MODERNIZING CHINESE MEDICINE
THE CASE OF ARMILLARIA AS GASTRODIA SUBSTITUTE
Gastrodia (tianma) refers to the tuber of an orchid, Gastrodia elata. In recent years, virtually all orchids have been placed on the international endangered species list. This is because their natural growth is often limited to relatively rare habitats, and they are considered highly desirable as decorative flowering plants. One can continue to obtain these endangered species, but not from wild stocks; they must be cultivated. In order to purchase orchids and their products (such as tubers used for herbal medicine), it is necessary for buyers to obtain an acceptable certificate that meets the international trade criteria.
Gastrodia grew in East Asia among the mountainous regions from Yunnan in the southwest to northeast China and Korea (mostly growing above 300 meters). It was often used as a food, eaten raw or steamed. Gastrodia is desirable as a food because of its large starchy root with mild flavor; in fact, potatoes, also enjoyed for their starchy tubers (but introduced to China relatively recently), are sometimes produced as fakes for gastrodia (1, 2). Gastrodia tuber is distinguished from potatoes by having a mild spicy taste and ridges on the surface that are not seen in potatoes (see Figures 1-2). With China's rapid population growth, this common plant had insufficient wild resources to meet the demand during the 20th century.
Gastrodia was listed in the ancient Shennong Bencao Jing (ca. 100 A.D.) and was later classified by Tao Hongjing as a superior herb, meaning that it could be taken for a long time to protect the health and prolong life (as well as treating illnesses). Gastrodia was originally called chijian, meaning red arrow, because of its red stem shaped like an arrow (Figure 3). Later it was named tianma, or heavenly hemp (ma, usually translated as hemp, refers to many plants that have fibrous stems). The herb material is sometimes referred to as tianmagen, meaning the root (or, in this case, tuber) of tianma.
Bencao Gangmu (Compendium of Materia Medica, 1596) recorded the herb as treatment for "all wind-damp blockages, stiffness of the limbs, paralysis, wind-deficiency dizziness, and headache" (see Appendix 1 for modern listing of properties). Despite the fact that gastrodia was described frequently in materia medica guides over the centuries, and attributed near magical properties (expelling all kinds of poisons, giving strength and virility, improving circulation, and improving memory), there are few traditional formulas with this herb that come to us today (see Appendix 2 for listing). Most of the ancient formulas with gastrodia are designed to treat convulsions, such as occurs with tetanus or epilepsy, stroke, and headaches. Modern research has confirmed these uses (see Appendix 3).
Today, the best-known traditional prescription with gastrodia is from the Qing Dynasty, Tianma Gouteng Yin, a formula of obscure origins and varying details of formulation that always includes the two herbs included in the formula name: gastrodia and uncaria (gouteng). This formula is used primarily for treatment of headaches and dizziness, mainly in cases of high blood pressure. Another formula, Banxia Baizhu Tianma Tang (Pinellia, Atractylodes, and Gastrodia Combination) is mainly used in Kampo medicine, popular in Japan and Taiwan. The formula is prescribed for headaches and dizziness in persons with weak digestion and obesity, with or without hypertension.
Gastrodia drew interest during the 20th century because of the increasingly widespread problem of hypertension. Of the Chinese herbs, uncaria and gastrodia appeared to have the greatest promise, though many other herbs have been investigated and put to use for hypertension (e.g., prunella, scute, and eucommia). Because of dwindling supplies of gastrodia during the time when this research began, its cost increased dramatically and a solution to the strained supplies was sought in cultivating the herb. Unfortunately, it was quite difficult to cultivate, a problem that was soon solved by finding the close relationship between gastrodia and the mycelium of the gastrodia mushroom, Armellaria mellea (Figure 4).
Gastrodia has an unusual requirement for growth and survival: it requires a fungus, Mycena osmundicola, to sprout the seeds, and it must have Armillaria mellea mushroom mycelia incorporated into the tuber in order to maintain its maturation and growth. The seeds lack a nutrient coat, thus, they require the assistance of Mycena to draw in nutrients from soil in order to germinate. The underground tubers lack the rootlets that normally gather up nutrients; they rely, instead, on the mycelia of Armillaria to do this. Once these two requirements were understood, cultivation of gastrodia became relatively easy. By the late 1980s, an adequate cultivated supply of gastrodia was developed. Still, the plant grows slowly and the demand has remained high, so it remains one of the more expensive herbs, nearly the cost of cultivated ginseng.
More importantly, the medicinal components of gastrodia were found to be mainly the metabolites of the Armellaria mushroom (3-9). In other words, if one could grow the mushroom or just culture its mycelium, the slow growing gastrodia tuber could be dispensed with and one could use just the mushroom material or the metabolites released into culture medium to get the desired therapeutic effects. Batch fermentation of Armellaria mycelia was easily accomplished: the mycelia grow well in a simple sugar solution with just a few basic nutrients. The mycelial material was tested in the 1970s, and, as a result of more than 25 years of continual work by many research groups, the mycelia or its culture medium is frequently used instead of cultivated gastrodia. Dozens of investigations have been undertaken to show that the chemical constituents, pharmacology, and clinical effects of Armellaria and its culture medium after growing the mycelia, are indistinguishable from that of the gastrodia tuber.
According to the research results, the main active ingredient of gastrodia is gastrodin, a simple glycoside, comprised of glucose attached to 4-hydroxybenzyl alcohol (HBA); HBA is also a component of gastrodia. Other active ingredients are the aldehyde form of HBA (4-hydroxybenzylaldehyde), vanillyl alcohol, and vanillin. The content of these ingredients varies from about 0.3-1.2% of the dried tuber, with an average of about 0.8%. All of these compounds are chemically similar, produced in the mycelia from the same starting materials; pharmacology studies indicate that they all have similar effects, such as relieving spasms. Thus, for example, vanillin, as well as gastrodia tuber and gastrodin, have been used clinically in the treatment of epilepsy.
Vanillin (3-methoxy-4-hydroxybenzaldehyde, thus, 3-methoxy HBA) is the molecule that gives the flavor and fragrance to vanilla extract. Although it is found in many plants, it is best known in relation to the beans of the plant Vanilla planifolia, a member of the orchid family. Vanillin is also found in potatoes and the styrax tree. Vanillin is often synthesized; one method is using mold and fungus fermentation of wood pulp.
Vanillin is a starting material for the preparation of drugs for the treatment of hypertension and Parkinson's disease (both classified by Chinese medicine as internal wind syndromes). Vanillin is converted to l-dopa (levodopa; see Figure 5) and related compounds that influence nerve transmission. The largest single use for vanillin as a starting material for chemical synthesis is for the production of the antihypertensive drug Aldomet (see Figure 6). It is likely that the active ingredients of gastrodia either behaves in a similar manner to these drugs or are metabolized in the body to produce compounds similar to these drugs.
Gastrodin, the only unique compound among gastrodia's five main active ingredients (the other compounds are found in several plants) has been synthesized and developed into a drug in China (10-13). Its activity is indistinguishable from that of gastrodia. Gastrodin makes up, on average, about 0.4% of the gastrodia tuber, and the other similar compounds together make up a similar amount.
Synthetic gastrodin has been produced in the form of tablets, intramuscular injection, and intravenous drip. The tablets are made with 25 mg each of gastrodin, which corresponds to the amount of total active ingredients from about 3 grams of gastrodia, so that a typical dose of 3-9 grams of gastrodia tuber in decoction corresponds, roughly to ingestion of 1-3 tablets. However, the dosage of the tablets used clinically is usually considerably higher, with a total daily dose of about 250 mg.
For comparison, Normopress Capsules (for hypertension), containing methyldopa, are prescribed at a dose of 0.5-2.0 grams daily of the pure compound (250 mg/capsule). For l-dopa, the dose is varied considerably, but is usually provided in units of 100 mg, with typical daily dosing in the 500-600 mg range. In clinical trials conducted in China using the intravenous drip of gastrodin, 600 mg/day was said to give better results than the tablets or other forms of gastrodin. It is not only a higher dose than the tablet form, but by using IV drip all of it enters the blood stream (by the oral route, a small portion is likely left in the intestinal tract). This dosage of gastrodin given by IV is consistent with the amounts of dopa-related compounds used in modern medicine. By contrast, the amount of gastrodia tuber commonly used in decoctions provides notably lower levels of the active components. So, these new preparations may provide better therapeutic action. Normally, gastrodia tuber is not used alone, but is combined with other herbs, and these other herbs may make up for a lower activity of whole gastrodia.
The gastrodia mushroom, Armellaria (also listed as Armillariella), is known in China as tianma mihuanjun (gastrodia honey mushroom; mihuan means honey). Armellaria is considered an edible mushroom, but is not a highly desired one, so it is not much used and is difficult to find anywhere in the world as a culinary item. Cultivation of it is avoided because the mycelia is a well-known cause of root rot for many plants; it is feared that cultivating it will simply spread around the spores to cause damage in the surrounding area. Therefore, the batch culture is preferred as a means of getting this material.
The New Drug Group of the Chinese Academy of Medical Science in Beijing was the first to review and confirm the value of Armellaria fermentation liquid in comparison to gastrodia. They performed pharmacology experiments showing the same anticonvulsant activity of the two materials. They confirmed reports from other centers that Armellaria fermentation liquid could achieve effects similar to gastrodia: for example, it could alleviate dizziness symptoms caused by various pathological factors (hypertension, insufficient blood supply via the vertebral basal artery, Meniere's syndrome, vegetative nervous functional disturbance). Since then, numerous other studies have confirmed its value. It is also effective in improving numbed limbs, insomnia, tinnitus, epilepsy, vascular headache, and post-stroke syndrome. Armellaria is more potent gram for gram than gastrodia tuber, and can be used in approximately one-half the dose of the tuber. Armellaria tablet, for example, is given orally in doses of about 3-4 grams/day.
The story of gastrodia and Armellaria brings several insights into the changing situation with herbal medicine in the 21st century. Among the key points to grasp are these:
The traditional use of gastrodia as described in the modern TCM system is to calm internal wind and dispel invading wind, and invigorate circulation in the meridians, thereby treating headache, dizziness, vertigo, convulsions, paralysis, and arthralgia. In the book Chinese English Manual of Common-Used Herbs in Traditional Chinese Medicine (14), the indications are these:
The Advanced Textbook on Traditional Chinese Medicine and Pharmacology (15) mentions that:
This herb is mild, and can subdue hyperactive liver yang, eliminate wind, and remove obstruction in the collaterals, and is indicated for all kinds of wind syndromes, either cold or heat type or due to internal or external wind. For such cases, it is combined with other herbs according to the specific conditions. It is an important herb to treat dizziness.
Examples of combining gastrodia with other herbs include these, from the Textbook:
A small number of other herbs are thought to have similar actions, namely uncaria (for internal wind), chrysanthemum (for both internal and external wind), and morus leaf (for external wind).
The first three formulas listed below all derive from the same basic treatment pattern of using gastrodia with typhonium (baifuzi) and arisaema (tiannanxing) to treat "wind-phlegm" disease, causing tonic paralysis (meaning inability to have free movement because the muscles are in spasm, as opposed to cases where there is no muscular activity), headache, and stroke. These formulas also include herbs for dispelling "external wind," such as angelica, cnidum, chiang-huo, and siler. In ancient times, there was little distinction between internal and external wind. The formulas are made of powdered herbs. Another simple formulation, with just two herbs used to treat headache, is presented next. Finally, four decoction formulas are presented; two for treatment of wind phlegm using the combination of gastrodia and the main ingredients of Erchen Wan (Citrus and Pinellia Formula, for resolving phlegm), and two with the combination of gastrodia and uncaria for calming agitated yang and extinguishing internal wind (16).
Yu Zhen San (True Jade Powder; Powder for Tetanus)
from Waike Zhengzong (True Lineage of External Medicine; 1617)
The herbs are ground to powder (equal parts of all the herbs), and taken 3-6 grams each time, with warmed wine. The formula is mainly used for tetanus and spasms of various origins.
Shen Bai San (Miraculous White Powder)
from Shenqiao Wanquan Fang (Wonderfully Skillful and Comprehensive Formulas; Qing Dynasty)
The herbs are ground to powder (equal portions), and taken with water or wine. It is used for treatment of headache due to the combination of internal and external wind.
Shenxian Jieyu Dan (Immortal's Speech Recovering Pellet)
from Xiaozhu Furen Liangfang (Academic Investigations of Women's Useful Formulas; Qing Dynasty)
The herbs are ground to powder (all equal parts, except saussurea, half as much as the others). The powder can be formed into water pills with flour, which are to be consumed with mentha tea. The formula is used for post stroke syndrome, where speech is affected (as part of the disorder; there may also be numbness and paralysis of the limbs).
Da Xiong Wan (Major Cnidium Pill)
from Shengji Zonglu (Comprehensive Treatise on Sage's Advice; Song Dynasty)
The herbs are ground to powder in equal parts, and formed into pills with honey; one pill each time (about 6 grams of herbs). This formula is used for dizziness, blurring of vision, and headaches. Cnidium refers to chuanxiong (Ligustcium walichii).
Tainma Banxia Tang (Gastrodia and Pinellia Decoction)
from Weisheng Baojian (Precious Mirror of Health, Yuan Dynasty)
This formula is ground to powder and then briefly decocted. It is applied to distention of the chest with copious sputum, blurring of vision, dizziness, and nausea.
Banxia Baizhu Tianma Tang (Pinellia, Atractylodes, and Gastrodia Combination)
from Yixue Xinwu (Medical Revelations; 1732)
To be decocted with a slice of ginger and 2 pieces of jujube. This formula is used for wind phlegm disorder with symptoms such as vertigo, headache, and stuffiness in the chest.
Gou Teng Yin (Gastrodia Decoction)
from Yizong Jinjian (Golden Mirror of the Medical Tradition; 1742)
The herbs are decocted. This formula is used mainly for convulsions in infants attributed to heat in the heart and lung, with high fever, head and neck extended, and lock-jaw. This is likely related to meningitis.
Tianma Gouteng Yin (Gastrodia and Uncaria Decoction)
from Zabing Zhengzhi Xinyi (New Significance of Patterns and Treatments in Miscellaneous Diseases; Qing Dynasty)
The herbs are decocted. This formula is used to treat headache, vertigo, insomnia, and other symptoms of liver wind agitation and hyperactivity of liver yang.
Huang Zhengliang of the Department of Pharmacology, at Gansu College of Traditional Chinese Medicine, presented an extensive review (8) of the pharmacology and clinical application of gastrodia, Armellaria, and derivative preparations that had been carried out initially (1977-1983). Below is his summary of the clinical applications. More recent studies (10-13) have focused on the use of gastrodin, especially by injection. Since the use of the herb materials outside of China are mostly limited to gastrodia tuber, and, increasingly, Armellaria products, this review is of current interest. Huang subdivided the studies (for which he presented 9 published sources as references) into five categories: treatment of neurasthenia (mostly the weakness following recovery from serious illness, but also chronic fatigue); epilepsy; neuralgia (various pain syndromes, including headache); vertigo (dizziness); and hyperlipidemia and hypertension.
Figure 2. Dried gastrodia tubers; vertical ridges are seen on close examination,
but displayed more clearly in the artists representation in Figure 3.
Figure 3. Artist's rendition of Gastrodia elata tuber and
red arrow-like stalk (left), photo of wild plant (right).
Figure 4. Armellaria mellea, the gastrodia mushroom.
Figure 5. Closely related compounds: vanillin (left) and the drug manufactured from it,
l-dopa (right), mainly used for treatment of Parkinson's disease.
Figure 6. Closely related compounds: l-dopa (left) and methyldopa (right), used in Aldomet and
other brands of drugs for hypertension. The ring structure for the two molecules is the same,
though presented differently in these two illustrations. l-dopa illustrated here and Figure 1 are the same,
but just laid out with different orientation and level of detail for the amino acid end.