Nature's Pharmacopeia: A World of Medicinal Plants

Chapter 15

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The Future of Medicinal Plants

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A pharmacy technician at a hospital of Chinese medicine in Beijing preparing an herbal formula from powdered ingredients using a machine that automatically measures the correct quantities of each component and electronically guides her work. Red lights indicate which herbs to add to the prescribed mixture.

Medicinal plants have been a part of human life since the earliest times. To learn about this enduring relationship, modern-day scholars are unearthing new evidence of these ancient connections in nearly every imaginable discipline of study. Archaeologists are digging for signs of medicinal plant use at ancient sites of habitation to understand better when, how, and why such plants came to be used. Meanwhile, historians are examining original texts to decipher how these herbs were harvested, prepared, and valued in times long before our own, and linguists are reconstructing how such plant knowledge was communicated within and between societies. Anthropologists are documenting the ways people all over the world employ plants in health-related practices and how their beliefs give rise to culturally significant roles for plants. For their part, botanists are working out the hereditary relationships among plants, weaving genetic data and physical characteristics to recapture their evolutionary history and telling the story of those traits so useful to mankind.

For centuries, people have challenged their best technologies and analytic methods to understand the material basis of medicinal plant actions, and chemists continue to refine approaches to isolate and characterize the active principles of plants. Biochemists and pharmacologists are examining the synthesis and formulation of herbal extracts and mixtures while establishing the biological bases of such drugs’ functions in cells, tissues, and living systems. Meanwhile, biomedical researchers are forging robust studies that aim to determine whether and how medicinal plants might treat disease and describe the basis of any side effects. Ongoing research into a large assortment of time-tested medicinal herbs owes its success to the knowledge built over centuries and transmitted to the present, along with new discoveries about their therapeutic potential. Likewise, as novel medicinal plants are being identified, they, too, become subject to a rich analysis from multiple perspectives.

Future advances in the study of medicinal plants will continue to follow the paths of multidisciplinarity, as several areas of investigation ultimately converge on the better understanding of how our medicinal plants came to be employed and how people can use them safely. The challenges ahead are substantial. The present era of population growth, rapid economic development in many parts of the world, unprecedented means of global communication and transportation, and environmental change gives impetus to document the many traditional medicines of the world and apply any new knowledge to address the most pressing of the world’s health problems. As Western biomedicine accommodates the entry of herbs as therapeutic agents, it is increasingly important to pursue strong methodologies for assessing efficacy and risk. While some medicinal plants have already drawn much attention from researchers of various stripes, far more can be learned from the vast untapped potential of the plant kingdom. Collaboration across diverse disciplines, recognizing the value of traditional knowledge and the strengths of biomedical approaches, will yield a new array of plants with well-characterized effects on human health.

FOLLOWING ETHNOMEDICAL LEADS

It seems that nearly as soon as a people developed the ability to write, they began to document the ways they used plants as drugs. Ancient Egyptian medical papyri, Mesopotamian clay tablets, and Chinese texts on slips of bamboo all attest to the common human activity of communicating medical information.1 Over the course of about 2000 years, through laboriously copied manuscripts and printed books, physicians and herbalists shared their knowledge in an ongoing conversation touching on theory and practice, folk wisdom and scholarly discourse, therapies and risks. These authors, now long passed, saw fit to contribute their accounts to a large corpus of medicinal plant knowledge. Their work tells of diverse ailments—some recognizable by today’s medical framework, others not—and of the ways these people learned to treat them. There is no doubt that to these authors, plants were essential to health.

Ancient texts are occasionally criticized for relating medical ideas that have since been dismissed as irrelevant or unsafe by modern biomedical knowledge.2 How could a medieval physician who advocates bleeding his patient’s bad humors have anything to offer about herbal remedies? Why would an ancient Chinese author who recommends mercury-containing drugs (now known to be toxic) have worthwhile advice on medicinal plants? While it would be unrealistic to expect that an eleventh-century British herbal, for example, should be taken word for word as a guide to health in the modern day, it is still reasonable to consider that such a text was written to document the real ways that therapists tried to help their patients, who, in that place and time, suffered from real ailments and wanted to be healthy.3

Based on the premise that ancient texts record the ways that people prepared medicinal plants, assessed their benefits, and warned of their risks, such literature can be a great resource for modern-day investigations (figure 15.1).4 At one level, simply compiling lists of medicines and therapeutic recipes into a large-scale database can allow associations and patterns to emerge that might be of interest to researchers. For example, are particular herbs mentioned in texts from diverse geographic or cultural settings for use against a certain type of ailment? It is possible that early physicians independently came upon an effective treatment that might be of interest to modern-day applications. Are certain herbs regularly paired together in ancient therapeutic recipes? Perhaps their formulation in this way is evidence of a beneficial combination that might be investigated today at the biochemical level.5

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FIGURE 15.1   Ancient texts can be used as a guide to selecting herbs to test using modern-day techniques. Authors long ago documented the numerous ways that people used plants for health and healing: (left) an apothecary’s assistant preparing medicine as eminent scholars—including Dioscorides, Pliny the Elder, and perhaps Avicenna—converse; (right) an apothecary and a physician in a medicine shop. ([left] Woodcut from Hamsen Schönsperger, Gart der Gesundheit [1487]; Peter H. Raven Library, Missouri Botanical Garden, St. Louis; [right] illumination from Mattheus Platearius, Circa instans [early fourteenth century]; British Library, Sloane 1977, fol. 49v)

It is also possible to query such a database of ancient medicinal plant uses with hypotheses that can be addressed with a variety of laboratory and clinical approaches. For example, ancient accounts of laxative plants such as aloe (Aloe spp.) and senna (Senna alexandrina) can now be explained in terms of specific stimulatory chemical agents acting in the human intestine. Since the parasitic condition of malaria affected people across a wide expanse of the Old World, searching for mentions of malarial symptoms (intermittent fevers) in ancient texts might help find useful plants to supplement the natural and synthetic medications presently available.6 Indeed, such an approach of mining classical Chinese texts yielded artemisinin, an effective antimalarial from sweet wormwood (Artemisia annua).7 Ancient authors provide useful detail on both the possible benefits and the risks of medicinal plants. For example, the Greek herbalist Pedanius Dioscorides (ca. 40–90) carefully noted the toxicity of thorn apple (Datura stramonium, also known as jimsonweed [figure 15.2]), saying that a dose of 1 drachma (about 3.5 grams) of its root, drunk with wine, produces “not unpleasant fantasies,” a quantity of 2 drachmai “drives a person out of his senses for up to three days,” while a dose of 4 drachmai “kills.”8 The legacy of such medical documents includes meticulous descriptions of the therapeutic applications as well as warnings about the health-related properties of plants.

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FIGURE 15.2   Thorn apple. (Illustration from Joseph Roques, Phytographie médicale [1835]; BIU Santé, pharma_105443x04)

Yet the use of ancient texts to identify plants for biomedical testing has some limitations. For one, a great many of these sources remain largely unexplored, sharing their secrets with those few scholars with the ability to read their script, whether, for example, classical Chinese, Old English, Latin, or Greek. Such works are being translated by historians of medicine, opening up new avenues of research into the medicinal plants they document.9 In many cases, however, the efforts of translation cannot span the chronological and cultural gap separating the modern scholar from the ancient author. So many Assyrian medical recipes excavated from Ashurbanipal’s (685–627 B.C.E.) library contain references to plants that have eluded translation.10 In the Egyptian papyri, as well, hide a large number of useful plants, for which there is no certain modern botanical equivalent.11

Descriptions of illness also depend on concepts of health prevalent in the time at which they were written. While today’s “cancer” refers to an uncontrolled, malignant growth of tissue, ancient authors wrote of tumors, swellings, lesions, abscesses, and pain.12 Are the latter symptoms indicative of the former ailment? If ancient texts discuss an herb’s role in the humoral framework, how can such an understanding be adapted to a biomedical way of thinking? It might not be possible to achieve such a correspondence, and the physicians and patients who could clear up the uncertainty are no longer available for questioning. Despite these challenges, ancient texts have provided a rich base of evidence for the biochemical study of potentially useful medicinal plants and, in the hands of historians and linguists with skills to make these past contributions available to a large, modern-day audience, will give rise to many fruitful investigations.

While ancient medical texts can inform modern-day investigations of the physiological properties of herbal preparations, such documents generally record only the knowledge of those privileged to publish. In regions without a written tradition, ethnographers have learned from the expertise of practitioners by studying with them, living among their people, and describing how they employ plants in medicine.13 Such studies can often take months or years, as generations of practical knowledge, embedded in a cultural setting, cannot be easily and quickly transmitted to a foreign visitor. Indeed, anthropologists who undertake these projects often try to integrate themselves into communities, learning prevalent languages and experiencing the pace and activities of local life as an insider.

This type of approach to documenting traditional knowledge of plants is worthwhile among people without a written heritage as well as in areas with a robust literature on herbal medicines, such as Europe and East Asia. Anthropologists are sensitive to the multiple levels of medicinal knowledge deployed in a complex society and know that many experienced individuals might not have the resources or inclination to commit their expertise to ink. For example, the plant-based treatments employed by midwives and folk-medicine experts might not be well represented in the medical literature of a region where a predominant, scholarly medical system produces the bulk of the written output. It is therefore important to learn about medicinal plants in all the cultural settings in which they are applied.

As economic development and transnational acculturation have come to touch even the remotest parts of the globe, many societies that had long relied on herbs in their traditional medical practices are adopting Western biomedical treatments. Furthermore, the move to new standards of hygiene, housing, religious practice, and employment has further eroded the close contact many groups maintained with medicinal plants. As tribal languages disappear and elders are no longer able to train their successors in the exercise of generations of accumulated knowledge about the local natural world, volumes of botanical wisdom vanish.14 While researchers can do little to slow the evaporation of knowledge occurring as traditional societies give way to the forces of globalization, ethnobotanists are preserving as much as they are able, documenting what they learn, and making available to a broader community information that might soon disappear.15 By cataloging the diverse medical uses of plants among so many people and describing their cultural contexts, ethnobotanists are providing a rich resource for those working in many other disciplines. Such detailed accounts are useful to researchers looking for possible novel therapies.16

There are also challenges in communicating the outcomes of ethnobotanic projects to an audience working according to biomedical conventions. At one level, most societies employ illness concepts that do not align with the categories of Western biomedicine.17 In many areas, people believe that supernatural entities play a role in health, and therefore people may resort to certain plants to appease offended spirits and heal their ailments. How can such properties be communicated usefully to investigators who have no equivalent disease concept? If a plant is said to have a heating or cooling nature, how can this information be used by biomedical researchers? Indeed, even in countries where Western medicine predominates, such as North America and Europe, most people who use herbs in their health-related practices converse in a vocabulary that makes sense to them, and rarely the precise language of formal medical training. Whether the outcomes of ethnobotanic study are presented using the terminology and conceptual framework of the traditional culture or “translated”—that is, converted judiciously into Western biomedical jargon—investigators must bear in mind the differences in the ways people conceptualize and treat their health.

Spanning the distance between local, culturally informed plant uses and the white-coat laboratory requires a language that accurately captures the former and is intelligible to the latter. While conveying the nuance of traditional illness concepts to researchers working in a world of scientifically defined disease agents is one aspect of this discourse, it is equally important to identify plants in a way that is useful to the broader community of researchers. With a multitude of local plant names, such a task is not as simple as asking an experienced informant to list the herbs that he engages in his practice. For example, the Lumbee Indians of North Carolina call the striped prince’s pine (Chimaphila maculata) by the names rat’s vein, pip, and lion’s tongue, and botany manuals also list pipsissewa and spotted wintergreen among its common names.18 Moreover, the common names of some plants might refer to more than one Linnaean species. For example, plants called snakeroot or chamomile are known botanically by several different scientific names.19 Researchers relying on only vernacular names might easily mistake one plant for another.

To minimize such possible confusion, field workers conducting surveys of medicinal plant use record as much botanic information as possible, which usually includes a physical specimen of relevant plants. Together with local names, date, and precise geographic coordinates, several pressed examples of the stem, leaves, and flowers, for example, of a plant can be deposited in research herbaria as a permanent reference sample (a voucher specimen) of the species identified in the field (figure 15.3).20 By documenting plants encountered in this way, botanists can assign Linnaean binomials and help ensure an accurate record. In the age of DNA, samples of genetic material also help laboratory researchers determine the identity of plants encountered in traditional medical settings. In this way, publications utilizing ethnobotanic information can denote plants unambiguously and support the type of interdisciplinary collaboration that characterizes the field.21

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FIGURE 15.3   An herbarium specimen of thorn apple. (Courtesy of United States National Herbarium [US] 1689278)

The study of medicinal plants in ancient texts and in their many cultural settings supports a long-standing effort directed at the identification of potentially novel drugs. (At the same time, scholarly work on ancient medical sources and among modern-day people enhances humanity’s knowledge of its history, traditions, and cultural diversity.) The leads uncovered in humankind’s past experiences with medicinal plants and the countless traditions involving medicinal plants around the world support an agenda of bioprospecting on the premise that human experience has generated hypotheses to test in the laboratory. Such a strategy is hardly novel; after all, it was the pioneering work of the English physician William Withering (1741–1799) that characterized the pharmacological properties of a folk remedy involving foxglove (Digitalis purpurea), resulting ultimately in the identification of an active principle, digitalis, capable of treating heart disease.22 Today, biomedical researchers are convinced that nature has many more undiscovered pharmaceuticals locked away in the molecular storerooms of plant cells.

The alternative to deriving medicines from natural sources is to synthesize chemically and test large numbers of molecules in the laboratory for effects on enzymes, cells, and tissues of therapeutic interest. This approach, called high-throughput screening, has certain benefits, in that researchers need not concern themselves with sourcing natural materials and dealing with their complex, challenging chemistries. But high-throughput screening of synthetic molecules has a low “rate of return” in terms of prospective new drugs—a “hit rate” (that is, the number of potential novel drugs discovered per synthetic molecules screened) of less than 0.001 percent is estimated in high-throughput screens.23 By deriving potentially active compounds from natural products and using chemistry to modify their structure and improve their activity, many pharmaceutical researchers are instead taking natural molecules as raw materials in the process of drug development, ultimately using some high-throughput technologies to identify the most active drug candidate molecules.24

High-throughput screening

The systematic, rapid testing of millions of (frequently synthetic) chemicals for biological activity using computer-aided experimental techniques

Therefore, cultural and historical leads enrich the pool of candidate species that might be subjected to drug development programs. While such investigations might identify one or more active principles as candidate pharmaceutical agents, certain rational chemical modifications undertaken in the laboratory might yield even more potency or other desirable physiological properties.25 For example, this approach has been used to generate the semisynthetic antimalarial agents chloroquine and mefloquine, more efficacious variations of the Peruvian fever tree’s (Cinchona spp.) active principle, quinine. Likewise, as the Plasmodium parasites responsible for malaria are gradually developing resistance to the drug artemisinin, derived from the sweet wormwood (Artemisia annua), pharmaceutical researchers have modified its structure to produce active analogs, including the molecule OZ277 and dimeric artemisinin (figure 15.4).26 Thus many modern-day drugs retain at their core the chemical signature of nature.

Useful medicinal plant knowledge comes from many sources, whether historical documents, folk wisdom, or formal traditional medical practices. It has been the work of countless scholars working in multiple disciplines to record, analyze, interpret, and ultimately disseminate a wealth of botanical information now available to a wide community, and there is more still to do. As the tools of chemistry can be applied to understand better the molecular constituents of herbs and their extracts, so are particular methodologies brought to bear on the questions of clinical efficacy and safety.

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FIGURE 15.4   Natural products as a basis for synthetic drug development: artemisinin, an antimalarial compound from sweet wormwood; semisynthetic artemisinin dimeric analog; synthetic OZ277. The possible active sites are shown in green.

EVOLUTIONARY RELATIONSHIPS AMONG MEDICINAL PLANTS

Combining the nuanced analysis of plants’ developmental patterns with new insight into their genetic heritage through DNA studies, botanists are constructing ever more accurate family trees (phylogenies) that place the hundreds of thousands of plant species among their most closely related kin. This increasingly detailed knowledge of plants’ evolutionary histories has allowed medicinal researchers to examine hypotheses about the origins and geographic distribution of species with possible health-related effects.

Closely related plants often have similarities in structures such as flowers or leaves, an outward manifestation of shared ancestry. Related plants also frequently exhibit certain chemical similarities, such as the capacity to produce particular types of medicinal compounds. For instance, it was observed long ago that many plants of the nightshade family (Solanaceae) possess the biochemical pathways to produce medically active alkaloids. Nightshades such as tobacco (Nicotiana spp.), mandrake (Mandragora officinarum), angel’s trumpet (Brugmansia spp.), and henbane (Hyoscyamus niger), although differing in growth habit and occurring in distinct parts of the world, have all been incorporated into traditional medical practices, presumably because of their potent psychoactive compounds.1 Likewise, the globally distributed mint family (Lamiaceae) includes numerous medicinal and culinary plants, such as sage (Salvia spp.), horehound (Marrubium vulgare), lemon balm (Melissa officinalis), and the chaste tree (Vitex agnus-castus).

Although physically diversified to occupy the countless niches of the world’s ecosystems, plants of a shared lineage often retain certain biochemical characteristics as part of their genetic heritage. It is therefore not surprising that human cultures have independently discovered the medicinal properties of plants separated by oceans yet bound together by their close ancestry. Some plant families appear to be greatly enriched in species that are used for health-related purposes in widely disparate places, a strong suggestion that certain species should be prioritized for further laboratory study of possible active principles.2

While the family trees of numerous medicinal plant species can provide hints to their possible chemical offerings, there are also some examples of convergent evolution, where particular medically relevant characteristics came about separately in species not closely related. For example, plants of numerous families can synthesize useful volatile-oil constituents such as eugenol, including clove (Syzygium aromaticum [myrtle family]), basil (Ocimum basilicum [mint family]), and bay laurel (Laurus nobilis [laurel family]). Similarly, many dozens of plant species across several families produce the alkaloid caffeine, including coffee (Coffea spp.), tea (Camellia sinensis), yerba mate (Ilex paraguariensis), and cola (Cola spp.).3

1. Tobacco produces nicotine; mandrake, angel’s trumpet, and henbane produce tropane alkaloids such as atropine and scopolamine. The nightshades are also known for their diverse and useful terpenoid compounds, such as capsaicin, from chili pepper (Capsicum annuum), and lycopene, from tomato (Solanum lycopersicum).

2. Feng Zhu et al., “Clustered Patterns of Species Origins of Nature-Derived Drugs and Clues for Future Bioprospecting,” Proceedings of the National Academy of Sciences USA 108 (2011): 12943–12948; C. Haris Saslis-Lagoudakis et al., “Phylogenies Reveal Predictive Power of Traditional Medicine in Bioprospecting,” Proceedings of the National Academy of Sciences USA 109 (2012): 15835–15840.

3. Edward O. Kennedy, Plants and the Human Brain (Oxford: Oxford University Press, 2014), 98.

BUILDING A BASE OF EVIDENCE

Medicinal plants have served many roles in their diverse cultural and historical settings—roles that cannot be easily aligned with Western biomedical concepts of health. In contemporary China, for example, practitioners of Chinese traditional medicine believe that magnolia (Magnolia officinalis) bark is a warming herb that “regulates the qi and directs it downward.”27 In sixteenth-century England, the herbalist John Gerard (1545–1611?) recommended that the snapdragon (Antirrhinum spp.) be worn on the body as an amulet to protect the bearer against bewitchment and be soaked in water to treat the eyes, if they are tearing from “a hot cause.”28 In many parts of the world, people regularly take time to drink coffee (Coffea spp.) or tea (Camellia sinensis) with friends and family, and it helps them affirm their social connections. Neither qi, nor bewitchment, nor hot causes of illness, nor social ritual have currency in the bio-medical framework that attributes health to the coordinated interactions of molecules, cells, and structures in an anatomical machine.

Although Western biomedicine has become the dominant approach to health care in the past century, originating in Europe and North America and subsequently adopted in much of the world, many people still value their traditional and folk practices. In reality, Western medicine coexists with local, indigenous medicine throughout the world. The scholarly medical traditions of East Asia, Europe, India, and elsewhere present consistent theoretical bases for maintaining health and addressing illness, replete with their repertories of herbs and other treatments. There are plants thought to have properties relevant to a prevailing medical framework, such as the Greek humoral system or indigenous Chinese medicine. Incorporated into medical texts over centuries, such plants are taken for their perceived heating or cooling properties, for their dryness or qi-directing ability, and so forth. The collective experience of practitioners and patients helped assemble a set of herbs with qualities found useful in treating illnesses and promoting health according to the tenets of these diverse scholarly traditions.

Meanwhile, folk medical practices and religious medicine employ plants in their herbal teas, healing salves, and ritual concoctions. These medicines resulted from many years of trial and error, in which practitioners discovered techniques they thought worked and avoided those they suspected were dangerous. By noting the apparent effects of various herbal combinations and differences in preparation, they shaped their techniques to suit the needs of their patients and profession. In many parts of the world, the vast folk medical experience is passed orally between the generations, a great part of it disseminating extensive encounters with plant-based remedies.

The long history of herbal medicine and refinement of formulas across generations notwithstanding, until the development of the scientific method, there was no way to determine objectively whether a given treatment was responsible for causing a particular physiological outcome. The scientific method, with its hypothesis-centered, experimental approach, is considered the most reliable way to examine therapeutic efficacy. Thus many investigators are subjecting medicinal plants and their extracts to laboratory assays and clinical trials to look for possible physiological activities. Yet such projects have their challenges. How should tests of medicinal plants be designed to yield the most useful results? How can effects described in traditional medical terms be examined using biomedical methodologies? What physiological mechanisms might explain the activities of plant-based treatments? The experimental sciences draw in ethnographic analyses, chemical methods, biological techniques, and clinical approaches collaboratively to address such questions.

Informed by historical and cultural knowledge, chemists and biologists since the nineteenth century have established clearly that active principles can be isolated from medicinal plant tissues and their effects on the human body rationalized in mechanistic terms. Morphine, they discovered, accumulates to a high level in poppy (Papaver somniferum) latex and is responsible for opium’s effects on the body, largely by activating opioid receptors in the brain. They explained that caffeine is present in coffee, tea, and other plants and that it interacts with the adenosine receptor in the nervous system. It is now possible to describe precisely the effects of morphine on sleepiness and caffeine on alertness in ways that were not imaginable before the advances offered by chemical analysis and cell biology. Having isolated the active principles, modern-day pharmacists can formulate treatments of known, precise doses and predict more reliably the physiological outcomes. Yet many of these advances came without recourse to clinical trials, without applying the scientific method.

Because the effects of medicinal plants such as coca (Erythroxylum coca) and hemp (Cannabis sativa) are so quickly perceived by human subjects, early investigators did not doubt that these drugs produced the marked responses associated with their consumption. For many more herbs, however, the link of causality between medicinal plant use and physiological response has not been so clear. For example, if a patient regularly takes an extract of purple coneflower (Echinacea spp.) during the winter and does not catch a cold, how can one determine whether such an outcome is truly attributable to the herbal supplement? It is possible that the patient might also avoid illness without taking the purple coneflower treatment. The scientific method addresses such questions of therapeutic efficacy by comparing the outcomes of defined, potentially active treatments with the outcomes of parallel, pharmacologically inert treatments. In the clinical-trial setting, the more reliable of such experiments evaluate large numbers of subjects who have been randomly assigned to receive either the study drug or a placebo, and neither the patients nor the direct investigators are aware of their group placement.29

Herbal preparations are now regularly subjected to the robust scientific methodology that allows researchers to determine whether particular ascribed medicinal effects are borne out by data. While many trials are conducted to high standards of experimental design, some efforts at clinical testing could be improved.30 At one level, investigators should choose their herbal treatments carefully and rationally. Various plant parts (root, shoot, leaf, flower, fruit, seed) can differ significantly in chemical makeup, and constituents can change across the growing season, in different geographic locations, and according to cultivation techniques.31 Furthermore, the inherent genetic diversity of plants means that the assorted cultivars or regional varieties, called chemotypes, can differ in their distribution and levels of medically active compounds. Ultimately, research that carefully selects and describes the plant material under investigation is more easily compared with others and replicated. Furthermore, the form of plant-based treatment (whole herb, extract in solvent), route of delivery (capsule, injection, nasal spray, lotion, herbal tea), dosing scheme (once daily, twice daily, weekly), and trial duration influence the possible outcomes of the project and the ways that its results might be contextualized. Placebo treatments should be credible in terms of flavor, smell, color, and other properties that might otherwise allow a patient to determine his or her group assignment. Additionally, the criteria by which patients are admitted to (or excluded from) the study can affect the observed results. At the level of outcomes, investigators must purposefully choose the ways they wish to measure the patients’ possible response to treatment, using appropriate clinical and laboratory as says yielding quantitative data. In summary, there are many variables that demand an herbal researcher’s attention in the conduct of clinical trials.

Chemotypes

Varieties of a single species that differ in chemical constituents

Quantitative data

Numerical experimental results (blood pressure, temperature, cell count, enzyme activity, and so on) that can be subjected to robust statistical analysis when collected from many test subjects

Many of these considerations are not unique to medicinal plants research but instead apply to clinical trials as a whole. To promote a strong and transparent methodology in clinical trials, many scientists have advocated the broad adoption by researchers of a basic set of experimental-design criteria. Since scientific journals are one of the primary outlets for reporting the results of clinical trials, the implementation of such standards by journals’ editorial boards has influenced the way scientists design, conduct, and report their clinical trials.32 Through improved standards of clinical trials and adherence to a set of global norms on the interpretation of experimental outcomes, herbal treatments are entering the realm of evidence-based medicine, the prevailing philosophy that demands that health-care decisions be grounded in the results of well-designed research yielding quantitative data. (That said, critics of evidence-based medicine point out that its emphasis on research findings diminishes the role of practitioner experience in health-related decisions. These critics also contend that forming clinical expectations from statistically derived trial data treats patients as uniform beings and ignores natural biological variation.)33

It is generally believed that larger clinical trials (having a greater number of subjects per treatment group) can produce more meaningful results than smaller ones, and statisticians have developed a methodology to combine the results of small trials into a larger, presumably more valid meta-analysis. Employing stringent inclusion criteria, researchers utilizing this approach search the scientific literature for trials involving a particular intervention on a therapeutic target of interest and select those that meet certain conditions.34 For example, a project like this might collect all the available reports on trials of the extract of the South African geranium (Pelargonium sidoides, also known as umckaloabo) against acute respiratory infections.35 Then the investigators might exclude those with poor design (according to established standards and their judgment) but otherwise include a variety of different plant preparations, data-collection strategies, and health-related endpoints in a wider analysis. For example, some of the included trials might test herbal tablets; others might test liquid preparations. Some might measure different aspects of respiratory disease—such as cough, sore throat, or fever—and track various outcomes, such as severity or duration, in ways that are difficult to compare. Meta-analyses can generate conclusions based on a much broader set of conditions and a larger number of subjects than the original trials, but the value of such projects depends to a great extent on the quality of the literature employed and the stringency of selection criteria. “A meta-analysis can show anything you want to show,” one scientific observer noted. “Junk in, junk out.”36

While clinical trials and their meta-analyses can lend support to the potential efficacy of herbal medicines, pharmacologists are establishing how the array of chemical constituents from plants interact with the body’s systems. At the most basic level, assays can be performed in test tubes to look for certain properties in plant extracts: antioxidant activity, for example, or the ability to inhibit a metabolic enzyme. Such tests can help investigators establish the likely cellular targets of medicinal plant compounds and the way they might cause a physiological change—that is, the mechanism of action. By carefully establishing how specific plant-derived agents interact with molecular targets in the body, isolating active principles, and demonstrating clinical efficacy in human trials, medicinal plant researchers are advancing their work to take on some of the most challenging health problems.

Among the most important herbal medical discoveries of the twentieth century were a series of anticancer agents identified by the National Cancer Institute, many in massive screens looking for activity among thousands of plant extracts from all over the world. This project, which lasted from the 1960s to the 1990s, identified the vinca alkaloids vinblastine and vincristine from the Madagascar periwinkle (Catharanthus roseus) and paclitaxel (sold as Taxol) from the Pacific yew (Taxus brevifolia), among many others (figure 15.5).37 The vinca alkaloids are commonly used in combination-chemotherapy regimens against leukemias, lymphomas, and breast and lung cancers, for example; paclitaxel is effective against breast, ovarian, non-small-cell lung cancer, and Kaposi’s sarcoma (figure 15.6). These agents work by binding to the molecular machinery of cell division, preventing the uncontrolled cell proliferation that characterizes cancers.38 Because the active constituents have been isolated, purified, and demonstrated effective by clinical trials, they were registered as drugs by the Food and Drug Administration and are available to patients by prescription. Since their discovery, chemists have learned to synthesize them from simpler chemical building blocks and make structural modifications to improve their effectiveness, ensuring that these agents—and many more such plant-derived cancer drugs—remain part of the armamentarium for a long time to come.

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FIGURE 15.5   Leaves of yew, a source of the cancer drug paclitaxel and its precursors.

While the vinca alkaloids, paclitaxel, and other pharmacological agents can act as isolated chemicals, it is also possible that combinations of active compounds might together have a physiological effect not present to the same degree in purified single compounds. This concept—“the mixture makes the medicine”—has led plant pharmaceutical development in a novel direction.39 Rather than seek to identify solitary active principles for clinical trials, researchers can instead purify and thoroughly characterize an assortment of chemicals that together have an effect on health, demonstrable in clinical trials.40 The first such botanical drug, a mixture of polyphenolic compounds from green tea effective against genital warts, received FDA approval in 2006.41 (Unlike foods and dietary supplements, registered botanical drugs claim to treat disease.) The green tea–derived drug, called sinecatechin (sold as Veregen), is dispensed by a physician’s prescription.

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FIGURE 15.6   Anticancer agents discovered in large-scale screens: vinblastine, from the Madagascar periwinkle; paclitaxel, from yew.

Another compelling example of this approach is the botanical drug crofelemer, from the South American tree sangre de grado (Croton lechleri [figure 15.7]). Also called sangre de drago, the tree produces a red latex that gives the plant its name: dragon’s blood. Indigenous people in Ecuador, Colombia, Peru, Bolivia, and Brazil use its bark and stem exudate as a treatment for diarrhea and dysentery, in a vaginal bath before and following childbirth, for treatment of intestinal and stomach ulcers, and to stop bleeding and heal wounds, among other applications.42 The extract crofelemer is a mixture of polyphenolic compounds that has been found effective against diarrhea by blocking the release of water from the cells lining the intestine (figure 15.8).43 The drug has been approved to treat patients suffering from loose stools as a result of HIV/AIDS antiretroviral therapy.44

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FIGURE 15.7   The bark of sangre de grado, for sale at an Amazonian market, exudes a red latex when cut.

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FIGURE 15.8   Crofelemer, an antidiarrheal botanical drug from the bark of sangre de grado. Crofelemer is a mixture of polyphenolic compounds.

Considering the sheer complexity of just a single plant’s chemical makeup, consisting of thousands of distinct molecular structures, it is no wonder that many efforts at developing new herbal pharmaceuticals center on the isolation and characterization of a very small number of active constituents. Lone chemical constituents can be more simply characterized and tested than combinations of many compounds together in a single preparation. Accounting for the chemical differences among plant parts, variations of processing, the blending together of several different herbs, and other common herbal medical practices, the challenges to identify possible therapeutic compounds are formidable. Yet many plant researchers recognize that mixtures of chemicals might be more effective than single agents. This scenario, where two or more constituents produce a far greater effect when administered together than separately, is called pharmacological synergy.45

One form of synergy can exist when several distinct chemical compounds in a single medicinal plant work together to produce their physiological effects. For example, the combination of Δ9-tetrahydrocannabinol, other cannabinoids, and a variety of terpenoid compounds in hemp (Cannabis sativa) is thought to offer advantages over individual constituents in the treatment of pain, inflammation, anxiety, and a number of other conditions.46 Synergies are also evident in herbal medicines formulated from more than one plant.

Synergy

A greater effect of a combination of drugs than would be predicted from their individual effects

One such synergistic pharmacological relationship occurs in a medicinal beverage prepared by members of the Shipibo, Tukano, and other Amazonian groups for spiritual-healing rituals. The drink, called ayahuasca, is carefully concocted by experienced shamans and contains the ayahuasca (Banisteriopsis caapi) vine, chacruna (Psychotria viridis) leaves, and other plants. When ingested, the mixture gives rise to powerful visions of supernatural animals, spirits, and complex geometric patterns. The ingredients of the ayahuasca drink are now known to act together to produce these experiences: chacruna leaves contain the chemical dimethyltryptamine (DMT), which can activate receptors for the neurotransmitter serotonin in the brain, and the ayahuasca vine contains harmaline, which inhibits the enzyme monoamine oxidase in the digestive tract and thereby allows DMT to enter the bloodstream, cross the blood–brain barrier, and exert its mind-altering effects.47 Indigenous peoples, then, discovered the combined activities of different medicinal plants long before chemists and pharmacologists came to understand their mechanisms of action.

Many herbal medical traditions employed combination therapies, mixtures of plants that were thought to work together. For example, indigenous Chinese medical practice relies on potentially thousands of herbal formulas, each composed of several (sometimes more than ten) medicinal plant ingredients (figure 15.9).48 In ancient literature, centuries before the advent of Western chemistry, the Chinese described the art of formulas by assigning to each herb a role drawn from a model feudal society. The chief herb, also called the lord, was deemed responsible for the primary therapeutic effect; the deputies or ministers assisted or enhanced the formula’s efficacy. The assistants were believed to help treat accompanying symptoms of the patient’s illness, counteract the harshness of one of the ingredients, and so forth. Finally, the envoys or couriers were thought to direct the formula to the proper channel or site of therapeutic activity.49 It is possible that Chinese doctors long before the present identified synergistic herbal interactions that modern-day investigators can study at the molecular level.50

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FIGURE 15.9   A Chinese herbal prescription containing more than two dozen ingredients.

In indigenous South Asian medicine, mixtures of plant-derived ingredients abound in medical prescriptions and therapeutic food recipes, such as those that combine turmeric (Curcuma longa), the flavorful, yellow root that is powdered and added to numerous traditional sauces, with the ground-up fruits of the black pepper (Piper nigrum) or long pepper (P. longum) vine, a sharp, pungent spice.51 Turmeric contains curcumin, a phenolic compound that is associated with anti-inflammatory and possible anticancer properties but is absorbed into the bloodstream rather inefficiently if taken alone.52 Interestingly, the pepper compound piperine blocks certain enzymes in the intestine and liver that would ordinarily prevent the uptake and circulation of curcumin.53 As a result, piperine enhances the ability of curcumin to reach the body’s tissues, where it might exert physiological properties. Therefore, age-old South Asian recipes include two ingredients that together produce effects not possible with either isolated chemical agent.

Pharmacologists have described four aspects of human physiology affecting the ultimate ability of a systemic drug to act on its target tissues: absorption, distribution, metabolism, and excretion. It appears that many synergistic drug effects are attributable to the complex roles of various plant-derived chemicals in the way the body handles drugs introduced to it. By improving DMT’s distribution into the brain, harmaline potentiates its psychoactive effect. By reducing barriers to curcumin’s absorption and inhibiting its metabolism (breakdown), piperine allows it to achieve a higher concentration in the bloodstream and thereby reach tissues throughout the body. While the complexity of chemical compounds in single plants and multiherb mixtures remains a challenge in assessing herbal efficacy, traditional knowledge and modern-day pharmacology can shed new light on the many ways that ancient medicines affect human health.

Parameters affecting drug levels in the body

Absorption

Uptake by the digestive tract, lungs, or other mucous membranes

Metabolism

Enzyme-mediated conversion into other molecules

Distribution

Transport in the body

Excretion

Removal from the body via the urine and feces

SAFETY

Physicians, shamans, apothecaries, and other specialists in the properties of medicinal plants have concerned themselves with the challenge of distinguishing therapeutic effects from possible toxicities for thousands of years. The task of determining the safest ways to use medically active herbs while avoiding negative outcomes was once a matter of trial and error: knowledge of therapeutic effects and risks was gathered by observation. Doctors remembered their experiences and passed along new warnings to future generations. As an Amazonian herbalist remarked, “Many of our brothers and sisters died so that we can have these medicines.”54 Now that herbal preparations are increasingly subject to the techniques of biomedical science, it is possible to assess their safety with a new rigor and to examine an age-old problem in its many contemporary dimensions.

Classic texts and ethnographic sources are valuable resources in garnering time-tested methods for harvesting, preparing, and administering herbs safely. However, until the advent of biochemical pharmacology techniques and scientific, statistical methodology, there was no robust way for a physician to determine whether negative experiences—in modern terminology, adverse events—were caused by a treatment. Certainly, immediate reactions to a medicine, such as acute allergy or rapid gastrointestinal response, might have been connected to a medication, but in patients already suffering serious health problems, even such drug-related outcomes might not have been distinguishable from the normal course of illness. For toxicities revealing symptoms over the course of months or years, any link would have been nearly impossible to detect.

Species in the birthwort genus (Aristolochia spp.) were employed in numerous world medical traditions until their toxic properties were more fully recognized in the twentieth century (figure 15.10). The Greek herbalist Dioscorides relayed that the herb was “very helpful to women during childbirth,” and one type, in an herbal tea, treated “asthma, hiccups, shivering, the spleen, ruptures, spasms, and pains in the side.”55In China, several Aristolochia species figure in the classical pharmacy, including the root of A. fangchi, an herb first mentioned in the Divine Husbandman’s Classic of the Materia Medica almost two millennia ago and thought to dispel wind, stop pain, clear heat, and promote urination.56 Despite a long history of use, birthwort is now known to be harmful. The plant accumulates the chemical aristolochic acid, a genotoxin that is particularly damaging to the kidneys and can cause cancer of the upper urinary tract.57 Numerous cases of kidney failure and cancer have been described in eastern Europe, where birthwort seeds were found to contaminate locally produced bread; western Europe, where patients at a weight-loss clinic were unintentionally treated with herbs including birthwort; and East Asia, where the herb is widely used in traditional medicine.58 While many governments have banned the import or sale of birthwort, it is still employed in folk health practices in Asia, grows wild around the globe, and is available on the Internet to willing customers, without mention of its deadly nature.59

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FIGURE 15.10   A South American species of birthwort.

The example of birthwort highlights the ways that biomedical science can help identify dangerous medicinal herbs and establish the biological bases of their toxicity. Since many herbs are sold in the United States as dietary supplements, they are not routinely tested for safety in laboratory and clinical experiments before being placed on the market, as are pharmaceutical drugs. Under the Dietary Supplement Health and Education Act of 1994, which governs such products, many herbs and their extracts can be assumed safe for consumption and freely sold, leaving responsibility to the FDA to demonstrate any significant risk to the consumer. Since the early 2000s, following several deaths attributable to supplements containing jointfir (Ephedra sinica), the government and herbal-supplement industry have adopted more rigorous safety practices.60 Manufacturers of herbal products are now required to submit reports of serious adverse events to the FDA. Reporting of serious adverse events includes those that result in death or are otherwise life threatening, cause birth defects, or require inpatient hospitalization, for example. The industry may voluntarily report mild or moderate adverse events, as may patients and practitioners. In addition, the industry must follow particular procedures regarding the processing, packaging, and storage of herbal supplements, called Current Good Manufacturing Processes.61

Some critics of the current state of affairs recommend that the FDA be given closer oversight of dietary-supplement safety, including the power to issue mandatory recalls if health concerns are suspected and required reporting of all adverse events.62 The FDA considers that adverse events associated with dietary supplements are significantly underreported, impairing its ability to detect potentially harmful products. Since many consumers of dietary supplements in the United States do not view them as “drugs,” they may be less apt to attribute side effects or other health problems to them. Many American patients neglect to share their herbal medicine use with physicians, and therefore clinicians cannot adequately discuss their health effects or report adverse events related to supplements.63 Furthermore, misleading advertising and dietary-supplement labeling that may encourage consumers to misuse certain herbs also present health risks. For example, a recent government study uncovered numerous examples of deceptive marketing on Web sites and dangerous medical advice from salespeople of dietary supplements.64 Therefore, it is likely that a combination of enhanced reporting of adverse events, improved communication between patients and health-care providers, and increased vigilance on the part of the FDA and other government agencies will help address herbal dietary supplement safety in the future.

In addition to the potential risks of herbs with undiscovered toxicity, there are concerns that some herbs may be misidentified, misrepresented, or adulterated during growth, harvesting, processing, or marketing. Because of the close physical resemblance of certain medicinal plants, it is possible that one species may be inadvertently collected in place of another, in either the field or the raw-herb market.65 For example, the roots of the North American black cohosh (Actaea racemosa) are often sourced in the wild, a range shared in Appalachia with the closely related yellow cohosh (A. podocarpa) and other species. These plants’ roots appear similar, especially when dry, and it is possible that they may be confused and the latter sold in place of the former. Furthermore, some samples of black cohosh root imported from China have been found to contain instead material from A. cimicifuga or A. dahurica.66 Such substitutions present possible health risks because chemical composition can differ between species of the same genus.

Another example of mistaken identity occurred in a health product said to contain common plantain (Plantago major), an herbal bulk laxative. When a Massachusetts woman became ill after taking the product, an investigation determined that the manufacturer probably had mistaken plantain for Grecian foxglove (Digitalis lanata), a plant of similar appearance but containing toxic cardiac glycosides.67 Some cases of herbal misidentification occur because of similar appearance; others occur because of similar names. For example, over 100 cases of aristolochic acid–attributable kidney disease in Belgium during the 1990s have been traced to the mistaken substitution of the Chinese herb hanfangji (Stephania tetrandra) with guangfangji (Aristolochia fangchi) in an herbal weight-loss treatment.68 A recent survey of bulk herb samples from American herbal retailers uncovered occasional substitution of look-alike plants for the labeled species, such as chamomile flowers of the genus Anthemis instead of Matricaria chamomilla, the former type associated with allergic reactions in some people.69 Whether accidental or deliberate, the mislabeling of medicinal plants poses potential health risks, and care should be taken to monitor this aspect of herbal quality.70

In recent years, academic and government investigators have tested the accuracy of herbal product labels by screening commercially available whole herbs and extracts using sensitive DNA-based technologies.71 These probes yielded data supporting the conclusion that some dietary supplements do not contain the advertised plant species and are instead composed of substituted plant material or fillers such as rice and wheat. While uncovering evidence of such inconsistencies calls into question the reliability of certain herbal product descriptions, it is worth noting that DNA-based techniques cannot adequately assess the origin of herbal extracts, whose source DNA is largely removed during manufacture. Instead, industry and university researchers recommend the testing of chemical content and microscopic analysis of plant material to assess the molecular makeup and botanical origin of commercial herbal products.72 Improved and standardized methodologies for monitoring the content of herbal supplements will be useful tools in the determination of product identity and the oversight of quality.

In addition to these concerns, some herbal products have been found contaminated by various chemical agents. For example, pesticides occasionally make their way into processed herbs, generally at very low levels.73 Heavy metals such as arsenic, lead, mercury, cadmium, and chromium have also been detected in some samples of raw herbs and products.74 Heavy-metal contamination may arise from the environment in which plants are grown or through processing. In some herbal medical traditions, certain heavy metals are considered medicinal and therefore added to the preparations before sale.75 It is also possible that herbs may be contaminated with microbes such as bacteria and yeast either before or after harvest.76 Together, these possible sources of contamination and adulteration can be addressed by improved agricultural and manufacturing processes, the enactment of stringent regulations or the enforcement of existing tolerances, and adherence to recognized standards of quality.77

Just as mixtures of pharmaceuticals, including plant-derived chemicals, can act together in a positive, synergistic fashion, they can interact in a way that poses risks to human health.78 Importantly, many such interactions cannot easily be predicted from laboratory studies that examine the effects of herbal extracts on isolated cells and tissues. On the contrary, by considering the complex pharmacological effects of medicinal plants, investigators are recognizing the role of the entire system on the absorption, distribution, metabolism, and excretion of their active constituents. As a result of such work, pharmacologists have discovered some risks associated with particular medicinal plants, whether taken in combination with other herbs or with synthetic drugs.

Interaction

A situation in which one drug interferes with another, often in a harmful way

A widely publicized interaction occurs between grapefruit (Citrus paradisi) and many prescription (synthetic) drugs, discovered when patients who drank grapefruit juice experienced signs of medication overdose. It was found that furanocoumarins in grapefruit juice inhibited the activity of metabolic enzymes in cells lining the intestine, allowing a far greater amount of drug to absorb into the bloodstream (figure 15.11).79 The enzymes blocked by grapefruit furanocoumarins are part of a large family called the cytochrome P450 (CYP) enzymes, expressed throughout the body and responsible for orchestrating much of the chemistry required for life. In the intestinal lining and liver, one of their principal roles is to break down foreign chemicals, such as herbal and synthetic drugs.

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FIGURE 15.11   6', 7'-dihydroxybergamottin, a furanocoumarin in grapefruit juice.

The effects of herbal products on CYP enzymes can lead to both elevated and reduced pharmacological activity. In contrast to grapefruit-juice furanocoumarins, which inhibit intestinal CYP, hyperforin from St. John’s wort (Hypericum perforatum) induces the expression of certain CYP enzymes in the intestine.80 In addition, hyperforin increases the activity of intestinal P-glycoprotein, a membrane channel that shuttles toxins from the body into the gastrointestinal tract.81 Through these actions, hyperforin increases the capacity of the human body to both break down and excrete drugs, and this has resulted in serious adverse events in patients taking St. John’s wort and prescription medication. For example, several instances of organ-transplant rejection have been attributed to concomitant use of St. John’s wort and immuno-suppressant drugs, and interactions are also known with heart medications such as foxglove-derived digoxin, blood lipid–lowering drugs such as atorvastatin, hormonal contraceptives, and many other pharmaceuticals. A recent analysis estimated that “more than 70% of all prescription medications are susceptible to [St. John’s wort]–mediated interactions.”82 Although much work remains to be done to identify possible herbal interactions involving CYP enzymes, several medicinal plants have been demonstrated to present such a risk, including the North American perennial goldenseal (Hydrastis canadensis) root and the medicinal berries of the East Asian Schisandra spp. vine.83 In addition to the CYP enzymes and P-glycoproteins, many physiological factors might influence drug absorption, distribution, metabolism, and excretion, and therefore more research is warranted to establish the safe parameters of herbal treatment.84

SUSTAINABILITY AND ETHICS

More than 2500 years ago, the people of the Greek city-state of Cyrene on the Mediterranean coast of North Africa harvested a medicinal sap from a local, wild type of fennel (Ferula spp.) they called silphion (figure 15.12).85 Aside from its great repute as a culinary flavoring, silphion was held to be a potent cough remedy and an effective oral contraceptive, among many health-related uses, so much so that it was one of the most valuable exports to cities throughout the dispersed Greek realm. Despite efforts to grow silphion elsewhere, to cultivate it for a more plentiful supply, the plant persisted only in the undomesticated state in a thin strip of land perhaps not much more than 175 kilometers in length, sandwiched between the inhospitable desert and the coastal farmlands in what is now Libya.86 As demand grew and wild resources dwindled, regulations were established to limit collection, but ultimately they were ineffective against the intense profit motive.87 The Roman natural historian Pliny the Elder (23–79) lamented, “Within the memory of the present generation, a single stalk is all that has ever been found [in Cyrene], and that was sent as a curiosity to the Emperor Nero.”88 Sometime in the first centuries of the new millennium, the esteemed medicinal plant silphion was harvested to extinction.

While some medicinal plants transition readily into cultivation, others resist domestication or require such an input of land, labor, and time that people find it disadvantageous to grow them. With silphion as an unfortunate precedent, the pressure of intensive harvesting of wild herbs has threatened entire plant populations. For example, government-sanctioned and illicit ginseng (Panax ginseng) collection in northeastern China nearly eliminated the species during imperial times.89 Likewise, North American ginseng (P. quinquefolius) has been threatened numerous times with local extinction because of both authorized digging and poaching in protected areas. Since wild ginseng is held to be more valuable than cultivated, diggers and merchants often take care to replenish the ginseng supply by replanting seeds where roots are removed, a conservation technique called wild crafting.90 Numerous medicinal plants are sourced exclusively in the wild, rendering them susceptible to overharvesting and threatened by urban and agricultural development.91 In addition to the careful stewardship of wild medicinal plants such as ginseng, black cohosh, and peyote (Lophophora williamsii), advances in biotechnology can be harnessed to protect native stands of valuable herbs.

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FIGURE 15.12   A gold coin from Cyrene, depicting a horseman on the obverse (left) and the silphion plant on the reverse (right), ca. 331–322 B.C.E. (Numismatica Ars Classica, auction 54, lot 893)

When the bark of the Pacific yew was found to contain a potent anticancer compound, some conservationists were justifiably concerned that existing forests might not be able to furnish enough material to meet the pharmaceutical needs. In time, these concerns were allayed with research demonstrating that chemical precursors could be isolated from leaves of a number of yew species, allowing a more sustainable approach to harvest and semisynthesis of the active drug agents.92 For industrial-scale production, the process has been made more efficient still, as pharmaceutical scientists have developed a method to propagate large quantities of cells in vats of culture medium and extract the desired chemicals directly, thereby circumventing any need to collect from whole plants. In the developing world, however, the infrastructure and financial resources for such technological solutions might not exist. Therefore, drug manufacturers resort to harvesting local populations of plants. As a result of such practices, the population of the Central Asian yew (Taxus contorta) is threatened.93

While targeted exploitation of medicinal plants exerts significant pressure on many species, the global impact of changing climate, human population growth, and runaway development will include the loss of herbs known to be medicinal and those whose properties have not yet been (or may never be) discovered. Estimates of imminent extinction reach mind-boggling levels. The organization Plantlife projected that 15,000 of the world’s 50,000 wild medicinal plants are at risk of extinction.94 Thirty percent of all plant species are in danger of being lost, according to scientists at Britain’s Royal Botanic Garden at Kew.95 The rich biodiversity of the tropics is especially pressured because of the replacement of forests with farmland, the encroachment of human settlements and livestock, the introduction of nonnative invasive species, and new weather patterns. In the temperate regions as well, habitat loss and other human-attributable forces imperil countless species.96

Declining biodiversity erases the work of millions of years of plant evolution. Many unique and complex chemical profiles may never be known to science. Some of the large-scale screening projects that sample plants more or less randomly and subject their extracts to tests of possible biological activity have reached perhaps only 60,000 species.97 Such screening programs, successful as they have been in identifying compounds such as paclitaxel, are never considered to rest as the final word on medicinal potential from the sampled plants. Indeed, plants sampled at different growth stages, specimens collected at different times of the year, and samples from different tissues are likely to present varying chemical repertoires. Taking into account also the many possible extraction techniques—using water, alcohol, organic solvents, and so on—any single species might render dozens of possible analytic units in terms of chemical profile. Furthermore, each isolate might be assayed in the laboratory against various models of cancer, virus infection, bacterial growth, diabetic conditions, and many more. In short, each lost plant species represents scores of experiments that can never be conducted and risks the permanent forfeiture of possible therapeutic agents against present and future diseases. Hundreds, and possibly thousands, of new drugs may never have a chance to be discovered.98 Protecting biodiversity includes the defense of resources that may be found to have therapeutic value in the future.

The urgency to protect the earth’s biological diversity is matched by the pressing need to preserve its cultural richness. As one indication of the loss of cultural diversity, it is estimated that 20 percent of the world’s languages have lost their last remaining native speakers since 1970, and many other languages hold on to just a few.99 About 90 percent of the world’s estimated 6000 languages are unlikely to survive the twenty-first century.100 Since human cultural diversity aligns geographically with plant and animal species richness, especially concentrated in the global band of the tropics, the decline of the world’s languages threatens a loss of tremendous medicinal plant knowledge.101 In regions with such biodiversity, indigenous peoples’ languages have evolved to express distinctions among plants learned over many generations, distinctions not evident to outsiders. For example, the influential ethnobotanist Richard Evans Schultes (1915–2001) relates that in the Colombian Amazon, native people have thirty words to describe natural variations in the ayahuasca vine, differences imperceptible to a foreign botanist. The “intensely thorough indigenous familiarity of the intricately meticulous individuality of species in one of the world’s richest floras,” Schultes wrote, demonstrates “the often hidden biodiversities [in] the forests.”102

The survival of indigenous languages is closely linked to the persistence and continued evolution of traditional knowledge about the environment and health. As the forces of acculturation advance, young people from tribal areas are increasingly drawn to a way of life in which information about useful plants and the skills to locate, cultivate, and prepare them are less salient. Seeking employment in multicultural towns and cities, adopting the predominant national and international languages, and frequenting clinics for health-related needs, recent generations are less likely to carry with them the traditional herbal knowledge of their ancestors. In many traditional societies, medical training consists of a young person’s apprenticeship under a practitioner possessing hereditary secret formulas and herbal techniques handed down orally and elaborated over the course of centuries. Without interested students to instruct, traditional doctors are sometimes finding themselves the last of their ancient medical lineage.103

One approach to preserve endangered medicinal plant knowledge is to document as fully as possible the information and practices associated with the roles of plants in a society. To do this, outside researchers and local collaborators are collecting inventories of plant names and cultural uses by people serving various medical needs in the community. They are using photography to record where the plants grow and how they are prepared for medicine and capturing videos of herbalists at work. By having a community’s long experiences with plants described and disseminated in academic publications, some aspects of its heritage can be made permanent against the forces of social change that might endanger it. Those projects perpetuating indigenous knowledge are more beneficial still. The recordings of expert plant specialists, donated to the source community, can help elders educate younger generations long after their passing. Maps, inventories, and guides prepared in collaboration with local people can serve as instructional aids. Academic, government, or industry outreach programs that generate revenue can be used to protect land and fund education in traditional herbal techniques among indigenous people.

Increasingly, programs to archive and prospect the traditional knowledge of indigenous people are undertaken within a framework of mutual benefit. Among the first to pursue this approach was the National Cancer Institute, which in the 1980s sought to collect tropical plant specimens for its large-scale bioassay screens. Before beginning its collection, it negotiated agreements with national governments to define the roles of foreign and domestic researchers and agencies in the collaboration and to establish an arrangement for the sharing of any revenues that might accrue from newly discovered products. The first such document was signed between the National Cancer Institute and the government of Madagascar in 1990, and numerous similar contracts have been developed since.104 One year earlier, an ethnobotanist working in a Samoan village established a compact with its chief and elders whereby the village received funds to support development of schools and protect the environment, even if the collaboration yielded no profitable drugs. A subsequent agreement to develop a novel potential antiviral compound identified from an indigenous hepatitis treatment stipulated the sharing of royalties among the government of Samoa, the village where the material had been collected, and the families of the village healers who had offered their knowledge.105

According to the Convention on Biological Diversity, an international agreement widely adopted after its signing in 1992, parties must uphold common standards toward the specified aims of conserving biological diversity, sustainable use of its components, and fair and equitable sharing of benefits.106 As nations assert sovereign rights to their natural resources, any research that might generate benefits, such as the study of potential medicinal plants, is subject to prior informed consent. That is, researchers wishing to conduct investigations in a particular country must first obtain an agreement on the nature of the work and, should discoveries be made, the way benefits are to be distributed. In practice, compliance with this principle raises many questions. With whom should an agreement be made? Do national governments represent the interests of all their people, including those of diverse ethnic groups? What is to be done if a national government has not established a procedure for making such agreements? Within the community of interest, who should represent the group in such discussions, and how should disputes be resolved? Certainly, the definition of “benefit” is complex and variable, encompassing tangible and intangible manifestations that differ culturally and on multiple time scales.107 For example, if some benefits of research are nonmonetary, how are they to be made equitable? As for the role of individuals with expertise in plant-based medicine, there is not yet consensus (and there might never be) on the appropriate sharing of benefit from indigenous common knowledge, secret knowledge, or community-held knowledge, for example.108

The convention and subsequent agreements provide a general framework for the conduct of responsible research and environmental stewardship. With so many more possible therapies yet to be found in the richly diverse but gravely threatened ecosystems on the earth, collaborations with those people who hold herbal lore can catalyze great benefit at many levels.109 Drawing on the expertise of a suite of academic disciplines, working among people and plants all over the world, medicinal plant researchers are improving our knowledge of herbs and their many roles in our planet’s cultures. To identify medicinal compounds, characterize their actions and interactions, work extends from ancient archives to culturally diverse communities and to the laboratory and clinic. Further study of medicinal plants will continue to follow the path of multidisciplinarity, helping address some of our greatest health challenges.