Black Cohosh

Black Cohosh is the colloquial term for the plant Actaea racemosa, also referred to as Cimicifuga racemosa. The supplement contains the dried rhizomes of the plant, and the plant itself is a coarse woodland perennial herb with a thick, knotted root system and growing up to 1-2.5m in height with compound, pinnate leaves up to 7cm in length. The plant is native to North America, spreading from Canada to Georgia.^[1] There are a 28 plants in the Actaea genus, of which 8 grow in North America and 5 along the Eastern side (of which Black Cohosh is one of those five).^[2] Some versions of the Actaea genus grow in China, and are given the name Shengma; these have traditionally usage for anti-inflammatory conditions, but should not be treated like Black Cohosh.^[2]

Black Cohosh has a variety of names such as bugbane or bugwort, blackroot or black snakeroot, or names associated with rattlesnakes (rattle root, rattle weed, rattlesnack root, rattletop).^[1] It has been reported to have been used traditionally by certain Native American tribes (Penobscot, Winnebago, Dakota) for the treatment of coughs, colds, constipation, fatigue and rheumatism, as well as to increase breast milk production^[3] and tinctures have been reported to have been used for the treatment of pain and inflammation associated with endometriosis, rheumatism, neuralgia and dysmenorrhea as far back as 1832.^[3][4]

As a herbal product, Black Cohosh contains a variety of bioactive compounds such as:

• Cycloartanol compounds such as acteol and actein, cimigenol and cimicifugoside; these tend to be seen as the active ingredients and are sometimes referred to simply as triterpene glycosides. There are about 50 of them.^{[5][6][7][8][9][10]}
• Flavonoids such as Formononectin
• (E)-isoferulic acid
• Dopargine, a derivative of dopamine^[11]
• Cimipronidine methyl ester and Cyclo-Cimipronidine^[11]
• Salsolinol^[11]
• N(omega)-methylserotonin^[12]

The root is said to have a slightly bitter taste to it.

Black Cohosh does not appear to affect P-Glycoprotein and modify the kinetics of drugs subject to P-gp.^[13] There is a statistically significant inhibition of CYP2D6 associated with Black Cohosh supplementation over 28 days, but the clinical relevance of it is minor as the enzyme function was inhibited 7.0%.^[14] No effect on the CYP2D6 enzyme has been seen over 14 days in another study.^[15]

Direct estrogenic action of Black Cohosh, both ethanolic and isopropanolic extracts, is not found when looking in vitro.^[16]Effects attributed to estrogen, such as increasing circulating prostacyclin and IL-6 levels from HUVEC cells, are not seen with Black Cohosh supplementation^[17] nor is an increase in breast density^[18] or uterine weight/thickness,^[19] two results attributed to estrogen treatment.

Studies that investigate circulating estradiol concentrations in the blood fail to find significant differences.^{[17][20][21][22]} Due to these results, Black Cohosh is typically seen as non-estrogenic and does not increase circulating estrogen levels.

Studies regarding breast cancer note that Black Cohosh may exert an anti-estrogenic effect, assessed via suppressing proliferation of estrogen-responsive breast cancer cells.^[23][24] Proliferation in these cells was inhibited at a concentration of 1ug/mL, and gene expression overall was suppressed at 100-1000ug/mL.^[16]

When looking at isolated compounds in Black Cohosh, the main four triterpenoids compounds (cimiracemoside A, 25-O-methyl-cimigenoside, actein, nor 26-deoxy-actein) fail to increase estrogen levels.^[25]

Does not actually possess estrogenic activity nor does it increase circulating estrogen levels. It may be anti-estrogenic as assessed by studies in breast cancer cell lines

In a study on Japanese Medaka (fish used as a research model), it was found that Black Cohosh was able to reduce circulating testosterone via testicular release.^[25] However, this effect was not seen after a single injection into male mice.^[26]

Not enough evidence to draw any conclusions

Acute supplementation of Black Cohosh in rats has been shown to suppress LH secretion after an injection of 62.5mg Isopropanolic extract (rather unpractical dose, orally).^[19]

12 weeks supplementation with 40mg isopropanolic extract Black Cohosh was found to not significantly influence Luteinizing Hormone secretion in post-menopausal women.^[21] This parallels a year-long study with Black Cohosh in post menopausal women that, even after double-blind, there were no influences on circulating LH.^[22]

Long term human studies suggest no practically relevant suppression of luteinizing hormone associated with Black Cohosh supplementation

Black Cohosh has been found to have no significant influences on FSH in health post-menopausal women.^[22]

About seven primary studies have been put forth at this moment in time showing Black Cohosh to be effective in reducing vasomotor symptoms (hot flashes, night sweats) associated with menopause (with a literature extending beyond a dozen studies).^{[27][28][29][30][31][20][32]} A meta-analysis has also been conducted with the inclusion criteria of 40-60 year old healthy peri-menopausal women, excluding studies on breast cancer, studies not in english, and studies without placebo controls (thus, only accepting double blind) and reviewed 9 studies while performing a meta-analysis on 7.^[33] Overall, symptoms improved by 26% (Confidence Interval of 11-40%) and this information was derived from a Forest Plot, but the trials were highly hetereogeneous. This conclusion is in accordance with previous literature reviews (but not meta-analysis') on the interactions of Black Cohosh and Vasomotor symptoms.^[34][35]

As mentioned in this study,^[36] the above studies that mention benefit associated with Black Cohosh tend to be under 3 months in duration and more often than not measure vasomotor symptoms via self-report rather than using empirical measures. Two studies were not blinded, and the placebo effect has been demonstrated to play a significant role in menopausal symptoms (up to 50% reduction in vasomotor symptoms^[37][33]).

In fact, one 12 month long blinded study comparing black cohosh to placebo found insignificant differences between the two^[38] and a double-blinded crossover study with 4 week testing periods failed to find any difference between placebo and Black Cohosh (with a dosage of up to 40mg, an extract similar to Remifemin).^[39] These two studies, due to a lack of confounds and lack of industry funding, are arguably of higher quality relative to other studies in Black Cohosh literature.

Of the double blinded studies mentioned in the meta-analysis, three has industry funding.^[40][41][42] The two studies excluded from meta-analysis due to lack of ability to analyze them both showed positive results.^[32][31] Five studies, although blinded, did not analyze Black Cohosh in isolation and either investigated the combination with St.John's Wort^[40][41] or a multi-botanical approach.^[42][43][44]

Overall, there appears to be a slight trend towards beneficial effects on hot flashes and night sweats associated with Black Cohosh. There is a large amount of studies showing this benefit, but many are unblinded (on a topic where the placebo effect can confer tons of benefit) and the double blind studies are many times confounded with other supplements (making it hard to attribute the benefit to Black Cohosh).

In a rat model of menopause, it has been demonstrated that although Black Cohosh was effective in reducing the abnormalities in thermoregulation associated with ovariectomization it's efficacy was delayed, taking longer to come into effect.^[45]

In post-menopausal rats, spiking the food with Black Cohosh is able to reduce a 53.7% bone loss over time to 38.7%.^[19] Beneficial trends are seen in humans as well in regards to bone metabolism when measuring urinary markers or when measuring alkaline phosphatase,^[31][46][47] but the only human trial to measure Bone Mineral Density found no effects of Black Cohosh Intervention.^[48]

Black Cohosh has been demonstrated to reduce menopausal symptoms during concomitant treatment with Tamoxifen with good tolerability.^[49]

Some rat studies note a passive decrease in food intake in foods spiked with Black Cohosh.^[50]

Acutely, Black Cohosh appears to activate human mu-opioid receptors with an EC₅₀ of 68.8+/-7.7 microg/mL, and can displace other ligands on the receptor.^[51]

Over a period of 12 weeks, Black Cohosh appears to increase binding activity for mu-opiod receptors in a variety of brain regions after ingestion of 40mg isopropanolic extract daily (Remifemin), ranging from 10% in the Nuclear Accumbens to a 61% increase in the posterior cingulate.^[21] This can potentially increase the effects of opioids in vivo.

Serotonin was investigated for Black Cohosh as the system is related to thermoregulation, and it was found that a component of Black Cohosh known as N(omega)-Methylserotonin was able to activate a serotonin receptor (5-HT7) and act as an SSRI, with a receptor binding IC₅₀ of 23pM and SSRI IC₅₀ of 490nM.^[12] The triterpenoid structures were found to not be active agonists of this receptor.

Remifemin is a proprietary blend of Black Cohosh. Served in tablets, each tablet contains 0.018–0.026mL liquid extract of black cohosh rootstock that varies in concentration from 6-11:1. This correlates to about 20mg active drug per capsule, or 2.5mg dry weight Black Cohosh (with a 40% vol/vol isopropanol extraction) per capsule.^[18][52] Remifemin aims to deliver 1mg triterpenoid glycosides per capsule.

BNO 1055 is a patented extract of Black Cohosh used in some research studies. It is an aqueous/ethanolic extract of the plant's rhizomes. The extraction is a process with five times the amount of 50% m/m/water/ethanol for 48 h with a percolation speed of 500 kg/h.^[50] After filtration the extract was concentrated in vacuum and evaporated to dryness at 100–140 mbar according to a patent protected process.^[53]

St.John's Wort is a herbal anti-depressant with the active compound of Hypericin and the botanical name of Hypericum perforatum; it is usually paired with Black Cohosh as St.John's Wort is also shown to decrease menopausal symptoms in pilot studies.^[54]

An isopropanolic extract of Black Cohosh paired with St.John's Wort has shown efficacy in reducing symptoms of menopause and also depression simultenaously in a double blind study^[40] and in reducing symptoms of hot flashes while simultaneously increasing HDL relative to control (but not baseline); this latter study was funded by the makers of the tested nutrient formulation, however.^[41]

The only study to compare Black Cohosh against the combination was an unblinded but controlled study, and found the combination to be superior but not synergistically so.^[55]

Both compounds seem to be complementary towards the same goals, but have not yet been shown to 'work together' or be synergistic

When looking at vaginal bleeding in postmenopausal women, one large scaled (yet unblinded) study noted no instances of vaginal bleeding in 90 women assigned to take 40mg of Remifemin daily.^[56]

A study on 400 women measuring endometrial thickness via biopsy after 52 weeks of supplementation with the BNO 1055 extract of Black Cohosh failed to show any increases in endometrial thickness or vaginal hyperplasia despite being able to reduce hot flashes.^[57]

No significant adverse effects related to menopause or estrogen have been reported with Black Cohosh supplementation, although an increase of breast tenderness and swelling has been noted in some studies

According to one review, at least 50 isolated cases associated with Black Cohosh supplementation have been reported,^[3] although none of these cases could causation be drawn to blame Black Cohosh.^[58] These case reports sprung up around 2002^[59] and the few years following.^[60][61]

A meta-analysis of past studies noted that clinical trials had over 2,000 participants leading up to 2010, with no cases of reported hepatotoxcity.^[62] This meta-analysis in particular analyzed data from 1,020 women and found no evidence of hepatotoxicity associated with Black Cohosh in the range of 40-128mg herbal extract using an isopropanolic mixture (Remifemin, usually).^[62] At least two scientific workshops from The National Centre for Complementary and Alternative Medicine National Institutes of Health in collaboration with The National Institutes of Health Office of Dietary Supplements found a significant discord between what the literature says and case reports.^[62]

When investigating this claim via trials, a trial of 87 otherwise healthy postmenopausal women (without pre-existing liver abnormalities) did not find any significant influences on the liver associated with Black Cohosh supplementation;^[63] no alterations in bilirubin, hepatic blood flow, or lipoproteins were recorded after 12 months of Black Cohosh usage.

Due to the popularity of Black Cohosh, ranking as the 10^th most popular nutraceutical in the year of 2008,^[2] it is possible that said hepatotoxicity is due to poor regulation and spiking of 'Black Cohosh' products. A study investigating popular sold Cohosh products found that some did not contain Black Cohosh, but asian varieties of the Actaea genus that have not been as adequately studied.^[64]

There are indeed case studies associating Black Cohosh supplementation with liver failure, but whether this is actually due to the Black Cohosh plant is not known. Attempts to prove toxic effects to the liver have failed and controlled trials have not noted any dysfunction to the liver's functions; the possibility of tainted supplements due to the popularity of Black Cohosh cannot be ruled out

One study noted a patient withdrawal from 32mg Black Cohosh associated with edema and athralgia^[65] and a large open study noted that 16% of women using 40mg of Remifemin daily experienced breast swelling.^[56] A pharmacodynamic study on enzyme interactions had one subject report 'vivid dreams'.^[15]

A large scale controlled trial on black cohosh (and a combination therapy of black cohosh and St.John's Wort) found that the possible treatment-related side effects in a sample of 6141 women was 0.16%, and all non-serious.^[55] A meta-analysis of 9 double blind trials noted that gastrointestinal upset was the only concern which could be attributed to Black Cohosh, at percentages ranging from 0.5% to 15% of subjects;^[33] systemic reviews also note lack of reliable and significant demonstrated harm associated with Black Cohosh.^[66][67]