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Pharmacist’s Guide to Black Cohosh for MenopauseByun, Connie; Park, Justin; Reese, Kimberly; Ricks, Jennifer; Thompson, Meghan; Walls, Amanda

Virginia Commonwealth University School of Pharmacy, 410 N 12th Street, Richmond, VA 23223

Acute hepatitis was reported in one patient taking 40mg black cohosh every day for two weeks, and another patient developed autoimmune hepatitis after using black cohosh for three weeks (Micromedex).

Evidence was found in the literature to indicate black cohosh as a agent that potientially causes hepatotoxicity. One patient that was taking 1000mg of black cohosh every day for eight months experienced hepatic failure. Two patients experienced elevated liver enzymes and mild liver toxicity after taking black cohosh for the treatment of menopausal symptoms, and upon discontinuation of black cohosh, their liver function normalized. One patient developed jaundice and required a liver transplant after taking black cohosh for one week (Micromedex).

A study of 629 patients taking black cohosh resulted in 7% complaining of GI upset, nausea, and vomiting (Micromedex).

Animal tests in rabbits and cats showed hypotension as a side effect of black cohosh administration, although hypotension was not observed in dogs. Vasodilatation was observed after black cohosh administration in dogs (Micromedex).Black cohosh is contraindicated in pregnancy because it’s estrogenic activity could interfere with maintenance of the pregnancy (Micromedex).

Chung, Da-Jung, et al. (2007). Black Cohosh and St. John’s Wort (GYNO-Plus) for Climacteric Symptoms. Yonsei Medical Journal, 48(2): 289-294.

Greenfield, Jackie. Black Cohosh (Actaea racemosa L.). NC State University: Horticulture Information Leaflets. September 2006. Kupferer, Elizabeth M. ; Dormire, Sharon L. ; and Becker , Heather. (2009). Complementary and Alternative Medicine Use for Vasomotor Symptoms Among Women Who Have Discontinued Hormone Therapy. JOGNN, 38: 50-59. Micromedex. Black Cohosh. Alternative Medicine Database. Thomson Reuters. April 2008.

Miller, Heather; Liu, Qui Ying (2004). Overview of Black Cohosh. NCCAM. Pockaj , Barbara A. (2006). Phase III Double-Blind, Randomized, Placebo-Controlled Crossove Trial of Black Cohosh in the Management of Hot Flashes: NCCTG Trial N01CC1. J Clin Oncol 24: 2836-2841. Qiu, Samuel X et al. (2007). A Triterpene Glycoside from Black Cohosh that Inhibits Osteoclastogenesis by Modulating RANKL and TNFα Signaling Pathways. Chemistry and Biology. 14( 7): 860-869. Rhyu, Mee-Ra; Lu, Jian; Webster, Donna E. ; Fabricant, Daniel S.; Farnsworth, Norman R.; and Wang, Z. Jim. Black cohosh (Actaea racemosa, Cimicifuga racemosa) behaves as a mixed competitive ligand and partial agonist at the human mu opiate receptor (2006). J Agric Food Chem. 54(26): 9852–9857. Shams, T., Setia, M., Hemmings, R., McCusker, J., Sewitch, M., & Ciampi, A. (2010). EFFICACY OF BLACK COHOSH-CONTAINING PREPARATIONS ON MENOPAUSAL SYMPTOMS: A META-ANALYSIS. Alternative Therapies in Health & Medicine, 16(1): 36-44.

References

Adverse Effects

Marketing and Regulation

Pharmacology

Pharmacokinetics, Pharmacodynamics, and SafetyAbstractBlack cohosh is a popular alternative medicine indicated for the treatment of

menopausal symptoms. There is conflicting data about its efficacy to relieve hot flashes, anxiety, and depression associated with menopause. Further study is warranted to determine safety and efficacy, due to its popularity among women experiencing climacteric symptoms. A literature search for black cohosh and its effects in regards to the treatment of menopausal symptoms was conducted and important information is summarized in the following poster with the aim of increasing pharmacists’ knowledge and ability to serve patients taking this remedy. Although black cohosh was found to be relatively safe and possibly effective, a patient seeking a herbal remedy for menopausal symptoms must be appropriately counseled on how to take the medication. Above all, pharmacists should be aware that patients may be taking this popular herbal remedy and be diligent in asking questions so as to prevent any drug-herbal interactions and improve patient safety.

Introduction

Figure 1. Black Cohosh, flowering plant

Black Cohosh is a herbal medicine that has

been used for hormonal modulation and treatment of menopausal symptoms such as hot flashes, night sweats, sleep disruption, anxiety, and depression. Possible other indications include treatment of migraine and osteoporosis. It is derived from the Actaea racemosa (otherwise known as Cimicifuga racemosa) plant, commonly referred to as black bugbane, black

snakeroot, or fairy candle (Figure 1). The root and rhizomes (root stems) are dried and made into powder for use as the drug. Black cohosh is available as capsules, fluid extract, tablets, or tinctures and is administered orally. Use of Black cohosh is associated with several side effects, including: bradycardia, dizziness, headache, tremors, giddiness, hepatitis, hepatotoxcitity, nausea, vomiting, hypotension, and vasodilatation.

The key active ingredient is a triterpene glycoside, specifically 27-deoxyacteine, which black cohosh is supposed to contain no less than 0.4% of, and clinical studies have been based on administering one to two milligrams of this substance twice daily (Micromedex).While open-label trials demonstrated that black cohosh was effective at treating menopausal symptoms, small double-blind studies showed no effect, and therefore larger controlled trials are necessary to support its use. There is inconclusive data proving black cohosh’s ability to relieve migraine pain or prevent osteoporosis. Black cohosh is believed to work by acting as a selective estrogen-receptor modulator (SERM), but it is unclear whether it acts by agonist or antagonist effect.

Out of nine randomized, placebo controlled trials, six showed menopausal symptoms improving relative to the placebo group, suggesting claims made by black cohosh for relieving menopausal symptoms may in fact be valid (Shams). Consumers seem to believe in black cohosh’s efficacy, indicated by one study’s findings that black cohosh is second only to multivitamins and calcium among alternative medicines chosen by women. However, only about 50% reported the use of these herbal medications to their health care providers (Kupferer). Because there is data available to support its use, pharmacists must be aware and informed about this popular herbal remedy and be held responsible to advise patients appropriately on its use. A literature search for black cohosh and its effects in regards to the treatment of menopausal symptoms was conducted and important information is summarized in the following poster to increase pharmacist’s knowledge and ability to serve patients taking this remedy.

Results and DiscussionActive Ingredients

Other ingredients may contribute to black cohosh’s activity (Table 1). There have been instances where a natural product was isolated from black cohosh, for example another triterpenoid glycoside, 25-acetylcimigenol xylopyranoside, which was found to block osteoclastogenesis in vitro, attenuating TNFα-induced bone loss in vivo (Qui).

Ingredient Description/Suspected Activityferulic and isoferulic acid Antioxidant; free radical scavengermethylcytisine Alkaloid; binds nicotinic receptorsracemosin bitter taste; undetermined activityactein Glycosides (molecules containing sugars);

possible astringent, antibacterial propertiescimicfugosidescimigosidescimicifugin Resin; possible nervous system effects

Table 1. Other ingredients found in black cohosh and suspected biological activities.

Efficacy

A double-blind randomized study of 89 Korean women (77 at completion) that were experiencing climacteric symptoms of menopause was conducted by the treatment group (42 women) receiving a combination of black cohosh and St. John’s Wort, while the control group (35 women) received a placebo. The patients’ symptoms were evaluated after 4 weeks and 12 weeks of treatment using the Kupperman Index (KI) which assesses the severity of menopausal symptoms. (Higher KI scores correspond to increased severity of menopausal symptoms.) Patients were also evaluated separately for the severity of their hot flashes, higher scores indicating increased severity of hot flashes (Figure 2). The KI scores for patients receiving the black cohosh and St. John’s Wort were significantly lower than the Kupperman Index scores than those patients in the placebo control group. However, the patients’ hot flash scores were not significantly different (Chung).

Figure 2. Hot flush scores of patients receiving black cohosh in combination with St. Johns Wort and placebo (Chung).

Another study (double-blind, randomized, cross-over method) of 132 women in

which the use of estrogen to treat hot flashes was not desirable required patients to keep daily journals of their hot flashes for nine weeks. Patients in the placebo-control group reported a 27% decrease in their hot flash score, while patients in the treatment group reported a 20% decrease in the hot flash score (Figure 3). More patients preferred the placebo (38%) over the black cohosh treatment (34%). Reported toxicity of the two groups was not different (Pockaj).

Figure 3. Hot flash scores of plaecebo group and group taking black cohosh for 9 weeks (Pockaj).

In vitro trials have suggested black cohosh had an antagonistic effect on estrogen receptor-positive breast cancer cells. However, there is human data available to suggest agonist activity at estrogen receptors on osteoblast cells, leading to black cohosh’s possible ability to improve bone metabolism and formation (Micromedex).

A study showed that black cohosh extracts contained components that have an affinity to the human µ opiate receptor . The opiate system in the brain is linked to mood, temperature, and sex hormonal levels which are all related to menopause symptoms (Rhyu).









Conclusions

Black cohosh is an herbal remedy commonly used by patients for the treatment of menopause, particularly in the management of hot flashes. Clinical data and safety trials on the herbal remedy lead to mixed results. Studies performed for this medication are rarely controlled and parameters for measuring the extent of a hot flash or inducing a hot flash are difficult. For this reason, data that either supports or disproves the efficacy of black cohosh are unsubstantial.

Also, there are few studies which give long term safety data for black cohosh or information for special populations, including safety in pregnant women. For this reason, use of black cohosh in the treatment of menopause and hot flashes is controversial and should be considered on a patient to patient basis.

Beyond recommending black cohosh to a patient seeking a herbal remedy for menopausal symptoms and appropriately counseling the patient on how to take the medication, it is important for pharmacists to also convey to the patient the discrepancies in the data for efficacy and warn of the potential side effects. Above all, pharmacists should be aware that patients may be taking this popular herbal remedy for menopausal symptoms and be diligent in asking questions so as to avoid any drug-herbal interactions and improve patient safety.

As with many research results for black cohosh, the exact pharmacokinetics and pharmacodynamics of the product are unclear. As stated, the initial mechanism of action for black cohosh was proposed to be an interaction between the compound and the estrogen receptors (ERα and ERβ). However, it is now thought that black cohosh works to relieve menopausal symptoms in another manner. One of these may be that black cohosh works at an unknown estrogenic receptor or, as stated, a serotogenic receptor (Chung).

Safety data for black cohosh indicates that the product is generally well tolerated. Liver toxicity has been reported, but a number of the patients in these trials were also on other hepatotoxic medications. Use should be cautioned in patients with liver disease as well as those that may be pregnant or lactating (Chung). This product should only be used for short term treatments and patients should be advised to not use the product for longer than six months (Miller).

Black cohosh is an herbal medication of growing popularity for its reported treatment of menopausal symptoms. The most common black cohosh product is Remifemin ®, manufactured by Enzymatic Therapy. Research suggests that prices for the plant as well as demand vary from year to year. Since 2001, prices have ranged anywhere from $1.50 to $25.00 per pound for the harvested plant (Greenfield).

Figure 3. Table of Adverse Reactions. This shows the adverse reactions seen for patients taking black cohosh as well as how many patients experienced these symptoms based on the study done by Miller an d Liu (Miller).

black cohoshposter draft 2 (1)

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