by Gabrielle Bangay

For most women, black cohosh is a medicinal plant encountered later in life. As a common treatment for menopausal symptoms and previously used by American tribes to treat rheumatism and fever, this species now has the scientific world divided. With numerous contradictory studies documented in the literature and concerns about its safety making international news, this elegant and innocent-looking herbaceous plant has a potentially dark medicinal side. Is it a beauty or a beast?

Introduction

Despite being an indigenous species to North America, Actaea racemosa L. (Ranunculaceae; syn.: Cimicifuga racemosa (L.) Nutt.), commonly known as black cohosh, is now a well-established decorative garden plant in many temperate regions of the world, found growing at the Mecklenburgh Square Gardens. One of 28 species of Actaea, it has even received a Royal Horticultural Society Award of Garden Merit (Gafner, 2015). As well as having high aesthetic value, black cohosh has been at the epicentre of decades of debate concerning its efficacy, safety and the quality of its medicinal products (Jiang et al., 2011). With increasing concerns about its conservation, potential toxicity and a surge in international trade, black cohosh continues to stand out in the world of herbal medicines as an elusive medicinal product, with debateable efficacy, yet immense economic value (Plants of the World Online, 2020) and a considerable reputation among many women.

A step back in time
History and modern use

Black cohosh is known by many common names, including black bugbane, snakeroot and macrotrys. Native American Cherokee and Iroquois, and Chinese herbalists, used black cohosh for the treatment of various indications, such as rheumatism, tuberculosis and as an insect repellent. Among the Iroquois, rheumatism was treated by washing the body with a decoction of black cohosh root. As for the Cherokee, their preferred treatment was an alcoholic spirt or root tea. The Cherokee also used a combination of black cohosh with other herbs, such as (Virginia) chokeberry (Prunus virginiana L., Rosaceae), to ‘treat’ fever, by blowing the infusion onto an individual presenting with symptoms. (Gafner, 2015). Black cohosh was used extensively in Eclectic medicine, a strand of American herbal medicine from the 19th century, as a uterine tonic to ease labour (Ulbricht and Windsor, 2014).

In modern phytotherapy, extracts of the root and rhizomes (underground stems) have been used since the 1950s to treat symptoms of menopause and perimenopause, such as hot flushes and night sweats, known as vasomotor symptoms (VMS) (Plants of the World Online, 2020). In 2013, black cohosh preparations were among the top five most popular over-the-counter products in the USA, not surprising when the use of conventional hormone replacement therapy continues to decrease, due to links with breast cancer. In 1956, the first medicinal product derived from black cohosh, an isopropanolic extract, was introduced into Europe by German manufacturers Schaper & Brümmer under the name Remifemin®. Since then it has been the subject of 60 years of research and continues to be a popular worldwide herbal medicinal product for reliving symptoms of menopause (Jiang et al., 2011).

Spot the species
Biological characteristics and identification

During summer, black cohosh can be identified by its wand-like white flowers, twisting towards the sun, scaling over 2m in height, with characteristic, dry, oval ribbed fruits. Its leaves are large and tri-ternate and its bountiful collection of slim filaments with creamy anthers make this species stand out from a distance in wooded habitats (Gafner, 2015).

The first description of black cohosh listed under the name Christopheriana facie, Herba spicata, ex Provincia Floridana was in 1705 by botanist Leonard Plukenet in his ‘Phytographia’ (Gafner, 2015). In 1753 celebrated Swedish botanist, Carl Linnaeus, published this herbaceous perennial as a member of the genus Actaea in Species Plantarum, naming it Actaea racemosa. Linnaeus later went onto divide this genus into two distinguishable genera; Cimicifuga and Actaea, keeping black cohosh in the latter. In the early 1800s, Thomas Nuttall, remarking on the dry fruits of this plant compared with other Actaea species, moved black cohosh into Cimicifuga, a genus named after the combination of cimex, Latin for bedbug, and fugare, meaning to drive away (Foster, 1999). An alternative name was also used in American botanical literature after C. S. Rafinesque placed it in a genus he named Macrotrys, from the Greek for ‘large bunch’, in reference to its sizeable cluster of flowers. However, this did not catch on. For over 240 years black cohosh officially remained as C. racemosa, until 1998 when James A. Compton and his team concluded, after extensive DNA sequencing, the two genera were so alike in chemistry that the entire Cimicifuga genus should return back to Linnaeus’ original notion of one genus Actaea, leading to the currently accepted binominal name, Actaea racemosa, once again (Foster, 2013).

Down to the basics
Phytochemistry

The metabjolites of black cohosh include the triterpene glycosides; acetin, 23-epi-26-deoxyactein (fig. 1) and cimiracemoside A. Other compounds include phenolic acids, including caffeic and isoferulic acid, flavonoids, volatile oils, alkaloids, such as Nω-methylserotonin, lignans and tannins. (Gafner, 2015). Despite the controversy surrounding the evidence that the 23-epi-26-deoxyactein triterpene has a pharmacological effect, it is currently used as the lead marker compound for standardisation (Dietz, et al., 2016). Since this marker compound is also present in A. dahurica (Turcz. ex Fisch. & C.A.Mey.) Franch., a common adulterant, using 23-epi-26-deoxyactein as a marker compound for black cohosh alone is potentially an unreliable tool in authenticating this species (Masada-Atsumi et al., 2014).

So, does it really work?
Efficacy (clinical evidence)

Despite its popular use as a treatment for VMS (vasomotor symptoms), the consensus on the efficacy and pharmacological effects of this plant is far from unanimous.

In 2008, a clinical data review provided evidence of the efficacy of black cohosh for alleviating menopausal symptoms. Using specific selection criteria, the researchers concluded that out of the six studies reviewed, including over 1,100 menopausal women, the evidence did not confirm a positive effect of black cohosh on reducing VMS (Borrelli and Ernst, 2008). Conversely, in 2010, Shams et al. reviewed the efficacy of black cohosh preparations for the treatment of VMS. They demonstrated that seven out of nine randomly controlled trials (RCTs), accounting for 1,400 perimenopausal or postmenopausal women, reduced the frequency of VMS by 26%, when compared to a placebo group. However, there was a substantial lack of homogeneity across all nine trials including five studies using a combination approach incorporating black cohosh with other herbs, such as, St John’s Wort (Shams et al., 2010; Foster, 2013; Mohammad-Alizadeh-Charandabi et al., 2013). Furthermore, in 2012, Cochrane calculated an average difference of only 0.07 hot flushes per day between placebo and treatment groups in sixteen RCTs, concluding that the use of black cohosh does not significantly reduce VMS (Leach and Moore, 2012). The discrepancy between the dosage size, lack of standardisation, language bias, inconsistency in the duration of the trials, the relatively low number of studies reviewed and poor reporting on data highlight some of the issues surrounding the validity of these reviews and illustrate the insufficient evidence to corroborate the use of black cohosh to treat VMS (Franco, 2016).

Well, how does it work?
Pharmacology

Previously, it was acknowledged that black cohosh exhibited oestrogenic activity. However, it is now accepted that its mode of action involves mechanisms associated with the presence of dopaminergic, noradrenergic and serotoninergic acting substances (Wuttke and Seidlová-Wuttke, 2015; Lopes et al., 2017). Serotonin receptor agonist activity, by the compound Nω-methylserotonin (fig. 2), working in a similar way to antidepressants and selective serotonin re-uptake inhibitors, is now believed to be the mode of action in black cohosh.

Nω-methylserotonin, a tryptamine alkaloid, binds to serotonin receptors 5-HT7 and 5-HT1A as a competitive ligand. Since both these receptors are located in the hypothalamus of the brain, thermoregulation can hence be influenced by this agonist, switching on these receptors, resulting in an effect on VMS (Ruhlen et al., 2008). This theory is supported by researchers who demonstrated no estrogenic effect on breast tissue of menopausal women ingesting a black cohosh extract containing 2.5% triterpenes over a period of twelve weeks. (Ruhlen et al., 2007; Dietz, et al., 2016). Aside from black cohosh being documented as having anti-inflammatory effects, other investigated pharmacological activities include antihistamine, antilipemic, and anti-oxidant, however these are far less prominent in the literature and require further exploration to establish their efficacy profiles (Gafner, 2015).

Several in vitro studies have investigated the anti-tumour and chemopreventive properties of phytochemicals present in extracts of black cohosh. One study found that cycloartane triterpenoids prompted mitochondrial apoptosis, programmed cell death, in breast cancer cells (Lopes et al., 2017). On the contrary, a study by Davis and colleagues demonstrated that in breast cancer-induced mice the ingestion of black cohosh could actually contribute to the proliferation of tumours (Davis et al., 2008).

Two too many?
Pharmacokinetics and interactions

As the number of people who seek to find cures to minor health problems from ‘natural’ sources increases, the use of herbal medicines as an alternative to, or, in combination with, clinical medicines has risen. As a result of herb-drug interactions, herbal drugs can interfere with the adsorption, distribution, metabolism and excretion of western medicines, particularly, by inducing or inhibiting drug metabolizing enzymes. One such example is the modulation of cytochrome P450 (CYP) enzymes. Since most clinically administered medicines are metabolised by these enzymes, interferences from herbal drugs can affect their pharmacological activity (Wanwimolruk et al., 2014).

An in vitro study on CYP enzyme inhibition from extracts of black cohosh, concluded that there was a strong correlation, predominately due to cimicifugic acids A and B and fukinolic acid (Ulbricht and Windsor, 2014). However, a 2014 review of herb-drug interactions in vitro and in vivo of plant extracts on CYP enzyme activity, concluded that among seven black cohosh products, no inhibition on CYP3A4 in human liver cells was detected (Wanwimolruk et al., 2014). Two further studies showed that healthy participants taking 40 and 80 mg respectively of black cohosh extracts, across a 14-day period, did not experience CYP3A modulation either (Newton et al., 2006). However, in another contrasting trial, researchers found a minor inhibitory effect on the CYP2D6 activity in participants who ingested standardised extracts of black cohosh, as much as 1090 mg, twice a day, for twenty-eight days (Ulbricht and Windsor, 2014). With the exception of an interaction between black cohosh and tamoxifen, there are no other reported interactions between black cohosh extracts and clinical medicines (Kligler, 2020; Edwards et al. 2015). Nonetheless, further in vitro studies identified gastrointestinal effects from black cohosh extracts inhibiting an organic anion-transporting polypeptide, involved in the adsorption of several drugs, by 47.2%, demonstrating the possible intervention of black cohosh products on the absorption of oral drugs when co-administered (Ulbricht and Windsor, 2014).

Safety first
Toxicology

Obtaining authentic black cohosh which has been sustainably cultivated is challenging, not only due to price and availability, but also misidentification and taxonomy issues. Since the medicinal part of the plant is the subterranean rhizome, the whole plant must be removed during harvesting resulting in very long periods of regrowth, up to eight years, to acquire roots large enough for medicinal use. This has resulted in the adulteration of black cohosh products, specifically with three Asian species of Actaea (A. cimicifuga L., A. dahurica (Turcz. ex Fisch. & C.A.Mey.) Franch. and A. heracleifolia (Kom.) J.Compton), used in Traditional Chinese Medicine in the treatment of toothache and diarrhoea. All four species share the common name Chinese cimicifuga, known as “sheng ma” and, confusingly and erroneously, the same pharmaceutical trade name, ‘Cimicifugae Rhizoma’. The sheng ma market is also frequently adulterated with Serratula chinensis S. Moore from the daisy family (Asteraceae), known as “guang dong sheng ma” (Gafner, 2015). Furthermore, morphological and microscopic differences among the species are subtle and phytochemical variability among plants is affected by seasonal and geographical location (Foster, 2013). Minor variations in phytochemical composition between species can result in dramatic differences in the effects on the body. By combining physical inspection, genetic fingerprinting, such as DNA barcoding and spectroscopic analysis, such as high-performance liquid chromatography (HPLC) and mass spectrometry (MS) a more effective method can be used in authenticating species (Gafner, 2015). One HPLC-MS analysis of 11 black cohosh products, demonstrated that cimifugin, the marker compound for Asian Actaea species, was present in three samples and in the seven samples containing solely black cohosh there were varying amounts of triterpene glycosides, demonstrating the complexity of authenticating products (Jiang et al., 2006).

In 2018, a review evaluating the safety of black cohosh products identified over 50 case reports documenting various intensities of liver toxicity (hepatoxicity), ranging from self-limiting hepatitis, to patients requiring an organ transplant (Khodor and Feldman, 2018). Hepatoxicity is thought to be due to oxidative damage from the build-up of proteins in the liver acting as autoantigens, triggering an autoimmune response (Levitsky et al., 2005; Borrelli and Ernst, 2008). Case reports include 44-, 51- and 59-year old women taking black cohosh products prior to presentations of jaundice, with no previous medical history, ultimately making a full recovery from acute hepatitis post-discharge and cessation, insinuating the probable likely cause from the black cohosh products (Khodor and Feldman, 2018). Even the Committee on Herbal Medicinal Products at the European Medicines Agency published a statement in 2006, acknowledging the potential link between hepatoxicity and black cohosh products, advising the general public to stop using products if they developed symptoms of jaundice (EMA, 2006). However, substantiating a causal relationship between hepatoxicity and black cohosh is challenging since in many cases the dosage and exact product was undocumented, and, with quality issues concerning unlicensed products, pinpointing the liver damage solely on black cohosh itself is unreasonable (Naser et al., 2011; Chow, 2008). In fact, a recent report by Health Canada stated that products from 5 out of 6 hepatoxic cases reviewed did not contain authentic black cohosh (Muqeet Adnan et al., 2014). Furthermore, of 69 cases reviewed by researchers in 2018 only one case could be confirmed as having hepatoxicity linked to black cohosh, all remaining studies had conflicting variables, including pre-existing medical conditions and products containing a combination of other herbs (Khodor and Feldman, 2018).

In contrast to the previous reviews, in 2011 a meta-analysis published of five RCTs, incorporating over 1,100 women, evaluated the safety of an isopropanolic black cohosh extract over an average of 4 months. Researchers collected data on patients’ liver enzymes and demonstrated there was no significant difference on the effect of the liver between the treatment and placebo groups (Naser et al., 2011).

And so, the verdict?
Conclusion

Public opinion that ‘natural’ inevitably means ‘safe’ is an important health misconception of our time. Given the conflicting evidence of safety and controversy surrounding the efficacy of black cohosh products in treating VMS, it is difficult to confirm black cohosh as a ‘beauty’, helping to reduce VMS, or as a ‘beast’, causing hepatoxicity. Not only is it essential for better-designed studies to be carried out, but caution and careful consideration should be exercised when using these products. At the very least, consumers ought to purchase their products from reputable companies that carry the Traditional Herbal Registration (THR) logo, guaranteeing high quality assurance, while ensuring they adhere to the correct dosage.

Written by Gabrielle Bangay, MSc Natural Products student at UCL and Holistic Yoga Teacher. After a successful career as a Secondary School Science Teacher, Gabrielle has returned to her studies to pursue a career in phytochemistry and drug research and development.

In this essay we do not to advise or recommend herbs for medicinal or health use. This information is intended for educational purposes only and should not be considered as a recommendation or an endorsement of any particular medical or health treatment. The use of any such product should be based on the appropriate advice of a health care professional or based on the information available in the patient information leaflets (i.e. for THR products).

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