ARE ARISTOLOCHIA PLANTS DANGEROUS?

by Subhuti Dharmananda, Ph.D., Director, Institute for Traditional Medicine, Portland, Oregon

REPORTS OF TOXICITY AND ENSUING FDA ACTION

On May 16, 2000, the U.S. Food and Drug Administration (FDA) sent out a letter cautioning manufacturers of herb products to avoid using herbs that contain a compound known as aristolochic acid (AA). The FDA indicated its intention to ban the import and distribution of products containing this compound or the plant materials that are known to contain it (1). Among the herbs presented in a list accompanying the letter were several plants of the Aristolochia genus, mainly those used in Chinese herbal medicine, though some species have been used in other herbal medicine systems (including Ayurvedic, European, and American herbal medicine). AA is a compound found in virtually all plants of the Aristolochia genus (see: Safety issues affecting herbs: the case of asarum). Also included in the listing were several non-Aristolochia plants for which the FDA expressed concern that they could be substituted by Aristolochia plants, thus inadvertently providing AA. The reason given for this FDA action was that similar actions were being taken in Canada and the United Kingdom (the U.K. order was announced almost simultaneously, on May 19th, to take effect June 16, 2000). However, the compelling factor was the conclusion about the possible role of AA in renal diseases presented in an article, with contents known to the FDA in advance, that appeared in the New England Journal of Medicine (NEJM) three weeks later (2).

The article reported on cases of urothelial cancer (cancer of the urinary system endothelial tissues) apparently induced by exposure to aristolochic acid. This article was a follow-up to several earlier reports about multiple cases of renal failure that occurred at a Belgian weight-loss clinic. The adverse impact of the complicated weight loss program had been blamed, by some, on the use of Chinese herbs, starting with a 1993 article in Lancet (3). Other investigators contested the role of the herbs, suggesting that drug treatments at the clinic caused the problem or, at the least, that the herbs became toxic to the kidneys only because of the inducing effects of the other treatments. The patients with urothelial cancer mentioned in the NEJM article were a subgroup of those who had suffered renal failure after attending this weight-loss clinic.

The authors of the New England Journal article stated (bracketed comments are added for clarification by the current author; parenthetical comments are from the original article):

The role of Chinese herbs (specifically, aristolochia species) as a cause of renal failure and urothelial carcinoma is still a matter of debate, for several reasons. First, promoters of Chinese herbs have claimed that the renal disease originated from the injection of a "hidden substance" (serotonin) at the time of mesotherapy [injection therapy]; this claim has not been confirmed. Second, analgesic nephropathy is a frequent type of renal disease in Belgium and could thus be misdiagnosed as Chinese herb nephropathy. Third, similarities between Chinese herb nephropathy and Balkan endemic nephropathy have been described, including the association with urothelial carcinoma. Some evidence suggests that Balkan endemic nephropathy is an environmentally induced disease, perhaps related to exposure to fungal or plant nephrotoxins such as ochratoxin A and aristolochic acids. Both compounds are nephrotoxic and carcinogens.

Our results enable us to address these issues. Thanks to the collaboration of the Belgian Ministry of Health and of pharmacists, we were able to quantify the cumulative doses of the compounds taken by our patients. Insofar as DNA adducts [compounds linked to DNA] in tissue samples are valid biomarkers, we assessed possible exposure to tobacco, aristolochic acid, and ochratoxin A. We found that renal failure with or without urothelial carcinoma developed in some patients who never received mesotherapy (and thus were not exposed to any "hidden substance"), who were not regular users of analgesics or tobacco, and who had not been exposed to ochratoxin A (which is classified as a possible carcinogen in humans)....

Conversely, all patients had been exposed to aristolochic acids and had aristolochic acid-related DNA adducts in specimens of renal tissue. Moreover, the risk of urothelial carcinoma was related to the cumulative intake of Aristolochia fangchi [the Chinese herb believed to have been given to the patients that is suspected of causing the renal failure and urothelial carcinoma]. Our evidence indicates that the regular intake of powdered Chinese herbs of the aristolochia species [i.e., the powdered extract of Aristolochia fangchi, as given to these patients] dramatically increases the risk of urothelial carcinoma.

Since most of our patients were treated with appetite suppressants as well as acetazolamide [a diuretic], we cannot exclude the possibility that the former, which are serotonin agonists or sympathomimetic drugs with vasoconstrictive properties, or the latter, which alkalizes the urine, enhances the toxicity of Aristolochia species....

Our data suggest that aristolochia toxins (aristolochic acids and also possibly other derivatives) cause renal disease and urothelial cancer. Until recently, Chinese herb nephropathy seemed to be limited to an outbreak in Belgium. Now, other cases have been reported in France, Spain, Japan, The United Kingdom, and Taiwan, where cases of urothelial carcinoma have also been detected. Our results should prompt physicians to inquire about the use of herbal medicine when patients have a renal disease or urothelial tumor of unknown origin.

This somewhat complex medical explanation is worthy of careful elaboration and analysis, but the main conclusion here is that at least one component of Aristolochia plants, aristolochic acid, appears to have contributed to two types of renal problems experienced by some people who attended to Belgian clinic: renal failure and urothelial carcinoma. While the authors say only that their data "suggest" that aristolochia toxins are responsible for the renal disorders, they have made efforts to overcome several reasonable objections that had been made since the initial suggestion that the Chinese herbs in the slimming program were the culprits.

This evidence, coupled with actions taken by governmental agencies in other countries, was sufficient to cause the FDA to take action. Some proponents of Chinese herbal medicine regard the FDA action against a long list of herbs as extreme or even political in nature (that is, that the agency is making this an opportunity to interfere with the use of herbs). However, the information in this report is reasonably sufficient for the halt of trade in potential sources of aristolochic acid, at least until more information comes forward to suggest otherwise. The California FDA, headed by Richard Ko, had been aware of the allegations that Chinese herbs, specifically Aristolochia plants, might cause renal failure at least since 1996, yet neither the California FDA nor the Federal FDA took any action. Thus, the FDA awaited the pending publication-in one of the most reputable medical journals-of a report indicating the potential role of the herbs before taking action. The FDA provided, in its letter, a warning to manufacturers in advance of taking formal action against continued import of the herbs, giving herb companies a chance to test and reformulate products. A commercial test for aristolochic acid first became available in the U.S. about the same time as this FDA letter was issued. During the months following the FDA letter, some herb companies recalled products that were found, upon testing, to contain aristolochic acid.

The section of the article quoted above makes reference to the debate that has gone on regarding the cause of renal failure at the Belgian weight-loss clinic. The patients received a multiplicity of drugs and herbs and they lived in a country where renal failure is highly prevalent (usually blamed on excessive use of analgesic drugs). These confounding factors were raised as possible alternative explanations to the one focusing on Chinese herbs that has been promulgated most vigorously by the nephrologist Vanherweghem, a principal investigator of the Belgian incident. In addition, one of the doctors who was working at the Belgian clinic, Jean Malak, pointed out that most of the patients at the clinic were receiving a type of therapy that had not been publicized in the early reports by Vanherweghem, called mesotherapy. This therapy involves injections with one or more substances intended to enhance the treatment effects. The contents of the injections were unknown to Dr. Malak (and, to this day, they have not been revealed); he reported that the treatment consisted of multiple injections of 5 ml solution in the subcutaneous tissues (personal communication). He suggested that they might either contain serotonin or something that stimulates serotonin production. Serotonin has an impact on eating behavior that is desired for weight loss (helps induce satiety) and at least one doctor at the clinic was investigating the use of serotonin or substances that produce it at the time. Serotonin injections have been known to cause an adverse effect on the kidney of laboratory animals (causing degeneration and necrosis) that was first revealed in 1953 and repeatedly confirmed in laboratory tests. Both serotonin and drugs that influence its levels can have adverse effects on the heart as well. Malak contended that 90% of the mesotherapy went to female patients; all of the cases of renal failure associated with attendance at the weight loss clinic were in females.

To bolster his contention, Malak obtained data to determine the dosage of capsules taken by each of the patients. According to Malak's analysis, there was no evident association between the dosage consumed and the incidence of renal failure. As a result, he concluded that it was not the contents of the capsules (which were the only source of the herbs in question) that were the problem, but some other hidden substance-most likely the mesotherapy, which varied from doctor to doctor at the clinic. Professional herb users (rather than promoters) then quoted Malak's evidence and conclusions in newsletters, providing health care providers with a sense that the herbs were not the cause of the renal failures that had been blamed on Chinese herbs.

Malak had also called into question the claim that DNA adducts had been detected, thus countering the suggestion that they actually played a role in the pathology. He mentioned the fact that aristolochic acid had been used in Germany as medicinal agent for 15 years without reported toxicity. Herbert Wagner, a medicinal plants researcher in Germany, presented aristolochic acid as a model substance for immune regulation in a paper presented at a 1983 conference in Hong Kong (7). He stated that: "Its [aristolochic acid's] immunostimulating activity has been proven in a variety of in vitro and in vivo test systems and has recently been confirmed in a double-blind study." It appeared, therefore, that the renal failure problem had something to do with the specific situation at the clinic, and not with aristolochic acid.

HERB SUBSTITUTION AT THE BELGIAN CLINIC

Initially, the herbs of concern at the Belgian clinic were described as Magnolia officinalis and Stephania tetrandra. Neither of these herbs had been known to cause any type or renal disease, and a search of the literature reveals no reason to expect such an outcome from their use. In fact, no evidence has emerged to this day that would support a negative impact of those two species. However, in the first Lancet report of renal failure at the Belgian clinic, the actual nature of the herb that was identified as Stephania tetrandra remained a mystery, because marker compounds sought by the investigators were not found. The discovery that the herb materials used as stephania were likely to have come from Aristolochia was not reported until 1994 (4), when samples of the raw materials were analyzed and new isolation and tests methods were developed. Tests of the capsules used at the Belgian clinic continued to come out negative for AA. In the letter to Lancet announcing the finding about the raw materials, it was not stated that the aristolochic acid was the cause of the renal failure at the weight-loss clinic, but this was implied, since the compound was described as a renal toxin. Still, it was not known if the aristolochic acid would be harmful to humans in conditions other than those that prevailed at that clinic with the mix of other drugs and herbs.

In 1997, a Belgian pharmacist, C. Violon, raised concerns about the analysis by Vanherweghem of causative factors in the cases of renal failure at the clinic (12). Violon said: "The ingestion of Aristolochia fangchi instead of the prescribed Stephania tetrandra, one of the components of the slimming therapy, was put forward as hypothesis for the etiology of the nephropathies in the literature. Questions however remain unanswered: Why have certain persons, among thousands similarly treated including ingestion of aristolochic acids, not withstood the treatment [suffered the renal disorder]? Why is there no correlation between the length of the treatment and the occurrence nor the degree of illness?" He goes on to raise concerns about other aspects of the treatment regimen: "Products are injected which are not proved safe for this method of administration. The administration during long periods of cocktails with anorectics (fenfluramine and diethylpropion) in association with a diuretic, a tranquilizer, plants with laxative and atropinergic action, are alike to be at the origin of susceptibility in the excretion system." He advised that the authorities should strictly regulate the use of Chinese herbs, mesotherapy, and cocktail treatments (multi-drug therapies).

Some investigations had been launched to see if this problem of renal failure occurred elsewhere as a result of using Chinese herbs, specifically, the Aristolochia materials used in the Belgian clinic. Initial reports indicated that no such problems had occurred elsewhere in Belgium: in fact, this was noted in the original article about the renal failure incident at the weight-loss clinic. Further, after finding two possible cases in France, an extensive evaluation was carried out in France (which borders Belgium to the south) where the same raw materials that had been used in Belgium were also distributed (5): no cases of renal failure could be directly linked (the two cases that stimulated the investigation were still considered possibly linked). It was suggested by the investigators in France that there was some other factor in the Belgian clinic that led to the renal toxicity, perhaps something that increased the toxicity of aristolochic acid. The lack of or small number of other cases of renal failure from use of the same herb materials certainly suggested that something additional or something different was a contributor in the Belgian clinic. One of the chemicals mentioned in the article is ochratoxin A, a substance that had been identified as a renal toxin. This substance, which is produced by some fungal species, might have somehow contaminated something at the Belgian clinic (this possibility has been suggested, but not pursued).

There is also mention in the NEJM article of an endemic renal problem in the Balkans. There is a very high incidence of renal failure in the Balkan region, and it can affect young people (as well as the elderly who are more likely to suffer renal failure from various causes, including genetic predisposition, long-term use of analgesics, and secondary effects of diseases, such as diabetes, that impact kidney function). Debates are ongoing as to the cause of the Balkan nephropathy, including the possibilities of genetic predisposition and environmental toxins. As to the latter, it has been suggested that the environmental toxins might be aristolochic acid that comes from plants growing along with wheat and thus contained in flour products, or ochratoxin that might come from fungus-contaminated food products. Other causes, including other environmental factors, have not been ruled out. The progression of the renal disease is somewhat similar to what was seen in Belgium, suggesting the possibility that the causes are either the same or similar, or that the pathological process that is induced involves a similar mechanism.

The authors of the 2000 NEJM article claim to have resolved some of these issues for the Belgian clinic patients by finding patients suffering from the renal failure that had no significant evidence of being subjected to the other possible causes, but having DNA adducts involving aristolochic acid. According to the theory that is thereby developed, the women at the Belgian clinic who suffered renal failure ingested aristolochic acid in the capsules they were given over an extended period (many months on a daily basis). The aristolochic acid linked to DNA in renal cells and remained there, accumulating gradually over time. This type of adduct formation is believed to be responsible for some pathological processes, such as transformation of cells from normal to cancerous. This is, for example, one theory of how ochratoxins and tobacco compounds lead to cancer (alluded to in the article). In essence, it was the development of the urothelial carcinoma in several of the renal failure patients that eventually indicated a contributory role of aristolochic acid in the initial pathology. The DNA adducts were part of the process by which the renal cells eventually were damaged (perhaps by inducing an autoimmune attack) with one or more of the cells then transformed to cancerous cells (19). The possibility of an immune component of the induced renal failure is bolstered by findings that corticosteroids can slow or halt the progression of the renal failure (13).

The authors also point out that cases of apparent renal failure or urothelial carcinoma have now been reported outside of the Belgian weight-loss clinic. It is not possible to know whether the alleged cases of herb-induced renal failure were, indeed, due to exposure to AA or due to some other factor, with herb ingestion as a coincidental finding. Still, the combination of the conclusions in the NEJM article with the additional reported cases, including cases in areas where traditional Chinese medicine is regularly practice (Japan and Taiwan), contributes to the contention that AA may play a role in causing renal damage in at least some of the cases.

WERE THE HERBS MISUSED?

Some proponents of Chinese herb use blame the alleged induction of renal failure and cancer to improper use of the herbs. Suggestions have been made that the herbs were used non-traditionally, in too high a dose, in the wrong form, and/or for too long. Certainly, the way that they were used in the Belgian clinic did not mirror any traditional practices in China. The combination of Western drugs and Western herbs, mesotherapy, and other techniques that were applied over an extended period at the clinic is not congruent with the traditional use of the herbs in China. However, the dosage used appears not to be excessive, and there is no other basis for considering the herb use inappropriate, in the sense that the herbs have a reputation for resolving accumulation of dampness, one of the syndromes associated with obesity.

While the dosage of herbs used at the clinic (a few hundred milligrams of extract powder in a daily dose) is not excessive, the total amount consumed through daily ingestion for many months, may be more than is typical of Chinese herbal practices. The NEJM article mentioned that there is a dose-response relationship for the herb-containing capsules in relation to the incidence of renal disease in patients who attended the Belgian clinic. The relationship, however, is both confirmed and contradicted by the comment of the authors in the article that the aristolochic acid content of the herb materials could vary by as much as ten fold, making it difficult to determine actual dosage consumed, especially since testing of the capsules failed to provide direct data. Still, the reported daily doses of aristolochia used in the Belgian clinic are lower than those used in traditional Chinese practices, raising the question of what happened uniquely at the clinic that may have also occurred in the few cases of renal failure reported elsewhere.

As to the form, it has been suggested that decocting the herbs, as is done traditionally in China, may prevent the toxicity. Dr. Ko of the California FDA, for example, has suggested that the problem of aristolochic acid toxicity arises only when decoction step is avoided (as when simply powdering the herbs), since aristolochic acid is poorly soluble in water and would therefore not be present. However, traditional Chinese practice includes powdering crude herbs and this has been described for Aristolochia plants. In Chinese Medicinal Herbs of Hong Kong (6), there are the following directions for use of Aristolochia fordiana roots: "pulverize and dilute in water for oral use." In the Pharmacopoeia of the People's Republic of China (14), there are several formulas that are to be made as pills, in which Aristolochia species (e.g., madouling or qingmuxiang) are to be powdered and incorporated into the pill. Components of herbs that are not soluble in water are often extracted into and suspended in the hot water used in making the decoction (this is how essential oils, which have very low water solubility, enter into the decoctions). Further, decoctions, dried decoctions, and powders have now each been blamed in cases of renal failure from using Aristolochia plants, and aristolochic acid has been detected in all of the preparations. It appears that the most common preparation to have been used in cases where the herbs have been suggested to have caused renal failure is the dried decoction. The material used in the Belgian clinic was a powdered extract. Most likely, this was a hot water extract, which is the traditional preparation; only the drying of the extract is an additional step (one which has been accepted in Asia since the 1940s).

It is possible that prolonged daily administration of herbs containing aristolochic acid is a problem and this may be the key issue, along with the contributions of drug therapies or other factors introduced at the Belgian clinic (and, possibly mimicked in a few other situations). There is relatively little information from China about the duration of use of herbs, but the practice at the Belgian clinic was to give the herbs daily for months or years at a time. It is possible that short term therapies with the herbs do not result in a renal problem, at least when the herbs are used in normal dosage.

It remains unclear what time limits, if any, were ever placed on repeated use of the Aristolochia plants in traditional herbal medicine practices and it is unclear what time limit would prove safe for all users. In the Belgian cases, most of the patients who suffered renal failure were taking the preparations that included AA for more than one year (some cases arose after ingesting the herbs for three years). This prolonged application of the herbs is not a typical pattern of herb use in China, but it is also not one that is specifically contraindicated. There are numerous situations reported in modern Chinese literature of regular treatment with herbs persisting over a period of a year or more.

In modern practice in the West, herbal remedies are often recommended by health professionals for long-term use, at least so long as they continue to provide symptomatic relief or are believed to be of continuing benefit on some other basis. In at least one case of renal failure in England claimed to be associated with Aristolochia, a woman had been taking a decoction intended to treat eczema that included mutong for two years. In one case presented in Japan, a woman had been taking what was described as a "health food" product that was a "traditional remedy" for atopic dermatitis for three years; presumably it contained mutong derived from Aristolochia.

The role of modern drugs might also be critical to the development of renal problems when taking herbs containing AA. In the U.S., it was recently reported that half of all adults now take an average of two prescription drugs a year and that more than a quarter of all adults take four or more prescription drugs (after age 65, the number of prescribed drugs rises further). Dozens of approved drugs have the potential for causing adverse renal effects. These figures for drug use do not include the myriad over the counter drugs that people may use, including some, such as analgesics, that can contribute to renal failure. It is possible that use of the herb medicines derived from Aristolochia plants when used alone rarely, if ever, cause renal failure, but that when combined with certain drugs, the toxicity develops. This scenario is consistent with the proposals that vasoconstrictive drugs that affect renal circulation and/or alkalinizing agents might make the relatively small amounts of aristolochic acid problematic. If this were the case, it would support the contention that it is the non-traditional use of the herbs that led to the problem, rather than the herbs themselves. Unfortunately, this conclusion, if justified, does not really help open the door to resuming use of Aristolochia plants since so many people take drugs of various types, and many of them may not even think twice about the fact that they are using the drugs regularly when embarking on an herbal therapy. It is unknown which drugs might lead to toxicity of AA and which might not.

Therefore, while Aristolochia plants may have been used with considerable freedom of adverse effects for centuries, and although there may exist safe ways to utilize plants that contain AA today, it remains unclear what those ways are or how to enforce sticking to the safe regimen when using the herbs. Therefore, a halt to their use remains one of the only safeguards, and the FDA action is thereby justified. Most of the Aristolochia herbs used in China are not critical to herbal therapeutics in the West. Indeed, it appears that the majority of Aristolochia plants that have been used in the West during the past three decades were imported as substitutes for other non-Aristolochia plant materials that may have equally well served the purposes of the herbalists.

A TERRIBLE SCENARIO

One concern expressed by proponents of Chinese herbal medicine is whether the Aristolochia herbs that are being blamed for adverse effects were being prescribed under the care of a properly trained professional. Thus, for example, it is suspected that the use of the Chinese herbs at the Belgian weight-loss clinic did not rely on such a professional, leading to the problem (if, indeed, the herbs are accepted as the cause). However, there is some question whether or not such a professional could have headed off this problem.

According to the information that has developed from the case of the Belgian weight-loss clinic and other purported cases of Aristolochia-induced renal failure, there are no side effects observed during the time when the herbs are consumed. In fact, one can take the herbs, perhaps with good effects, for many months or years without experiencing any signs or symptoms of adverse effects. Then, according to the scenario that has developed, many months later, even after the herb use has been completely discontinued, the initial signs of renal failure will show up (such as elevated creatinine levels) in a few users of the herbs. Of those who show signs of renal dysfunction, some will experience renal failure that will rapidly progress to the point that dialysis or transplant becomes required within a few months of the renal impairment symptoms. Even later, signs of urothelial cancer may show up. Accordingly, one can have absolutely no sign of harm during the entire time that the herbs are used, and no reason to believe that the patient should stop taking the herbs. In traditional herbal practice, if a patient develops some early adverse signs, such as indications of yin deficiency or spleen weakness, one may think to halt an herbal therapy or change it. This is entirely consistent with the methodology depicted in traditional medical books. However, if such signs do not develop, especially from using a low to moderate dose of the herbs, then one might continue utilizing the herbs, noting only that they are proving helpful. If the scenario is correct, then these plant materials present a very unusual type of toxicity; it is unlike the reversible problems that are normally encountered when an herb is used in too high a dosage or for too long a time.

The inability to detect adverse effects during administration of the herb while inducing a long-term serious adverse effect would be reason to stop use of these plants, under the enforcement of an agency such as FDA. Without the intervention of the regulatory agency, it is up to every individual practitioner to decide whether the herb is safe based on the conflicting medical reports. Given the concept that is prevalent in the field of herbal medicine, that drugs are harmful and herbs are safe, it would be natural to side with the medical reports that suggest the adverse effects were due to the use of drugs, and not the herbs.

Certainly, a well-trained practitioner of Chinese medicine might have been able to avert a problem by knowing enough about the different herbs on the market and about their potential toxicities. However, the Aristolochia plants used in Chinese medicine, either as directly indicated or as substitutes, were not known to be harmful according to the majority of literature available to practitioners (see next section). The possibility of significant harm has only been revealed by the unusual course of events that started in Belgium. The person responsible for the herbs at the Belgian clinic, might have, with enough knowledge, specifically requested hanfangji (which is supposed to be sourced from Stephania tetrandra) rather than guangfangji (which is usually sourced from Aristolochia fangchi) for treatment of obesity, since the former is considered better at removing excess water accumulation and the latter is considered better at treating painful joints (so-called wind-damp syndrome). However, the materials received at the clinic pharmacy were reported to be powders in foil bags. It is doubtful that even a well-trained practitioner could have distinguished between the two; indeed, it appears that Hong Kong herb merchants who had access to the root slices had trouble separating the two varieties of fangji. In much of the Chinese literature, only fangji is specified, not the particular type. Therefore, it is unlikely that highly advanced training in Chinese herbs would have successfully averted the problem at the clinic, nor at other sites where it is claimed that aristolochic acid toxicity has been experienced from the use of Chinese herbs.

SEARCHING THE LITERATURE FOR EVIDENCE OF HARM

How would a well-trained herbalist specializing in Chinese herbs become concerned about harm from Aristolochia plants based on standard training or a review of the common literature? Given the widespread use of these plants (see Appendix) without serious accompanying warnings, it seems doubtful that a serious concern would arise. Herbalists and other authorities who have written Chinese herb texts might not have known whether the information they were relaying actually applied to Aristolochia plants or others that were used interchangeably. That aside, we can examine the literature and seek hints that there might have been evidence of harm prior to or independent of the report from the Belgium weight-loss clinic.

A review of the translated Chinese literature shows that many of the guides to Chinese herbs, or other herb books, fail to mention anything about toxicity of the Aristolochia plants. It would be easy for a reader to fail to see any evidence of toxicity or any caution that would cause one to stop using the herbs. Even if toxicity is mentioned, the references are frequently obtuse or unclear.

There are three herbs included in most of the Chinese guide books that can come from Aristolochia: fangji, mutong, and madouling. Fangji is obtained from root stocks, mutong is obtained from stems, and madouling is obtained from fruits (its root is also used in Chinese medicine, as qingmuxiang). All of these are reported to contain aristolochic acid (in the same books that make no mention of toxicity) and the content of this compound appears to always be less than 1% of the dried herbal materials (according to laboratory analysis, reported in books that incorporate such information). There are many other Chinese herbs that come from the Aristolochia (see the Appendix), but they are not included in the standard texts, which focus on the most frequently used herbs.

The herb guide required at most American colleges of Chinese medicine is Chinese Herbal Medicine Materia Medica by Bensky and Gamble (8), updated in 1993. This book lists separately guangfangji (Aristolochia fangchi) and hanfangji (Stephania tetrandra). There is no indication of toxicity in the main sections of the text for either species, though both are contraindicated for yin deficiency. This contraindication is a standard one for herbs that are diuretic. Stephania, but not Aristolochia, is further said to be contraindicated "in cases with interior dampness." There is a toxicity section at the end of each herb description when any modern information exists, and for these two herbs, the LD₅₀ is given. Under Aristolochia, only the LD₅₀ for injection of trilobine is given; under Stephania, the oral LD₅₀ for the herb is given, and it is very large: 241 grams/kg; by changing to intraperitoneal injection, the LD₅₀ drops to 2.3 grams/kg, still a very large dosage.

The section on mutong explains that: "Akebia trioliata and Akebia quinata are the plants most often listed in premodern pharmacopoeias as this herb. However, at present in China these plants are rarely used. Instead, Aristolochia manschuriensis is most often used, and then either Clematis armandi or Clematis montana." Although the herb is not described as toxic as one of its "properties," there is an extended section on cautions and contraindications, which reads:

Contraindicated during pregnancy and in the absence of interior damp-heat. This herb easily injures the fluids and should be used with extreme caution in patients with any sign of yin deficiency. Do not overdose: acute renal failure was reported following a dose of 60 grams.

An examination of the Chinese medical literature reveals that the reference here to acute renal failure refers to a single case report (made in 1965 in China) of a person who took 60 grams of mutong in one dose. The species was not clearly identified, but has been assumed to be Aristolochia manschuriensis. Since the normal dose for mutong is 3-6 grams, the ingestion of 10-20 times that dosage might, indeed, be considered dangerous by just about any herbalist, and thus a report like this may fail to alert herbalists. Extreme overdosing with herbs would naturally be expected to cause damage to internal organs such as liver, kidney, lungs, or heart, so the finding of renal failure is not sufficient to imply that this is a problem for the herb at lower dosage. Thus, for example, essential oils are often referred to as kidney irritants, and it is understood that high doses are dangerous, but that low doses are not. This single incident doesn't shed much light on the situation with using small amounts of the herb regularly: one is only cautioned to limit its dosage, presumably within the normal range of 3-6 grams.

Under madouling, the text refers to the source materials as Aristolochia debilis or Aristolochia contorta. The text does not indicate any special toxicity, but the cautions and contraindications section states: "Contraindicated in cases of diarrhea due to spleen deficiency, cough due to cold from deficiency, or wheezing. May cause nausea or vomiting if the dosage is too large." The normal dosage range is listed as 3-9 grams and it is stated that honey-frying can reduce the side effects of nausea or vomiting. There is no separate toxicity section. There is an addendum describing use of the root of the same plant, as qingmuxiang, with no warnings or mention of toxicity. Nausea and vomiting is not mentioned elsewhere for aristolochic acid or other Aristolochia plants, so this side effect may be due to other components found in the fruits.

The official Pharmacopoeia of the People's Republic of China, first published in English in 1988 (14), has a listing for Radix Aristolochiae Fanghci (guangfangji); there are no precautions or mention of toxicity. Caulis Aristolochiae Manshuriensis (guanmutong) is listed, offering only one precaution: "Used with caution in pregnancy." Under Fructus Aristolochiae (madouling), there are no precautions listed. Thus, the official book of the PRC does not indicate toxicity of these Aristolochia materials.

In the book Thousand Formulas and Thousand Herbs of Traditional Chinese Medicine (9), by the president of the Heilongjiang College of TCM, published in 1993, there is an entry for "Stephania Root (fangji), which mentions both Stephania tetrandra and Aristolochia fangchi as botanical names for the source materials, and describes the properties and uses of the herb without any indication of toxicity. The dosage recommendation is 5-10 grams. There is also an entry for Akebia Stem (mutong), which lists Aristolochia manschuriensis, Clematis armandi, and Clematis montana as botanical sources. There is no mention of toxicity, but it is "contraindicated in pregnancy." Under Birthwort Fruit (madouling), the botanical sources are listed as Aristolochia contorta and Aristolochia debilis. No mention is made of toxicity, but it is stated that "overdosage can cause nausea and vomiting." The normal dosage is 3-10 grams.

One of the authoritative modern texts on Chinese medicine is the four volume Advanced Textbook on Traditional Chinese Medicine and Pharmacology (10). This is produced by the State Administration of Traditional Chinese Medicine, and was first published (in English) in 1995. Under the heading Radix Stephaniae Tetrandrae (fangji), there is a description which makes no mention of toxicity or cautions. There is a section of remarks which states:

Both Radix Aristolochia fangchi and Radix Stephaniae Tetrandrae eliminate wind-dampness and promote water metabolism. The former is particularly effective in eliminating wind-dampness and stopping pain; the latter in promoting water metabolism and relieving edema. Both are bitter and cold, and likely to injure the antipathogenic qi.

In this rendition, the two herbs are linked in terms of their taste and nature (bitter and cold) and their ability to "injure antipathogenic qi." This does not infer possibly causing renal failure; it is, in fact, one of the concerns commonly raised about herbs that are bitter and cold in nature (of which there are many). Antipathogenic qi is the normal qi that helps to fight disease. It can be impaired, according to traditional theory, by herbs that are cold, especially those that are bitter and cold. In accordance with the nature and taste of the herbs, the text ends: "They are contraindicated for patients with poor appetite and yin deficiency and those without pathogenic dampness in the interior."

One would not think, from these descriptions, that substituting Aristolochia for Stephania would do any serious harm, nor that one needs to be more cautious than with other herbs that are classified as bitter and cold. Those cautions are to avoid excessive dosage and to avoid prolonged use in patients with certain pre-existing conditions (e.g., yin deficiency). Most professional herbalists would try to limit the duration of use of such herbs in order to avoid any chance of reducing the antipathogenic qi.

In the same text is a description of the herb Caulis Akebiae (mutong). Again, there is a description without mention of toxicity, followed by these remarks:

There are different kinds of Caulis Akebiae, and Caulis Aristolochia Manschuriensis is the one most commonly used at present. The drug is rather bitter and cold, and purges heart fire. Ancient physicians pointed out that a large dose of the drug may consume the primordial qi of the human body.

What does it mean to consume the primordial qi of the body? This could be a serious warning, but is aimed at what happens with a "large dose." Which type of Caulis Akebia were the ancients using? According to Bensky and Gamble above, it seems that it is Akebia that was used by the ancients, so the concern may have nothing to do with Aristolochia. However, the reason for including this comment in the text is made clear by what follows, which indicates that the authors were trying to demonstrate foreknowledge: "Modern medical literature also has reported that Caulis Aristolochia Manschuriensis, used in large dosage, may cause renal failure, and so attention should be paid to limiting its dosage." This appears to be the same reference as the one made in the text above, to a single case of overdose at 60 grams, the only case in the modern Chinese literature up to the time of this book's publication. In the same book, there is reference to Fructus Aristolochiaee (madouling). It has a description with no indications of toxicity, or of any contraindications.

In a lengthy review book (not available to most herbal practitioners) of plants used medicinally in East and Southeast Asia, there are one and a half pages devoted to species of Aristolochia (11). In this section of the book, there is only one mention of toxicity:

They [madouling, fruits of Arsitolochia debilis] are a bechic-expectorant and, like the roots, an antidote for snake poison, but must be used cautiously as they are poisonous [comment credited to Ch'iu]. In contrast, Stuart says the fruits are not poisonous....

This reference to being poisonous (or not poisonous), most likely refers to the potential of producing nausea and vomiting in large dosage, as mentioned in the other texts. The aristolochic acid content of medicinal species used in China is mentioned repeatedly in A New Compendium of Materia Medica, published in 1995, but there is no mention of toxicity of this substance (15).

Overall, there are some hints of toxicity, and even one case of renal toxicity at extreme dosage, but little to alert one to the possibility that use of Aristolochia can be deadly if used at normal dosage. Since herbalists are in general agreement that substantial overdosage can be harmful with most any herb, the texts do not seem to warn herbalists not to use the herbs under ordinary circumstances. If anything, one would be more hesitant about using mutong than fangji based on this literature. Yet, it was the latter herb that was implicated as a "renal toxin" in the Belgian weight-loss clinic. Concerns about mutong were not raised until 1996, during a follow-up on the Belgian events. Two years later, two cases or apparent mutong-related renal failure were reported in England.

In sum, evidence has been accumulated that indicates the potential for aristolochic acid found in Aristolochia plants to contribute to renal failure in some circumstances. Clearly, only a very small percentage of those who ingest the plant materials are so affected, and there were likely other circumstances at the Belgian weight-loss clinic that strongly contributed to the pathological consequences. Based on the current evidence, it is appropriate to discontinue use of all herb materials containing aristolochic acid.

APPENDIX: Use of Aristolochia Plants in
Chinese Medicine and Other Herbal Systems

Artistolochia plants are commonly used in China as a source of medicinal herbs. According the British Medicines Control Agency, 63 samples of prepared Chinese herbal medicines and individual ingredients being sold in the U.K. believed to be at risk for confusion with Aristolochia were sampled: of those, 28 (44%) contained aristolochic acids. These were mainly herbal materials described as fangji and mutong.

Table 1 provides an extensive, though not complete, list of Aristolochia plants currently in use in China, based on a review of books and journal articles at the ITM library. Table 2 presents reported botanical sources of fangji and Table 3 presents reported botanical sources of mutong.

Table 1: The following is a partial list of Aristolochia plants currently used in China.

Table 2: Botanical sources of the herb known as fangji. The roots are used.

Table 3: Botanical sources of the herb akebia (mutong). The stem of the plant is used. Guangmutong is most often exported from Hong Kong.

Aristolochia is also a well-known medicinal plant of India. The main species used, Aristolochia indica, is reported to be a stimulant, tonic, and febrifuge; it is used for snake bites, diarrhea, and intermittent fevers. Other species used in India are A. longa, A. rotunda, A. roxburghaiana, and A. serpentaria. The Indian Materia Medica (16) does not list cautions about their use.

In America, Aristolochia serptentaria had been used as an herbal remedy. In A Guide to the Medicinal Plants of the United States, no toxicity was mentioned (17). The authors stated:

The earliest use of this plant was based on the belief that it could protect a person from poisoning. The finely powdered root was combined with white wine (1 part root to 3 parts wine) and used to induce sweating in the treatment of malaria. The root was also used to treat typhus fever, smallpox, and pneumonia, and applied as a poultice on open wounds and skin ulcers.

In her British herb guide, A Modern Herbal (18), Grieve describes use of several species of Aristolochia in Europe, India, and South America, under the heading birthwort. The root is used, and it is: "Said to be useful as an aromatic stimulant in rheumatism and gout and for removing obstructions, etc., after childbirth. Dose: 1/2 to 1 drachm of the powdered root [2-4 grams]." For the seven species mentioned in this section, there is no comment about toxicity. There is another section devoted to snakeroot that features Aristolochia serptentaria, an herb used in America and said to be official there (meaning that it was included in the National Formulary). Here Grieve has a section on toxicity that states: "According to Pohl, aristolochine in sufficient dose produces in the higher animals violent irritation of the gastro-intestinal tract and of the kidneys, with death in coma from respiratory paralysis. The celebrated Portland powder for the cure of gout contained aristolochia, with gentian, centaury, and other bitters in the dose of a drachm [4 grams] every morning for three months, afterwards diminishing for a year or more, but its prolonged use injured the stomach and nervous system, bringing on premature decay and death." Here there is finally a description of prolonged use of a formula containing aristolochia with apparent serious adverse effects. However, the other ingredients in Portland powder, notably gentian and undisclosed bitters, might have been blamed for the effects on the stomach and nervous system, so this reference remains a somewhat obscure caution in relation to the current concerns, but possibly foreseeing what happened at the Belgian clinic when a formula containing Aristolochia was used for a prolonged time. Yet, the patients there were not reported to suffer from stomach or nervous system problems, so that it is difficult to know if their experience is linked to what was described in this book. Rather, the problem may have been related to bitter alkaloids.

Clearly, the Aristolochia plants have a widespread use in herbal medicine. There are very diverse presentations concerning the potential for harmful effects, with many sources indicating none and others suggesting harm from large doses or prolonged use. When taken in combination with the current knowledge regarding the potential adverse effects of aristolochic acid, herbalists should regard Aristolochia plants as ones that have a noble history (aristo = noble), but a limited future.

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