Challenges and Thoughts about the Integration of Traditional Chinese Medicine (TCM) and Western Medicine - Part 2

The MaHuang Story

MR Lee in The History of Ephedra (Ma-Huang) concludes, “Ephedra and ephedrine deserve an honored place in the history of pharmacology and therapeutics. To paraphrase the ancient Roman poet Horace, the abuse of a substance does not weigh against its right or proper use.” 1 Ma-Huang (ephedra, the whole herb) was first documented in Shen Nong Ben Cao Jing (Divine Husbandman's) Classic of Materia Medica over 2,000 years ago; however, it was not until 1885 that ephedrine was isolated as the active ingredient by the Japanese chemist Professor Nagayoshi Nagai. In 1913 it was discovered that ephedrine was a sympathomimetic catecholamine that raised blood pressure and heart rate, and could relax bronchial smooth muscles. Other catecholamines in this category that include ephedrine are pseudoephedrine, tyramine, adrenaline, isoprenaline, salbutamol, amphetamine and methamphetamine.

It was this identification and isolation of the active ingredient ephedrine from the whole herb Ma-Huang (ephedra) that led to Ma-Huang's fame and notoriety. I would like to use this as an example to demonstrate how this amazing active ingredient, ephedrine, used in isolation and of out context of TCM, led to it's ban in the US and how ephedra, used as a whole herb in the context of a TCM formula, is still being used effectively and safely today in the treatment of asthma in China, Taiwan and Japan. In addition, there are some unique effects of the formulas containing Ma-Huang that render them potentially superior to existing treatment protocols for asthma.

Much has been written about the abuse and misuse of the active ingredient of Ma-Huang; from ephedrine’s role as a central nervous system stimulant (it readily crosses the blood-brain barrier) to enhance athletic performance, to a street drug (it is used as a source of methamphetamine), to its use as a weight loss product particularly when stacked with caffeine. In the 1930’s it was established that an overdose of ephedrine could result in cardiac failure and hyperthermia; however, it was not until ephedrine abuse contributed in the case of a high profile fatality in 2003 that it was totally banned by the FDA in 2004. Clinically, ephedrine was successfully used as a bronchodilator from the 1930's until the 1960’s when Salbutamol became the bronchodilator of choice. The reason that ephedra and ephedrine "deserve an honored place in the history of pharmacology and therapeutics" is that it was through the work with ephedrine and other catecholamines by Professor Raymond Ahlquist in the 1940's that alpha- and beta- adrenergic receptors were discovered.

So what is Ma-Huang's right or proper role in Chinese herbal medicine today? In TCM, the active ingredient, ephedrine, is never what is used medicinally. The whole herb or ephedra stem, called Ma-Huang, is used. There are specific preparation instructions, and it is never used raw. It is decocted (cooked) and the foam removed first before use in a formula. It is also never prescribed as a single stand-alone herb. It is always part of a multi-ingredient formula. It is classified as a strong acrid (dispersing), slightly bitter and warm herb. The use of formulas containing Ma-Huang is elaborated upon extensively in the Zhong-Jing's Shang Han Lun (Discussion on Cold Damages), which is estimated to have been written around 200 BC.

Ma-Huang is documented in the 2010 (current) Chinese Pharmacopoiea p. 300-301. The formula Ma-Huang Tang, known as Maoto in Japan, is listed in the Japanese Pharmacopoiea # 16 (Supplement 2) p. 174-176. Chinese herb function has been demystified through pharmacological studies, high performance liquid chromatography (HPLC) monographs, standardization and quality control; however, clinical use of the formula is still guided by traditional indications. Biochemistry alone does not define clinical application.

What evidence is there that supports the use of Ma-Huang in the Chinese herbal medicine pharmacy of today? Are there any studies to suggest the benefit of formulas containing Ma-Huang go beyond that of existing pharmaceutical drugs or at least rival them in efficacy? In Japan, TCM herbal formulations from the Han Era (200 BC - 200 AD), specifically from the Shang Han Lun, incorporated into the mainstream medical system, are called Kampo. "Kam" comes from the word "Han" and "po" means formula. The Japanese Ministry of Health formally recognizes and insurance reimburses for 200 Chinese herbal (Kampo) formulas. Designing a robust RCT on TCM is challenging because of the changing nature of Zheng during the disease process. However, in Japan Western evidence-based models of research are used for Kampo and this has led to an expansion of the use of herbal formulas in doctor's offices and hospitals. Examples of formulas containing Ma-Huang that are currently safely prescribed by doctors as herbal prescription medications in China, Japan and Taiwan, and that have undergone recent scientific study include; Ma-Huang Tang (Ephedra Decoction), Xiao Qing Long Tang (Minor Bluegreen Dragon Decoction), Ma Xing Shi Gan Tang (Ephedra, Apricot Kernel, Gypsum, and Licorice Decoction), and Ding Chuan Tang (Arrest Wheezing Decoction). These formulas treat a Zheng or syndrome, defined as the "aetiology, pathology and disease location" or "clinical outcome of the disease" at that particular moment. 2

Ding Chuan Tang (DCT) is cited as the most commonly prescribed formula for adults and children with asthma in Taiwan. 3 4 Another study identifies Ma Xing Shi Gan Tang (MXSGT) as the most commonly prescribed Chinese herbal medicine for childhood asthma. 5 Studies show the use of DCT results in significant improvement in airway function 6 and a reduction in allergen-induced airway inflammation 7 in asthmatics. Xiao Qing Long Tang (XQLT) has immunomodulatory effects, reducing bronchial inflammation in the allergen-sensitized mice 8 9 and reducing airway hyper-responsiveness. 10 In addition, MXSGT has been shown to have broad-spectrum inhibitory activity against different strains of influenza A viruses 11 and the respiratory syncytial virus (RSV) 12 as well as the effect of reducing lung microvascular hyperpermeability and inflammation 13. The original classical formula Ma-Huang Tang (MHT) (ingredients: Ma-Huang, Gui Zhi, Xing Ren, Gan Cao) has been shown to have antiviral activity, in particular for treatment of the seasonal influenza virus. 14-20 In summary, these formulas exhibit local anti-inflammatory effects, anti-allergic effects, and they have much-needed anti-viral properties—a very unique and desirable combination. Ma-Huang is an ingredient in all these formulas which have a multi-dimensional effect on the Zheng, one not attributable to a single active ingredient.

There are some classical TCM combinations of herbs found in these formulas that have been more closely studied. One such combination is Ma-Huang (Ephedra) and Shi Gao (Gypsum), which is in the formula Ma Xing Shi Gan Tang (ingredients: Ma-Huang, Shi Gao, Xing Ren, Zhi Gan Cao). This pair has antipyretic (fever reducing) and anti-asthmatic properties 21-24. Since Ma-Huang is a warm herb whose acrid, bitter, dispersing properties are needed, Shi Gao is used to cool this formula that is used for a pattern of heat. The Zheng or pattern treated by MXSGT can be asthma (coughing, panting, labored breathing and wheezing) but specifically with heat signs (such as fever, thirst, and a rapid pulse). TCM pattern differentiation of biomedical conditions is a crucial component of diagnosis and formula prescription. Ding Chuan Tang (ingredients: Bai Guo, Ma-Huang, Zi Su Zi, Gan Cao, Kuan Dong Hua, Xing Ren, Sang Bai Pi, Huang Qin, Ban Xia) is also used for a heat pattern; however, Xiao Qing Long Tang (ingredients: Ma-Huang, Gui Zhi, Gan Jiang, Xi Xin, Wu Wei Zi, Bai Shao, Ban Xia, Gan Cao) is used for a cold pattern. It has been demonstrated that the original Ma-Huang based formula Ma-Huang Tang (ingredients: Ma-Huang, Gui Zhi, Xing Re, Gan Cao) is significantly superior to the antiviral oseltamivir and similar in efficacy to zanamivir in the treatment of influenza. 15 Another study showed Ma-Huang Tang plus oseltamivir resulted in decreased fever duration compared to a oseltamivir only group of children with influenza. 17 Furthermore Ma-Huang Tang has been shown to ameliorate the progression of childhood allergic asthma marked by steroid-resistant eosinophilic inflammation 25 26

In summary, Chinese herbal medicine (including formulas with Ma-Huang as an ingredient) offers an attractive alternative treatment modality for chronic asthma because of its long history of safe use, the absence of systemic side effects seen in long term use of Western pharmaceutical bronchodilators and corticosteroids, and because of the multiple-systems benefits offered. 27 Current substitutes for Ma-Huang in the United States include Bai Qian (cynanchum), Fang Feng (saposhnikovia), Jing Jie (schizonepeta) and Zi Su Ye (perilla leaf). However, none of these herbs have the same dispersing and anti-asthmatic qualities as Ma-Huang and thus in countries where it is not banned, Ma-Huang continues to be used because of its superior effects. As a licensed Chinese herbal medicine practitioner I would like to be able to use Ma-Huang in the United States.

(1) MR Lee. The history of Ephedra (ma-huang) J R Coll Physicians Edinb 2011;41:78-84.

(2) Yu et al. Traditional Chinese medicine and Kampo: a review from the distant past for the future. J Int Med Res. 2006 May-Jun;34(3):231-9. http://www.ncbi.nlm.nih.gov/pubmed/16866016

(3) Wang et al. Prescription pattern of Chinese herbal products for adult-onset asthma in Taiwan: a population-based study. Ann Allergy Asthma Immunol. 2014 May;112(5):465-70. Epub 2014 Mar 19. http://www.ncbi.nlm.nih.gov/pubmed/24656660

(4) Huang et al. Characteristics of traditional Chinese medicine use in children with asthma: a nationwide population-based study. Allergy. 2013 Dec;68(12):1610-3. Epub 2013 Oct 14. http://www.ncbi.nlm.nih.gov/pubmed/24117783

(5) Chen et al. Identifying core herbal treatments for children with asthma: implication from a chinese herbal medicine database in taiwan. Evid Based Complement Alternat Med. 2013;2013:125943. Epub 2013 Aug 28. http://www.ncbi.nlm.nih.gov/pubmed/24066007

(6) Chan et al. Ding Chuan Tang, a Chinese herb decoction, could improve airway hyper-responsiveness in stabilized asthmatic children: a randomized, double-blind clinical trial. Pediatr Allergy Immunol. 2006 Aug;17(5):316-22. http://www.ncbi.nlm.nih.gov/pubmed/16846448

(7) Kao et al. Effects of Ding-Chuan-Tang on bronchoconstriction and airway leucocyte infiltration in sensitized guinea pigs. Immunopharmacol Immunotoxicol. 2004 Feb;26(1):113-24. http://www.ncbi.nlm.nih.gov/pubmed/15106736

(8) Kao et al. The effect of Chinese herbal medicine, xiao-qing-long tang (XQLT), on allergen-induced bronchial inflammation in mite-sensitized mice. Allergy. 2000 Dec;55(12):1127-33. http://www.ncbi.nlm.nih.gov/pubmed/11117269

(9) Wang et al. Xiao-Qing-Long-Tang attenuates allergic airway inflammation and remodeling in repetitive Dermatogoides pteronyssinus challenged chronic asthmatic mice model. J Ethnopharmacol. 2012 Jul 13;142(2):531-8. Epub 2012 Jun 1. http://www.ncbi.nlm.nih.gov/pubmed/22658987

(10) Chang et al. Xiao-Qing-Long-Tang shows preventive effect of asthma in an allergic asthma mouse model through neurotrophin regulation. BMC Complement Altern Med. 2013 Sep 8;13:220.http://www.ncbi.nlm.nih.gov/pubmed/24010817

(11) Hsieh et al. Mechanism by which ma-xing-shi-gan-tang inhibits the entry of influenza virus. J Ethnopharmacol. 2012 Aug 30;143(1):57-67. Epub 2012 Jun 16. http://www.ncbi.nlm.nih.gov/pubmed/22710290

(12) Chen et al. Antiviral effects of Jinxin oral liquid against respiratory syncytial virus infection in the BALB/c mice model. J Ethnopharmacol. 2015 Jan 12. [Epub ahead of print] http://www.ncbi.nlm.nih.gov/pubmed/25593018

(13) Ma et al. Posttreatment with Ma-Xing-Shi-Gan-Tang, a Chinese medicine formula, ameliorates lipopolysaccharide-induced lung microvessel hyperpermeability and inflammatory reaction in rat. Microcirculation. 2014 Oct;21(7):649 -63. http://www.ncbi.nlm.nih.gov/pubmed/24809727

(14) Nagai et al. Alleviative Effects of a Kampo (a Japanese Herbal) Medicine "Maoto (Ma-Huang-Tang)" on the Early Phase of Influenza Virus Infection and Its Possible Mode of Action. Evid Based Complement Alternat Med. 2014;2014:187036. doi: 10.1155/2014/187036. Epub 2014 Mar 20. http://www.ncbi.nlm.nih.gov/pubmed/24778699

(15) Nabeshima et al. A randomized, controlled trial comparing traditional herbal medicine and neuraminidase inhibitors in the treatment of seasonal influenza. Journal of Infection and Chemotherapy. 2012;18(4):534–543 http://www.ncbi.nlm.nih.gov/pubmed/22350323

(16) Kubo T et al. Antipyretic effect of Mao-to, a Japanese herbal medicine, for treatment of type A influenza infection in children. Phytomedicine. 2007 Feb;14(2-3):96-101. Epub 2006 Dec 1. http://www.ncbi.nlm.nih.gov/pubmed/17141491

(17) Nabeshima S, Kashiwagi K, Ajisaka K, et al. A comparison of oseltamivir with maoto, a traditional herbal medicine, for the treatment of adult seasonal influenza A. Journal of Traditional Medicines.2010;27(4):148–156.

(18) Hokari et al. In vivo anti-influenza virus activity of Japanese herbal (kampo) medicine, "shahakusan," and its possible mode of action. Evid Based Complement Alternat Med. 2012;2012: Epub 2012 Dec 26. http://www.ncbi.nlm.nih.gov/pubmed/23346216

(19) Yamada et al. In vivo antiinfluenza virus activity of Kampo medicine Sho-seiryu-to through mucosal immune system. Methods Find Exp Clin Pharmacol. 1998 Apr;20(3):185-92. http://www.ncbi.nlm.nih.gov/pubmed/9646280

(20) Nagai et al. In vivo anti-influenza virus activity of Kampo (Japanese herbal) medicine "Sho-seiryu-to"--effects on aged mice, against subtypes of a viruses and B virus, and therapeutic effect. Immunopharmacol Immunotoxicol. 1996 May;18(2):193-208. http://www.ncbi.nlm.nih.gov/pubmed/8771367

(21) Mei et al. Antipyretic and anti-asthmatic activities of traditional Chinese herb-pairs, Ephedra and Gypsum. Chin J Integr Med. 2014 Nov 16. [Epub ahead of print]. http://www.ncbi.nlm.nih.gov/pubmed/25399307

(22) Yuan et al. Pharmacological properties of traditional medicines (XXVII). Interaction between Ephedra Herb and Gypsum under hyperthermal conditions in rats. Biol Pharm Bull. 2002 Jul;25(7):872-4. http://www.ncbi.nlm.nih.gov/pubmed/12132660

(23) Yuan et al. Pharmacological properties of traditional medicines. XXV. Effects of ephedrine, amygdalin, glycyrrhizin, gypsum and their combinations on body temperature and body fluid.Biol Pharm Bull. 1999 Feb;22(2):165-71. http://www.ncbi.nlm.nih.gov/pubmed/10077436

(24) Yuan et al. Pharmacological properties of traditional medicines. XXIV. Classification of antiasthmatics based on constitutional predispositions. Biol Pharm Bull. 1998 Nov;21(11):1169-73. http://www.ncbi.nlm.nih.gov/pubmed/9853407

(25) Ma et al. Ma Huang Tang ameliorates asthma though modulation of Th1/Th2 cytokines and inhibition of Th17 cells in ovalbumin-sensitized mice. Chin J Nat Med. 2014 May;12(5):361-6. http://www.ncbi.nlm.nih.gov/pubmed/24856759

(26) Saglani et al. Eosinophils in the pathogenesis of paediatric severe asthma. Curr Opin Allergy Clin Immunol. 2014 Apr;14(2):143-8.
http://www.ncbi.nlm.nih.gov/pubmed/24500296

(27) Song et al. Effects and mechanisms of actions of Chinese herbal medicines for asthma. Chin J Integr Med. 2011 Jul;17(7):483-91. Epub 2011 Jul 3. http://www.ncbi.nlm.nih.gov/pubmed/21725872

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