Herbal Therapeutics: The Top 12 Remedies

The astounding growth in the sale of herbal remedies and the reluctance of patients to report their use has created an urgent need for physicians to become more familiar with them. The author begins a series on this subject with an overview of the trend and an examination of the top three sellers: ginkgo, St. John's wort, and ginseng.

By R. W. Watkins, MD, MPH, FAAFP

Dr. Watkins is assistant clinical professor of family medicine at UNC School of Medicine in Chapel Hill, North Carolina, and has a private practice in Summerfield, North Carolina.

In recent years, the growth of the herbal marketplace has been staggering. This three-part article will address some of the possible reasons for this growth, the extent and consequences of the growth as it relates to patient care, and the important recent developments in research and medical education relating to herbal medicine in the United States. The 12 top-selling herbal remedies in the United States will be discussed, including a brief historical account, active constituents and mechanism of action, clinical indications, usual dosages, safety concerns, and potential drug-herb interactions for each herb. Regulation of herbs in the United States also will be addressed, and a guide to further learning will be provided to help the clinician navigate through the vast amount of information that is available in this increasingly influential field.

TRENDS IN HERBAL MEDICINE

Herbal supplements are the fastest growing segment of the dietary supplement market in the United States. According to the publication Natural Foods Merchandiser, sales increased from $570 million in 1992 to more than $3.87 billion in 1998, most rapidly at supermarkets, drug stores, and mass merchandisers.

Just what is driving this explosive growth is not completely clear, but it is almost certainly multifactorial. On one hand, surveys point to a connection with the increasing percentage of older people in the American population. The results indicate that members of the "baby boom" generation, now mostly in their 50s, are seeking a more holistic approach to health care as their ailments become more chronic in nature. These ailments include arthritis and other degenerative conditions, such as diabetes, heart disease, and cancer, as well as anxiety, depression, and headaches. And there are either real or perceived limitations to conventional treatments for many of these conditions. On the other hand, sales figures show that the most popular uses of herbal medications are for acute problems like colds, flu, and burns (see chart below).

Reluctance to rely on a single authority for health care is another common theme in surveys of herb users. And many respondents voice concern about being asked to take more and more synthetic drugs because there is a higher incidence of adverse effects, they believe, with these chemically based products. They tend to subscribe to the idea that "natural is better–and safer" than conventional medicines and are seeking alternatives derived from natural sources. Some consumers are attempting to take greater control of their health care in a proactive fashion, adopting preventive practices and healthier lifestyles, rather than reacting to disease when it occurs. Many of these people include herbal medicines in their paradigm.

A great deal of information–with a wide variation in reliability-about self-diagnosis and treatment in the media, including the Internet, is providing support for these views and efforts. The popular press keeps an eye on the scientific press and tends to pick up and disseminate stories dealing with herbal medicine when meta-analyses of clinical studies are published.

And there are supply-side factors as well, such as changes in advertising practices. Major sellers of natural remedies have begun using television to bring their messages to a mass audience. Sundown, for one, increased its advertising budget by nearly 370% in 1999, spending over $14 million on its top-selling glucosamine product, Osteo-bioflex, alone, according to Drug Store News (May 17, 1999). Meanwhile, the Internet not only is a growing source of information but has emerged over the past few years as an entirely new channel for sales. Some health plans have aligned themselves with complementary and alternative practitioners. And major players in the pharmaceutical industry have either bought up supplement manufacturers or begun actively promoting their own lines of natural remedies.

These trends obviously raise some serious issues for physicians, the first and foremost of which is the safety of the herbal medicines their patients are taking. This concern has two aspects: drug-herb interactions and herbal product quality. Both are certainly valid.

DRUG-HERB INTERACTIONS

A number of recent studies and surveys have demonstrated the breadth of the problem of drug-herb interactions. Some surveys have reported that almost one-third (32%) of adult Americans use at least one herbal medicine per year (Prevention magazine, 1997). Roughly 15 million adults in the United States (18.4% of all users) in 1997 took prescription medications concurrently with herbal medications, megadose vitamins, or both, yet only 38.5% of this usage was reported to the user's physician.

A University of Chicago survey found that up to 50% of patients scheduled for surgery were using herbal preparations that might cause surgical complications unless their physicians were aware of their use. Garlic, for example, often used to lower blood pressure, also prevents clotting, which may lead to serious bleeding. The use of any form of garlic should be discontinued at least seven days prior to surgery.

A recent Mayo Clinic prevalence study of 752 persons 18 years of age and older in the Minneapolis-St. Paul area showed just how often these products are being used. In their survey, investigators found that 61% of survey respondents had used an herb over the past year. Of those, 25% had used garlic, 30% had used ginseng, and 12% had used ephedra, all known to affect blood pressure regulation.

Herbs can interact with conventional medicines in many ways. Sometimes the effect of the medicine is enhanced. Such is potentially the case between warfarin and Ginkgo biloba or warfarin and ginseng. Or sometimes the effect of a drug is diminished, as when St. John's wort is given to AIDS patients taking cyclosporin. Herbs can mimic, augment, or reduce the bioavailability of prescription drugs in ways that are not always taken seriously enough. For example, taking lithium or digoxin concurrently with powdered psyllium seeds can interfere with absorption of the drugs enough to compromise their effectiveness, which might, indeed, put the patient at significant risk. It is always possible that an herbal remedy will affect the absorption, excretion, or metabolism of the drug in question, whether or not the herb has a directly attributable action that is antagonistic to the drug.

QUALITY–OR THE LACK OF IT

Herbal supplements do not require the approval of the FDA; under the 1994 Dietary Supplement Health and Education Act, they are considered food supplements. Safety and efficacy are not guaranteed, and no outside monitoring programs are currently available for the identity and potency of herbs. Thus, there are no definitive standards or regulations by which to judge the quality of herbal supplements. Herbal products may be adulterated, misidentified, or contaminated. The literature clearly indicates that such problems are more prevalent with herbs and herbal combinations produced outside of Europe and North America. Nevertheless, there is reason to be concerned about products manufactured in the United States, as evidenced by a recent survey of 25 commercial ginseng preparations from a health food store, which found concentrations of the active constituents varying from 15- to 200-fold in both capsule and liquid forms.

A similar situation was found in a recent survey of ephedra-containing products, with half of the entries exhibiting discrepancies in ephedra alkaloid level of more than 20% between the label claim and actual content. However, there are reputable sources for information regarding the safety of herbal products (see sidebar below).

HEALTH PROFESSIONALS NEED MORE INFORMATION

There has been in the past a distinct lack of education among allopathic physicians in the United States on the merits of herbal medicine. Many physicians also lament the fact that there has not been enough quality research in the area of herbal medicine. Both of these conditions are slowly changing. The National Institutes of Health (NIH) had a budget increase for the Office for Alternative Medicine (OAM) from $2 million in 1991 to over $50 million in 1998 with the injunction "to conduct basic and applied research." Along with this increased funding came a name change from OAM to the National Center for Complementary and Alternative Medicine (NCCAM).

More recently, NCCAM (with co-funding by NIH) set up 13 cooperative research centers at major medical schools around the country to continue and expand research into the fields of herbal and alternative medicine. More than 90 medical schools in the United States offer programs in complementary and alternative medicine, and the World Health Organization's Collaborating Center for Traditional Medicine at the University of Chicago does much work in this area.

Despite all that, resident physicians still possess little knowledge in the arena of herbalism, according to a survey reported in Archives of Internal Medicine (161:13, 1679, 2001) last year. When asked to name three commonly used herbs, 35% of the residents could not even name one, and 24% could name only one. When asked about conventional medicines that could interact with herbs, 48% claimed ignorance, and of the remainder, 35% named warfarin, 8% named digoxin, and only 2% mentioned phenytoin. Only 79% believed herbs deliver any clinical benefit, and only 26% had inquired about the use of alternative therapies in the last five patients they had seen.

Elsewhere around the globe, research and education on herbs are in progress at various centers, including the Department of Complementary Medicine at the University of Exeter in the United Kingdom and, in Australia, the University of Sydney's Department of Pharmacy, which has established the Herbal Medicines Research and Education Center. In fact, when it comes to herbal medicine, physicians in the United States are still playing catch-up. In Europe, herbalism and "non-orthodox" systems of healing have been part of medical education for many years. In Germany and France, 30% to 40% of physicians rely on herbal remedies as their primary therapeutic tools.

Marketing statistics show that 10 herbs account for 54% of total herb sales worldwide. In the United States, the top 12 selling herbs make up about 95% of sales (see table below). And although herbal medicine continues to grow, the sharp rise of the mid-90s has shown signs of leveling off. From 1998 to 1999, it grew by a relatively modest 15.8%. And there was no change in the top 12, suggesting that the physician who can find time to study these most popular herbs will gain some very practical knowledge.

GINKGO

Ginkgo biloba photo © 2002 www.stevenfoster.com

Ginkgo biloba. Ginkgo is the earth's oldest living tree species, dating back to the Permian period some 230 million years ago, and has rightfully been called a "living fossil." Individual trees may live over 1000 years. Ginkgo was the only tree to survive the atomic blasts at Hiroshima and Nagasaki. Medicinally, it dates back to the earliest Chinese Materia Medica (2800 BC) and has a long history of use for memory impairment in the elderly and respiratory problems in patients of all ages.

The active constituents of ginkgo fall into two main groups of components: the ginkgo flavone glycosides and the terpene lactones. These are bioflavonoids that are believed to be responsible for the antioxidant and platelet-inhibiting effects of ginkgo biloba extract (GBE).

Primarily, ginkgo has been used in cases of vascular insufficiency, both cerebral insufficiency and peripheral. There have been more than 50 double-blind studies indicating a beneficial effect of GBE on cerebral insufficiency. It has been shown to enhance the utilization of oxygen and glucose by the brain and preferentially re-establish effective tissue perfusion in areas of ischemia.

Perhaps ginkgo is best known in the popular press for its effects in Alzheimer's and other dementias. Evidence from multiple studies lasting from three months to a year shows that GBE can stabilize or improve some measures of cognitive and social function in patients suffering from several types of dementia. There is also considerable evidence that GBE may be effective in depression (particularly in the elderly), erectile dysfunction due to lack of blood flow or secondary to drug treatment with selective serotonin reuptake inhibitors (SSRIs), and peripheral vascular disease.

Most studies have used a daily dose of 120 to 160 mg of GBE, standardized to contain 6% terpene lactones and 24% flavone glycosides and divided into two or three doses. Amounts of up to 240 mg per day have been used in patients with cerebrovascular insufficiency, resistant depression, or sexual dysfunction due to SSRIs. Ginkgo can take a minimum of six to eight weeks to produce results.

Safety issues mainly center on GBE's ability to prevent platelet aggregation. Ginkgolide B is indeed a potent inhibitor of platelet aggregating factor. Thus, concomitant use of aspirin or other NSAIDS, as well as warfarin and heparin, should be done with care, and ginkgo extracts should be stopped at least one week prior to surgery. A recent case report implicated GBE in a case of postoperative bleeding after a laparoscopic cholecystectomy.

There have been two other recent reports that warrant attention. One involved a man taking small amounts of trazodone (20 mg twice daily) and ginkgo extract (80 mg/day) who became comatose. Ginkgo may have an inhibitory effect on cytochrome P450 CYP 3A4, which could have caused the loss of consciousness, researchers say. The other involves ginkgo's potential to induce hypoglycemia. It is proposed that GBE induces beta-cell function in the pancreas. Thus, patients taking insulin, or insulin stimulators or sensitizers, should be alert to this effect.

In a large post-marketing surveillance study of ginkgo involving 10,815 patients, mild side effects were reported in just 1.7%. Most associated side effects are gastrointestinal in nature. Headache, dizziness, palpitations, and allergic skin reactions have also been reported.

ST. JOHN'S WORT

St. John's wort Hypericum perforatum photo © 2002 www.stevenfoster.com

Hypericum perforatum. Derived from the Greek, the name can be translated "over an apparition," meaning that the smell of the herb was so obnoxious to evil spirits that a whiff of it would cause them to depart. Thus, as is often the case with herbal remedies, the name reflects its use: warding off the "evil spirits" of depression and mental illness. The other story regarding the name states that the flowers of St. John's wort (SJW) have their brightest appearance on June 24th, believed to be the birthday of John the Baptist. References to the herb have been found in the writings of Dioscorides, Pliny, and Hippocrates, all of whom used it to treat a variety of illnesses. In Europe, it is used as a food coloring and flavor additive and many people use it topically as a treatment for burns and wounds.

The active constituents of SJW involve at least 10 groups of components that may contribute to its effects. Most research grade product is standardized to the hypericin content, but recently interest has focused on the hyperforin component. Hyperforin modulates the effects of serotonin, possibly through serotonin reuptake inhibition and 5-HT3 and 5-HT4 receptor antagonism. Hyperforin also inhibits uptake of gamma-butyric acid (GABA) and L-glutamate. St. John's wort inhibits reuptake of serotonin, norepinephrine, and dopamine and catechol-O-methyl transferase (COMT) and monoamine oxidase (MAO) in vitro. But it is unclear how much clinical significance one should infer from this. There are no case reports of MAO inhibition with SJW in the literature.

The primary indication for this herb is mild to moderate depression. There have been more than 6000 patients taking SJW for depression in more than 425 studies, of which more than 100 were double-blinded and placebo-controlled. It has gone head-to-head with conventional antidepressants in 27 studies to date, making it the most fully studied of all herbal preparations. Overwhelming evidence shows that SJW works for many people, performing at least as well as the tricyclic antidepressants (with many fewer side effects) and possibly as well as fluoxetine, sertraline, and other established SSRIs.

Most research in depression has used a daily dosage of 900 mg (some studies have used up to 1800 mg per day) standardized to contain 0.3% hypericin divided into three doses. Therapy often must continue for 6 to 12 weeks before an effect is seen.

Recently, SJW has come under fire for its ability to induce cytochrome P450 3A4 and thus change the pharmacodynamics of a number of medications. The herb can decrease plasma cyclosporine levels by 61%. In patients with heart, kidney, or liver transplants, SJW can cause subtherapeutic cyclosporine levels and acute transplant rejection.

Using SJW with protease inhibitors in the treatment of AIDS can significantly reduce serum concentrations of these drugs. In a study of healthy volunteers receiving indinavir, SJW reduced the drug's serum area under the curve by 57% and its extrapolated trough by 81%. As with other antimicrobials, subtherapeutic concentrations are associated with therapeutic failure and development of resistance.

Other drugs metabolized by cytochrome P450 3A4 might be affected as well. Possibilities include amitriptyline, carbamazepine, cyclosporin, digoxin, and perhaps even birth control pills.

Theoretically, the possibility of inducing "serotonin syndrome" and thus negatively affecting blood pressure control should be entertained when combining SJW with the SSRI antidepressants, the triptans (5-HT1 agonists), fenfluramine, nefazodone, and monoamine oxidase inhibitors. Combining these medications should either not be done or done by someone with experience.

Photosensitivity can occur with higher doses of SJW in susceptible individuals or in those also taking photosensitizing drugs like tetracycline or the quinolones.

GINSENG

Panax Ginseng photo © 2002    www.stevenfoster.com

Panax ginseng. Panax or "Asian" ginseng has been part of traditional Chinese medicine for more than 2000 years. Historically it was called jen shen or "man root," which became ginseng. The Chinese Materia Medica has uses for ginseng to treat almost any malady imaginable. It has attained great popularity in the United States, where more than 6 million people use it daily. Interestingly, almost the entire crop of American ginseng is exported to China.

Ginseng is widely popular as a general tonic or for coping with stress. The main active constituents appear to be primarily the ginsenosides. There are 13 identified subtypes. These are thought to be responsible for increasing energy, countering stress, and enhancing intellectual and physical performance. Other constituents include pectin, B vitamins, and various flavonoids. There is some evidence that ginseng may affect the hypothalamic-pituitary-adrenal axis and alter the stress response in that way; it seems to stimulate adrenal function and increase serum cortisol concentrations. It may also raise dehydroepiandrosterone sulfate levels in women.

Ginseng seems to stimulate natural killer cell activity and possibly other immune system activity, including antitumor activity. Ginsenosides also interfere with platelet aggregation and coagulation. In addition, a group of ginseng polysaccharides, known as the panaxans, have been shown to reduce fasting blood glucose levels and hemoglobin A_1C in people with type 2 diabetes. Unfortunately, there are a number of well-conducted studies that show ginseng has little effect on improving athletic performance.

There is some evidence that a Panax ginseng root extract can inhibit cytochrome P450 2D6 activity by approximately 6% in humans, a mild effect. However, it appears to have no effect on 3A4 activity.

Dosage should be standardized to the ginsenoside content of the product. Most research has been done with 100 to 200 mg of Panax ginseng standardized to 4% to 7% ginsenoside content. This would be equivalent to ingesting roughly 2 to 4 grams of ginseng root. Many experts suggest cycling two to three weeks on and one to two weeks off. Few studies have looked at ginseng's effect for longer than three months, and traditionally, the Chinese have only used it short-term.

However, there is at least one problem with this approach: the great variability in commercial ginseng products. A recent survey of 25 commercial ginseng preparations showed that concentrations of marker compounds differed significantly from what was on the package label, with ginsenoside concentration varying by 15- to 36-fold in capsules and liquids.

In general, Panax ginseng is well tolerated, but it is definitely one of those herbs of which more is not better. Safety concerns with ginseng mainly center on its inhibition of platelet aggregation. Like gingko, it should be stopped at least a week before elective surgeries and prothrombin times should be monitored in those taking warfarin.

A number of case reports have depicted Panax ginseng's central nervous system-stimulating effects (nervousness, insomnia, and headache). It should not be given to those who are manic-depressive or anxious. Other case reports suggest estrogen-like effects, such as mastalgia and even vaginal bleeding, although this notion is controversial. In addition, there are reports of a "ginseng abuse syndrome" from the 1970s that included hypertension, insomnia, nervousness, and increased libido. Like the estrogenic effects, this syndrome is not a consistent finding and is quite controversial among experts.

Given ginseng's immune-stimulating properties, it makes sense to administer it with care to those on immune-modulating drugs and in those with rheumatoid or connective tissue diseases. One condition that should be monitored closely when adding ginseng to the medication list is diabetes. As outlined above, ginseng may affect blood sugar levels in healthy, nondiabetic patients as well as those with type 1 or type 2 diabetes.

In part 2 of this article next month, Dr. Watkins will profile garlic, echinacea, saw palmetto, grapeseed extract, kava kava, and evening primrose.

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