1.1. HERBAL MEDICINE: A GROWING FIELD WITH A LONG TRADITION

Traditional medicine is “the knowledge, skills and practices based on the theories, beliefs and experiences indigenous to different cultures, used in the maintenance of health and in the prevention, diagnosis, improvement or treatment of physical and mental illness” (World Health Organization, http://www.who.int/topics/traditional_medicine/en/). There are many different systems of traditional medicine, and the philosophy and practices of each are influenced by the prevailing conditions, environment, and geographic area within which it first evolved (WHO 2005), however, a common philosophy is a holistic approach to life, equilibrium of the mind, body, and the environment, and an emphasis on health rather than on disease. Generally, the focus is on the overall condition of the individual, rather than on the particular ailment or disease from which the patient is suffering, and the use of herbs is a core part of all systems of traditional medicine (Engebretson 2002; Conboy et al. 2007; Rishton 2008; Schmidt et al. 2008).

Traditional Chinese medicine (TCM) is an important example of how ancient and accumulated knowledge is applied in a holistic approach in present day health care. TCM has a history of more than 3000 years (Xutian, Zhang, and Louise 2009). The book The Devine Farmer’s Classic of Herbalism was compiled about 2000 years ago in China and is the oldest known herbal text in the world, though the accumulated and methodically collected information on herbs has been developed into various herbal pharmacopoeias and many monographs on individual herbs exist.

Diagnosis and treatment are based on a holistic view of the patient and the patient’s symptoms, expressed in terms of the balance of yin and yang. Yin represents the earth, cold, and femininity, whereas yang represents the sky, heat, and masculinity. The actions of yin and yang influence the interactions of the five elements composing the universe: metal, wood, water, fire, and earth. TCM practitioners seek to control the yin and yang levels through 12 meridians, which bring and channel energy (Qi) through the body. TCM is a growing practice around the world and is used for promoting health as well as for preventing and curing diseases. TCM encompasses a range of practices, but herbal medicine is a core part (Engebretson 2002; Nestler 2002; Schmidt et al. 2008; Xutian, Zhang, and Louise 2009). Three of the top-selling botanical products, namely Ginkgo biloba, Allium sativum (garlic), and Panax ginseng, can be traced back to origins in TCM and are today used to treat various diseases (Li, Jiang, and Chen 2008; Xutian, Zhang, and Louise 2009).

Over the past 100 years, the development and mass production of chemically synthesized drugs have revolutionized health care in most parts of the word. However, large sections of the population in developing countries still rely on traditional practitioners and herbal medicines for their primary care. In Africa up to 90% and in India 70% of the population depend on traditional medicine to help meet their health care needs. In China, traditional medicine accounts for around 40% of all health care delivered and more than 90% of general hospitals in China have units for traditional medicine (WHO 2005). However, use of traditional medicine is not limited to developing countries, and during the past two decades public interest in natural therapies has increased greatly in industrialized countries, with expanding use of ethnobotanicals. In the United States, in 2007, about 38% of adults and 12% of children were using some form of traditional medicine (Ernst, Schmidt, and Wider 2005; Barnes, Bloom, and Nahin 2008). According to a survey by the National Center for Complementary and Alternative Medicine (Barnes, Bloom, and Nahin 2008), herbal therapy or the usage of natural products other than vitamins and minerals was the most commonly used alternative medicine (18.9%) when all use of prayer was excluded. A survey conducted in Hong Kong in 2003 reported that 40% of the subjects surveyed showed marked faith in TCM compared with Western medicine (Chan et al. 2003). In a survey of 21,923 adults in the United States, 12.8% took at least one herbal supplement (Harrison et al. 2004) and in another survey (Qato et al. 2008), 42% of respondents used dietary or nutritional supplements, with multivitamins and minerals most commonly used, followed by saw palmetto, flax, garlic, and Ginkgo, at the time of the interview.

The most common reasons for using traditional medicine are that it is more affordable, more closely corresponds to the patient’s ideology, allays concerns about the adverse effects of chemical (synthetic) medicines, satisfies a desire for more personalized health care, and allows greater public access to health information. The major use of herbal medicines is for health promotion and therapy for chronic, as opposed to life-threatening, conditions. However, usage of traditional remedies increases when conventional medicine is ineffective in the treatment of disease, such as in advanced cancer and in the face of new infectious diseases. Furthermore, traditional medicines are widely perceived as natural and safe, that is, not toxic. This is not necessarily true, especially when herbs are taken with prescription drugs, over-the-counter medications, or other herbs, as is very common (Canter and Ernst 2004; Qato et al. 2008; Loya, Gonzalez-Stuart, and Rivera 2009; Cohen and Ernst 2010).

Regardless of why an individual uses it, traditional medicine provides an important health care service whether people have physical or financial access to allopathic medicine, and it is a flourishing global commercial enterprise (Engebretson 2002; Conboy et al. 2007; Evans et al. 2007). In 1990, expenditure associated with “alternative” therapy in the United States was estimated to be US$13.7 billion. This had doubled by the year 1997, with herbal medicines growing faster than any other alternative therapy (Eisenberg et al. 1998). In Australia, Canada, and the United Kingdom, annual expenditure on traditional medicine is estimated to be US$80 million, US$1 billion, and US$2.3 billion, respectively. These figures reflect the incorporation of herbal and other forms of traditional medicine into many health care systems and its inclusion in the medical training of doctors in many parts of the developed world.

The total commercial value of the ethnobotanicals market cannot be ignored. For example, in 1995, the total turnover of nonprescription-bound herbal medicines in pharmacies was equal to almost 30% of the total turnover of nonprescription-bound medicines in Germany, and in the United States, the annual retail sales of herbal products was estimated to be US$5.1 billion. In India, herbal medicine is a common practice, and about 960 plant species are used by the Indian herbal industry, of which 178 are of a high volume, exceeding 100 metric tons per year (Sahoo 2010). In China, the total value of herbal medicine manufactured in 1995 reached 17.6 billion Chinese yuan (approximately US$2.5 billion; Eisenberg et al. 1998; WHO 2001). This trend has continued, and annual revenues in Western Europe reached US$5 billion in 2003-2004 (De Smet 2005). In China, sales of herbal products totaled US$14 billion in 2005, and revenue from herbal medicines in Brazil was US$160 million in 2007 (World Health Organization; http://www.who.int/topics/traditional_medicine/en/). It is estimated that the annual worldwide market for these products approached US$60 billion (Tilburt and Kaptchuk 2008).

Currently, herbs are applied to the treatment of chronic and acute conditions and various ailments and problems such as cardiovascular disease, prostate problems, depression, inflammation, and to boost the immune system, to name but a few. In China, in 2003, traditional herbal medicines played a prominent role in the strategy to contain and treat severe acute respiratory syndrome (SARS), and in Africa, a traditional herbal medicine, the Africa flower, has been used for decades to treat wasting symptoms associated with HIV (De Smet 2005; Tilburt and Kaptchuk 2008). Herbal medicines are also very common in Europe, with Germany and France leading in over-the-counter sales among European countries, and in most developed countries, one can find essential oils, herbal extracts, or herbal teas being sold in pharmacies with conventional drugs.

Herbs and plants can be processed and can be taken in different ways and forms, and they include the whole herb, teas, syrup, essential oils, ointments, salves, rubs, capsules, and tablets that contain a ground or powdered form of a raw herb or its dried extract. Plants and herbs extract vary in the solvent used for extraction, temperature, and extraction time, and include alcoholic extracts (tinctures), vinegars (acetic acid extracts), hot water extract (tisanes), long-term boiled extract, usually roots or bark (decoctions), and cold infusion of plants (macerates). There is no standardization, and components of an herbal extract or a product are likely to vary significantly between batches and producers.

Plants are rich in a variety of compounds. Many are secondary metabolites and include aromatic substances, most of which are phenols or their oxygen-substituted derivatives such as tannins (Hartmann 2007; Jenke-Kodama, Müller, and Dittmann 2008). Many of these compounds have antioxidant properties (see Chapter 2 on antioxidants in herbs and spices). Ethnobotanicals are important for pharmacological research and drug development, not only when plant constituents are used directly as therapeutic agents, but also as starting materials for the synthesis of drugs or as models for pharmacologically active compounds (Li and Vederas 2009). About 200 years ago, the first pharmacologically active pure compound, morphine, was produced from opium extracted from seeds pods of the poppy Papaver somniferum. This discovery showed that drugs from plants can be purified and administered in precise dosages regardless of the source or age of the material (Rousseaux and Schachter 2003; Hartmann 2007). This approach was enhanced by the discovery of penicillin (Li and Vederas 2009). With this continued trend, products from plants and natural sources (such as fungi and marine microorganisms) or analogs inspired by them have contributed greatly to the commercial drug preparations today. Examples include antibiotics (e.g., penicillin, erythromycin); the cardiac stimulant digoxin from foxglove (Digitalis purpurea); salicylic acid, a precursor of aspirin, derived from willow bark (Salix spp.); reserpine, an antipsychotic and antihypertensive drug from Rauwolfia spp.; and antimalarials such as quinine from Cinchona bark and lipid-lowering agents (e.g., lovastatin) from a fungus (Rishton 2008; Schmidt et al. 2008; Li and Vederas 2009). Also, more than 60% of cancer therapeutics on the market or in testing are based on natural products. Of 177 drugs approved worldwide for treatment of cancer, more than 70% are based on natural products or mimetics, many of which are improved with combinatorial chemistry. Cancer therapeutics from plants include paclitaxel, isolated from the Pacific yew tree; camptothecin, derived from the Chinese “happy tree” Camptotheca acuminata and used to prepare irinotecan and topotecan; and combretastatin, derived from the South African bush willow (Brower 2008). It is also estimated that about 25% of the drugs prescribed worldwide are derived from plants, and 121 such active compounds are in use (Sahoo et al. 2010). Between 2005 and 2007, 13 drugs derived from natural products were approved in the United States. More than 100 natural product-based drugs are in clinical studies (Li and Vederas 2009), and of the total 252 drugs in the World Health Organization’s (WHO) essential medicine list, 11% are exclusively of plant origin (Sahoo et al. 2010).

1.2. HERBAL MEDICINE AND THE AGING POPULATION

Average life expectancy at birth has increased from around 41 years in the early 1950s to approaching 80 years in many developed countries. Consequently, the percentage of elderly people (65 years and above) in our populations is increasing. The graying of our populations brings an increasing burden of chronic age-related disease and dependency. Aging is associated with a progressive decline in physiological function and an increased risk of pathological changes leading to cancer, cardiovascular disease, dementia, diabetes, osteoporosis, and so on. Lifestyle factors such as nutrition or exercise play an important role in determining the quality and duration of healthy life and in the treatment of chronic diseases (Bozzetti 2003; Benzie and Wachtel-Galor 2009, 2010). It is most likely that there is no one cause of aging, and different theories of aging have been suggested over the years. Genetic factors are undoubtedly important, but among all the metabolic theories of aging, the oxidative stress theory is the most generally supported theory (Harman 1992; Beckman and Ames 1998). This theory postulates that aging is caused by accumulation of irreversible, oxidation-induced damage (oxidative stress) resulting from the interaction of reactive oxygen species with the DNA, lipid, and protein components of cells. However, even if the aging process itself is found to be unrelated to oxidative stress, highly prevalent chronic age-related diseases all have increased oxidative stress (Holmes, Bernstein, and Bernstein 1992; Beckman and Ames 1998; Finkel and Holbrook 2000; Rajah et al. 2009). Antioxidants in herbs may contribute at least part of their reputed therapeutic effects (Balsano and Alisi 2009; Tang and Halliwell 2010).

With the growing popularity of herbal medicine, the “traditional” ways of identification and preparation of herbs need to be replaced with more accurate and reproducible methods (see Chapter 20) so as to ensure the quality, safety, and consistency of the product. Given the market value, potential toxicity and increasing consumer demand, particularly in the sick and elderly members of our populations, regulation of production and marketing of herbal supplements and medicines require attention.

1.3. HERBAL MEDICINES: CHALLENGES AND REGULATIONS

WHO has recognized the important contribution of traditional medicine to provide essential care (World Health Organization, http://www.who.int/topics/traditional_medicine/en/). In 1989, the U.S. Congress established the Office of Alternative Medicine within the National Institutes of Health to encourage scientific research in the field of traditional medicine (http://nccam.nih.gov, last access: November 5, 2010), and the European Scientific Cooperative on Phytotherapy (ESCOP) was founded in 1989 with the aim of advancing the scientific status and harmonization of phytomedicines at the European level (www.escop.com, last access: November 5, 2010). This led to an increase in investment in the evaluation of herbal medicines. In the United States, the National Center for Complementary and Alternative Medicine at the National Institutes of Health spent approximately US$33 million on herbal medicines in the fiscal year 2005; in 2004, the National Canadian Institute committed nearly US$89 million for studying a range of traditional therapies. While this scale of investment is low compared to the total research and development expenses of the pharmaceutical industry, it nevertheless reflects genuine public, industry, and governmental interest in this area (Li and Vederas 2009).

With tremendous expansion in the interest in and use of traditional medicines worldwide, two main areas of concern arise that bring major challenges. These are international diversity and national policies regarding the regulation of the production and use of herbs (and other complementary medicines) and their quality, safety, and scientific evidence in relation to health claims (WHO 2005; Sahoo et al. 2008).

1.4. RESEARCH NEEDS

Research needs in the field of herbal medicines are huge, but are balanced by the potential health benefits and the enormous size of the market. Research into the quality, safety, molecular effects, and clinical efficacy of the numerous herbs in common usage is needed. Newly emerging scientific techniques and approaches, many of which are mentioned in this book, provide the required testing platform for this. Genomic testing and chemical fingerprinting techniques using hyphenated testing platforms are now available for definitive authentication and quality control of herbal products. They should be regulated to be used to safeguard consumers, but questions of efficacy will remain unless and until adequate amounts of scientific evidence accumulate from experimental and controlled human trials (Giordano, Engebretson, and Garcia 2005; Evans 2008; Tilburt and Kaptchuk 2008). Evidence for the potential protective effects of selected herbs is generally based on experiments demonstrating a biological activity in a relevant in vitro bioassay or experiments using animal models. In some cases, this is supported by both epidemiological studies and a limited number of intervention experiments in humans (WHO 2001). In general, international research on traditional herbal medicines should be subject to the same ethical requirements as all research related to human subjects, with the information shared between different countries. This should include collaborative partnership, social value, scientific validity, fair subject selection, favorable risk-benefit ratio, independent review, informed consent, and respect for the subjects (Giordano, Engebretson, and Garcia 2005; Tilburt and Kaptchuk 2008). However, the logistics, time, and cost of performing large, controlled human studies on the clinical effectiveness of an herb are prohibitive, especially if the focus is on health promotion. Therefore, there is an urgent need to develop new biomarkers that more clearly relate to health (and disease) outcomes. Predictor biomarkers and subtle but detectable signs of early cellular change that are mapped to the onset of specific diseases are needed.

Research is needed also to meet the challenges of identifying the active compounds in the plants, and there should be research-based evidence on whether whole herbs or extracted compounds are better. The issue of herb–herb and herb–drug interactions is also an important one that requires increased awareness and study, as polypharmacy and polyherbacy are common (Canter and Ernst 2004; Qato et al. 2008; Loya, Gonzalez-Stuart, and Rivera 2009; Cohen and Ernst 2010). The use of new technologies, such as nanotechnology and novel emulsification methods, in the formulation of herbal products, will likely affect bioavailability and the efficacy of herbal components, and this also needs study. Smart screening methods and metabolic engineering offer exciting technologies for new natural product drug discovery. Advances in rapid genetic sequencing, coupled with manipulation of biosynthetic pathways, may provide a vast resource for the future discovery of pharmaceutical agents (Li and Vederas 2009). This can lead to reinvestigation of some agents that failed earlier trials and can be restudied and redesigned using new technologies to determine whether they can be modified for better efficacy and fewer side effects. For example, maytansine isolated in the early 1970s from the Ethiopian plant Maytenus serrata, looked promising in preclinical testing but was dropped in the early 1980s from further study when it did not translate into efficacy in clinical trials; later, scientists isolated related compounds, ansamitocins, from a microbial source. A derivative of maytansine, DM1, has been conjugated with a monoclonal antibody and is now in trials for prostate cancer (Brower 2008).

1.5. CONCLUSIONS

Plants, herbs, and ethnobotanicals have been used since the early days of humankind and are still used throughout the world for health promotion and treatment of disease. Plants and natural sources form the basis of today’s modern medicine and contribute largely to the commercial drug preparations manufactured today. About 25% of drugs prescribed worldwide are derived from plants. Still, herbs, rather than drugs, are often used in health care. For some, herbal medicine is their preferred method of treatment. For others, herbs are used as adjunct therapy to conventional pharmaceuticals. However, in many developing societies, traditional medicine of which herbal medicine is a core part is the only system of health care available or affordable. Regardless of the reason, those using herbal medicines should be assured that the products they are buying are safe and contain what they are supposed to, whether this is a particular herb or a particular amount of a specific herbal component. Consumers should also be given science-based information on dosage, contraindications, and efficacy. To achieve this, global harmonization of legislation is needed to guide the responsible production and marketing of herbal medicines. If sufficient scientific evidence of benefit is available for an herb, then such legislation should allow for this to be used appropriately to promote the use of that herb so that these benefits can be realized for the promotion of public health and the treatment of disease.

ACKNOWLEDGMENTS

The authors thank the Hong Kong Polytechnic University for funding this work.

REFERENCES

1. Balsano C, Alisi A. Antioxidant effects of natural bioactive compounds. Curr Pharm Des. 2009;15:3063–73. [PubMed: 19754380]
2. Barnes P. M, Bloom B, Nahin R. Complementary and alternative medicine use among adults and children: United States, 2007. CDC National Health Statistics Report # 12. 2008. www.cdc.gov/nchs/data/nhsr/nhsr012.pdf access date: 5 Nov. [PubMed: 19361005]
3. Beckman K. B, Ames B. N. The free radical theory of ageing matures. Physiol Rev. 1998;78:47–81. [PubMed: 9562038]
4. Benzie I. F. F, Wachtel-Galor S. Biomarkers in long-term vegetarian diets. Adv Clin Chem. 2009;47:170–208. [PubMed: 19634781]
5. Benzie I. F, Wachtel-Galor S. Vegetarian diets and public health: Biomarker and redox connections. Antioxid Redox Signal. 2010;13(10):1575–91. [PubMed: 20222825]
6. Bozzetti F. Nutritional issues in the care of the elderly patient. Crit Rev Oncol Hematol. 2003;48:113–21. [PubMed: 14607374]
7. Brower V. Back to nature: Extinction of medicinal plants threatens drug discovery. J Natl Cancer Inst. 2008;100:838–9. [PubMed: 18544733]
8. Calapai G. Drug Saf. Vol. 31. 2008. European legislation on herbal medicines: A look into the future; pp. 428–31. [PubMed: 18422385]
9. Canter P. H, Ernst E. Herbal supplement use by persons aged over 50 years in Britain: Frequently used herbs, concomitant use of herbs, nutritional supplements and prescription drugs, rate of informing doctors and potential for negative interactions. Drugs Aging. 2004;21:597–605. [PubMed: 15260514]
10. Chan M. F. E, Mok Y. S, Wong ST. F, Tong FM. C, Day CC. K, Tang K, Wong D. H. H. Attitudes of Hong Kong Chinese to traditional Chinese medicine and Western medicine: Survey and cluster analysis. Complement Ther Med. 2003;11(2):103–9. [PubMed: 12801496]
11. Cohen P. A, Ernst E. Safety of herbal supplements: A guide for cardiologists. Cardiovasc Ther. 2010;28:246–53. [PubMed: 20633025]
12. Conboy L, Kaptchuk T. J, Eisenberg D. M, Gottlieb B, Acevedo-Garcia D. The relationship between social factors and attitudes toward conventional and CAM practitioners. Complement Ther Clin Pract. 2007;13:146–57. [PubMed: 17631257]
13. De Smet P. Herbal medicine in Europe: Relaxing regulatory standards. N Engl J Med. 2005;352:1176–8. [PubMed: 15788494]
14. Eisenberg D. M, Davis R. B, Ettner S. L, Appel S, Wilkey S, Van Rompay M, Kessler R. C. Trends in alternative medicine use in the United States, 1990-1997: Results of a follow-up national survey. JAMA. 1998;280:1569–75. [PubMed: 9820257]
15. Engebretson J. Culture and complementary therapies. Complement Ther Nurs Midwifery. 2002;8:177–84. [PubMed: 12463606]
16. Ernst E, Schmidt K, Wider B. CAM research in Britain: The last 10 years. Complement Ther Clin Pract. 2005;11:17–20. [PubMed: 15984219]
17. Evans S. Changing the knowledge base in Western herbal medicine. Soc Sci Med. 2008;67:2098–106. [PubMed: 18952343]
18. Evans M, Shaw A, Thompson E. A, Falk S, Turton P, Thompson T, Sharp D. BMC Complement Altern Med. 25. Vol. 7. 2007. Decisions to use complementary and alternative medicine (CAM) by male cancer patients: Information-seeking roles and types of evidence used. [PMC free article: PMC2000907] [PubMed: 17683580]
19. Finkel T, Holbrook N. J. Oxidants oxidative stress and the biology of ageing. Nature. 2000;408:239–47. [PubMed: 11089981]
20. Food and Drug Administration (FDA). 2010. Overview of dietary supplements. website: www.fda.gov/food/dietarysupplements/consumerinformation (accessed November 5, 2010)
21. Giordano J, Engebretson J, Garcia M. K. Challenges to complementary and alternative medical research: Focal issues influencing integration into a cancer care model. Integr Cancer Ther. 2005;4:210–8. [PubMed: 16113028]
22. Harman D. Free radical theory of aging. Mutat Res. 1992;275:257–66. [PubMed: 1383768]
23. Harrison R. A, Holt D, Pattison D. J, Elton P. J. Who and how many people are taking herbal supplements? A survey of 21,923 adults. Int J Vitam Nutr Res. 2004;74:183–6. [PubMed: 15296076]
24. Hartmann T. From waste products to ecochemicals: Fifty years research of plant secondary metabolism. Phytochemical. 2007;68:2831–46. [PubMed: 17980895]
25. Health Canada, Drugs and Health Products. Nat Health Prod Regul. 13. Vol. 137. 2003. Food and drugs act. available at www.hc-sc.gc.ca.
26. Holmes G. E, Bernstein C, Bernstein H. Oxidative and other DNA damages as the basis of aging: A review. Mutat Res. 1992;275(3006):305–15. [PubMed: 1383772]
27. Jenke-Kodama H, Müller R, Dittmann E. Evolutionary mechanisms underlying secondary metabolite diversity. Prog Drug Res. 2008. pp. 121–40. [PubMed: 18084914]
28. Kantor M. The role of rigorous scientific evaluation in the use and practice of complementary and alternative medicine. J Am Coll Radiol. 2009;6:254–62. [PubMed: 19327658]
29. Li W. F, Jiang J. G, Chen J. Chinese medicine and its modernization demands. Arch Med Res. 2008;39:246–51. [PubMed: 18164973]
30. Li J. W. H, Vederas J. C. Drug discovery and natural products: End of an era or an endless frontier? Science. 2009;325:161–5. [PubMed: 19589993]
31. Loya A. M, Gonzalez-Stuart A, Rivera J. O. Prevalence of polypharmacy, polyherbacy, nutritional supplement use and potential product interactions among older adults living on the United States-Mexico border: A descriptive, questionnaire-based study. Drugs Aging. 2009;26:423–36. [PubMed: 19552494]
32. Mahady G. B. J Nutr. Vol. 131. 2001. Global harmonization of herbal health claims; pp. 1120S–3S. [PubMed: 11238830]
33. Nestler G. Traditional Chinese medicine. Med Clin North Am. 2002;86:63–73. [PubMed: 11795091]
34. Qato D. M, Alexander G. C, Conti R. M, Johnson M, Schumm P, Lindau S. T. Use of prescription and over-the-counter medications and dietary supplements among older adults in the United States. JAMA. 2008;300:2867–78. [PMC free article: PMC2702513] [PubMed: 19109115]
35. Rajah M. N. et al. Biological changes associated with healthy versus pathological aging: A symposium review. Ageing Res Rev. 2009;8:140–6. [PMC free article: PMC2671241] [PubMed: 19274854]
36. Ribnicky D. M, Poulev A, Schmidt B, Cefalu W. T, Raskin I. The science of botanical supplements for human health: A view from the NIH botanical research centers: Evaluation of botanicals for improving human health. Am J Clin Nutr. 2008;87:472S–5S. [PubMed: 18258641]
37. Richter R. K. Herbal Medicine: Chaos in the Marketplace. New York: Haworth Herbal Press; 2003.
38. Rishton G. M. Natural products as a robust source of new drugs and drug leads: Past successes and present day issues. Am J Cardiol. 2008;101:43D–9D. [PubMed: 18474274]
39. Rousseaux C. G, Schachter H. Regulatory issues concerning the safety, efficacy and quality of herbal remedies. Birth Defects Res B. 2003;68:505–10. [PubMed: 14745988]
40. Routledge P. A. The European herbal medicines directive: Could it have saved the lives of Romeo and Juliet? Drug Saf. 2008;31:416–8. [PubMed: 18422382]
41. Sahoo N, Choudhury K, Manchikanti P. Manufacturing of biodrugs: Need for harmonization in regulatory standards. BioDrugs. 2009;23(4):217–29. [PubMed: 19697964]
42. Sahoo N, Manchikanti P, Dey S. Herbal drugs: Standards and regulation. Fitoterapia. 2010;81(6):462–71. [PubMed: 20156530]
43. Schmidt B, Ribnicky D. M, Poulev A, Logendra S, Cefalu W. T, Raskin I. A natural history of botanical therapeutics. Metabolism. 2008;57:S3–9. [PMC free article: PMC2981029] [PubMed: 18555851]
44. Tang S. Y, Halliwell B. Medicinal plants and antioxidants: What do we learn from cell culture and Caenorhabditis elegans studies? Biochem Biophys Res Commun. 2010;394:1–5. [PubMed: 20188074]
45. Tilburt J. C, Kaptchuk T. J. J. Herbal medicine research and global health: An ethical analysis. Bull World Health Organ. 2008;86(8):594–9. [PMC free article: PMC2649468] [PubMed: 18797616]
46. U.S. Government Accountability Office (GAO). 2010. Herbal dietary supplements: Examples of deceptive or questionable marketing practices and potentially dangerous advice. GAO-10-662T.
47. Vlietinck A, Pieters L, Apers S. Legal requirements for the quality of herbal substances and herbal preparations for the manufacturing of herbal medicinal products in the European Union. Planta Med. 2009;75:683–8. [PubMed: 19204891]
48. World Health Organization (WHO). General Guidelines for Methodologies on Research and Evaluation of Traditional Medicines. 2001.
49. World Health Organization (WHO). National Policy on Traditional Medicine and Regulation of Herbal Medicines. Geneva: 2005. Report of WHO global survey.
50. World Health Organization (WHO). “Traditional Medicine.” http://www​.who.int/topics​/traditional_medicine/en/ (accessed July 21, 2010)
51. Xutian S, Zhang J, Louise W. New exploration and understanding of traditional Chinese medicine. Am J Chin Med. 2009;37:411–26. [PubMed: 19606504]