Herbal Medicine Research

Barriers to Herbal Medicine Research in the United States

The regulatory lockout of natural remedies has crippled natural products research in U.S. universities and hospitals. There is no dedicated

level of support by the Federal Government for herbal medicine research. Herbalists may apply under existing guidelines for approval of new

pharmaceutical drugs, but this burden is unrealistic because the total cost of bringing a new pharmaceutical drug to market in the United

States is an estimated $140 million to $500 million (Wall Street Journal, 1993). Because botanicals are not patentable (although they can be

patented for use), an herbal medicine manufacturer could never recover this expenditure. Therefore, herbal remedies are not viable candidates

for the existing drug approval process: pharmaceutical companies will not risk a loss of this magnitude, and herb companies lack the

financial resources even to consider seeking approval.

Another major barrier is that the academic infrastructure necessary for proper study of ethnomedical systems has seriously eroded in recent

decades and must be reinvigorated to accommodate the newly recognized need for preserving traditional medical systems and biological

diversity. Pharmacognosy and other academic studies of medicinal plants have declined alarmingly in the United States. North American

scientists, once at the forefront of this research, lag behind their European and Japanese colleagues, reducing the likelihood that they will

discover useful new medicines from plants. This problem is exacerbated by the fact that much of the discResearch Needs and Opportunities

Much modern-day medicine is directly or indirectly derived from plant sources, so it would be foolish to conclude that plants offer no further potential for the treatment or cure of major diseases. Worldwide, the botanical pharmacopoeia contains tens of thousands of plants used for medicinal purposes. Hundreds, perhaps thousands, of definitive texts, monographs, and tomes on herbal remedies exist. But most of this information is outside current databases and remains unavailable to physicians, researchers, and consumers.

Globally, herbal remedies have been researched under rigorous controls and have been approved by the governments of technologically advanced nations. The scientific validation is good to excellent, and the history of clinical use is even stronger. Many phytomedicines have been used by thousands of physicians in their practices and are consumed under medical supervision by tens of millions of people.

A great deal of literature exists on the use of phytomedicines in Europe and within native medical systems in China, Japan, India, and North America. Much of this literature can be found in a unique database developed and maintained by the University of Illinois at Chicago, College of Pharmacy. The database, NAPRALERT (Natural Products Alert), holds references for more than 100,000 scientific articles and books on natural products (plant, microbial, and animal extracts). NAPRALERT includes considerable data on the chemistry and pharmacology (including human studies) of secondary metabolites of known structure, derived from natural sources. About 80 percent of the references are from post-1975 literature, the rest from pre-1975 literature (see the "Research Databases" chapter for more information on NAPRALERT).

In 1981 the U.S. Department of Agriculture (USDA), in conjunction with the National Cancer Institute, concluded a 25-year study of plants with possible anticancer properties. One result is published in the Handbook of Medicinal Herbs (Duke and Ayensu, 1985). This work lists 365 folk medicinal species and identifies more than 1,000 pharmacologically active phytochemicals. Toxicity estimates are given for many of these biologically active compounds. More recently, Dr. James Duke of USDA published databases on biologically active compounds of more than 1,000 species of plants with potential medicinal uses (Duke, 1992a, 1992b). Duke proposed to FDA a computer-calculated toxicity index to parallel the Ames Human Exposure Rodent Potency (HERP) index for carcinogenicity. He calls his index the Better Understanding of Relative Potency (BURP) index.

Much of the literature on traditional Chinese and other Asian countries' herbal medicine is only now beginning to be translated into English. While much of this information is in the form of folklore, there is a growing body of data from scientifically valid literature on herbal medicine research in China as well as India and Japan. In 1986, the book Chinese Herbal Medicine: Materia Medica was published by Dan Bensky and Andrew Gamble, both of whom are fluent in Chinese dialects and studied herbal medicine in Asia. Revised in 1993 (Bensky and Gamble, 1993), it presents an indepth study of 470 herbs used in traditional Chinese medicine. Each entry details the traditional properties, actions and indications, principal combinations, dosage, and contraindications of the herbs, as well as summaries of abstracts regarding pharmacological and clinical research conducted in Asia. The revised edition also provides a brief description of the appearance of each herb.

Although very little laboratory or clinical research has been performed on Native American Indian herbal remedies, extensive listings of herbs and their uses have been compiled by ethnobotanists for several tribes. One source, American Indian Medicine (Vogel, 1970), cites references in the professional ethnobotanical literature on herbal medicines for the following tribes: Alabama-Koasati, Arakara, Algonquian, Arapaho, Aztec, Catawba, Cheyenne, Chickasaw, Choctaw, Comanche, Congaree, Creek, Dakota, Delaware, Hoh, Hopi, Houma, Huron, Illinois-Miami, Iroquois, Kwakiutl, Lake St. John Montagnais, Mayan, Menomini, Mescalero Apache, Malecite, Meswaki, Michigan, Mohawk, Mohegan, Natchez, Navajo, Nebraska, Oglala Sioux, Ojibwa, Omaka, Pawnee, Penobscot, Ponca, Potawatomi, Quileute, Rappahannock, San Carlos Apache, Seminole, Sioux, White Mountain Apache, Ute, Winnebago, Yuma, and Zuni. Moerman's database (Moerman, 1982) lists more than 2,000 species of Native American Indian medicinal plants, and Duke (1986) lists more than 700 eastern ones.

These sources--the NAPRALERT database, USDA laboratory research, the Bensky and Gamble book, and the Native American Indian herbal medicinal books--are the foundation on which the U.S. Government, particularly the National Institutes of Health (NIH), can begin substantial research into herbal medicines.

Much unwritten knowledge resides in the hands of healers in many societies where oral transmission of information is the rule. Unfortunately, in many regions this information is endangered because there are no young apprentices to whom elderly healers can pass on their unwritten wisdom; the knowledge that has been refined over thousands of years of experimentation with herbal medicine is being lost. A major research opportunity in this area would be to catalog information on herbal medicines from thousands of traditional healers in cultures where these skills are normally transmitted through an apprentice system. Some organizations have recently increased their efforts to catalog endangered herbal knowledge from traditional medical systems in Latin America, such as those practiced in the rain forests of Belize (Arvigo and Balick, 1993) and Peru (Duke and Martinez, in press).

Basic Research Priorities

Basic research into characterizing these plant products and compounds in terms of standardized content and potential toxicity is needed to allow safe and replicable research to document clinical efficacy. Basic science research should be conducted to evaluate research on the biochemical effects of traditional herbal prescriptions from Western, Ayurvedic, oriental, and other traditions (see the "Alternative Systems of Medical Practice" chapter).

Clinical Research Priorities

Research in phytomedicines in the United States could follow on the results of existing high-quality European and Asian research on plant medicines and should focus on replicating results of key studies or addressing weaknesses in those studies. Reviews of foreign literature and translations of non-English literature would be helpful. Current widespread use of herbal medications as "food supplements" in the United States provides a ready base of users, producers, and practitioners for clinical research in traditional and modern applications of botanical medicine.

Key Research Issues

Before a comprehensive research agenda is developed, several key issues must be addressed, including the following: the impending loss of knowledge about traditional healing in many societies; the impending loss of large numbers of plant species of potential medicinal value; impediments to the use of herbal remedies outside the cultures in which they originated; and determination of the conditions under which herbal medicines are most appropriate, safe, and effective. Additionally, several regulatory issues hamper research into herbal medicines.

Loss of Knowledge

The knowledge of traditional healers in remote Amazonian or Central American regions may have the potential to make a significant contribution to Western society. But few, if any, practitioners of these lesser known medical systems practice outside their native range, and those who still practice within these regions are elderly and often have not found younger disciples.

Loss of Plant Species of Potential Medicinal Value

This loss of knowledge from traditional healers comes at a time when native flora in many areas, especially tropical regions, are being destroyed at an alarming pace. In the United States alone, an estimated 10 percent of all species of flowering plants will be extinct by the year 2000, including an estimated 16 species of medicinally useful plants (Farnsworth et al., 1985).

One hopeful sign is that the U.S. Government recently formed a cooperative biodiversity group including representatives from NIH, the National Institute of Mental Health, the National Science Foundation (NSF), and the U.S. Agency for International Development. This group intends to fund research to locate and catalog medicinally active substances that can be analyzed and used for new pharmaceutical drug development, while working to preserve biological diversity in developing countries.

Use in Practice

Basic to the use of medicinal herbs in many societies is the practice of using whole, unrefined plant material. The material may be leaves, buds, flowers, bark, or roots, separately or in combination. In some cases an herbal remedy is a complex mixture of many plants. There is an age-old belief that whole-plant medicines have fewer dangerous side effects and provide a more balanced physiological action than plant-derived pharmaceutical drugs whose single ingredient has been isolated, concentrated, and packaged as a pill or liquid.

Herbs and herbal preparations generally are self-administered. Often they are purchased through native herbalists who prescribe one or more herbs or preparations on the basis of medical and health approaches that often include concepts of attaining balance in the client's body, psychology, and spirit (see the "Community-Based Medical Practices" section of the "Alternative Systems of Medical Practice" chapter). Consequently, it is often difficult to assess the relative value of herbal remedies versus prescription drugs on a one-to-one basis.

Indeed, herbal remedies of all types, including those from China, are composed of a multitude of ingredients whose interactions with the body are exceedingly complex. A high level of sophistication of research methodology is necessary to describe the interaction between the human body and substances as complex as those contained in many herbal remedies. Only recently has such a rigorous methodology begun to be developed. For example, the Chinese herb Herba hedyotidis diffusae (bai hua she she cao) has been shown clinically effective in the prevention and treatment of a variety of infectious diseases. However, it has not been demonstrated to have a significant inhibitory effect in vitro against any major pathogen. Only as techniques became available to test the immunological system did it become apparent that at least part of the herb's effect was due to its enhancement of the body's immune response (Bensky and Gamble, 1993).

Another complicating factor in researching traditional Chinese herbal medicine is the fact that Chinese medicine characteristically tries to treat the whole body to alleviate disease stemming from one body organ. Therefore, it rarely relies on a single herb to treat an illness. Instead, formulas usually contain 4 to 12 different herbs (Duke and Ayensu, 1985).

Beyond the problem of trying to test herbal preparations that may contain many active ingredients is the question of whether the research eventually will lead to the isolation of single active ingredients that can be packaged and sold separately. Intense debate surrounds the issue of how to conduct clinical trials of herbal medicines according to Western pharmaceutical clinical standards. Critics say there is an inherent problem with the single-active-ingredient approach preferred by pharmaceutical companies that are actively involved in herbal medicine research. The problem, they say, is that isolating a single compound may not be the most appropriate approach in situations where a plant's activity decreases on further fractionation (separation of active ingredients by using solvents) or where the plant contains two or three active ingredients that must be taken together to produce the full effect (Chaudhury, 1992). Beckstrom-Sternberg and Duke (1994) have documented several cases where synergy has been lost by using the single-ingredient approach to developing drugs from plants.

A good example of this single-active-ingredient versus whole-plant debate is illustrated by intense interest among pharmaceutical companies in the compound called genistein. Genistein is part of a class of compounds called flavonoids that occur naturally in plants such as kudzu, licorice, and red clover. Soybeans contain high concentrations of genistein, and lima beans reportedly are even higher in genistein than soybeans (Duke, 1993). There is increasing evidence that genistein may inhibit the growth of cancers of the stomach (Yanagihara et al., 1993), pancreas (Ura et al., 1993), liver (Mousavi and Adlercreutz, 1993), and prostate (Peterson and Barnes, 1993). Genistein is believed to inhibit the growth of cancers because of its antiangiogenetic properties (i.e., it prevents the growth of new blood vessels--a process known as angiogenesis--to tumors).

Genistein is being intensely studied as a possible preventive or treatment for breast cancer, which kills an estimated 44,000 women in the United States each year (Duke, 1993). Studies indicate a correlation between a high intake of foods containing genistein (soy products) and a low incidence of hormone-dependent cancers such as breast cancer (Hirayama, 1986) and prostate cancer (Baker, 1992). The growth of certain cancers, especially breast cancers, has been shown to depend on the female sex hormone estrogen. Genistein exhibits estrogenlike activity in plants and is often called a phytoestrogen. In humans it binds to estrogen receptors (Baker, 1992). It has been suggested that these phytoestrogens may compete with endogenous estrogen on the cellular level, further reducing the cellular proliferation and the potentially carcinogenic effects of estrogen (Tang and Adams, 1981). Thus, it may prevent the growth of estrogen-dependent cancer by competing for estrogen sites on the tumor cells.

If genistein is developed as an isolated pharmaceutical drug, it may have some action against cancer, but the purified compound may not be as potent as genistein in its natural state, and trials may give misleading results. The reason is that all plant species containing genistein also contain other flavonoid compounds, which may have synergistic effects when ingested with genistein. Formononetin--a precursor of equol, which also occurs with genistein--is said to be more active estrogenically than genistein (Spanu et al., 1993). Although genistein clearly inhibits angiogenesis, several other compounds are pseudoestrogens. With this in mind, the question arises: Is a mixture of genistein, formononetin, and other flavonoids, as occurs in many plants, more estrogenic (and antiangiogenic) than an equivalent quantity of any one of these components? If so, the herbal or dietary approach may make more sense than a genistein "silver bullet" approach.

Safety, Efficacy, and Appropriateness

Opinions about the safety, efficacy, and appropriateness of medicinal herbs vary widely among medical and health professionals in countries where herbal remedies are used. Some countries' professionals accept historical, empirical evidence as the only necessary criterion for herbal medicine's efficacy. Others would ban all herbal remedies as dangerous or of questionable value.

The problem is further complicated by the fact that many "patent medicines" available in world trade often are sold as herbal medicinal preparations when they include nonherbal substances. These nonherbal additives often include toxic metals (cinnabar, i.e., mercury) (Kang-Yum and Oransky, 1992), poisonous substances (powdered scorpion), or refined prescription drugs (Catlin et al., 1993). Usually labeled "Chinese herbal medicine," many of these products are manufactured in Thailand, Taiwan, or Hong Kong and exported to the United States, where they are sold in retail outlets. The California Department of Health Services, in conjunction with the Oriental Herbal Association, recently published a list of 20 popular Asian patent medicines (see app. E) that contain toxic ingredients.

Regulatory Issues

The increased use of plant medicines has potential for improving public health and lowering health care costs. Phytomedicines, if combined with the preventive model of medical practice, could be among the most cost-effective, practical ways to shift the focus of modern health care from disease treatment to prevention. But drug regulatory policy prevents the United States from taking advantage of these phytomedicines for two reasons. The first is the exorbitant expense involved in investigating each chemical compound in a given plant extract before it can be tested for clinical usefulness. Hence there is an urgent need to rework current research guidelines to allow the whole plant material or combination mixture (an herbal remedy containing more than one plant) to be evaluated instead of requiring separate evaluations of each chemical component of the therapeutic ingredients.

The second reason is that regulatory requirements for proof of safety and efficacy constitute an economic disincentive for private industry to conduct additional scientific studies. Relaxing regulatory requirements for efficacy for herbal products might make it economically feasible for more private companies to pursue research into issues of safety and quality control. Even with such regulatory change, some public funding of research is needed to confirm the remedies' validity. Public funds are needed because private industry has no incentive to develop an herbal product that might displace a patented drug from an approved treatment regime.ipline of botany has moved away from

field studies and into molecular and laboratory approaches. Today only a handful of active full-time ethnobotanists are trained to catalog

information on the medicinal properties of plants.

In contrast to the United States, many European and Asian countries have taken a more holistic approach to researching the efficacy of herbal

remedies. In Germany, France, and Japan, the past 20 years have seen a rapid increase in research into and use of standardized, semipurified

(still containing multiple individual chemicals) herbal extracts called phytomedicines. In Europe and Japan, phytomedicines treat conditions

ranging from serious, life-threatening diseases such as heart disease and cancer to simple symptomatic relief of colds, aches and pains, and

other conditions treated by OTC drugs in the United States. Phytomedicines include preventive medicines, an often-neglected area of medicine

in the United States. The FDA has approved many plant-derived "heroic" cures, but never a plant-derived preventive medicine.