HerbalGram: Black Cohosh: A Literature Review

Black cohosh, Cimicifuga racemosa (L.) Nutt., is a member of the buttercup family (Ranunculaceae) native to deciduous forests of eastern North America. Its use for gynecological conditions predates European settlement of the New World. In the 19th century it emerged as an important treatment for several female-related conditions, championed by Dr. John King, an Eclectic physician. Preparations of the root of this American medicinal plant have been used in European phytotherapy for the treatment of menopausal symptoms for over 50 years. Clinical experience, coupled with chemical, pharmacological, and controlled clinical studies have confirmed that black cohosh preparations are a safe and effective alternative for hormone replacement therapies in the treatment of menopause.

The genus name Cimicifuga is derived from the Latin cimex, the generic name for the bedbug (Cimex lectularius L., Cimicidae) and the Latin fugare, meaning to drive away. This refers to the fact that some species, including the European C. europaea Schipcz., the Asian C. foetida L., and the North American C. elata Nutt., among others, have herbage with a strong, unpleasant fragrance, hence were used as insect repellents. C. racemosa leaves do not have a strong fragrance. The common name "bugbane" also honors folk use as an insect repellent. The plant known today as black cohosh was known throughout much of its American history as "black snakeroot," in the United States Pharmacopoeia (USP)— in the first edition published in 1820 through the seventh revision of 1890. Thereafter, it is known in USP as Cimicifuga, Black Cohosh, Black Snakeroot, and Macrotys, remaining official through the 10th decennial revision (1926), but dropped from the 11th decennial revision (1936). Other common names by which Cimicifuga racemosa has been known include rattleweed, rattleroot, snake root, rattle snakeroot, rattlesnake root, and blacksnake root.²

Black cohosh is an erect, smooth-stemmed perennial growing from four to eight feet in height. The large, alternate, tri-ternately compound leaves are borne on short, clasping petioles. The ovate, acute leaflets, two to three inches in length, are thin, smooth, two or three-lobed with sharp double-serrate margins. The long, wand-like, white flowers, about an inch in diameter, are borne on a terminal branching spike-like raceme. The main feature of the flowers is the numerous showy stamens, consisting of slender filaments with white anthers. Four or five white, small concave sepals are larger than the nearly inconspicuous, stamen-like petals. The solitary white pistil is smooth and sessile. The fruit is a dry oval ribbed follicle splitting along a ventral suture with eight to ten triangular brown seeds in two rows. In the south, it begins blooming in mid to late June. Toward the northern part of its range, blooming begins as late as early August. During the flowering period the conspicuous flowering stalks can be seen from a distance even in wooded habitats. In rich deciduous woods it is common on hillsides, generally growing under heavy shade, though in open woods that have been selectively cut or even clear-cut, it will survive for a year or two in nearly full sun. It occurs in woodlands from Massachusetts south to South Carolina, west to Arkansas and Missouri, and north to southern Ontario.³

Delving into its botanical history requires little more than paraphrasing John Uri Lloyd and Curtis Gates Lloyd’s exhaustive treatment of Cimicifuga in what was to be a monumental series on American medicinal plants, Drugs and Medicines of North America (Vol. 1, 1884-85). The series was abandoned after only two volumes were published.

According to Lloyd and Lloyd, the first description of our subject comes in the Amaltheum Botanicum (1705), the final of six volumes of Leonard Plukenet’s "Phytographia" series published between 1691 and 1705. Plukenet (1641-1706) was named Regius Professor of Botany and appointed to oversee the gardens at Hampton Court in 1689. His "Phytographia" was a catalog of plants which came into the possession of this medical doctor who followed botanical pursuits to the neglect of medicine. Black cohosh was crudely figured under the name "Christopheriana facie, Herba spicata, ex Provincia Floridana."^4,5,6 Pre-Linnaean (before ca. 1750) writers classed it under the generic concept of Actaea (under Tournefort’s designation, Christopheriana) with descriptors recognizing the plant’s long spike.⁷ Several German review works cite R. Morrison (1680) for providing the first description of the plant as Christopheriana canadensis; however, Morrison is not listed as a reference by Linnaeus.⁸

The first modern botanical name is Actaea racemosa L., published in Species Plantarum (1753). Later, Linnaeus separated the genus Cimicifuga from Actaea based on characteristics of the fruit (in Actaea a fleshy berry, in Cimicifuga dry follicles), of the European species C. foetida (L.) L., but did not move the North American C. racemosa from Actaea to his later concept of Cimicifuga.

The evolution of the name Cimicifuga racemosa takes some interesting turns of nomenclatural nuance. The plant was first considered under the genus Cimicifuga as C. serpentaria (L.) Pursh in Frederick Pursh’s Flora Americae Septentrionalis (1814).⁹ Pursh (1774-1820), as the Lloyds point out, was actually the first to publish the name under the present concept of the genus; therefore, his designation C. serpentaria, they state, should have been the correct scientific name for the species. However, some of Pursh’s designations have since been deemed illegitimate names by botanical authorities.

Four years later, Thomas Nuttall (1786-1859) again used the old specific name (racemosa), calling it C. racemosa in his 1818 work, The Genera of North American Plants. It is interesting to note that Nuttall was Pursh’s predecessor in the service of Benjamin Smith Barton (1766-1815), botanical patron and professor of natural history and botany (later, also professor of materia medica) at the University of Pennsylvania. Nuttall began revising Pursh’s 1814 Flora, but his work evolved into an entirely new botanical treatment of North American plants, widely praised by his contemporaries. In the same year, Cimicifuga racemosa was also mentioned by William Paul Crillon Barton (1786-1856), nephew of B. S. Barton, in his Compendium florae Philadelicae (vol 2., p. 12), but without acknowledgment of Nuttall having named the plant. Since Barton mentioned Nuttall’s 1818 Genera, the Lloyds assumed Nuttall’s work was published first. Thus, botanical luminaries of the day, such as Augustin Pyramus de Candolle (1778-1841), erroneously attributed authorship of the name to Barton.¹⁰

The name C. racemosa was also published by Stephen Elliot (1771-1830), a prominent South Carolina citizen and botanist, six years after publication by Nuttall and Barton. The eminent American botanists John Torrey and Asa Gray, in their important works on American botany, both credit Elliot as the author of the name "Cimicifuga racemosa." Hence, the plant is seen designated as "Cimicifuga racemosa Elliot" (incorrect), "Cimicifuga racemosa W. Barton" (incorrect), and Cimicifuga racemosa (L.) Nutt. (correct until recently).11 ,12 The Lloyd brothers point out these discrepancies, but they themselves perpetuate the citation as Cimicifuga racemosa Elliot, presumably following Asa Gray, the leading American botanical authority of the time.13

C. S. Rafinesque (1783-1840) correctly observed that C. racemosa did not conform to Linnaeus’s description of the fruit, and differs in several technical aspects from all other Cimicifuga species. Therefore, in 1808 he proposed to place it in a separate genus he designated Macrotrys (from the Greek for "large" and "bunch," referring to the large raceme of fruit). The name was adopted by few authors, though Amos Eaton (1776-1842), the first to attempt to popularize American botany, used Rafinesque’s name Macrotys (misspelled, dropping the second "r"), in his popular Manual of Botany, published in eight editions from 1817 to 1840. "Macrotys serpentaria" was used by Eaton in the fourth edition of his Manual, published in 1824. In the fifth edition (1829), Eaton reverted to using Macrotys racemosa. In the first volume of his Medical Flora (1828), Rafinesque again changes the name, this time designating the plant as Botrophis serpentaria.

Rafinesque explains, "I did so ever since 1808, calling it Macrotrys, which meant long raceme, which name Decandolle has adopted as a subgenus of Actaea; but this name being delusive, too harsh, and an abbreviation of Macrobotrys, I have framed a better one meaning Snake raceme: the raceme or long spike of flowers being mostly crooked, and like a snake."¹⁴

All of these nomenclatural shifts are significant when looking up black cohosh in 19th century American medical literature. In the first half of the 19th century, physicians of the Eclectic school, like most of the people, relied on Eaton’s Manual of Botany as the standard botanical text for North American plants. Therefore, as a drug, black cohosh is known throughout much of the Eclectic medicine literature, and well into the 20th century, as "macrotys."¹⁵

Another reason this taxonomic error is relevant in 1999 is because James A. Compton and colleagues at the University of Reading (Reading, U.K.), after extensive morphological and DNA sequence studies, have placed the entire genus Cimicifuga back into Linnaeus’s original generic concept of Actaea. Thus, as of August 1998, C. racemosa, once again, after a hiatus of 245 years, is Actaea racemosa L.¹⁶ Further work by Compton and colleagues will require revisiting the entire generic concept of Cimicifuga as it relates to Actaea not only in North America, but in Asia and Europe as well.^{17 ,18} Name changes and distribution as cited by Compton and colleagues relative to Cimicifuga are summarized in Table 1.

Since it will take another 100 years for the world botanical, herbal and medical literature to either accept or reject this name change, this paper will continue to use the now obsolete name "Cimicifuga racemosa" to refer to the source plant of the herbal medicine known today as "black cohosh."

In North America, six species of Cimicifuga are listed by Kartesz.19 From eastern North America, species include C. americana Michx. [Actaea podocarpa DC.]; C. racemosa (L.) Nutt. [A. racemosa L.], and C. rubifolia Kearney [A. cordifolia DC., C. cordifolia (DC.) Torr. & A. Gray]. American bugbane (C. americana) occurs in deciduous woodlands on steep slopes in deep shaded rocky soils from southern Pennsylvania to South Carolina and eastern Tennessee. It differs from C. racemosa primarily in technical characteristics of the flowers and fruits (C. americana with 3 ovaries and papery follicles). Appalachian bugbane (C. rubifolia) is an uncommon cool mountain woodland species, occurring in rich deciduous forests on north-facing slopes, often near streams from southwest Virginia to North Carolina, Tennessee, adjacent Kentucky, and southern Illinois. Cimicifuga racemosa, best known as black cohosh (formerly black snakeroot), is the most common American species.²⁰

Western North American species include C. arizonica S. Wats. [A. arizonica (S. Watson) J. Compton]; C. laciniata S. Wats. [A. laciniata (S. Watson) J. Compton]; and C. elata Nutt. [Actaea elata (Nutt.) Prantl]. Arizona bugbane, C. arizonica, is a rare species occurring in deciduous woodlands by streams on north-facing slopes or in canyon bottoms from Coconino County, Arizona. Tall bugbane, C. elata, is found primarily on north-facing slopes in mixed or deciduous forest in the coastal ranges from Lane County, Oregon, to Clallam County, Washington, and British Columbia. Mount Hood or cut-leaved bugbane, C. laciniata, is a rare species found in boggy ground or open deciduous woodlands, once known only from Lost Lake at Mount Hood, but since found in other localities north to Silver Star Mountain in Washington. The western North American species appear to be absent from the ethnobotanical literature, probably reflecting their rarity.

Early American medical authors ascribe knowledge of the use of black cohosh to eastern North American indigenous groups. Little reliable ethnobotanical data establishes clear information on use. The Oklahoma Delaware used black cohosh combined with elecampane (Inula helenium L., Asteraceae) and stoneroot (presumably Collinsonia canadensis L., Lamiaceae) as a "tonic."³⁰ Among the Iroquois, whose common names for the plant translate to "horse smells" and "smells like horse," Herrick records that the root decoction was used to promote the flow of milk. To treat rheumatism, a decoction of the root was used as a foot bath (while washing the affected parts). A steam sweat bath was also used. The leaves were also used as a poultice to treat a baby’s sore back.³¹

The Cherokee used alcoholic spirits of the roots for the treatment of rheumatism; also as a tonic, diuretic, anodyne, emmenagogue and for its slight astringent activity. The root tea was used to treat colds, cough, consumption, constipation, fatigue, hives, rheumatism, backache, and to make a baby sleep.32 A combination of white baneberry root (Actaea pachypoda Ell, Ranunculaceae), black cohosh, chokecherry (Prunus virginiana L., Rosaceae), and crawling phlox (Phlox stolonifera Sims, Polemoniaceae) was made into an infusion, then blown four times onto a feverish patient with chills to help reduce the fever.33 This use is sometimes cited in the literature relative to the use of black cohosh root for the treatment of fever, though the use is obviously ritualistic rather than pharmacologic in its basis.

The northeastern Algonquians (cited as Penobscots in Moerman,34 but including the Montagnais, Penobscot, and Mohegan in Moerman’s cited source, Speck) used the root of black cohosh as a common remedy for kidney trouble, or "feeling all played out." Two or three small pieces of the root were infused to make a quart of tea, drunk in one-cup doses two or three times a day. According to Speck, "At times they drink a good deal of this, which is rather pleasant to taste."³⁵

Moerman also cites Micmac use as a diuretic, however, the primary reference cited, "Herbal Remedies of the Maritime Indians,"36 also cites Speck’s 1917 paper on medicine practices of the Northeastern Algonquians. Since black cohosh’s distribution reaches only into York County, Maine, the southernmost county of the state, it is unlikely that it was gathered by either the Penobscot or the Micmac since the plant is well beyond those tribes’ inhabited range. If used, black cohosh must have been traded with other groups. Correct identity of the plant is not assured in the fragmented extant ethnobotanical literature of the northeastern United States.

When the primary references cited by Moerman are examined, it becomes clear that the ethnobotanical record of use of black cohosh by indigenous groups within the plant’s range is extremely limited, if not almost entirely lost.

Some writers add additional fragmented ethnobotanical notes to the literature. Lloyd and Lloyd quote Elisha Smith’s Botanic Physician published in 1830, (p. 427, "The Indians cure the ague by sweating with the root."³⁷ Ague is normally defined as fever attack or recurrent chills or shivering.

Benjamin Smith Barton also made cursory observations of use by native groups. "The Actaea racemosa, or Black-Snake-root, is also a valuable medicine," he writes. "It is sometimes called Squaw-root, I suppose from its having been used as a medicine by our Indians. The root of this plant is considerably astringent. In a putrid sore throat which prevailed in Jersey, many years ago, a strong decoction of the roots was used, with great benefit, as a gargle. Our Indians set a high value on it. A decoction of it cures the itch. In North-Carolina, it has been found useful, as a drench, in the disease of cattle called the murrain."³⁸

In 1822, Jacob M. Bigelow, eminent professor of materia medica at Harvard University and an important contributor to early USPs, in his commentary on the first USP adds to early ethnobotanical notations: "We are told that the Indians made great use of it in rheumatism; also as an agent ad partum accelerandum."³⁹ However, J. U. Lloyd states that it was included in the 1820 USP as Cimicifuga serpentaria, but was only included in the secondary list through the first two revisions, and appeared for the first time on the primary list in the 1840 USP.⁴⁰

Barton’s notations represent the beginning point in ethnobotanical and American medical literature on black cohosh. While mentioned earlier by Schoepf in 1785 and Gronovius in 1762, medicinal uses were scant.⁴¹ However, Schoepf does note the root to be a diuretic and anodyne.⁴²

In 1818 William Hand, listing the herb under "Cimicifuga serpentaria," wrote, "Black Cohosh, Squaw-weed, Rattle-weed, Bug-bane—Recent root. In strong infusion, promotes fluid, secretions, and is anodyne in chronic rheumatism, slow fevers, flatulent colics, and in hysterical affections."⁴³ This work establishes use as a home remedy in early 19th-century America.

Even before its admission to the USP, Cimicifuga seems to have been well-known both as a home remedy and in medical circles. Most authors from the time of Benjamin Smith Barton’s notations on the use of the plant until the time of Rafinesque generally quote Barton. Rafinesque expands the list of applications, calling it astringent, diuretic, sudorific, anodyne, repellent, emmenagogue, and subtonic.44 He notes that it is a primary remedy of Indian groups for rheumatism, but also as a gargle for sore throat. Even Bigelow (1822) largely paraphrases Rafinesque in enumerating uses. Lloyd later explains that the early writers from Schoepf (1785) through Rafinesque (1828) added little about the use of black cohosh that had not already been learned from Indians.,⁴⁵ The first "new" use he attributes to Horton Howard who in 1836 related case histories citing the value of a decoction of the root in the treatment of smallpox.⁴⁶ Later, in 1872, Dr. G. H. Norris read a paper before the Alabama State Medical Association reporting on the value of black cohosh preparations in an epidemic of smallpox in Huntsville, Alabama.⁴⁷

Use for various nervous afflictions (chorea), rheumatism, as a potent diaphoretic in cases of fever, and other wide-ranging uses abounded in early 19th century medical literature. By the mid-nineteenth century medical writings on the plant began to focus on use for female conditions. In 1849, the newly formed American Medical Association, then two years old, began to focus on these uses in their publications. Frances Porcher begins his description of use: "The root is used in the debility of females attendant upon uterine disorder, and in its action, is thought to have a special affinity for this organ."⁴⁸

As the century progressed, black cohosh became of less interest to physicians of the allopathic school. By the late 1800s its use was little more than a curious entry in many publications on materia medica. Flückiger and Hanbury claim it "has been employed chiefly in rheumatic affections. It is also used in dropsy, the early stages of phthisis [tuberculosis or wasting away of the lungs], and in chronic bronchial disease."⁴⁹

From: Schaper & Brümmer. Remifemin — Active Substance: Liquid Cimicifuga Extract. The Herbal Preparation for Gynecology [Product Detail Manual] 1997; 43 pp. Two additional studies in the product brochure are not mentioned as at the time of this writing. They have not been published in peer review journals.

Flückiger and Hanbury make an interesting observation: "The American practitioners called Eclectics prepare with Black Snake-root in the same manner as they prepare podophyllin [resin from mayapple, Podophyllum peltatum L., Berberidaceae], an impure resin which they term Cimicifugin or Macrotyn."⁵⁰ While the so-called "regular school" (physicians) showed interest in black cohosh early on, in the second half of the 19th century black cohosh evolved to become one of the mainstays of Eclectic materia medica, primarily through its promotion by Dr. John King. Since the Eclectics and their allopathic counterparts were often at philosophical, economic, political, and legal odds, remedies adopted by the Eclectics were largely ignored by the regular physicians.

The eminent Eclectic physician, John King (1813-1893), gave it considerable space in the first edition of The Eclectic Dispensatory of the United States of America (with R. S. Newton, 1852), as well as in subsequent editions, written by King or co-authored by John Uri Lloyd, later by Harvey Wickes Felter and J. U. Lloyd.

King became the main proponent of black cohosh in the Eclectic school, and spoke of it to his students as his "favorite remedy." He had used it in his practice since 1832. Offered almost exclusively by Eclectic physicians under the name "macrotys," black cohosh was a primary remedy in both acute and chronic cases of rheumatism and in related inflammatory conditions, pulmonary afflictions, chorea, and neuralgic affections. It served as a remedy, as King put it, "in abnormal conditions of the principal organs of reproduction in the female." King stated that he found black cohosh "very efficacious in maladies of the female reproductive organs, as in chronic ovaritis, endometritis; menstrual derangements, as amenorrhea, dysmenorrhea and menorrhagia, frigidity, sterility, threatened abortion, uterine subinvolution and to relieve severe after-pains." King was not only one of the leading 19th-century physicians in Eclectic medicine, but specialized in obstetrics and gynecology, serving as Professor of Obstetrics and Diseases of Women in the Eclectic Medical Institute, Cincinnati, and authored several works on obstetrics.⁵¹

Chemical Investigations

The first rudimentary chemical studies on the root began in 1827. G. W. Mears obtained tannin, gallic acid, a resin, gum, starch, bitter substances, and extractive matter from the rhizome. His attempt to find an alkaloid in the plant failed.53 In the early 20th century Finnemore confirmed phytosterin, isoferulic acid, salicylic acid, sugars, tannins, and long-chain fatty acids. Separate chemical investigations by Corsan and Linde in the 1950s and ‘60s resulted in isolation of chemical components to which biological activity was attributed. These were a number of triterpene glycosides, including the xylosides acetin, cimicifugoside, and 27-deoxyactein. An isoflavone, formononetin, has also been reported.54 Isoflavones are ubiquitous in the legume family (Leguminosae or Fabaceae), but are relatively rare in other plant families. Recent attempts to validate levels of formononetin and the flavone kaempferol in isopropyl alcohol and ethanol extracts along with five commercial preparations of black cohosh failed to identify appreciable levels of the flavonoids. Depending upon analytical methodology the flavones can be found only in trace amounts.55 Its presence in Cimifuga rhizome is, however, doubtful and might be due to unintentional admixture of other, similar-looking drug species.

European Experience: 1743-1980

Like other American medicinal plants such as Echinacea (Echinacea spp., Asteraceae) and saw palmetto (Serenoa repens (W. Bartram) Small, Arecaceae), black cohosh was introduced into Germany in the late 19th century, following Eclectic acclaim of its therapeutic value. The first person in Europe to recommend use of Cimicifuga was Colden, who suggested use to stimulate uterine contractions as early as 1743, apparently inspiring Linnaeus to add the plant to his Materia Medica in 1749.^{57, 58} In the early 20th century it became primarily a homeopathic remedy, then as phytotherapy evolved as a separate aspect of medical practice in the 1930s, black cohosh became a legitimate therapeutic agent, supported by pharmacological and clinical research.

In 1944, Gizycki provided the first modern pharmacological evidence in animal experiments related to estrogen-like effects. Much of the literature until the end of the 1950s was clinical reports on experience in using black cohosh preparations. Empirical clinical data tended to emphasize the use of black cohosh for overweight patients with delayed menstruation, functional nervous conditions, neuralgia with myalgia and arthralgia, premenopausal patients with endocrine imbalances, or premenstrual patients with depression. It was found to be particularly useful in general practice in rural areas where gynecologists were not available.⁵⁹

By the late 1950s, black cohosh preparations were in wide use by clinicians in Germany. A debate played out in the scientific literature in the first half of the 20th century, dominated by clinical case reports (empirical knowledge) and rather crude animal studies (pharmacological proof), prompted an experimental pharmacological direction to proving or disproving empirical observations. In 1959 J. Földes conducted a series of experiments to assess the estrogenic action of an alcoholic extract of black cohosh root (Remifemin) in mice in response to this debate.

Dose-dependent induction of estrus (with increased uterus weight) was observed in several test groups of animals. Ovariectomized rats in three groups received doses of 0.1 ml b.i.d. [two times daily] (six animals); 0.2 ml b.i.d. (six animals) and 0.3 ml b.i.d. (nine animals) for three days. The first group at the lowest dose showed no change. In the second group (0.2 ml b.i.d.), estrus was induced in only two of six animals. In the third group at the highest dose, estrus was induced in eight out of nine animals. In another experiment 12 three-week-old female mice were given 0.2 ml of a black cohosh extract (Remifemin) for four days. Increased uterine weight of the test animals was interpreted to support the concept of an estrogenic effect for the herb. In another experiment, 40 female rats were given the extract for two weeks to determine if any histological changes of the ovaries were induced. No changes were seen compared with controls. Since a sedative effect was reported for black cohosh, 60 mice were given Remifemin and 20mg/kg of amphetamine. If a sedative effect could be shown, the black cohosh should theoretically protect against the effect of amphetamine. No positive results were shown. Twenty rats were given 0.3 ml of the black cohosh extract for a week, and, on the eighth day, injected with a thyroid marker to examine any changes in suppressing thyroid function. No differences were observed between controls and the test group. Another experiment with six rats did not find any change in thyroid hormone mobilization.⁶⁰

While the animal experiment on sedative effects failed to produce sedation, a sedative effect was observed in women enrolled in a follow-up study. The preparation was given to 41 pre-menopausal and perimenopausal women, who received placebo before treatment (run-in period) followed by one tablet t.i.d. [three times daily] of a black cohosh extract (Remifemin). Thirty-one women in the treatment group experienced a marked reduction in symptoms (hot flashes, headache, nervousness). While receiving placebo, 37 complained of no improvement. The author concluded after these early animal experiments followed by a poorly controlled clinical study, that the preparation had a favorable effect on pre-menopausal and perimenopausal symptoms, with an emphasis on sedative action. Gastric symptoms were experienced in three of 41 patients. No other side effects were observed. He believed that the experiments showed a hormone-like activity.

Other authors of the same period, however, did not believe that black cohosh had a hormonal effect. Stiehler, based on clinical observation in 53 patients, rather than controlled experiments, concluded that black cohosh intervenes in (without interfering with) hormonal mechanisms, producing a normalizing effect without overriding pituitary control. His experience found black cohosh strikingly successful for premenopausal and menopausal dysfunction, and juvenile menstrual irregularities with a shortened follicular phase. However, he believed it was not indicated for menstrual disorders in general. Of particular note in this clinical observation, once again, is a mild mood-enhancing activity.⁶¹

A paper delivered at the Karlsruhe Therapy Congress in 1956 further catapulted the herb to prominence in the treatment of menopause. Practitioners were concerned with finding an alternative to hormone-replacement therapy, which by that time was showing unwanted side effects in a large number of patients. Practitioners also recognized the value of black cohosh preparations as a concomitant or alternative therapy to hormone replacement treatment or the use of potent sedative in cases of female conditions relative to the onset of puberty, menstrual difficulties, and menopause symptoms. One thread that continues throughout clinical reports of this period is a positive effect on mood swings, depressive disorders and psychological instability sometimes associated with hormonal imbalances. Stefan particularly recommended black cohosh for juvenile menstrual disorders accompanied by psychological disorders. In his experience, normal menstruation, interrupted by stress and transition because of job stress or adjustment to new surroundings, was achieved after administration for about eight weeks. He concluded that it is particularly valuable in a clinical context from pre-puberty to menopause, because it combined a mild sedative action with a hormone-like effect, without being habit-forming, inducing increased bleeding, or producing other untoward side effects even with long-term administration.⁶²

By 1960, 1,256 case reports in 11 published studies by gynecologists, general practitioners, internists, and neurologists had evaluated the use of a black cohosh preparation (Remifemin) for the treatment of menopausal symptoms with positive benefits, and a marked lack of adverse effects, particularly unphysiological bleeding, then considered a major limitation of hormone therapy. The largest review (517 patients, by A. Brücker), reports that a dose of 20-30 drops of a liquid preparation or one tablet t.i.d., taken over a relatively long period of time (at least eight weeks), produced benefits in 79 percent of women treated. Like other authors, he suggested that the liquid preparation should be retained in the mouth as long as possible, and that the tablets should be sucked on rather than swallowed. Psychological benefits (mood enhancement) were also emphasized.⁶³

Langfritz reported success in using Remifemin in treating juvenile hormone disorders of young women suffering from dysmenorrhea, oligomenorrhea, premenstrual syndrome, and other conditions. All patients were observed to have uterine or ovarian hypoplasia, complaints of cold feet, and underdeveloped breasts. In the treatment of 73 patients over a four-year period, he concluded that the preparation helped to normalize juvenile menstrual disorders and relieve or eliminate neurovegetative symptoms associated with hormonal disorders, without side effects. Langfritz regarded the treatment not as a hormone substitute, but rather a modifier of autonomic-hormonal processes (after pathological causes are ruled out).⁶⁴

By 1962, at least 14 clinical studies or reports involving over 1,500 patients were published on the use of a black cohosh extract. While most studies were not rigorously controlled by modern standards, results consistently revealed the preparation was effective in premenopausal and menopausal symptoms such as a reduction in hot flashes, improvement of "depressive moods," and improvement of neurovegetative symptoms and various dysfunctions during menopause. A 1964 clinical report adds treatment for premenstrual syndrome, then emerging as a recognized and treatable indication, to the list of potential applications for black cohosh. In reviewing 135 cases of premenstrual syndrome, neurologist E. Schildge administered a black cohosh extract (Remifemin) at an average dose of 20 drops three times per day over a period of three to six months. Improvement in general well-being and a relaxant sedative effect in mood swings and mild depression were observed. No side effects were reported.⁶⁵

Studies of the 1980s and 1990s

A number of studies, both pharmacological and clinical, published in the 1980s and ’90s have shed further light on mechanisms of action, mode of administration, and efficacy. These studies serve to confirm safety and efficacy and further elucidate mechanisms of action for the long-standing clinical experience of use of black cohosh preparations for menopause and postoperative gynecological dysfunction. Clinically, the treatment is used to improve symptoms such as hot flashes, depression, and sleep disturbance. Virtually no significant new studies on pharmacology and clinical use of black cohosh extracts appeared in the 1970s. However, results of clinical reports from the 1950s and 1960s provided collective data on 1,738 patients (20 percent of whom also received additional hormone therapy) in clinical and general practice for treatment of menopausal complaints.

In 1982, a retrospective, open, multi-center study involving 704 patients (mean age 51 years) by 131 general practitioners and gynecologists evaluated how a black cohosh preparation (Remifemin) improved menopausal complaints. The patients received 40 drops of Remifemin liquid two times per day, and were evaluated after four, six, and eight weeks of treatment. Results were evaluated subjectively by patients and objectively by physicians’ diagnoses. Data on 629 patients was available. In 80 percent of cases, favorable results were attained after six to eight weeks of treatment. Therapeutic success included relief of neurovegetative complaints such as hot flashes (86.6 percent improvement, with 43.3 percent experiencing no hot flashes and 43.3 percent improved), sweating (88.5 percent improvement, with 49.9 percent experiencing no profuse perspiration and 38.6 percent improved), headache (91.9 percent improvement with 45.7 percent experiencing complete relief, 36.2 percent improved), vertigo (86.8 percent improvement, with 51.6 percent experiencing complete relief, 35.2 percent improved), heart palpitation (90.4 percent improvement, with 54.6 percent experiencing complete relief, 35.8 percent improved) and tinnitus (92.9 percent improvement, 54.8 percent experiencing complete relief, 38.1 percent improved). Complete removal of evaluated symptoms was achieved in an average of over 49 percent, with an additional average of 37.8 percent experiencing improvement (but not complete relief) of symptoms. Improvement of psychiatric symptoms included nervousness and irritability (85.6 percent improvement) sleep disturbances (76.8 percent) , and related depressive moods (82.5 percent improvement). Two hundred and four patients had previously been treated with hormone therapy. Physicians observed that the black cohosh treatment had advantages over hormone treatment in 72 percent of cases. In some cases of hormone-treated patients, black cohosh had no effect, highlighting the need for each patient to be evaluated individually for treatment. In 93 percent, no side effects were reported. Transient stomach upset was reported by seven percent of patients, but did not result in discontinuing treatment. The authoress, H. Stolze, concluded that the black cohosh preparation was safe and effective as a hormone-free therapeutic treatment for menopause. Its great advantage in general practice was that it could be administered over a long period of time without serious risk of side effects.66 A 1983 open study involving 36 women (45 to 62 years old) with menopausal complaints, most of whom had refused hormone therapy, was evaluated according to the Kupperman and Clinical Global Impression scales. They received 40 drops of Remifemin twice a day for 12 weeks. Rates of success similar to those reported by H. Stolze were achieved.⁶⁷

In 1984 Vorberg reported on the results of an open study in gynecological practices on 50 patients with menopausal complaints for which hormone therapy was contraindicated. Forty drops of a black cohosh preparation (Remifemin) were given two times per day for six to eight weeks. Efficacy was measured by Kupperman Menopausal Index, Clinical Global Impression and Profile of Mood States. Improvement according to the Kupperman scale was greater than 15 percent; improved mood states including decrease in weariness, amelioration of despondency, and increase in motivation were also reported.⁶⁸

In 1985 Warnecke published results of an open, controlled, comparative study in 60 female patients with menopause. The 12-week study compared a black cohosh preparation, a hormone, and a psychopharmaceutical drug in treating ‘neurovegative, psychological, and somatic disturbances in menopause. Divided into three groups, patients received either Remifemin (40 drops b.i.d.), estrogens (0.625 mg daily), or Diazepam (2 mg daily). Efficacy was measured according to several criteria, including the Kupperman Menopausal Index, Clinical Global Impression and Profile of Mood States. Both Remifemin and conjugated estrogens produced stimulation of vaginal mucosa, with a clear increase in cytological indices. All three therapies were comparatively good. Tolerance of the black cohosh preparation was deemed to be excellent. Given the fact that the black cohosh extract performed as well as the hormone therapy for neurovegetative symptoms and the psychopharmaceutical for depressive moods, and its lack of side effects, it was considered an excellent first choice medication for mild to moderate menopausal symptoms.⁶⁹

In a 1985 pharmacological study by Jarry and Harnischfeger, the authors conducted experiments to measure levels of serum concentrations of pituitary hormones using an animal model corresponding to inducing pituitary hormone levels typical of those measured during menopause in women. After a three-day period, there was a significant and selective reduction in luteinizing hormone (LH), while serum concentrations of follicle-stimulating hormone (FSH) and prolactin were unaffected. Occurences of and increases in hot flashes have been linked to spikes in LH release, and serve as a parameter by which the endocrinological activity of black cohosh can be measured. A glycoside fraction of an extract was concentrated by dichloromethane and believed to be responsible for the effect. The active principle contained in the lipophilic fraction, believed to be triterpene glycosides, showed definite endocrinological effects in the animal model, selectively reducing LH serum concentrations, while not affecting FSH and prolactin release. This study seemed to confirm previous speculation in both pharmacological and clinical literature of an endocrine-like efficacy of the root extract.⁷⁰

Jarry, Harnischfeger, and Düker sought to further characterize the mechanism of action and the active constituents. They demonstrated endocrine activity of the rhizome in the in vitro system of the estrogen receptor assay and the in vivo model of the ovariectomized rat. They identified at least three principles in a methanol extract that are believed to compete with the hormone estradiol for binding sites on specific receptor proteins. Three fractions were found that: (1) do not bind to estrogen receptors but suppress the release of LH; (2) bind to estrogen receptors and suppress the release of LH; and 3) bind to estrogen receptors but do not suppress LH. One was identified as the isoflavone, formononetin. The compound, while binding to estrogen-receptive cells, failed to demonstrate an LH-suppressant effect. This led them to speculate that other active principles in the methanol extract have a synergistic effect leading to a LH-suppressant effect.⁷¹ A recent study55 cited by Gruenwald failed to confirm the occurrence of formononetin in black cohosh or its preparations.⁷²

In 1987, Stoll published the results of a double-blind study comparing the effects of conjugated estrogens, a black cohosh extract, and placebo. Eighty volunteers were admitted: 30 received 0.625 mg of an estrogen preparation per day; 30 received 8 mg of black cohosh extract per day (Remifemin), while 20 patients received placebo. Three parameters were measured. Neurovegetative symptoms (using the Kupperman Menopausal Index) such as hot flashes, profuse perspiration, headache, vertigo, heart palpitation, and tinnitus, and the Hamilton anxiety scale (measuring nervousness, irritability, sleep disturbances, and depressive moods) were evaluated at four-week intervals. Proliferation status of vaginal epithelium was measured at the beginning of the study and after 12 weeks of treatment. Treatment was continued for three months. All three parameters were significantly improved in the black cohosh group compared with placebo. Estrogen therapy proved to be delivered at too low a dose for reliable comparative results. The lowest possible dose had been chosen to limit known side effects of estrogen therapy. The black cohosh preparation was well-tolerated and produced significant improvement in the measured criteria. The author concluded that black cohosh not only produced safe and efficacious results, but was suitable as a treatment of choice in menopausal symptoms.⁷³

In 1987 Pethö reported the results of an open study in 60 female patients converting from hormone injection therapy to black cohosh over a six -month period. Two tablets of a black cohosh extract (Remifemin) 40 mg b.i.d. were administered. Efficacy was measured according to the Kupperman Menopausal Index and subjective observations reported by patients. The number of hormone injections needed after initiation of therapy was also a criterion of efficacy. Eighty-two percent of patients reported the black cohosh preparation as good or very good and 58 percent did not require additional hormone injections. No side effects were reported over the six-month period.⁷⁴

A 1988 German clinical study by Lehmann-Willenbrock and Riedel compared treatment with the hormone estriol, conjugated estrogens, estrogen-gestagen sequential therapy, and an extract of black cohosh in 60 women under 40 years of age all of whom had at least one ovary removed, and still complained of climacteric symptoms. Patients were randomized into four groups. At intervals of four, eight, 12 and 24 weeks, LH and serum-FSH levels were measured. A modified Kupperman Scale (measuring psychological, neurovegetative, and trophic [pertaining to nutrition] symptoms of menopausal symptoms) was also used for assessment. Among the ovarian deficiency symptoms scored in this system are hot flashes, sweating, sleep disturbances, depressive moods, and other related symptoms. Treatment with the black cohosh extract (Remifemin) was found to be comparable to successful treatment with the three conventional drug preparations tested. LH and FSH-levels did not change in any group during treatment. The authors concluded that in cases where conventional hormone therapy is contraindicated, the plant extract is the therapy of choice.⁷⁵

In 1991, Düker et al. obtained three types of endocrinologically active fractions from a commercial isopropanolic extract of black cohosh rhizome (Remifemin). The study confirmed an LH secretion inhibitory effect in both ovariectomized rats and in menopausal woman. In the clinical phase involving 110 menopausal women, for a two-month period, 55 received two 2 mg tablets of Remifemin (8 mg per day), while the other 55 women received placebo. They demonstrated for the first time that the extract selectively suppresses LH secretion in menopausal women, and further confirms an estrogen-like effect of the alcoholic fractions of the root of the plant. This controlled study confirms long-standing clinical experience in use of the preparation in the treatment of menopausal-related symptoms for women who either refuse to take steroid hormone replacement therapy or when such treatment is contraindicated.⁷⁶

Although a number of studies, including Düker et al., 1991, have described the action of black cohosh as "estrogen-like," a clear mechanism of action has not been described. Therefore, estrogen-like effects have been proposed based on LH-lowering effects and the assumption that the steroid hormone-like chemical structures of the triterpene glycosides resulted in interfering with receptors in the hypothalamus and pituitary gland.⁷⁷ However, a recent animal study failed to show estrogenic effects, with no indications of uterotropic or vaginotropic activity, leading to the conclusion that decreases in LH levels are caused by interference with neurotransmitters, rather than an estrogenic effect.⁷⁸ A recent double-blind randomized clinical study by Liske and colleagues looked at the effects of two different dosages of an isopropanolic black cohosh extract (Remifemin) in 152 patients with climacterica complaints. The dosages were 40 mg vs 127 mg of the preparation per day for six months. According to the authors the two dosage regimes showed similar results in efficacy and safety. Hormone levels of LH, FSH, SHBG. prolactin and estradiol were not influenced by the product. Vaginal cytology (degree of proliferation) was also not influenced. According to the authors the study clearly demonstrated that the product had a non-hormone (non-estrogenic) effect. This study serves to settle the former controversy on whether or not black cohosh produced an estrogenic effect. ⁷⁹

Safety and Toxicity

In a 1995 review, Beuscher cited older review works that reported large (unspecified) doses of black cohosh result in dizziness, nausea, severe headaches, stiffness, and trembling limbs. However, these symptoms can be traced to literature on 19th-century homeopathic provings of the herb. In this context, irrelevant to dosage in conventional phytotherapy, these "provings" result from administration of ultramolecular doses over a period of time to develop symptoms by which to match disease conditions. Studies on mutagenicity, and carcinogenicity have proved negative. A study on long-term administration (six months) in rats failed to show chronic toxicity at about 90 times the human dose equivalent. Occasional stomach pain or intestinal discomfort has been reported. These findings concur with over 60 years of safe clinical experience, particularly in Germany.⁷⁹ Occasional gastric discomfort is listed as a potential side effect. Duration is limited to six months (presumably because of lack of long-term toxicity studies of longer duration).⁸⁰

Concerns have arisen over the previously described "estrogen-like" activity in estrogen-receptor-positive patients with mammary carcinomas. However, recent studies have clarified the situation. Unlike estrogen, a marked inhibition of the proliferation rate of breast carcinoma cells is reported for a black cohosh extract (Remifemin). Nesselhut (1993) first confirmed non-proliferation rates of breast carcinoma cells.⁸²

Results of a recent study on the "influence of an isopropanolic aqueous extract of Cimicifugae racemosae rhizoma on the proliferation of MCF-7 cells" was presented by J. Freudenstein and C. Bodinet at the 23rd International Symposium o