Figure 1: Aristolochic acid.
Figure 2: Asarum sieboldii.
Figure 3: Asarum heterotropoides.
Figure 4: Representative chemical structures for the allylbenzenes.
SAFETY ISSUES AFFECTING CHINESE HERBS:
The Case of Asarum
essay by Subhuti Dharmananda, Ph.D., Director, Institute for Traditional Medicine, Portland, Oregon
Eastern and Western herbalists learn about asarum early in their training. For Western herbalists, Asarum canadense (known as wild ginger due to its spicy hot taste, reminiscent of ginger) is often among the first herbs learned. It is seen on almost any herb walk that takes place in the northern half of the U.S. or in Canada, and books that list herbs by botanical names will have this herb right up front. It has a long history of use by Native Americans, and is described in herb books from America and Europe as a stimulant, carminative, diuretic, and diaphoretic. According to The Eclectic Materia Medica (16), asarum is "a very pleasant stimulating carminative, diaphoretic, and emenagogue, of considerable value in amenorrhea from recent colds, in atonic dysmenorrhea, and in flatulent colic. A warm infusion is a very good diaphoretic with which to break up a cold. Asarum may be added to cough mixtures, and with syrup forms a very agreeable vehicle for the administration of pectoral medicines to be used in the chronic coughs of debility to aid expectoration." There is also a European variety, Asarum europaeum, which is not widely used: it acts as an emetic and cathartic.
For those who study Oriental medicine, asarum is again among the first to be learned. It is usually grouped into the category of warming, surface-relieving herbs, which are placed at the front of the Materia Medica guides. In Oriental Materia Medica (20) it is said that asarum "dispels cold and wind, warms the lungs to resolve accumulated fluids." The indications for asarum are: "sinusitis, toothache, rheumatoid arthritis due to wind and dampness, retention of phlegm and fluid, cough with dyspnea, general coughing." There are many species of Asarum collected for the medicinal herb material to be used in making the Chinese formulations, though Asarum sieboldii and Asarum heterotropoides are the most commonly mentioned (see Figures 2 & 3). Asarum was widely utilized in the Shanghan Lun, the earliest existing formula guide of the Chinese tradition, and it occurs in many traditional formulas that have been passed down to modern times, recorded in major herb guides.
Asarum has not been of significant concern in regard to its safety in common herbal usage until very recently. It had not been banned in any country, nor did herb trade organizations have it on their list of herbs to be concerned about. Herb guides do not list it under the main headings as toxic or even slightly toxic (for example, Chinese herb guides will list an herb as being toxic as part of its properties such as nature and taste). Yet, in the changing circumstances of modern herb use, safety questions about several commonly used herbs are just beginning to be raised. Wild ginger (Asarum canadense) was included on a list issued by the FDA as an herb containing aristolochic acid, a compound that has been banned from the herb trade in the year 2000. The main process of removing aristolochic acid is by eliminating potential sources of it (alternatively, every batch of material that is of concern can be tested for the compound). Since asarum is so central an herb to the practice of Chinese herbal medicine, the issues surrounding its safety should be understood as a reflection of concerns that can be raised about many other herbs.
The conception of herbal safety has undergone a shift in recent years. Previously, two concepts depicting the fundamental safety of herbs have prevailed. One was religious: God had put the herbs on this earth to heal the illnesses of mankind, they were designed to be helpful and not harmful. Man, turning away from God's teachings, dabbled in things that were outside man's more limited role, and could then cause harm. Therefore, returning to God's natural pharmacy would assuredly provide help. The other concept was based on the scientific view of nature: plants and animals had evolved together over hundreds of millions of years, and there was a natural balance in the constituents of plants and in their interaction with animals (and, therefore, with humans). Thus, while isolated chemicals from plants and their synthetic derivatives used as drugs would be harmful because they lacked nature's balance, whole herbs would be healing because each of the myriad ingredients balanced the others and produced a harmonious interaction with the numerous substances in the body of the consumer. Both the religious and scientific interpretations converged on the concept that herbs and natural foods are inherently safe, while those substances modified or created by man often do harm.
However, this broad view of safety in nature was usually not fully adopted, even by its proponents. Hence, for many such proponents, herbs were deemed good, but caffeine-containing herbs were not; vegetable foods were good, but the animal foods were not; wheat and dairy products, long favored as food sources by Westerners, were deemed to be causing phlegm accumulation and allergies, while rarer foreign grains (e.g., amaranth) and soy milk products were not. In essence, what was deemed safest was not simply that which was natural and untouched by chemicals (organic), but also that which was not favored by the mainstream. Medicinal herbs fit this paradigm, especially if they were organically grown, as they were no longer a part of mainstream medicine and were, in fact, largely rejected from the medical system. Thus, layered over a basic trust in nature was a distrust over those portions of nature that had been widely adopted by society.
The positive view of herbs and their safety began to crumble during the past few years. Heavy metals and drugs were found in imported herbal patent medicines from the Orient; these were products that had previously been viewed by proponents as being all natural and safe alternatives to drugs. Ma-huang was claimed to cause serious cardiovascular reactions, even death; stephania was blamed for renal failure in a Belgian weight-loss clinic; and the popular Western herbs comfrey, chaparral, and germander were blamed for liver inflammation, as was a remarkably effective patent imported from China named Jin Bu Huan (which contained neither heavy metals nor added drugs). Pretty soon, other common herbs were being avoided by those who read the warnings and took them to heart: licorice (fear of an estrogen-related effect or adverse cardiac effect), ginseng (fear of a stimulant effect), and tang-kuei (reports of carcinogenic potential). Then came concerns about herb-drug interactions, with warnings against popular herbs such as St. John's Wort and Ginkgo biloba and salvia (danshen). Any or all of these adverse reactions that led to the concerns might be attributed to human meddling with otherwise healthful herbs, thereby retaining the philosophy that they are fundamentally safe. Nonetheless, the widely held perception of herbs as safe health products was irrevocably altered in the minds of many, if not most, people who otherwise favored their use.
At this point, the potential harm of natural products is one of the first issues raised by anyone considering using them. There is now a general fear of Chinese herbs, with some doctors warning their patients to strictly avoid them, claiming they are frequently associated with liver or kidney damaging effects, not to mention the presumed contamination with heavy metals and other unknown toxins. In making these warnings, the physicians are supported by articles in the medical literature that are alarming; this is not merely a spontaneous attack by the medical profession against an alternative healing system.
While there are calls for eliminating potentially harmful herbal materials and instituting better controls over all natural products, it is still the case that the matter of safety is a difficult one and a relative one. There is no level of control that will prove to be entirely satisfactory. Indeed, as more and more herbs are eliminated from consideration and use on the basis of safety concerns, people will retreat back to the better controlled drug products: exactly what was to be avoided when people turned to herbs. The demand for safety has its own hazards, which must be dealt with in a manner that effectively improves the human condition.
There is really nothing that can be assured to be entirely safe; even pure water becomes toxic at a high enough dose: pure water will eventually dilute the body's mineral stores when enough is consumed. In the absence of absolute safety, it is essential to become more familiar with the safety issues that exist, and also to determine one's own tolerance for questionable safety. Asarum is selected here as an example of herbal safety concerns. An effort has been made to find as many concerns about the herb as possible, which may give the impression that the herb is more dangerous than it is. Still, there is no way to assign a clear level of safety for this or other herbs.
Asarum belongs to the Aristolochiaceae family, and this membership already raises some red flags for those investigating the safety of the herb. The Aristolochiaceae family gives rise to numerous medicinal plants that have been widely respected in many countries for many centuries, especially in China. The most extensively utilized genus of plants within the family is the one the family is named after: Aristolochia. This group of herbs is well-known for diuretic, antiinflammatory, and birth-easing effects in all cultures that have used it. Today, efforts are underway to ban the use of all members of this genus in herbal medicine outside of China. The principal active constituents of that genus (but not of the other genera of the family), are known as aristolochic acids (see Figure 1). These compounds have been shown to have immune enhancing and anticancer properties. Unfortunately, they also appear to have the potential to cause renal failure in some individuals under some circumstances that have not yet been fully elucidated.
The situation is confusing, as there is contradictory data about the incidents of renal failure that have been reported, including conflicting data from animal and human studies. The theory of how an adverse affect arises has developed. The diuretic effects of the herb come from an interaction with the kidney. Apparently, in susceptible individuals (mostly women), some of the aristolochic acid can enter the kidney cells and attach to the DNA (forming DNA adducts). The affected kidney cells may then produce a new or modified surface protein that will subject the kidney cells to autoimmune attack (this requires certain genetic background to occur); once initiated, the attack can proceed in the absence of further exposure. The autoimmune process takes months and may only be evidenced long after the herbs have been discontinued. Autoimmune attack against the kidneys can arise from other causes, and there are numerous other contributors to delayed renal failure (such as use of non-steroidal antiinflammatory drugs), confounding the analysis of individual cases. Corticosteroids can inhibit the progression of the renal failure if caught early enough. The result of this mechanism, in rare instances, can be complete kidney failure that does not require a very high dosage of herbs (as would normally be the case with toxic substances), so long as the compound is ingested over a prolonged period of time (several months). There is also the potential for inducing kidney cancer via the same mechanism of DNA interaction in the susceptible individuals; this appears to be a problem only among those who suffer renal damage.
Aristolochia fangchi has been used as a major source of fangji (also spelled fang-chi), commonly called stephania (also derived from Stephania tetrandra, from which the common name was derived). Aristolochia fangchi was used in the Belgian weight-loss clinic where about 70 women had some degree of kidney failure (see: The strange story of stephania). The aristolochic acid in this herb has been blamed for the kidney disorders. Follow-up investigations in Hong Kong revealed that the slices of Stephania tetrandra root (which contain no aristolochic acid) is very difficult to distinguish from the slices of the botanically unrelated Aristolochia fangchi roots, so that herbalists who requested Stephania would frequently receive the more commonly used item, Aristolochia. Prior to the incident in Belgium, this interchangeable use of the two plant sources appeared to make no difference: they both had similar effects (Aristolochia may well have had superior action); in normal use, there was no evidence of toxicity for either of them.
The Chinese herb xiexin, commonly known as asarum, is mainly derived from Asarum sieboldii (Figure 2) Asarum heterotropoides (Figure 3) and there have been no reports of aristolochic acid in these plants. However, aristolochic acid has been found in some other species of Asarum (= Asiasarum) by Japanese researchers (13). In the normal practice of traditional Chinese medicine, about a dozen species of Asarum are used as sources of xiexin, making the presence of aristolochic acid in some of the raw materials, and the formulas produced with them, a possibility. Also, as detection methods improve, minute amounts of aristolochic acid might be found in most, or even all, of the Asarum species. This would be deemed reason enough for asarum to become included in the list of herbs to be banned from use since no acceptable level of this compound has been set or is likely to be established. Fortunately, aristolochic acid has not yet been found in any other plant families, and there are few other natural compounds that have a similar structure. This means that a ban on plants specifically known or suspected of containing aristolochic acid might have a limited impact on the overall availability of herbs. On the other hand, the extent of substitution of Aristolochia plants for other herbs is not fully known and may lead to halt of trade in several other herbs that are entirely free of the compound. For example, alerts have been made for species of Clematis because there is a species of this plant that is a substitute for Aristolochia (not the other way around, however).
The main active ingredients of the various Asarum species are not aristolochic acids, which represent an incidental component (by contrast, in the Aristolochia plants, it is a major active constituent that explains many of the traditionally-claimed therapeutic effects). Instead, there are essential oils in asarum, including safrole, methyleugenol, and asarone (see Figure 4), that are understood to be the main active ingredients. Safrole, methyleugenol, and asarone have been suggested to be carcinogenic. based on laboratory animal studies (aristolochic acid is also carcinogenic in laboratory animal studies). The story of safrole, and the issue of animal studies for carcinogenicity, is instructive.
In the U.S., sassafras (Sassafras varifolium) was a popular herb, especially along the Appalachian range where it was commonly consumed during the spring as a "blood purifier." In Eclectic Materia Medica, it is said that "Sassafras tea is a popular alterative [helps interrupt the disease process and begin healing], diaphoretic, and carminative. It and the oil are decidedly stimulant." Due to its strong and long-standing reputation as a valuable natural remedy, sassafras became one of the major American herbs in the emerging herb trade of the late 1960's and thereafter. Sassafras was also the key flavor ingredient in root beer, a carbonated beverage made from about a dozen roots and barks. The principal active constituent and flavor of sassafras is safrole, which has a pleasant spicy taste.
Laboratory animal tests conducted during the 1970s showed that high doses of safrole would cause liver tumors in rats. On the basis of these studies and a new food additives law, sassafras flavoring was removed from root beer. Concerns about the safety of chemical food additives had led to a law, known as the Delaney Amendment (amending a prior food additives law) that imposed the following restriction: no substance shall be added to foods that has been shown to cause cancer in laboratory animals. When the law was established, it had not been imagined that natural food additives were going to be a problem; instead, the growing list of artificial chemical additives was of concern. Since it takes far too long to determine if a new chemical will cause cancer in humans (from time of exposure to time of diagnosis is usually more than 20 years; even then, it is difficult to determine whether the chemicals were responsible for the human cancers), animal studies, which often take just months, were utilized as a screening method to satisfy the desire to keep carcinogens out of the food supply.
Scientists recognized that ordinary foods contained small amounts of natural carcinogens. It would not be possible to strip the entire food supply of carcinogens, but one could halt the intentional addition of suspected carcinogens to common foods, by explicitly restricting the category of food additives. Therefore, every food additive was subjected to testing in laboratory animals.
Since sassafras extract was deemed a flavor additive in root beer, in which safrole was the main intended ingredient to be added, it was withdrawn from the product. We will never know whether or not root beer is safer as a result, but it doesn't taste the same. It is entirely possible that new formulations of root beer are less safe overall than the old, but it fits the safety requirements that exist; the popularity of the drink has plummeted.
As an herb rather than a food additive, sassafras itself was technically beyond the Delaney regulation. However, the FDA tried to pursue a tactic for regulation of the herb under the Delaney Amendment. The FDA declared that when making tea, the hot water was the food and the herb was the food additive; when providing capsules of herbs, the capsule was the food and the herb was the food additive. It was a weak argument that couldn't stand on its own, but the FDA was able to convince the herb industry to voluntarily withdraw sassafras products rather than fight a protracted legal battle and risk having all herbs declared food additives. Many years later, some herb companies had tried to reintroduce the herb, realizing that it was beyond the FDA to ban it or enforce a ban, but by then the demand for the herb was gone.
In the meantime, both the regulatory situation and the popularity of herbal products had changed, and most attempts at herbal regulation were dropped. On the one hand, the FDA was too busy and underfunded to actively pursue herbal regulations and, on the other hand, the growing interest in herbs as health aids led to public and political calls for the FDA to keep their hands off such products. One recent exception was the attempt to regulate distribution of ephedrine products (see: Ephedrine: actions and dosage), and this was a somewhat unique situation involving a combination of herbal materials and purified ephedrine extracts (which correspond to a drug product) that were being used increasingly for weight-loss regimens (also as an energy booster and sport performance enhancer). Another recent exception was an attempt to regulate the Chinese red yeast product hongqu (hung-chu) which contained small amounts of a chemical identical to a drug product used for lowering cholesterol. Extracts were marketed as a substitute for the drug; the FDA efforts to regulate this failed in court.
The situation with sassafras and cancer is a complex one. The laboratory animal studies (involving rats) yielded only one type of cancer: liver tumors. The question arises: could the herb cause liver cancer in humans? Primary liver cancer in humans mainly occurs as the result of chronic viral hepatitis infection, which has been a problem in the Orient, but (until recently) not in the U.S. One way to see if sassafras is a human liver carcinogen is to examine data on incidence of liver cancer by county for the U.S., for which statistics have been available for many decades. If sassafras tea were causing liver cancer in humans, this might show up as an elevated incidence rate of this otherwise rare cancer in the Appalachian region where sassafras had regularly been consumed by many people for many decades (little sassafras had been used outside that area until the 1970s). The liver cancer rates along the Appalachian range (based on data up to 1970) have been among the lowest in the entire country. The same was true for Utah, which is the only state outside the Appalachian area where herb use, including sassafras, was fairly common during the time period of concern.
The laboratory animal studies showed that very high doses of safrole caused liver cancer, but there was also evidence that safrole, at more modest dosages, could stimulate the conversion of other carcinogens to non-carcinogenic metabolites, thus potentially being an anticarcinogen. Indeed, there was some research indicating the high doses of safrole were overwhelming the animals, causing accumulation of toxic metabolites resulting in cancer. It was eventually determined that safrole functioned as a carcinogen only after being transformed into one of its metabolites (via a hydroxylation reaction) by liver enzymes; these metabolites were found in the urine of laboratory animals fed safrole, but not in the urine of humans given safrole (12), suggesting that safrole might not be carcinogenic in humans, only in animals (those animals that could metabolize it to the hydroxy form). Together, the information raised a serious question about the application of the animal study to human use of sassafras. The issue of actual safrole carcinogenicity in humans has been all but ignored. The Delaney Amendment does not have a waiver for items that might be carcinogenic only in animals, but not in humans.
Safrole as a liver carcinogen in animals has become a major subject of scientific investigation and all cancer researchers know that safrole is carcinogenic. The current thinking with regard to translating the animal data to human carcinogenicity is summed up in an article in Food and Chemical Toxicology (11): "It is likely that the use of these high doses [in animal studies] markedly overestimates the potential hazard to humans of allylbenzenes [e.g., safrole], which generate only very small quantities of genotoxic [potentially carcinogenic] metabolites."
It was found that a number of ordinary kitchen spices, particularly cloves and nutmeg, which were widely used in flavoring, also contain small amounts of safrole. These materials were not banned from use as flavoring additives, because the FDA stated that safrole was not the main ingredient, but incidental. Since the spices had been used safely for a long time, the agency decided not to attempt regulatory action against them. Nonetheless, studies that may result in eventual removal of some of these natural ingredients from products in which they are used as flavorings are underway. For example, mice were given cola drinks, which are flavored with small amounts of nutmeg, and were shown to form DNA adducts from safrole and related compounds in their livers, suggesting a carcinogenic potential (in the animals). Myristicin and safrole were considered the main components of concern. Both clove and nutmeg are used in Chinese herbal medicine, though not frequently. Like asarum, they are employed in formulas that dispel internal chilliness.
To put the carcinogenicity situation of safrole in context, the changing regulatory status of another food additive is instructive. Recently, saccharin, which had been listed as a carcinogen based on laboratory animal testing, was taken off the human carcinogens list. Saccharin caused bladder cancers in rats, but it was by a metabolic pathway that was relatively unique to those test animals, not occurring in humans. An effort to clear saccharin of its adverse reputation as a carcinogen was pursued because of the continued widespread use of the compound, which had required a Congressional exemption from the Delaney Amendment, along with warnings that had to be posted in stores that sold the products. By contrast, the possible clearing of safrole for human use has not been pursued because there is no public interest in it. It is possible that safrole is anticarcinogenic in the quantities that humans are exposed to when consuming it in herb products; the point is moot.
Eugenol and methyleugenol, chemicals very similar to safrole (the class of compounds is called, variously, allylbenzenes, alkenylbenzenes, or phenylpropenes), have essentially the same effect in laboratory animal testing: they cause liver cancer when given in high doses. Asarone, which is a main ingredient in the Western herb Acorus calamus (known as calamus root), is blamed for the carcinogenic effects of its extract in laboratory animals. The FDA was able to ban the use of calamus root in the U.S. based on a single laboratory study. The Chinese herb Acorus gramineus has not been the subject of regulatory action. According to Pharmacology and Applications of Chinese Materia Medica, Acorus calamus (shuichangpu) contains 3% volatile oil with about 50% asarone. By contrast, Acorus gramineus (shichangpu) has only about 1/10 the amount of essential oil; it contains 0.1-0.4% essential oil, of which more than 2/3 is asarone. According to the reports on side effects, no side effects were seen in 60 patients taking 10 grams of Acorus gramineus decoction daily for three months to three years; for Acorus calamus, stomach irritation was sometimes a problem.
Table: Essential Oil Components of Two Commonly Used Species of Asarum Used as a Source of Xixin. Each of these herbs has about 2.5% essential oil, and the figures shown are the proportions of that oil (6). A dash (-) indicates that the content is relatively low, less than 1% each. According to Japanese studies (8), the essential oil content can vary markedly, depending on growing conditions, so these figures should be considered as only one example of the distribution of amounts of component ingredients.
| Essential Oil Content | A. heterotropoides | A. sieboldii |
| methyl eugenol | 51.6% | 42.4% |
| safrole | 12.0% | - |
| eucarvone | 9.8% | - |
| sabinene | 3.8% | - |
| Elemicin | 3.4% | - |
| estragole | 1.9% | - |
| croweacin | - | 14.5% |
| asaricin | - | 9.3% |
| beta-pinene | 1.1% | 2.8% |
| alpha-terpineol | - | 2.6% |
| others | 27.4% | 28.4% |
To what extent should herbs with safrole (and/or methyleugenol, asarone, etc.) be avoided? Would one avoid small amounts of kitchen spices that contain such ingredients? Such questions are difficult to answer, but the issue comes down to several matters: the translation of animal data to human situations (or even in vitro studies with human cells versus actual human exposure to the substance); the dosage and duration of exposure; and one's sense of the safety or lack thereof for these natural compounds.
One could argue that asarum has been widely used in herbal medicine and has not been deemed dangerous; therefore, the investigation of minute quantities of certain chemicals that it contains is not relevant to use of the herb in complex formulas. There is little or no aristolochic acid in the herb materials that are in common use, and the carcinogenicity of the essential oil ingredients may be limited to animals exposed to large doses. In short, one could take the view that historical experience and the preponderance of literature about the herb raises little or no concern about using it.
However, a more extensive and careful study of the Chinese literature indicates that there are safety concerns with regard to asarum. While some materia medica guides give no indications of any potential problems, and one (10) even specifies that asarum is "non-toxic" (usually, this is not a characteristic mentioned for common herbs), others give warnings that make one take notice.
In Chinese Herbal Medicine Materia Medica (1), under the heading "contraindications" it is warned that one should "Use [asarum] with caution in patients with renal problems as it can be nephrotoxic." The same comment is found in Pharmacology and Applications of Chinese Materia Medica (2): "Asarum is nephrotoxic, hence it must be used with caution in patients with renal insufficiency." This statement is referenced to the Pharmacopoeia of China published in 1977, but it is unclear what the basis was for these comments. Was it based on laboratory animal studies; were there clinical observations that could truly link the herb to this adverse effect? Such questions might be resolved if one could find the original source materials, which are not further referenced and may be deeply buried in the Chinese literature of the revolutionary times. One possibility, given what we know now but was unknown then, is that a variety of Asarum that did contain aristolochic acid was used either in laboratory animal studies or in clinical work and actually caused the adverse reaction at the level of the kidneys. In Chinese Herbal Medicine (14), based on information gathered at the end of the 19th Century, it is stated that: "A caution is offered in regard to a plant called muxixin [woody asarum], which is considered to be poisonous, and the similarity of names to tuxixin [local asarum] might lead to error." Under the heading of xixin, which is identified as Asarum sieboldii, it is stated that "this drug seems to be confused with tuxixin, Asarum forbesi in commerce." This would suggest that, at least in the past, toxic varieties of asarum have been mixed in with the ones of low toxicity, and this may be the cause of the nephrotoxicity that is briefly mentioned. However, there are many other possible explanations.
In the 1988 English-language Pharmacopoeia of China (17), asarum is not included, so one can't know if this earlier caution about toxicity has been retained. Aristolochia fangchi, which definitely contains aristolochic acid, is included, and there are no cautions or warnings about it, since no problems with this herb had been reported in China, at least by the date of this Pharmacopoeia. In fact, an extensive report on toxic effects of herbs that was presented at an international conference in Hong Kong in 1984 (18) did not include asarum or Aristolochia fangchi, even though there was a section devoted to herbs that could cause adverse effects on the renal system.
Essential oils, which are a component of asarum, are known to herbalists as "kidney irritants" if taken in large quantities. Thus, for example, pennyroyal, a member of the mint family, became known as a dangerous herb when at least one woman took a substantial quantity of the oil (being used as an emenagogue) and suffered kidney failure. It is possible that the concern about asarum expressed in the above-mentioned texts was related to its essential oil content (if the dosage were high enough) rather than aristolochic acid.
The essential oil of asarum is reported to be toxic to animals. In Medicinal Plants of East and Southeast Asia (5), it is said that: "the rhizomes contain 3% essential oil, which, if administered to frogs, rats, or rabbits, first causes great irritability, then paralysis, then death." The dosage that causes such reactions may be many times higher than what could reasonably be consumed in any human applications, so this statement that sounds rather alarming, may not be clinically significant. In Chinese Materia Medica (6), the dosage needed to produce such toxic reactions is more clear, in that this same commentary about the essential oil is repeated and then followed by an LD50 value (dosage at which 50% of animals die), which is 12 grams/kg, a very high amount (this dosage may pertain to the raw materials equivalent). For the European asarum, commonly called asarabacca, Health Plants of the World (9) notes that "Although it is mentioned in classical writings and official in some pharmacopoeias to the end of the 19th Century, recent writers make special mention of its poisonous properties....The essential oil of asarabacca is toxic, and in large doses can cause nephritis, metritis, hyperemia of the internal organs, and, in extreme cases, death." While this herb, being a powerful emetic and expectorant, is clearly different in its composition from the Chinese asarum, the warnings about the essential oil confirm what has been claimed for that component of the other Asarum species. In this case, a kidney reaction, nephritis, is said to be an effect of the essential oil (which would not include aristolochic acid, a non-volatile and non-oily component).
The main problem with use of asarum, as understood by Chinese herbalists, is related to overdosing. In the Advanced Textbook of Traditional Chinese Medicine and Pharmacology (3), where asarum is classified with herbs to warm the interior rather than with herbs to relieve the surface, it is said that "Large doses should be avoided." The dosage range indicated is 1-3 grams (the same as that indicated in the other materia medica guides), which, compared to many Chinese herbs, is already quite low. The vast majority of herbs used in Chinese medicine are given indicated to be used in doses in the general range of 3-15 grams/day. In the book Thousand Formulas and Thousand Herbs of Traditional Chinese Medicine (4), the caution about asarum dosage is stronger: "Never over dose."
Despite the caution about excessive use, the amounts sometimes indicated for dosage of asarum in formulas can be relatively high. In Formulas and Strategies (7), the commonly-used prescription Xiao Qinglong Tang (Minor Blue Dragon Combination) indicates the asarum dosage at 9 grams per day in decoction. However, in the subtext it is said that "Today, the dosage of dry ginger and asarum is reduced to 3 grams because of the very hot nature of these herbs." In the same book, asarum is again used at 9 grams in decoction for Shegan Mahuang Tang (Belamcanda and Ma-huang Combination), and at 6 grams in Danggui Sini Tang (Tang-kuei and Evodia Combination), both without commentaries indicating a dosage reduction in modern times. In the book Thousand Formulas and Thousand Herbs of Traditional Chinese Medicine, most of the formulas with asarum have been adjusted to indicate 1.5 grams or 3.0 grams per day for this herb. Nonetheless, there are some formulas indicating 5 or 6 grams per day in decoction.
Although most of the Materia Medica guides do not present any traditional-style contraindications to the use of asarum, there are some that appear on occasion and are represented by this statement in the Advanced Textbook:
Since asarum has a strong acrid and aromatic flavor and dispersive action, it is contraindicated in patients with profuse sweating due to qi deficiency, headache due to yin deficiency leading to hyperactive yang, and cough due to deficient yin and lung heat.
These contraindications are consistent with the concept that asarum is hot and spicy; however, some other hot and spicy herbs do not have these contraindications specifically associated with them, suggesting that reactions to asarum have, in fact, been noted in clinical practice.
Clearly, the total body of Chinese literature, most of which lists few if any cautions or adverse reactions for asarum, conveys the sense that when used properly and at reasonable dosage, asarum is a safe and reliably effective herb. Still it appears evident that it readily becomes harmful if used in doses that are excessive or in situations that are inappropriate.
A possibility that must be faced in modern times is that even at doses that are smaller than were ever noted to be problematic before, the herb might become harmful under the conditions some patients present. There are chronic diseases that were not characteristic of Chinese experience, use of drugs that alter metabolism, circulation, and other conditions, and dietary and lifestyle patterns that might make herb users more sensitive than the Chinese population that used the herbs during the development of the tradition. Also, it is possible that some toxic reactions did occur among the Chinese but that these were not directly attributed to any specific herb because of the delay from time of dosing to when the effects become apparent, or attributing the reaction to prescribing an incorrect formula (that didn't match the patients symptoms and signs) rather than the specific herb.
The statement in Formulas and Strategies that the dosage of an herb has been lowered because it has a very hot nature would not imply, to most readers, that the herb is dangerous to use; rather, one might take from this statement the idea that it would make the patient feel uncomfortable, such as a burning sensation in the stomach after ingesting it, or a feverish condition with sweating some time later. Indeed, most practitioners of Chinese medicine have used the herb without observing any adverse effects and would likely be concerned only that it be used appropriately.
Even if asarum is entirely safe in the hands of qualified practitioners of traditional Chinese medicine who are knowledgeable about the traditional and modern literature, there remains a potential for blaming the herb for coincidental adverse effects. For example, if a patient takes some Chinese herbs and, either soon after or some time later, displays a serious health problem, the Chinese herbs might be deemed suspect. If asarum is used in the treatment, a quick search of the medical literature for the formula ingredients will reveal issues surrounding both safrole (carcinogenicity; liver-related reaction) and aristolochic acid (renal toxicity). Asarum can fit the picture, developing in the minds of medical doctors, that Chinese herbs are dangerous for the liver and kidneys.
The ease with which people are now able to access a large body of information taken outside of any context, especially via the internet, gives the presence of any safety concerns new significance. One of the first Chinese herbs to become widely known after the introduction of professional Chinese herb prescribing in the U.S. was astragalus. The herb became known largely because of its immune-enhancing properties that had been researched not only in China but also in the U.S. When some individuals who were prescribed astragalus by an acupuncturist or other natural health care provider then asked their physicians about it, considerable alarm was generated. The physicians did not have access to Chinese medical books, but when they turned to American books about herbs, they readily found reference to astragalus. What they found was that astragalus poisoned cattle and other livestock. Rushing back to warn their patients that they had been prescribed a very toxic herb, the flaws in the literature drove a wedge between the herbalists and doctors, with patients caught in-between. What was found in the American literature was true: astragalus, known as "loco weed" because of the bizarre behavior of animals after they consumed it, has poisonous leaves. But, the Chinese herb, obtained from the roots of a different species, did not contain the poison in the leaves. The situation is, in fact, identical to that with potatoes and tomatoes. People can eat the food portion of the plant regularly without any concern for their safety, but the leaves of the same plants are highly toxic and can cause severe reactions and deaths. A person not familiar with potatoes and tomatoes looking up their botanical name, Solanum, would be horrified at the toxicity described in the literature.
Today, with the ability of doctors and patients to scan a vast literature, one could easily become quite alarmed about the use of asarum. Indeed, some texts about herbs focus on the expanding information about harmful effects, mostly based on laboratory animal studies. In the German book Chinese Drugs of Plant Origin (19), most of its analysis of the pharmacology of asarum is devoted to the carcinogenicity studies of safrole, since this is the information that comes up on an international literature search. Pharmacology studies performed in China on positive effects of the herb (such as on cough), rarely appear in the abstracts that are available to researchers. Therefore, when a patient or physician looks into the ingredients of a prescribed formula and they search for information on asarum, the results may not be favorable.
This potential concern about asarum's inclusion in a formula becomes more significant in some instances: in some traditional formulas, asarum is combined with other herbs that have also given rise to recent safety questions. For example, Mahuang Fuzi Xixin Tang, of the Shanghan Lun, is comprised of just three herbs: ma-huang, asarum, and aconite. As noted above, ma-huang has been a target of regulation due to claims of adverse effects of its major active constituent: ephedrine. The processed aconite used in this formula has not been reported to cause harm, but the unprocessed root is still used in China and is the principal traditional herb known to cause adverse reactions to Chinese herbs (therefore, the literature on aconite appears quite alarming). The formula was designed for the treatment of weak patients suffering from congestion with watery sputum.
Today, practitioners are cautioned to not give herbs such as ma-huang and asarum to weak patients based on the concept that they have strong "dispersing actions." Thus, even some practitioners who are comfortable with prescribing most Chinese herbs will be worried about the formula and its ingredients. By contrast to the cautions that these practitioners have learned, both aconite and asarum were traditionally considered to benefit cold, weak individuals, and ma-huang was not deemed to be harmful for weak patients when these other herbs were present in the formulation. This situation reveals that worries about traditional herbs can spread over time, even without the influence of modern chemical and pharmacological analysis.
Another Shanghan Lun formula is Tang-kuei and Jujube Combination (Danggui Sini Tang), which contains both asarum and akebia. Akebia has frequently been substituted by Aristolochia species that contain aristolochic acids. As with the above-mentioned formula, this prescription is also for patients who are weak and cold (the remainder of the formula is derived from Cinnamon Combination, with tang-kuei replacing fresh ginger). Still another example is the formula Gleditsia and Asarum Formula (Tongguan San) formulated by the famous physician Zhu Danxi. The formula contains only two herbs: asarum and gleditsia fruit; the latter is listed in materia medica guides as "slightly toxic." The toxicity may be due to the high concentration of saponins, which leads to a strong hemolytic effect and an irritant action on the stomach.
The future of asarum in Chinese herbal medicine is unclear. At this time, it remains available for use, and there are no indications that low dosage over a moderate period of time has been associated with any signs of toxicity. When it is used, the dosage should be limited to 3 grams per day by decoction or the equivalent in dried decoction; the dosage of the powdered herb should be limited to about 1 gram per day. Duration of continuous therapy should be limited to three months, as is characteristic of most treatment strategies using this type of herb (interior warming, surface relieving). It might be used again, if needed, at a later time.
Beginning in the year 2000, ITM has been deleting asarum from its formulas in anticipation that this herb will eventually be deemed unacceptable based on the possibility of containing minute amounts of aristolochic acid. In the absence of that finding, the herb may still become restricted due to content of safrole and related compounds, as the amount present in some species of asarum places these as major constituents rather than incidental ones. Seven formulas produced by ITM were affected by this action: four were mainly used in the treatment of sinus congestion due to various causes (including viral and bacterial infections and allergies), one was mainly for headache, one was mainly used for arthralgia, and the other was for general wind-cold syndromes, which could include sinus congestion and arthralgia. In each of these formulas, asarum comprised only 5% of the prescription, with one exception, Asarum 14, at just 10%. Even then, at a high dose of 15 tablets per day (well above that suggested on the label, but consistent with dosing for short-term treatments), the amount of the asarum herb powder would be just 1 gram. The herb is being substituted by different items in each formula, depending on the role that asarum was intended to fill in the overall prescription.
Ultimately, all herbs are toxic at some dosage level, and all herbs contain ingredients that can be shown to be carcinogenic or mutagenic in a laboratory test. Therefore, herbs cannot be reasonably rejected solely on the content of an individual ingredient or solely on the basis of laboratory evaluations that involve massive overdosing of the herb. In the case of aristolochic acid, it has been proposed recently that even small amounts can be problematic in susceptible individuals, making it difficult to find an acceptable dosage level. By contrast, safrole and other allylbenzenes, as well as numerous other essential oil ingredients that may be mutagenic or carcinogenic (in animals), may be of limited concern for human consumption and would not cause one to avoid an herb altogether. Since asarum is such an important herb to the Chinese tradition, efforts will no doubt be made to obtain material that is free from aristolochic acid so it can continue to be utilized.
The American Herb Products Association (AHPA) has recently recommended that herb product manufacturers avoid all herbs containing pyrrolizidine alkaloids. These are alkaloids that can accumulate in the liver if high enough quantities are taken and laboratory animal studies show them to be carcinogenic. They are very widely distributed in nature, and, if such restriction is followed, the effect would be to eliminate numerous herbs. The Western herb comfrey, which had become popular worldwide, was banned from internal use on the basis of the content of these alkaloids, but only after one individual, who consumed huge amounts of the herb tea daily, suffered from liver damage (thus, a human case of herb effect, not just laboratory animal studies). However, this herb appears to have been used safely in the usual doses. A ban on European tussilago (coltsfoot), for which the Chinese herb is still used, was enforced later in the U.S. In Europe, the German Commission E (15) put tussilago onto the unapproved list, based on this consideration of its alkaloid constituents, thus preventing it from being widely used.
Product liability insurance carriers in the U.S. added a waiver for products containing any amount of ephedrine, whether from the herb (ma-huang) or any other source. This means that if a manufacturer wishes to include a formula with ma-huang, they have to forego protection from any legal actions taken against them based on use of the product. Given the litigious orientation of our time, this restriction all but forces herb product manufacturers to discontinue inclusion of the herb in any formulations, despite the fact that the FDA has proposed safe levels (not to exceed 8 mg ephedrine per dosage, 24 mg per day).
The approach of either banning herbs or otherwise making them unmarketable due to inclusion of a substance-at any dosage-is disconcerting. While it helps protect the public from perceived potential dangers and any actual dangers, it gives the impression that by eliminating a few herbs one can make herbal remedies safe. In fact, such safety is only relative. The question that arises is how many herbs will be eliminated before one determines that herbal medicine is no longer a separate therapeutic interest? Will it instead be incorporated into the realm of drug therapy where there is plenty of safety testing and the adverse effects are quantified and put on the warning label (or the drug is simply not approved)? If so, we may be left with a few beverage herbs and the rest (only a few) being sold as drugs. The case of asarum gives some insights into how this issue is developing.
August 2000
Figure 2: Asarum sieboldii.
Figure 3: Asarum heterotropoides.
Figure 4: Representative chemical structures for the allylbenzenes.