Herbal Medicine--- An Introduction to Its History, Usage, Regulation, Current Trends, and Research Needs
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).
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
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).
International Diversity and National Policies
The diversity among countries with the long history and holistic approach of herbal medicines makes evaluating and regulating them very challenging. In addition, there are a great number of different herbs used. Legislative criteria to establish traditionally used herbal medicines as part of approved health care therapies faces several difficulties. In a survey conducted across 129 countries, WHO reported the following issues regarding herbal medicines: lack of research data, appropriate mechanisms for control of herbal medicines, education and training, expertise within the national health authorities and control agency, information sharing, safety monitoring, and methods to evaluate their safety and efficacy. The support needed from different countries includes information sharing on regulatory issues, workshops on herbal medicines safety monitoring, general guidelines on research and evaluation of herbal medicines, provision of databases, herbal medicine regulation workshops, and international meetings. National policies are the basis for defining the role of traditional medicines in national health care programs, ensuring that the necessary regulatory and legal mechanisms are established for promoting and maintaining good practice, assuring the authenticity, safety, and efficacy of traditional medicines and therapies, and providing equitable access to health care resources and their resource information (WHO 2005). Another fundamental requirement is harmonization of the market for herbal medicines for industry, health professionals, and consumers (Mahady 2001). Herbal medicines are generally sold as food supplements, but a common regulatory framework does not exist in different countries. As a result, information on clinical indications for their use, efficacy, and safety are influenced by the traditional experience available in each place. A brief outline of the legislation in United States, Canada, and Europe is given in this section, and could be used to guide the legal aspects of the herbal medicine industry in other countries. In the United States, under the Dietary Supplement Health and Education Act (DSHEA) of 1994, any herb, botanical and natural concentrate, metabolite and constituent of extract, is classified as a dietary supplement. Dietary supplements do not need approval from the Food and Drug Administration (FDA) before they are marketed (FDA 2010). Under DSHEA, herbal medicines, which are classified as dietary supplements, are presumed safe, and the FDA does not have the authority to require them to be approved for safety and efficacy before they enter the market, which is the case for drugs. This means that the manufacturer of the herbal medicine is responsible for determining that the dietary supplements manufactured or distributed are indeed safe and that any representations or claims made about them are sustained by adequate evidence to show that they are not false or misleading. However, a dietary supplement manufacturer or distributor of a supplement with a “new dietary ingredient,” that is, an ingredient that was not marketed in the United States before October 1994, may be required to go through premarket review for safety data and other information. Also, all domestic and foreign companies that manufacture package labels or hold dietary supplements must follow the FDA’s current good manufacturing practice (GMP) regulations, which outline procedures for ensuring the quality of supplements intended for sale (FDA 2010; Gao 2010). Regarding contamination, the FDA has not issued any regulations addressing safe or unsafe levels of contaminants in dietary supplements but has set certain advisory levels in other foods (FDA 2010; Gao 2010). A product being sold as an herbal supplement (dietary supplement) in the United States cannot suggest on its label or in any of itspackaging that it can diagnose, treat, prevent, or cure a specific disease or condition without specific approval from the FDA. A claim also cannot suggest an effect on an abnormal condition associated with a natural state or process, such as aging (FDA 2010; Gao 2010). In Canada, herbal remedies must comply with the Natural Health Products Regulations (Health Canada 2003). According to these regulations, all natural products require a product license before they can be sold in Canada. In order to be granted a license, detailed information on the medicinal ingredients, source, potency, nonmedicinal ingredients, and recommended use needs to be furnished. Once a product has been granted a license, it will bear the license number and follow standard labeling requirements to ensure that consumers can make informed choices. A site license is also needed for those who manufacture, pack, label, and import herbal medicines. In addition, GMPs must be employed to ensure product safety and quality. This requires that appropriate standards and practices regarding the manufacture, storage, handling, and distribution of natural health products be met. The GMPs are designed to be outcome based, ensuring safe and high-quality products, while giving the flexibility to implement quality control systems appropriate to the product line and business. Product license holders are required to monitor all adverse reactions associated with their product and report serious adverse reactions to the Canadian Department of Health. In Europe, the European Directive 2004/24/EC released in 2004 by the European Parliament and by the Council of Europe provides the guidelines for the use of herbal medicines (Calapai 2008). The directive establishes that herbal medicines released on the market need authorization by the national regulatory authorities of each European country and that these products must have a recognized level of safety and efficacy (Calapai 2008). The registration of herbal medicinal products needs sufficient evidence for the medicinal use of the product throughout a period of at least 30 years in the European Union (EU), at least 15 years within the EU, and 15 years elsewhere for products from outside the EU. With regard to the manufacturing of these products and their quality, products must fulfill the same requirements as applications for a marketing authorization. Information is based on the availability of modern science–based public monographs in the European Pharmacopeia and their equivalents developed by the pharmaceutical industry. The standards put forward allow not only to define the quality of products but also to eliminate harmful compounds, adulteration, and contamination. Within the EU, a number of committees were set up to attempt and standardize the information and guidelines related to herbal medicines. A variety of materials has been produced, such as monographs on herbs and preparations, guidelines on good agricultural and collection practice for starting materials of herbal origin, and guidelines on the standardization of applications and setting up pragmatic approaches for identification and quantitative determination of herbal preparations and their complex compositions (Routledge 2008; Vlietinck, Pieters, and Apers 2009).
Quality, Safety, and Scientific Evidence
Herbal medicine has been commonly used over the years for treatment and prevention of diseases and health promotion as well as for enhancement of the span and quality of life. However, there is a lack of a systematic approach to assess their safety and effectiveness. The holistic approach to health care makes herbal medicine very attractive to many people, but it also makes scientific evaluation very challenging because so many factors must be taken into account. Herbal medicines are in widespread use and although many believe herbal medicines are safe, they are often used in combination and are drawn from plant sources with their own variability in species, growing conditions, and biologically active constituents. Herbal extracts may be contaminated, adulterated, and may contain toxic compounds. The quality control of herbal medicines has a direct impact on their safety and efficacy (Ernst, Schmidt, and Wider 2005; Ribnicky et al. 2008). But, there is little data on the composition and quality of most herbal medicines not only due to lack of adequate policies or government requirements but also due to a lack of adequate or accepted research methodology for evaluating traditional medicines (WHO 2001; Kantor 2009). In addition, there is very little research on whole herbal mixtures because the drug approval process does not accommodate undifferentiated mixtures of natural chemicals. To isolate each active ingredient from each herb would be immensely time-consuming at a high cost, making it not cost-effective for manufacturers (Richter 2003). Another problem is that despite the popularity of botanical dietary and herbal supplements, some herbal products on the market are likely to be of low quality and suspect efficacy, even if the herb has been shown to have an effect in controlled studies using high-quality product. There is a belief that herbs, as natural products, are inherently safe without side effects and that efficacy can be obtained over a wide range of doses. Although herbs may well have undesirable side effects, there are no set “doses,” and herb–drug or herb–herb interactions are possible. A major hypothetical advantage of botanicals over conventional single-component drugs is the presence of multiple active compounds that together can provide a potentiating effect that may not be achievable by any single compound. This advantage presents a unique challenge for the separation and identification of active constituents. Compounds that are identified by activity-guided fractionation must be tested in appropriate animal models to confirm in vivo activity. Ideally, the composition of the total botanical extract must be standardized and free of any potential hazards, and plants should be grown specifically for the production of botanical extracts under controlled conditions and originate from a characterized and uniform genetic source with a taxonomic record of the genus, species, and cultivar or other additional identifiers. Records should be maintained for the source of the seed, locations and conditions of cultivation, and exposure to possible chemical treatments such as pesticides. Because the environment can significantly affect phytochemical profiles and the efficacy of the botanical end product, botanical extracts can vary from year to year and may be significantly affected by temperature, drought, or flood as well as by geographic location. Therefore, biochemical profiling must be used to ensure that a consistent material is used to produce a botanical. The concentration step can also be challenging, and the process to concentrate active compounds to a sufficient level can negatively affect their solubility and bioavailability. Therefore, improving efficacy by increasing concentration can be counterproductive, and the use of solubilizers and bioenhancers needs to be considered just as for drugs (Ribnicky et al. 2008). However, there are major challenges to achieving this. Although in theory botanicals should be well characterized and herbal supplements should be produced to the same quality standards as drugs, the situation in practice is very different from that of a pure drug. Herbs contain multiple compounds, many of which may not be identified and often there is no identifier component, and chemical fingerprinting is in its early stages and is lacking for virtually all herbs (see Chapter 20). This makes standardization of botanicals difficult, although some can be produced to contain a standardized amount of a key component or class of components, such as ginsenosides for ginseng products or anthocyanins for bilberry products (see chapter 4 on bilberry and chapter 8 on ginseng in this volume). However, even when such key compounds have been identified and a standard content is agreed or suggested, there is no guarantee that individual commercial products will contain this. Another interesting point to consider is that herbal materials for commercial products are collected from wild plant populations and cultivated medicinal plants. The expanding herbal product market could drive overharvesting of plants and threaten biodiversity. Poorly managed collection and cultivation practices could lead to the extinction of endangered plant species and the destruction of natural resources. It has been suggested that 15,000 of 50,000–70,000 medicinal plant species are threatened with extinction (Brower 2008). The efforts of the Botanic Gardens Conservation International are central to the preservation of both plant populations and knowledge on how to prepare and use herbs for medicinal purposes (Brower 2008; Li and Vederas 2009).
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; Tiburt 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).
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.
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).
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
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).
International Diversity and National Policies
The diversity among countries with the long history and holistic approach of herbal medicines makes evaluating and regulating them very challenging. In addition, there are a great number of different herbs used. Legislative criteria to establish traditionally used herbal medicines as part of approved health care therapies faces several difficulties. In a survey conducted across 129 countries, WHO reported the following issues regarding herbal medicines: lack of research data, appropriate mechanisms for control of herbal medicines, education and training, expertise within the national health authorities and control agency, information sharing, safety monitoring, and methods to evaluate their safety and efficacy. The support needed from different countries includes information sharing on regulatory issues, workshops on herbal medicines safety monitoring, general guidelines on research and evaluation of herbal medicines, provision of databases, herbal medicine regulation workshops, and international meetings. National policies are the basis for defining the role of traditional medicines in national health care programs, ensuring that the necessary regulatory and legal mechanisms are established for promoting and maintaining good practice, assuring the authenticity, safety, and efficacy of traditional medicines and therapies, and providing equitable access to health care resources and their resource information (WHO 2005). Another fundamental requirement is harmonization of the market for herbal medicines for industry, health professionals, and consumers (Mahady 2001). Herbal medicines are generally sold as food supplements, but a common regulatory framework does not exist in different countries. As a result, information on clinical indications for their use, efficacy, and safety are influenced by the traditional experience available in each place. A brief outline of the legislation in United States, Canada, and Europe is given in this section, and could be used to guide the legal aspects of the herbal medicine industry in other countries. In the United States, under the Dietary Supplement Health and Education Act (DSHEA) of 1994, any herb, botanical and natural concentrate, metabolite and constituent of extract, is classified as a dietary supplement. Dietary supplements do not need approval from the Food and Drug Administration (FDA) before they are marketed (FDA 2010). Under DSHEA, herbal medicines, which are classified as dietary supplements, are presumed safe, and the FDA does not have the authority to require them to be approved for safety and efficacy before they enter the market, which is the case for drugs. This means that the manufacturer of the herbal medicine is responsible for determining that the dietary supplements manufactured or distributed are indeed safe and that any representations or claims made about them are sustained by adequate evidence to show that they are not false or misleading. However, a dietary supplement manufacturer or distributor of a supplement with a “new dietary ingredient,” that is, an ingredient that was not marketed in the United States before October 1994, may be required to go through premarket review for safety data and other information. Also, all domestic and foreign companies that manufacture package labels or hold dietary supplements must follow the FDA’s current good manufacturing practice (GMP) regulations, which outline procedures for ensuring the quality of supplements intended for sale (FDA 2010; Gao 2010). Regarding contamination, the FDA has not issued any regulations addressing safe or unsafe levels of contaminants in dietary supplements but has set certain advisory levels in other foods (FDA 2010; Gao 2010). A product being sold as an herbal supplement (dietary supplement) in the United States cannot suggest on its label or in any of itspackaging that it can diagnose, treat, prevent, or cure a specific disease or condition without specific approval from the FDA. A claim also cannot suggest an effect on an abnormal condition associated with a natural state or process, such as aging (FDA 2010; Gao 2010). In Canada, herbal remedies must comply with the Natural Health Products Regulations (Health Canada 2003). According to these regulations, all natural products require a product license before they can be sold in Canada. In order to be granted a license, detailed information on the medicinal ingredients, source, potency, nonmedicinal ingredients, and recommended use needs to be furnished. Once a product has been granted a license, it will bear the license number and follow standard labeling requirements to ensure that consumers can make informed choices. A site license is also needed for those who manufacture, pack, label, and import herbal medicines. In addition, GMPs must be employed to ensure product safety and quality. This requires that appropriate standards and practices regarding the manufacture, storage, handling, and distribution of natural health products be met. The GMPs are designed to be outcome based, ensuring safe and high-quality products, while giving the flexibility to implement quality control systems appropriate to the product line and business. Product license holders are required to monitor all adverse reactions associated with their product and report serious adverse reactions to the Canadian Department of Health. In Europe, the European Directive 2004/24/EC released in 2004 by the European Parliament and by the Council of Europe provides the guidelines for the use of herbal medicines (Calapai 2008). The directive establishes that herbal medicines released on the market need authorization by the national regulatory authorities of each European country and that these products must have a recognized level of safety and efficacy (Calapai 2008). The registration of herbal medicinal products needs sufficient evidence for the medicinal use of the product throughout a period of at least 30 years in the European Union (EU), at least 15 years within the EU, and 15 years elsewhere for products from outside the EU. With regard to the manufacturing of these products and their quality, products must fulfill the same requirements as applications for a marketing authorization. Information is based on the availability of modern science–based public monographs in the European Pharmacopeia and their equivalents developed by the pharmaceutical industry. The standards put forward allow not only to define the quality of products but also to eliminate harmful compounds, adulteration, and contamination. Within the EU, a number of committees were set up to attempt and standardize the information and guidelines related to herbal medicines. A variety of materials has been produced, such as monographs on herbs and preparations, guidelines on good agricultural and collection practice for starting materials of herbal origin, and guidelines on the standardization of applications and setting up pragmatic approaches for identification and quantitative determination of herbal preparations and their complex compositions (Routledge 2008; Vlietinck, Pieters, and Apers 2009).
Quality, Safety, and Scientific Evidence
Herbal medicine has been commonly used over the years for treatment and prevention of diseases and health promotion as well as for enhancement of the span and quality of life. However, there is a lack of a systematic approach to assess their safety and effectiveness. The holistic approach to health care makes herbal medicine very attractive to many people, but it also makes scientific evaluation very challenging because so many factors must be taken into account. Herbal medicines are in widespread use and although many believe herbal medicines are safe, they are often used in combination and are drawn from plant sources with their own variability in species, growing conditions, and biologically active constituents. Herbal extracts may be contaminated, adulterated, and may contain toxic compounds. The quality control of herbal medicines has a direct impact on their safety and efficacy (Ernst, Schmidt, and Wider 2005; Ribnicky et al. 2008). But, there is little data on the composition and quality of most herbal medicines not only due to lack of adequate policies or government requirements but also due to a lack of adequate or accepted research methodology for evaluating traditional medicines (WHO 2001; Kantor 2009). In addition, there is very little research on whole herbal mixtures because the drug approval process does not accommodate undifferentiated mixtures of natural chemicals. To isolate each active ingredient from each herb would be immensely time-consuming at a high cost, making it not cost-effective for manufacturers (Richter 2003). Another problem is that despite the popularity of botanical dietary and herbal supplements, some herbal products on the market are likely to be of low quality and suspect efficacy, even if the herb has been shown to have an effect in controlled studies using high-quality product. There is a belief that herbs, as natural products, are inherently safe without side effects and that efficacy can be obtained over a wide range of doses. Although herbs may well have undesirable side effects, there are no set “doses,” and herb–drug or herb–herb interactions are possible. A major hypothetical advantage of botanicals over conventional single-component drugs is the presence of multiple active compounds that together can provide a potentiating effect that may not be achievable by any single compound. This advantage presents a unique challenge for the separation and identification of active constituents. Compounds that are identified by activity-guided fractionation must be tested in appropriate animal models to confirm in vivo activity. Ideally, the composition of the total botanical extract must be standardized and free of any potential hazards, and plants should be grown specifically for the production of botanical extracts under controlled conditions and originate from a characterized and uniform genetic source with a taxonomic record of the genus, species, and cultivar or other additional identifiers. Records should be maintained for the source of the seed, locations and conditions of cultivation, and exposure to possible chemical treatments such as pesticides. Because the environment can significantly affect phytochemical profiles and the efficacy of the botanical end product, botanical extracts can vary from year to year and may be significantly affected by temperature, drought, or flood as well as by geographic location. Therefore, biochemical profiling must be used to ensure that a consistent material is used to produce a botanical. The concentration step can also be challenging, and the process to concentrate active compounds to a sufficient level can negatively affect their solubility and bioavailability. Therefore, improving efficacy by increasing concentration can be counterproductive, and the use of solubilizers and bioenhancers needs to be considered just as for drugs (Ribnicky et al. 2008). However, there are major challenges to achieving this. Although in theory botanicals should be well characterized and herbal supplements should be produced to the same quality standards as drugs, the situation in practice is very different from that of a pure drug. Herbs contain multiple compounds, many of which may not be identified and often there is no identifier component, and chemical fingerprinting is in its early stages and is lacking for virtually all herbs (see Chapter 20). This makes standardization of botanicals difficult, although some can be produced to contain a standardized amount of a key component or class of components, such as ginsenosides for ginseng products or anthocyanins for bilberry products (see chapter 4 on bilberry and chapter 8 on ginseng in this volume). However, even when such key compounds have been identified and a standard content is agreed or suggested, there is no guarantee that individual commercial products will contain this. Another interesting point to consider is that herbal materials for commercial products are collected from wild plant populations and cultivated medicinal plants. The expanding herbal product market could drive overharvesting of plants and threaten biodiversity. Poorly managed collection and cultivation practices could lead to the extinction of endangered plant species and the destruction of natural resources. It has been suggested that 15,000 of 50,000–70,000 medicinal plant species are threatened with extinction (Brower 2008). The efforts of the Botanic Gardens Conservation International are central to the preservation of both plant populations and knowledge on how to prepare and use herbs for medicinal purposes (Brower 2008; Li and Vederas 2009).
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; Tiburt 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).
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.
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