Phytochemistry Letters 10 (2014) xxviii–xl

Contents lists available at ScienceDirect

Phytochemistry Letters
journal homepage: www.elsevier.com/locate/phytol

Phytochemistry and traditional medicine—The revolution continues§

Geoffrey A. Cordell a,b,*
a
Natural Products, Inc., Evanston, IL, USA
b
Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL 32601, USA

A R T I C L E I N F O A B S T R A C T

Article history: The use of traditional medicines, phytotherapeuticals, and dietary supplements, should be based on
Received 3 May 2014 quality, safety, efficacy, and consistency (QSEC). Evidence relating to each of those facets of a plant-based
Received in revised form 31 May 2014 medicine is being hampered, in part, by fourteen myths. While these myths are both powerful and
Accepted 5 June 2014
persistent, they must be debunked for significant progress to be made in enhancing integrated global
Available online 19 June 2014
health care. This paper, an update on an earlier report, will examine these myths, and the roles that
phytochemistry should play in this process. Some examples of the use of the new strategies will be
Keywords:
presented from the contemporary literature, together with a brief summary of a clinical trial of a
Traditional medicine
Myths
traditional medicine treatment for obesity, and a summary of activities in the European Union to address
Quality safety and efficacy issues related to the approval and marketing of traditional Chinese medicine (TCM) products.
Phytochemistry ß 2014 Phytochemical Society of Europe. Published by Elsevier B.V. All rights reserved.
Integrated approaches

1. Introduction medicines in order to place patient expectations on a more assured

In a previous article in this journal (Cordell, 2011b), a brief
summary was presented of the tightly interwoven links between
phytochemistry and traditional medicine* (* includes phytother-
apeuticals, dietary supplements, and cosmeceuticals) from both a
historical and contemporary perspective. Emphasis was placed on
the new technologies that were being introduced, particularly
barcoding and principal component analysis, and how they were
contributing to strengthening the evidence base for enhancing the
quality, safety, efficacy, and consistency (QSEC) of traditional
§
This paper forms part of a special issue of Phytochemistry Letters dedicated to the
memory of Andrew Marston (1953–2013), an outstanding phytochemist who is
much missed by his friends.
Abbreviations: ADR, adverse drug reaction; CAE, caraway aqueous extract; CBD,
convention on biological diversity; CCDS, characteristic components data set; ESI,
electrospray ionization; GC, gas chromatography; HPLC, high performance liquid
chromatography; LC-IT-TOF-MS, liquid chromatography-ion trap-time-of-flight
mass spectrometry; MS, mass spectrometry; NHSQP, Niuhuang Shangqing pill;
NMR, nuclear magnetic resonance; PLS-DA, partial least squares-discriminant
analysis; QSEC, quality, safety, efficacy, and consistency; SFDA, State Food and Drug
Administration; TCM, traditional Chinese medicine; TLC, thin layer chromatogra-
phy; TM, traditional medicine; TRIPS, trade related aspects of intellectual property
rights; UPLC, ultra performance liquid chromatography; WHO, World Health
Organization; WPRO, Western Pacific Regional Office; WTO, World Trade
Organization.
* Correspondence address: Natural Products, Inc., Evanston, IL, USA.
Tel.: +1 847 903 1886.
E-mail address: pharmacog@gmail.com
footing. This brief report will describe some selected developments
occurring in traditional medicine from a phytochemical perspec-
tive. In the previous report, mention was made of four ‘‘myths’’
associated with traditional medicine which needed to be debunked
in order for significant progress to be achieved toward the
provision of sustainable, evidence-based traditional medicines in a
health care system. Further examination has revealed ten
additional myths, for a total of fourteen (so far!). An important
question to address is whether any or all of these myths are serving
as an intellectual barrier to providing a continuum of evidence of
the QSEC of traditional medicines. This paper will examine these
myths, and the role that phytochemistry is acquiring in challenging
them, and will identify some recent examples of success through
consortial developments, and experimental reports the Chinese
literature and elsewhere. Areas where additional phytochemical
effort is needed will also be discussed. A fundamental underpin-
ning to all chemical and biological studies involving plant-based
traditional medicine is appropriate chemical analysis. How
effective that analysis is in a given setting will determine, to a
large extent, the quality and the consistency of the final product,
and therefore the anticipated health benefit for the patient.
1.1. Ethnopharmacology background
As humankind spread, indigenous groups all over the world
turned to an abundant, renewable local resource, plants, for healing
purposes (Balick and Cox, 1996). Their clinical experimentation,

http://dx.doi.org/10.1016/j.phytol.2014.06.002
1874-3900/ß 2014 Phytochemical Society of Europe. Published by Elsevier B.V. All rights reserved.
 G.A. Cordell / Phytochemistry Letters 10 (2014) xxviii–xl
passed on through the centuries, forms the basis of traditional
medicine today. Prior to 1899, when aspirin was introduced, it was
the only form of drug-based healing; in many parts of the world, for
reasons of access, it still is. For those patients, little has changed in
thousands of years.
Until the start of the globalization of medicinal plants in the
early Sumerian period, and subsequently with the development of
the land and sea ‘‘Silk Road’’ passages (Wood, 2002), the medicinal
plants used were sourced locally. Today, most medicinal plants in
commerce remain locally-derived, and are used based on local
traditional medicine practices and customs (Lange, 2004). Indica-
tions of the safety and efficacy of these plants, as passed on through
generations, came through trial and error – it was classical, low
throughput clinical screening.
Over time, locally, regionally, and globally, vast numbers of
plants, may be more than 50,000, have been described as
possessing useful biological activity (IUCN, 2007; Schippmann
et al., 2006). This represents at least 12% of the estimated global
wealth of higher plants (Kew, 2014). During these thousands of
years a vast amount of information regarding the preparation and
use of medicinal plants for the ailments that inflict humankind has
been acquired. However, this information describing the possible
biological and clinical significance of these plant preparations is
extremely widely dispersed. There are no, readily available,
regional or global databases which have attempted to cumulate
this knowledge. What knowledge has been consolidated is
partially available through books, both ancient and new, reports
in the primary and secondary literature, and sporadic focused
databases in various parts of the world. From an intellectual
property perspective, this acquired, albeit crudely organized,
information is already in the public domain.
There is also an unknown volume of ethnomedical information
being held and used every day by medicine men and women,
shamans, curanderos, hakims, dukuns, etc. throughout the world.
This indigenous knowledge may or may not be in the public
domain, and that which is not, is therefore protected as the
intellectual property of the individual or group by the Convention
on Biological Diversity (CBD) of 1992, and the subsequent Nagoya
Protocol of 2010. It is worth mentioning that only three countries
in the world are not signatory parties to the CBD, the United States,
Andorra, and the Holy See (Convention on Biological Diversity,
2014). Access to this locally held, ethnopharmacological informa-
tion, in a manner akin to indigenous bioresources, requires
negotiated agreements, and other considerations deemed impor-
tant by the holders of the knowledge. These issues, together with
the relationship to the TRIPS Agreement, which holds an opposite
view of what constitutes ownership of intellectual property by
indigenous groups, are discussed in detail elsewhere (Cordell,
2010; Union for Ethical Biotrade, 2010).
Whereas human beings have consistently sought to consoli-
date various aspects of recorded knowledge and make it readily
available, sometimes for a price (Encyclopedia Britannica), at
other times for free (Wikipedia), on a global scale, this has not
occurred for the knowledge regarding the use of plants for
healing purposes. This has occurred even though good health is a
core facet of the human existence on a moment to moment basis.
Ironically, the astronomical sciences have, over hundreds of
years, created preliminary detailed maps of the estimated 176
billion galaxies in the universe (Anonymous, 2012). Thus while
maps of the sky and the movements of planets in galaxies
abound, there is no database to indicate where the medicinal
plants are on Earth, how they are being used in primary health
care each day, and what research has already been reported to
assure their quality, safety, and efficacy for patients. This is an
inexplicable and unconscionable gap in the basic knowledge of
human life on Earth.
xxix
1.2. R-E-S-P-E-C-T
Ethnopharmacological information, depending on the culture
and the relationship to ‘‘modern’’ medicine, and the use of associated
plants and practices, may or may not be respected and recognized
formally as an active and contributing component within a health
care system. In some countries, the two systems of medicine operate
under government authority and regulation in parallel. In other
countries, traditional medicine is not included as a part of the health
care system, and thus is not regulated, or covered by insurance, even
though it may be very widely used. It is essentially dismissed at the
government, and consequently at the scientific, levels, as being
irrelevant in the society. A WHO global survey of the regulations and
status of traditional medicine conducted in 2003 (World Health
Organization, 2005) provided some interesting insights. Only 141
Member States (74%) provided a completed survey, and of those,
only 45 (32%) had a national policy on traditional medicine or
complementary and alternative medicine (TM/CAM). With respect
to regulations, 53 (37%) countries had laws and regulations
governing TM/CAM practices, although 86 (61%) countries had a
registration system for traditional medicine products. Seventy-five
countries (53%) reported having a national office in charge of TM/
CAM. A further WHO survey in underway and results are expected to
show a steady improvement. However, even in Member States
where TM/CAM is an important aspect of health care, status and
investment in enhancing the systems for oversight of products and
services is lacking.
Without that respect, and the awareness that traditional
medicines have contributed to ‘‘modern’’ medicine significantly
in the past 210 years, beginning with the studies on opium, and
that these practices are both widespread and medically significant
in the global population, the appropriate level of strategic
investment will not be available. While this intellectual and fiscal
‘‘health care gap’’ is a very shameful situation which affects most of
the people in the world, and needs to be ‘‘minded’’ (Cordell and
Colvard, 2012), another aspect of this ‘‘failure to appreciate’’
traditional medicine also affects those who are a little wealthier or
even rich; that aspect is polypharmacy. Many patients taking
regulated medications in the world, through physician recom-
mendation, or self-medication, concurrently take both ‘‘modern’’
and traditional medicines. This is frequently a ‘‘black box’’ of
potential biological responses, a step into the abyss of health care
outcomes, particularly with poorly regulated products. With few
exceptions (Fugh-Berman, 2000; Shaw et al., 2012; Zhang et al.,
2012), the clinical effects of taking both forms of medicine are
unknown, and, unless mechanistically defined, not predictable in
terms of pharmacokinetics, metabolism, synergy, antagonism,
pharmacokinetics, etc. From a modern medical viewpoint, often
supported by local medical associations, this situation pertains in
many countries because the plants in the complementary or
traditional medicines are regarded as innocuous, that they will do
no harm. Thus, the more ‘‘powerful’’, ‘‘modern’’ medicine will be
the dominant chemical force, and prevail. Under these circum-
stances of prejudicial thinking, clinically significant adverse events
may not be reported. This aspect of traditional medicine usage
with respect to healthcare outcomes is also of concern to WHO
(World Health Organization, 2004).
The reporting and analysis of these plant drug-drug interactions
is known as pharmacovigilance, and is defined as ‘‘the study of the
safety of marketed drugs under the practical conditions of clinical
usage in large communities’’ (Mann and Andrews, 2007). In
addition to plant drug–drug interactions, pharmacovigilance (also
known as adverse drug reactions, ADR) includes side effects,
reactions due to overdose, tolerance, hypersensitivity, and toxic
effects (either inherent in the plant or as a result of adulteration or
contamination). It should be readily apparent, from an analytical
xxx G.A. Cordell / Phytochemistry Letters 10 (2014) xxviii–xl
perspective, that manufacturing standards, the addition of potent,
cheap synthetic drugs, and other analytical chemistry issues
relating to pesticides, herbicides, fungicides, and heavy metals, are
also of great concern. The presence of any of these contaminants in
a contemporary traditional medicine completely undermines the
philosophy and concepts of a traditional medicine in a historical
context.
2. Role of mythology in social systems
A myth is defined as: ‘‘an unproved or false collective belief that
is used to justify a social institution’’ (http://www.dictionary.com).
Myths are important in supporting the structures of societies in the
world, and almost every culture has them deep within their roots,
and frequently expressed in contemporary situations. The holders
and purveyors of the myths, those with the accumulated folk lore
in the indigenous group, frequently held great power in their
society, and thus it was, and remains, in their interest to maintain
the myths. Many of the myths related to travel, to images of
beautiful sirens imagined by weary ocean voyagers, and to the
natural solar and lunar cycles.
Plants were also associated with myths (Schultes and Hofmann,
1979), including those plants used for ‘‘truth-telling’’, for traveling
to other levels of awareness, for inducing death, and for healing.
Bordering on these myths are ‘‘the legendary tales’’ and aphorisms,
many of which are related to human health. Some examples
include: ‘‘an apple a day keeps the doctor away’’, ‘‘eating chocolate
leads to acne’’, and ‘‘carrots improve vision’’.
The global practices of traditional medicine are based on a
number of profound assumptions. These assumptions, because of
their high level of acceptance, to the point of almost disappearing
within the core teachings of traditional medicine itself, are
approaching, or have become, myths. They serve, in a very core
manner, to maintain critical aspects of the status quo in traditional
medicine, and have, for centuries, brought tranquility to those
societies through the practitioners. At the same time, these myths
are so deeply embedded in the systems of traditional medicine,
that they are now serving to inhibit an open and unbiased
approach to the study of traditional medicine. In some instances
this is reflected in a resistance to investigate traditional medicines
because they may not be shown to be effective, and thus the
system and/or the practitioner would lose status. Another example
would be those chemical, biological, and clinical studies which aim
to ‘‘validate’’ the safety and/or effectiveness of a traditional
medicine. ‘‘Validation’’ cannot mean constructing experiments to
assure a positive outcome. Evaluation and assessment must come
from a place of neutrality and curiosity to demonstrate a real
biological effect, not a presupposition of effectiveness.
What are these powerful myths of traditional medicine? When
revealed they are obvious, to unearth them (an on-going process!)
has taken several years. As mentioned, the previous article spoke of
only four (Cordell, 2011b). Further ‘‘peeling of the onion’’ has
revealed another ten, for a total of fourteen myths. Probably, there
are more to be discovered. Before they are presented however, a
brief background on the approach of the World Health Organiza-
tion (WHO) toward traditional medicine is needed, and in
particular, the emphasis on the evidence-based research to
promote the acceptance of traditional medicine. There is also a
need to introduce the practices of sustainability and network
pharmacology as they apply to traditional medicine.
3. WHO background regarding the need for evidence-based
research on TMs
The World Health Organization has recognized this need for an
evidence base for all aspects of traditional medicine for many
years, making it clear in the original WHO Traditional Medicine
Strategy 2002–2005 that progress in the acceptance of traditional
medicine (TM) into health care systems must be based on evidence
of QSEC, and calling for more clinical evidence to support TM
claims (World Health Organization, 2002). One of the recent
initiatives of the Western Pacific Regional Office of WHO was the
development of a revised Regional Strategy for Traditional Medicine
in the Western Pacific 2011–2020 (World Health Organization,
2012; World Health Organization et al., 2012). The strategic
directions and associated recommendations describe possible
approaches to improve the QSEC of traditional medicinal plants in
health care in the region, and recognize that the 37 regional
countries and territories embrace broad stages of economic
development and research capacity. Cooperation within and
between countries to address the issues of QSEC of botanical
materials of known or standardized content, based on phytochem-
ical analysis, was strongly encouraged to enhance regional health
care.
More recently, WHO has presented a Traditional Medicine
Strategy for 2014–2023 (World Health Organization, 2014) which
establishes two goals: (i) to harness the potential contribution of
TM to health, wellness, people-centered health care, and universal
health care, and (ii) to promote the safe and effective use of
traditional medicine through the regulation, research and integra-
tion of TM products, practices, and practitioners into the health
system. It reaffirms that for TM ‘‘to be considered an integral part of
health care, it must be supported by evidence.’’ The strategy asks
Member States to monitor the safety of TM products and identify
sources of evidence which support or invalidate a particular
therapy, and determine the risk/benefit profile, promote research
development, innovation and knowledge management, develop
methods and criteria for evaluating the QSEC of TM products, and
underpin this with the regulation of standardized products,
prevent misappropriation of intellectual property, foster dialog
and partnership between stakeholders, publish standard treat-
ment guidelines, and develop a list of essential herbal medicines
based on evidence, including clinical trials. Progress toward these
objectives will be assessed after 5 years.
One of the most important concepts which is integral to these
initiatives is that of the patient, the individual expecting, among
other attributes, a health beneficent effect. As discussed elsewhere
(Cordell, 2011a,b,c; Cordell and Colvard, 2012), if the research
focus is always patient-centered then it will probably have an
optimum impact in the health care system.
4. Sustainability
An emerging factor, which is crucial to both medicinal plant
research and development, and to clinical practice, is sustainabili-
ty, which was raised as a concern in the first WHO strategy
document (World Health Organization, 2002). The term ‘‘sustain-
able medicines’’ was developed (Cordell, 2009, 2011b,c; Cordell
and Colvard, 2012) to describe the importance of considering the
long-term use of both traditional medicines and synthetic drugs
from a perspective of reliable and non-destructive sourcing for
the future. This is of prescient importance where population and
the use of traditional medicines are expanding rapidly, where the
globalization of products is increasing demand, or where climate
change (drought, excess moisture, or saline) may impact areas for
growing traditional medicines. In the research component of this
scenario, preferable consideration is given to studies on those plant
materials which are already established as sustainable commercial
entities, or which are easily grown agronomically in order to derive
or maintain an accessible (affordable and sustainable) product
(Cordell, 2012; Cordell and Colvard, 2012). These and several other
outcomes are embraced in a new awareness of medicinal plants
 G.A. Cordell / Phytochemistry Letters 10 (2014) xxviii–xl
and natural product drug discovery which is summarized as
‘‘ecopharmacognosy’’, ‘‘the study of sustainable biologically active
natural products’’. This topic is explored in greater detail elsewhere
(Cordell, 2014a,b,c). Suffice to say here that in terms of medicinal
plant quality control, in new drug discovery research and
development, and in potentiating traditional medicine usage,
ecopharmacognosy engages considerations of sustainable, long-
term sourcing (location, plant part, etc.) at an early stage in the
process, so that access to health care can be maintained and
research appropriately prioritized.
Another aspect regarding the sustainability of traditional
medicine applies to the accumulated indigenous knowledge of
the use of medicinal plants, how that information is recorded and
maintained from generation to generation of practitioner, and how
it is protected from abuse and exploitation as an intellectual
property asset, as required by the parties to the CBD. Without
systems to maintain that knowledge and optimize (not exploit) its
use through an evidence-based approach, the health care of
millions of people is likely to be adversely affected. Developing
those systems of protection of property rights are both local and
global responsibilities, and must be respected by scientists from
academia and industry.
In addition, there is the consideration of multicomponent plant
mixtures which contain 10–20 plants in the formula. Both from a
functional perspective, as well as from sustainability consider-
ations, it is important to examine, chemically and biologically,
whether all of the components are necessary for safety and
effectiveness, or whether the formula can be simplified. A simpler
medicinal plant formula would reduce the consumption of needed
medicinal plant material. Closely related to this goal is whether
new medicinal plant formulas can be developed, based on existing
traditional medicines, to treat alternative disease states which
have been evaluated biologically at the gene level (Li and Zhang,
2013). These two goals may evolve as practical, health beneficent,
evolutionary outcomes of the development of the sciences of
network pharmacology.
5. Network pharmacology
Network pharmacology changes the fundamental philosophy of
interpreting the mechanism of drug action, and therefore of drug
discovery, irrespective of the context (Hopkins, 2007). It shifts the
rationale from ‘‘one target, one drug’’ to ‘‘network target, multiple
components’’, a disease therefore is also viewed as a series of
potential multiple targets, and is projected as a very significant
alternative paradigm for drug discovery (Hopkins, 2008). It is the
inverse of the classical reductionist approach that has been used
for drug discovery in the West for the past 70 years or so. Network
pharmacology offers the potential to define, at the genome level,
the mechanistic impact and pathways of individual bioactive
compounds, both from a positive (health beneficent) and a
negative (untoward side effect, toxicity) perspective (Zhang
et al., 2013b). From a drug discovery perspective it is therefore
important to discern the network of drug targets as a prioritization
step with the anticipation of reducing the high attrition of drugs in
clinical trials (Chen et al., 2008). Since a single plant extract is a
substantial matrix of compounds, and a combination of plant
materials an even larger, minimally overlapping matrix, then the
potential number of network targets is vast. This is both a serious
complication which requires extensive unraveling, and a profound
opportunity to examine how traditional medicines work and,
where possible improve those functions (Li and Zhang, 2013;
Zhang et al., 2013b).
Li and Zhang (2013) suggest that the elucidation of network
pathways may explain why traditional medicine plant mixtures
can have multiple uses, either within or between traditional
xxxi
medicine systems. On personal reflection, such mechanistic
multiplicity, reflected in a diversity of clinical action, should be
anticipated. They also point out that because a network target can
provide for a systematic investigation to disease modulation, this
approach allows for a predictive and quantitative assessment of
the mechanistic role of a TM. In addition, over time, as more and
more data are collected through the genome mapping of
compounds, so it may become apparent whether the philosophical
elements of TCM theory are supported through science. About 726
compounds have been genome mapped so far (Li and Zhang, 2013)
which has allowed numerous correlations to be made both for
uniqueness and for potential overlap of genome targets. This
information can be used in several ways, including using
compound information to identify potential active compounds
in complex matrices, without bioactivity-directed fractionation,
and the reverse, looking for new potential uses for known bioactive
compounds, a very interesting approach to drug discovery,
particularly if the safety has been established previously. An
example which emerged from these studies was the identification
of vitexicarpin from Vitex rotundifolia L. f. (Lamiaceae) as a new
potential anti-angiogenesis agent (Li et al., 2010). This was
achieved when vitexicarpin was found to target specifically AKT
and SRC in the VEGF pathway (Zhang et al., 2013a).
Another use of network pharmacology might involve the
detection, and rationalization of synergistic effects in existing
combinations, or the directed potentiation of new synergistic
combinations of plant materials or purified fractions. A number of
important TCM databases have been established for network
pharmacology research, and these will undoubtedly form the basis
for the rapid development of this field of traditional medicine (Li
and Zhang, 2013; Zhang et al., 2013b). An unstated, basic
assumption in establishing network pathways is phytochemistry,
the in-depth analysis of an appropriate extract, or the establish-
ment of purity of a ‘‘pure’’ compound. This serves as a reminder
that all biological testing, of extracts, fractions and pure
compounds (including control compounds) require knowledge
of what is actually being tested (Cordell, 2011b,c; Cordell and
Colvard, 2012). Very challenging elements to integrate into
network pharmacology considerations for a TCM are the pharma-
cokinetic and pharmacodynamics parameters (He et al., 2011).
One eventuality of network pharmacology which has not been
considered, and which could become an important beneficial
result of the analysis of the network targets, and is also based on
ecopharmacognosy principles, is the impact on sustainability. For
example, network pharmacology should be able to address the
aforementioned issue of whether all the plants in a TCM formula
are truly necessary for clinical activity, or whether some plants can
be eliminated, while still maintaining effectiveness.
Interestingly, phytochemistry is at the core of network
pharmacology, and in the future may be a new niche. Network
pharmacology is based on the known compounds which have been
isolated from a given plant, whether they are regarded as the
‘‘active’’ principles or not. These isolates are then evaluated for
their potential gene interactions. Clearly, not all natural products
which have been encountered at present in the prominent
databases, many known compounds will not have been studied
yet. In addition, many traditional medicines have been studied
poorly or not studied at all. Without a knowledge of the
phytochemistry of the medicinal plant there can be no basis for
a network pharmacology analysis.
6. The fourteen myths of traditional medicine
With this brief background, the thirteen myths that exist within
Traditional Medicine can be presented. They are:
xxxii G.A. Cordell / Phytochemistry Letters 10 (2014) xxviii–xl
 This traditional medicine has been used for thousands of years
(ergo it is safe and effective)
 Using the ‘‘correct’’ plant is adequate
 The biological effects are the same from different plant parts
 The biological effects are the same irrespective of the origin of
the plant
 The biological effects are the same irrespective of the plant
preparation
 Older plant material is less effective (or more toxic)
 ‘‘Wild’’-collected plants are more active than cultivated plants
 All of the materials in a complex prescription are necessary for
effectiveness
 Complex mixtures of plants cannot be standardized
 This medicinal plant product is already well-regulated
 Medicinal plants are safer than synthetic drugs
 The medicinal plant will always be available
 The traditional knowledge will always be there
In addition, there is a fourteenth myth that operates from the
perspective of the modern medicine system about traditional
medicine. This is the myth that ‘‘traditional medicines are not
effective, and are therefore not worth considering as a part of a
contemporary health care system’’. This myth, namely that plants
are not powerful enough to heal, indeed are innocuous, may be
prevalent, irrespective of whether the health care system does or
does not include traditional medicine preparations in its health
care system. In addition, this view may, or may not, encompass the
reality of polypharmacy, and include that clinical perspective in
patient treatment plans. It is worth noting that in the WHO List of
Essential Medicines, there are no traditional medicine products
listed, one factor undoubtedly being the absence of evidence-based
quality, safety, and efficacy (World Health Organization, 2013).
WHO has also expressed concerns about the concurrent use of both
modern and traditional medicine preparations from a commu-
nications perspective, i.e. are all of the practitioners appropriately
informed of potential interactions (World Health Organization,
2014).
With respect to myths, the American philosopher Joseph
Campbell has suggested that: ‘‘There are two pathologies. One is
interpreting myth as pseudo-science, as though it had to do with
directing nature instead of putting you in accord with nature, and
the other is the political interpretation of myths to the advantage of
one group within a society, or one society within a group of
nations’’ (Boa, 1994). His assessment applies well to the myths of
traditional medicine. The practices of traditional medicine are
frequently regarded as pseudo-science, or worse, by those who are
not familiar with the history of modern drug discovery, or who are
unaware of the breadth, depth, and importance of medicinal plants
in health care on a global basis. As a health care modality,
application of a traditional medicine does indeed place the patient
in accord with nature when taking a product grown in a field or a
forest.
There are groups in several developed societies, including those
associated with allopathic drug discovery, development, sales, and
prescribing, the pharmaceutical companies and physicians alike,
whose best interest (advantage) is to offer no credence or support
to the fact that traditional medicine has health beneficent effects,
and to retain, actively, the purported innocuous nature and
ineffectiveness of traditional medicines as a ‘‘myth’’. They refer to
these plants as ‘‘herbs’’, in parallel with the culinary herbs, rather
than as ‘‘medicinal plants’’. Ironically, many of these ‘‘herbs’’, such
as turmeric, garlic, cinnamon, etc. are now being shown to possess
potent medicinal properties (O’Hara et al., 1998).
It is important to recognize that, in contrast, since 2005, the
Chinese Government has invested vastly in examining these myths
scientifically, in encouraging research and innovation, in establishing
TCM as a sound healthcare modality, and in promoting its
development on a global basis. In 2011, the Chinese government
announced a new initiative to create over one million new biotech
industry jobs through an investment of $308 billion by 2015. A part of
the investment will be dedicated to TCM product development. As
will be seen, these investments have led to new pathways of
development for the philosophy of TCM, for pioneering studies
related to QSEC, and for the development of new TCM products on a
scientifically rational basis (Wu et al., 2014).
7. The role of phytochemistry in debunking the myths of
traditional medicine
The previous discussion has briefly identified the myths that
pervade traditional medicine. Recognizing the current capacity of
phytochemistry to define the constituents of a plant sample
chromatographically and spectroscopically or spectrometrically,
what are the areas within these myths which are being, or can be,
addressed through the application of phytochemical techniques?
In this respect, myths 4, 9, and 14 are not discussed.
7.1. Myth 1: This traditional medicine has been used for thousands of
years (ergo it is safe and effective)
Without doubt, the most dominant myth that is used as an
argument against the need for thorough experimentation on
traditional medicines, and which is used globally as a marketing
adjunct, is a reputation of long-term safety and use. The concept
that a plant is both safe and effective because it is widely used and
respected, and has been used in the system for hundreds, or even
thousands, of years, is very powerful. Such a statement is not,
however, based on accurate identification of the plant, on
chemically consistent plant material or extractive, or on biological,
pharmacological, toxicological, or clinical evidence. What it does
provide is a marvelous advanced starting point for the unbiased
investigation of a medicinal plant, whose discovery was based on
slow throughput clinical screening. As discussed elsewhere,
information systems, botany, chemistry, and biology then become
powerful tools in providing the evidence base (Cordell, 2009,
2011a,b,c, 2012; Cordell and Colvard, 2012). Within these four
areas of investigation there are many bumps in the road and
slippery curves to be negotiated. As an example, there is the
important issue of ‘‘what’s in a name’’, or what is the actual plant
material that has been investigated, or is claimed to be in the
product, and how was that scientifically assured? Which leads to
Myth #2.
7.2. Myth 2: Using the ‘‘correct’’ plant is adequate
‘‘An accurate, lucid and complete classification of plants is. . .the
only secure basis upon which botany as a whole can rest.’’ So stated
Benjamin Lincoln Robinson at the annual Botanical Society of
America Meeting in 1901 (as cited by Constance, 1964); and the
statement is even more valid today as we delve into what
constitutes appropriate quality control parameters for a botani-
cally-derived medicinal material from regulatory and QSEC
perspectives. How is the plant material in a plant-based medicine
identified? What are the requisite quality control parameters, and
how they evolving?
Advances in the DNA-based identification of plant materials,
and the expanding data systems of genetic information regarding
medicinal plants, bring into question the notion of the nomencla-
ture of plants advanced since 1753. That system is based on an
assumption that visual morphological and simple chemical testing
are adequate technologies to provide the correct identification of a
plant. Those inferences continue to be the basis of most
 G.A. Cordell / Phytochemistry Letters 10 (2014) xxviii–xl
pharmacopeial entries relating to plants around the world.
Technologically, it is a different era, and how plant systematics
should respond to that in the future is an interesting deliberation
(Sytsma and Pires, 2001). The identification of plants for medicinal
purposes is a separate discussion, which also relates directly to the
regulated identification of plant products for the market place, and
will not be pursued here (Sucher and Carles, 2008). Suffice to
indicate that barcoding parameters are now being introduced into
national pharmacopeias as a way to standardize medicinal plants
(Song et al., 2009). A pertinent question to be answered in the
future is what is the relationship between the barcoding
parameters used for identification and the genes of secondary
metabolite production for the bioactive compounds (Cordell,
2011b,c; Cordell and Colvard, 2012). Unless this correlation can be
established, and possibly quantified, for the medicinally-used,
particular plant part (see Myth 3), the plant could be identified
accurately, but not be genetically capable of producing the
necessary compounds at a high enough level to be effective at a
given dose.
In addition to the factors mentioned previously regarding
systematic nomenclature, is using the ‘‘correct’’ plant in a
traditional medicine adequate quality control? For at least three
reasons, the answer is definitely not. (i) Many traditional
medicines are identified at the forest collection site by a local
name. That name may be the same as a different plant also
available in the same or a different system of medicine, and used
for the same or a different purpose. As mentioned earlier, there are
efforts underway to try to rationalize and harmonize some of these
situations between pharmacopeias, particularly in South-east Asia
(Western Pacific Regional Forum for the Harmonization of Herbal
Medicines, 2007). (ii) Authentication in the field and in the market
place is absent. There is no trained botanist examining market-
place traditional medicines either microscopically, macroscopical-
ly, or though DNA analysis. Closely related species, varieties, and
chemical races are not considered important in the commercial
sector, for the most part, it just has to ‘‘look’’, morphologically, like
the correct plant. (iii) Since the concerted phytochemical analysis
of plants was first initiated in the mid-nineteenth century, it has
been known that different plant parts will have different metabolic
profiles, and therefore different biological outcomes. An example is
illustrative.
The name ‘‘pegaga’’ is used in Malaysia for three closely-related,
albeit botanically different plants, namely Centella asiatica (L.) Urb.,
Hydrocotyle bonariensis Comm. ex Lam., and H. sibthorpioides Lam.,
all of which are used as vegetables in salads. Pegaga is also widely
used in many traditional medicine preparations for dysentery,
leprosy, liver complaints, and rheumatism (Maulidiani et al.,
2011). 1H NMR metabolomics analysis allowed for facile, PCA-
based clustering and chemical differentiation between the
samples, based on the saponins and the chlorogenic acids.
Saponins and flavonoid levels were increased when C. asiatica
plants were grown in full daylight, resulting in a significantly
higher level of antioxidant activity.
Another aspect of ‘‘what’s in a name’’, and also of concern to the
World Health Organization, is the harmonization of the terminol-
ogy of plant names (World Health Organization, 2014). For
example, where the same local name of a plant may be applied
to more than one plant as in the case of ‘‘pegaga’’, or where
different parts of the same plant are used for different purposes,
with either the same or different names. Furthermore, there is the
confusion which arises when the same plant has different names in
different medicine systems.
In addition to common name confusion, a quite different aspect
of plant nomenclature is the accurate identification and botanical
naming of the plant being studied, and the data that is published in
the literature. This relates directly to the reliability of any
xxxiii
phytochemical, biological, or clinical data associated with that
plant, and therefore the reproducibility of the research. A recent
study (Rivera et al., 2014) has brought an alarming focus to this
issue. Of 428 recent articles examined in the Journal of
Ethnopharmacology and the journal Phytomedicine, 308 articles
cited the name of the plant incorrectly, and of the 9178 Latin
scientific names cited in the articles, 3445 had some form of error.
This staggering result led to a proposal for natural product journals
to ensure more accurate authentication of the resources being
studied and reported.
7.3. Myth 3: The biological effects are the same from different plant
parts
It is well-known now, after many years of phytochemical and
chemotaxonomic study, that the metabolite profile, and therefore
the biological profiles of different plant parts (root, stem, leaf, fruit,
etc.) are different, and while one part may invoke a health
beneficent effect, another may be toxic.
As an example of different biological effects in different plant
parts, consider Garcinia atroviridis Griff. ex. T. Anderson (Clusia-
ceae). The fruits of G. atroviridis are used in Malaysian cuisine in
curries and in fish dishes, and also have a number of medicinal uses
(Mackeen et al., 2000). However, separate extracts of the fruits,
leaves, stem bark, trunk bark, and roots, showed a range of
antimicrobial and anti-oxidant activities. Distinctively, the roots
had the highest antibacterial activity, while the fruits had the
highest antifungal and anti-oxidant activities.
7.4. Myth 5: The biological effects are the same irrespective of the
plant preparation
The myriad of metabolites within a plant will have very
different solubility parameters in solvents varying between hexane
and water. Most traditional medicine preparations are based on an
aqueous solvent system, either hot or cold, and the plant materials
are steeped for varying lengths of time. Such processes drastically
limit the extracted metabolite profile compared with a tincture or
alcoholic extraction. Any change in the metabolite profile in a
preparation will change the biological outcome. In practical terms,
and clearly related to Myth 1, if a plant preparation is not the same
as that made traditionally, it is not reasonable to expect that the
clinical outcomes will be the same. Thus, marketing a capsule or
tablet which is comprised of crude plant material, rather than a
lyophilized form of the traditional, boiled aqueous preparation,
and then claiming the effects will be the same, without a scientific
basis, is taking plant-based medicine back to the days of the snake-
oil salesman of the early 1900s.
Metabolic fingerprinting has an important role to play in this
regard (Krishnan et al., 2005; Sheridan et al., 2012). Studies which
examine phytochemically, the significant role of the preparation
and extraction process for a traditional medicine are relatively
rare, however. They are important because, as documented, co-
metabolites can have an important influence from a synergistic or
bioavailability or pharmacokinetic perspective (Sheridan et al.,
2012). A series of studies of the preparation Danggui Buxue Tang,
which contains Astragali Radix (AR) and Angelicae Sinensis Radix
(ASR) in the ratio 5:1 and summarized by Sheridan et al. (2012),
began by varying the ratio of the plants. The traditional ratio
afforded the best yields of the active compounds and the lowest of
the unwanted metabolite ligustilide. Following the traditional,
specific, extraction protocol also afforded the highest yield of
biomarkers, and a significantly different profile was obtained when
the plants were separately extracted and the extracts combined.
Processing with rice wine afforded a higher yield for the key
biomarkers. Thus a multitude of factors may contribute to the
xxxiv G.A. Cordell / Phytochemistry Letters 10 (2014) xxviii–xl
processing of a TCM, beyond those which might be inferred from
the simple combination of two plant extractives. Sheridan et al.
(2012) also reviewed aspects of a range of non-traditional
extraction techniques, after recognizing the significant drawbacks
of the traditional aqueous extraction method, and the opportu-
nities that analytical fingerprinting techniques provide for
metabolite analysis.
7.5. Myth 6: Older plant material is less effective
Does the age of a plant, post-harvesting, have an impact on the
secondary metabolite profile, and therefore the biological re-
sponse? An extreme, very special instance of the study of aging on
traditional medicines is the contemporary investigation of the 60
plant materials held for over 1250 years in the Imperial storehouse
Shosoin, adjacent to the magnificent Todaiji Temple in Nara, Japan.
Phytochemical studies have revealed similar chemical profiles for
several of the stored plants to those of contemporary plant
materials (Kitajima et al., 1998; Shibata, 1994). These plant
materials were, however, stored in a highly protective environ-
ment with respect to exposure to light, air, and humidity.
Medicinal plants are not typically stored in such a refined manner.
Consequently, their phytochemical profile needs to be monitored
carefully over time as a part of the initial quality control process.
Unless the medicinal plant material is acquired fresh, there is
usually little known about the age and origin of the plant materials
being sold in the markets around the world. In general terms, the
impact of drying, transportation, storage, aging, and preliminary
preparation are also unknown, and not controlled. Indeed these
effects are rarely investigated from an analytical chemistry and
subsequent biological perspective. This issue is acute because the
active constituents in most traditional medicines are unknown.
Traceability, through phytochemical analysis, as one aspect of the
‘‘quality’’ element in QSEC is essentially non-existent. While it may
be the case that the active principle in a plant is at the highest
concentration in the fresh plant material, and this level degrades
over time, the reverse could also be the case. Namely, that the most
active metabolite is a degradation product which builds up over
time, so that like a good wine, the worth of the plant material as a
medicinal agent is enhanced with age. Alternatively, the active
constituent(s) may degrade only when extracted, as a result of
exposure to air and heat. On the converse, the formation of toxic
metabolites may occur during the growth of the plant or
subsequently. It may be a stable metabolite in the matrix of the
plant material, or it may degrade with time, in which case the plant
material will become ‘‘safer’’ with age. It is also the case that the
biological activity of a medicinal plant may be derived from an
associated parasitic organism (fungus, bacteria) which may or may
not be present depending on the growing location (Linhart and
Grant, 1996). This phenomenon may also explain why recollection
of medicinal plants from different locations also results in
extensive biological variation.
7.6. Myth 7: ‘‘Wild’’ collected plants are more active than cultivated
plants
As populations expanded thousands of years ago, it was
vegetables, fruits, and grain crops which were initially brought
under cultivation. Garden plots for medicinal plants evolved to
avoid treks into the forest, and from a sustainability perspective,
assure a supply when needed (Balick and Cox, 1996). Part of this
particular myth, however, arises from the notion that medicinal
plants have a certain ‘‘wholeness’’ when derived from the forest,
rather than from a cultivated plot. Is there any basis for that idea?
The question of the metabolic changes occurring between wild
and cultivated food species has been under study for over 50 years,
at least since Harborne first looked at the flavonol glycosides of
potatoes (Solanum spp.) (Harborne, 1962). The wild and the
cultivated species typically had similar profiles of the flavonol
glycosides, but at unpredictable levels.
Another example includes an evaluation of the carnosic acid
content of rosemary (Rosmarinus officinalis) using supercritical
fluid extraction (Hidalgo et al., 1998). The content was highly
variable (almost 100%) in the content in wild leaves, with a higher
content in young compared with older leaves. There was
significant (>2-fold) seasonal variability (highest in the summer
period), and higher levels of carnosic acid were consistently
observed for the cultivated plants.
In terms of medicinal plants, the leaves of Sclerocarya birrea (A.
Rich.) Hochst. (Anacardiaceae) have been developed in Mali as a
marketed antidiabetic product, and in order to assure sustainabili-
ty, the results of cultivation and harvesting of the 2-year-old
cultivated plant vs. 10-year-old wild leaves were examined. The
methanol extract of the wild leaves was three times richer in
flavonoids than that of the cultivated leaves, although the
metabolite profiles were very similar (Braca et al., 2003).
Does scientific evidence support this notion of ‘‘wild’’ vs.
‘‘cultivated’’ biologically? When the antimalarial activity of Bidens
pilosa L. (Asteraceae) was examined for plants collected from
different locations and cultivated specimens, the wild plants were
the most active (Andrade-Neto et al., 2004). The anti-oxidant
potential of wild strawberries was found to be significantly greater
than cultivated ones (Scalzo et al., 2005). Comparison of the
essential oils from wild and cultivated laurel leaves (Laurus nobilis
L.) indicated different terpenoid and phenylpropanoid profiles
between wild and cultivated plants, and different antioxidant
activities, with the wild type showing the highest activity (Conforti
et al., 2006). Further investigation is clearly needed, and if the trend
continues, a rational explanation, perhaps related to environmen-
tal and microbial stress, should be explored. Of course, once the
active principle(s) are identified, it may be possible to enhance the
levels of active metabolites biotechnologically, which, at the same
time, would also permit a degree of standardization. Schippmann
et al. (2006) have discussed various aspects of the market needs for
wild and cultivated species, and the commercial advantages to
cultivation (reduced genetic diversity, continuity of supply,
standardization, labeling, pricing, etc.). They also presented some
of the challenges that face the sustainable harvesting of medicinal
plants from the wild. These include lack of information on the wild
resource in terms of population distribution, open access to
collectors, and lack of government support for conservation and
sustainability efforts.
Infamously, ginseng root is a traditional medicinal plant where
the age of the root material at harvesting remains a determinant
factor in market value. Lee and co-workers (Kim et al., 2011) have
described a metabolomics approach using UPLC-QTOF/MS to
examine the metabolite profiles of 59 ginseng root samples aged
from 1 to 6 years using multivariate analysis. Of the 1361
metabolites detected, 198 metabolites were used in partial least
squares-discriminant analysis (PLS-DA) which allowed for age
classification with 99.9% accuracy. The 4–6-year-old materials,
which are in the highest market demand, showed 1155 metabolites
in 30 samples, and PLS-DA using 606 metabolites provided 100% age
verification. The relationship between the age of the plant material
and biological activity was not discussed, although it is known that
ginsenoside levels are highest in 5-year-old roots (Soldati, 2002).
Ginseng is an example where the wild roots are more like to have a
‘‘human’’ form than the cultivated (greater ‘‘wholeness’’), and thus
command a 5–10-fold enhancement in market value (Robbins,
1998). Thus, changing the origin of a plant (wild vs. cultivated) will
almost certainly change the metabolic profile, and thus the effective
dose, but not in a predictable manner.
 G.A. Cordell / Phytochemistry Letters 10 (2014) xxviii–xl
The ‘‘pressures’’ of this myth toward ‘‘wild’’ collected plant
material are part of a cycle which has as its outcome an estimate
that less than 1% of all the medicinal plant species used are
cultivated commercially (Schippmann et al., 2006). For the reasons
mentioned above concerning the globalization of traditional
medicine use and a burgeoning population needing medicinal
plants, this is not a sustainable situation, as has been discussed
elsewhere (Cordell, 2011a,b,c, 2012; Cordell and Colvard, 2012).
7.7. Myth 8: All of the materials in a complex prescription are
necessary for effectiveness
Metabolomic studies on plants are phytochemistry on a grand
scale (Sumner et al., 2003). Although dating back to the early 1970s
studies on the metabolites in urine, the field of metabolomics lay
relatively dormant until the functional genomics era evolved to
include proteomics, and eventually metabolomics, based on yeast
metabolites (Oliver, 1997). The aim of metabolomics is the
qualitative and quantitative analysis of all of the compounds in
an organism (Fiehn, 2002). For a plant material, there are no
techniques presently available which permit this, and no-one has a
realistic idea about how to address the scope of that task. About
3000 secondary metabolites have been identified from tobacco
(Nugroho and Verpoorte, 2002), although not all at the same time!
Presumably, this metabolic diversity also represents a mirror of the
approximate number of genes involved in their biosynthesis
(recalling that undoubtedly some ‘‘metabolites’’ are artifacts of
isolation and detection). What is not known at this time is the
relationship between the number of genes in a plant genome, and
those which encode enzymes to produce secondary metabolites at
a given point in time, and how those are modulated by regulatory
genes based on age, season, water, etc. All of these are factors
which are likely to impact metabolite profile and thus biological
outcome. In addition, there is the complication of a structure
activity relationship. In other words, the most active metabolite(s)
are unlikely to be the most dominant compounds, even within a
compound class such as flavonoids or benzylisoquinoline alkaloids,
and within those compound groups, some metabolites will be
more active than others from a reductionist perspective.
Several techniques are available for examining the metabolome
profiles of plants, including chromatography (TLC, HPLC, and GC),
nuclear magnetic resonance, mass spectrometry, and phenotype
microarrays (Sumner et al., 2003), and their advantages and
disadvantages have been discussed (Verpoorte et al., 2006).
Chromatographic techniques, particularly when coupled with
MS, have an advantage with respect to sensitivity and specificity,
however, for quantification they require a calibration curve for
each metabolite. Proton NMR spectroscopy is highly reproducible,
although relatively insensitive. It typically allows for the quanti-
tative comparison of metabolites at the same field strength, but
only of the most abundant metabolome constituents. Calibration
curves are not needed, only a single internal standard. When
overlapping proton signals are present in the spectra of a complex
extract, 2D-J-resolved spectra may be useful in delineating
metabolites (Choi et al., 2004). UPLC-QTOF-MS-MS analysis is
the current technique which is likely to offer the broadest
analytical capability in terms of identifying multiple metabolites
in a single experiment.
Depending on the purpose of the metabolomic profiling, it may
be necessary to establish baseline data in order to define the
biological variability for the particular organism. For comparisons
between genera, this is much less important than comparisons
between plant metabolite formation based on soil pH, water
administration, or light/shade conditions.
A 10- or 20 plant prescription is likely to contain thousands of
metabolites to be separated chromatographically. In former times
xxxv
such complex component matrices would have been impossible to
analyze. Now, with improved chromatographic techniques and
detection options, selecting a range of several compounds to
analyze from each plant in a mixture is a phytochemical challenge
that can be met, assuring the presence of the plant, and possibly a
quantitative perspective (Liang et al., 2013).
7.8. Myth 10: This medicinal plant product is already well-regulated
The regulation of traditional medicines, phytotherapeuticals,
and dietary supplements as botanically, chemically, and biologi-
cally defined entities is typically very limited in scope. Some
countries may regulate the plant materials to a formula (requiring
certain plants to be present) in a marketed product, but make no
stipulation with respect to the anticipated ranges of ‘‘active’’
constituents, or to QSEC. This myth of product regulation is
actually prevalent in the more developed countries, where
traditional medicines and phytotherapeuticals are marketed
adjacent to well-regulated, over-the-counter medications in
pharmacies and health food stores. In addition, some products
will also be marketed in the United States indicating that they are
‘‘FDA-approved’’, strongly implying to the naı̈ve patient that the
content has been approved for a medicinal purpose. In reality, what
has been approved is the language used on the labeling of the
product, the name of the plant, and making sure that there is no
medical claim which would relate to diagnosis, curing, mitigation,
treatment, or prevention. Indeed, rather than placing the onus on
the manufacturer to show safety and efficacy, since these are not
provided for in the law, it is the FDA who, once a product is in the
marketplace, must show why it is not safe in order for it to be
withdrawn. This bizarre situation is the antithesis of the drug
approval process and of rational health care practices which would
serve the patient.
Numerous studies have found the quality control of dietary
supplements in the United States to be dubious or absent, and a
classic study (Gurley et al., 2000) cites several early examples. This
particular study of twenty Ephedra-containing supplements
revealed that the total alkaloid content ranged from 0.0 to
18.5 mg per dosage unit, with many samples containing added
stimulants, such as caffeine, which was specifically banned from
combination with ephedrine in 1983. In over half of the products,
discrepancies between alkaloid content and label claim exceeded
20%. A study of the ginsenosides in ginseng products on the market
in the US also revealed wide discrepancies (Harkey et al., 2001).
Twenty-five Panax products were analyzed, and the ginsenoside
contents varied by 15- and 36-fold in capsules and liquids,
respectively.
China has been revising and refining its laws relating to drug
administration and regulatory approval since 1984, with major
changes occurring in 2001 and 2007. The registration of drugs was
introduced in 2002 and the State Food and Drug Administration
(SFDA) was established in 2005, with an expressed desire to
expand TCM globally in line with international drug practices.
Order 28 of the SFDA was enacted in October 200, and this provided
for an assessment of the QSEC for all drugs. Under these rules, the
registration requirements of new TCM products is the same as
synthetic drugs in terms of safety data, chemical characterization,
and clinical trials (Wu et al., 2014). The only compound approved
as a single agent since 2007 is 20(R)-ginsenoside Rg3 for cancer,
particularly non-small cell lung cancer, as well as gastric cancer,
and colorectal cancer. A further 24 single agents derived from
TCMs are in active development for a range of indications,
including anti-inflammatory, antiangina, antiviral, anti-hepatitis,
anticoagulant, and anti-cerebral ischemia. Another class of drugs
in China are those which are active fractions derived from TCM
materials. Over 50% of the content must be pharmacologically
xxxvi G.A. Cordell / Phytochemistry Letters 10 (2014) xxviii–xl
active, and there are 25 preparations approved in this category,
mostly for cardiac disease. Another new drug category comprises
the preparations of TCM formulas which have not been marketed
previously. These are typically combination TCM products, with a
long history of use, which may exempt them from Phase I or Phase
II clinical trials. Their formulation is based on contemporary
pharmacological evaluation, and they are subject to preclinical
studies in animal model systems. There are 88 top-selling drugs
approved in this category. This accumulation of analytical,
biological and clinical data debunks the myth that traditional
medicines, such as TCMs, are not effective, and cannot be subjected
to modern standards of drug approval.
Globalization of traditional medicines is changing many of the
parameters of self-medication. Products from TCM, from Ayurveda,
and from many systems of medicine are appearing on shelves of
supermarkets, health stores, and pharmacies all over the world. As
we have seen, some of those products are regulated to a varying
extent, for marketing in those countries. In the clouds, the e-
commerce of traditional medicine globalization is being con-
ducted, above and beyond, at least at the present time, regulatory
oversight. What is in these products? Where do they come from?
Who is responsible for their regulation, for their quality control
(identity, age, preparation, heavy metals, pesticides, etc.), for their
safety, for their efficacy, and for their medical claims and
marketing? The marketing of these products is part of a much
larger concern, the cyber-pharmacies (Scaria, 2003). So far there
seems to be no answers forthcoming; for dietary supplements and
traditional medicines on the Internet, it is now definitely caveat
emptor. The only recourse thus far in the United States appears to
be the application of the ‘‘Unfairness Doctrine’’ of the Federal Trade
Commission, which only applies to labeling claims and their
substantiation and not to product content (Beltramini, 2003).
7.9. Myth 11: Medicinal plants are safer than synthetic drugs
Synthetic drugs are notorious for being sold with an extensive
and detailed product description, instructions, and warnings
which typically includes a long list of possible side effects or
adverse effects as a result of contraindications. Safety is a relative
(absence of) effect, and in the case of a synthetic drug is
determined through extensive toxicological and mutagenic testing
over many years. It can be argued that safety of a traditional
medicine is established through historical use and dosage, and to a
certain extent, depending on the method of preparation, this may
be accurate. However, many medicinal plants are also known to be
highly toxic, and dosing of an Aconitum species, for example,
typically presents a high risk in the absence of quantitative
aconitine alkaloid determination (Yang et al., 2014). This myth is
also an extension of the ‘‘nature is safe’’ philosophy, which fails to
inculcate that the most toxic materials on the planet are derived
from nature, including plants.
7.10. Myth 12: The medicinal plant will always be available
The loss of availability of medicinal plants is a global
phenomenon, and has been discussed for at least the past 25
years (Akerele, 1993; Alves and Ierecê, 2007; Anyinam, 1995;
Cordell and Colvard, 2012; Farnsworth and Soejarto, 1991). Causes
include the globalization of particular traditional medicines with
resulting over-harvesting in the wild (Kala et al., 2006; Schipp-
mann et al., 2006), the loss of habitat due to rain forest destruction
(Shanley and Luz, 2003), climate change (Hoegh-Guldberg et al.,
2008), and loss of habitat due to urbanization (Alves and Ierecê,
2007). As discussed elsewhere (Cordell, 2011c, 2012; Cordell and
Colvard, 2012), there is an urgent need to determine which
important medicinal plants are threatened or even endangered.
WPRO has encouraged Member States to conduct country-wide
surveys to establish the ecological status of medicinal plants,
particularly addressing issues related to the conservation of
resources (World Health Organization, 2012; World Health
Organization et al., 2012).
Globalization of traditional medicines, particularly those from
the Chinese system, and to a lesser extent some from the
Ayurvedic, Unani, and other South Asian systems, is increasing
the overall demand for medicinal plant materials. In addition, with
dramatic population increases occurring in many parts of the
world (Anonymous, 2014), the number of people relying on
medicinal plants for primary health care is likely to rapidly
increase. Although not a phytochemical issue, more one of an
agronomic development one, until the plant is suddenly no longer
available in the forest or in a village medicinal plant garden, the
belief is that it will be available, forever. This is not thinking in a
sustainable manner (Cordell, 2011a,c, 2012).
The disappearance of medicinal plants from their traditional
habitats has, in some instances, prompted cultivation to meet
demand. This is a somewhat contentious issue from an economic
perspective, depending on the relationship of the medicinal plant
acquisition to the local economy. In other words, does the
establishment of medicinal plant cultivation sites help or hinder
the local economy? Can the local population still afford the plant
materials for their health care? Is the local population, typically the
women, still earning money from medicinal plant collection? And
what is the environmental impact of conservation through
cultivation? (Schippmann et al., 2006). As noted in earlier myths,
from a health care perspective, how this material varies in
metabolic profile is fundamental question which requires constant
analytical attention for a successful health care outcome.
As an example of cultivation and conservation of a medicinal
plant for commercial purposes, consider ginseng. The excessive
collection of wild Korean ginseng (Panax ginseng) led the
government to take over the ginseng trade in 1899 in order to
meet global requirements as demand spread, and that monopoly
control of a sustainable product did not end until 1996. For more
than 30 years there have been concerns expressed about the over-
harvesting of American ginseng (P. quinquefolius) from the wild in
North America (Charron and Gagnon, 1991), and at that time only
20 stands remained in all of the Province of Quebec. However,
much earlier, the sustainable development of ginseng became a
very lucrative business for farmers in the State of Wisconsin,
beginning in the 1700s (Iritani, 1998).
7.11. Myth 13: The traditional knowledge will always be there
Although considerable indigenous knowledge has been collect-
ed and described in various formats over the past thousand years
or so, an unknown amount of traditional medicine acumen and
wisdom is retained by thousands of sources, the local medicine
person. Unless that knowledge keeper has a person training as an
apprentice with them, when they die, the knowledge of the plants
and their preparation, developed over perhaps thousands of years,
is also lost (Posey, 1990). WHO, in conjunction with the World
Intellectual Property Organization and the World Trade Organiza-
tion has again requested (WHO, WIPO, WTO, 2012; WHO, 2014)
that governments, with appropriate arrangements regarding
intellectual property rights, collect, accumulate, and analyze this
information so that it can be retained and appropriately
compensated, for the benefit of contemporary and future popula-
tions.
Our relationship with, and the evidence-based study of, the
quality, safety and efficacy of traditional medicines also relies on
indigenous knowledge, its collection, comparative analysis, and
prioritization from both a local and global perspective (Cordell, 2012).
 G.A. Cordell / Phytochemistry Letters 10 (2014) xxviii–xl
There has been much written about the disappearance of the
undocumented knowledge, and what that might mean to future
generations locally where the knowledge is being held, and globally
to health care. Cox (2000) discusses a poignant example of the
disclosure of the use of Homolanthus nutans in Samoa for treating
hepatitis from a local medicine woman, and its translation into the
potent antiviral agent prostratin. A study of traditional Arab healers in
Israel (Azaizeh et al., 2003) found a dramatic drop in their number in a
20-year period, that there was no systematic training of apprentices,
and little communication between practitioners. In Palestine,
indigenous knowledge of the 100 wild medicinal plants in the area
of five major communities was found to be disappearing (Ali-Shtayeh
et al., 2008). The high desert region of Ladakh in the States of Jammu
and Kashmir in northern India was surveyed over a 3-year period for
the use of medicinal plants in 105 villages from 47 Amchis (medicine
practitioners) (Ballabh et al., 2008). The results for kidney and urinary
disorders indicated the use of 68 plant species, all in multicomponent
regimens, but the Amchis are mostly aged, and their knowledge is
already shared between villages, where there is almost no other
health care access. The disappearance of traditional knowledge has
also been documented in Latin America as urbanization has taken
place in indigenous communities (Alves and Ierecê, 2007; Calixto,
2005).
8. Examples of myth debunking from the recent literature
An examination of recent issues of the Chinese Journal of Natural
Medicines provides some indications regarding the range of
analytical approaches of the natural products contained in
traditional medicines which are being applied to the exploration
of the scope of these myths.
The flowers of Trollius chinensis Bunge (Ranunculaceae) are used
prophylactically against viral infection in China, and the activity is
attributed to the C-flavonoid glycosides orientin and vitexin. When
five separate flower parts (calyx, corolla, stalk, stamens and pistils,
and ovary) were examined by HPLC, substantial differences were
observed with percentages being 76.99% and 71.93%, 9.60% and
8.33%, 9.21% and 8.10%, 2.17% and 6.62%, and 2.03% and 5.02%,
respectively (Yuan et al., 2013). The calyx also provides 42% of the
mass of the flowers. The concentration of orientin between 11
flower samples was in the range 0.87–8.12 mg/g. This study
therefore demonstrates both the concentration differences of the
active principles between both plant parts and sample batches.
The biological effects of medicinal plant samples from different
locations are now being scrutinized more carefully for their
biological profile. When five germplasm samples of Aloe vera (L.)
Burm. f. (Xanthorrhoeaceae), collected from different geographic
regions in India, were evaluated for mushroom tyrosinase
inhibition activity, significant differences (ca. 2-fold) were noted
for both the lyophilized gel at 2 mg/mL and the methanol extract at
6 mg/mL (Dutta Gupta and Masakapalli, 2013).
Analysis of the essential oil of the aerial parts of Tanacetum
polycephalum Sch.-Bip. (Asteraceae) from samples collected at
1600, 2400, and 3200 m, the best quality (based on 79
constituents) and greatest quantity (1.32%) was found to be from
plant material grown at the highest altitude. The yield of essential
oil from the lower altitude plant material was 0.74% and contained
fewer components (Mahdavi et al., 2013).
Three bioactive compounds present in Semen Cassiae, the seeds
of Cassia obtusifolia L. (Caesalpiniaceae), chrysophanol-1-O-b-D-
glucopyranosyl-(1!3)-b-D-glucopyranosyl-(1!6)-b-D-glucopyr-
anoside, rubrofusarin-6-O-b-D-gentiobioside, and toralactone-9-O-
b-D-gentiobioside, were used as marker compounds to investigate
the quality of 66 samples of Semen Cassiae from six major regions in
China (Diao et al., 2013). The study found a wide range of metabolite
production, with total contents of the three constituents varying
xxxvii
7-fold, from 8.21 mg/g in Hubei Province to 55.56 mg/g in Jiangsu
Province. The data allowed for recommendations for minimal
concentrations of the individual components, as well as 26.9 mg/g
for the three components combined. Based on this, only 41 of the 66
samples (62.1%) met this specification.
The effect of processing on the biological effects of Radix
Bupleuri and vinegar-baked Radix Bupleuri was examined against
cytochrome P450 enzymes in rats (Cheng et al., 2013). These
preparations have different uses in TCM, but the rationale was not
known. Based on challenging the rats with six drugs (caffeine,
midazolam, dextromethorphan, tolbutamide, omeprazole, and
chlorzoxazone) simultaneously, the induction effects on different
CYP enzymes were clarified through HPLC-MS/MS analysis. It was
determined that the two preparations have different effects on
CYP2C9 and CYP2C19, although the specific metabolites responsi-
ble remain to be investigated.
Chromatographic analytical techniques coupled with mass
spectrometry are now standard practice for the analysis of
medicinal plant extracts. The use of HPLC-electrospray ionization
quadrupole time-of-flight tandem mass spectrometry (ESI-QTOF
MS/MS) allowed the direct determination of thirty-six compounds
in the roots of Scrophularia ningpoensis Hemsl. (Scrophulariaceae)
following characterization of the individual compounds in an HPLC
run that took only 54 min (Chen et al., 2014).
Complex traditional Chinese medicine preparations with more
than ten constituent materials are known as da-fu-fang, and their
analysis and standardization is regarded as extremely challenging.
Guo and co-workers (Liang et al., 2013) have recently described an
effective approach for the analysis of Niuhuang Shangqing pill
(NHSQP), composed of 19 TCMs, using a HPLC-QTOF-MS-oriented
characteristic components data set (CCDS) and chemometric
analysis. Fingerprint profiling of NHSQP by HPLC-QTOF-MS
allowed the characterization of 190 compounds. From this
analysis, a CCDS containing 60 characteristic components was
constructed based on MS spectral differentiation of the crude
drugs, a laboratory-made NHSQP powder, and negative control
preparations. This permitted simultaneous monitoring of 16 out of
the 19 drugs present in the preparation in a single HPLC run of
20 min. When the technique was used for the quality control of 26
NHSQP samples acquired from different vendors in different parts
of China, 15 were found to be of lesser quality. This addresses
aspects of the issues raised in Myth 4.
In addition to plant materials, the traditional medicinal use of
fish is being explored, for example with studies on the sharp nose
sting ray Dysatis jenkinsii which is used for inflammatory diseases
and arthritis (Ravitchandirane et al., 2013). Both analgesic and
anti-inflammatory activities were found in the crude diethylether
extract at 95 mg/kg in standard animal models supporting the
traditional use.
Pharmacokinetic studies of individual active compounds from
traditional medicines and their metabolic products are being
examined, and one example is salvianolic acid B from the roots of
Salvia miltiorhiza Bunge (Lamiaceae), known as dan shen (Qi et al.,
2013). Nine metabolites in rat bile, plasma and urine were
identified and quantified by LC-IT/TOF-MS and the metabolic
pathways determined.
Finally, an example of the clinical effects of a traditional
medicine. Obesity is now a global issue in health care, contempo-
rarily and inevitably for the future, and a wide range of traditional
medicines have been used to assist in weight loss (Kazemipoor
et al., 2012). In terms of clinical experimentation relating to
examining the effectiveness of a traditional medicine, a recent
study on the use of caraway will be briefly discussed (Kazemipoor
et al., 2013). In several Middle East cultures, particularly in Iran,
caraway seeds, Carum carvi L. (Apiaceae), are used for inducing
weight loss. These anti-obesity properties were examined using a
xxxviii G.A. Cordell / Phytochemistry Letters 10 (2014) xxviii–xl
standardized caraway aqueous extract (CAE) at 30 mL/day in a
randomized, triple-blind, placebo-controlled clinical trial in
Iranian women. The CAE group, compared with placebo, showed
a significant decrease in weight, body mass index, body fat
percentage, and anthropometric indices after 12 weeks, with
clinical and para-clinical assessments of participants remaining
constant, and no negative clinical effects (Kazemipoor et al., 2014).
While significant clinical research in larger populations, evaluation
of different dosages, more extended administration periods, and
mechanistic studies are warranted, supportive early clinical
indications are encouraging in developing a standardized formu-
lation of CAE.
9. Strategy
Reference was made earlier in this article to the WHO Strategy
2014–2023 (World Health Organization, 2014) and the WPRO
Regional Strategy for 2012–2020 (World Health Organization,
2012; World Health Organization et al., 2012) documents. These,
and earlier documents have, as their fundamental underpinning,
the concept of the evidence-based establishment of quality, safety,
and efficacy for traditional medicines for the benefit of the patient.
The fourteen myths discussed here are, not unexpectedly, at the
core of any strategic response to changing the status of traditional
medicine in health care systems in various countries.
In 2005, China made it very clear that globalization of
traditional Chinese medicine was a strategic goal, and that this
would be based on products that were demonstrated to be both
safe and effective (Anonymous, 2005). In 2009, the European Union
established a Coordination Action group dedicated to examining
‘‘good practices, priorities, challenges, and opportunities’’ in
traditional Chinese medicine research and product development
and approval (Uzuner et al., 2012). The group is comprised of about
200 scientists working in 24 (15 EU) countries and 107 institutions.
Seven groups are dedicated to TCM plant research, one to
acupuncture research, one to overall leadership and management,
and one to meetings and events. The seven main groups are
designated to examine: (i) quality control of TCM, (ii) component
extraction and analysis of TCM, (iii) toxicology of TCM, (iv)
pharmacology in vitro, (v) pharmacology in vivo, (vi) pharmacolo-
gy clinical, and (vii) regulatory and commercial R & D.
As indicated by the title, the focus is on ‘‘good practice’’
guidelines at every stage of TCM research development, including
Good Agriculture and Collection Practice, Good Laboratory
Practice, Good Research Practice, Good Manufacturing Practice,
Good Clinical Practice, and Good Information Technology Practice.
In a deliberate manner, the group broke away from the reductionist
research model, and sought to find practice solutions which
reflected a holistic systems approach to health and disease
matching, through an evidence-base, the philosophies of TCM.
Ironically, the keys to a successful approach are the timely
developments of the various ‘‘-omics’’ technologies which look at
whole systems, in humans, mammals, cells, and plants. The
consortium conducted an interesting survey of the ‘‘Grand-Issues’’
of TCM between scientists and an external participant group, with
fascinating results (Uzuner et al., 2012). In terms of priorities the
scientist group ranked ‘‘high quality research to evaluate the
quality and safety of CHM’’ and ‘‘high quality clinical efficacy
studies of CHM and acupuncture’’ as the top items, and
‘‘development of a national policy for TCM supporting integration
into mainstream health care’’ as the lowest priority. This last item
was ranked first by the external group, mostly practitioners. The
Grand challenges also showed a similar diversity in opinion with
the registration of practitioners being highest in the practitioner
group and quality control being highest priority in the scientist
group, together with lack of funding. Where there was substantial
agreement between the two groups was in the area of opportu-
nities, including treatment of chronic diseases, investigating
possible adverse reactions, joint EU-China funding of clinical
studies, enhanced sources of information, and education regarding
all aspects of TCM. The development of omics technologies for TCM
was regarded as a very significant opportunity by the scientist
group.
A major strategic issue sits like an elephant in the room of
traditional medicine myths, and overarches most of the myths.
How should the myriad of products based on various traditional
medicine systems that are now an integral aspect of e-commerce
be regulated? Who will be assuming that responsibility, the import
country or the export country? How can these materials be
regulated in terms of QSEC? Where and how do the health needs of
the patient fit in this scenario? What is the role of phytochemistry
to pro-actively investigate these materials? The saga of PC-SPES is
probably relevant at this point (Cordell, 2002).
10. Conclusions
Maintaining the fourteen myths associated with traditional
medicines is detrimental to the enhancement of plant-based
health care globally. Only by challenging these myths through an
evidence-based approach can greater progress be made to assess
their appropriateness. Considerable phytochemical research is
underway which addresses some of the myths which underpin
traditional medicine practices in order to place the use of
traditional medicines on an evidence-base.
However, many aspects of exploring these myths are thus far
poorly studied, and are critical to patient health care, and need to
be studied in a more sophisticated and dedicated manner. These
include the aspects of conservation and location of wild medicinal
plants, the stability of the bioactive constituents in the plant and in
matrices derived from the plant, the optimization of the time to
collect a traditional medicine with respect to the bioactive
constituents, and the traceability of the plant material from the
field or forest to a final product and its shelf-life stability for
effectiveness. In several countries and areas of the world,
investment in traditional medicine development is significant
and large groups of scientists, practitioners and government are
beginning to develop pathways for improvement.
Addressing these myths of traditional medicine will allow for a
profound and fundamental change in the quality of traditional
medicines globally, of their potential with respect to integration
into the health care systems around the world as quality, safe and
effective and consistent products. Understanding their mechanism
of action through network pharmacology will also support new
approaches to both natural product, as well as synthetic, drug
discovery.
It is hoped that this appraisal of the role of phytochemistry in
the quality control of traditional medicines will stimulate further
their function as sustainable medicines in health care systems, and
will foster the investment in collaborative, focused research to
enhance the role of evidence-based traditional medicines in health
care systems. Also, that it will encourage the involvement of
phytochemists to tackle some of the challenging analytical
opportunities in many different phases of traditional medicine
research using the broad range of available and future technolo-
gies.
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