all in women, ages 51 to 75 years, and 13 were liver related; no details provided).