Introduction

by Mark Blumenthal

Founder and Executive Director, American Botanical Council

Part I: Background on Herbal Medicine

A Brief History of Medicinal Herbs in North America

Herbs have enjoyed a long history of use as medicines in North America. Native Americans had medicinal uses for at least 2,582 species of plants, including such uses as analgesic, contraceptive, laxative, sedative, and remedies for colds, tuberculosis, and cancer (Moerman, 1998).

Until about 1930, herbs and herbal products constituted a significant proportion of the materia medica of North America during the 17th, 18th, 19th, and early 20th centuries. The first edition of the United States Pharmacopeia (USP) in 1820 contained 425 botanical substances (67% of all entries). Herb and herb product monographs reached their peak of 636 botanical substances (66%) in USP V in 1870, but by the time USP X was published in 1926, the total number of botanically-related monographs dropped to 203 botanical substances (36%) (Boyle, 1991). This reflected the trend that botanical medicine was widely used in the U.S. until about 1920 when herbs began to be replaced with pharmaceutical drugs, not because they were determined unsafe or ineffective, but because their actions were generally not as pharmacologically dramatic, and they were not as economically profitable as the newer synthetic drugs.

In 1888, the American Pharmaceutical Association published the National Formulary (NF), a compendium of formulae of primarily herb-based prepared medicines. In 1975 the publication of the NF was taken over by the USP and combined with the USP to create the USP-NF in 1980. In the 1990s, the USP renewed its efforts to address the issue of establishing quality standards for conventional dietary supplements (e.g., vitamins, minerals, etc.) and, in 1995, after the passage of the Dietary Supplement Health and Education Act of 1994 (DSHEA), USP began the development of monographs defining identity and purity standards for many of the best-selling herbs in the U.S. market. From 1995 to 2002, USP has published 86 standards monographs on 25 herbs (Blumenthal, 2003).

The recognition of the biological activity of herbs and medicinal plants is as old as medicine and pharmacy where many herbs have been used as medicines (so-called “crude drugs”) and, in more recent times, as the sources of widely accepted pharmaceutical drugs. Table 1 contains a partial listing of modern plant-derived drugs.

Recent Market and Consumer Use Information

[NOTE: The following information is from 2003. For more recent market information, look here.]

The need for professionally-oriented information and continuing education on the potential risks and benefits of herbal preparations is motivated by market factors in the past decade where consumers are using these products in larger numbers than ever before.

Consumers utilize herbs and other dietary supplements for a variety of purposes. A survey of 3,226 users of the ConsumerLab.com website stated they used supplements (herbal and non-herbal combined) for general health (67%), colds (53%), osteoarthritis (39%), energy enhancement (37%), cholesterol lowering (29%), cancer prevention (28%), allergy (27%), and weight management (25%). Fifty-four percent indicated that they used supplements for four or more conditions, with satisfaction with supplement brands being assessed as generally high, ranging from 97–63% of consumers being highly satisfied with their brands (ConsumerLab.com, 2002).

A recent survey of 2,590 respondents in the Slone Survey (Kaufman et al., 2002) found the following 10 most common reasons for taking herbal and non-herbal dietary supplements (i.e., non vitamin and mineral supplements): “health/good for you (16%); arthritis (7%); memory improvement (6%); energy (5%); immune booster (5%); joints (4%); supplement the diet (45%); sleep aid (3%); prostate (3%); don’t know/no reason specified (25%); all others (45%). There has been significant growth in other categories (e.g., menopause, weight loss, etc.) not noted specifically in this survey.

Over the past few years various surveys have reported differing statistics, but they tend to move in the same general direction. For example, in April and May 1999, Prevention magazine and Princeton Survey Research Associates conducted a survey of 2,000 adults indicating that 91 million consumers, about 49% of all the adult Americans, were estimated to have used an herbal product during the previous year. The survey also showed that about 24% (44.6 million) had used herbs frequently during the previous year, (Johnston, 2000), although another review and survey suggests that only 16–18% of adult Americans regularly use dietary supplements (which includes not only herbs, but also vitamins, minerals, amino acids, etc.) (Blendon et al., 2001).

An earlier report estimated that 70 million Americans are using herbal supplements (Wasik, 1999). An often-cited study in the Journal of the American Medical Association (JAMA) (Eisenberg et al., 1998) estimated that 46% of Americans saw an alternative practitioner in 1997, up from 36% in 1990, and spent $27.2 billion in 1998 on alternative care practitioners. Herb use reported in this survey grew from the baseline of 2.5% of the adult population measured in 1990 (Eisenberg et al., 1993) to 12% of adults using herbs in a one-year period as measured in 1997, a growth factor of 380%.

In the 1990s, sales of herbal products became a phenomenon in mass market retail stores increasing from 1994 levels to their highest levels in 1998, then leveling off and subsequently dropping. Sales in this sector reached the high point of $688,352,192 (including Wal-Mart sales) in 1998 declining to $337,207,360 in 2001 (excluding Wal-Mart sales) (Blumenthal, 1999, 2002). Market sales statistics as of April 2003 are shown in the Appendix, page 409. More recent information is here.) The decline of consumer demand in the mainstream market has been attributed to the following factors: negative media articles focusing on poor quality of some herbal products, adverse reaction reports and reports of interactions, the “myth” that the herb industry is unregulated—a message that lowers consumer confidence, unreasonable consumer expectations for the benefits of herbal products, and the cyclical nature of businesses (Blumenthal, 1999).

Meanwhile, sales in the natural/health food channels of trade continue to climb (albeit at a slower rate than previously.) This growth is explained by the fact that the more committed consumer shops for herbs and related supplements in health and natural food stores and appears to be less easily influenced by positive and negative publicity, rising 9% from $123,009,009 in 2000 to $134,086,587 in 2001 (Blumenthal, 2002).

Herb Safety

In general, it would appear that there are fewer adverse event reports (AERs) in the U.S. on a per capita basis for herbs than for conventional pharmaceutical drugs. On the other hand, it is also possible that the generally low incidents of AERs for herbs may be a result of poor reporting mechanisms and the possibility that many herb users simply may not report adverse events, because such events may be relatively minor (e.g., gastrointestinal upset, headache, etc.) and/or because many herb users may consider themselves outside the medical mainstream and may have a bias against making such a report. The truth of the situation in the U.S. is likely that both explanations are equally plausible; i.e, most commercially available herbs are generally gentler and safer than conventional drugs, and there needs to be better reporting mechanisms for herb-related adverse events.

The general safety of phytomedicines (advanced herbal preparations, often chemically standardized; see Standardization section on page xix) has been well documented in Western Europe, where the regulatory systems in many countries treat herbs and phytomedicines in the same way as they treat conventional drugs. That is, phytomedicines are made from raw materials and extracts that meet national or the European pharmacopeia standards for identity and purity, they are required to be manufactured by proper good manufacturing practices (GMPs: the body of federal requirements governing how food or drug manufacturers must operate their production facilities in order to ensure safe, properly labeled consumer foods and drugs), they are evaluated and approved by national governments for indications as nonprescription drugs and for safety parameters (e.g., the German Commission E), and any adverse effects are routinely reported within the same pharmacovigilance system designed for conventional drugs. In the European Union, the AERs for herbs and phytomedicinal preparations are lower than the AERs for conventional drugs, even when adjusted for total doses sold.

There are several voluntary reporting systems for herb and dietary supplement-related AERs in the U.S. One is the American Association of Poison Control Centers in Washington, D.C., the results from which are available on fee-for-service basis, usually for companies who check on reports on their specific products. Another is the Food and Drug Administration’s (FDA) MedWatch system for drugs, used primarily by health professionals (sometimes considered controversial insofar as the reports are not always fully documented with adequate information). A new, improved system at FDA for reporting adverse events related to foods and dietary supplements is managed by the agency’s Center for Food Safety and Applied Nutrition (CFSAN) and is called CAERS (CFSAN Adverse Event Reporting System). CAERS is replacing the older and much less reliable Special Nutritionals/Adverse Event Monitoring System (SN/AEMS) which was created in 1998. There were many problems associated with poor documentation of AERs associated with AEMS, as was eventually acknowledged on the AEMS website before it was removed in August, 2002: “There is no certainty that a reported adverse event can be attributed to a particular product or ingredient. The available information may not be complete enough to make this determination.” (FDA, 2002a). The new CAERS system is expected to be pilot tested in 2003 and operational by 2004 (FDA, 2002b).

The FDA’s 10-year work plan addresses the areas of safety, labeling, boundaries (related to appropriate definitions, etc.), enforcement activities, enhancement of the FDA’s science/research capabilities, and outreach to consumers and manufacturers (Levitt, 2000). Included in the “Safety” section of the FDA’s 10-year work plan, is the agency’s commitment not only to publish regulations on GMPs, but also improve the AER system, as well as develop a database to enhance mechanisms for identifying potential health hazards related to foods and dietary supplements (Levitt, 2000). This is being implemented, as noted above.

The increasing use of herbs by consumers invariably suggests potential for interactions with conventional medications (Blumenthal, 2000; Fugh-Berman, 2000; Fugh-Berman and Ernst, 2001). Eisenberg et al. (1998) estimated that 15 million adults in 1997 used prescription drugs simultaneously with herbal remedies and/or high dose vitamin supplements, concluding that these persons were potentially at risk for adverse herb-drug or drug-supplement interactions. In a survey conducted by Princeton Survey Research Associates for Prevention magazine, researchers noted that 36% of herb users employ herbal remedies in place of prescription drugs; 31% with prescription drugs; 48% instead of over-the-counter (OTC) drugs; and 30% with OTC drugs (Johnston, 2000). In the Slone Survey (Kaufman et al., 2002) of 2590 participants from about the same period of time, 81% stated that they used at least one medication (Rx or OTC), 50% took at least one prescription drug, and 7% took five or more drugs simultaneously. Fourteen percent said they used herbs and supplements during the previous week while 16% of the prescription drug users acknowledged also taking an herbal supplement. These authors conclude that one in seven adults consume at least one herbal supplement annually and that one in six patients taking a prescription drug is concurrently taking one or more herbal supplements, raising the potential for interactions.

A recent systematic review of herb-drug interactions (Fugh-Berman and Ernst, 2001) concluded that of the 108 interactions evaluated, 74 cases (68.5%) were considered unable to be evaluated due to the lack of adequate information, 14 (13%) were considered “well-documented” and thus likely, and 20 (18.5%) were considered “possible” interactions. The authors emphasize the need for better documentation of all relevant data in case studies of potential interactions. The most authoritative, evidence-based database of herb-drug interactions has been compiled by Brinker (2001).

Standardization

Many of the herbal preparations in this book upon which clinical trials were conducted are characterized as “standardized.” This is one of the most misunderstood concepts in botanical medicine. While usually referring to the chemical process of “normalizing,” “adjusting,” or fixing a particular chemical or groups of chemicals, the concept of standardization has several meanings that warrant clarification.

There are numerous areas in which standardization occurs in the field of preparing botanical medicines and dietary supplements. First, there is nomenclature. The scientific terms (Latin binomials) are a standardized means used in botany and other sciences. In the U.S., there is also an initiative to standardize common names; the American Herbal Products Association (AHPA) has published a listing of about 1,650 herbs used in commerce in the U.S., with the “standardized common name” linked to the most recent Latin binomial; “other common names” are also noted, although they are not preferred (McGuffin et al., 2000). An earlier version of this self-regulatory initiative listing approximately 550 herbs was published in 1992 (Foster, 1992). In 1997, the U.S. Food and Drug Administration (FDA) adopted Herbs of Commerce as an official list for common names of herb products sold in the U.S. and thus federal regulations [21 C.F.R. Sec 101.4(h)(1)-(2)] require that common names used on herbal dietary supplement products be consistent with the names standardized in the 1992 edition of Herbs of Commerce. It is possible that the FDA will also similarly acknowledge the later publication.

The most frequently employed meaning of standardization refers to chemistry. Standardization often refers to the control of a particular marker compound or group of compounds (see discussion below). However, in a larger sense standardization can also refer to the entire process of controlling the supply chain of raw material quality and manufacturing process including, but not limited to, controlling various chemical components of the preparation (Eisner, 2001).

“Standardized” herbal products contain botanical ingredients that are chemically “standardized” to contain a consistent level of a major active constituent or marker compound or the botanical extract is defined by declaring the drug-to-extract ratio (e.g., 7–8:1), the extraction solvent (e.g., ethanol 60%), and the grade or quality of raw material that was used to make the extract (e.g., Senna Leaf USP). Chemical standardization has allowed manufacturers to offer greater consistency from batch to batch. In general, however, the term standardization encompasses far more than guaranteeing specific levels or ranges of certain constituents occurring in the final preparation. It involves the use of consistent, documented processes and standards throughout every step of production including adherence to Good Agricultural Practices (GAP), Good Manufacturing Practices (GMP) and Good Laboratory Practices (GLP), among others. AHPA has published its standardization guidance manual in 2001 (Eisner, 2001).

Standardizing herbal products does not necessarily guarantee potency because the medicinal activity is often not due to a single chemical but to a mixture of constituents (many still unidentified), and often to the additive, synergistic (or antagonistic) activity of several components (Robbers and Tyler, 1999). It is inherently difficult to control all the factors that affect a plant’s chemical composition. For example, hypericins, a group of two naphthodianthrones, have long been held to be the active constituent of St. John’s wort (Hypericum perforatum) (even though most commercial extracts incorrectly state that they are standardized to hypericin [singular] instead of hypericins). However, recent research suggests that the phloroglucinols hyperforin and adhyperforin, may be the prime active principles, and flavonoids such as amentoflavone have received consideration lately as possible active compounds (Awang, 1999). Other components may also be involved in biological activity.

Legal and Regulatory Status of Herbs and Phytomedicines in the U.S.

There appears to be considerable confusion about the regulation of herbs and other dietary supplements in the U.S. The herb and dietary supplement industries are characterized by a substantial level of laws, regulations, and proposed regulations on the federal level. Former FDA Commissioner Jane Henney, M.D. testifying before the House Committee on Government Reform (March 25, 1999) stated, “The FDA has tools at its disposal to take enforcement actions against dietary supplements found to have safety, labeling, or other violations of the Food, Drug and Cosmetic (FD&C) Act, as amended by DSHEA.” (Soller, 2000). As a result of DSHEA, dietary ingredients used in dietary supplements do not require pre-market documentation of safety for submission to the FDA unless they are new dietary ingredients (i.e., ingredients not sold before the passage of DSHEA in October 1994), subject to the notification requirement in Section 413(a)(2) of the FD&C Act. This has led critics of DSHEA to fear a potential “safety meltdown.” Despite legitimate concerns about herb safety, the general lack of epidemiological evidence to the contrary suggests such a meltdown has not occurred since the passage of DSHEA, probably as a result of a combination of factors. These include the following considerations: (1) most dietary supplements have a very long history of relatively safe use; (2) consumers usually use self-care products, such as dietary supplements, in a responsible manner; (3) most companies are meeting the legal requirements of DSHEA; and, importantly, (4) the FDA and the FTC have sufficient enforcement authority in this area and have engaged in the development of the new regulatory framework for dietary supplements (Soller, 2000).

DSHEA places responsibility for ensuring herbal supplement safety on manufacturers, identifies how literature may be used in connection with sales, specifies types of statements of nutritional support that may be made on labels, specifies certain labeling requirements and provides for the establishment of regulations for GMPs. The FDA must model dietary supplement GMPs after food GMPs and may not impose standards for which there is no current and generally available analytical methodology. It is also important to point out that many dietary supplement companies have already been operating under GMPs that meet or exceed the proposed dietary supplement GMPs, particularly those companies who market their products outside of the U.S. or companies that also manufacture OTC drugs. Additionally, U.S. companies whose products are licensed as Traditional Herbal Medicines (THMs) in Canada or as Therapeutic Goods in Australia must meet the GMP requirements of those countries, respectively. At press time (early 2003) the FDA had not yet published proposed rules for GMPs for dietary supplements, although such publication is considered imminent.

In passing DSHEA, Congress noted in the “findings” section of the Act that “consumers should be empowered to make choices about preventive health care programs based on data from scientific studies of health benefits related to particular dietary supplements.” One of the purposes of passing DSHEA, therefore, was to provide consumer access to products and truthful information about those products, while maintaining authority for the FDA to take action against products that present safety problems or are improperly labeled (Soller, 2000).

Under DSHEA, dietary supplements are typically classified as foods, and defined as any product intended for ingestion as a supplement to the diet; but are not intended to replace food in the diet. They are specifically exempted from the definition of drugs (i.e. intended to diagnose, cure, mitigate, treat, or prevent diseases) and thus are not subjected to the same rigorous testing and approval processes required by the FDA for drugs. Manufacturers must label dietary supplements as such. Effective March 1999, supplement labels must carry a “Supplement Facts” panel, granting easier access to ingredients and suggested dosage.

One of the most misunderstood aspects of DSHEA is the issue of the FDA’s ability to protect the public from unsafe dietary supplements. Once a supplement is on the market, the FDA must prove that it is unsafe before imposing restrictions on its use. The “burden of proof” has now shifted from the manufacturer proving safety to the FDA proving that a substance poses an “imminent health hazard” once that determination has been made by the Secretary of Health and Human Services. The issue of regulation, herb safety, and the impact on the general public can often be mischaracterized and exaggerated in the media to the extent that even FDA officials have misstated the agency’s authority. According to Stephen H. McNamara, an attorney who specializes in food and drug law and formerly an attorney at the FDA, there are numerous provisions in the FDCA and DSHEA that give the FDA adequate authority to remove unsafe supplements from the market: “…it appears that the FDA has substantial and sufficient regulatory authority to protect the American public from any dangerous or otherwise unsafe herbs or other dietary supplement products despite statements to the contrary from FDA officials.” (McNamara, 1996).

DSHEA also required the establishment of an Office of Dietary Supplements (ODS) within the National Institutes of Health (NIH) and a Commission on Dietary Supplement Labels. The ODS is responsible for conducting and coordinating research relating to dietary supplements (including botanicals) and collecting and compiling a database of scientific research on botanicals (ODS, 2002).

Consumer and professional confidence in herbal preparations and other dietary supplement products underwent a considerable degree of erosion during the late 1990s as various news organizations and independent groups reported that many of these products failed to meet a variety of labels claims related to content of certain ingredients, standardization markers, or other elements. While in some cases, these reports accurately reflected the wide variation in quality of herbal products, they sometimes were based upon improperly conducted analyses and/or inappropriate analytical methods (Raffman, 2000; Foreman, 2000).

For an extensive account of the legal and regulatory history of herbs in the U.S., see Blumenthal and Israelsen (1998).

Lack of Regulatory Assessment and Recognition of Benefits

One of the primary problems associated with the botanical products market in the U.S. is the lack of an official system to evaluate and recognize the benefits and risks of herbal preparations. While there is much attention focused on potential risks (for obvious reasons of concern for public safety and perhaps the less obvious reasons that many conventional health professionals are not adequately trained on the appropriate uses of these products), there is virtually no official recognition of the benefits of herbal products, except for the few herbs that are approved by the FDA for use as OTC drug ingredients (see Table 2). This lack of recognition of benefits fosters a situation in which safety problems become magnified and often disproportionately exaggerated relative to their actual public health implications. Thus, media reports of an adverse reaction to an herb or herbal product or an herb-drug interaction are viewed without any countervailing recognition of the benefits of the herb. This does not occur with OTC or prescription drugs as most of these ingredients have successfully undergone some form of formal risk-benefit assessment, i.e., the benefits outweigh the risks.

Some legislators and industry leaders are looking to countries with established herbal medicine regulatory systems. The Commission E in Germany is one such system frequently proposed as a potential model for consideration. There, herbal drugs are regulated in much the same way as conventional drugs, have to meet similar criteria of quality and safety that the country requires of all drugs (although herbal drugs are approved by a standard of “reasonable certainty” as compared to a stricter standard for pharmaceutical drugs), and are sometimes eligible for reimbursement by the national healthcare system (Blumenthal et al., 1998). Commission E’s findings on safety and efficacy have been called “the most accurate body of scientific knowledge on that subject available in the world today” (Robbers and Tyler, 1999). This statement is still probably true with respect to evaluations of herb safety and efficacy as sponsored by a Western industrialized nation. Commission E is a federally mandated panel of 24 experts from various disciplines associated with medicinal plants, including physicians and pharmacists. They met from 1978 to 1995 to assess the safety and efficacy of about 300 herbs and fixed herbal combinations to determine their approval as nonprescription drugs. Commission E conducted literature reviews as the primary method of determining safety and efficacy and did not employ the formal risk-benefit assessments used for conventional drugs. Nevertheless, of the 380 monographs published by Commission E, 254 were for herbs deemed positive (i.e., safe and effective—approved) while 126 were deemed either neutral (safe but insufficient data to approve use) or negative (unsafe and/or ineffective—unapproved) (Blumenthal et al., 1998). Without a Commission E-like system or some other similar process for the rational and scientific evaluation of herb safety and benefits, and the eventual official recognition of these findings, it is highly likely that reports of adverse effects associated with herbs will continue to be viewed in an unbalanced manner without acknowledgement of their corresponding benefits.

Integrating Botanical Medicine into Modern Clinical Practice

Growing consumer use of herbs creates pressure on physicians and other healthcare providers to learn about their potential risks and benefits. Additionally, articles have begun to appear in medical journals urging conventionally trained physicians to become familiar with alternative medicine and to treat respectfully their patients who use such therapies (Eisenberg, 1997). Conferences and continuing medical education modules offer a variety of options, including information on medicinal herbs. For example, a week-long course on “Botanical Medicine in Modern Clinical Practice” has been offered by the Rosenthal Center for Complementary and Alternative Medicine at the Columbia University College of Physicians and Surgeons (www.rosenthal.hs.columbia.edu) since 1996.

Previous reports suggest that people who have used complementary medicine do not tell their physicians, as they are often concerned that the physician may either not understand or will criticize them; some of this is borne out in a recent survey summarized in Table 3 (Eisenberg et al., 2001). As in all therapeutic relationships, communication and trust between doctor and patient are of primary importance (Zollman and Vickers, 1999). A University of Iowa study, however, suggests that herb users believe that herbs are generally safe, can improve their health, and that their physicians and their families share their positive perceptions about herbs. This same study noted the surprising finding that herb users tend to be heavier users of prescription drugs and to have more negative attitudes towards those medications than non-users (Klepser et al., 2000).

Nearly two-thirds (64%) of the nation’s medical schools now have courses on complementary and alternative medicine (CAM); many designed to help physicians answer patients’ questions (Wetzel et al., 1998; Stolberg, 2000). Of the 123 CAM courses reported in a survey, 68% were stand-alone electives and 31% were part of required curriculum (Wetzel et al., 1998). Herbal medicine is usually included in the complementary medicine courses in these curricula, but the herb information is often relegated to cursory reviews and basic but incomplete information on only the most popular herbs in the market.

Nearly half of British medical schools offer some courses in complementary medicine and some postgraduate medical centers offer a basic introduction to complementary disciplines (Zollman and Vickers, 1999). In a survey of 550 European universities (141 having medical faculties), 43 (40%) universities of the 107 responding schools offer coursework in CAM; 8 teach herbal medicine/phytotherapy; 4 employ phytotherapy in university clinics; and 3 report clinical research on herbs (Barberis et al., 2001).

The level of credibility in herbs and phytomedicines increased in the past decade among members of the conventional medical community in the U.S. after the publication of several papers in mainstream medical journals that support the safe and effective use of some of the more well-researched herbs. These papers include (in chronological order) the meta-analysis of clincal trials on St. John’s wort for mild to moderate depression in the British Medical Journal (Linde et al., 1996), the first American trial on ginkgo (Ginkgo biloba) leaf extract for early stage Alzheimer’s dementia in the Journal of the American Medical Association (JAMA) (LeBars et al., 1997), the meta-analysis of saw palmetto berry (Serenoa repens) extract for the treatment of symptoms of benign prostatic hyperplasia in JAMA (Wilt et al., 1998), the meta-analysis of clinical trials on horse chestnut seed (Aesculus hippocastanum) extract for the treatment of chronic venous insufficiency in the Archives of Dermatology (Pittler and Ernst, 1998), and a clinical trial on a Chinese herbal combination formula demonstrating safety and efficacy in the treatment of irritable bowel syndrome in JAMA (Bensoussan et al., 1998). Additional meta-analyses are being continually produced by the Cochrane Collaboration, an international group of reviewers from various medical centers who have been conducting evidence-based reviews on many of the more well-researched herbs and phytomedicines (as well as reviews on other modalities used in both conventional and complementary and alternative medicine <www.cochrane.org>). One example of such a review is the recent meta-analysis of trials on kava (Piper methysticum) for relief of symptoms of anxiety (Pittler and Ernst, 2002), based, in part, on an earlier meta-analysis of the same trials (Pittler and Ernst, 2000), and the meta-analysis of 33 clinical trials conducted on ginkgo standardized extract showing “promising evidence” for the treatment of dementia in older patients (Birks et al., 2002).

Healthcare providers should consider several important points when counseling patients on herbal treatments including: (1) herbal remedies are not usually as concentrated as conventional pharmaceuticals with some exceptions (i.e., some concentrated standardized extracts, e.g., milk thistle extract, ginkgo extract) and results may take longer; (2) like conventional pharmaceutical drugs, herbal remedies can produce unwanted side effects and adverse drug interactions; (3) many herbal remedies are not standardized like pharmaceutical drugs (which are almost always one single chemical entity), and different products may vary widely in chemistry, potency and activity; (4) although there is a growing body of data from controlled clinical trials on an increasing number of herbs, much of the data on herbs is based on empirical and/or anecdotal evidence. Reliable references for efficacy, dose, and safety should be consulted (D’Epiro, 1997).

In working with patients, healthcare professionals should ask about botanical medicine use when the patient has chronic or relapsing disease, is experiencing or concerned about adverse drug reactions, or there is unexplained poor compliance with treatment or follow-up. Useful questions when inquiring about use of botanical medicine include: “Have you tried other treatments for this problem?” “Have you changed your diet because you thought it might help this problem?” “Are you using or have you used any herbal remedies or other dietary supplements?”

Contrary to some publications suggesting that the relative high use of CAM therapy in the U.S. represents a large-scale rejection of orthodox and conventional medicine (Astin, 1998; Druss and Rosenheck, 1999), a recent survey by Eisenberg and colleagues (2001) found that “the use of CAM therapies cannot be attributed primarily to perceived dissatisfaction with conventional medical care or caregivers. Many adults seek, explore, and experience benefits from both conventional and CAM therapies….Only a minority of individuals seek the professional services of a CAM practitioner before seeking conventional medical care. As such, conventional medical doctors and other conventional caregivers who are knowledgeable about CAM practices and the evidence to support or refute their application have a unique opportunity to advise patients on the use or avoidance of individual CAM therapies on a case-by-case basis.” (emphasis added) (Eisenberg et al., 2001).

The authors continue, “As evidence-based evaluation of CAM therapies materializes, let us be reminded that many adults currently choose to use CAM therapies to treat their most serious medical problems and appear to value both conventional and CAM approaches. Moreover, when patients choose not to tell their physicians that they use CAM therapies, they appear to be less concerned about their physician’s disapproval than their physician’s perceived inability to understand or incorporate CAM therapies into their overall medical management.” (emphasis added) (Eisenberg et al., 2001).

Another recent survey reported that 44% of supplement consumers believe that physicians know “little” or “not much at all” about dietary supplements and 72% said they would continue using such products for their health even if a government-sponsored clinical trial resulted in negative findings (Blendon et al., 2001).

Many users of herbs do not reveal this use to their primary physicians. Eisenberg et al. (2001) noted the main reasons that survey respondents gave for nondisclosure to their physicians of their use of CAM therapies with a “recognized potential for risk for adverse effects:” patients did not think it was important for the physician to know about the herb use and the physician did not inquire. (See Table 3 for more details.)

One of the biggest issues regarding herbal supplements facing conventional practitioners today is the question of trust. Many practitioners may be willing to recommend a particular herb for a patient, or counsel a patient who is already using an herbal remedy (e.g., the use of black cohosh to help treat symptoms of menopause, using saw palmetto to treat symptoms associated with BPH). However the clinician is often concerned about which brand of product to recommend, since there appears to be so much confusion about quality control among the many products that are available. One physician has proposed the following guidelines: In the absence of a clinical trial on a particular product, products manufactured or distributed by reputable herbal products manufacturers or major pharmaceutical firms, which have experience with and can ensure a high level of quality control, may be more safely recommended. Alternatively, standardized formulations, or those carrying a certified trade group seal, should be selected. Products with detailed labeling, including batch number, contact information, and expiration date, are also favored (Rotblatt, 1999).

However, these guidelines may not be adequate. Many manufacturers offer relatively detailed information on their product labels, including batch or lot numbers and expiration dates. These are required as part of federal regulations and good manufacturing practices (GMPs) and do not necessarily reflect the inherent quality of the herbal materials in the product, or the clinical reliability of the product. Many companies offer “standardized” herbal products, where the compound (or group of compounds) to which the product is standardized may or may not be based on activity-related parameters; products are often standardized to “marker” compounds simply for quality control purposes.

In the opinion of the editors of this publication, the first place to look for answers to the question “Which products should I recommend?” is the clinical literature. Although there may be numerous high quality, reliable herb products from which to choose, it seems reasonable to evaluate the clinical literature on each herb for which clinical trials have been conducted and determine which brand of commercial product was used in each study. While this may be only one criterion, the editors consider it a rational basis from which to consider making a product selection. Accordingly, such brand-related information is included in the monographs in this publication, intended as a guide for healthcare practioners, although it should not be construed as a recommendation or endorsement by the editors or publishers of this volume. This information is found in the “Branded Products” section of each monograph (see description on page xxviii).

Rational Phytotherapy

Many people consider herbs and phytomedicines as CAM, which is the term that is now frequently employed in the U.S. However, in many modern European nations, the employment of herbs and phytomedicines in conventional medical practice is not considered alternative medicine but “rational phytotherapy,” as these preparations are generally considered nonprescription medications and are regulated as such as far as their quality, safety, and efficacy are concerned.

According to the late Varro E. Tyler, the former Dean and Distinguished Professor of Pharmacognosy Emeritus at the School of Pharmacy and Pharmacal Sciences at Purdue University:

Rational herbal medicine is conventional medicine. It is merely the application of diluted drugs to the prevention and cure of disease. The fact that the constituents and, sometimes, even the mode of action of these drugs are often incompletely understood and that instruction in their appropriate application is not a significant part of standard medical curricula does not in any way detract from their role in conventional medicine. If it did, we would be forced to discontinue the use of a number of popular products such as psyllium seed and senna laxatives, together with about 25% of our current materia medica that is derived from such sources. We would also have to conclude that some 62% of all German adults are unconventional because that is the percentage that turns first to a natural remedy (herbs or phytomedicines) to treat their illnesses….Although herbal therapy may not be mainstream American medicine, it certainly is conventional (Schulz et al., 2001).

Evidence-Based Medicine

In the view of the editors, the term “evidence-based” presupposes a formal, systematic process in which clinical trials are ranked according to their size, design, and statistical power. This was not done in the preparation of The ABC Clinical Guide to Herbs, although such information is provided for most of the trials summarized in the clinical tables in each monograph. The editors have employed a relatively informal evidence-based approach in determining the “Primary Uses” of each herb in the herb’s respective monograph, basing such uses on the availability of supporting clinical trials. However, in the view of the editors, this process did not meet the standards of a systematized process that is usually associated with the strict definition of “evidence-based.” Therefore, the editors have chosen to use the phrase “science-based” rather than “evidence-based” when describing The ABC Clinical Guide to Herbs.

Interpreting Product Labels

Example of Product Label

1.   Brand name

2.   Product/herb name

3.   Herbal products and other “dietary supplements” may make “statements of nutritional support,” often referred to as “structure/function claims,” as long as they are truthful and not misleading, are documentable by
scientific data, and do not claim to diagnose, cure, treat, or prevent any disease, and carry a disclaimer on the product label to this effect. The disclaimer must also note that FDA has not evaluated the claim. The product manufacturer must also notify the FDA of the structure/function claim within 30 days of bringing the product to market. According to current FDA regulations, examples of acceptable structure/function claims include “supports the immune system” and “supports a healthy heart,” while claims such as “helps treat the common cold” and “helps prevent heart disease” are considered unacceptable, as these are considered drug claims. Thus “helps maintain urinary tract health” is acceptable while “helps prevent urinary tract infections” is not.

4.   A structure/function claim requires this disclaimer when it appears on the label of a dietary supplement, as well as in any brochures or advertising. The disclaimer must be in bold type and in a box.

5.   Number of tablets, capsules, and net weight of each in package.

6.   Directions for Use and Cautions.

Items 7-10 are part of the “Supplement Facts Panel”

7.   “Serving Size” is the suggested number of tablets, capsules, softgels, tea bags, liquid extract, or tincture to take at one time.

8.   “Amount per Serving” first indicates the nutrients present in the herb and then specifies the quantity. The following items must be declared if in excess of what can legally be declared as zero: calories, fat, carbohydrates, sodium, and protein. In addition, the following nutrients must also be declared if present in quantities exceeding what can legally be declared as zero: vitamins A, C, D, E, K, B-1, B-2, B-3, B-6, B-12, folic acid, biotin, calcium, iron, phosphorus, iodine, magnesium, zinc, selenium, copper, manganese, chromium, molybdenum, chloride, and potassium. Most herbal products contain negligible amounts of these nutrients.

9.   “Percent Daily Value” (%DV) indicates the percentage of daily intake provided by the herb. An asterisk under the “Percent Daily Value” heading indicates that a Daily Value is not established for that dietary ingredient.

10. Herbs should be designated by their standardized common names as listed in the book Herbs of Commerce, published in 1992 by the American Herbal Products Association. If the common name is not listed in Herbs of Commerce, then the common name must be followed by the herb’s Latin name. The plant part must be listed for each herb. The amount in milligrams of each herb must be listed unless the herbs are grouped as a proprietary blend—then only the total amount of the blend need be listed. For herbal extracts, the following information must be disclosed: 1. the ratio of the weight of the starting material to the volume of the solvent (even for dried extracts where the solvent has been removed, the solvent used to extract the herb must be listed); 2. whether the starting material is fresh or dry; and 3. the concentration of the botanical in the solvent.

11. Standardization. If a product is chemically standardized, the product label may list the component used to measure standardization (e.g., ginsenosides in Asian ginseng, valerenic acids in valerian, etc.) and the level to which the product is standardized (e.g. 4% ginsenosides). Therefore, if a product contained 100 mg of Asian ginseng extract per capsule and the extract was standardized to 4% ginsenosides, one capsule would contain 4 mg of ginsenosides. In most, but not all, cases, the component used to measure standardization is bioactive, although the standardization component may not be responsible for the intended primary activity of the herbal supplement, other active compounds may be responsible. Products can also be standardized to “marker compounds” for purposes of quality control. Those markers may or may not be active.

12. A list of all other ingredients, in decreasing order by weight, must appear outside the Supplement Facts box. In herb formulas containing multiple herbal ingredients, the herbs must be listed in descending order of predominance.

13. The proper location for storage of herbal products is typically labeled as a cool, dry place.

14. All herbal products and other dietary supplements should be kept out of the reach of children.

15. The herb should be used before the expiration date for maximum potency and effectiveness. Expiration dates are often arbitrarily established by the manufacturer, regardless of the ingredients and their relative stability. Such dates are routinely set at two years from the date of manufacture of the finished dietary supplement, although this period may be longer or shorter depending on the manufacturer’s policies, stability testing, dosage form, and other variables.

16. The product must list the manufacturer or distributor’s name, city, state, and zip code.

Part II: About this Book

The Purpose of this Book

This book originally began on a significantly more modest scale as a continuing education (CE) module for medical doctors. It was to be patterned after the American Botanical Council’s previous publication of brief monographs on 26 leading herbs, “Popular Herbs in the U.S. Marketplace,” (Blumenthal and Riggins, 1997). Since the inception of this present publication in late 1998, The ABC Clinical Guide to Herbs has evolved into a comprehensive and up-to-date CE course on medicinal botanicals and is accredited for healthcare professionals including physicians, pharmacists, nurses, dieticians, and others.

This book provides a detailed review of relevant therapeutic and clinical data concerning some of the most frequently used medicinal herbs and their preparations that patients are likely to take. Therefore, The ABC Clinical Guide to Herbs (The Guide) can serve as a reference in clinical practice and in the curricula of medical, pharmacy, nursing, and dietician schools, among others. We have taken great care to provide clear differentiation between the specific products that have been the subject of clinical studies, the qualitative and quantitative standards that define them, along with corresponding pharmacopeial standards for herbs and herbal preparations, and correlations that can be made between specific product qualities and the results documented from published clinical trials.

The editors accessed a comprehensive range of authoritative data on the herbs and phytomedicines. However, the research has not been exhaustive, and it is possible that some clinically relevant research information was omitted. The editors anticipate the possibility of electronic versions of these monographs to be accessible on the American Botanical Council’s website (www.herbalgram.org), and to be updated regularly as new clincally-relevant data is published.

Regardless of whether a healthcare professional chooses to incorporate an herb or phytomedicinal product in clinical practice—for treatment or prevention—the overwhelming fact is that many patients/consumers are using these natural products for their health in the belief that they provide some form of benefit. It is thus essential that conventionally trained healthcare providers learn as much as possible about the clinical pharmacology of these products, their relative safety, and their potential applications, as suggested by the published literature. This is the primary purpose of this book and continuing education course.

Potential Bias

It is understandable that some healthcare providers may hold a negative bias against herbs and herbal medicines. Most health professionals have not been taught about the potential benefits and relative risks of these therapeutic agents. They may also believe that herbs are not routinely screened by scientific evaluation of their safety and efficacy, and/or that they are not regulated as stringently as pharmaceutical drugs, etc. Thus, many healthcare professionals are quick to dismiss the validity of what others may consider a “reasonable” level of evidence in the form of clinical trials of various sizes and designs suggesting that an herb may provide some effective benefits. Such dismissal is frequently the result of a priori biases. This epistemological process occurs in both alternative and conventional medicine. According to a review by Vandenbroucke and de Craen (2001), physicians do reject seemingly solid evidence because it is not compatible with a pre-existing theory. They may be willing to discard a theory in the light of new data, but at other times they might also cling to an outmoded theory despite the compelling data suggesting otherwise. The authors write, “We propose that rational science is compatible with physicians’ behavior, provided that physicians acknowledge the subjective element in the evaluation of science…” The editors of this publication are aware of these biases and have attempted to present evidence on the potential benefits and/or risks of these products in an open and straightforward manner.

Why the Herbs in this Book Were Selected

Most of the herbs in this book were selected because they consistently rank high in retail sales, in most channels of trade, particularly in 1999 when this project was initiated. A table of the top-selling herbal supplements in food, drug, and mass market retail outlets for the 52 weeks ending October 13, 2002, can be found in the Appendix on page 409.

Several herbs in this book are not listed among the top-selling herbs in mass markets, but were selected because they still are considered to be among the most popular herbs. Neither chamomile (Matricaria recutita) nor peppermint (Mentha x piperita) are highly popular as dietary supplements, however they are two of the most popular herbs sold as herbal tea ingredients. American ginseng (Panax quinquefolius) and eleuthero (Eleutherococcus senticosus) sales are high, but their sales data is usually subsumed under the generic term “ginseng” with Asian ginseng (P. ginseng). Chaste tree (Vitex agnus-castus), ephedra (Ephedra sinica), goldenseal (Hydrastis canadensis), and horse chestnut (Aesculus hippocastanum) are not top sellers in mainstream outlets. However, they are among the 35 top-sellers in the natural foods outlets (NBJ, 2002) and, with the exception of goldenseal, varying amounts of clinical research have been performed on each of these herbs.

Description of Herb Chapters

Each herb chapter contains a 2-page clinical overview, a 1-page patient information sheet, and a comprehensive monograph. The monographs include the following sections.

Overview. This section includes a brief background on the herb, geographical origin, brief historical data, market status, and other relevant background information. In the case of the relatively controversial herb ephedra (a.k.a. ma huang, Ephedra sinica), the Overview section has been expanded intentionally in order to provide the reader some detailed background on the legal and regulatory issues related to this herb over the past decade or so.

Description. This section provides a description of the crude herb material used in commerce and/or parameters for powdered crude material and/or extracts. This section is not intended to offer a detailed botanical description, since this book deals with materials of commerce and is not intended as a field guide or other type of reference where detailed botanical descriptions are needed.

Uses. The Uses section is divided into two parts: “Primary Uses” and “Other Potential Uses.” By listing these as uses instead of indications, the editors are emphasizing that the herbs generally are not approved by the U.S. FDA (there are a few exceptions, e.g., the use of capsaicin, a primary active compound from cayenne or red pepper [Capsicum spp.]). Instead, Primary Uses refers usually to the most common use(s) of the herb or phytomedicine, especially as documented by published clinical trials. Other Potential Uses refers to the fact that there may be one or more trials suggesting possible use, that these trials may be small-scale pilot studies, that the design of the trial may be wanting for controls, and/or the trial’s outcome may be equivocal. Uses documented in authoritative monographs (e.g., the German Commission E monographs, World Health Organization, or ESCOP [European Scientific Cooperative on Phytotherapy]), or uses that are acknowledged from long-standing empirical use in European or other forms of traditional medicine, may also qualify for mention as “potential or, in some cases, as Primary.” Thus, the editors employed a type of evidence basis in qualifying the levels of use for an herb. By including potential uses, the editors are ensuring that healthcare professionals are aware that, as is often true with conventional pharmaceutical drugs, botanical medicines may have numerous possible applications beyond those documented by published clinical trials, or uses suggested by one or more trials.

It is not the intention of this book to determine the efficacy of particular herbs to a degree equivalent to those required for new drugs in a new drug application (NDA). Nor have the herbs been evaluated by a formal systematic review for the purposes of determination of their efficacy. However, an expert panel reviewed much of the literature upon which these monographs are based to assess the relative safety and potential efficacy for various uses.

Thus, the “Uses” are not meant to be considered in the same way as officially approved uses or indications for conventional drugs. The editors have based these uses on a variety of factors and the practitioner will have the opportunity to review the evidence presented in a variety of ways in the monographs and thus determine for him- or herself the appropriateness of using the herb or phytomedicine in a clinical setting. Thus, the primary or potential uses are proposed as a result of the totality of the evidence presented in the monograph and the appropriateness of their use is left to the judgment of the practitioner. In this sense, the uses are meant to be considered as guides, but are not necessarily presented as definitive uses as would be the case for approved conventional drugs.

Dosage. This section provides the recommended amount for effectiveness based on clinical research, authoritative monographs, or other sources. Unlike many herb publications currently available, the editors have gone to considerable length to provide various doses correlated to different types of preparations. Although authoritative monographs like those produced by the Commission E often refer to one or two types of preparations (e.g., dried herb [“crude drug”], liquid extracts, or solid extracts, etc.), they usually also add, “or equivalent preparations” to denote that other dosage forms of the herb (teas, concentrated extracts, etc.) might be substituted as long as their dosage is appropriately calculated. The challenge with this type of information is that it is often difficult to calculate such doses. When appropriate, the editors provide this information as a convenience to the practitioner. The doses are usually referenced from various authoritative sources, official monographs, clinical trials, and related sources. The reader may notice that there is often a range of dosage on any particular form of an herb, depending on either the intended use and/or the source of the information. This is a result of differences in the various sources and is indicative of the relative safety of many of these herbal preparations; i.e., precise dosing is often not as critical as it is with many pharmaceutical drugs.

Duration of Administration. This usually refers to periods of minimum or maximum use to ensure efficacy and/or reduce potential adverse reactions. However, in some monographs, the duration limit may also reflect the advisability of the patient’s revisiting the physician, as is the case with the maximum of six months duration for preparations made from black cohosh rhizome (Actaea racemosa, syn. Cimicifuga racemosa). In this example, there is no evidence that use of black cohosh preparations for more than six months creates any risk; the six-month limit is based on the preference in Germany that women on hormone replacement therapy for the treatment of menopausal symptoms see their gynecologists every six months for a checkup. This duration was initially prescribed by the Commission E.

Chemistry. The chemistry of herbs and herbal preparations (phytomedicines) is by its nature very complex—a consideration that is especially important to maintain in relation to conventional pharmaceutical drugs, which are usually single chemical entities, whether they are naturally derived or synthetic. Medicinal plants contain hundreds of chemical compounds, most of them being relatively dilute. This section provides a brief listing of primary chemical constituents, particularly those believed to be related to the herb’s known pharmacological activity.

Pharmacological Actions. This section provides information on activity of the herb and/or some of its isolated constituents. Many books on botanical medicine simply list all published actions as derived from the literature. This can be misleading, as animal data are not always clinically relevant to humans, especially when an isolated compound is given via injection. Additionally, much pharmacological data is published from in vitro studies (laboratory experiments in glass dishes on isolated cells or organs from animals or humans). While potentially insightful, in vitro studies suffer from the inability to fully recreate the environment of a living organism. Thus, their results are limited in scope and relevance to clinical considerations. The editors have separated pharmacological studies into three sections (human, animal, and in vitro) in order to put this information into clearer perspective. With most herbs (for example garlic [Allium sativum], Asian ginseng [Panax ginseng], ginkgo [Ginkgo biloba]), there are literally hundreds, in some cases thousands, of animal and in vitro studies in the literature, requiring the editors to limit the number of these studies referenced. While the editors have tried to include many that are representative of the actions of the herb, these sections are by no means exhaustive.

Mechanisms of Action. Mechanistic information regarding biochemical processes induced by an herbal preparation, studies showing where certain key compounds bind at receptor sites, and related data can be considered a subset of pharmacology. However, the editors have included some of this information in a separate section for the benefit of those researchers and clinicians having a special interest in such matters. Again, as with pharmacological actions, the editors have provided some data that provides insights into these areas, but did not embark on a quest to collect exhaustive data.

Contraindications. Safety data are clearly a matter of primary concern for clinicians, consumers, regulators, and manufacturers. The editors have attempted to provide as much data as they considered clinically relevant, although recent developments in herbal science and pharmacovigilance continue to provide new data that may require revision of these sections at any time. A case in point is the monograph on kava (Piper methysticum). After several drafts of the kava monograph were completed in late 2001, new data became available regarding potential hepatotoxicity associated with kava use (as suggested by AERs from Switzerland and Germany), and the subsequent regulatory concern in those and other countries. This situation required a significant revision of the kava monograph sections on contraindications and adverse events, even though several published reports by qualified pharmacologists and toxicologists who evaluated the kava AERs did not find adequate evidence of a causal relationship between kava use and most of the cases of hepatotoxicity (many of which were the result of pre-existing liver disease, concomitant use of hepatotoxic drugs, combination with alcohol, excessive dosage, etc.) (Waller, 2002).

The contraindications mentioned in this section are derived from various published reviews, official and unofficial monographs, etc. It should be noted that DSHEA allows for the disclosure of risk on the labels of herbs and other dietary supplements, but does not require such disclosure. However, the increased litigiousness in the American healthcare marketplace has created a deep concern from a product liability perspective to the extent that most companies will be compelled to publish more safety information on herbal products, although not currently required by law (Rubin, 2002).

In some monographs there are “no known” contraindications This usually means that the herb is generally safe to use with no known condition or known subset of individuals being precluded from use. However, this does not necessarily preclude pregnant or lactating women. A special subsection is provided in which specific information is given on pregnancy and lactation.

Adverse Effects. Adverse effects from herbs and herbal products are a reasonable expectation as is the case with any pharmacologically active agent. Historically, adverse effects from herbs and herbal products have been reported infrequently in the U.S. literature in comparison to the levels of use of these products. The argument has often been proffered that with the rise in widespread use of herbs in the U.S. there has not been a corresponding rise in herb-related AERs. This situation has been used as an indicator of the relative safety of the most popular herbs, which are generally known to exert more gentle, less dramatic physiological effects than conventional drugs. While this assertion is generally accurate, it is also true that adverse effects of herbs have not been collected in the same systems established for AERs for conventional medicines in the U.S., thereby suggesting that many may go unreported. However, in some leading western European countries (e.g., Germany, Switzerland), where herbs are routinely reported in the same systems of pharmacovigilance as conventional medications, herbs and phytomedicines have shown a remarkable record of relative safety. The monograph on St. John’s wort provides an example: Between October 1991 and December 1999, over 8 million patients are estimated to have been treated with Germany’s leading St. John’s wort preparation (Jarsin^® or Jarsin^®300, manufactured by Lichtwer Pharma, Berlin); during this period only 95 reports of side effects were received by the German Adverse Drug Reaction Recording System. While it is possible that additional adverse reactions may have occurred and that there are additional reports relating to other St. John’s wort products, this data strongly suggests a reasonable degree of safety relative to the levels of use.

One problem that arises in the reporting of herb adverse effects is the high degree of acceptance of poorly substantiated case reports and uncontrolled studies as evidence of risk. This stands in high contrast to the levels of evidence that health professionals normally require to document efficacy of a therapeutic agent. Another persistent problem plaguing the accurate reporting of adverse effects of herbs in the medical literature is the lack of adequate documentation of the botanical identity of the putatively offending herb.

The monographs in this publication contain adverse effects documented from the literature, including case reports, clinical studies, and authoritative monographs, often with explanatory data to help frame the clinical significance of the reports. In many cases, clinical trials suggest that a low percentage of subjects experienced gastric distress and/or nausea or headache—symptoms that are common in most clinical trials on pharmacological substances. In numerous trials, the adverse effects reported for an herb were consistent with those in the placebo group.

Drug Interactions. One of the biggest areas of concern in conventional medicine and the media is the issue of the potential interactions of herbal dietary supplements with prescription and/or OTC drugs. The April and May 1999 Prevention magazine survey reported that of patients taking prescription medications, 18.4% were also ingesting an herbal dietary supplement or a high-potency multivitamin and mineral supplement, which suggests the possibility of herb-drug interactions. The Prevention study indicates that many consumers use herbal supplements with drugs: 31% with prescription drugs, and 48% with OTC drugs (Johnston, 2000). Many of these patients acknowledge that they do not regularly report the use of dietary supplements to their physicians, so the need for physicians and pharmacists to request such information is increasingly compelling (Eisenberg et al., 2001).

The recent revelations regarding the interaction of St. John’s wort with drugs that are metabolized by the P450 system are examples of the developing body of knowledge being accumulated on the potential for herbs to interact with conventional medications. Only recently has systematic documentation of herb-drug interactions been published in the professional literature. The leading example of this trend is Francis Brinker’s Herb Contraindications and Drug Interactions, 3rd edition (Brinker, 2001). Following the guidance of Brinker, the interactions noted in these monographs are based on a rational hierarchy of evidence, with usually only those reported in humans being listed. If other interactions are listed that are based on animal or in vitro data, or merely speculation, such levels of evidence are noted.

AHPA Safety Rating. The safety rating as assigned by the American Herbal Products Association’s Botanical Safety Handbook (BSH) (McGuffin et al., 1997) is noted, and in some other cases, some European organizations’ assessments are also included. The AHPA safety classifications were based on data from more than 30 primary references (including the German Commission E) plus clinical trials, case reports and other forms of evidence. The BSH was developed as a voluntary form of self-regulation by the leading herb industry trade group in order to provide guidelines on the uniform disclosure of potential risk of approximately 550 of the most popular herbs sold in the U.S. The evaluation followed the passage of DSHEA in 1994 in which disclosure of potential risk on herb product labels was allowed for the first time.

The ratings are as follows:

Class 1: Herbs that can be safely consumed when used appropriately.

Class 2: Herbs for which the following use restrictions apply, unless otherwise directed by an expert qualified in the use of the described substance:

2a: For external use only.

2b: Not to be used during pregnancy.

2c: Not to be used while nursing.

2d: Other specific use restrictions as noted.

Class 3: Herbs for which significant data exists to recommend the following labeling: “To be used only under the supervision of an expert qualified in the appropriate use of this substance.” Labeling must include proper use information: dosage, contraindications, potential adverse effects and drug interactions, and any other relevant information related to the safe use of this substance. [None of the herbs in the monographs in this book are designated as Class 3.]

Class 4: Herbs for which insufficient data is available for classification.

Regulatory Status in U.S. and Other Industrialized Nations. Although it may not be deemed directly relevant to the self-care or clinical applications of an herb, the editors considered it potentially constructive to include information on how the herbs are regulated in other industrialized nations. The status of these herbs ranges from food to dietary supplement, traditional medicine, nonprescription drug, etc.

Clinical Review. This section provides an overview of various clinical studies that are summarized in the table of clinical studies. Comments about specific studies, systematic reviews and meta-analyses, as well as other relevant observations on clinical trials are included. With a few exceptions, the editors have not devoted much space to discussing specific studies, since many of the most prominent trials are summarized in the Table of Clinical Studies on each herb.

Table of Clinical Studies. The purpose of the tables is to give the reader an at-a-glance view of summaries of many of the published clinical trials on a particular herb. In the case of herbs in which a significant number of trials have been published (e.g., garlic, ginkgo, Asian ginseng, saw palmetto, St. John’s wort, etc.), it is not feasible to include all the studies in the literature. In these cases, many of the primary and most recent trials are included. In the case of other herbs (e.g., ginger [Zingiber officinale] and valerian [Valeriana officinalis]), as many of the clinical trials as the editors could locate are included. In the case of goldenseal root (Hydrastis canadensis), no clinical trials have been published in the literature, so the table instead summarizes clinical trials on the alkaloid berberine, generally considered goldenseal’s primary active compound. In the case of cayenne pepper (Capsicum spp.), clinical trials are summarized on the herb as well as the isolated primary active compound capsaicin, which is approved as a nonprescription drug ingredient.

Most tables are divided into various subsections dealing with the primary research parameter of the studies in each section (e.g., cardiovascular, chemoprevention, cognitive, diabetes, immunology, psychomotor response, etc.). The columns of the tables include the author and year, subject, design (including number of subjects, randomization, controls, etc.), duration, dose, preparation used (including brand name, if given), and results/conclusion. A key is provided in each table to clarify abbreviations.

An innovative feature of this book is the inclusion of the names of specific commercial brands of herbs and phytomedicinal products which are included in the Table of Clinical Studies. This is provided to give the clinician as much information as possible to make informed decisions and to underscore the issue of phytoequivalence. Phytoequivalence is the herbal counterpart to bioequivalence, an issue of concern in the prescription and generic drug industries. The concept refers to the fact that many of the clinical trials documenting the safety and the (actual or potential) efficacy of a particular herb are often conducted with one or a few leading proprietary phytomedicinal products. This is particularly true in studies on black cohosh, chaste tree, garlic, ginkgo, Asian ginseng, horse chestnut seed extract, milk thistle, and St. John’s wort, among others.

Branded Products. This is a listing of the commercial products found in the Preparation column of the Table of Clinical Studies. It lists the brand name, manufacturer name, city and country, and a brief description of the product or parameters of the herbal extract. The reader should note that the listing of a brand in these monographs is not to be construed as an endorsement of the particular product by the editors or publisher (the American Botanical Council). Mention of specific brands in each monograph and elsewhere in this publication is done solely as an acknowledgement of the research that has been conducted on the specific phytomedicinal product. This has been done in response to numerous requests for such information from healthcare professionals, members of the media, and others. A table in the Appendix (see page 398) provides a cross-reference of the foreign brands and their U.S. counterparts if they are imported and marketed in this country. This is a unique feature of this publication and may become a valuable tool for clinicians to determine which specific herb products sold in the U.S. have been investigated in published clinical trials.

References. As with all publications of this type, complete references of all citations are included. These can be broken down into the following general categories: clinical trials, pharmacological studies, toxicological studies, epidemiological studies, chemical analyses, and profiles, monographs (official and nonofficial), general botanical and herbal reference books, government reports, review articles, meta-analyses and systematic reviews, historical accounts, national and international pharmacopeias, etc. For more information on General References, please see the listing on page 397. The editors have attempted to cite authoritative sources whenever possible, including secondary sources.

Clinical Overview

Clinical Overviews are intended to provide health professionals with quick, at-a-glance information on the most widely used product forms, their primary and other potential uses, and their key safety information. In order to give the clinician and general reader this quick look at the basic, clinically-relevant aspects of each herb, the essential elements of the monographs have been distilled into the two-page Clinical Overview that precedes each monograph. The editors anticipate that readers may refer to this section frequently for the sake of convenience. The editors suggest that readers refer to the monographs for in-depth guidance and to review the basis of the information in the Clinical Overviews.

An example of the type of “filtration” of the information from the monographs to the Clinical Overview, and subsequently, to Patient Information Sheets, can be seen in the monograph on horse chestnut seed extract (Aesculus hippocastanum). In this monograph, information on dosage and use of purified escin (a.k.a. aescin) preparations was removed from the Clinical Overview since to the editors’ knowledge these preparations are not marketed in the United States. While the presence of such products in the European market warrants their inclusion in the monograph, since they are not available in North America, the editors did not consider this information relevant to the Clinical Overviews.

Patient Information Sheet

In order to assist both the practitioner and the patient, the Clinical Overviews have been further distilled into one-page Patient Information Sheets that are meant for photocopying and distribution to the patient. The editors have attempted to accurately and responsibly convey the essence of the information provided in the monographs; however, as is always the case in a process of simplification, important detailed information and nuance has been omitted. Although every effort has been made to ensure the accuracy of the data in the Patient Information Sheets, the clinician is advised to carefully evaluate them and provide to the patient whatever additional information the clinician deems appropriate.

Proprietary Products

This section reviews the clinical research on proprietary products including one monopreparation (i.e., containing one herb or herbal extract), Pycnogenol^®, and 12 multi-herb products representing various herbal medicine traditions. The review of each product includes a table of clinical studies. The editors have included these proprietary products because monopreprations are the exception rather than the rule in most systems of traditional and indigenous medicine. Additional information is provided in the introduction to the proprietary products section on page 366.

References

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Awang DVC. Standardization of Herbal Medicines. Alternative Therapies in Women’s Health 1999;July:57–9.

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Blendon RJ, DesRoches CM, Benson JM, Brodie M, Altman DE. Americans’ views on the use and regulation of dietary supplements. Arch Int Med 2001;161:805-810.

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Blumenthal M. Herb Sales Down in Mainstream Market, Up in Natural Food Supermarkets. HerbalGram 2002;55:60.

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Blumenthal M, Busse WR, Goldberg A, Gruenwald J, Hall T, Riggins CW. et al. (editors). Klein S, Rister RS (trans). The Complete German Commision E Monographs: Therapeutic Guide to Herbal Medicines. Austin (TX): American Botanical Council; 1998.

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