SAFETY ISSUES AFFECTING CHINESE HERBS:
The Case of Ma-huang
Ma-huang (see Figure 1), a widely used Chinese herb, was discovered by Western herb enthusiasts 25 years ago and converted from an herbal treatment for diseases to an energy stimulant and a weight-loss product. The reputation of ma-huang has been permanently damaged by allegations that such non-Chinese and non-traditional products caused several deaths in the U.S., including persons who did not seem to have life-threatening health problems at the time. So adverse has become the publicity about this herb that even proponents of Chinese herbal therapies rail against it, despite the fact that none of the therapeutic Chinese herb formulas have been connected with serious adverse reactions. ITM received a letter (by e-mail) in September of 2000 with the following opening lines from a distributor of Chinese herbal medicine products in London:
Autumn is in the air here in London, with a flourish of bright berries, though all eyes are turning to Sydney and the Olympics. Will any athletes be kicked out for use of any of your ma-huang products?
This antagonistic question is not from an anonymous complainant who is simply attacking the products of another organization; this is from a distributor of ITM's formulas distancing themselves by designating the herbal formulas as "your products." There weren't any athletes kicked out for use of the formulas, first and foremost because it is highly unlikely that any of the athletes would even consider using any of the formulas. But one young and talented female athlete lost her gold medal because her team doctor prescribed a cold remedy to her that included pseudoephedrine, a compound that was originally derived from ma-huang; this compound, along with others that have a stimulant activity, is banned by the Olympic Committee.
The concerns raised by practitioners of Chinese medicine predate the 2000 Olympics. Several practitioners have expressed worry about the small amount of ma-huang contained in the ITM formula Pinellia 16, fearing in some cases that it would raise blood pressure and in other cases that it would be too stimulating and, in yet other cases, that it wouldn't be suitable for a person of weaker constitution. The formula provided about 0.34 mg of ephedrine (the main alkaloid component and the one responsible for most of ma-huang's actions) per tablet; when used at the highest dosage on the label (9 tablets per day; which might be doubled by recommendation of the prescriber), the intake would be 3 mg (or 6 mg if doubled in dose). This amount should be a safe. Nonetheless, beginning in the year 2001, ITM's Pinellia 16 contains no ma-huang.
Soon after the Olympics, new questions about ma-huang were raised when a drug, phenylpropanolamine (PPA), which is chemically similar to ephedrine (see Figure 2), was suddenly banned by the FDA (with recommendations that people who have the drug in their possession immediately discontinue its use). Evidence had accumulated that rare cases of cerebral hemorrhage, causing potentially fatal strokes, occurred rarely in women using the product (the same may occur as well in men, but women were monitored due to the prevalence of suspected cases in women initially reported). The deaths that had been attributed to ma-huang involved sudden death associated with the cardiovascular system.
PPA has been one of the most frequently used decongestant drugs, with pharmacological properties and potency similar to ephedrine but with less stimulant action (making it more desirable). When PPA is used as a weight loss product, it is relied on as an appetite suppressant, for which it is stronger than ephedrine. PPA was also found useful as an ingredient in products for stress incontinence. In all uses, PPA was known to cause transient elevations of blood pressure and was contraindicated for patients with hypertension. Another compound recently in the news, synephrine (see: Synephrine: Is chih-shih toxic?), is also chemically similar to ephedrine, and has been used in products to promote appetite suppression and weight loss. Laboratory animal studies showed that high doses could cause irregularities in the electrocardiograph and, in some cases, deaths (adverse reactions in humans are not yet reported).
As with a growing list of traditional herbs, ma-huang may eventually need to be deleted from several of the ITM formulas. In some cases, the entire formulation would have to be changed, since ma-huang is a key component (in Blue Earth Dragon, Cinnamon 14, and Pueraria 10). This action would be taken because of fears of the practitioners and their patients, as the formulas are in compliance with the FDA proposal to limit the level of ephedrine in products to 8 mg per dose and 24 mg per day (the FDA proposal has been dropped due to lack of support for it). There are some existing restrictions: ma-huang is banned in Ohio, has an age limit (17 years) for use in Texas, and is not permitted in Canada. The PPA ban, and the perceived linkage between PPA and ephedrine, may cause even greater restrictions. The insurance industry, which provides product liability insurance to companies that manufacture or sell herbs, is now putting stipulations that they will not cover products that contain any ma-huang or its active constituent, ephedrine. Due to the high rate of product litigation in the U.S., lack of insurance coverage is a considerable disincentive to provide the herb. There is even a web site (http://www.ephedrine-ephedra.com) for persons to contact lawyers to handle liability cases, such as one against Metabolife (a marketer of one of the products that has been blamed for adverse effects).
How does a medicinal herb go from one that is greatly respected to one that is strongly rejected? Here is part of the story which may reveal the larger problem of traditional medicine becoming incorporated into the modern setting.
By the mid-1970's, much of the American population was enthralled with the apparent value of drugs: prescription drugs, recreational drugs, and a revived class: herbal drugs. To take something in order to feel better, to do more, and to have a better experience had become an ingrained message for millions. When Chinese herbs were introduced to the U.S., they quickly became a source of new stimulus to this trend. One of the early Chinese herb importers and distributors for the non-Chinese population in America frankly stated that his interest was in finding an herbal alternative for the popular (and illegal) recreational drugs.
A product called "Chi Power" was one of the first entrants of ma-huang into the mass market, combining a heavy dose of ma-huang extract with small amounts of astragalus and ho-shou-wu (two herbs that had been popularized at the time). For many consumers, the product was viewed as an alternative to caffeine, which was deemed by them to be a harmful stimulant. Others thought of ma-huang as an alternative to expensive cocaine or to the nerve-wracking amphetamine (more recently, ephedrine was included in alternatives to the street drug "ecstasy"). Like caffeine, cocaine, and amphetamine, the active ingredient in ma-huang is an alkaloid. Most alkaloids affect the nervous system, producing either stimulation or sedation (sometimes one effect at low dose and the other effect at high dose). In fact, the chemical structure of ephedrine differs only slightly from that of amphetamine (see Figure 3). As mentioned above, the newly banned drug PPA was used as a decongestant and weight loss aid, the same functions for which ma-huang and isolated ephedrine have been applied.
Combining caffeine and ephedrine, as was done in some efforts to increase the "energizing" effect or to further promote weight loss by stimulating metabolism, could yield an especially powerful effect on the nervous system. Currently, the two compounds put together are considered to have an interaction (see: The interactions of herbs and drugs) yielding a potentially dangerous effect in sensitive individuals.
Competitors with the manufacturer of the popular Chi Power worked on getting more ephedrine per capsule, until the ephedrine doses became excessive. Some companies used synthetic ephedrine as an easy way to boost up the total dose of the chemical in a single capsule or tablet. Once the energizing effects were maximized, companies turned more attention to the weight loss characteristics. Amphetamine has long been deemed an effective weight loss agent; ephedrine is a milder and safer compound, and was used instead. Unfortunately, ephedrine doesn't have the appetite suppressing action of amphetamine (nor PPA) and its metabolism boosting effect turns out to be just enough to produce a small, detectable weight loss benefit. Nonetheless, considerable poor quality research was done to show that ephedrine (alone or with caffeine) could burn fat (especially the so-called "brown fat"), and this led to a booming industry in weight-loss products that has continued up to today. It was these products that led to most of the claimed serious adverse effects.
Ma-huang products are also used for improving sports performance; its effectiveness is one reason the substance is banned in Olympic competitions (pseudoephedrine, as found in the Olympic-banned cold remedies, may have much less effect on performance). It is also touted for building muscle mass, but this is not known to be a legitimate claim. This plethora of modern applications had nothing to do with the traditional Chinese use of the herb, something that has been repeatedly pointed out, without significant effect, by most educators involved with Chinese medicine.
In general, modest doses of ephedrine do not produce adverse effects. However, some people with elevated blood pressure may be sensitive to it, and there has been no formal regulation on the dosing of the over the counter products. In medical practice, doses over 100 mg/day might be used as a drug therapy for asthma under careful medical supervision; some commercial products for energy, mood change, or weight loss have approached this dosage. Thus, to doctors and regulators, the product appeared to have dangers that would outweigh its benefits. This herb then became one of the rallying points for those who said that herb products should simply be regulated like drugs. Inherently, such an approach eventually eliminates herbs from any use, as occurs with drugs. As early as 1984, it was said about PPA that "Since serious adverse reactions occur and long-term effectiveness of the drug has not been demonstrated, the usefulness of PPA as an aid to weight reduction is limited." This statement shows the clear understanding that the future of the drug was not very great; it was 16 years until it was completely banned from all uses, and there will be recriminations that it should have been banned much sooner.
Side effects of PPA (used in over-the-counter drug products), for which there is more experience in the West than with ma-huang or even ephedrine, tend to occur when the dosage exceeds 75 mg/day. The effects, similar to those for ma-huang, include nervousness, restlessness, insomnia, dizziness, tinnitus, headache, nausea, and excessive elevation of blood pressure. It has been reported that PPA may interact with monoamine oxidase inhibitors (MAOIs) and with prostaglandin synthesis inhibitors (which include many of the non-steroidal antiinflammatory drugs); these same interactions may occur with ephedrine in ma-huang. Many of the diet products using ephedrine (as ma-huang extract) had recommended doses of 20 mg each time, three times per day, for a total of 60 mg. The proposed FDA limit of 24 mg/day ephedrine for over the counter herb products should be well within the safe zone, but rare cases of sensitivity at such levels must now be taken into consideration.
There is little doubt that the medicinal effects of ma-huang were evident in ancient times. In the Shennong Bencao Jing (1), ma-huang is described this way:
Bitter and warm; it is non-toxic, treating mainly wind stroke cold damage, headache, and warm malaria. It effuses the exterior through sweating, eliminates evil heat qi, suppresses cough and counterflow of qi, eliminates cold and heat, and breaks concretions and hardness, accumulations and gatherings.
The description has nothing to do with any of the recent non-traditional applications for the herb or its extract: boosting energy, aiding weight loss, improving sports performance and muscle building. Certainly, the stimulant effects of ma-huang were readily experienced by early consumers of ma-huang, but there was simply no interest expressed in this activity, which had no apparent utility for the ancient Chinese.
The herb was used in numerous traditional Chinese herb formulas, and those that are especially popular in the Orient to this day are the ones listed in the ancient Shanghan Lun (2). Unfortunately, students of Chinese medicine in the West are usually told only that the herb is used for cases of wind-cold invasion, such as the common cold, thus restricting interest in the herb to a very limited application. This interpretation of ma-huang is mainly the result of analyzing the Shanghan Lun applications in a way that fits Western sensibilities about herb use (see: A modern view of the Shanghan Lun). The treatments in that ancient text were actually for a very serious epidemic disease for which a dramatic remedy might be needed. In that context, Ma-huang formulas were mentioned for treatment of taiyang disorders, with stuffiness of the head, headache, shoulder/neck tension, and cough-symptoms that fit the pattern of the common cold. Other symptoms mentioned in the text for the taiyang disorders (such as high fever, spontaneous bleeding, wheezing, and pain) are often put aside in modern descriptions. Ma-huang formulas with applications other than wind-cold invasion are often ignored.
In Oriental Materia Medica (2), which serves as a modern guide to Chinese herbs in English, ma-huang is described this way:
Actions: induces diaphoresis, resolves surface, ventilates the lungs to relieve asthma, regulates water metabolism.
Applications: febrile diseases due to exterior-excess, fever, chillphobia [aversion to cold], anhidrosis [lack of perspiration], ostealgia [bone pain], arthralgia, cough with dyspnea, edema, edema due to wind.
Here, one can see some extension of the applications of the herb (common cold and influenza are not mentioned). One result of narrowing the understanding of ma-huang's use to conditions such as the common cold and nasal congestion is that when fears about ma-huang are raised as the result of its misuse in modern products, it is easy to set it aside as a non-essential herb.
Of all the prescriptions containing ma-huang recorded in ancient texts, the formula that is most frequently used in modern times is Xiao Qinglong Tang (Minor Blue Dragon Combination). The formula is described in Chinese Herbal Medicine: Formulas and Strategies (3), as being comprised of equal parts (9 grams each in decoction) of ma-huang, cinnamon twig, dried ginger, asarum, schizandra, peony, pinellia, and baked licorice. In the explanatory text, it is stated that:
Patients with chronic water metabolism problems and congested fluids usually have weak lungs and spleen. When they contract external wind-cold, the fluids and the cold are locked in battle, causing the interstices and pores to close. This results in fever and chills without sweating....The efficacy of this formula is attributed to its ability to simultaneously release wind-cold from the exterior and transform congested fluids in the interior.
A principal objective of using this formula is to resolve problems of water metabolism and congested fluids. The text goes on to mention the roles of ma-huang, which are: "releases the exterior, arrests wheezing, and moves water by facilitating the flow of lung qi." In Commonly Used Chinese Herb Formulas with Illustrations (4), an extensive list of potential applications for the formula is given, revealing the emphasis on treating watery conditions and disorders of the respiratory system:
All of the herbs in the prescription, except peony, are warm-natured and help to improve the fluid metabolism by their warming action, following the dictum that cold causes fluids to accumulate, while heat causes fluids to circulate and evaporate. Ma-huang, cinnamon twig, and asarum release the exterior, which has the effect of alleviating congestion in the head and extremities, in the skin and muscles. Peony and schizandra act as astringents to counteract the strong dispersing action of the exterior-releasing herbs. Pinellia helps dry the excess fluids. Thus, this formula is primarily one for resolving fluid accumulations characterized by cold-etiology and where the surface is affected.
Although the dosage of ma-huang in this prescription is high, up to 9 grams per day (corresponds to an ephedrine dosage of about 60 mg/day), the Chinese literature includes no warnings about its safety, not even any cautions about use in persons of weak constitution, except for long-term use. In Chinese Medicinal Herbs (5), the caution about ma-huang is that "its use should not be long continued, lest it weaken the body." Minor Blue Dragon Combination is today viewed as a treatment suitable for persons of weak constitution. By warming the body and resolving fluid excess, the prescription will have a strengthening effect.
Ma-huang is not only used for fluid accumulations involving surface congestion, but also for fluid accumulations in the interior. A good example is the formula Yang He Tang (Cinnamon and Rehmannia Combination) which has been adopted for modern use in treating ovarian cysts (see: Treatment of ovarian cysts with Chinese herbs). According to Formulas and Strategies, ma-huang in this formula "opens up the interstices and pores and helps lead out the cold;" the coldness is the cause of the fluid accumulation. As with Minor Blue Dragon Combination, this formula is directed at warming the body. Although the formula was originally developed for soft swellings beneath the skin (thus, being found at the body surface), modern applications of the formula (sometimes with modifications), include: "coughing, wheezing, pain in the joints, dysmenorrhea, thromboangitis obliterans, aseptic suppuration, lymphatic tuberculosis, tubercular joint disease, chronic osytomyelitis, fibrocystic breasts, and lower back pain (including sciatica)."
There are frequent mentions of ma-huang for treatment of arthralgia in the medical literature. The herb is commonly used as an adjunct to other arthritis herbs (see: Analysis of Chinese herb formulas for arthritis). It is particularly used when the joint is swollen, indicating a fluid accumulation. Thus, for example, Cinnamon and Anemarrhena Combination (Guizhi Shaoyao, Zhimu Tang) is indicated for arthritis, but especially for cases in which there is swelling of the joints, as most often occurs at the knees, but also if there is accompanying swelling of the feet (this symptom may accompany gout, a painful condition that usually begins with symptoms in the feet). As with most other ma-huang formulas, there is an emphasis on dispelling chill: the formula also contains cinnamon, ginger, and aconite to aid in warming the body. In this case, the formula is designed for a disease caused by cold factors, but which produces localized heat (the joints are warm to the touch).
The three formulas reviewed above illustrate the fact that ma-huang is used for diverse disease conditions, and is not limited to treatment of minor disorders such as the common cold. It is used both for short-term therapies (an acute febrile disease) and longer term applications (ovarian cysts, tubercular disorders, arthritis). As such, one would wish to take steps to assure its continued availability. The benefits, when the herb is used properly, are likely to outweigh the risks, especially when the formula is prescribed by a health professional.
The dominant problem with ma-huang is that the main alkaloid ingredient, ephedrine, typically present in amounts of 0.7% by weight of the crude ephedra leaves, can cause a rise in blood pressure that is usually transient but may sometimes persists for many hours. There may also be a slight increase in heart rate. This effect is not observed in healthy persons with normal blood pressure taking 20 mg ephedrine at one time (6), but has been reported in persons who are already hypertensive at this dose. Hypertension is a common health problem in persons over age 40 and increases with age. Hypertension is associated with risk of sudden death due to stroke or other cardiovascular events. There was one reported case of a young, apparently healthy, college student who took high doses of multiple stimulants, most of them in a product called Ultimate Xphoria, which had a large amount of ephedrine (the product also contains caffeine) and was intended as an herbal alternative to street drugs like cocaine and amphetamine. Unlike others who have taken this product at the same or higher doses, this student died, possibly because he was more sensitive to the ingredients, so that the amount he took was an overdose for his system. The problems of overdose should not be a reflection on normal dosing, but because products are available for use at high dose, and because combinations of stimulants, such as caffeine plus ephedrine, have been recommended for weight loss, the problem must be publicized, with the effect that people will worry about low dosage forms as well.
One may ask if there is a safe substitute for ma-huang. When ma-huang is a relatively minor constituent of a formula, it may well be replaced by other herbs that aid in warming the body, distributing fluids, and alleviating pain: examples are siler, fresh ginger, chiang-huo, and cinnamon twig. However, these alternative herbs do not have the same strong effect on the lungs, so that they are not as useful for alleviating wheezing, cough, and other symptoms of respiratory distress. Such substitutes are best reserved for certain more limited applications of the formulas for surface congestion. When lung disorders dominate, ma-huang might be replaced by other herbs that have a warming quality and alleviate wheezing, such as platycodon, sinapis, or magnolia bark. None of the substitute herbs have the same action as ma-huang, which is, in Chinese herbal medicine, a unique component. However, there are formulas without ma-huang that address many of the same syndromes as for those that do contain ma-huang, so substitution remains a possibility, perhaps with significant change in the formulation.
In an evaluation of ma-huang adverse effects commissioned by the FDA, researchers at University of California at San Francisco provided the following information (7).
The following is an analysis of 140 recent complaints (1997-1999). In this table, the reference to "ma-huang use" may be misleading, as it may refer to use of a non-medical product containing ephedrine isolates.
Result of Claimed Adverse Effect of Using Ma-Huang
% of Claims Definitely or Probably Related to Ma-Huang Use
% of Claims Possibly Related to Ma-Huang Use
% of Claims Unrelated to Ma-Huang Use
Ongoing treatment for adverse effect
Full recovery from adverse effect
Unknown current status
The researchers stated that ma-huang should not be taken by anyone who is pregnant, has a history of heart disease, stroke, psychiatric disorders, asthma, thyroid or kidney disease, diabetes, or seizures. Proponents of the dietary supplement industry have contested the analysis, saying that the criteria, especially for the cases "possibly related" to ma-huang use, were not sufficient to eliminate cases due to underlying disease conditions and other factors. At this time, the FDA has not received sufficient convincing evidence to ban the sale of the herb or to enforce a specific dosage limitation.
Analyzing the few cases without full recovery that are "probably" or "possibly" related to use of ma-huang will be important in determining whether ma-huang is a threat in normal use. If 12 million persons use this herb (or its isolated active components) each year, and there are only a few reports of serious and persistent adverse effects (about 20 per year), those few may turn out to be due to other substances, or to dosages that are so high as to not reflect normal usage.
Figure 1: Ephedra sinica.
Figure 2: (a) ephedrine; and (b) phenylpropanolamine.
Figure 3: Amphetamine.