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A New Look at Botanical Medicine

BOTANY and medicine have been the closest of friends and the most distant of strangers. Two hundred years ago, anyone be a physician had to study botany, because most medical prescriptions were made from plants. Today it is unheard of for premedical students to major in botany, and interactions between the two fields are minimal. Yet drugs of plant origin still account for a respectable percentage of doctors' prescriptions, and for a number of reasons, research interest in natural pharmaceuticals is again on the upswing.

One motivation for renewing this work is the challenge of diseases for which we have no good treatments. Allopathic (regular) medicine is essentially powerless in trying to contend with viral infections, for example. It can prevent some of them (poliomyelitis, yellow fever, hepatitis) by immunization, but has no drugs to counteract them once developed. The recent epidemic of acquired immune deficiency syndrome (AIDS) points up our helplessness in this area and has greatly stimulated the search for better drugs. Other frustrating problems are Alzheimer's disease, many forms of cancer, autoimmunity, and atherosclerosis. Studies of natural products may reveal new antiviral, antitumor, immune-modulating, and anti-ageing agents, as well as materials to fill other gaps in the pharmacopeia.

Another impetus in this direction is the growing demand from patients for natural remedies, which is itself an aspect of a larger movement away from exclusive reliance on standard, allopathic treatments. Many naturopaths, chiropractors, herbalists, and practitioners of Oriental medicine now dispense and recommend botanical products to patients who are dissatisfied with the high cost, toxicity, and inadequacy of pharmaceutical drugs. Whether we like these trends or not, it is important to realize that more people are turning to nonallopathic practitioners than ever before in this century, and that a major source of their discontent with the regular system is its exclusive reliance on synthetic drugs.

Accordingly, a strong market has developed for herbal products. I sometimes require my students at the University of Arizona College of Medicine to visit health-food stores to see the extent to which people now take medical problems there rather than to pharmacists. Retail sales of botanical remedies have increased to many millions of dollars, creating economic incentive for botanists, natural products chemists, medical researchers, and entrepreneurs to collaborate.

Normalization of relations between the United States and the People's Republic of China has further strengthened the field of medical botany. American scientists are just now beginning to appreciate the value of that nation's impressive traditional pharmacopeia, most of which is herbal. Not long ago, only a few items in it were known here, such as Ephedra sinica, the natural source of the bronchodilating drug ephedrine. (Ephedra is the oldest recorded medicinal plant; Chinese doctors knew it as ma huang at least five thousand years ago and recommended it for asthma and respiratory congestion).

Recent studies by Western investigators suggest that the Chinese herbal repertory contains many effective remedies. For example, the antimalarial effect of qing-haosu, derived from Artemisia annua (annual wormwood, a common weed), was confirmed in 1985 by researchers at Walter Reed Hospital and found to work by a mechanism different from any of the known antimalarial drugs.1 Such successes have led Western pharmaceutical companies to take a serious interest in Chinese herbal medicine. Some of them have already obtained exclusive rights to develop new drugs from promising species.

Enthusiasm for this cross-cultural effort may obscure the fact that Chinese doctors and Western doctors think very differently about these plants. The Chinese prescribe them in whole form: as dried leaves, barks, or roots to be steeped and boiled in water alone or (more usually) in combination, or as concentrated liquid or solid extracts. Westerners identify "active principles" of plants, then isolate them, and prescribe them in purified form.

In Western pharmaceutical science, drugs are held in highest esteem that exert the most specific effects: the ideal drug is a "magic bullet" against a particular disease. Chinese practitioners consider drugs with specific effects in specific conditions to be inferior to drugs with general effects, useful in many conditions. Superior drugs, in their conception, are panaceas and tonics that strengthen internal resistance and bodily defenses. Ginseng is one of these superior drugs; its botanical name, Panax, comes from "panacea."

Panaceas and tonics have a bad reputation in the West. We associate them with the traveling medicine shows of a bygone era and the worthless nostrums they promoted. Many physicians and pharmacologists today regard the whole field of botanical medicine in this same light. They maintain that plants cannot have effects different from those of their purified derivatives, that prescribing whole plants is at best inexact and old-fashioned, at worst actively dangerous, that the claims made for products sold in health food stores are outrageous, that great harm is likely to result from self-medicating with them, that practitioners of herbal medicine are using "empirical" as opposed to "scientific" methods, and that medical botany has no rea-son-for-being in the world of modern science.

The booming business of herbs has only inflamed this controversy, creating much ill will between proponents of botanical remedies and medical professionals. Here are some recent promotional claims by herbal practitioners and manufacturers:

   Gingko biloba extract may be of great benefit in many cases of senility, including Alzheimer's disease.

   Tablets containing extracts of comfrey (Symphytum officinale) and papaya (Carica papaya) improve digestion.

   Daily doses of the leaves of feverfew (Tanacetum par-thenium) prevent migraine headaches.

   Traditional Chinese medical herbs, like Astragalus membranaceous and the mushroom Polyporus umbellatus, stimulate the human immune system.

And here is a comment about some of these claims by the editor of the Harvard Medical School Health Letter (William Bennett, M.D., a Cambridge internist): "The use of herbs or nutrition to stimulate or strengthen the immune system is a nonsense claim . . . and to the extent that people wind up believing such claims, we can say that their brains are damaged. . . ." (Medical Tribune, Oct. 13, 1988, p. 16.)

As a botanist and a physician with long experience in both studying and using medicinal plants, I would like to examine these conflicting beliefs in order to draw some meaningful conclusions about this field. To introduce the subject, let me describe the properties of a few plants that I find useful in my medical practice.

Echinacea is a genus of the Composite (daisy) family known to horticulturalists as Purple Coneflowers. The roots of two species, E. purpurea and E. angustifolia, are widely used by phytotherapists in Europe and America for their antibiotic effects, but few medical doctors today know the plants or products made from them. A native of the American plains, Echinacea was highly valued as a remedy by the Plains Indians, especially for infectious diseases. In the mid-19th century its use was taken up by physicians of the Eclectic School, an alternative medical movement favoring botanical treatments.

By 1900, tincture of Echinacea had become the most popular medicine made from a native American plant, despite denunciations of it (and of eclectic practice in general) by the American Medical Association.

With the rise of the modern pharmaceutical industry in the early 20th century, plant drugs fell into disfavor, Echinacea among them. In recent years, naturopathic doctors have been its main champions, bringing it back to- popularity. Once again, tincture of Echinacea is in great demand. It is available in most health-food stores and herb shops along with freeze-dried extracts of the root, encapsulated ground roots, and other products. Most practitioners and patients use Echinacea in the treatment of colds, flus,. chronic and recurrent infections, and presumed states of deficient immunity.

Since 1950 there has been considerable scientific work on Echinacea, most of it in Germany, much of it verifying the properties attributed to the plant by Indians and by eclectic and naturopathic physicians. The chemistry of Echinacea root is rich and complex. Several fractions show antibiotic activity and inhibition of hyaluronidase, an enzyme associated with infectious agents that weakens connective tissue.2 Echinacea extracts also have antiinflammatory properties and an interferon-like effect that protects cells against influenza and herpes viruses.3 Even more interesting is the discovery of two high-molecular-weight polysaccharide compounds that enhance phagocytosis and activate macrophages;4 these are clear immunostimulatory effects.

If a piece of Echinacea root is held in the mouth, a sensation of tingling and numbing will develop gradually, becoming quite intense. Echinacea products lacking this property are likely devoid of therapeutic effect as well. The toxicity of this plant is low. Occasional users experience gastrointestinal disturbances, but adverse reactions of all kinds are infrequent.

Another medicinal plant much better known in Germany than in the United States is milk thistle, Silybum marianum. A European species, widely naturalized in North America and throughout the world, this robust and heavily spined thistle is a noxious weed for gardeners on the California coast. Its seeds are most valuable, however, having effects on liver cells not duplicated by any pharmaceutical drugs.

Use of milk thistle in liver disorders is a tradition in European folk medicine. In the past 15 years German investigators have identified a complex of active compounds in the seeds, which they have named "sily-marin." These compounds are of a chemical class called flavonoids, very common plant pigments often showing bioactivity in animals. The components of silymarin are unusual variants of flavonoids ("flavanolignins"), possibly representing a new class of bioactive molecules.5

When milk-thistle seeds or extracts are ingested, silymarin concentrates in the liver, is excreted in bile, then reabsorbed through the portal vein to the liver, a process known as enterohepatic recirculation. In the liver, these compounds stimulate protein synthesis by increasing activity of ribosomal RNA. By this mechanism they appear to protect liver cells from toxic injury and boost their regenerative capacity.6

In a dramatic experiment demonstrating these effects, injected silymarin has been shown to protect rats from one of the most powerful liver toxins known: alpha-amanitin, the lethal principle of the death cup mushroom, Amanita phalloides. Administered before the toxin, it prevents liver damage; given up to 24 hours after the toxin, it greatly reduces mortality and the amount of liver damage.7 Although silymarin has been used in Europe to treat some victims of deadly Amanita poisoning with good results, U.S. doctors and poison control centers remain unaware of it.

Modern allopathic medicine has no treatments for chronic hepatitis and alcoholic cirrhosis, two very serious liver disorders. Milk-thistle extracts appear to be useful in these conditions, and, since they have no significant toxicity, should certainly be tried. Products made from Silybum marianum are widely sold and used in Europe and have recently become available on the American market.

Anyone who has ever brushed against a stinging nettle {Urtica dioica) will not forget that plant. It is covered with stinging hairs that inject formic acid, histamine, acetylcholine, and serotonin under the skin, causing a spectacular reaction. Wild-food enthusiasts and herbalists have long held nettles in high esteem, recommending them for a pleasant tea, cooked greens, and a natural source of iron and other minerals. You gather the leaves with gloves on; once dried or cooked, they lose their sting.

In 1985 an accidental discovery of an antiallergic effect of Urtica opened new markets for this common plant. Researchers at the National College of Naturopathic Medicine prepared freeze-dried nettles and noted that they retained their stinging ability. The point of this work was to compare the chemistry and properties of air-dried versus freeze-dried botanicals. One of the investigators, a hay-fever sufferer, swallowed some capsules of powdered, freeze-dried nettles and experienced rapid relief of her hay fever symptoms.

Since then, a great many victims of seasonal pollen allergy have found to their delight that this harmless remedy enables them to do away with antihistamines, drugs with significant toxicity and such undesirable side effects as sedation, depression, and interference with mental activity. The ability of freeze-dried Urtica to diminish hay fever symptoms has since been confirmed in one controlled clinical trial.8

This discovery was pure serendipity and an example of empirical medicine at its best. A chance observation of an unexpected effect of a well-known plant prompted uncontrolled clinical trials and, eventually, a controlled experiment. As a result a new and useful product, both safe and effective, has become available.

I have described these three plants for several reasons. I offer them as examples of the usefulness of botanical remedies not known to most doctors and patients in this country. They suggest the range of bioactivity available in plants; who knows how many other unusual compounds and properties are out there waiting to be noticed? American readers should be aware that other countries are ahead of us in the investigation and use of medicinal plants. I hope they will also consider that folk wisdom, anecdote, and empirical method have their place in medicine, sometimes providing us with ideas that hold up under scientific scrutiny.

What of the concerns of some medical scientists about the dangers of botanical remedies? Obviously, some plants are toxic, and, less obviously, some of these have found their way into folk usage. One to know about is comfrey, Symphytum officinale, a Eurasian native of the Borage family, widely grown in this country. "Symphytum" comes from Greek roots meaning "to knit together," and the specific epithet "officinale" suggests the status of this species in European herbal medicine. Comfrey has a long history of use by human beings and enjoys a strong reputation as a healing plant, one that helps wounds heal, broken bones mend, and respiratory and digestive functions to improve.

I have met many people who attribute miraculous virtues to comfrey. They make "green drinks" of comfrey leaves, eat bowls full of the leaves as salads, or take concentrated extracts of leaves and roots, sometimes mixed with extracts of papaya or digestive enzymes. I have read books and pamphlets from health food stores touting the health benefits of comfrey. Some say it is the only vegetarian source of vitamin B-12. It is not. All say that it is perfectly safe. It is not.

Research in the past decade shows unequivocally that comfrey contains pyrrolizidine alkaloids, compounds widely distributed in plants, known to be toxic, and often causing sickness and death in grazing livestock. These chemicals are particularly dangerous to the liver, where they can cause a distinctive and potentially fatal reaction (veno-occlusive disease, Budd-Chiari syndrome) in which the hepatic veins become blocked as a result of chemical injury.

Outbreaks of pyrrolizidine alkaloid poisoning in humans are usually the result of accidental contamination of grains with toxic seeds of other plants, but some cases are on record of individuals, especially children, who succumbed to acute liver failure after drinking various herbal teas. For example, a Mexican-American infant in Arizona died in 1977 after being given a folk remedy for sore throat; the tea, purchased at a pharmacy that carried herbal remedies, turned out to be mislabeled. Instead of a harmless species of Gnaphalium (cud-weed), the package contained an unrelated species of Senecio, a desert plant with high content of pyrrolizidine alkaloids.

The alkaloid content of comfrey roots is higher than that of its leaves, and some commercial preparations of the plant have enough of these compounds to be harmful. One brand of comfrey-pepsin capsules (a "digestive aid" made from Symphytum roots) will easily deliver enough pyrrolidines to damage the liver of anyone who takes two tablets per meal over several months.10 Even if catastrophic liver disease does not occur, other possible consequences of long-term comfrey use include the gradual development of cirrhosis, liver cancer, and damage to lungs and other organs.

Comfrey lovers are often resistant to these warnings, believing them to be establishment propaganda against an innocent herb. Scientists interested in making people aware of the danger do not help their cause when they go well beyond their data to condemn all herbal teas. In fact, the chance of poisoning from comfrey tea, leaves, and juice is probably small, both because the alkaloid content of these forms is usually low, and because the particular alkaloids in comfrey may be less toxic and less easily absorbed from the gut than related compounds in Senecio and other species. Still, given the known toxicity of this family of alkaloids, it is hard to see why anyone would eat comfrey.

Topical application of the plant is another matter, as it does, indeed, have excellent wound-healing properties. (Systemic absorption of alkaloids by this route is minimal.) Poultices of comfrey leaves and roots figure prominently in European folk medicine, especially to treat sores that refuse to heal. I have found these treatments to be effective in cases of diabetic ulcers and stasis ulcers (bedsores) and ulcerated bites of the brown recluse spider, lesions that are notoriously long-lasting and resistant to drug treatment. I have also seen them stimulate healing of staphylococcus-infected wounds that surfers contract on tropical beaches; often, these are also resistant to conventional therapy.

The lessons I draw from the all the information I have reviewed on comfrey are: 1) medicinal plants cannot be considered safe just because they have a long record of use in folk medicine; 2) chemical analysis of popular medicinal plants is always worthwhile; 3) the mere presence of toxins in a plant may not mean that occasional use of dilute preparations of it is harmful; 4) it is important to try to inform users about the real hazards of plant products in ways that will not cause them to stop listening.

In my own private practice of general medicine in Tucson, I have come to rely on plants as mainstays of treatment. For every prescription I now write for a pharmaceutical drug, I give out 40 or 50 for botanical remedies. In the five years that I have been prescribing in that manner, I have not produced a single adverse reaction. I do not know any physician who uses pharmaceutical products exclusively who can match that record of safety..

If one avoids plants that are probably or possibly toxic, this kind of medicine is relatively safe for the simple reason that plants are naturally dilute forms of drugs. Coca leaves, the source of cocaine, contain only one-half of one percent of that notorious alkaloid. One reason coca-chewing Indians of Peru and Bolivia have few of the problems of toxicity, abuse, and addiction that we do is that they ingest a dilute preparation of cocaine rather than inhale, smoke, or inject a concentrated one.

Because plants supply bioactive compounds in low concentration by an indirect route to the bloodstream and target organs, their effects are usually slower in onset and less dramatic than those of purified drugs administered by more direct routes. Doctors and patients accustomed to the rapid, intense effects of synthetic medicines may become impatient with botanicals for this reason.

Of course, many medical emergencies demand rapid, intense pharmacological intervention, and for these crises the modern pharmacopeia is well stocked. In non-crisis situations, however, the much
greater safety of medicinal plants may be a distinct advantage, and it seems a shame that most doctors do not have this option because they are untrained in it.

Not only are plants safer than their refined and concentrated active principles, they may also produce qualitatively different effects. This is a difficult point to explain to pharmacologists and physicians, because few of them today have first-hand experience with the natural sources of classical drugs- They see no reason to question what the books say: that cocaine is coca in a more concentrated form, that the pharmacology of coffee is identical to the pharmacology of caffeine, that all of the virtues of Digitalis leaf are embodied in purified digoxin, a more conveniently administered form.

In fact, the properties of coca leaf, especially therapeutic properties attributed to it in Andean folk medicine, are not reproduced by isolated cocaine; the leaf contains thirteen other alkaloids plus vitamins, minerals, and essential oils. The other constituents modify the actions of cocaine and contribute effects of their own.11 Coffee is more powerful, more addictive, and more irritating to several systems of the body than an equivalent dose of caffeine, either in pure form or as teas made from such other plants as yerba mate (Ilex para-guaiensis) and guarana (Paullinia cupana). It contains an oil-soluble fraction of active compounds about which we know little. One of them, chlorogenic acid, is the main stomach irritant in coffee. It is present in decaffeinated coffee, which is not pharmacologically inert, as most users believe.

Similarly, the components of foxglove (Digitalis) leaf that cause nausea and vomiting in overdose are distinct from the cardiotonic (heart-stimulating) components.12 Purified digoxin, a most useful drug for correcting abnormal heart function, has a very narrow margin of safety; in overdose, it produces dangerous arrhythmias without the early warning signals of nausea and vomiting. Few American physicians would know how to use Digitalis leaf if it were available to them. We have lost the option of using the slower-acting but safer form of this plant with its complex chemistry.

I must stress my belief, based both, on my research as a botanist/physician and on my experience as a practitioner, that whole plants have different effects from those of isolated active principles, that the beneficial effects of botanical remedies are likely to represent synergistic and holistic interactions of all the active components: secondary compounds along with the dominant principles.

Resistance to this idea is understandable, because for well over a century, teaching in pharmacology has equated the activity of plants and their purified derivatives. The historical origin of this point of view was the isolation of morphine from opium by a German pharmacist in 1803. That event marked the beginning of modern pharmaceutical science because it was the first identification of a major drug from a medicinal plant. It promised a new era of therapeutics in which doctors would be able to administer exact doses of known compounds, thus ending the inexactness, confusion, and superstition of old-fashioned herbalism. Of course, it is one thing to identify morphine as the active principle of opium, make it available to researchers, and provide it to doctors and patients as a powerful (and dangerous) medicine; it is another to believe and teach that all of the properties of opium are embodied in morphine, albeit in a more concentrated form.

Only good information about medicinal plant; and their derivatives can correct this kind of error, but American schools of medicine and pharmacy now pay little attention to information from the fields of botany, natural-products chemistry, and pharmacognosy. In fact, courses on pharmacognosy (the science of identifying new drugs from natural sources) have been dropped from the pharmacy curriculum in the past few years.

Many practical problems confront physicians and patients wishing to try out medicinal plants. There are few good books on the subject. Many botanical products may be unstandardized, ineffective, and not subject to the regulations and quality controls governing pharmaceutical drugs. (There is progress, however. Given the demand for reliable products today, a number of companies have come into existence that market high-quality extracts of medicinal plants, standardized for activity in terms of quantitative analysis of active fractions or by bioassay in animals.) Medical doctors who prescribe plants may feel professionally vulnerable in practicing outside accepted standards of their peers. Medical insurance will cover costs of pharmaceutical drugs but not of most herbal medicines.

As bothersome as these problems are, they are insignificant compared to the conceptual problems that are holding American medicine back in this area. For many years we allowed our stands of native ginseng (Panax quinquefolium) to be overharvested to the brink of extinction for export to the Orient. During that time, our medical scientists ignored ginseng, dismissed Chinese claims of its many effects as superstition, and did not consider looking at the chemistry and pharmacology of the root. A panacea said to increase resistance to stress, improve skin and muscle tone, increase libido, and retard ageing must be a placebo, after all, because it does not fit the Western conception of a drug.

Only in recent years have researchers looked into the constituents of American ginseng and its Oriental relative, P. ginseng. The roots of both species are full of bioactive glycosides that affect the pituitary-adrenal axis, a mechanism that can explain all of the properties attributed to Panax in traditional Chinese medicine.

One of the most promising areas of research in botanical medicine at the moment is the search for safe enhancers of immune function. Many of the tonics in the Chinese herbal pharmacopeia are of interest, but, again, American medical science has ignored them because it does not recognize the concept of a tonic and because the plants are devoid of compounds that look like drugs in the Western sense. Most plant drugs are alkaloids (nitrogen-containing compounds that give alkaline reactions in solution) or glycosides (compounds that yield one or more sugars upon hydrolysis). The Chinese tonic plants that may be immuno-potentiators do not owe their effects to alkaloids or glycosides. Instead they contain high-molecular-weight polysaccharides, long-chain sugar molecules that are structural components of the cells of many organisms and have never been of much interest to pharma-cognocists.

Huang qi, a traditional Chinese remedy made from the root of Astragalus membraceous, is one of the most popular of these polysaccharide-containing plants. All pharmacies in China carry Astragalus preparations; they are widely used to treat and prevent colds and flus and promote the "defensive energy" of the body. Recent animal research in both China and the West has shown that polysaccharides from Astragalus root reverse immunosuppression caused by administration of corticosteroids and other immunosuppressive drugs.13 (Astragalus, by the way, is a large genus in the pea family. The leaves of some species are toxic to livestock; they are known as "locoweed" in the American West. We know nothing about the chemistry of the roots of these and other American species of Astragalus. Some may have the same useful effect as A. membranaceous).

Another valued remedy in traditional Chinese medicine is zhu ling, obtained from the underground tuberlike growths (sclerotia) of an edible mushroom, Polyporus umbellatus. Western medicine has never looked to mushrooms as sources of new drugs, but in China and Japan mushrooms are prized for their therapeutic effects as much as for food. Chinese researchers have demonstrated anticancer effects of water extracts of P. umbellatus in both animals and humans.14 These are not cytotoxic effects: there is no inhibition of tumor growth in vitro, only in intact animals with intact immune systems. The mushroom is nontoxic and, again, is full of large polysaccharide molecules.

Recall that Echinacea root also stimulates immunity and contains polysaccharides. One possibility is that these compounds are chemically similar to antigenic components of bacterial cell walls. Perhaps they stimulate immune responses for that reason. In any case there appear to be species of plants and fungi that are safe and effective at increasing our resistance to infections and cancer. The main obstacle to our taking advantage of these in the West is conceptual. We must be open to the possibility of new kinds of medicines that do not fit present models of drug action.

A surprising amount of information is in print on the effects of botanical medicines, much of it published very recently, most of it unread by American medical doctors. Included in this material are some well-designed, controlled studies verifying empirical and folk-medical attributes of plant remedies. For example, concentrated extracts of the leaves of Gingko biloba, the Chinese tree that lines many city streets throughout the world, do, indeed, increase cerebral blood flow15 (though I know of no good evidence that they help victims of Alzheimer's disease). Daily doses of the leaves of Tanacetum parthenium (feverfew, a common ornamental) do, indeed, reduce the frequency of migraine attacks in some patients, and they have none of the considerable toxicity of pharmaceutical drugs used for this condition.16

Western pharmacology, medicine, and pharmaceutical science have accomplished so much. They could do so much more by looking again to botanical origins. I believe American medicine, in particular, could increase its record of safety and effectiveness while better satisfying the needs of patients by reclaiming the option of using plant remedies along with synthetic drugs. For that reason I hope that in this country botany and medicine will renew acquaintances and again, eventually, become friends.