Evodia: Traditional and Modern Uses
Evodia refers to the Chinese herb wuzhuyu, the immature (nearly ripe) fruit with stems removed from Evodia rutaecarpa. The herb is one of the few classified in traditional Chinese medicine as hot in nature, and some texts indicate that it is “extremely hot” (1). While the description of hotness is primarily from the effect the herb has on the tongue, herbs with this property are said to dispel internal coldness, a type of therapy that alleviates pain and rectifies the flow of qi. Evodia is classified along with cinnamon bark, dry ginger, zanthoxylum (Sichuan pepper; from the same plant family as evodia), and other hot peppers in a small section of the Materia Medica dedicated to herbs for dispelling chill and warming the interior.
Evodia is one of the strong acting herbs that remain in use today. Strong acting herbs may be defined as those that have a notable effect even at relatively small doses. Because of their strength, these herbs have the potential for adverse effects, so are rarely used at elevated doses, other than for a short period of treatment. Many of the strong acting herbs are categorized as having a nature which is evidently hot or cold, rather than the common descriptions as warm, cool, or neutral; they usually have strong taste. Evodia has a very spicy and bitter taste, one which may dominate the decoction that includes it, even when a minor ingredient.
The dosage of evodia in decoction is most often indicated to be 3–9 grams. Jiao Shude (2) gives more detail about dosing, saying that the usual dose is 0.9–3.0 grams, with up to 9 grams used for “severe cases,” and the Advanced Textbook of Traditional Chinese Medicine (3) gives a dosage range of 1.5–5.0 grams, noting that evodia should first be soaked in licorice decoction (a traditional method of ameliorating slight toxicity and strong taste; licorice processed and raw evodia showed similar low toxicity in testing). An instance of high dosage administration was reported over 40 years ago, in which 6–12 grams/day of evodia was utilized in the treatment of painful uterine contractions; an example of relatively long-term use—treating hypertension at 8 grams per day (alcohol extract) for one month—was also reported around the same time (4).
Among the active components of evodia are quinolone and indoloquinazoline alkaloids, such as evodiamine and rutaecarpine (structure image shown here). Evodiamine was one of the first alkaloids isolated from an herb specific to the Chinese tradition, the task accomplished about 100 years ago by a Japanese researcher, Kashiwaki Asahina; it is the major alkaloid of this herb. Rutaecarpine, also isolated by Asahina, appears to interact with the vanilloid receptors that make nerves sensitive to capsaicin, the primary hot component of chili peppers that is now used for analgesic purposes. A significant portion of the analgesic effects of evodia are attributed to these alkaloids. Rutaecarpine has also been shown to have anti-inflammatory action that is related to inhibition of COX-2, as well as other mechanisms (5). Among the very bitter components of evodia are some non-alkaloid substances, mainly limonin derivatives, such as evodol; among the spicy components are essential oil ingredients, such as evodin. The essential oil is thought to contribute to beneficial effects of evodia on the stomach.
Although alkaloids may have adverse neurological effects with elevated dosage, toxicity of the alkaloids of evodia has not yet been reported. The essential oil of evodia is known to be toxic to insects and has been evaluated for potential insect inhibiting use. As for the traditional cautions, in the Advanced Textbook of Traditional Chinese Medicine it is noted that “Evodia is acrid, hot, and dry and likely to produce fire and consume body fluid. It is, therefore, not advisable for prolonged use. In addition, it is contraindicated for patients with yin deficiency due to internal heat.”
The selection of evodia for use in a Chinese herb formula usually depends upon the intention to alleviate pain. Applications include treatment of abdominal pains in women associated with menstruation (e.g., with Wen Jing Tang), painful diarrhea (e.g., with Si Shen Wan); pains associated with acid reflux (e.g., using coptis plus evodia as in Zuo Jin Wan), and headache or migraine, especially when it occurs along with vomiting (treated, for example, by Wu Zhu Yu Tang). In most cases, evodia is used for a short treatment period in order to gain rapid improvement; sometimes a small amount of evodia is used for a prolonged therapy, such as for persistent gastric disease that is resistant to cure.
Evodia for Acid Regurgitation
Evodia has the reputation of correcting the perverse flow of stomach qi that carries upward the contents of the stomach; hence it is used in the treatment of vomiting and acid regurgitation. The problem of acid reflux is very common in the modern era, so evodia is extensively used for this particular application. The most common method is to combine it with coptis (huanglian). In Formulas and Strategies (6) three variants of this pairing are mentioned: coptis and evodia alone (Zuo Jin Wan); with peony added (Wu Ji Wan); and with saussurea (muxiang) added (Xiang Lian Wan). This method of therapy was advised by Zhu Danxi (1281-1358). In a recent translation of Dan Xi Xin Fa (The Heart and Essence of Zhu Danxi’s Methods of Treatment), the chapter on acid regurgitation is presented and includes this section (7):
When damp heat has been depressed and has accumulated for a long time in the liver, it is unable to gush out on its own and is confined somewhere between the lungs and stomach. In this case, one must take coarse foods and vegetables to nurture oneself and use evodia to comply with the nature of the disease in order to thwart it. This is the counter-assisting method. A formula to treat acid swallowing consists of evodia (15 grams, stems removed, boiled for a short time, soaked for half a day, and dried in the sun for use), citrus (chenpi, 15 grams), red atractylodes (cangzhu, 22.5 grams, soaked with rice water), coptis (30 grams, stir-fried with old wall clay which is removed afterwards, and scute (huangqi; 15 grams, also stir fried with old wall clay which is removed afterwards. Powder the above and make into pills with shen-chu (shenqu). To treat acid regurgitation, use coptis and evodia, both stir fried separately as the assistant and envoy depending on the season, and red atractylodes and hoelen (fuling) as the adjuncts. Soak with boiled water, prepare into cakes by steaming and make into small pills, and take. Still, one should take vegetables to nurture oneself. Then the disease will be easy to overcome.
This discourse is worth some further explanation. The origins of the damp and heat that Zhu was describing as depressed and accumulated were primarily of environmental origin, and correspond to conditions of southeast China which are also common in the southeast U.S. However, in the modern situation, where there are better environmental controls (including air conditioning) and fewer pathogens flourishing in these warm climates (and treatable by modern drugs), damp heat still arises, but occurs more often as the result of dietary influences and emotions. As to diet, it is common to associate stomach acid and regurgitation with foods like pepperoni pizza, where fatty cheese and spicy meat combine to provide the dampness and heat (which can be exacerbated by consuming wine along with it); anxiety, depression, and unexpressed anger, often associated with stressful work and/or family situations, contribute to the stagnation and accumulation of damp heat, especially as it affects the liver. The normal response to accumulation through “gushing out” of constrained damp and heat would correspond to its being distributed to and then utilized in the function of the organs, and finally eliminated. Instead, in this scenario, the damp and heat are trapped, and the pressure is felt in the area of the diaphragm (“between the stomach and lungs”). Acid swallowing and acid regurgitation in this description of the syndrome refer to the same basic disorder and involve the upward flow of hot fluid. Coarse foods are ones that are high in fiber, with vegetables not being a separate group, but an example of them. The fibrous foods help to alleviate constipation and aid the downward movement of the stomach constituents; evodia is called upon to aid the process of recovery by directing the flow of stomach qi downward (the direction in which it should move) and by dispersing the heat of the liver. Because it is a hot herb used in treating a hot condition, the method of therapy is referred to as “counter-assisting.” The use of coptis, by contrast, is applying a cold herb for a hot condition, “counter-acting.”
One can see the meticulous details of herbal processing that were prevalent during this ancient period, when herbs were not much used. Today most of the herbs are provided only with the standard processing that prepares them for the market. The “old wall clay” (fulonggan) refers to material that accumulates in clay ovens that had been used for a long time with burning of dry grass and wood; it was used to harmonize the stomach and control vomiting. It is a charcoal-clay mixture that absorbs substances. Today, one would consume capsules of purified charcoal for a similar purpose. By stir-frying the coptis and scute with this clay, the herbs are rendered less cooling and better at treating stomach disorders. In the first formulation, coptis and scute are used to clear damp-heat, and citrus and red atractylodes get rid of damp. The digestion-promoting shen-chu, a mass of fermented wheat and herbs, is used here as a material for making pills. In the second formula, hoelen is used in place of citrus for clearing damp and coptis is used without adding scute. Of the herbs mentioned, only evodia and coptis are “strong-acting.”
A tablet incorporating several of the herbs mentioned above has been in use in the U.S. for the past 15 years, called “Coptis/Evodia Tablets.” The formulation (8) that is dominated by coptis and evodia includes scute, peony, and saussurea. A portion of the large amount of coptis indicated in the traditional Chinese prescriptions (typically 6 times the amount of evodia) is replaced by phellodendron (from the same plant family as evodia and also containing rutaecarpine), which permits longer term applications of the formula because of its milder nature. Damp-removing herbs, such as hoelen, red atractylodes, and citrus are available with other formulations that might be used along with this one, while the focus of Coptis/Evodia Tablets is dispersing stagnated qi and lowering of uprising qi, while alleviating stomach heat and inflammation of the gastro-intestinal tract. Adverse effects of the formula have not been reported; it remains a frequently chosen herbal therapy for acid reflux and is sometimes administered for several months.
Potential New Uses of Evodia
While the use of evodia in traditional Chinese medicine formulas has probably declined in recent years due to concerns about using hot natured herbs, the active component evodiamine has gotten increasing attention as a potential therapeutic agent. The most intensive research activity has been preliminary investigation of anti-cancer effects, with particular attention to prostate and breast cancer, though several other lines (such as liver cancer, leukemia, and melanoma) have been studied and appear responsive to this compound. Because the work has been limited to cell cultures and a few laboratory animal studies, the results can not be given clinical significance at this time. The laboratory testing has suggested that evodiamine may be of help in reducing metastasizing of cancer cells and inhibiting cancer cell growth, including cell lines that are resistant to several existing drugs (9-14).
The hot nature of evodia and its purported negative impact in traditional Chinese medicine terms (increasing fire, consuming yin) has been harnessed in claimed therapies for obesity, namely for increasing metabolic fire and consuming the excess body material (yin) stored as fat. Several diet products have been produced for this application and a small number of laboratory animal trials yielded results indicating possible mechanisms of action that would be supportive of the anti-obesity claim (15-17).
References
- Hsu HY, et.al., Oriental Materia Medica, 1986 Oriental Healing Arts Institute, Irvine, CA.
- Jiao SD, Ten Lectures on the Use of Medicinals, 2001 Paradigm Publications, Brookline, MA.
- Huang YR, compiler, Advanced Textbook on Traditional Chinese Medicine and Pharmacology, volume 2, 1996 New World Press, Beijing.
- Chang HM and But PPH, Pharmacology and Applications of Chinese Materia Medica, 1987 World Scientific, Singapore.
- Lee SH, et.al., Progress in the studies on rutaecarpine, Molecules 2008; 13: 272–300.
- Bensky D and Barolet R, Formulas and Strategies, 1990 Eastland Press, Seattle, WA. [revised ed. 2009]
- Yang SZ, translator, The Heart and Essence of Zhu Danxi’s Methods of Treatment, 1993 Blue Poppy Press, Boulder, CO.
- Dharmananda S, A Bag of Pearls, 2004 Institute for Traditional Medicine, Portland, OR.
- Huang DM, et.al., Induction of mitotic arrest and apoptosis in human prostate cancer pc-3 cells by evodiamine, Journal of Urology 2005; 173(1): 256–61.
- Kan SF, et. al., Anti-proliferative effects of evodiamine on human prostate cancer cell lines DU145 and PC3, Journal of Cellular Biochemistry 2007;101(1):44–56.
- Liao CH, et.al. Antitumor mechanism of evodiamine, a constituent from Chinese herb Evodiae fructus, in human multiple-drug resistant breast cancer NCI/ADR-RES cells in vitro and in vivo, Carcinogenesis 2005; 26(5):968–975.
- Wang XN, et.al, Enhancement of apoptosis of human hepatocellular carcinoma SMMC-7721 cells through synergy of berberine and evodiamine, Phytomedicine 2008;15(12):1062–1068.
- Zhang C, et.al., Evodiamine induces caspase-dependent apoptosis and S phase arrest in human colon lovo cells, Anticancer Drugs 2010; 21(8): 766–767.
- Chen MC, et.al., Anti-proliferative effects of evodiamine on human thyroid cancer cell line ARO, Journal of Cellular Biochemistry 2010; 110(6): 1495–1503.
- Wang T, et.al., Evodiamine improves diet-induced obesity in a uncoupling protein-1-independent manner: involvement of antiadipogenic mechanism and extracellularly regulated kinase/mitogen-activated protein kinase signaling, Endocrinology 2008; 149(1): 358–366.
- Shi J, et.al., Intragastric administration of evodiamine suppresses NPY and AgRP gene expression in the hypothalamus and decreases food intake in rats, Brain Research 2009; 1247:71–78.
- Bak EJ, et.al., Inhibitory effect of evodiamine alone and in combination with rosiglitazone on in vitro adipocyte differentiation and in vivo obesity related to diabetes, International Journal of Obesity 2010; 34(2): 250–260.
July 2010