Cimicifuga racemosa

Identification

Logo pink
Are you a
new drug developer?
Contact us to learn more about our customized products and solutions.
Name
Cimicifuga racemosa
Accession Number
DB13975
Type
Biotech
Groups
Approved, Experimental
Description

Black cohosh (Actaea racemosa or Cimicifuga racemosa), a member of the buttercup family, is a perennial plant which native to North America. Historical names for this plant include snakeroot, black bugbane, rattleweed, macrotys, and rheumatism weed. Black cohosh has a long history of use. Native Americans used it for its purported benefits in treating musculoskeletal pain, fever, cough, pneumonia, sluggish labor, and menstrual irregularities. European settlers were said to use black cohosh as a tonic to support female reproductive health 10.

Hormone replacement therapy (HRT) is the standard treatment for early symptoms in post-menopausal women, however, increases the risk of stroke, heart diseases, as well as breast cancer in older women. Various studies have shown that the number of post-menopausal women using hormone replacement therapy is currently low and that the effects of hormone replacement therapy in reducing menopausal symptoms are not as positive as expected. For these reasons, there has been a trend toward using alternative therapies to relieve menopausal symptoms 8.

Black cohosh has been associated with serious safety concerns 1. Results from studies suggest that C. racemosa possesses a central activity instead of a hormonal effect 2.

The American College of Obstetrics and Gynecology guidelines on the use of botanicals, such as black cohosh, for the management of menopausal symptoms the use of for up to six months, especially in treating the symptoms of sleep and mood disturbance, and hot flushes 12.

Synonyms
  • Black cohosh
  • Black snakeroot
  • Cimicifuga racemosa rhizome
  • Cimicifuga racemosa root
  • Cimicifuga racemosa root with rhizome
  • Cimicifugae rhizoma
  • Fairy candle root
  • Rattleroot
Over the Counter Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Black Cohosh Root PowderCapsule100 mgOralSwiss Herbal Remedies Ltd.1998-10-232006-07-25Canada
Black Cohosh TabletTablet40 mgOralPurity Life Health Products A Division Of Sunopta Inc.2002-06-012006-08-28Canada
Ethical Herbals Menstrual/menopause Symptom ReliefTablet75 mgOralAshbury Research CorporationNot applicableNot applicableCanada
Women's FormulaCapsule75.00 mgOralNatures Sunshine Products, Inc.1999-12-152009-08-07Canada
Additional Data Available
  • Application Number
    Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

    Learn more
  • Product Code
    Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

    Learn more
Categories
UNII
K73E24S6X9
CAS number
Not Available

Pharmacology

Indication

Treatment of menopausal symptoms and menstrual dysfunction 12.

Pharmacodynamics

This agent is purported to relieve some of the vasomotor symptoms of menopause, including hot flashes and night sweats 8, 10, 11.

A 2012 Cochrane review analyzed 16 randomized clinical trials on the effectiveness of black cohosh in reducing menopausal symptoms, including hot flushes, night sweats, vaginal dryness, and numerous combinations of symptoms which were measured by validated rating scales 8. There is currently insufficient evidence to support the use of black cohosh for menopausal symptoms 8. The studies were quite heterogeneous in design, duration, type and amount of black cohosh used, and main findings 8.

A 2016 systematic review and meta-analysis of randomized clinical trials analyzed four studies of herbal and plant-based therapies that included black cohosh to treat menopausal symptoms 5. It was suggested that composite and specific phytoestrogen supplementations were associated with small reductions in the incidence of hot flashes and vaginal dryness, however, no significant reduction in night sweats 5.

Mechanism of action

Although the mechanism by which black cohosh relieves menopausal symptoms is unknown, several hypotheses have been made. It is believed to act through the following mechanisms/effects 9:

1) as a selective estrogen receptor modulator 2) through serotonergic pathways 3) as an antioxidant 4) on inflammatory pathways

The primary active component of the black cohosh root is believed to be the terpene glycoside fraction, including actein and cimifugoside 9. The triterpenes are one of the most ubiquitous and diverse groups of plant natural products 13. They are classified as complex molecules that are beyond the reach of chemical synthesis in the laboratory. Simple triterpenes are constituents of surface waxes and specialized plant membranes and may possibly serve as signaling molecules. More complex glycosylated triterpenes (also known as saponins) provide protection against pathogens and pests 13. The rhizome (stem portion of the plant) also contains other potentially biologically active substances, including alkaloids, flavonoids, and tannins. The therapeutic activity of black cohosh was initially believed to be the activation of estrogen receptors; however, more recent studies show that although some components of the extract bind to at least one subtype of estrogen receptor, the receptor binding produces very little (if any) estrogenic effect, and may selectively block some of the effects 9.

An early study reported that treatment with black cohosh leads to a decrease in luteinizing hormone (LH) levels consistent with its purported estrogenic effect. Despite this, more recent studies have shown no effect on levels of LH, follicle-stimulating hormone (FSH), or prolactin. To this day it is unclear whether black cohosh exerts its effect via estrogen receptors or through another mechanism 12.

One study observed that while the most prominent triterpene in black cohosh, known as 23-epi-26-deoxyactein, inhibits cytokine-induced nitric oxide production in brain microglial cells, the complete black cohosh extract demonstrated to enhance this pathway 9. A variety of activities have been reported for black cohosh and its compounds, however, the absorption and tissue distribution of these compounds is not known 9.

Cimicifuga racemosa (black cohosh) is used most often to treat symptoms occurring during menopause. However, in recent years, several concerns regarding its safety have been voiced 1.

Absorption
Not Available
Volume of distribution
Not Available
Protein binding
Not Available
Metabolism
Not Available
Route of elimination
Not Available
Half life

Approximately 2h 7

Clearance
Not Available
Toxicity

The oral LD50 for rats is 17,000 to 27,211 mg/kg MSDS.

Clinical trials using a variety of black cohosh formulas to manage menopausal symptoms have shown that its use is associated with a low incidence of adverse effects. The most commonly reported side effects are gastrointestinal discomfort and rashes, both of which have shown to be mild and transient. Some other adverse effects in clinical trials have included breast pain or enlargement, infection, vaginal bleeding or spotting, and musculoskeletal discomfort. The incidence of these symptoms, however, was similar in women taking black cohosh and those taking a placebo 10.

Reports have been made globally of at least 83 cases of liver damage—including hepatitis, liver failure, elevated liver enzymes, and various other liver injuries—associated with black cohosh use. However, no evidence of a causal relationship exists. It is possible that a subset of reported cases of hepatotoxicity were due to impurities, adulterants, or incorrect Acteae species in the black cohosh products used. However, no independent analysis of these drugs has been done to confirm the existence of these problems 10.

The American Herbal Products Association recommends that pregnant women not ingest black cohosh, except under the supervision of their healthcare provider because studies have not thoroughly evaluated its use during pregnancy. The U.S. Pharmacopeia advises that individuals with liver disorders should also avoid the use of black cohosh. In addition, users who develop symptoms of liver disease, such as abdominal pain, dark urine, or jaundice, while taking the supplement should discontinue use and contact their healthcare provider 10.

As with other drugs believed to have potential estrogenic effects, there has been concern about the safety of black cohosh in women with a personal history or family history of breast cancer. Though further research is warranted, at least one tissue-culture study showed no stimulation of estrogen receptor-positive breast cancer cell lines by black cohosh extract 6. This study found that black cohosh extract amplified the inhibitory action of tamoxifen (Nolvadex) on breast cancer cell lines. Because this question has not yet been fully answered, physicians should discuss this issue with their patients who are at risk of breast cancer while considering taking black cohosh 12.

Black cohosh is contraindicated during pregnancy due to its potential ability to promote uterine contraction. The safety of black cohosh in breastfeeding mothers and the level of transmission of black cohosh in breast milk are both unknown 12.

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe serum concentration of (R)-warfarin can be increased when it is combined with Cimicifuga racemosa.
(S)-WarfarinThe serum concentration of (S)-Warfarin can be increased when it is combined with Cimicifuga racemosa.
3,5-diiodothyropropionic acidThe metabolism of 3,5-diiodothyropropionic acid can be decreased when combined with Cimicifuga racemosa.
4-hydroxycoumarinThe metabolism of 4-hydroxycoumarin can be decreased when combined with Cimicifuga racemosa.
4-MethoxyamphetamineThe metabolism of 4-Methoxyamphetamine can be decreased when combined with Cimicifuga racemosa.
5-androstenedioneThe metabolism of 5-androstenedione can be decreased when combined with Cimicifuga racemosa.
6-O-benzylguanineThe metabolism of 6-O-benzylguanine can be decreased when combined with Cimicifuga racemosa.
7-ethyl-10-hydroxycamptothecinThe metabolism of 7-ethyl-10-hydroxycamptothecin can be decreased when combined with Cimicifuga racemosa.
8-azaguanineThe metabolism of 8-azaguanine can be decreased when combined with Cimicifuga racemosa.
8-chlorotheophyllineThe metabolism of 8-chlorotheophylline can be decreased when combined with Cimicifuga racemosa.
Additional Data Available
  • Extended Description
    Extended Description

    Extended description of the mechanism of action and particular properties of each drug interaction.

    Learn more
  • Severity
    Severity

    A severity rating for each drug interaction, from minor to major.

    Learn more
  • Evidence Level
    Evidence Level

    A rating for the strength of the evidence supporting each drug interaction.

    Learn more
  • Action
    Action

    An effect category for each drug interaction. Know how this interaction affects the subject drug.

    Learn more
Food Interactions
Not Available

References

General References
  1. Borrelli F, Ernst E: Black cohosh (Cimicifuga racemosa): a systematic review of adverse events. Am J Obstet Gynecol. 2008 Nov;199(5):455-66. doi: 10.1016/j.ajog.2008.05.007. [PubMed:18984078]
  2. Borrelli F, Izzo AA, Ernst E: Pharmacological effects of Cimicifuga racemosa. Life Sci. 2003 Jul 25;73(10):1215-29. [PubMed:12850238]
  3. Mohammad-Alizadeh-Charandabi S, Shahnazi M, Nahaee J, Bayatipayan S: Efficacy of black cohosh (Cimicifuga racemosa L.) in treating early symptoms of menopause: a randomized clinical trial. Chin Med. 2013 Nov 1;8(1):20. doi: 10.1186/1749-8546-8-20. [PubMed:24499633]
  4. Fritz H, Seely D, McGowan J, Skidmore B, Fernandes R, Kennedy DA, Cooley K, Wong R, Sagar S, Balneaves LG, Fergusson D: Black cohosh and breast cancer: a systematic review. Integr Cancer Ther. 2014 Jan;13(1):12-29. doi: 10.1177/1534735413477191. Epub 2013 Feb 25. [PubMed:23439657]
  5. Franco OH, Chowdhury R, Troup J, Voortman T, Kunutsor S, Kavousi M, Oliver-Williams C, Muka T: Use of Plant-Based Therapies and Menopausal Symptoms: A Systematic Review and Meta-analysis. JAMA. 2016 Jun 21;315(23):2554-63. doi: 10.1001/jama.2016.8012. [PubMed:27327802]
  6. McKenna DJ, Jones K, Humphrey S, Hughes K: Black cohosh: efficacy, safety, and use in clinical and preclinical applications. Altern Ther Health Med. 2001 May-Jun;7(3):93-100. [PubMed:11347288]
  7. van Breemen RB, Liang W, Banuvar S, Shulman LP, Pang Y, Tao Y, Nikolic D, Krock KM, Fabricant DS, Chen SN, Hedayat S, Bolton JL, Pauli GF, Piersen CE, Krause EC, Geller SE, Farnsworth NR: Pharmacokinetics of 23-epi-26-deoxyactein in women after oral administration of a standardized extract of black cohosh. Clin Pharmacol Ther. 2010 Feb;87(2):219-25. doi: 10.1038/clpt.2009.251. Epub 2009 Dec 23. [PubMed:20032972]
  8. Efficacy of black cohosh (Cimicifuga racemosa L.) in treating early symptoms of menopause: a randomized clinical trial [Link]
  9. Black Cohosh: Insights into its Mechanism(s) of Action [Link]
  10. Black Cohosh [Link]
  11. Treatment of Vasomotor Symptoms of Menopause with Black Cohosh, Multibotanicals, Soy, Hormone Therapy, or Placebo [Link]
  12. Black Cohosh [Link]
  13. Triterpene Biosynthesis in Plants [Link]
  14. Isolation of CYP3A4 Inhibitors from the Black Cohosh (Cimicifuga racemosa) [Link]
  15. Cytochrome P450 enzyme mediated herbal drug interactions (Part 2) [Link]
External Links
Wikipedia
Actaea_racemosa
ATC Codes
G02CX04 — Cimicifugae rhizoma
AHFS Codes
  • 92:01.00* — Herbs and Natural Products
MSDS
Download (57.3 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentMenopause1
1TerminatedTreatmentMenopausal Hot Flushes1
2CompletedTreatmentEffect of Drugs / Safety Issues1
2CompletedTreatmentMenopausal Hot Flushes / Menopause1
2CompletedTreatmentMenopausal Hot Flushes / One to five years postmenopausal / Postmenopausal Osteoporosis (PMO)1
2WithdrawnTreatmentMenopausal Hot Flushes1
3Unknown StatusTreatmentMenopausal Hot Flushes1
4RecruitingTreatmentSexuality1
4Unknown StatusTreatmentVasomotor Symptoms Associated With Menopause1
Not AvailableCompletedTreatmentMenopausal Hot Flushes / Menopause1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
CapsuleOral100 mg
TabletOral40 mg
TabletOral75 mg
CapsuleOral75.00 mg
Prices
Not Available
Patents
Not Available

Properties

State
Liquid
Experimental Properties
PropertyValueSource
boiling point (°C)290MSDS

Taxonomy

Classification
Not classified

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inhibitor
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Isolation of CYP3A4 Inhibitors from the Black Cohosh (Cimicifuga racemosa) [Link]
Kind
Protein
Organism
Rat
Pharmacological action
No
Actions
Inhibitor
Inducer
General Function
Testosterone 6-beta-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
Cyp3a2
Uniprot ID
P05183
Uniprot Name
Cytochrome P450 3A2
Molecular Weight
57731.215 Da
References
  1. Cytochrome P450 enzyme mediated herbal drug interactions (Part 2) [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inhibitor
General Function
Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP1A2
Uniprot ID
P05177
Uniprot Name
Cytochrome P450 1A2
Molecular Weight
58293.76 Da
References
  1. Yokotani K, Chiba T, Sato Y, Nakanishi T, Murata M, Umegaki K: [Effect of three herbal extracts on cytochrome P450 and possibility of interaction with drugs]. Shokuhin Eiseigaku Zasshi. 2013;54(1):56-64. [PubMed:23470874]
  2. Gurley BJ, Gardner SF, Hubbard MA, Williams DK, Gentry WB, Khan IA, Shah A: In vivo effects of goldenseal, kava kava, black cohosh, and valerian on human cytochrome P450 1A2, 2D6, 2E1, and 3A4/5 phenotypes. Clin Pharmacol Ther. 2005 May;77(5):415-26. doi: 10.1016/j.clpt.2005.01.009. [PubMed:15900287]
  3. Cytochrome P450 enzyme mediated herbal drug interactions (Part 2) [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inhibitor
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2C9
Uniprot ID
P11712
Uniprot Name
Cytochrome P450 2C9
Molecular Weight
55627.365 Da
References
  1. Cytochrome P450 enzyme mediated herbal drug interactions (Part 2) [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inhibitor
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic...
Gene Name
CYP2D6
Uniprot ID
P10635
Uniprot Name
Cytochrome P450 2D6
Molecular Weight
55768.94 Da
References
  1. Cytochrome P450 enzyme mediated herbal drug interactions (Part 2) [Link]

Drug created on January 17, 2018 16:01 / Updated on July 15, 2019 21:46