Brody's Human Pharmacology: With STUDENT CONSULT

Chapter 7 Herbals and Natural Products

Therapeutic Overview

Since prehistoric times, humans have used plants as medicines. Of the 520 new prescription drugs approved between 1983 and 1994, 39% were natural products or were derived from plants or animals, with 60% to 80% of antimicrobials and anticancer drugs obtained from such products. Over millions of years, plants have developed the capacity to synthesize a diverse array of chemicals, which attract or repel other organisms, serve as photocollectors or protectants, and respond to environmental challenges. For example, phytochemicals can assist plants in resisting pathogens, make them unpalatable, aid in collecting light energy, protect plants from photo-oxidation, or help dissipate excess light energy as heat. With the advent of modern scientific medicine, phytochemicals have been refined, or altered, to produce a share of the modern pharmacopoeia. Despite the increasing availability of many potent and selective drugs, there remains an increasing interest in folk remedies, including herbal medicines.

Herbal medicine is the most commonly used form of alternative medicine. Alternative medicine refers to those practices other than the conventional medicine practiced and taught in Western medical institutions. In a 1998 survey, alternative medicine visits surpassed visits to conventional health care providers, with the highest rates of use in middle-aged (35 to 64 years old) individuals. Furthermore, in 2002, $18.7 billion per year were spent on dietary supplements, with herbs/botanicals accounting for approximately 23% of this total.

The reasons for such common use of alternative therapies are varied. These include dissatisfaction with conventional medicine, the view that alternative therapies are empowering because of more patient control, and the perception that alternative therapies are more compatible with personal values or ethical beliefs. Predictors for use of alternative therapies include a higher educational level, poorer health status, holistic orientation to health, having had a transformational experience changing one’s world view, and having a chronic health condition such as diabetes, chronic pain, or cancer that has not responded to conventional treatment. It should be emphasized that most people using alternative medicine do not report such use to their physicians or other conventional medical providers.

The biologically-based alternative therapies include the use of botanicals (e.g., herbs) and supplements (e.g., amino

Abbreviations

DHEA

Dehydroepiandrosterone

DNA

Deoxyribonucleic acid

DSHEA

Dietary Supplement Health and Education Act

FDA

Food and Drug Administration

HIV

Human immunodeficiency virus

MAOI

Monoamine oxidase inhibitors

NE

Norepinephrine

acids, vitamins, minerals), often referred to a nutraceuticals, a term coined in 1989 that refers to any substance considered “a food or part of a food that provides medical or health benefits, including the prevention and/or treatment of a disease.”

The Dietary Supplement Health and Education Act (DSHEA), passed by the United States Congress in 1994, defines a dietary supplement as a product that is intended to supplement the diet and contains a vitamin, mineral, amino acid, herb, or other botanical product intended for ingestion in the form of a capsule, powder, or extract. Dietary supplement products must bear an ingredient label that includes the name and quantity of each ingredient or the total quantity of all ingredients (excluding inert ingredients) in a blend. Labeling of products containing herbal or botanical ingredients must state the part of the plant from which the ingredient is derived. Botanicals may be obtained in many formulations listed in Box 7-1.

BOX 7–1 Major Botanical Preparations

Bulk herbs are raw or dried, essentially unprocessed plants or plant parts (leaves, roots, stems, flowers).

Oils are concentrates of the fat-soluble components of herbs.

Essential oils are the distillates of the volatile components of herbs.

Tablets or capsules are prepared from powdered herbs with the intent of providing a fixed, easily administered dose.

Teas are hot or cold water extractions of herbs. Teas are traditionally brewed 1-2 minutes.

Infusions are aqueous extracts of herbs that are steeped at least 20-30 minutes.

Decoctions are prepared by extracting plant material for 10-20 minutes in boiling water.

Tinctures are alcohol extracts that are usually mixed with water for oral administration.

Poultices or plasters are bulk herbs, moistened and prepared in a form suitable for applying to the skin.

Federal regulations provide for the use of various types of statements on the label of dietary supplements, but claims cannot be made about the use of a dietary supplement to diagnose, prevent, mitigate, treat, or cure a specific disease without sufficient clinical evidence. For example, a product may not carry the claim “cures diabetes” or “treats cancer,” unless that claim is supported by clear evidence. Some health claims can be made, if the product has been so approved. For example, the claim that calcium may reduce the risk of osteoporosis has been approved by the Food and Drug Administration (FDA). Products can make claims about classical nutrient deficiency diseases, provided the statements disclose the prevalence of the disease in the United States. In addition, manufacturers may describe the effects of a supplement on “structure or function” of the body or the “well-being” achieved by consuming the dietary ingredient. To use these claims, manufacturers must have substantiation that the statements are truthful and not misleading.

Mechanisms of Action

Like any other drug or chemical, the components of herbal medicines are presumed to exert their effects on physiological or biological systems. One major difference is that botanicals contain large numbers of chemicals, which may interact synergistically or antagonistically. Some remedies consist of mixtures of several herbs, so that the number of chemicals in a single preparation can reach into the hundreds or thousands. The most commonly used botanicals are shown in Box 7-2.

BOX 7–2 Most Commonly Used Botanicals/Supplements

Echinacea—to treat colds

Ginseng—to boost energy, to treat type II diabetes

Gingko biloba—to improve memory

Garlic—to treat hypertension and high cholesterol

Glucosamine—to treat osteoarthritis

St. John’s wort—to treat depression

Peppermint—to treat nausea and vomiting (pregnancy, chemotherapy)

Omega-3 fatty acids—for heart health and to treat inflammation and depression

Ginger—to treat nausea and vomiting (pregnancy, chemotherapy)

Soy—to treat symptoms of menopause

Antioxidant Effects

Oxidation of deoxyribonucleic acid (DNA), proteins, carbohydrates, and lipids by reactive oxygen species has been implicated in normal aging and a number of different diseases, including arthritis, cancer, and Alzheimer’s disease. Oxidative stress occurs when there is an imbalance between free radical generation (by the action of reactive oxygen species) and endogenous antioxidants in cells and tissues. Reactive oxygen species are produced by some toxins, ultraviolet light, normal biochemical pathways (e.g., nitric oxide synthase), and pathological events in cells (e.g., free radicals that escaped from the mitochondrial complex). Endogenous antioxidants include reduced glutathione and the enzymes superoxide dismutase, catalase, and glutathione peroxidase. Many plants contain antioxidants (Box 7-3), including several typically used as food; some vitamins also have antioxidant activity. Although there is little clinical evidence that supplementation with dietary antioxidants ameliorates or prevents any disease, there is a wealth of scientific evidence for the free radical scavenging ability of many plant-derived antioxidants; thus interest in this mechanism of action remains strong.

BOX 7–3 Plants Used as Antioxidants

Tea

Garlic

Milk thistle (Silymarin)

Soy (isoflavones)

Ginkgo biloba

Red grape

Green vegetables, carrots, tomatoes

Red clover

Immunomodulation

Some herbals are thought to act by modulation of immune function (Box 7-4). This modulation can be indirect, via antioxidant effects, or direct, via effects on immune cells. In general, herbal remedies are thought to enhance immune function by removing toxins from the body (a common concept in herbalism).

BOX 7–4 Herbs Commonly Used for Immunomodulation

Milk thistle

Dandelion

Echinacea

Cleavers

Marigold

Beet root juice

Elderberry

Astragalus root

Licorice

Olive leaf

Cat’s claw

Thunder God vine

The herbal approach to immunomodulation is holistic and focuses on boosting liver function and cleansing the blood. In the herbal philosophy, detoxification by the liver has a crucial role in health and in regulating immune function. Again, there is a dearth of clinical evidence for the efficacy of any herbal medicine in altering the course of disease, but some evidence in animal models and cell cultures suggests possible effects on immune function.

Actions on Neurotransmission

Many plants contain compounds that are used or abused for their psychoactive qualities, usually for sedative, stimulant, or analgesic purposes. These include coffee (caffeine), tobacco (nicotine), coca (cocaine), opium poppy (opiates), marijuana (cannabinoids), and peyote (mescaline). Ethnobotanical studies of shamanism in native populations have revealed many other hallucinogenic plants. A variety of herbal products are commonly used for sedative, stimulant, analgesic, and antiemetic effects (Table 7-1).

TABLE 7–1 Herbs Proposed to Act on the Central Nervous System

Sedatives

Stimulants

Kava

Lobelia

Valerian

Coffee

Skull cap

Tea

Passion flower

Tobacco

Lavender

Ginseng

Antiemetics

Analgesics

Black horehound

Cayenne

Lemon balm

White willow bark

Cayenne

Feverfew

Clove

Jamaican dogwood

Dill

St. John’s wort

Lavender

Ginseng

Meadowsweet

Corydalis (Corydalis yanhusuo)

Ginger

 

Plants contain many compounds that may act on neurotransmitter receptors in the central and peripheral nervous systems. Plants also contain compounds that can: (1) interfere with the uptake of neurotransmitters, prolonging their action; (2) stimulate or block neurotransmitter release; or (3) alter the enzymatic degradation of neurotransmitters. Many of these compounds have been isolated and modified to produce drugs in common use today. The classic examples are the opiate narcotics found in the opium poppy. Compounds from the opium poppy have been modified chemically to yield products with increased specificity in terms of opioid receptor subtype and ability to activate or block these subtypes.

Hormonal Actions

Some herbs contain compounds that mimic or block the actions of hormones, notably estrogen. Currently used products include highly concentrated extracts of phytochemicals, synthetic derivatives, and even steroids like dehydroepiandrosterone (DHEA) and androstenedione, which are classified as dietary supplements because they are produced from plant precursor sterols (Box 7-5).

BOX 7–5 Herbs Commonly Used for Hormonal Problems

Menopausal Symptoms

Vasomotor instability (hot flashes)

• Soy, black cohosh, evening primrose, dong quai (angelica)

Mood disorders

• St. John’s wort, valerian

Loss of libido, vaginal dryness, dyspareunia

• Chasteberry (vitex)

• Ginseng

• Wild yam

• Raspberry leaves

Androgen Alterations

• Saw palmetto

• Tongkat Ali (Eurycoma longifolia)

• Tribulus Terrestris

• Yohimbe bark

• Pygeum

• DHEA

Phytoestrogens can be classified into three groups. Isoflavones are plant sterol molecules found in soy and other legumes. Lignins are a constituent of the cell wall of plants and become bioavailable as a result of the effect of intestinal bacteria on grains. The highest amounts are found in the husk of seeds used to produce oils, especially flaxseed. Coumestans are found in high concentrations in red clover, sunflower seeds, and bean sprouts. The plant lignan and isoflavonoid glycosides become hormone-like compounds with weak estrogenic and antioxidant activity after modification by intestinal flora. These compounds exert measurable effects on circulating gonadotropins and sex steroids, suggesting they have biological activity. High isoflavone intake may depress luteinizing hormone levels and secondarily depress estrogen production. Phytoestrogens can also act on intracellular enzymes, protein synthesis, growth factors, cellular proliferation, differentiation, and angiogenesis. Bean foods provide large amounts of fiber, and fiber modifies the level of sex hormones by increasing gastrointestinal motility. Fiber also alters bile acid metabolism and partially interrupts the enterohepatic circulation, causing increased estrogen excretion by decreasing the rate of estrogen reuptake.

Other botanicals have been proposed to modify hormonal balance in men. Saw palmetto contains steroid-like compounds that may antagonize the actions of testosterone and is suggested for treatment of benign prostatic hyperplasia and prostate cancer. Tribulus and Tongkat Ali are thought to enhance testosterone production through stimulation of luteinizing hormone production. Yohimbe contains yohimbine, an antagonist at α2-adrenergic receptors known to increase norepinephrine (NE) release by blocking inhibitory presynaptic autoreceptors, thus enhancing sympathetic activity (see Chapter 11). Synthetic yohimbine is regulated as a drug and prescribed for erectile dysfunction, whereas yohimbe bark is sold as a dietary supplement. Pygeum may interfere with testosterone production by inhibition of 5-α-reductase and aromatase and is used for treating benign prostatic hyperplasia. DHEA is a naturally occurring adrenal hormone that is a precursor of estrogen and testosterone. Levels of DHEA decline with aging, so it is often used as a supplement to restore those levels toward more “youthful” values.

Anticancer Effects

There are several approaches to herbal therapy of cancer (Box 7-6). Some herbal products have been suggested to prevent cancer by stimulating the immune system or by their antioxidant effects. Others are thought to act by direct toxic effects on neoplastic cells; for example, by inhibition of topoisomerases, inhibition of polyamine synthesis, or stimulation of apoptosis pathways. Other postulated mechanisms include blockage of angiogenesis (e.g., shark cartilage) and reversal of multidrug resistance pumps (e.g., flavonoids).

BOX 7–6 Common Uses of Dietary Supplements

Treatment of Cancer

Antioxidant micronutrients (vitamin E, vitamin C, betacarotene, selenium)

Immunomodulatory herbs (see above)

Soy protein

Polyunsaturated fatty acids

Increased Athletic Performance (Ergogenics)

Antioxidants

Amino acids (arginine, lysine, aspartate, glutamine)

Caffeine

Carbohydrates

Creatine

DHEA

Glucosamine

Glycerol

HMB (β-hydroxy-β-methylbutyrate, a branched chain metabolite of leucine)

Ornithine

Protein

Pycnogenol

D-ribose

Sodium bicarbonate

Other Uses

Glucosamine/chondroitin for osteoarthritis

Melatonin for insomnia

Acidophilus (probiotics) for lactose intolerance and the gastrointestinal side effects of antibiotics

Lutein for retinal health

Grapeseed (antioxidant effects)

Cranberry for urinary tract infections

Lycopene as an antioxidant

Bitter melon (momordica), ginseng, and gymnema for diabetes

Herbs are also used to treat either the symptoms of cancer or the adverse effects of conventional chemotherapy and radiation treatments.

Several potent conventional cancer treatments (see Chapter 54) are derived from plants and other natural products. These include taxol from Pacific yew and the vinca alkaloids (vincristine, vinblastine) from Madagascar periwinkle.

Many patients with cancer take large doses of vitamins and antioxidants with the belief that these compounds may boost immune function and prevent further neoplastic transformation. Patients believe that, at worst, these supplements can do no harm. However, current research indicates this may be incorrect. Because conventional cancer therapy frequently depends on oxidative mechanisms, it is possible that the use of antioxidants could interfere with this treatment. Also, recent evidence suggests that apoptosis of cancer cells is increased by reactive oxygen species, and antioxidants can slow or block this process. The American Institute for Cancer Research has concluded that supplementation with individual or combined antioxidants above levels established by the Institute of Medicine’s Dietary Reference Intakes cannot be recommended as either safe or effective. Patients undergoing either chemotherapy or radiation therapy should be advised not to exceed the upper limits for vitamin and mineral supplements and to avoid dietary supplements that contain high levels of antioxidants.

Ergogenics

Ergogenics are substances that increase energy production, use, or recovery. Many products claim to give athletes a competitive edge through an ergogenic effect (see Box 7-6). Surveys have shown that 75% of college athletes and 100% of body builders take supplements for this purpose. A handful of supplements on the market have been shown to be effective in high-quality clinical studies.

Oral creatine supplementation can increase muscle phosphocreatine stores by 6% to 8%, leading to faster regeneration of adenosine triphosphate. Elevated levels of muscle creatine also buffer lactic acid produced during exercise, delaying muscle fatigue and soreness.

Caffeine increases contractility of skeletal and cardiac muscle and stimulates fat metabolism, thereby sparing muscle glycogen stores. It is also a central nervous system stimulant, which can aid in activities that require concentration. However, ergogenic doses of caffeine (250 to 500 mg) may cause restlessness, nervousness, insomnia, tremors, hyperesthesia, and diuresis.

Protein and amino acid supplements are used by some athletes to enhance muscle repair and growth. Athletes in training have increased protein needs, and inadequate protein intake causes a negative nitrogen balance, which slows muscle growth and causes fatigue.

Carbohydrates, specifically muscle glycogen, are the body’s main source of rapidly available energy. Loading, or increasing the carbohydrate content of the diet for several days before an athletic event, has been suggested as a means to prolong exercise endurance. A meal before exercise will ensure that muscle and liver glycogen stores are maximized. Studies investigating ingestion of food 2 to 4 hours before exercise have shown a positive effect, regardless of the “glycemic index” of the foods ingested. Replenishment with carbohydrate-containing fluids during an endurance event may also help delay fatigue. Eating a mixture of carbohydrates and protein within 2 hours after exercise has also been associated with benefits, including replenishment of depleted muscle and liver glycogen stores and decreased muscle catabolism.

Pharmacokinetics

In most cases it is not possible to determine the pharmacokinetics of herbal products because of their complex nature. When the active components are unknown, it is difficult to select the key components to follow in a pharmacokinetic study.

An important issue that needs additional investigation is the interaction of herbal products with other drugs. Drug-herb interactions can occur at the level of absorption, distribution, metabolism, or excretion (see Chapter 2), but metabolic interactions have received the most attention. These interactions go in both directions, with drugs either interfering with or enhancing the effects of herbs, and herbs or other supplements either interfering with or enhancing the effects (and side effects) of drugs.

Drugs such as cholestyramine, colestipol, and sucralfate may bind to certain herbs, forming an insoluble complex and decreasing absorption of both substances. Absorption of herbs may also be adversely affected by drugs that change the pH of the stomach. Antacids, H2-histamine receptor antagonists, and proton pump inhibitors (see Chapter 18) such as cimetidine and omeprazole are used to neutralize, decrease, or inhibit secretion of stomach acid for treatment of ulcers or gastroesophageal reflux. With decreased stomach acid, herbs may not be broken down properly, leading to poor absorption in the intestines. Drugs that affect gastrointestinal motility may also affect herb absorption. Slower motility would mean the herbs stay in the intestines longer, thus increasing absorption. Metoclopramide and cisapride can increase gastrointestinal motility and decrease absorption of herbs. Haloperidol and some opiate narcotics decrease gastrointestinal motility and may increase absorption of herbs.

Many herbs induce the cytochrome P450 system (see Chapter 2), although the specific herbal components that induce P450s may be different from those responsible for therapeutic efficacy. Induction of P450s leads to increased metabolism of other concomitantly administered drugs that are metabolized through the same pathways.

Conversely, drugs that inhibit cytochrome P450s can increase the accumulation of herbs. Examples of drugs that inhibit liver metabolism include, but are not limited to, cimetidine, erythromycin, ethanol, and antifungal drugs such as fluconazole, itraconazole, and ketoconazole (see Chapter 50).

Drug-food interactions are numerous and often overlooked. These interactions occur most often with diuretics, antibiotics, anticoagulants, antihypertensives, thyroid drugs, antiretrovirals, and antidepressants. For example, grapefruit is a potent inhibitor of specific cytochrome P450s. Some common drugs metabolized by these enzymes are cyclosporin, estrogens, benzodiazepines, human immunodeficiency virus (HIV) protease inhibitors, and simvastatin. Grapefruit juice can increase peak serum concentrations of some of these drugs as much as tenfold, and the effects can last as long as 24 hours.

Broccoli, cabbage, and related cruciferous vegetables can induce CYP1A2, whereas carrots can inhibit the enzyme. Drugs metabolized by CYP1A2 include warfarin, theophylline, and clozapine.

Foods that contain vitamin K, such as brussels sprouts, asparagus, avocado, and liver, can interfere with the actions of anticoagulants by direct action on the clotting cascade. Green tea contains vitamin K and can reduce the efficacy of warfarin.

Flavonoids, present in hops (beer), soybeans, and many herbs, can also inhibit certain P450s. Garlic inhibits CYP2E1, whose substrates include the general anesthetics halothane and methoxyflurane.

An herb-drug interaction that has received much media attention is the induction of CYP3A4 by St. John’s wort, commonly ingested to treat depression. CYP3A4 is involved in the metabolism of more than half of all prescribed drugs, including antiretrovirals used to treat HIV infection and oral contraceptives, making this a very important source of potential herb-drug interactions.

Relationship of Mechanisms of Action to Clinical Response

The complex nature of herbal medicines creates a major challenge to determining their mechanisms of action. The level of clinical evidence to support the efficacy of these agents is minimal at best; in only a few cases is there strong clinical evidence for efficacy (Box 7-7).

BOX 7–7 Levels of Clinical Evidence for Efficacy of Dietary Supplements (From Strongest to Weakest)

Randomized Controlled Clinical Trials

Participants are assigned by chance to separate groups for the comparison of different treatments. These trials can be “double-blinded” or “nonblinded.” Double-blinded trials have a stronger study design because expectations are not a factor in determining outcome.

Double-blinded

None of the participants know which groups are receiving the therapy under study or the comparison treatment. Comparison treatments can be no treatment, placebo treatment, and/or a different treatment, for example, standard of care.

Nonblinded

The researcher(s) and the study participants know what treatment is being given. This design must be used when characteristics of the treatment cannot be disguised (e.g., massage therapy).

Nonrandomized Controlled Clinical Trials

Participants are assigned to a treatment or control group based on criteria that are known to the researcher, such as birth date, chart number, or day of clinic appointment. This type of study design is weaker because the composition of the treatment and control groups may not be equivalent.

Case Series

Studies that describe results from a group or series of patients who were given the treatment that is being investigated. These studies are weaker because there is no control group. Different types of case series, in descending order of strength, are as follows:

Population-based, consecutive case series

The study population is defined and is either the entire population of interest or a representative random sample of the population. The study subjects receive treatment in the order in which they are identified by the researcher.

Consecutive case series

Studies describing a series of patients who were not limited to a specific population and who received treatment in the same order in which they were identified by the researcher.

Nonconsecutive case series

Studies describing a series of patients who were not limited to a specific population and who do not represent a consecutive series of patients identified and treated by the researcher.

Best Case Reports

The study population consists of only the patients who benefited from the treatment under study. There is no control group, and patients who did not benefit from the treatment are not included. A best case report of one patient is an anecdote.

Pharmacovigilance: Side Effects, Clinical Problems, and Toxicity

Difficulties in identifying side effects of herbs also arise because the identity of herbal ingredients is largely unknown, most reports are anecdotal, and effects may be attributed to herbs simply because there is no other obvious cause.

Because of the complex nature of herbal products, the potential for side effects would be expected to be large. However, a central tenet of herbalism is that complex composition minimizes side effects because of the presence of chemicals that exert the desired effect and other chemicals that antagonize side effects. However, these tenets have not been tested in controlled studies. In addition, the potency of an herbal product may be very low compared with that of typical drugs that are administered in the milligram or even microgram range.

Concurrent use of herbs and drugs with similar therapeutic actions creates the risk of pharmacodynamic interactions. The highest risk of clinically significant interactions occurs between herbs and drugs with sympathomimetic, cardiovascular, diuretic, anticoagulant, and antidiabetic effects. Some herbs contain salicylates and coumarins, which have antiplatelet activity that may potentiate prescribed anticoagulants. Ginger and ginseng have direct antiplatelet activity and can potentiate anticoagulant therapy and alter bleeding time. Licorice, consumed as an herbal remedy or as candy, raises blood pressure and should be avoided by people with hypertension. Hawthorn, a cardiotonic herb, may potentiate the actions of digoxin. St. John’s wort may potentiate the actions of antidepressants such as serotonin and NE reuptake inhibitors and monoamine oxidase inhibitors (MAOIs).

Provisions in DSHEA state that the manufacturer is responsible for ensuring that its dietary supplement products are safe before they are marketed. Unlike drug products that must be proven safe and effective for their intended use before marketing (see Chapter 4), there are no provisions in the law for the FDA to “approve” dietary supplements for safety or effectiveness before they reach the consumer. Also, unlike manufacturers and distributors of drugs, those of dietary supplements are not currently required by law to record, investigate, or forward to government agencies any reports they receive of injuries or illnesses that may be related to the use of their products. Under DSHEA, once the product is marketed, the FDA has the responsibility for showing that a dietary supplement is “unsafe” before it can take action to restrict its use or remove it from the marketplace.

The pharmacological actions of herbal products can give rise to serious safety concerns. Ephedra was used for many years for weight loss, as a stimulant, and to improve athletic performance. It was frequently mixed with caffeine, caffeine-containing herbs, or other herbs. Ephedra represented an interesting aspect of the current regulatory framework for herbs, because it contains ephedrine and other ephedrine-like compounds that, when prepared synthetically, are regulated as drugs. For example, low doses of ephedrine, an effective decongestant, were present in numerous over-the-counter cold remedies. The potential adverse effects of ephedrine were well known and include stroke, cardiac arrhythmias, and hyperthermia, caused by its sympathomimetic actions. Because there is no system for reporting adverse events that occur after ingestion of a dietary supplement, the incidence of these events linked to ephedra is not well established. However, evidence began to accumulate and reanalysis of the few clinical studies of ephedra, in conjunction with the untimely death of a well-known athlete, led the FDA to conclude that ephedra was unsafe, and it was removed from the market in 2004.

A second safety issue is that of contaminants. Because herbs are agricultural products or wild-crafted (i.e., gathered in the wild), they can be contaminated with pesticides, herbicides, and soil contaminants such as heavy metals, fungi, and bacteria. In addition, contaminants can be introduced through the manufacturing process, such as solvents used for extraction. The liver toxicity of kava appears to be related to acetone extraction. Whether residual acetone is responsible for this toxicity, or whether acetone extracts additional chemicals from the bulk plant material that are not normally present in the teas made by native populations that use kava, remains to be determined. However, it is clear that some people who used a commercially available kava extract suffered liver damage, which led the FDA to ban acetone-extracted kava preparations.

A third safety issue is adulteration. Unscrupulous herb dealers and manufacturers of herbal remedies have been known to add pharmaceuticals to their products. Some complex herbal mixtures have been found to contain indomethacin, warfarin, and diethylstilbestrol. Because these pharmaceuticals could account for any therapeutic effect, it can be impossible to determine whether the herbal components of a remedy possess any efficacy. If the presence of pharmaceuticals is confirmed, the herbal product would be banned from the market.

A fourth safety issue is misidentification. A pharmacologically active herb may be only one species of a large genus of plants. Proper identification of the species can often be difficult. One example of this is ginseng. American ginseng is highly sought after for its tonic effects, but the collection of wild American ginseng is strictly controlled to avert decimation of the species. There are other ginseng varieties that, according to herbalists, are much less efficacious but could appear as American ginseng in the marketplace. There are essentially no guarantees that the plants identified on the label of an herbal remedy are actually the plants present.

Finally, herbs are natural products, and the chemistry of the plant is determined by growing conditions, including seed stock. This can lead to considerable variation in the chemical composition of any given batch of herbs (Fig. 7-1). There are no “standards” or methods of certification that are accepted across the industry. When the active ingredients are not known, it is obviously impossible to standardize preparations to achieve a reproducible pharmacological effect. Not only does this make the clinical use of herbs difficult, but it is also a major impediment to research in this area.

image

FIGURE 7–1 Relative concentrations of active ingredients in plants are known to be affected by environmental conditions. In this illustration, growing strawberries in a high CO2 environment increased the content of the endogenous antioxidants, glutathione, and flavonoids.

Data from Wang et al. J Agric Food Chem 2003; 51:4315–4320.

New Horizons

Centuries of use have created the impression that herbal remedies are both safe and effective. The challenge to science is to provide controlled, clinical evidence for these claims. In a typically reductionist fashion, Western science has approached the study of herbs via a drug development model. Once an effect has been established, bioassay-directed fractionation of the plant extract can lead to isolation of a single active chemical. However, it is also of interest to investigate the more holistic philosophy, which requires development of research strategies for the study of highly complex systems. These might include complex mixtures of herbs, or a complex, individually tailored treatment plan using several different herbs at different times in conjunction with dietary changes. Research is also needed to determine potential mechanisms of action and to more rationally guide design of clinical trials. The concept of detoxification, with consequent increases in well-being and ability to ward off disease, is central to herbal medicine but has not been well studied by Western scientists. Safety concerns about herbal medicines require well-designed toxicological and pharmacokinetic studies and may lead to more restrictive approval and marketing requirements and more stringent monitoring of adverse effects (Box 7-8). Herbal medicine is practiced by several types of alternative medicine providers, including doctors of traditional Chinese medicine, naturopaths, homeopaths, and Ayurvedic physicians (the traditional medicine of India). An expanding trend in health care is the concept of complementary medicine, where such therapies are combined with conventional Western approaches. More research is needed to determine the advantages (or disadvantages) of these combined, integrated approaches, because this trend is being driven by patient demand as well as evidence for improvements in health care and outcomes.

BOX 7–8 Important Considerations in Using Herbals and Natural Products

• Labeling an herbal supplement as “natural” does not mean it is safe or without any harmful effects.

• Herbal supplements contain pharmacologically active chemicals. Therefore they can cause medical problems, if not used correctly or if taken in large amounts.

• Women who are pregnant or nursing, children, the elderly, and people with liver or renal insufficiency should be especially cautious about using herbal supplements.

• It is important to consider other drugs taken with an herbal supplement, because some herbal supplements interact with medications.

• In the United States, herbal and other dietary supplements do not have to meet the same standards as drugs and over-the-counter medications for proof of safety, effectiveness, and what the FDA calls “good manufacturing practices.”

• The active ingredient(s) in many herbs and herbal supplements are not known. There may be dozens, even hundreds, of such compounds in a single herbal supplement preparation.

• Published analyses of herbal supplements have found differences between what is listed on the label and what is in the bottle. Also, the word “standardized” on a product label is no guarantee of higher product quality, because in the United States there is no legal definition of “standardized” (or “certified” or “verified”) for supplements.

• Some herbal supplements have been found to be contaminated with metals, unlabeled prescription drugs, microorganisms, or other substances.

FURTHER READING

Information on herbal medicine from the National Library of Medicine available online at: http://www.nlm.nih.gov/medlineplus/herbalmedicine.html.

National Center for Complementary and Alternative Medicine available online at: http://www.nccam.nih.gov.

Searchable herb database from Memorial Sloan Kettering Cancer Center available online at: http://www.mskcc.org/mskcc/html/11570.cfm.

SELF-ASSESSMENT QUESTIONS

1. The strongest type of evidence for efficacy comes from:

A. Case reports.

B. Randomized, controlled experiments.

C. Case-controlled comparisons.

D. Personal experience.

2. Herbal products are regulated by:

A. USP.

B. DSHEA.

C. NCCAM.

D. NAFTA.

3. An herb commonly used to increase immune function is:

A. Kava.

B. Cayenne.

C. Echinacea.

D. Ginger.

4. An herb commonly used to treat mild depression is:

A. Milk thistle.

B. Marigold.

C. Licorice.

D. St. John’s wort.

5. Herbal products can make certain claims on their labels. For a hypothetical product, which statement is not allowed?

A. This product will improve the function of the female reproductive system.

B. This product will reverse a deficiency in calcium.

C. This product will cure cancer.

D. This product will give you increased energy.

6. Herbal products are more likely to be used by:

A. Middle-aged compared with older people.

B. Adolescents compared with the elderly.

C. High-school graduates compared with college graduates.

D. People with acute pain compared with people with cancer.