For over a decade it has been the policy of the American Botanical Council (ABC) to attempt to adequately describe and fully identify the phytomedicinal preparations featured in our HerbalGram Research Reviews, our HerbClip summaries and critical reviews, press releases, monographs, books, and other ABC publications. For example, in the tables summarizing clinical trials in The ABC Clinical Guide to Herbs,1 we identified the actual name of the proprietary product used in each trial (i.e., if and when the trial was conducted on a proprietary and not a generic product). Likewise, in an appendix, we provided the names for those phytomedicines and their corresponding trade names in the North American market (i.e., when such clinically-researched products were produced by non-American companies, as most of the clinically-researched phytomedicines have been, to date).
We have done this for a variety of reasons, some of which are no doubt obvious to regular readers of ABC publications.
First, ABC has recognized that much of the pharmacological and clinical literature on herbs and phytomedicinal products are frequently based on specific proprietary commercial products. Such research is often, but not always, funded by the manufacturers of such products, generally in an attempt to substantiate the products’ safety and efficacy, as well as for marketing purposes. For the past 20-30 years or so a majority of such proprietary phytomedicinal research has been in Western Europe—particularly Germany—where the regulatory systems have been based on a drug model, often requiring substantiation dossiers on specific products as a precondition of their being licensed for sale in the respective countries.
A second reason is the appropriateness of publicly acknowledging those companies (and their products) that do invest in clinical research. Over the past several decades there has been a growing tendency by the media and the market in the United States and elsewhere to “genericize” the categories of herbs where clinical research is based on only one or a few leading commercial products. In some cases, this has led consumers, some inadequately informed health professionals, and others to refer to all the commercial products of an herb as if they were all the same. Thus, all black cohosh (Actaea racemosa, Ranunculaceae; syn. Cimicifuga racemosa) products, or all garlic (Allium sativum, Liliaceae) products, are often viewed as either similar or the same, even though the research is usually based on a chemically distinct preparation (i.e., the manufacturers of the clinically-tested phytomedicinal products may have employed techniques of chemical standardization to ensure levels of specific chemical compounds and/or a group of similar compounds, such as ginsenosides in root extracts of ginseng [Panax spp., Araliaceae]).
One of the salient examples here is black cohosh, increasingly popular in the past decade for its safety and effectiveness in helping to treat symptoms related to menopause in women. Most of the clinical research conducted on black cohosh, as cited in the Black Cohosh clinical monograph in The ABC Clinical Guide to Herbs, is based on the well-known isopropanolic extract of the root and rhizome of black cohosh, Remifemin®, manufactured and marketed since the mid-1950s by Schaper & Brümmer of Salzgitter, Germany. Further, if one were to look at the literature of the past 5 years, many of the black cohosh trials have been conducted on either Remifemin or an ethanolic extract known as BNO 1055 (Klimadynon®, Bionorica AG, Neumarkt, Germany).
Similarly, the first standardized extract of the leaf of ginkgo (Ginkgo biloba, Ginkgoaceae)—which is still the leading phytomedicinal ginkgo preparation worldwide, both in sales as well as in extent of pharmacological and clinical research—is the extract of ginkgo known officially as EGb 761®. (This is known as Tebonin® in Germany, Rokan® in France, Ginkgold® in the United States, etc., and it is manufactured and marketed by Dr. Willmar Schwabe Pharmaceuticals in Karlsruhe, Germany.)
Further examples abound, including garlic. The leading product is Kyolic® Aged Garlic Extract, produced by Wakunaga of Japan, and secondarily, Kwai® made by Lichtwer Pharma of Berlin. Research based on these 2 products dominates the clinical literature. Likewise the leading clinically researched product for St. John’s wort (Hypericum perforatum, Clusiaceae) extract or aerial parts is LI 160® or Jarsin® by Lichtwer. For more information on clinically-researched herbal preparations, see The ABC Clinical Guide to Herbs1 and Marilyn Barrett’s two-volume Handbook of Clinically Tested Herbal Remedies.2
All this is not to imply that the somewhat “generic” herbal products are not effective. Such a suggestion would be hubristic. It should be noted here that the lack of published clinical trials on any particular product is not evidence of its lack of efficacy; it is simply a lack of positive published clinical evidence of any defined or suggested activity. People have successfully employed herbs and herbal preparations medicinally for millennia, long before the advent of randomized controlled trials in the past few decades.
In order to help the public access a comprehensive state-of-thescience compilation of the published (and in some cases, unpublished) pharmacological and clinical literature available on specific products and ingredients made from medicinal plants, as well as some common foods, ABC has initiated a new series of publications that we are describing as Product-Specific Monographs (PSM). The first such PSM was initially introduced online by ABC in March 2007, announcing the e-publication of the monograph on the proprietary and patented extract known as CVT-E002, or COLD-fX®.3,4 CVT-E002 is a unique phytomedicinal product and represents a new generation of botanically-based preparations. Instead of being simply a standardized extract from the roots of American ginseng (Panax quinquefolius, Araliaceae), CVT-E002 is made from only the saccharide fraction of the American ginseng roots and standardized to at least 80 to 90% poly-furonosyl-pyranosyl-saccharidess, without the biologically active ginsenosides, the triterpene glycosides that characterize most herbal products made from the roots of various species of Panax.
In producing the PSM on CVT-E002 ABC is not endorsing the manufacturer, CV Technologies of Edmonton, Alberta, Canada, or the product itself. In producing this PSM, and publishing the Clinical Overview section on the following two pages, ABC is introducing its new PSM series. The complete monograph, including discussion of the product’s chemistry, patents, pharmacology, dosage recommendations, reviews of the clinical trials, and references, as well as a one-page Patient Information sheet and the Clinical Overview, is available on the ABC Web site at http://content.herbalgram.org/abc/ Press/files/5594COLD-fX.pdf.
Additional PSMs are scheduled to follow in 2008 and beyond. These will include PSMs on POM® Wonderful Pomegranate Juice made by POM Wonderful in Los Angeles, California; Pycnogenol® French Maritime Pine Bark Extract made by Horphag Research in Geneva, Switzerland; and i-flexTM Danish Rose Hip Powder produced by Hyben Vital ApS of Tranekaer, Denmark, and marketed internationally by DSM, an international manufacturer and supplier of fine chemicals and other ingredients for the pharmaceutical and nutrition markets.
Interestingly, the POM Wonderful monograph may be the first-ever peer reviewed clinical monograph on a conventional food product, often referred to in the US market as a so-called “functional food” (a marketing term for which there is no corresponding regulatory category). Further, both Pycnogenol and i-flex are actually clinically-tested ingredients; they are not products per se. Unlike COLDfX and POM Wonderful, which are commercial retail products, Pycnogenol and i-flex are intended to be sold as ingredients in other branded commercial products.
We should emphasize that ABC’s agreement to produce a PSM on a particular product or ingredient should be interpreted as ABC’s recognition that the current level of clinical research is sufficient to support potential use or application of such a product or ingredient. In numerous cases, the research ranges from studies with outcomes that are merely suggestive (with more clinical research needed), to highly compelling, with more research perhaps still advisable. In either case, we welcome additional research to help document suggested uses and possibly additional therapeutic applications.
We are deeply grateful for the excellent services of our good friend and ABC Advisory Board member Don Brown, ND, who has acted as the consulting editor and co-author of three of these new publications.
Herbal, phytomedicinal, “nutraceutical,” and related natural products and ingredients are experiencing a maturational stage in their evolution, particularly here in the United States, characterized in part by attempts by manufacturers to differentiate their ingredients and products via the filing of patents (either composition, process, and/or use patents) and a growing body of pharmacological and clinical research. This increased research will result in a wider variety of high-quality natural ingredients and dietary supplement products with more documented safety and efficacy. Ultimately, this trend portends wider nutritional and therapeutic options and greater benefits for both consumers and health professionals.
On the following pages we offer the Clinical Overview on COLDfX, clinically-relevant information condensed from the COLD-fX PSM. We offer this as an example of a product that represents a new class of phytomedicinal products, based on a chemical and pharmacological technology blended with modern clinical research. As a service to our readers and to the general public, in the future, we may also make available in these pages other Clinical Overviews of other clinically researched products or ingredients.
- Blumenthal M, Hall T, Goldberg A, Kunz T, Dinda K, Brinckmann J, Wollschlaeger B. The ABC Clinical Guide to Herbs. Austin, TX: American Botanical Council, 2003.
- Barrett M. The Handbook of Clinically Tested Herbal Remedies. Binghamton, NY: Haworth Herbal Press; 2004.
- Barrett B, Brown DJ. Proprietary Phytomedicinal Product Therapeutic Monograph and Clinical Overview for CVT-E002 (COLD-fX®). American Botanical Council, 2007. Available at: http://content.herbalgram. orgfiles/5594COLD-fX.pdf.
- Herb experts report on benefits of Canadian remedy for cold and flu symptoms [press release]. Austin, TX: American Botanical Council; March 1, 2007.
by Bruce Barrett, MD, PhD, and Donald J. Brown, ND
This Clinical Overview is based on the full monograph covering the published and unpublished scientific and clinical research on CVT-E002 (COLD-fX®), a proprietary herbal preparation made from the roots of North American ginseng (Panax quinquefolius, Araliaceae). Because CVT-E002 is a chemically distinct fraction (a group of chemically similar compounds, in this case polysaccharides, complex sugars) derived from American ginseng roots, it has pharmacological properties different from less homogeneous extract preparations made from the root of American ginseng.
[Note: In the text below, the term “CVT-E002” is used to denote the patented, proprietary extract, especially when referring to basic research (chemical analyses, in vitro and in vivo pharmacology, etc.). In most cases, the term “COLD-fX,” the product’s retail name, has been used when reference is made to human clinical trials, market experience, and other situations that imply the oral dosage form available to the public. In some instances both terms are used.]
In vitro and in vivo pharmacological research studies have determined that saccharides from American ginseng root exhibit various immunomodulatory effects. In 1992, the co-founders of CV Technologies, a company in Edmonton, Alberta, Canada, began the development of a phytomedicinal preparation comprised of saccharides from American ginseng roots. Their research culminated in the production and patenting of and research on CVT-E002 (marketed as COLD-fX in Canada and the United States).
COLD-fX is marketed as a Natural Health Product in Canada. The scientific and human clinical research on this product has been reviewed by the Natural Health Products Directorate, a branch of Health Canada in the Canadian government, which has approved the following claim for COLD-fX: “helps reduce the frequency, severity and duration of cold and flu symptoms by boosting the immune system.”
Prevention of Acute Respiratory Infections. The primary use of CVT-E002/COLD-fX as documented by clinical trials is for the prevention of acute respiratory infections (ARI) associated with colds (chronic use) and flu and for the reduction of the severity and duration of these symptoms (short-term treatment). In studies with adult populations, including the elderly, COLD-fX has been shown to reduce the incidence of ARI when used preventively during the cold and flu season.
According to human, animal, and in vitro data, CVT-E002/ COLD-fX has immunomodulating activity. Human studies have found an increase in natural killer (NK) cells and CD4 helper cells. Animal studies have found increased levels of NK cells as well as IgG (immunoglobulin G) levels.
Dosage and Administration
Each capsule of COLD-fX contains 200 mg of a patented, dried, powdered aqueous extract of American ginseng root (CVT-E002), standardized to greater than 80% poly-furanosyl-pyranosyl-saccharides. The standard daily dose is usually 2 capsules (total 400 mg), depending on intended use (see below). In a clinical trial with adults aged 65 and over, the dosage was 400 mg once daily for 4 months. The same dose was used in a prevention trial (also 4 months) with adults aged 18–65 years. A third clinical trial, with adults aged 60 years and older, employed a dose of 200 mg 2 times daily for 8 and 12 weeks.
Manufacturer dose recommendations: For adults and children 12 years and over the recommended dosage is 1 capsule (200 mg) 2 times (total 400 mg) daily for chronic/preventive use. For acute use, 3 capsules (600 mg) 3 times on the 1st day (total = 9 capsules, 1800 mg), 2 capsules (400 mg) 3 times on the 2nd day (total = 6 capsules, 1200 mg), and 1 capsule (200 mg) 3 times on the 3rd day (total = 3 capsules, 900 mg). Continued use is recommended at 1-2 capsules per day until the patient feels better. The product should be taken on an empty stomach.
Note: “Chronic use” implies use for prevention of ARI, supported by studies of up to 16 weeks. The acute recommended dose applies to use at the onset of symptoms associated with the common cold or influenza (flu). The average age in the most important study was 42 years.
Contraindications and Precautions
There are no clear contraindications for CVT-E002/COLD-fX. However, because of potential harm that could result from stimulation of various immune processes, persons with autoimmune disease are advised to consult their physician before use. Potential areas of theoretical concern include use by persons with inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus, although such concerns are speculative and not based on any clinical reports. Persons with more common immune-related diseases, such as allergic rhinitis, asthma, and eczema, might also want to contact their physicians, although there is no clear or even suggestive evidence of harm. To date, there are no known reports of these conditions occurring in association with the use of COLD-fX. Because the immune system is highly complex and only partially predictable, it is possible that COLD-fX or other more conventional ginseng extracts would be beneficial rather than harmful in such conditions. For this reason, and without substantive evidence one way or the other, no blanket warnings can be supported at the time of writing of this Clinical Overview and the full monograph.
Although there have been no reports, persons with diabetes may want to use COLD-fX with caution. While some studies demonstrate the hypoglycemic actions of American ginseng root powder in both diabetic and healthy volunteers, the preparation used in these studies contained ginsenosides, the characteristic saponin glycosides found in roots of the genus Panax. While earlier studies found that saccharides extracted from either P. ginseng or P. quinquefolius had hypoglycemic actions in mice, a study using healthy adults suggests that the ginsenoside, rather than saccharide, fraction may play a more significant hypoglycemic role, since the American ginseng root product with a depressed ginsenoside profile was found not to affect postprandial hypoglycemia.
Pregnancy and Lactation: There is no available safety data on the use of COLD-fX during pregnancy or lactation. The American Botanical Council advises pregnant or lactating women to consult a healthcare practitioner before using any herbal product, dietary supplement, or conventional medication.
There are limited published safety data specific to COLD-fX. The randomized controlled trials summarized in the Clinical Review section in the full monograph provide clinically useful data sets, which, on the whole, suggest reasonable safety for the duration and doses tested. Reasonable adverse event monitoring was incorporated into trial methods, and no statistically significant differences in the rate of adverse effect occurrence were noted between COLD-fX and control groups. Adverse event monitoring included self-reported symptoms, and, in the case of the 2-year McElhaney trial (2004), standard blood laboratory tests.
Post-marketing surveillance of COLD-fX in Canada follows standard operating procedure for all government-approved Natural Health Products, including receipt and analysis of spontaneous reports of adverse reactions. Despite over 200 million doses of COLD-fX sold to consumers in Canada for approximately 10 years, from 1996 through 2006, less than 100 such reports have been filed. Of these, rare allergic reactions, including hives and other skin reactions, may be considered attributable to ingestion of the product. A potentially confounding factor is that rashes are occasionally observed as a symptom of influenza or other infectious diseases that present similarly to cold and flu.
One serious adverse event has been reported. A person experienced an anaphylactic-like event characterized by mouth and tongue swelling during both an initial event and an event 2 weeks later following a second exposure. [Note: Allergy history of this person is not available.]
It is important to note that allergic reactions can occur with virtually all foods, dietary supplements, natural health products, and drugs. Given the data available, the apparent rate of allergic reaction does not appear to be higher with COLD-fX than with many other substances in common use such as foods, dietary supplements, or drugs.
Other reported reactions or adverse side effects have not formed patterns suggesting causal linkage to COLD-fX. These include headache, insomnia, dizziness, drowsiness, confusion, nausea, vomiting, abdominal pain, diuresis, lowered blood pressure, and joint pain. As these could all easily be due to underlying health conditions, causal linkage is considered possible, but unlikely.
An assortment of small studies, including those detailed in the full monograph, have failed to find any substantial dose-dependent or serious adverse effects attributable to CVT-E002 or conventional full-spectrum P. quinquefolius extracts. It appears reasonable to conclude that serious adverse effects from CVT-E002 are unlikely because of the following: (1) CVT-E002 is comprised primarily of oligosaccharides and polysaccharides, complex sugars which are generally recognized as safe; (2) randomized trial and post-marketing surveillance data are reassuring regarding safety; and (3) the overall safety record of ginseng products is good to excellent.
There are no known specific drug interactions for CVT-E002/ COLD-fX. Limited animal and in vitro studies have found no effect of CVT-E002 on cytochrome P450 isoenzymes, an important source of drug-drug and herb-drug interactions. Based on studies with different preparations of American ginseng root, theoretical concerns may exist for patients taking warfarin, digoxin, insulin, and oral hypoglycemic medications. No interactions of this kind have been reported to date for this product in clinical studies or post-market surveillance.
Three randomized controlled clinical trials have tested CVT-E002/ COLD-fX for prevention of acute respiratory infection (ARI). Two of these, which are perhaps best classified as preliminary or phase 2 trials, were in elderly adults. The third, which can be classified as a confirmatory or phase 3 trial, tested COLD-fX among 323 adults aged 18 to 65. All three of these found some evidence of preventive efficacy. Two small, unpublished and preliminary trials have tested COLD-fX for prevention of ARI and immune modulating effects in athletes. More details are available in the full monograph.