SAFETY ISSUES AFFECTING CHINESE HERBS:

The Case of Dictamnus and Herbs for Skin Diseases

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

BACKGROUND

During 1990-1992, several articles and letters appeared in the British journal Lancet and in dermatology journals commenting favorably about the use of Chinese herbs for treatment of pediatric eczema (1-7). The reports had evolved from work done during the late 1980s by a Chinese doctor practicing near London's Chinatown: Dr. Luo Dinghui, then president of the Association of Traditional Chinese Medicine. She had been prescribing herb decoctions-following a basic prescription-with evident success in treating eczema, including cases where prior treatment with modern medicine had been unsuccessful. In a letter to Lancet, it was stated that (1): "We have seen many children with moderate to severe eczema who have been treated with this herbal tea and the response is undoubtedly impressive, with a noticeable improvement in the skin condition and a reduction of pruritis occurring within 2-7 days in all children." As described by Dr. Atherton and his colleagues at the Department of Dermatology, Hospital for Sick Children, London (2):

The effectiveness of such treatment was first suggested to us about six years ago, when a child with severe atopic eczema under the care of one of us was taken by his parents to see a Chinese doctor, Dr. Luo. The boy was treated with a daily decoction prepared from a mixture of dried medicinal plant materials. It was impressively effective and had no obvious adverse effects. Subsequently, we followed the progress of some 30 other children treated by this doctor and observed sustained and substantial improvement in about 75%. In most cases, the eczema had been severe and inadequately controlled by any of the treatments that had previously been used, despite good compliance. It became clear to us that decoctions of traditional Chinese medicinal plants might be generally more effective than the conventional treatment used for atopic eczema in Europe and North America. Furthermore, careful observation of patients receiving this therapy failed to reveal evidence of any obvious toxicity."

The formulation appeared sufficiently successful that a company, Phytopharm, decided to market it as a standardized preparation under the trade name Zemaphyte (zema from eczema; phyte from Phytopharm). The 10-herb formula used for conducting further research on Dr. Lu's approach was listed as (5):

Botanical identifications for these herbs are uncertain (the author stated that they were "provisionally identified"); the species for licorice is probably incorrect, as the Chinese material is from Glycyrrhiza uralensis. Some of the herbs have common substitutes, such as mutong (from Akebia species, Clematis species, and Aristolochia species). In the first published letter about this formula (1), viola (zihuadiding) was listed in place of potentilla (weilingcai or fanbaicao), and mutong was described as "Caulis akebiae." Also, the Paeonia species for the original formula was listed as Paeonia suffructicosa (mudanpi). In the 1995 patent application for processing the herbs to make Zemaphyte, licorice is specified as Glycyrrhiza uralensis, dictamnus is specified as Dictamnus augustifolia (rather than the more commonly mentioned D. dasycarpus) and mutong is specified as Akebia trifoliata. Articles describing the herb therapy sometimes refer to the brand name Zemaphyte, but it is not always clear whether this term is being used to describe the Phytopharm version or other preparations that were used previously.

The therapeutic principles involved in this formulation are standard for eczema therapy. The disease (eczema, atopic dermatitis) is commonly defined in China as a wind-damp-heat syndrome affecting the surface (skin); herbs that dispel or calm wind, dry damp, and clear heat are indicated. In one of the early journal letters (4), it was proposed that the main active component of the treatment was paeonol, an active component found in the Chinese herbs white peony, red peony, and moutan.

After an initial controlled study for pediatric eczema (5), a follow-up was done using a cross-over clinical research model (placebo followed by herb therapy; or herb therapy followed by placebo) to see how well the Chinese herbs would fair under careful observation in adults (7). Side effects were monitored and said to be mild: of 40 patients enrolled in the study (31 completing it), only 2 patients reported possible adverse responses (mild abdominal distention and headaches) while taking the herbs.

The various reports about the efficacy of the formulation were reviewed (8), indicating a positive outcome (here is the review abstract):

A traditional Chinese herbal therapy (Zemaphyte) for the treatment of atopic eczema is currently being assessed. This review attempts to highlight its success in patients who are recalcitrant to Western forms of treatment and the rationale behind its use. The herbal preparation is a mixture of 10 herbs with some known pharmacological agents and actions. The concept of such a complex mixture in clinical treatment is anathema to Western medicine but acceptable in traditional Chinese medicine. As this formulation has been shown to be effective in two double-blind crossover trials, investigative work on components from the mixture must be established in order to find the active constituent(s) and describe their mode of action. This research will also lead to a greater understanding of the complex immunopathology of atopic eczema.

Amidst this favorable opinion of Chinese herbal medicine (published in 1994), there was a great growth in demand for Chinese medicines and use of Chinese medicines for treatment of eczema. Nonetheless, some skepticism arose, even among those who initially reported favorably. For example, J. Harper, who contributed to the first favorable letter, wrote again in 1994, reiterating the positive comments and then saying (19):

Nevertheless, the effect is usually temporary, with relapse after treatment is stopped. Even if the treatment is continued, its effectiveness often wears off after a variable period, usually around six to 12 months....Large numbers of parents are taking their children for this type of treatment, often in the misguided belief that this is a cure and that so-called natural products are safe. It needs to be realized that the beneficial effect of traditional Chinese medicine for eczema is temporary....Some of these plant materials are variable in the yields of their constituents; the paeoniflorin content of 12 samples of red peony root (Paeonia lactiflora) bought in London varied from 0.01% to 4.5%. This raises questions about the standards and quality assurance procedures used for Chinese medicinal plants available in the United Kingdom."

THE SITUATION CHANGES

Unfortunately, beyond the skepticism, bad news was beginning to accumulate and more was to follow. Words of caution had been raised from the beginning, and now they seemed prophetic. In the first medical letter about the apparently successful treatment published in 1990 (1), the authors cautioned: "This tea possibly contains novel compounds that could be developed for treatment of eczema. However, until more is known about the chemical nature of these herbs, there remains concern about possible long-term toxicity." In the second report of a controlled study (7), the authors warned:

Herbal treatments are potentially toxic, and hepatotoxicity caused by herbal remedies is well recognized. To our knowledge, there has been one published case of hepatitis in a child receiving traditional Chinese herb therapy for atopic dermatitis, though the formula given to the child differed from that studied here and no pre-treatment liver function tests were done. Nevertheless, we strongly recommend that, before receiving this therapy, all patients should have hepatic and renal function testing, which should be repeated at least every 6 months throughout the course of treatment. Furthermore, all patients with a history of jaundice or alcohol misuse should be excluded. Women of childbearing age should have adequate contraception during treatment. To date, animal studies have revealed no evidence of short or medium term toxicity (unpublished) although the possibility of idiosyncratic reactions in individual patients cannot be ruled out.

Indeed, news of adverse reactions soon followed. There was a report of potentially reversible liver damage from use of Chinese herb formulas for eczema found during a one-year follow-up to the study by Atherton and Sheenan (9) involving children treated with the Chinese herbs. A second notice about hepatic reactions appeared that sounded more alarming (10); here is the abstract:

Traditional Chinese herbal remedies are widely available in the United Kingdom for the treatment of chronic skin disorders. Their benefits are considerable, but their use is completely unregulated. Two patients are described here who suffered an acute hepatitic illness related to taking traditional Chinese herbs. Both recovered fully. The mixtures that they took included two plant components also contained within the mixture taken by a previously reported patient who suffered fatal hepatic necrosis. These cases highlight the need for greater awareness of both the therapeutic and toxic potential of herbal remedies, as well as greater control of their use.

The two herbs that were reported to be common to all the mixtures were dictamnus and species of Paeonia, possibly moutan (P. suffructicosa). The formula blamed for fatal hepatic necrosis, one quite similar to Luo's basic prescription, was reported to have caused liver inflammation during an initial use for 3-5 months and then the fatal consequences upon re-exposure to the herbs later for a period of 2-3 weeks.

Next, there was a report of cardiomyopathy attributed to Chinese herbs for treating eczema (11). The abstract:

Chinese herbal medicines are increasingly being used as an alternative treatment for chronic skin disease. Most patients and many doctors remain insufficiently aware of their potential toxicity. We report a patient with eczema who developed a severe cardiomyopathy following a 2-week course of Chinese herbal medicine. The connection between the two conditions was not made until 2 weeks after presentation when the patient was specifically asked if she had ingested any unusual substances. The belief that herbs, as natural products available without prescription, are harmless, is commonplace and patients may not consider them worthy of mention during a standard medical history.

The initial favorable impression of Chinese medicine for eczema began to turn more sharply. In a 1999 systematic review (12) of the Western clinical trials involving Chinese medicine and eczema, nothing beyond the two controlled trials mentioned above were found, and the issue of safety began to loom large:

Chinese herbal treatments are being promoted as a treatment for eczema. The aim of this study was to systematically review the evidence for or against this notion. METHODS: Extensive literature searches were carried out to identify all randomized clinical trials on the subject. Data were extracted from these in a predefined standardized fashion. RESULTS: Only two randomized clinical trials were located. Both imply that a complex mixture of Chinese herbs is more effective than placebo in treating eczema. Yet, several caveats exist, most importantly the lack of independent replication. Adverse effects have also been reported. CONCLUSIONS: At present it is unclear whether Chinese herbal treatments of eczema do more good than harm.

In the same year, the results of another double-blind clinical trial were published (15), in which the herb preparation Zemaphyte was tried in a group of Chinese patients. The study indicated no significant effect from Zemaphyte, leading the authors to speculate that there might be some racial factors involved in the different results. They assumed that the positive studies involving mainly Caucasian London patients were correct, so that the failure of the Chinese patients to respond in their study might indicate that a genetic factor was critical to gaining the response from herbs (e.g., differences in binding or metabolism of active components). The question about whether adverse reactions outweigh positive effects no doubt seemed even more significant in light of no significant positive response.

Also in 1999, further reports of adverse effects of Chinese herbs for eczema emerged. In this case, renal failure occurred in two women undertaking long-term Chinese herbal therapy for eczema in London (24). The toxicity was blamed on aristolochic acid, found in the herb mutong (when derived from Aristolochia manshuriensis). Mutong (which is also derived from species of Akebia and Clematis that don't have aristolochic acid) is a common ingredient in therapies for eczema, including the formulation of Dr. Luo that was being widely used. This was the first indication that akebia was a potential safety hazard; prior to that, only stephania (substituted by Aristolochia fangchi) was considered a risk. Soon after these two reports, the use of all Aristolochia species was banned in the U.K. and then in the U.S. (see: Are Aristolochia plants dangerous?).

The cases of hepatic reactions apparently due to use of Chinese herb formulas for skin diseases were sufficiently numerous to require further investigation by those involved with prescription of herbs in the U.K. Richard Blackwell, of the Northern College of Acupuncture in London, detailed background information for 6 such patients (13), including patients mentioned previously (9, 10). He also described efforts that were being made to determine which herb or herbs could be responsible, a process that is still underway.

Dictamnus (Dictamnus dasycarpus; baixianpi) is one of the most commonly used Chinese herbs for treatment of eczema, and was found to be an ingredient, usually a major ingredient, in the formulas taken by each of the 6 patients who had a reported hepatic reaction. Currently, the only reason that dictamnus is suspected as being a possible rare cause of herb-induced hepatitis is the fact that these cases all had dictamnus in common (see next section). The herb has not shown up as a liver toxin in laboratory animal testing, and it is not reported in the medical literature from other countries (outside the U.K.) as being suspect for causing adverse liver reactions. However, a similar situation-finding no laboratory animal or early clinical reports of liver toxicity-existed when another herb that had appeared safe, kava, became suspect for causing rare adverse liver reactions. Most of those reactions were reported in Germany and Switzerland.

The implication of dictamnus as a potential culprit in the liver toxicity cases in England was relayed in a recent British review article (14). Another Chinese remedy, a patent called Jin Bu Huan, was also mentioned as a cause of liver toxicity reactions in England. This patent had been removed from the U.S. market in 1994 as a result of liver toxicity reports (the patent contains tetrahydropalmatine, an alkaloid that was used for alleviating pain and promoting sleep). Comfrey, a Western herb, was removed from the U.S. market recently due to a small number of reports of adverse liver reactions, coupled with knowledge of a specific active ingredient that can cause liver toxicity (see: Pyrrolizidine alkaloids). The Zemaphyte product was not granted marketing authorization or a pharmaceutical license in the U.K. because of the growing concerns.

Unfortunately, when rare liver reactions occur (if, indeed, they can be blamed on the herb), it is usually not possible to know the specific mechanism of action. These are likely idiosyncratic reactions where a person is sensitive to an herb component that does not adversely affect most other people. Practitioners who use the herbs should alert their patients to the potential adverse effects, with emphasis on their rarity, unpredictability, and serious consequences. Alternatively, the herbs can be avoided altogether. However, these cases illustrate that herbs considered generally safe may later be revealed to have rare adverse effects when they become popular and are used more frequently, in a wider range of doses, and for increasing durations. Therefore, one cannot assure complete absence of potential idiosyncratic reactions in any herbal therapy. Instead, one can reasonably expect a very low probability of serious incidents by minimizing patient exposure to those herbs that appear to have a somewhat elevated rate of adverse events-including not using the herb or using it in only moderate dosage and short duration.

In a 1995 report from London about apparent hepatic reactions to Chinese herbs when treating skin diseases (16), the authors described the difficulty in pinning the blame on a specific herb or reaction:

From January 1991 to December 1993, we received reports of 11 cases of liver damage following the use of Chinese Herbal Medicine (CHM) for skin conditions. There was strong evidence of an etiological association in 2 cases in which recovery after dechallenge and recurrence of hepatitis after rechallenge were observed. The time-course relationship, recovery after ceasing CHM, and absence of alternative causes of liver damage suggested an association in 2 further symptomatic cases following a single period of exposure. Herbal material was available for analysis in 7 cases. The plant mixtures varied, so no single ingredient could account for liver injury in this case series. The mechanism of toxicity is unclear; effects do not appear dose-related and are probably idiosyncratic. Liver function should be monitored in patients who use CHM for skin disorders and its use discontinued if problems occur. The complexity of these cases illustrates the requirement for continuous surveillance of CHM including pharmacognostical investigation of ingredients.

It may be the case that people with skin diseases have a higher sensitivity to herb components than others, and several different herbs could be problematic for them. Proponents of herbal medicine commonly discuss "liver toxicity" as a cause of skin diseases, implying that a defect in the hepatic condition related to ability to process and eliminate substances is a root cause. There is currently no evidence in support of this contention, but these practitioners of herbal medicine may agree that there would be a higher chance of hepatic reactions to herbs (and drugs) amongst this group of people. Recently, a report from Italy described adverse hepatic reactions to Chinese herbs used for psoriasis (17). Therefore, with long-term herbal therapy, the recommendation to have baseline laboratory results for liver function tests and to get follow-up testing from time to time seems consistent with the fundamental approach to treating skin diseases safely and effectively.

DICTAMNUS

In the reports about hepatotoxicity of Chinese herbs used for skin ailments, the only two specific plant materials mentioned as a potential focus of concern are dictamnus and species of Paeonia. Paeonia materials (as white peony, red peony, and moutan) are among the most widely used in Chinese medicine, and have not been associated with hepatotoxicity in other contexts. By contrast, dictamnus is less commonly used and primarily applied in treatments for skin diseases, especially those with itching, such as eczema and other forms of atopic dermatitis, and psoriasis. Toxicity reports for dictamnus are absent from the Chinese literature.

The chemical composition of dictamnus has been investigated during the past 25 years, revealing a very broad range of potentially active components, including:

• alkaloids: dictamnine, trigonelline, skimmianine (Β-fagarine), γ-fagarine, dasycarpamine, platydesmine
• lactone: dictamnolactone (also called obaculactone)
• citrus limonoids (triterpenoids): limonin, obacunone
• degraded limonoids (terpenoids): fraxinellone, isofraxinellone
• sesquiterpenes: dictamnol, dictamnoside
• steroids: pregnenolone, progesterone, stigmasterol, sitosterol

The sheer diversity of components with pharmacological activity could give rise to greater opportunities for hepatic reactions. Thus far, however, none of these compounds are known to be hepatotoxic. Dictamnine and fraxinellone are among the main active components in the herb. Dictamnine is found in a few other Chinese medicinal plants (skimmia aerial part, zanthoxylum root, fagara root) of the same plant family (Rutaceae) that are even more rarely used than dictamnus. Fraxinellone is found in few medicinal plants; there are small amounts in roots of Melia azedarach (neem, used in Ayurvedic medicine). There is a remote possibility that liver reactions are the result of combining one or more of the dictamnus ingredients with those of another herb, such as a Paeonia species.

Liver enzymes that have a role in detoxifying alkaloids may produce, in some instances, toxic metabolites of certain alkaloids. For example, it has been suggested (18) that the enzyme nicotinamide methyltransferase may play such a role and have the unintended adverse consequence with quinoline alkaloids (dictamnine is a furo-quinoline alkaloid). If, for example, some individuals have a variant of the enzyme that more readily converted dictamnus alkaloids to hepatotoxic compounds, then regular consumption of the herb could lead to liver inflammation and damage. The idiosyncratic nature of the reaction would then be based on the particular genetic background that leads to a modified enzyme structure.

Unfortunately, in the search for a liver toxin in the eczema formulas, some misleading information about dictamnus was relayed in a letter to the British Medical Journal. The letter by Vautier and Spiller (20), mentions a case of fulminant hepatic failure in a 32-year-old man. He was reportedly taking a Chinese herbal remedy labeled "eternal life," and was using it as a treatment for his lipomas. Within about 5 weeks, he had advanced liver damage, and received an emergency liver transplant, but died. A cause for the liver damage could not be found among obvious viral, immunological or metabolic factors. Analysis of the formula was said to reveal the presence of Dictamnus dasycarpus, which was already of concern in relation to the Chinese herb treatments for skin ailments. The authors of this letter then stated that: "This plant contains a wide range of potential toxins, including xanthotoxin and psoralens, along with steroid-like compounds, vasoactive substances, coumarins, and flavonoids."

In a responding letter (21), Hla Myat Saw, President of the Register of Chinese Herbal Medicine, pointed out that the psoralens and xanthotoxin are in the aerial part of the plant. In fact, they are not found in the root bark, which is the part that is used in the Chinese herb formulas. The psoralens (including bergapten, 5-methoxypsoralen and xanthotoxin, 8-methoxypsoralen) are photosensitizers; they are considered a cause of photo-dermatitis that occurs in some people who brush up against the live plants. It has been proposed more recently (22) that these compounds may have some liver toxicity, but since they are not in the herb material in question (i.e., root bark), that is a moot point.

In the mean time, three doctors had already written a response (23) to Vautier and Spiller in which they relayed a second case of liver damage due to the formula labeled "eternal life." This situation involved a 27-year-old man who was an insulin-dependent diabetic. In an attempt to investigate the component of the formula that might have contributed to the event, the authors discovered that the formulation was apparently unrelated to the one that Vautier and Spiller described. It turned out that the herbalist was labeling his various formulas with this one moniker.

It remains unclear whether dictamnus was a contributor to the cases of liver inflammation and damage that have been reported, but it does remain the most frequently mentioned herb of concern in this series of British commentaries over the past 10 years, and it is worth taking note of the potential for serious reactions.

April 2003

REFERENCES

1. Harper JL, et al., Chinese herbs for eczema, Lancet 1990; 335: 795
2. Atherton D, et al., Chinese herbs for eczema, Lancet 1990, 336: 1254
3. Davis EG, Pollock I, and Steel HM, Chinese herbs for eczema, Lancet 1990, 336: 177
4. Galloway JH, et al., Chinese herbs for eczema, the active compound?, Lancet 1991, 337: 566
5. Atherton D, et al., Treatment of atopic eczema with traditional Chinese medicinal plants, Pediatric Dermatology 1992; 9(4): 373-375.
6. Sheehan MP and Atherton DJ, A controlled trial of traditional Chinese medicinal plants in widespread non-exudative atopic eczema, British Journal of Dermatology 1992; 126: 179-184.
7. Sheehan MP, et al., Efficacy of traditional Chinese herb therapy in adult atopic dermatitis, Lancet 1992; 340: 13-17.
8. Latchman Y, et al., The efficacy of traditional Chinese herbal therapy in atopic eczema; International Archives of Allergy and Immunology 1994; 104(3): 222-226.
9. Sheehan MP and Atherton DJ, One-year follow up of children treated with Chinese medicinal herbs for atopic eczema, British Journal of Dermatology 1994; 130(4): 488-493.
10. Kane JA, Kane SP, and Jain S, Hepatitis induced by traditional Chinese herbs; possible toxic components, Gut 1995; 36(1): 146-147.
11. Ferbuson JE, Chalmers RJ, and Rowlands DJ, Reversible dilated cardiomyopathy following treatment of atopic eczema with Chinese herbal medicine, British Journal of Dermatology 1997; 136(4): 592-593.
12. Armstrong NC and Ernst E, The treatment of eczema with Chinese herbs: a systematic review of randomized clinical trials, British Journal of Clinical Pharmacology 1999; 48(2): 262-264.
13. Blackwell RJ, Adverse events involving certain Chinese herbal medicines and the response of the profession, Journal of Chinese Medicine, 1996 50, 12-22.
14. McRae CA, et al., Hepatitis associated with Chinese herbs, European Journal of Gastroenterology and Hepatology, 2002; 14(5): 559-562.
15. Fung A, et al., A controlled trial of traditional Chinese herbal medicine in Chinese patients with recalcitrant atopic dermatitis, International Journal of Dermatology, 1999; ( 38): 387-392.
16. Perharic L, Shaw D, De Smet PAGM, Murray SG, Possible association of liver damage with the use of Chinese herbal medicine for skin disease, Veterinary and Human Toxicology 1995; 37(6): 562-566.
17. Verucchi G, et al., Acute hepatitis induced by traditional Chinese herbs used in the treatment of psoriasis, Journal of Gastroenterology and Hepatology 2002; 17(12): 1342-1343.
18. Alston TA, Abeles RH, Substrate specificity of nicotinamide methyltransferase isolated from porcine liver, Archives of Biochemistry and Biophysics 1988; 260(2): 601-608.
19. Harper J, Traditional Chinese medicine for eczema, British Medical Journal 1994; 308: 489-490.
20. Vautier G and Spiller RC, Safety of complementary medicines should be monitored, British Medical Journal 1995; 311: 633.
21. Saw HM, Safety of complementary medicines should be monitored, British Medical Journal 1996; 312: 122.
22. Diawara MM, et al., Dietary psoralens induce hepatotoxicity in C57 mice, Journal of Natural Toxins, 2000; 9(2): 179-195.
23. Sanders D, Kennedy N, and McKendrick MW, Monitoring the safety of herbal remedies, British Medical Journal 1995; 311: 1569.
24. Lord GM, et al., Nephropathy caused by Chinese herbs in the UK, Lancet 1999; 354: 481-482.

APPENDIX: Reports of Liver Toxicity from Herbal Medicines

In the article Making a Diagnosis of Herbal-Related Toxic Hepatitis by Christine A Haller (et al.) of the California Poison Control System (West Journal of Medicine 2002; 176(1): 39-44), a table of liver toxicity reports was included. An edited version is produced below. The cases are limited to those found in English-language case reports, case series, case-control studies, and clinical reviews from 1996-2002 that were found in response to a MEDLINE search. The number of reported cases of liver toxicity is remarkably small. Of the items listed, only three involved use of Chinese herbs: the eczema herbs, Jin Bu Huan, and ma-huang.

Additional information: reports of liver reactions to kava preparations appeared in 2002, and included approximately 30 cases, mainly in Germany and Switzerland. The number of cases of liver reaction to Chinese herbs for eczema mentioned in a 1995 article (16), included 11 cases of liver reaction (compared to 6 mentioned above), with the other five not confirmed. Similarly, the Poison Control Center in Denver, Colorado, which was monitoring the Jin Bu Huan cases in the U.S., had unofficial reports of additional cases of liver reactions, about five more than that reported here. Two additional cases of liver reactions to herbs for psoriasis were noted in Italy (17). Haller et al., included in their table reported epidemics of liver reactions due to contamination of food grains with Crotalaria species, a source of pyrollizidine alkaloids; but this did not involve reports of use of the medicinal tea (called bush tea).