The characteristic stems of jointfir. Plants of the genus Ephedra produce the powerful stimulant drug ephedrine.
With the advent of scientific methodology during the twentieth century, it became possible to determine with greater certainty the causal relationships between medical treatment and perceived physiological effects. A new understanding of anatomy and biochemistry gave investigators the tools to assess how pharmaceuticals act in the human body. While traditional medical systems described the role of herbs in regulating the humors, directing qi, and so forth, the biomedical system seeks to establish how molecules and cells interact and influence health. The specific ways that medicinal plant constituents affect the body at the biochemical level—their mechanisms of action—are of great interest, as they form the basis of many modern-day therapies, suggest new avenues for pharmaceutical research, and elucidate how the body carries out its complex functions.
For many age-old herbal remedies, science has not yet established just how these treatments may work. While the scientific approach questions all claims of efficacy grounded solely in folk wisdom and philosophical dictates, it also provides a means to test whether therapeutic actions exist and to describe how they exert themselves physiologically. Applying the methods of science to traditional medicine can be challenging. To begin, the outcomes of therapy in traditional medicine and biomedicine can be difficult to align. For example, people of the indigenous North American Houma tribe in modern-day Louisiana employed a liquid made from the roots and bark of the coastal plain willow (Salix caroliniana) as a “blood medicine,” taken “for ‘feebleness’ due to thin blood.”1 It is unlikely that the Houma and biomedical practitioners have the same idea of how “thin blood” can be assessed, so any attempts to subject the coastal plain willow to laboratory testing would probably redefine “thin blood” as some measure of cell count or blood chemistry. Testing traditional herbs in a biomedical setting usually requires the investigator to reframe the health-related outcomes from the conceptual milieu of their historical, indigenous uses and expectations into objective laboratory assays involving cell counts, chemical analyses, heart rate, blood pressure, and the like. The process of redefining traditional and historical medical ideas in biomedical terms is fraught with potential biases and mistranslations, especially if researchers lack sufficient understanding of the cultural setting from which the idea comes.
Biomedical researchers working with traditional medicinal plants must also define the source, dose, and route of administration of the herbs they wish to test, and they must apply the material uniformly across many test subjects while delivering inactive treatments (placebo) to another set of subjects. This sort of experimental approach lends itself to strong inferences and is widely regarded as crucial to determining therapeutic efficacy. However, it cannot account for the way medicines are prepared in many traditional settings, where doses are formulated according to an individual patient’s symptoms and modified through the course of treatment. Furthermore, when researchers in different locations and at different times subject medicinal plants to testing, they frequently choose dosing schemes and delivery methods that do not match those of fellow workers, which results in a diverse set of experimental outcomes that are difficult to compare. Nevertheless, more than a century of laboratory research and decades of clinical study have demonstrated that many herbs long employed in medicine are efficacious by the standards of experimental science. For those herbs whose medicinal properties are purported, speculated, or held on faith but not demonstrated scientifically, future work will certainly attempt to resolve methodological differences between studies and ultimately establish whether they are effective in ways that can be measured and, if so, by what mechanism.
At the same time, it is possible that some plants valued in traditional medicine might never demonstrate therapeutic effects in well-designed experiments (figure 3.1). Undoubtedly, a great number of herbal remedies must derive a large part of their ascribed activities from the strength of the patient’s belief in the medicine.2
FIGURE 3.1 Some schools of traditional European medicine applied the Doctrine of Signatures to relate particular plants to the body parts for which they were thought effective. (Illustration from Michael Bernhard Valentini, Medicina Nov-Antiqua ; National Library of Medicine, A030218)
ACTIONS OF MEDICINAL PLANTS AND THEIR DERIVATIVES
Once a medicinal plant’s physiological effects are demonstrated, researchers attempt to identify the chemical component responsible for causing them; this component is termed the active principle. Ultimately, the goal of such work is to determine at the biochemical level how the active principle exerts its effects on the system.
A chemical responsible for the biological activity of a medicinal preparation
This approach to isolating pharmacological agents and establishing their mechanism of action is possible because of the chemical basis of life. All living things—from bacteria, to plants, to people—are composed of tiny atoms bonded together in particular ways to form molecules. While atoms of the element carbon are the most abundant components of biological molecules, atoms of oxygen, nitrogen, hydrogen, sulfur, and other elements also contribute, forming compounds—that is, molecules incorporating more than one type of atom (figure 3.2). Compounds can vary tremendously in size and complexity, and the ways that the atoms form together give them their unique properties in living systems (figure 3.3). Importantly, when atoms of carbon and those of other elements link together in compounds, they take on particular shapes that can interact with other molecules in a biological setting.
FIGURE 3.2 A structural formula (chemical diagram) conveys the spatial arrangement of atoms in a molecule. Atoms of carbon are represented as the points at the end of lines. The lines, usually either single or double, stand for chemical bonds. Other atoms are indicated by abbreviations: oxygen (O), hydrogen (H), and nitrogen (N): (left) molecule with four carbon atoms; (center) molecule with six carbon atoms in a ring; (right) compound with two carbon atoms and an alcohol (–OH) portion: ethanol (or fruit/grain alcohol).
Life depends on the specific interactions of molecules. For example, very large molecules called enzymes have three-dimensional shapes that match closely the shapes of other molecules on which they act. Because of their structural affinities, enzymes can bind to their target molecules and do their work, which often involves the transformation of the target molecule in some way; for instance, its shape may be changed, or it may have atoms added or removed. Enzymes in human tissues process molecules taken up in food into other molecules of a different form, molecules capable of delivering cellular energy, for instance. Enzymes can build up smaller molecules into larger and more complex forms or break down large molecules into simple ones. The activity of the body’s enzymes is called metabolism.
FIGURE 3.3 Molecular bonds occupy three-dimensional space, symbolized by triangular lines joining atoms. The two molecules pictured here are distinct because their –NH2 groups are attached at different angles.
Another example of a specific molecular interaction takes place in biological signaling. Microscopic chemical messages travel between cells and tissues in living systems, and these signals can influence development, growth, and behavior. For example, hormones are complex compounds that can circulate in the bloodstream and are perceived in cells having the appropriate receptors, which are relatively large molecules that reside either inside a cell or embedded in its outer membrane. Because hormones have a specific structure (spatial arrangement of atoms), they match up with the three-dimensional shape of their corresponding receptors. Some biochemists think of this relationship as analogous to pieces of a jigsaw puzzle that line up together precisely, or the exact fit of a key in a lock. The specific interaction (binding) of hormone to receptor can cause an array of effects inside the cell, including a change in expression of genes, movement, physiological changes, and so on.
Plants produce a large set of chemical compounds that support their own metabolism, growth, and development, compounds that enable them to convert sunlight into biological energy, reproduce, and serve their important ecological roles. Some plant molecules can also affect human health, and it is the work of pharmacologists to discover their mechanisms of action. Through their active principles, medicinal plants can exert a diverse array of effects on the body and psyche. Some plant-derived chemicals work by directly altering human metabolism or by mimicking hormones. Others specifically prevent the growth of harmful bacteria, fungi, or viruses in human tissues. Still others act on the nerve cells with a whole host of downstream effects. A theme common to the active principles of medicinal plants is that many of them function by binding to human receptors, initiating or blocking signals in the body, in a sense “tricking” the human body’s physiology to respond by circumventing or overpowering the normal, human-derived signal molecules. Still, many herbs appear to exert effects through their major chemical constituents, although by means thus far unknown. For those plants whose active principles have been identified but whose mechanisms of action have not yet been established, discoveries await. The following sections will explore some of the body’s systems in which plants and their constituents have been found useful.
CATEGORIES OF PLANT MEDICINAL COMPOUNDS
Plants produce an enormous diversity of chemical products. Some of them serve central roles in plant growth and development, such as enabling the photosynthetic processes that capture the sunlight’s energy to fuel metabolism and building the microscopic structures that sense the environment around them, to allow their roots to penetrate deeply into the soil below and their shoots to reach upward toward the light. Some molecules help support and protect plants, such as those that form the strong fibers of their cell walls and the waxes that coat their leaves. Others act as signals to communicate with nearby plants, bacteria, and fungi. In an age-old back-and-forth with the animal kingdom, evolution has also shaped the form of countless plant molecules that affect the fauna around them. Some compounds serve as attractants, such as the fragrance and color products of flowers that appeal to insect pollinators, or as repellents, such as the bitter-tasting chemicals that herbivores abhor. Some are poisons, honed to inconvenience an offending creature by paralyzing it, stopping its heart, disorienting it, or causing some other misfortune. Collectively, a single plant can produce many thousands of different chemicals, a profile that differs among roots, leaves, flowers, fruits, seeds, and so forth, and that depends on age, growing condition, and other factors. Some of these compounds may affect human health, and botanists, chemists, and physicians are working to understand their functions both in the plant and in the human body. Medicinal plant products are diverse in composition, size, and biological roles and can be classified into three groups.1
About 12,000 alkaloids have been inventoried in plants, many of which are of medical importance (figure B.1). They usually contain one or more atoms of nitrogen (N) as part of a ring structure. Alkaloids can accumulate in various parts of the plant, and some are synthesized in response to injury.
Most of the approximately 8000 phenolic compounds derive from biosynthetic pathways using phenol as a base unit (figure B.2). This class of compounds contains among the largest molecules in plants, including products with many repeating units of simpler structures. (When there are many phenol units in a molecule, it is called polyphenolic.) The phenolics include a diverse group of molecules with the flavonoid core structure, among them anthocyanins, proanthocyanidins, and isoflavones. Other types of phenolic compound are the coumarins and stilbenes. Many phenolic and polyphenolic molecules oxidize (often observed as turning brown) when exposed to air. Also, many are tannins—chemicals with the property of binding to protein.
There are over 25,000 terpenoids in plants, comprising a heterogeneous group of molecules that share a basic building block called isopentane (figure B.3). By joining together isopentane units in various configurations, adding or deleting chemical adornments, plants can generate these compounds, many of which may be found in the essential oil.
Other Types of Compounds
In addition to the alkaloids, phenolics, and terpenoids, medically active plant compounds can take many other forms. For example, there are numerous carbohydrates with health-related properties, including complex molecules forming gels, starches, and fibers, as well as the sugars in plants. There are also protein-based plant products that have effects on physiology, and many of the building blocks of proteins, amino acids, also play roles. Certainly, the numerous vitamins that plants provide are essential to human health and are of great interest to those studying herbal medicine and nutrition.
1. Rodney Croteau, Toni M. Kutchan, and Norman G. Lewis, “Natural Products (Secondary Metabolites),” in Biochemistry and Molecular Biology of Plants, ed. Bob B. Buchanan, Wilhelm Gruissem, and Russell L. Jones (Rockville, Md.: American Society of Plant Biologists, 2000), 1250–1318.
FIGURE B.1 Alkaloids contain atoms of nitrogen, often in a ring structure. Examples include nicotine, cocaine, and caffeine.
FIGURE B.2 Phenolics usually contain phenol or closely related components in their structure. Examples include resveratrol (a stilbene), epigallocatechin gallate (a flavonoid), and 8-methoxypsoralen (a coumarin).
FIGURE B.3 Terpenoids are produced from units of isopentane. Examples include menthol (a volatile oil), artemisinin, and Δ9-tetrahydrocannabinol, whose “tail” classifies it as a terpenoid.
PLANT CHEMISTRY IN THREE DIMENSIONS
The particular bonding arrangement of the atoms in a molecule determines how the chemical occupies three-dimensional space and, ultimately, how it interacts with structures that it encounters. The bonding of carbon atoms, nitrogen atoms, hydrogen atoms, and so forth is usually represented as schematic drawings including lines and letters. Much can be communicated in such structural formulas, and chemists are generally accustomed to this form of depiction. While such two-dimensional schematics have proved to be a useful shorthand, many of those working in the field of medicinal plant research also seek to visualize the important three-dimensional aspect of a molecule’s form (figures B.4 and B.5).
FIGURE B.4 Chemists have devised several methods to represent the arrangement of atoms in molecules. Taking the molecule caffeine as an example, its structure can be depicted in letters and lines (A), as colored balls joined by sticks (B), or in a computer-generated model of how its atoms occupy three-dimensional space (C).
FIGURE B.5 Three-dimensional models can lend insight into the function of active principles. While the human molecule anandamide (A, B, and C) and the cannabis-derived active principle Δ9-tetrahydrocannabinol (D, E, and F) are thought to act similarly in the brain, very little resemblance is apparent in their structures until they are modeled in three dimensions (C and F). The similar positions of the oxygen atoms (in red) and the carbon–hydrogen tails (protruding to the right) imply a common mechanism of action in the body.
Using computational methods, chemists can produce models of how physiologically active molecules likely occupy space in their microscopic cellular environments. Such informed predictions have given scientists special insight into the mechanism of action of countless plant-derived chemicals, as the shape of a molecule can suggest how it might interact with specific contours of the human biological machinery. Many physiologically active molecules exert their effects by binding to sensitive parts of human proteins. As a result of these interactions, some botanical chemicals can block enzymes or mimic the fit of a natural signaling molecule into a particular surface of a receptor, initiating a suite of responses.
In some cases, a three-dimensional appreciation of a chemical’s structure can be key to understanding its biological function. For example, scientists studying the effects of marihuana (Cannabis sativa) attributed many of its mind-altering properties to the interaction of the compound Δ9-tetrahydrocannabinol (THC) with a human receptor in the brain that had evolved to detect native brain-signaling molecules such as anandamide. Yet THC and anandamide bear little resemblance to each other in two-dimensional structural formulas. When visualized in three dimensions, however, it becomes clear that the molecules occupy space similarly, each protruding analogous bulges. This observation implies that the molecules may act very much alike, binding to the same cellular receptors by virtue of a shared portion of their three-dimensional structures.
The digestive system consists of the body’s apparatus to bite, chew, digest, absorb, and eliminate material ingested for sustenance. It is essentially a long muscular tube starting at the mouth, where food is taken in, and ending at the anus, through which waste passes. Various structures along this path perform critical roles in extracting nutrition from the diet. After swallowing, material enters the stomach, a highly acidic compartment, where enzymes and muscular activity substantially break down complex foods. The bolus of semidegraded organic materials enters the small intestine, where continued enzymatic activity further breaks down biomolecules, and nutrients pass into the bloodstream via the semipermeable intestine wall. The large intestine absorbs much of the remaining water from the contents, resulting in a thick paste of undigestible waste products that accumulate at the terminal end of the digestive canal: the colon and rectum. From there, the feces pass as stool.3 In cases of exposure to toxins or illness, muscular contractions of the stomach can lead to vomiting (emesis). Other disorders of digestion include overly loose or watery stool (diarrhea) and overly hard or difficult-to-pass stool (constipation).
In many parts of the world, people developed treatments that helped them expel the contents of their stomach and bowels, whether to draw up perceived unhealthy matter in vomit, rid themselves of their waste when constipated, or eliminate unwholesome internal substances as part of a medical ritual. For example, a well-documented aim of traditional medicine of the European pedigree is to regulate the balance of bodily humors by periodically vomiting and cleansing the bowels.4 Apothecaries produced herbal concoctions to ensure prompt emesis. In some cases, doctors recommended enemas to remove perceived toxins or overabundances from the body. Also in widespread practice was the use of laxative agents, which gently cause the feces to pass, and purgative agents, which do so violently. Within the framework of the humoral system, physicians treated a large number of ailments in this manner, the release of stool serving to allow the evils within to escape.
The ancient Egyptians were probably the first to document an arsenal of laxatives in the Ebers papyrus of around 1550 B.C.E. Among the most important is one still in use for this purpose: they chewed the oil from castor (Ricinus communis) seeds and consumed it with beer to procure a bowel movement.5 Ricinoleic acid, a component of castor oil, acts in the large intestine to reduce water resorption and triggers rhythmic muscle contractions (peristalsis) by binding to receptors on the intestinal lining (figure 3.4).6 Among the ancient Greeks and Romans, aloe served as a laxative, one of a large number of its medicinal uses. Aloe’s role in bowel motility is ascribed to the compound aloin, which accumulates in the plant’s yellow latex (but not in the leaf’s juice or gel). When eaten and passed through the digestive tract, aloin is activated by bacteria in the large intestine to form the chemical aloe-emodin. Aloe-emodin reduces the uptake of water by the colon and stimulates muscle contraction. Aloe latex was used for this purpose until modern times, although since 2002, the Food and Drug Administration has banned aloe as an ingredient in over-the-counter laxatives, safety data lacking.7
FIGURE 3.4 Castor oil has been used as a laxative for thousands of years. This humorous, early-twentieth-century postcard plays on its well-known physiological effects. (National Library of Medicine, A28757)
Whether for ritual purgation, as in traditional medicine, or to treat constipation, as frequently practiced in the modern day, plants produce a variety of compounds that strongly stimulate bowel motility. Europeans first learned of the purgative use of Alexandrian senna (S. alexandrina, also known as tinnevelly senna) from the Arabs during the ninth or tenth century.8 Plants of the genus Senna (and related Cassia) are widely distributed, and indigenous medical systems around the world have recognized the potent laxative nature of their leaves, stems, seeds, and roots. The young leaves of Alexandrian senna from North Africa are a primary source of the purified senna drug, sold commercially as Ex-Lax and Sennekot. Senna’s active compounds are sennoside A and B, which are acted on by bacteria in the colon to produce stimulatory agents.9
Buckthorns, such as the glossy buckthorn (Rhamnus frangula) of Europe, North Africa, and northern Asia and the North American cascara buckthorn (R. purshiana), also produce potent purgatives documented in traditional herbal medical practice.10 The American buckthorn bark was apparently more effective than that of the Old World species, and it was commercialized during the nineteenth century by American pharmaceutical firms and sold worldwide.11 Buckthorn stands in the northwestern United States and in Canada became threatened by overharvesting, and plantations were established beginning in the 1920s to maintain a supply of the drug.12 Much like other plant-based laxatives and purgatives, buckthorn’s frangulin A and B molecules are converted to the active emodin compound by intestinal bacteria. Along with aloe, the FDA has banned cascara buckthorn from over-the-counter laxative use.13 Aloe, buckthorn, senna, and other traditional laxatives such as Chinese rhubarb (Rheum spp.) act in the colon through similar mechanisms, as their active principles bear a close structural resemblance.14
Diarrhea can result from a variety of causative agents, including gastrointestinal infection, food poisoning, structural abnormalities, or metabolic defects. In cases of diarrhea caused by microbial infection (dysentery), herbal compounds that break up microorganism colonies may help alleviate symptoms and shorten the duration of the disease. In modern medicine, it is common to use natural microbial-derived or synthetic antibiotics to treat dysentery. In traditional health systems, people have used the astringent plant resins known medically as kino, often prepared from the stem exudates of trees.15 Kino contains complex plant chemicals called tannins that bind to biological molecules such as proteins and act as general antimicrobials and drying agents. (Tannins derive their name from their long use in the tanning process, which preserves and toughens animal skin to produce leather.) The bark of white oak (Quercus alba), among other oaks, contains about 10 percent tannin. Indigenous Americans used oak bark extensively against diarrhea. As European settlers moved across the continent, they too employed oak bark to alleviate dysentery.16
Plant-derived polyphenolic compounds that can bind to proteins and coat cell surfaces. They tend to be bitter and astringent.
In addition to the tannins, which are widely distributed among both woody and herbaceous plants, the peoples of Europe, Asia, and northern Africa historically used extracts of the poppy (Papaver somniferum) to treat diarrhea. The poppy compounds morphine and codeine slow the rate of intestinal peristalsis by binding to receptors on the nerves controlling the muscles that line the intestine. This allows more time for the intestine to absorb liquid from the stool. Because of the risk of addiction, it is now considered preferable to use the synthetic compound loperamide (sold as Imodium, and others), which acts similarly to the poppy’s active principles but without effects on the central nervous system at usual doses.17
In modern-day Western medicine, the induction of vomiting is generally restricted to emergency poison control or in cases of aversion therapy. In traditional medicine, however, emesis is sometimes utilized in medicinal cleansing rituals and to regulate the internal humors and other substances related to health. A great number of plants serve as emetics, and most are also highly poisonous. Therefore, the people who prepared them for therapeutic and spiritual uses must have developed great expertise in selecting the correct dose of such medicines. One of the best known emetic plants is the Brazilian native ipecacuanha (Carapichea ipecacuanha), whose roots can be boiled into a syrup known as ipecac (figure 3.5).18 The active principles emetine and cephaeline both irritate the lining of the stomach and stimulate the chemoreceptor trigger zone of the brain, which leads to vomiting. It was also discovered that emetine is toxic to the amoebic microorganisms responsible for some forms of dysentery. Along with these properties, ipecac can have unpleasant effects on a person’s nervous system and can alter the heartbeat, and for that reason its use has been discouraged since the 1990s.19
FIGURE 3.5 An eighteenth-century apothecary jar that once contained ipecacuanha root, a potent emetic. (Smithsonian Institution, National Museum of American History, 1991.0664)
One of the primary functions of the circulatory system is to maintain the flow of blood throughout the body in order to collect oxygen at the lungs and deliver it into the tissues. The blood circles in a closed loop, returning to the lungs to give up the waste product carbon dioxide formed by the body’s cells and release it via the lungs to the atmosphere. The blood also serves to distribute the nutrients gathered from digestion and as a conduit for the defensive immune system’s cells to reach sites of foreign invasion wherever they occur. Propelling the constant movement of blood is the muscular heart, composed of chambers separated by valves that prevent fluid from moving against the direction of flow. The blood is nearly always contained in vessels: the arteries, which transport blood away from the heart under pressure; ultrathin capillaries, which permeate the tissues and allow rapid nutrient exchange; and the veins, which allow blood to return to the heart.20 The cellular components of blood—the oxygen- and carbon dioxide–carrying red blood cells, the defensive white blood cells, and others—usually stay within the vessels. The liquid fraction of blood, plasma, can leak out of the thinner vessels as lymph and thus bathes the tissues in fluid. When tissue is injured, whole blood can escape from its vessels. It usually forms a clot, a dense network of blood cells and fibers that prevent further blood loss and allow the tissue slowly to heal.21
While the heart and blood have long been considered important in the world’s traditional and folk medicines, various historical and indigenous interpretations of the role of the heart, blood, and circulation are generally different from the biomedical understanding. In Chinese traditional medicine, for example, the Heart is considered to be yin in nature, the center of thought and emotion. (Heart is capitalized to distinguish the traditional Chinese term from the Western anatomical structure.) In classical European medicine, blood is one of the four critical humors. According to beliefs that held sway for centuries in Europe and beyond, illness could be remedied by bleeding a patient and allowing the body to regain its appropriate balance of humoral qualities. Despite an awareness of the heart’s structure and the existence of blood, Western physicians did not link anatomy with function until the seventeenth century, when the role of the heart in the circulation of blood through vessels was recognized.
PLANT CHEMISTRY IN THE ECOSYSTEM
While humans have been keen to exploit plants for their medicinal properties, many of the active chemicals that exert such potent effects in people evolved long before the advent of civilization. Fated to a stationary life under the sun, surrounded by all variety of creatures, plants at an early stage in their history developed the capacity to produce chemical compounds that contributed to survival in their diverse environments. Some of the chemicals now valued in medicine probably evolved to shield plants exposed to potentially harsh surroundings. Among certain plant lineages, chemicals came about that profoundly affected the behavior of creatures of all types, to the benefit of the plants. As active participants in complex ecosystems, plants employed their chemical capabilities in a way that helped them persist and thrive.1
Although plants need the sun to propel the life-sustaining process of photosynthesis, which converts carbon dioxide in the air into useful, energy-rich sugar molecules, the sun’s intense rays can actually damage plant tissues under some conditions. Many plants produce protective compounds that help guard their cells against such injury. For example, certain phenolics, such as the flavonoid kaempferol, are thought to protect against the ravages of ultraviolet radiation.2 As the energy transformations inherent to plant life can produce potentially dangerous chemicals called free radicals that tend to destroy delicate cellular structures, it is fitting that plant tissues generate a wide range of antioxidant compounds with the property of quenching free radicals.3 It is possible that the antioxidant properties of plant-derived chemicals might have similar protective effects in humans, which is why numerous studies have investigated their potential benefits against diseases in which free radicals are implicated.4
Plants also produce chemicals that can alter the behavior of, or even physically harm, animals. In general, plants are thought to accumulate toxic or repellent chemicals as a form of defense against herbivory.5 Certain alkaloid and polyphenolic compounds, for example, are thought to taste bitter to insects and mammals and to deter the creatures from making a meal of the plants that synthesize them.6 Meanwhile, some of the strongly scented and flavored terpenoid compounds, such as camphor, discourage herbivory by many animals.7 Beyond deterrence, a great number of plant-produced chemicals are toxic to insects or mammals, some especially affecting their nervous systems.8 For example, the pyrethrin terpenoid compounds produced by the Dalmatian chrysanthemum (Tanacetum cinerariifolium) are neurotoxic to insects but not to mammals or birds, an observation that has led to the development of naturally derived pesticides and synthetic analogs that are safe to use on food and around many noninsect animals.9 Strikingly, many alkaloid compounds exert especially potent effects on animals that ingest them. For instance, nicotine (in tobacco, Nicotiana spp.) can paralyze insects, probably by interfering with nervous system signaling.10 Cocaine (in coca, Erythroxylum spp.) and morphine (in poppy, Papaver spp.) are likewise thought to be toxic to the nervous systems of hungry pests. It is therefore not surprising that the synthesis of many defensive compounds is induced by damage to the plant tissue, such as might occur during insect or mammal feeding.11 Furthermore, plant compounds such as digitalis (in foxglove) can interfere with circulatory function in grazing animals, and hormone-mimicking chemicals can interrupt normal insect development.12
Since plants that accumulate more defensive poisons in their tissues tend to be better protected against the attacks of herbivores than plants with a lower concentration of these compounds, evolutionary forces would select plant lineages with increasing levels and potency of such chemicals.13 At the same time, animals whose diet includes these types of plants develop the physiological capacity to neutralize or sequester the potentially dangerous products, a phenomenon that can lead to further escalation of toxin levels in plants. This biochemical tit-for-tat between plant and herbivore species is a type of evolutionary arms race.14
In addition to producing toxic compounds that deter herbivory, plants can synthesize chemicals that attract beneficial animals. Numerous scent compounds and floral color patterns are associated with cues for pollination, and nectar acts as a reward for the service of the animals that carry pollen from one flower to another, assisting in perpetuating the plant species. Interestingly, some members of the Citrus and Coffea genera secrete a low level of the alkaloid caffeine in their nectar, which, rather than being toxic to insects, serves a useful role in pollination.15 The trace of caffeine seems to help insects remember where they obtained the nectar and encourages them to revisit the plant multiple times and spread its pollen more widely.
Among the diverse array of plant chemicals that protect against environmental threats and advance the species’ survival in the ecosystem are compounds that humans have found also to serve as medicines. By learning of their properties, manipulating the dose, and recording health-related outcomes, practitioners and researchers have transformed such naturally occurring chemicals into pharmaceuticals, a fascinating and unprecedented event in an ancient evolutionary story.
1. The evolution and ecological roles of numerous plant compounds are explored in David O. Kennedy, Plants and the Human Brain (Oxford: Oxford University Press, 2014).
2. Kaempferol protects against ultraviolet-B radiation. See Rodney Croteau, Toni M. Kutchan, and Norman G. Lewis, “Natural Products (Secondary Metabolites),” in Biochemistry and Molecular Biology of Plants, ed. Bob B. Buchanan, Wilhelm Gruissem, and Russell L. Jones (Rockville, Md.: American Society of Plant Biologists, 2000), 1303–1334.
3. Elizabeth A. Bray, Julia Bailey-Serres, and Elizabeth Weretilnik, “Responses to Abiotic Stresses,” in Biochemistry and Molecular Biology of Plants, ed. Buchanan, Gruissem, and Jones, 1189–1191. Plant antioxidant compounds include chemicals such as ascorbate (vitamin C), tocopherol (vitamin E), and certain terpenoids and polyphenols.
4. A sampling of such studies is reviewed in, among others, Daniele Del Rio et al., “Dietary (Poly)phenolics in Human Health: Structures, Bioavailability, and Evidence of Protective Effects Against Chronic Diseases,” Antioxidants and Redox Signaling 18 (2013): 1818–1892; and Christine M. Kaefer and John A. Milner, “The Role of Herbs and Spices in Cancer Prevention,” Journal of Nutritional Biochemistry 19 (2008): 347–361.
5. Peter Scott, Physiology and Behaviour of Plants (Chichester: Wiley, 2008), 243–251.
6. Croteau, Kutchan, and Lewis, “Natural Products,” 1274, 1303.
7. Jonathan Gershenzon and Rodney Croteau, “Terpenoids,” in Herbivores: Their Interactions with Secondary Plant Metabolites, 2nd ed., ed. Gerald A. Rosenthal and May R. Berenbaum (San Diego: Academic Press, 1991), 1:165–219.
8. David O. Kennedy and Emma L. Wightman, “Herbal Extracts and Phytochemicals: Plant Secondary Metabolites and the Enhancement of Human Brain Function,” Advances in Nutrition 2 (2011): 32–50.
9. Gershenzon and Croteau, “Terpenoids”; Walter Lewis and Memory P. F. Elvin-Lewis, Medical Botany: Plants Affecting Human Health (Hoboken, N.J.: Wiley, 2003), 597.
10. Thomas Hartmann, “Alkaloids,” in Herbivores, ed. Rosenthal and Berenbaum, 1:112–113; Anke Steppuhn et al., “Nicotine’s Defensive Function in Nature,” PLoS Biology 2 (2004): e217.
11. Croteau, Kutchan, and Lewis, “Natural Products,” 1272–1274.
12. Stephen B. Malcolm, “Cardenolide-Mediated Interactions Between Plants and Herbivores”; and M. Deane Bowers, “Iridioid Glycosides,” both in Herbivores, ed. Rosenthal and Berenbaum, 1:262–263, 275–278; 312–314.
13. Paul Feeny, “The Evolution of Chemical Ecology: Contributions from the Study of Herbivorous Insects,” in Herbivores: Their Interactions with Secondary Plant Metabolites, 2nd ed., ed. Gerald A. Rosenthal and May R. Berenbaum (San Diego: Academic Press, 1992), 2:1–44.
14. Judith X. Becerra, Koji Noge, and D. Lawrence Venable, “Macroevolutionary Chemical Escalation in an Ancient Plant–Herbivore Arms Race,” Proceedings of the National Academy of Sciences USA 106 (2009): 18062–18066. For a nuanced review of plant-herbivore interactions in evolution, see Douglas J. Futuyma and Anurag A. Agrawal, “Macroevolution and the Biological Diversity of Plants and Herbivores,” Proceedings of the National Academy of Sciences USA 106 (2009): 18054–18061.
15. G. A. Wright et al., “Caffeine in Floral Nectar Enhances a Pollinator’s Memory of Reward,” Science 339 (2013): 1202–1204.
Differences of mechanical understanding aside, traditional medicine identified a number of plants to treat a range of circulatory ailments. One such illness was a widespread condition known as hydrops or dropsy. Sufferers of dropsy accumulate fluid (a condition called edema) first in their extremities and finally throughout their bodies, puffing them like balloons and terminating in death (figure 3.6). Likely unaware that the condition was caused by a heart too weak to propel the return circulation of blood plasma (congestive heart failure), surgeons drained the swollen tissues by knife, which treated the symptoms but not the source of the illness.22 Folk medicine, though, had an herbal treatment, in preparations of the European native purple foxglove (Digitalis purpurea) plant (figure 3.7). It is not known who first harvested foxglove for this purpose or where in Europe it occurred, but it was likely employed as a remedy for circulatory problems for many hundreds of years before being recorded in medical texts. The herbalist John Gerard’s treatise of 1597 recommends foxglove “boiled in water or wine, and drunken” to “cut and consume the thicke toughnesse of grosse and slimie flegme and naughtie humours.”23 It is hard to tell whether this description is a reference to the symptoms of dropsy or of other conditions producing watery mucus. In any case, an application to dropsy was not universally recognized: like most texts of the era, another English herbal of 1666 recommends foxglove to cleanse wounds, heal sores, and as a purgative.24
FIGURE 3.6 A woman suffering from dropsy, with swollen belly and limbs. (Lithograph from Jean-Louis-Marie Alibert, Nosologie naturelle ; National Library of Medicine, A012332)
The English physician William Withering was the first to test doses of foxglove systematically on patients with dropsy, the results of which he published in 1785.25 Through this important work, Withering described the first cardiotonic agent, a drug that specifically strengthens the pumping action of the heart muscle, making it useful against congestive heart failure. By increasing blood flow, foxglove increases the amount of fluid removed via the kidneys (that is, it acts as a diuretic), reduces edema, and helps the heart overcome structural weaknesses.
FIGURE 3.7 Foxglove. (Woodcut from Rembert Dodoens, Histoire des plantes ; Wellcome Library, London, L0021131)
The active principles of foxglove are a group of related molecules called cardiac glycosides, which block the channels regulating the electrochemical state of heart muscle cells.26 One effect of this activity is the generation of increased pressure in the heart’s pumping ability. The principal cardiac glycosides are digoxin (figure 3.8) from the foxglove D. lanata, and the D. purpurea/D. lanata compounds digitoxin, lanatoside C, acetyldigitoxin, and deslanoside. Although digoxin remains widely prescribed in the United States and both digoxin and digitoxin are used abroad, in recent years new agents have been developed to treat congestive heart failure.27 Administration of digitalis must be undertaken carefully, since toxicity occurs just beyond the effective dose, resulting in irregular heartbeat.28
While the pumping action of the heart and muscular walls of the blood vessels ensure that the blood courses through its circulatory system under pressure, an excess of blood pressure (hypertension) or an insufficiency (hypotension) is considered a disease state. Extracts of the Indian snakeroot (Rauvolfia serpentina, also called serpentine wood and snakewood) and African poison devil’s pepper (R. vomitoria) contain the active principle reserpine, an important hypertension reducer employed during the twentieth century (see figures 3.8 and 3.9).29 Reserpine interferes with the transmission of nerve signals from the brain to the muscles lining the blood vessels, allowing them to relax and dilate.30 This action, combined with its depressive action in the vasomotor center of the brain, reduces blood pressure, which is accompanied by pupil constriction and a lowering of body temperature.31 Other side effects include depression, difficulty in concentration, and other psychological changes. Its use has declined since the late twentieth century because of its unpleasant side effects and with the development of more effective synthetic drugs.32
FIGURE 3.8 Plant-derived active principles that affect cardiovascular health: reserpine, from Indian snakeroot, among others; digoxin, from foxglove.
Vasopressors (drugs that can increase blood pressure) of plant origin include compounds from the genus Ephedra, such as ephedrine and pseudoephedrine, which increase the heart rate and constrict the blood vessels (figure 3.10). These compounds have numerous physiological effects, including the alteration of respiratory function.33
FIGURE 3.9 Rauvolfia leaves and fruits. Members of this genus produce the active principle reserpine, which can lower blood pressure.
Humans, like many animals, breathe to draw in fresh oxygenated air, which is necessary for cellular activities, and exhale to remove the metabolic waste gas carbon dioxide. The action of breathing is under both voluntary and involuntary control through the action of the diaphragm muscle, situated at the lower edge of the ribcage. Air enters the mouth or nostrils and passes through a cartilage-reinforced tube (trachea) that branches into two trunks (bronchi) in the chest cavity. The branches split several times over into a treelike series of increasingly smaller tubes (bronchioles) ending in membrane-thin air sacs (individual units called alveoli) where gas exchange takes place. The network of branched tubes and air sacs constitute the two lungs. The bronchioles have muscular walls that can constrict or expand the air passage.34 The nasal passages and bronchi also secrete mucus, which traps dust and potentially infectious particles before they can enter the deepest parts of the lungs.35 Diseases of the respiratory tract include overly constricted bronchial tree (asthma), inflamed bronchial tree (bronchitis), damage related to smoking or other inhalation hazards (for example, emphysema), and respiratory infections.
FIGURE 3.10 Jointfir compounds: ephedrine and pseudoephedrine.
Localized response to tissue damage or irritants, usually characterized by swelling and pain
A number of plants in traditional medicine serve to treat chest congestion, although few have been examined for efficacy in clinical studies, nor have mechanisms of action been determined. For example, indigenous people of the Pacific coast of North America such as the Chumash steeped the leaves of the yerba santa (Eriodictyon californicum) shrub to treat chest pain and other respiratory concerns.36 In South Asia, practitioners of traditional and folk medicine use roots and leaves of the Malabar nut tree (Justicia adhatoda) to treat various lung conditions.37 However, the medicinal properties of these plants have not yet been thoroughly studied experimentally.
In the case of excess mucus and respiratory irritation, some patients seek relief from the impulse to cough. Antitussives serve this purpose by suppressing the brain’s cough signals or by soothing the throat. Opium poppy–based drugs are used for the former, and a variety of cough syrups, powders, and teas are used for the latter. People of numerous eastern North American Indian tribes prepared hot-water infusions of cherry (Prunus serotina [black cherry] and P. virginiana [chokecherry]) bark as a cough medicine.38 The Cherokee taught early Appalachian settlers to chew the stem or brew a root tea of yellowroot (Xanthorhiza simplicissima) as a treatment for sore throat.39 In European traditional and folk medicine, a syrup of horehound (Marrubium vulgare) was valued against cough, sore throat, and asthma.40 The efficacy and mechanisms of action of these herbs have not yet been systematically tested.
Medicines that relax the smooth muscles lining the bronchioles, thereby allowing them to pass more air (bronchodilators), treat chronic and acute asthma and other conditions of poor respiration. A plant with a long history of use against these symptoms is the traditional Chinese medicinal herb ma huang (the jointfir Ephedra sinica), first mentioned in a medical text 2000 years ago.41 According to Chinese medicine, ma huang “disseminates and facilitates the Lung qi, calms wheezing, and stops coughing.”42 (Lung is capitalized to distinguish the traditional Chinese physiological element from the Western anatomical structure.) Related species of ephedra have similar properties, although species vary in their bioactive chemis-tries.43 In northern India and Pakistan, traditional medicine values the dried stems of Gerard jointfir (E. gerardiana) against asthma.44 The jointfirs contain chemicals that act as central nervous system stimulants by altering nerve cell communication and circulating hormones, tricking the body into a higher state of alertness and more rapid energy metabolism. The active principles ephedrine and pseudoephedrine are responsible for bronchodilation and increase blood pressure, with side effects of restlessness and insomnia (see figure 3.10).45 Because of these strong central effects, doctors and patients must take care in their use: the toxic dose is approximately 30 to 45 grams of plant material (a regular dose is in the range of 2 to 9 grams), which is equivalent to about 15 to 30 milligrams of the active principles.46 (Clinical preparations of ephedra consist of carefully measured doses of ephedrine.) Between the 1930s and the 1970s, ephedrine, delivered as a vapor by inhalation or swallowed as a tablet, was the leading biomedical treatment for asthma. It was made obsolete during the 1970s and 1980s by synthetic molecules with a more specific set of therapeutic actions and fewer side effects, but ephedrine and pseudoephedrine remain useful as nasal decongestants.47
Another class of bronchodilator drugs is based on the structure of the theophylline molecule from the tea (Camellia sinensis) plant. In cases of asthma and chronic obstructive pulmonary disease, inhaled theophylline can open the airways, probably by modulating specific signaling pathways inside the cells lining the bronchioles.48 Theophylline also acts as an anti-inflammatory agent via a separate mechanism, which can further ameliorate such breathing conditions. While theophylline is employed less frequently in the treatment of the airways in recent decades in favor of newer agents, it remains in wide use as part of combination therapy.49
Other distresses of the respiratory system originate as microbial infections, such as influenza, tuberculosis, the common cold, many forms of bronchitis, and viral and bacterial diseases that result in lung inflammation and the accumulation of liquid and pus (pneumonia). For cold and flu symptoms—such as nasal discharge, sore throat, low-grade fever, and chills—a variety of plants containing volatile oils seem to reduce the severity of illness. For example, the Ojibwa of the northern Great Lakes region heated the needles of balsam fir (Abies balsamea) over coals in sweat baths and inhaled the aromatic fumes to treat colds.50 A common folk remedy in much of the world involves herbal teas or lotions including mint (Mentha spp.), whose oil, menthol, serves as a soothing agent that gives the feeling of easier breathing in cases of respiratory discomfort (figure 3.11). The menthol molecule binds specifically to receptors in the nasal passage that signal the sensation of cool.51
FIGURE 3.11 Menthol, a volatile oil that produces a cooling sensation.
The potential antibiotic and antiviral properties of certain traditional herbals have been tested in the laboratory; however, the clinical trials conducted to date have not consistently demonstrated efficacy in patients. Efforts are ongoing to identify herbal compounds that boost immune system health, reduce the severity of the cold nuisance, and treat or prevent the flu.
The kidneys, a pair of organs located to either side of the spinal column in the lower back, regulate blood volume and chemical balance as well as excrete metabolic waste products and toxins. The excreted chemicals and fluid filtered from the blood (urine) travel through thin collecting tubes (ureters) to the bladder, where the urine is stored. During urination, urine travels through another tube, the urethra, and exits the body.52 As the urinary system is critical to the proper hydration state of the body and the removal of unhealthy substances, it has long been the target of medical treatment.
In medieval Europe, for example, examination of the urine was considered a key diagnostic aid to physicians, who believed that the health of a patient could be assessed by wisely interpreting its color and consistency.53 Therefore, it is not surprising that many plant-based medicines were selected for their effect—direct or indirect—on the urine. Chinese medicine employs numerous herbal treatments affecting the urinary system, such as tong cao (rice-paper plant [Tetrapanax papyrifer]), which is said to allay “urinary difficulty and dark urine due to damp-warm disorders,” according to the indigenous framework of health.54
One of the longest-standing uses of medicinal plants for the urinary system is to increase the quantity of urine by exerting a diuretic effect.55 Raising the urine volume can help ease the symptoms of high blood pressure and edema (such as associated with congestive heart disease) by reducing blood volume.56 Although dozens of diuretic herbs are catalogued by traditional medicine, their efficacy has generally not been tested in clinical trials, and their mechanisms of action are largely unknown.57 Certainly, some may function as stimulants that increase the rate of blood flow, and thus filtration, through the kidneys. Others may act in more specific ways, but these remain to be scientifically resolved.
For example, traditional European, Middle Eastern, and East Asian medicine employed dandelion (Taraxacum spp.) for a wide variety of therapeutic uses, including the improvement of urine flow.58 (The French, Italian, and English vernacular names for the plant—pissenlit, piscialetto, and piss-abed—tend to reinforce this folk idea.) However, very little experimental evidence for dandelion’s diuretic properties has been gathered.59 In contrast, a potent family of diuretics contains the xanthine chemicals produced by the coffee (Coffea arabica), tea, and cacao (Theobroma cacao) plants, whose activities have been well characterized.60
Bacterial infections of the urinary tract usually begin at the urethra and ascend toward the bladder. Extracts of cranberry (Vaccinium macrocarpon), blueberry (V. corymbosum), bilberry (V. myrtillus), and lingonberry (V. vitis-idaea) fruits are considered to have therapeutic benefit, although experimental evidence is mixed.61 The mechanism of action by which Vaccinium products either prevent or treat infections remains unclear. It is speculated that polyphenolic compounds in these fruits interfere with the adherence of pathogenic bacteria to the walls of the urethra and bladder.62 Bacteria then are washed out in the urine.
The male reproductive system consists of two testes, which produce the reproductive sperm cells, and a suite of accessory glands that manufacture the seminal fluid. During intercourse, the penis engorges with blood, becomes rigid, and releases semen into the female vagina. Only a small number of sperm cells reach an “egg cell” (ovum), one of which may penetrate into the cell, resulting in conception (fertilization). The male reproductive system is regulated by the nervous system and by male sex hormones, including testosterone.63
The prostate is an organ located under the urinary bladder and surrounding the urethra in the lower abdomen. It serves a role in the production of seminal fluid and can become enlarged as men age (the noncancerous condition benign prostatic hyperplasia), which sometimes leads to painful, intermittent urination.64 During the nineteenth century, American herbal practitioners harvested the fruit of the North American saw palmetto (Serenoa repens), a shrub native to the southeastern United States (figure 3.12). They used the fruit dried, in a tea, and in other forms to treat a variety of male reproductive system ailments, including the characteristic urination symptoms of an enlarged prostate.65 In modern times, manufacturers have produced capsules containing fat-soluble fruit extract and whole fruit that are thought to contain a potent array of compounds capable of treating benign prostatic hyperplasia. However, a recent review of clinical evidence concluded that under the conditions tested in clinical trials, saw palmetto extract is not more effective than placebo for the treatment of urinary symptoms associated with benign prostatic hyperplasia.66 Although saw palmetto does not appear to improve symptoms in men with enlarged prostate, a mechanism of action has been speculated. While the male sex hormone dihydrotestosterone promotes prostate enlargement, various fat-soluble compounds in the plant are thought to interfere with an enzyme that produces dihydrotestosterone from its precursor, testosterone.67
FIGURE 3.12 Saw palmetto: (left) plant; (right) dried berries. Evidence for its effect on male reproductive health is mixed.
The central and southern African stinkwood (Prunus africana, also called African cherry and pygeum) is widely used in the medical practices of indigenous people for a variety of health concerns, including as a remedy for witchcraft, treatment for stomachache and intestinal parasites, and for male and female sexual health.68 Since the mid-twentieth century, stinkwood bark and bark extracts have been used outside Africa to treat benign prostatic hyperplasia, particularly in Europe. Clinical evidence is gathering that the herb modestly reduces the severity of urinary symptoms in men with enlarged prostate.69 However, the mechanism of action is not yet clear. Perhaps it acts by blocking the prostate’s response to dihydrotestosterone, possibly together with other effects on inflammation and cell proliferation.70
The female reproductive system is composed of a pair of ovaries that alternate in the release of an ovum monthly, in response to regular hormonal fluctuations, and the apparatus to nurture a fertilized ovum through the development and birth of a child. The egg, once released, descends one of the narrow uterine (fallopian) tubes into the womb (uterus), where, if fertilized by a sperm, it implants into the uterine wall and rapidly develops. If not fertilized, the ovum and the uterine lining are shed (menstruation) through the vagina. At term, the fetus is delivered by muscular contractions of the uterus. The monthly hormonal changes that govern the female reproductive cycle are attributable to the activities of the ovaries and reproductive control regions in the brain.71
Since the earliest known times, women have sought pharmaceutical means to improve their fertility, on the one hand, and prevent conception or terminate a pregnancy, on the other. For example, the traditional Chinese medicine ai ye (leaf of the mugwort Artemisia argyi) is an ancient treatment for irregular menstruation and infertility.72 Meanwhile, the author of the Egyptian Ebers papyrus (ca. 1550 B.C.E.) prescribed the following recipe to induce abortion: “dates, onions, and the fruit-of-the-Acanthus” (Phoenix spp. palm fruit, Allium cepa bulb, Acanthus spp.), crushed with honey and applied to the genitals.73 For many centuries in Europe, pennyroyal (Mentha pulegium) has been considered effective to bring about menstruation in women whose periods are delayed, perhaps even those delayed by pregnancy.74 As the seventeenth-century English herbalist John Parkinson relayed, a pennyroyal tea “provoketh womens monthly courses [and] expelleth the dead child and afterbirth.”75 Other medicinal plants have been used to improve the outcomes of pregnancy and expedite labor. For example, in Central Africa, Cameroonian midwives prepare the fresh leaves of Vernonia guineensis (also known as Baccharoides guineensis) to ease delivery, among many other uses of the plant.76 These are just a small number of the hundreds of fertility-related traditional medicinals identified over thousands of years around the world. What remains unknown is their safety and efficacy. Furthermore, their mechanisms of action—if truly active as ascribed—have not yet been demonstrated. Therefore, the following examples consider medicines for which some evidence exists.
The chaste tree (Vitex agnus-castus), native to the Mediterranean region, has long been regarded as an important medicinal plant for the female reproductive system, employed in ancient times to treat discomfort of the uterus and promote menstruation (figure 3.13).77 Furthermore, it also has documented use in preventing male and female sexual desire, from which it derives its English name.78 In the late sixteenth century, Gerard wrote that chaste tree leaves are “a singular medicine and remedie for such as would willingly live chaste,” preventing “all desire to the flesh.”79 The chaste tree’s dry fruits were once called “monk’s pepper,” in reference to their role in helping medieval monks maintain their vows of celibacy.80 In modern times, chaste tree fruits or chemical extracts have been used to treat a range of menstrual concerns, such as irregular menstruation, pain, breast tenderness, and symptoms associated with menopause.81 Recently, some of the present-day uses have been subjected to clinical testing. Although studies vary in size and quality of design, treatment with chaste tree fruit extract has largely been demonstrated effective against symptoms of premenstrual syndrome, premenstrual dysphoric disorder, and other measures of discomfort.82 Current models suggest that chaste tree compounds bind to specific receptors for signaling molecules involved in pain and stress, thereby alleviating the anxiety and discomfort associated with the condition.83 Chaste tree’s roles in suppressing sexual desire and regulating menstruation remain to be validated in the laboratory and clinic.
FIGURE 3.13 Chaste tree flowers and leaves.
Given the long-standing human interest in sex for procreation and pleasure, it is not surprising that some of the oldest medicines claim to improve sexual ability or desire. Aphrodisiacs comprise treatments to increase libido or enhance performance. Some of the herbs associated with this use, such as poppy, seem to function not as specific agents to enhance the sex drive but by reducing inhibitions and lowering tactile sensitivity. Other treatments, such as plants containing strong stimulants, including cocaine, from coca (Erythroxylum coca), and caffeine, from a variety of plant sources, may have some general effect on sexuality by improving alertness and increasing blood flow throughout the body. Many of these substances produce pleasurable feelings that might be enhanced by sex.
In some cases, there is gathering evidence for the roles of certain traditional herbal medicines as aphrodisiacs. West African folk medicine employs the bark of the yohimbe (Pausinystalia johimbe) tree as an aphrodisiac.84 Studies in animals indicate that yohimbe extracts increase sexual activity, although human research has been troubled with poor experimental design.85 With mixed results, recent trials have shown some possible clinical efficacy in treating impotence (erectile dysfunction).86 Yohimbe’s active compound, the alkaloid yohimbine, alters the nervous system’s regulation of blood flow in the body, probably improving erection to some degree through secondary effects.87
The early traditional Chinese texts recognized value in the aerial portions of yin yang huo (Epimedium spp.), which often goes by the loose English translation “horny goat weed” (figure 3.14). About 2000 years ago, the medical texts declared that this herb “governs impotence, infertility, pain in the penis, facilitates urination, [and] augments the power of qi.”88 Numerous Chinese materia medica prescribe its use for male sexual dysfunction, and even its name dates to the fifth century in Sichuan province, when writers noted that livestock that ate this plant copulated frequently.89 While studies involving rats demonstrate the effectiveness of Epimedium extracts in causing erections, well-designed human trials have not yet been conducted.90 Some of the therapeutic value, if it is found to exist, might come from the dozens of compounds that structurally mimic the animal sex hormones estrogen and testosterone. By binding to receptors for these hormones in the body, it is possible that Epimedium constituents may alter sexual development and response. However, the precise mechanisms have not been determined.91 In addition to hormone-like molecules, the plant produces the phenolic compound icariin, which in laboratory studies appears to inhibit the constriction of blood vessels in the penis, facilitating erection.92 With centuries of plant-related knowledge documented in ancient texts and perpetuated in the medicines of many cultures, there will no doubt be ongoing interest in examining the clinical effectiveness and mechanisms of action of traditional aphrodisiacs.
FIGURE 3.14 Horny goat weed, native to Asia and speculated to improve male sexual performance.
The skeleton is a living structure composed of cells and their calcium-rich matrix, making bones stiff and supportive. They are the base of attachment for the muscle fibers that allow the body to move. The muscles are supplied with blood to provide the sugars and oxygen that fuel their contraction and relaxation. The three types of muscle fibers—skeletal, smooth, and cardiac—are structurally and functionally distinct. Skeletal muscle is attached to the bones and generally under conscious control by nerve fibers originating in the brain. Smooth muscle, which lines the gastrointestinal tract and other organs, and cardiac muscle, the tissue of the heart, are under unconscious control. The nerve fibers signal muscle contraction by releasing the neurotransmitter-signaling molecule acetylcholine at the nerve–muscle junction, which triggers an electrical change in the muscle fiber and ultimately causes it to tighten or contract.93
FIGURE 3.15 Curare: (left) a group of hunters, photographed in the late nineteenth century in the Brazilian Amazon, carrying weapons tipped with curare poison; (right) tubocurarine, an active principle of curare poison. ([left] Library of Congress, Prints and Photographs Division, LC-USZ62-83657).
The muscles normally respond to the neural signals that induce their movement, but interfering pharmacological agents can block this and paralyze the body. Several South American tribes recognized this phenomenon long ago and developed toxic plant mixtures with which to tip their hunting spears or darts. When stalking animal prey, people such as the Achuar, Huambisa, and Aguaruna in Amazonian Ecuador and Peru have used poison-tipped weapons to immobilize and eventually kill small animals by means of respiratory failure (figure 3.15). The poison, called curare, is usually prepared as a mixture of many plant extracts.94 The most commonly used plants are of the genera Strychnos, Curarea, and the curare vine (Chondrodendron tomentosum). The poison applied to blow darts and used to such deadly effect includes the active principle of C. tomentosum, the alkaloid compound tubocurarine.95 Once injected into the blood and distributed to muscle tissues, molecules of this chemical bind to the skeletal muscle fiber’s nicotinic acetylcholine receptors, blocking the transmission of signals from the brain. The muscles affected by curare are unable to contract, resulting in paralysis that spreads slowly from the site of injection to the entire body. As the curare toxins are poisonous only at the muscle–nerve junction, game felled in this manner is safe to consume.
During the twentieth century, the application of tubocurarine to medicine allowed tremendous advances in surgery. Prior to the advent of tubocurarine, surgeons used high doses of agents such as ether and chloroform to induce a deep anesthesia in their patients and prevent reflexive muscle twitching that might hinder the operation. However, such strong anesthesia carried a significant risk of death. By administering controlled doses of tubocurarine to their patients, surgeons beginning in the 1940s were able to procure a safer “balanced anesthesia,” one where the dose of anesthetic is low and the patient’s muscles are relaxed, prevented from spasms, by the neuromuscular block.96 In the 1980s, pharmaceutical firms introduced the synthetic compounds atracurium and vecuronium, which are widely used today and serve the same function as the natural tubocurarine.97
Damage or strain in the body’s tissues is transmitted back to the brain through a series of molecular signaling events subjectively perceived as discomfort or pain. Painful, chronic disorders of the bones, ligaments, tendons, and muscle (rheumatism), including inflammation and pain in the joints (arthritis), are among the most common diseases to strike an aging population.98 Undoubtedly, people long ago suffered from these ailments and found plants to ease their discomfort. In Chinese traditional medicine, the symptoms of arthritis are attributed to the cold and damp properties of nature, causing obstruction of the qi channels and undernourishment of the joints.99 Numerous herbs are employed to counter the cold and moist aspects of the patient and to improve the movement of qi.
In South Asia, the shrublike tree guggul (Commiphora wightii) produces a gum resin that has long been used in medicine to treat a wide variety of concerns, including the pain and swelling characteristic of rheumatism.100 While human trials have not yet demonstrated the efficacy of guggul for these conditions, laboratory research lends support to the notion that constituents of this age-old remedy might act at the molecular level to reduce inflammation.101
One of the more useful medicines to treat pain is a substance that itself, paradoxically, causes pain. The heat of the American native chili pepper (Capsicum annuum) is attributable to the compound capsaicin, which binds and activates pain receptors in the skin (figure 3.16).102 It has a particularly harsh effect on the mucous membranes of the mouth, nose, and eyes, which is why people chopping peppers for cooking must be careful not to touch sensitive areas without having thoroughly washed their hands. When used in a topical patch on the skin above a muscle or joint, capsaicin binds to the tissue pain receptors and dampens pain signals sent to the brain, thus reducing the sensation of discomfort.103 Medicinal preparations contain approximately 0.075 percent capsaicin, sometimes in concert with other pain- and inflammation-reducing drugs.104
FIGURE 3.16 Capsaicin, a compound from chili pepper that activates pain receptors.
IMMUNE SYSTEM AND INFECTIOUS DISEASE
The body’s natural defenses against infections include the skin and mucous membranes, which act as a physical barrier to potentially harmful microbes; various secretions of the body, such as mucus and tears, which can trap and disable infective agents; and the immune system, an active cellular system that attacks infections inside the body. The immune system functions by allowing specialized cells to circulate throughout the body, identify invading microbes (such as bacteria, fungi, or viruses) or chemicals (such as proteins or particles), and selectively destroy the foreign material.105 If the immune system prevents illness by resisting the harmful agent before it can exert effects or spread in the body, the response is called immunity. When the system is unable to control the growth or spread of the microbe, the result is infectious disease. When the system mounts an inappropriately strong response to a foreign substance, the effect is allergy. Cases of allergy can range from mild swelling and localized irritation of tissues to severe swelling and loss of blood pressure, a dangerous, incapacitating condition called anaphylaxis.106
Infectious disease agents (pathogens)
Simple single-celled organisms
Yeasts and multicellular organisms related to mushrooms
Single-celled organisms of complex structure
Nonliving particles with genetic instructions to infect living cells and replicate
Since all these pathogens are very small, they are considered microorganisms, or microbes. Although viruses are not technically organisms, they are still loosely grouped with other pathogens.
The immune system derives from specialized cells whose role is to recognize, via cell-surface proteins, a wide variety of human and nonhuman substances. They can then identify foreign materials in the body and eliminate them. During early development, the body produces millions of lymphocytes (one class of specialized immune cells) that have cell-surface proteins of a wide variety of shapes. The cell-surface proteins act as sensors for a nearly unlimited number of molecules. On the one hand, the body uses these cell-surface proteins to learn which molecules are “self,” belonging to the body that produced them. That way, the body’s immune system does not mount a protective reaction against its own tissues. (When this safeguard fails, a self-destructive autoimmune disease results.) On the other hand, the immune system can recognize a tremendous variety of potentially pathogenic agents and target them specifically for destruction.
The sensor proteins capable of identifying foreign substances, called antibodies, also circulate freely in the bloodstream. When the body experiences the invasion of a microbe, for example, specialized antibodies bind to parts of the microbe and serve as flags to beckon phagocytes, the cells that engulf and remove the foreign object. Pharmaceutical agents can enhance or inhibit the ability of these systems to function, altering the body’s responses to self- or non-self-structures in the body.
Through most of history, people had no microbial and immunological explanation for infectious disease. Instead, traditional medicine attributed such illnesses to the natural properties of the environment, temperament, and diverse supernatural origins. Regardless of the cause, people facing infections sought treatments, many of them plant-based. For example, medieval Europeans considered leprosy (now called Hansen’s disease, known to be caused by the bacterial pathogen Mycobacterium leprae) to result from moral decay or wickedness.107 While prayer and virtuous living were certainly part of the prescription, herbalists such as Gerard offered plants including dodder (Cuscuta spp.) and black hellebore (the author suggests both black hellebore [Helleborus niger] and false black hellebore [Veratrum nigrum]).108 It is now possible to investigate such herbs in the laboratory and clinic.
FIGURE 3.17 Purple coneflower, which may improve immune system function.
North American Plains Indians employed a native herbaceous plant, the purple coneflower (Echinacea purpurea, and also E. angustifolia and E. pallida), for a wide variety of purposes (figure 3.17).109 They chewed the roots to treat toothache and sore gums and applied the leaves and juice externally for burns and snakebite. The Sioux were known to have used the plant to reduce the sores of syphilis, caused by a bacterium. The Crow tribe of Montana and eastern Wyoming harvested the purple coneflower to treat the common cold, a viral infection.110 It was white settlers who picked up on the native use of the plant against infection, and by the late nineteenth century, purple coneflower was a mainstream herbal remedy.111 During the mid-twentieth century, purple coneflower extracts for injection were sold in Europe under the name Echinacin, supposedly effective against infections and cancer.112 Today, purple coneflower is widely available in the United States as a dietary supplement in various forms of liquid extract and capsules, suggested to boost resistance to the common cold and other respiratory infections.
Experiments in the laboratory have established a wide spectrum of possible activity. Using various types of extracts and test conditions, researchers have found that constituents of purple coneflower may activate phagocytes, suppress the inflammatory response to infection, and kill bacteria and viruses directly.113 However, active principles have not yet been identified. Numerous human studies have attempted to test whether purple coneflower extracts improve immune system function or reduce the intensity or duration of infections such as the common cold. Most suffer from problematic experimental design, including nonstandardized extracts or dosing schemes and reliance on small numbers of patients. An analysis of several purple coneflower experiments showed enormous diversity in the type of coneflower extract used, the presence of concomitant supplements, the outcome measures, the duration of the experiment, and the size of the experimental groups.114 The support for purple coneflower’s activity in boosting the immune system and fighting respiratory disease remains anecdotal and the scientific evidence mixed. The medical consensus is that purple coneflower extracts are neither helpful nor harmful to patients wishing to reduce the incidence and duration of infection.
An herb long employed in European and Asian medicine, licorice (Glycyrrhiza spp.) has been used to treat wounds, diabetes, cough, stomachache, digestive ailments, and sexual concerns, among other health matters (figure 3.18).115 Traditional Chinese medicine uses the root for a wide variety of symptoms, viewing it as a moderator of many other herbs when formulated together as a mixture. As the most commonly used plant in the Chinese materia medica, it is not surprising that it would be applied for coughs and infection among so many other ailments.116 Some laboratory studies support the notion that the sweet-tasting terpenoid compound glycyrrhizin and its derivatives from licorice can reduce the severity of viral infections, including those targeting the respiratory tract, skin, and liver. The mechanism of action appears in these studies to be a combination of reduction of the virus’s ability to bind to and infect cells as well as the stimulation of the body’s immune defenses.117 Despite a long history of use and some bioactivity observable in the laboratory, therapy by licorice root extract has not yet been thoroughly demonstrated through clinical trials.
FIGURE 3.18 Licorice flowers. Licorice has a long history in Asian and European medicine.
It is evident that many plants have traditional uses as broadly described immunomodulators that somehow boost the body’s defenses against infectious agents. Some proponents of such herbs might not be concerned with the mechanisms by which they improve natural resistance, but scientific evidence will be required before these plants and their constituents gain wider use through biomedical health-care channels. There have not been any herbal compounds yet identified that can specifically improve the ability of phagocytes to attack invading microbes or the propensity of antibodies to flag their targets for destruction. However, the antibody-producing cells and phagocytes themselves are responsive to the overall level of physical or emotional stress, which can suppress the immune system. Perhaps it is through the modulation of stress that some herbal immune stimulants function. Whether through physical or psychological means (that is, direct cellular effect or placebo effect), plant medicines may reduce the anxiety associated with illness and thereby allow an improved immune response.118 Herbs reported to promote the body’s ability to cope with stress are termed adaptogens.119
In contrast to plants without strong clinical support for immune system function, there are many herbal components with antimicrobial and antiparasitic functions. While most modern pharmaceutical antibiotics (drugs primarily targeting bacteria) are fungal or bacterial in origin, some plants produce compounds that may be useful to combat such infections. However, the use of plants as specific antibiotic agents remains limited. Numerous traditional uses of plants include broad anti-inflammatory, antioxidant, and analgesic functions, but the technical challenges to identifying single antimicrobial agents in complex botanical chemical mixtures have meant that few plant-derived “penicillins” have emerged. Moreover, many of the antimicrobial plant compounds consist of volatile oils and agents that are generally (rather than specifically) toxic to cells, such as those of billy-goat weed (Ageratum conyzoides, also known as tropical whiteweed) or the noxious antibacterial sulfur-containing compounds of onion and garlic (Allium cepa and A. sativum).120
Although malaria was once thought to originate from the unwholesome influence of a moist, foul environment (mala aria [bad air]), it is now known that the disease is microbial in origin. Malaria, which remains a significant threat in the tropics, is caused by a mosquito-borne Plasmodium parasite that infects the human victim’s liver and blood, replicating and causing often-fatal fever and anemia. Yet long before the advent of biomedicine, traditional medicine identified a host of active agents that combat this ailment. The most renowned of these is the Peruvian fever tree (Cinchona spp.), native to tropical South America. This plant produces the alkaloid quinine in its bark and is effective against the parasites responsible for malaria. The medicinal use of fever tree bark extract became known to Europeans following their sixteenth-century conquest of South America and soon served as an important pharmaceutical shield to missionaries and explorers wishing to protect themselves from malaria as well as to those facing its characteristic intermittent fevers in Europe. The active principle quinine was isolated in the early nineteenth century, and commercial production rapidly destroyed the native fever tree stands. Breeding programs were established to increase the quinine yield from 4 percent to more than 13 percent of bark, which maintained a steady plantation-derived supply of quinine into the early twentieth century.121 Chemists synthesized quinine-like compounds, such as chloroquine and quinacrine, beginning in the 1930s, which allowed for a greater supply of drug to treat the millions living under malarial peril (figure 3.19). As much of the Plasmodium parasite threatening the tropics has become resistant to chloroquine, the original quinine has again been advanced for malaria treatment.122
Fever tree bark influenced European history in a significant way by serving the military and economic expansion of France, Britain, Holland, and Spain during the seventeenth through twentieth centuries. As these powers brought tropical territories in the Americas, Africa, and Asia under their control, they did so with the protective medicine quinine coursing through their veins. It is no wonder that the nineteenth-century British military forces added quinine to their tonic water during the conquest of India—drinking it with gin to create a medicinal cocktail. The quinine molecule and modern synthetics based on its structure are toxic to the parasite reproducing in human red blood cells. While quinine does not protect a person from becoming infected by the parasite, the drug does halt the organism’s replication and maturation, limiting the development of symptoms and spread of infection. Quinine and its analogs have some degree of toxicity in the human body, experienced as nausea, thought disturbances, and other effects. However, the side effects are generally considered mild and balanced by the benefit of malaria protection.
FIGURE 3.19 Antimalarial active principles and synthetic derivatives: the natural alkaloid quinine, from trees of the genus Cinchona; the synthetic chloroquine; the synthetic primaquine; the natural terpenoid artemisinin, from sweet wormwood.
Asia has its traditional antimalarial as well: the sweet wormwood (Artemisia annua), native to temperate Asia and described in Chinese herbals more than two millennia ago.123 In Chinese medicine, the herb is known as qinghao and is used against the intermittent fevers associated with malaria. Its terpenoid active principle, artemisinin, is particularly valued in areas where the Plasmodium parasites have become resistant to quinine-based medications (see figure 3.19). Artemisinin is toxic to Plasmodium maturing in the red blood cells and highly effective in resolving a patient’s symptoms and reducing the transmission potential of an infection.124 Although resistance is also developing against artemisinin and its derivatives, it remains largely effective when used as part of combination therapy.125
The world’s traditional medicines include countless herbs thought to treat illnesses and promote good health. Although people have assigned varying roles to the body’s systems and attributed ailments to diverse causes, the collective experiences of so many have yielded a wealth of plants potentially useful in biomedicine. Armed with the methods of clinical trials, researchers can determine whether a treatment causes its purported effects. Employing the laboratory techniques of chemistry and biology, scientists can decipher how plants’ active principles interact at the molecular level with targets in the body. While many plant-derived compounds have entered the Western biomedical pharmacopeia, a great number of plants’ uses remain to be subjected to testing. The results of such efforts yield a better understanding of historical and traditional plant uses as well as biochemical agents that can be harnessed against some of the most challenging health concerns that humans face. Importantly, by elucidating the molecular mechanisms of action of herbal agents, investigators are able to decipher much about the workings of the human body. These efforts are perhaps most advanced in the study of the brain and nervous system, where plant-derived chemicals enabled progress in unraveling the molecular and anatomical basis of sensation, perception, and behavior.