Comments on Specific Monographs
Although the Commission E monographs are considered authoritative in their review of safety and efficacy criteria, we have included an "e;editor's note"e; in brackets when we want to clarify a statement in the monograph, or when we may question a statement or conclusion of the Commission, or if we wish to direct the reader to another monograph on a plant in the same genus. For example, some herbs that are Approved are also found in the Unapproved section, according to the species or plant part used. Examples include two types of Echinacea in each section, two monographs for Ginkgo biloba, four for Hawthorn, and two for Horse Chestnut. However, insofar as we have made such comments on a case-by-case basis, our review and possible challenge of such statements by Commission E have not been carried out in a comprehensive manner; we have commented in areas that we considered worthy of mention. The following specific comments provide additional information on commonly used herbs. Also we have included editor's notes in brackets in numerous monographs where we have chosen to provide additional information to help explain the text (e.g., the four stages of heart disease in the Hawthorn leaf with flower monograph and the stages of benign prostatic hyperplasia in Saw Palmetto).
German Chamomile is approved for both internal use (digestive) and external use. However, there is no approval for chamomile internally for its reputed mild sedative effects. This is presumably because no scientific literature supported any central nervous system effects of chamomile when the Commission published the monograph in 1984 or when it was revised in 1990. However, in 1994 and 1996 two pharmacological studies on apigenin, a constituent in the extract of chamomile, found that the compound binds at benzodiazepine receptor sites in the human brain (Viola et al., 1996). This research, although still preliminary, offers for the first time a molecular-pharmacological rationale for understanding a potential sedative action for chamomile. Therefore, if the Commission were still evaluating herbs which it is not German Chamomile flowers could be reviewed in light of this new data; however, chamomile still would not be approved for mild sedative purposes because the experimental data cannot be transferred to human experiencewithout clinical confirmation (Schilcher, 1997b).
Of the four Echinacea monographs, two are positive ( Echinacea pallida root and E. purpurea leaf) and two are negative ( E. purpurea root and E. angustifolia root). Echinacea expert Steven Foster has noted that based on a historical confusion of plant identity and the persistence of adulterated commercial supplies of E. purpurea root with Parthenium integrifolium, the assumption was made by some observers that the Commission decided to place E. purpurea root in a negative category. Work on the chemistry of vouchered Echinacea species from 1988 onward by R. Bauer and H. Wagner at the Institute for Pharmaceutical Biology in Munich revealed clear chemical profiles for E. angustifolia and E. pallida (Bauer and Wagner, 1991). As a result, it became obvious that earlier pharmacological studies on E. angustifolia actually involved E. pallida . Historically, E. pallida and E. angustifolia have been offered to the trade in mixed lots under the name Kansas Snake root. Therefore, lack of current pharmacological and clinical studies on E. angustifolia root and E. angustifolia/E. pallida aerial (above-ground) parts resulted in the issuance of a negative monograph until further scientific information becomes available (Foster, 1996).
However, despite previous problems concerning the botanical identity of Echinacea species in commercial preparations and research materials, the true reason for the disparity in approvals is based on the availability of the research on the respective species. According to Prof. Schilcher, experimental and clinical studies are available on the flowering tops (herb) and roots of E. purpurea , roots of E. pallida , and roots of E. angustifolia . The Commission decided that only the results from the research conducted on the fresh plant juice from the flowering herb of E. purpurea and from the water-alcohol extract of E. pallida roots are adequate for a positive monograph. In the meantime there have been additional studies based on the alcoholic extract of the roots of E. purpurea , that in Schilcher's personal opinion should become a positive monograph (Schilcher, 1997b). Clinical research was carried out in 1992 on an extract of the root of E. purpurea , suggesting clinical benefits in patients with colds and flus (Brunig et al., 1992). The same year Commission E published a monograph on E. purpurea root as an Unapproved Component Characteristic, although not all members of the Commission supported this decision (Schilcher, 1997b).
The monograph on Echinacea Pallida root is an example of a case where specifications based on a proprietary extract of an herb were approved. This preparation consists of a "tincture (1:5) with 50 percent (v/v) ethanol prepared from a native dry extract (50 percent ethanol, 7 to 11:1) corresponding to 900 mg of the dried plant."
It should also be noted that in Germany, physicians previously had access to injectable drug products made from either a monopreparation of E. purpurea herb juice or a fixed combination that contained E. pallida . Thus, the monographs for E. purpurea herb and E. pallida root both note that there are adverse side effects associated with intraperitoneal (injectable) forms of these echinacea products. There are no contraindications or adverse effects reported for echinacea products taken orally.
Eleuthero (Siberian Ginseng)
The Commission notes an interesting contraindication for the drug made from the roots and rhizomes of the herb Eleuthero (Siberian ginseng, Eleutherococcus senticosus , sometimes still referred to in the Chinese literature by its former Latin binomial, Acanthopanax senticosus ). The monograph states that it is contraindicated for hypertension. Eleuthero is generally considered by most herbalists in the U.S. to be milder in activity than the more stimulating root of Asian Ginseng ( Panax ginseng ). However, there is documentation in the literature of at least two studies in which it was recommended that Eleuthero not be given to persons with a blood pressure in excess of 180/90 mm Hg (Farnsworth, 1985). Presumably, this information prompted the Commission to note this possible adverse effect in some people and thus the contraindication.
An example of a warning about which we have taken issue can be found in the monograph on Ginger root. Commission E contraindicates the common spice as a remedy for morning sickness during pregnancy. However, there is no evidence that the therapeutic dosage for antinauseant activity cited by Commission E (1 gram of dried root) produces any harm to either the fetus or the mother. The Commission presumably based its caution on two studies published in the 1980s in Japan on 6-gingerol, one of the compounds isolated from ginger rhizome. In vitro tests indicated that the gingerol had mutagenic activity in vitro at high doses (Namakura and Tamamoto, 1982; Nagabhushan et al., 1987). However, other compounds in ginger have been found to exhibit anti-mutagenic activity (Kada et al., 1978). Ginger is also widely used in Traditional Chinese Medicine (TCM), but without contraindications in pregnancy. "On the contrary, ginger has been traditionally used for nausea and vomiting in pregnancy, though as in typical TCM usage, rarely by itself. There is no lack of remedies for these conditions using ginger. Also, there is no contraindication of ginger in any of the recent issues of the Pharmacopoeia of the People's Republic of China (newest edition, 1995); the dosage is 3-9 grams for both fresh and dried ginger." (Leung, 1998). A literature review of all available clinical studies on ginger could find no scientific or medical evidence for Commission E's contraindication during pregnancy (Fulder and Tenne, 1996). Prof. Schilcher agrees with this assessment of ginger's presumed safety during pregnancy (Schilcher, 1997b).
Using the fact that ginger is approved by Commission E as a nonprescription remedy for motion sickness in Germany, in 1995 the European-American Phytomedicine Coalition (EAPC) filed a citizens petition with the FDA for ginger to be reviewed as an OTC drug for anti-nausea and motion sickness (Pinco and Israelsen, 1995). The petition included clinical studies on ginger in experimental conditions as well as in situ (e.g., with first-time sailors at sea). It also contained extensive market data in Europe and other countries where ginger is employed as a medicine. The totality of the materials support the safety and efficacy of ginger as a medicine. By spring 1998 the FDA had not yet responded to this petition.
A monograph for ginkgo leaf and various types of extracts from Ginkgo leaf is listed as unapproved; a standardized dry extract of Ginkgo biloba leaf is listed in the approved section. The 1993 and 1994 monographs on Ginkgo biloba clearly focus on specific extracts or preparations rather than on the plant as a whole. For instance, the approved Ginkgo extract is the extract on which almost all the scientific and clinical studies on the effectiveness of Ginkgo biloba extract have been carried out (Foster, 1996). Thus, only the acetone-water extract of Ginkgo would be approved. The Commission's evaluation on ginkgo was based on the review of a 210-page monograph on ginkgo research submitted by the Kooperation Phytopharmaka in which no effects were documented for dried ginkgo leaf (Schilcher, 1997b).
In May 1997, the BfArM sent a letter to manufacturers of ginkgo extracts and other preparations regarding the levels of ginkgolic acid in these products (Thiele, 1997). The letter stated that, based on the present level of knowledge, the BfArM considered it necessary to reduce the content of ginkgolic acid in finished ginkgo preparations to a maximum level of 5 ppm (parts per million). If proof of this level cannot be documented, "the registration for these pharmaceuticals will be canceled since in this case, there is the well-founded suspicion that the pharmaceuticals when used in accordance with the instructions [in the monographs] produce damaging effects which exceed a justifiable degree according to the knowledge of medical science." (Thiele, 1997.) The discussion on this issue had not yet been finalized by the end of 1997. Numerous responses from members of industry (both pro and con the 5 ppm proposal) were submitted to the BfArM (Steinhoff, 1997). However, according to Prof. Schilcher, the Commission did discuss the maximum 5 ppm level and agreed to the requirement (Schilcher, 1997b).
In January 1984 all the preparations of Hawthorn berry, leaf, and flower were approved in one monograph on the basis of historical experience, many pharmacological studies, about 20 open clinical studies, and many patient case reports (Schilcher, 1997b). The originally approved monograph indications were for functional stages I and II of NYHA (New York Heart Association assessment of the four stages of heart disease). This earlier monograph also included sensation of pressure in the chest, cardiac degeneration not yet requiring digitalis ( Altesherz ), and slight forms of bradycardic arrhythmias (Steinhoff, 1997).
Later, however, the pharmacodynamics (the effects of a substance on the physiological processes) of a 45 percent ethanol extract or 70 percent methanol extract of flowering leaf tops with defined content of flavonoids and proanthocyanidins were elaborated. The other three Hawthorn preparations were reevaluated: "the flowers, leaves, and fruits as single compounds received a negative assessment because there no longer seemed to be sufficient scientific evidence to justify their inclusion." (Steinhoff, 1993/1994a.)
Commenting on the Hawthorn monograph changes, Prof. Schilcher has written that in 1984 the Commission had an abundance of scientific material, although none were studies carried out according to GCP (good clinical practices). The studies (both experimental and clinical) in the past six years confirmed the previous knowledge of Hawthorn's activity and resulted in a more precise indication for the approved monograph, i.e., NYHA Stage II only (Schilcher, 1997b). This brought the monographs in line with the 10th edition of the French Pharmacopeia, which specifies "dried flowering tops" of Crataegus monogyna. For this reason, there are four Hawthorn monographs: the Approved flower with leaves, and the three Unapproved for berry, flower, and leaf individually. These four monographs were published in July 1994 and replaced the original monograph. Presently, the only approved indication (in the leaf with flower monograph) is limited to "decreasing cardiac output according to functional stage II of the NYHA." The approval of the one Hawthorn preparation based on the extract of leaf with flower is another example of the trend by the Commission not only to rely on new scientific data for evaluations, but also to reassess and approve specific, well-defined extract preparations, often ones that are proprietary. (See pages 34 and 39 for related information.)
Horse Chestnut Seed
The 1994 revision of the Horse Chestnut seed monograph includes a detailed description of the pharmacokinetics (the absorption/resorption of substances in the human body) of the approved herb. The 1993 monograph on Horse Chestnut leaf and flower was written without benefit of detailed pharmacokinetic findings, and thus the herb was not approved. Also, the approved formulation for Horse Chestnut was much more stringently defined than earlier. The old monograph (December 5, 1984) defined the drug as Horse Chestnut seed with 3 percent triterpene glycosides calculated as aescin, and indicated a daily dose corresponding to 30-150 mg aescin. The new monograph (April 15, 1994) allows only a defined extract with an aescin content of 16-21 percent in a slow-release dosage form.
Sarsaparilla (Unapproved) has been a commonly used botanical in herbal teas as well as a flavoring for soft drinks in the U.S. for over a century. Oral ingestion has produced few reports of adverse reactions. It is thus curious that the Commission would note the &qout;risk" that "Taking sarsaparilla preparations leads to gastric irritation and temporary kidney impairment." However, per our note in this monograph, "Contrary to the undocumented claims of gastric irritation due to saponin content of sarsaparilla root, we can find nothing in the scientific literature that substantiates this assertion. It is well known that many commonly consumed vegetables contain saponins and sarsaparilla root is a common ingredient in soft drinks, e.g., root beer and many herbal teas. Therefore, we disagree with the Commission that potential gastric irritation is a problem associated with the ingestion of this plant in normal quantities."
Prof. Schilcher of the Commission agrees with our assessment; he notes that the Commission's cautions were based on "a theoretical standpoint and we have in Germany little experience with sarsaparilla"; he also conjectures that any gastrointestinal problems potentially attributable to saponins in sarsaparilla may be a function of dosage (Schilcher, 1997b).
In 1994 the EAPC filed a citizens petition to amend the OTC drug monograph for nighttime sleep-aid drug products to include preparations made from the root of valerian (Pinco and Israelsen, 1994). The petition included clinical studies documenting the activity of valerian as a non-habit-forming sedative, plus extensive market data in Europe and other countries where valerian is employed as a medicine both supporting the safety and efficacy of valerian as a medicine. By spring 1998 the FDA had not yet responded to this petition.