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.
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