Black Cohosh Clinical Trial Not Representative of
Previous Research Showing Positive Results
American Botanical Council Clarifies Recent Clinical Trial
Date: December 21, 2006
To:
Selected ABC Members and Stakeholders
From: American Botanical Council
A recently-published clinical trial testing the popular herb black cohosh is inconsistent with the
positive outcomes for treating menopause symptoms seen in the majority of published clinical trials,
says the American Botanical Council. [1]
“The medical literature contains many controlled and uncontrolled trials that support the efficacy of
the two leading black cohosh preparations for treating menopause symptoms,” said Mark Blumenthal,
founder and executive director of ABC, the leading herbal nonprofit research and education
organization.
Numerous herb experts cautioned that this trial must be seen in context of the entire body of clinical
research on black cohosh. According to Mary Hardy, MD, a physician in Los Angeles who has been
researching herbal dietary supplements for over a decade, and an expert on black cohosh clinical trials,
“This study should not be considered the definitive study on black cohosh. These results should be
placed in the context of all of the black cohosh trials -- many of which have shown efficacy for other
commercially available products.”
Gail Mahady, PhD, an associate professor of pharmacognosy at the University of Illinois, said, “Since
2003 there have been about 10 clinical studies on black cohosh published and all were positive.”
Dr. Mahady, one of the principal authors of the black cohosh monograph for the World Health
Organization, has reviewed these trials in several journal publications. [2,3] She added, “Thus, one
negative study does not neutralize all of the other 10 positive trials.” Dr. Mahady is also currently a
co-investigator on an ongoing black cohosh trial funded by the National Institutes of Health (NIH) and
the National Center for Complementary and Alternative Medicine (NCCAM) which also funded the
recently-published trial.
The year-long trial did not show any significant benefit in reducing hot flashes or night sweats for two
different black cohosh preparations -- one a black cohosh extract and the other black cohosh with other
herbs added -- or a combination of the black cohosh/herbal mixture with an enhanced soy diet. (The
authors acknowledged that it was difficult to ensure compliance of the added soy diet for an entire
year.) One group of women in the trial used conventional hormone replacement therapy (HRT) but
this treatment was terminated after researchers in another trial on HRT discovered adverse
cardiovascular and cancer effects associated with the conventional hormones in 2002.
Called the Herbal Alternatives for Menopause Trial (HALT), the study, published in the Annals of
Internal Medicine on December 19, was a one-year, randomized, double-blind, placebo-controlled, 5arm trial.
Researchers at the Center for Health Studies in Seattle assigned 351 women aged 45 to 55 to one of 5
different groups (arms): (1) a black cohosh extract (CimiPure®, produced by Pure World Inc. of
Hackensack, NJ), (2) a multi-herb pill with black cohosh and 9 other ingredients* (Progyne, Progena,
Albuquerque, NM), (3) the same multi-herb pill plus counseling to ensure the increased consumption
of dietary soy, (4) conventional hormone replacement therapy (estrogen with or without progestin;
this was terminated before the other arms when the Women’s Health Initiative trials were prematurely
halted in 2002 due to observations that HRT actually increased the incidence of cardiovascular disease
and cancer), (5) a placebo (dummy pill).
The lead researcher was Katherine M. Newton, PhD, of the Group Health Center for Health Studies,
Seattle, and the University of Washington, and colleagues. The trial was funded by the National
Institute on Aging (NIA) and NCCAM. Criteria for inclusion of the women in this trial consisted of at
least 2 or more vasomotor symptoms per day (e.g., hot flashes, night sweats, etc.).
Although this study appears to be the longest placebo-controlled trial on black cohosh and one of the
largest, there are still some potentially serious limitations, which the trial authors have acknowledged.
By dividing the total number of women into 5 groups (arms) to test 4 different therapies (including
HRT) against placebo, the number of women in each group drops to a point where the statistical
significance of the outcomes (whether positive or negative) are greatly diminished. The authors wrote,
“The study was too small to detect small changes in symptom frequency (less than 1.5 hot flashes per
day).” [1]
Dr. Hardy also noted that “despite the relatively large number of participants, the complex design (5
arms) means that each group had relatively few participants and thus the study was not powered to
find any but large effects.” The trial had set a criteria for inclusion at a minimum of 2 hot flashes per
day, a relatively low level at which reductions are more difficult to produce and/or monitor in a trial
like this (although the actual median level was actually 6).
In a corresponding editorial Carol M. Magione, MD, MSPH of the David Geffen School of Medicine
in Los Angeles wrote, “Black cohosh is not effective.” – basically relying on this trial as the sole
arbiter of the efficacy of black cohosh. [4] Dr. Mangione’s conclusion contrasts with other randomized
controlled trials (RCTs) that have shown measurable efficacy for the two most well-researched black
cohosh preparations (e.g., Remifemin® and Klymadynon®, both from Germany). At least 15 clinical
trials attest to the efficacy of Remifemin (Schaper and Bruemmer, Salzgitten, Germany, imported by
Enzymatic Therapy, Green Bay, WI) and 6 do so for Klymadynon® (Bionorica, Neumarkt, Germany,
imported by Bionorica USA, Eugene, OR).
Several experts noted that some information on this trial has been published previously.
According to Dr. Hardy, “This is the second time data from this trial has been reported in the medical
literature, so care must be taken not to count this study twice in looking at the whole body of
literature.”
Referring to the relatively large placebo response in this trial (about 30% of the women on placebo
reported beneficial effects, Dr. Hardy stated that “Research in menopausal treatments, besides
estrogen, are often confounded by very large placebo effects.”
Daniel Fabricant, PhD, Vice-president of Scientific Affairs at the Natural Products Association with a
doctorate in Pharmacognosy from the University of Illinois, which is also conducting an NCCAMfunded grant on the same black cohosh extract, said in an email to ABC, "The body of clinical
evidence on black cohosh preparations spans more than 3,000 subjects and 50 years using the herbal
extract for relief from climacteric (menopausal)/vasomotor symptoms. The weight of the evidence
from those studies has been overwhelmingly positive.”
Dr. Fabricant also noted that a potentially significant flaw in the trial is the lack of data on secondary
trial outcomes in this article: “vaginal cytology; serum lipids (total cholesterol, HDL and LDL
cholesterol, triglycerides); bone mineral density (hip and spine dual energy x-ray absorptiometry
scan); glucose metabolism (insulin, fasting blood glucose); and coagulation factors (fibrinogen, PAI-1)
would all provide valuable information regarding both the botanicals and the risks that have been seen
with conjugated equine estrogens (CEE) in previous studies.”
Another question about the study was raised by Francis Brinker, ND, of the University of Arizona
Program for Integrative Wellness and author of several highly-regarded reference books on herbal
medicine, including Herb Contraindications & Drug Interactions 3d ed. Dr. Brinker states, “I do not
have a problem with acknowledging the negative outcome, but I reject the extrapolation of the results
to all forms of black cohosh products. The more medical (and herbal) minds are challenged on this sort
of lazy assumption, the sooner they'll recognize legitimate distinctions among various herbal
preparations and their effects. Not all products from the same herb are created equal, so we shouldn't
blame, say, Peter Cohosh for the failings of Paul Cohosh (or reward Peter for Paul's success), unless
there is some good evidence for bioequivalency” -- the ability to show that one preparation has the
same physiological effect as another. That has not been demonstrated in this trial, so it is not possible
to extend the results of this trial to other clinically tested black cohosh products.
Dr. Brinker also commented that the extract studied in this trial was a daily dose of 160 mg of a 70%
ethanolic extract, whereas the positive studies with Remifemin tablets used 40 mg daily of a 40%
isopropanolic extract.
Eckehard Liske, PhD, research director at Schaper & Bruemmer, the German company that
manufacturers and markets Remifemin, the most clinically-researched black cohosh product, observed
that the black cohosh product used in this trial did not appear to have met stability testing that should
have been required of any herbal substance that was being employed for a 12-month trial. “The
primary packaging does not protect the study medication as well as a blister packaging,” he wrote.
This was acknowledged by the trial authors in their writing that they were not able to detect several
characteristic [chemical] marker substances. Thus, this absence of blistered medication, according to
Dr. Liske, suggests a possible instability of the study medication (i.e., the black cohosh extract may
have degraded in some manner over time).
Fredi Kronenberg, PhD, professor of clinical physiology at Columbia University College of Physicians
and Surgeons, an expert in menopause, and author of a review paper on complementary and alternative
approaches to menopausal symptoms, [5] cautions that in science one must look at the whole body of
research in a field.
“This study,” she said, “must be considered in the context of the other studies over years of research
on black cohosh, the majority of which have positive outcomes. The study was as well designed, if not
better than some others. It has a negative outcome on hot flash frequency. But each study uses slightly
different populations of women, some only postmenopausal women, some, like this study, examining
both menopausal and peri-menopausal women. Half of the women in this study were peri-menopausal
– with estrogen levels still fluctuating and thus impacting hot flashes. While the investigators did
control for this in their analysis, it points out the challenges for interpreting results across studies.”
Dr. Kronenberg, who is also a Trustee of ABC, continued, “Of critical importance when reviewing
black cohosh studies is that we know little about how the different extraction techniques of black
cohosh preparations and resulting formulations may impact hot flash physiology. The extract in this
study was an ethanolic extract. There have been positive studies with both ethanolic and isopropanolic
black cohosh extracts. We are in a phase of poorly funded research, so we must accumulate the results
of many relatively small studies since we do not have any large studies underway at this time. The
media does a disservice to the public by using catchy headlines and not taking the time for the in-depth
analysis so needed in reporting on what are complex issues.”
In sum, Dr. Fabricant emphasized, “This new study should not be called conclusive by any stretch.”
About Black Cohosh
Black cohosh, also known by either its scientific names (Actaea racemosa and Cimicifuga racemosa)
is a member of the buttercup family (Ranunculaceae) and is native to the Eastern United States. The
roots and rhizomes (lateral roots) of the herb have a long history of traditional use by native American
tribes to deal with genitourinary complaints in women. An isopropanolic extract of black cohosh
(Remifemin®) has been used in German clinical practice since the mid-1950s with safe and effective
results, and black cohosh preparations have been approved by the German government as safe and
effective nonprescription medications for treatment of menopausal symptoms. [6]
In the past few years black cohosh has become increasingly popular as the most widely-used natural
alternative to hormone replacement therapy (HRT). The herb’s popularity with middle-aged women
and gynecologists grew significantly after the summer of 2002 when a large-scale governmentsponsored clinical trial on HRT was halted prematurely after evidence that HRT was responsible for
an increase in cancer and cardiovascular disease in menopausal women.
Black cohosh preparations ranked eighth of all single-herb supplements sold in mainstream retail
outlets in 2005, according to data from Information Resources in Chicago as reported in the new issue
of HerbalGram (#71), ABC’s quarterly journal.[7]
* Ingredients in :Progyne: Black cohosh, alfalfa (Medicago sativa), boron citrate, chaste tree (Vitex
agnus-castus), dong quai (Angelica sinensis), false unicorn root (Chaemelirium luteum), licorice root
(Glycyrrhiza glabra), oat straw (Avena sativa), pomegranate (Punica granatum), “Siberian ginseng”
(Eleutherococcus senticosus)
References
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Newton KM, Reed SD, Lacroix AZ, Grothaus LC, Ehrlich K, Gultinan J. Treatment of
vasomotor symptoms of menopause with black cohosh, multibotanicals, soy, hormone therapy or
placebo: A randomized trial. Ann Intern Med 2006;145:869-879.
Mahady GB, Doyle B, Locklear T, Cotler S, Guzman-Hartman G, Krishnaraj R. Black cohosh
(Actaea racemosa) for the mitigation of menopausal symptoms: recent developments in clinical
safety and efficacy. Women’s Health 2006;2;773-783.
Mahady GB. Black cohosh (Actaea/Cimicifuga racemosa): review of the clinical data for
safety and efficacy in menopausal symptoms. Treat Endocrinol. 2005;4(3):177-184.
Mangione CM. A randomized trial of alternative medicines for vasomotor symptoms of
menopause [editorial]. Ann Intern Med 2006;145:924-925.
Kronenberg F, Fugh-Berman A. Complementary and alternative medicine for menopausal
symptoms: A review of randomized controlled trials. Ann Intern Med. 2002;137:805-813.
Blumethal M, Busse WR, Goldberg A, Gruenwald G, Hall T, Riggins CW, Rister RS (eds.).
Klein S, Rister RS (trans.). The Complete German Commission E Monographs – Therapeutic
Guide to Herbal Medicines. Boston: Integrative Medicine Communications; Austin: American
Botanical Council, 1998.
Blumenthal M, Ferrier GKL, Cavaliere C. Total sales of herbal supplements in the United
States show steady growth. HerbalGram. 2006;71:64-66.