Herbal Therapeutics: The Top 12 Remedies, Part 3

After profiling the remaining three of herbal medicine's 12 most-used remedies—goldenseal, cranberry, and valerian—the final installment of this series looks at the regulatory status of herbal products and offers some tips for navigating the sea of information about them.

LAST OF THREE PARTS

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.

Herbal remedies, always widely accepted in Europe, have been embraced and reaffirmed in the United States to a remarkable extent in the past decade. St. John's wort, ginseng, ginkgo biloba, garlic, echinacea, saw palmetto, grape seed extract, kava, evening primrose, goldenseal, cranberry, and valerian lead the pack of botanicals reclaiming a place in America's medicine chest. In this third and final article on the subject, I will profile the last three of these herbs before moving on to an overview of the regulatory status of herbal products and the resources available to physicians and patients wishing to learn more about them.

GOLDENSEAL

Goldenseal photo © 2002 www.stevenfoster.com

Hydrastis canadensis. Goldenseal makes the list because of the volume of sales of echinacea-goldenseal combinations. (See part 2 of this article in the April issue for information about echinacea.) It is worth learning about goldenseal mostly for the ways it is misused by the public.

Goldenseal grows in deep woods from New England to the hills of Arkansas. Its name originates from the fact that when the stem is broken near the base of the plant, the scar resembles the gold wax used to seal letters in the 18th century. Native Americans traditionally have used it as a clothing dye and medicinally for skin conditions, eye irritation, and digestive problems including diarrhea.

Goldenseal has gone through a number of booms and busts over the years. It was so over-harvested in the 1980s that it is now considered an endangered species and was listed under the Convention on International Trade in Endangered Species (CITIES) of Wild Flora and Fauna in 1997. Its export from the United States is now controlled, and it is being cultivated as a cash crop in the state of Washington due to its limited supply.

Goldenseal's active constituents are primarily the isoquinoline alkaloids, of which berberine has been the most widely investigated. Berberine can be found in the stem bark of the plant, but the largest amount is extracted from the roots and rhizomes. Berberine is also found in barberry (Europe), Oregon grape, and goldthread (China). It has a long history of use in both traditional Chinese and Ayurvedic medicine.

The herb's primary clinical uses are based on its antibacterial and amoebicidal properties. The list of organisms against which goldenseal has activity is long and varied. It includes Diphtheria, Chlamydia, Gonorrhea, Treponema pallidum, Leishmania donovani, Salmonella, Shigella, Pseudomonas aeruginosa, Escherichia coli, Staphylococcus aureus, and a number of fungi. It may also have activity against Entamoeba histolytica, Giardia lamblia, and Trichomonas vaginalis.

For most types of infections, however, absorption of goldenseal is so poor that it is believed serum concentrations could never reach high enough levels to be effective in humans. It has been shown to concentrate in the bladder and to prevent E. coli from attaching to mucosal surfaces such as the bladder wall, so its utility in the treatment of urinary tract infections is plausible, although not validated by controlled studies. Goldenseal may also be beneficial in the treatment of sore throats and infections of the gastrointestinal tract because it is in direct contact with the site of infection. This has been validated in a number of human and animal studies. Clinical trials done in India on children with Giardia-positive stools showed berberine improved symptoms and reduced Giardia counts in the stools nearly as effectively as metronidazole at half the dose.

Another problem that is endemic in many parts of the world is ocular trachoma infections. One of several clinical studies of this infection found that an aqueous berberine chloride solution was superior to sulfacetamide in dropping serum antibody titers for C. trachomatis and in improving the clinical course of the infection.

As effective as goldenseal and other berberine-containing extracts may or may not be against bacteria, fungi, or protozoa, they do not seem to be at all helpful in the prevention or treatment of colds. In the United States, it is for this purpose that most goldenseal is purchased.

The other myth that has helped drive the sales of goldenseal is the widespread belief that it can mask illegal or controlled substances in the urine. The origin of this misconception is a work of fiction published in 1900 by a pharmacist and writer named John Uri Lloyd. In Stringtown on the Pike, Lloyd's most successful novel, a man who had taken goldenseal regularly (and correctly) as a digestive aid is found dead. A toxicology expert mistakes the traces of goldenseal in his stomach for strychnine and deduces that the man was murdered. This work of fiction created a folkloric connection between goldenseal and drug testing that somehow evolved into a notion quite the opposite of what happened in the story—that goldenseal can make urine drug screens come out negative. A word to the wise: it doesn't work.

Dosage for oral use in the treatment of intestinal infections is typically 250 to 500 mg of goldenseal three times a day. It should only be taken for two to three weeks. To make a decoction for tea, a gargle for sore throats, or a mouthwash, you would simmer 0.5 to 1 gm of the dried root or rhizome in 150 ml of water for 10 minutes and then strain. The liquid extract (1:1, 60% ethanol) is usually taken as 0.3 to 1.0 ml three times daily. Dosage for the tincture (1:10, 60% ethanol) is 2 to 4 ml three times daily.

Safety concerns with goldenseal are generally minor if the herb is taken as directed. However, high doses for prolonged periods can lead to significant toxicity, specifically cardiac toxicity (there have been reports of cardiac "spasms" and even death) and central nervous system stimulation, with reports of hallucinations, irritability, and occasionally delirium. There is also concern that another alkaloid in goldenseal, hydrastine, may cause hypotension at low doses and peripheral constriction and potential hypertensive effects at high doses. Some preliminary studies have shown a potential inhibition of cytochrome P450 3A4, which could raise circulating levels of drugs like most statins, most antifungals, fexofenadine, and many others in a patient taking goldenseal concomitantly.

Another possible problem is adulteration, common in goldenseal products because the herb is costly. However, a high-performance liquid chromatography test was recently developed to detect and quantify berberine and hydrastine in goldenseal samples.

CRANBERRY

Cranberry photo © 2002 www.stevenfoster.com

Vaccinium macrocarpon. Only three fruits can claim a North American heritage: the Concord grape, the blueberry, and the cranberry. Native Americans used cranberries for food, in dyes, and as medicine, mainly for urinary tract problems and arrow wounds—but they also believed that cranberry had tranquilizing properties. The name given to the fruit is thought to have originated with the early Pilgrims, who called it "crane berry" because the plant's stem and pink blossoms resembled the neck, head, and beak of a crane. A Pilgrim cookbook from 1663 described cranberry sauce.

Although for many years it was believed that cranberry was effective in the treatment of urinary tract problems because of its ability to acidify the urine, we now know that this is not the case. The primary effect of cranberry is to interfere with the attachment of fimbriated urinary pathogens (primarily E. coli) to the bladder wall. And it is the proanthocyanidin component that is thought to be responsible for this action. There is even some research to suggest that the fructose in cranberries may also contribute to its effects. Cranberry juice has shown antibacterial activity in culture medium against E. coli, S. aureus, Klebsiella pneumoniae, P. aeruginosa, and Proteus mirabilis. Whether the concentration of active constituents reached levels high enough in the urine to be of significant benefit is still debated.

There are a number of well-designed studies showing cranberry's efficacy in prevention of urinary tract infections (UTIs) in young women and in all older adults when 8 to 16 oz of pure cranberry juice is consumed daily. One recent study showed drinking 16 oz of cranberry juice per day eliminated recurrent bladder infections in 73% of 44 women and 16 men. Even more recently, a randomized trial comparing a cranberry-lingonberry juice blend with a drink containing lactobacillus GG (a patented strain of Lactobacillus rhamnosus) showed a 20% reduction in recurrent UTIs in the juice group.

Perhaps the best evidence to date came from the June 2001 meeting of the American Urological Association, where data was presented from a year-long, double-blind, placebo-controlled study involving 150 sexually active women who were randomized to either cranberry extract tablets, cranberry juice, or placebo. Results revealed both forms of cranberry were superior to placebo in the reduction of the number of bladder infections. This is the first trial in which taking tablets produced significant results. One prior study using cranberry extract tablets did not reach statistical significance in terms of reducing recurrent UTIs (although there was a positive trend), and recent evidence suggests that taking the tablets may increase the risk of nephrolithiasis by increasing urinary oxalate levels. There was also a negative study involving the use of cranberry juice extract in UTI prevention in children with neurogenic bladder who needed to be intermittently catheterized.

Cranberry compounds may protect the stomach from adhesion of H. pylori and thus improve outcome or aid management in patients with duodenal ulcer. Similarly, it may tend to prevent and control gum disease by blocking the coaggregation of plaque-producing species in the mouth. There is evidence from animal studies that cranberry products may improve outcome or delay onset of cancer, possibly due in part to the antioxidant properties of cranberry compounds. They also may boost the antioxidant capacity of serum, thereby contributing to inhibition of LDL cholesterol oxidation and potentially helping to prevent heart disease.

Optimal dosage of cranberry juice for the prevention of UTIs has not been validated. Most studies have used between 1 and 10 oz per day of pure cranberry juice (a few did use cranberry juice cocktail). It is thought that 6 capsules of cranberry extract are equal to roughly 3 oz of cranberry juice. Encapsulated extracts are usually recommended at doses of 300 to 400 mg twice daily.

Cranberry compounds and juice are generally well tolerated at recommended dosages. Excess consumption can, of course, lead to "acid stomach" and diarrhea. Also, high doses of juice or tablets over a prolonged period may promote the formation of kidney stones.

VALERIAN

Valerian photo © 2002 www.stevenfoster.com

Valeriana officinalis. Valerian is a native plant both to Europe and North America. From June through September, small, rose-colored flowers bloom on a stem that grows to a height of 2 to 4 feet. Medicinally, the rootstock is used.

Historically, valerian has been used as a sedative for insomnia and anxiety and to mitigate pain. Galen, in his writings, recommended it for insomnia in the second century A.D. In Europe, it has been a very popular sedative since the 16th century. Medical literature from the late 1700s mentions valerian as particularly useful in those with a "nervous stomach." In 1985, Germany's Commission E169 approved it as a sleep aid. Its extracts and essential oils are also used in the manufacture of flavorings for foods and beverages.

Valerian's pharmacologic effects have been attributed primarily to several volatile oils, including valeric acid (which gives the extract the unpleasant aroma of dirty socks) and the valepotriates (monoterpenes and sesquiterpenes). The primary monoterpene is berneol and the primary sesquiterpenes are valerenic acid, valerenone, and kessyl glycol. Valerenic acid also appears to inhibit the breakdown of gamma-aminobutyric acid, thus increasing concentrations of that amino acid in the brain and decreasing central nervous system activity. However, there is evidence that valerian extracts without some of these constituents can act similarly, suggesting that multiple compounds, some currently unknown, are responsible for valerian's actions.

The main clinical indication for the use of valerian extracts is insomnia. Two excellent review articles have been published recently. A number of small placebo-controlled studies have shown consistent benefit in reducing sleep latency (time to sleep onset) and improving sleep quality in patients using valerian extracts. There have been several head-to-head studies in which valerian, sometimes in combination with lemon balm or hops, compared favorably with low-dose benzodiazepines. It seems from the bulk of the literature that valerian is better at relieving insomnia if taken consistently over an extended period of time rather than on an as-needed basis. Some patients may require from one to four weeks of continuous nightly use to obtain significant relief.

Benzodiazepines often provoke complaints of grogginess and poor concentration the morning after ingestion. No such effects from valerian, even after multiple, consecutive 600-mg doses, were reported by 102 male volunteers in a randomized, controlled, double-blind study of the herb's effect on reaction time, alertness, and concentration.

Dosage for insomnia is 2 to 3 gm of dried herb decocted to a tea, 270 to 450 mg of an aqueous extract, or 400 to 900 mg of an ethanol extract, taken 30 minutes to 2 hours prior to bedtime. Several studies have lasted 28 days.

Adverse reactions to valerian are usually mild and rare when it is used short-term in recommended doses. More than 12,000 patients involved in clinical trials with valerian have taken it for up to 28 days with no untoward effects. At higher doses over longer periods of time, benzodiazepine-like withdrawal symptoms may occur when the herb is stopped. There is one case report of a man taking multiple medications who developed delirium and sinus tachycardia after surgery. The patient had been taking between 2.5 and 10 gm of valerian root extract daily for many years to "help him rest." Although there were many confounding variables, the case was reported as valerian withdrawal. Patients who have taken valerian for a long time should be weaned off the medication over the course of a couple of weeks.

There have been four case reports of hepatotoxicity associated with long-term valerian usage, with no agreement as to their significance. All involve confounding variables and the possibility of adulterated compounds, and it is thought that some of them may represent idiosyncratic reactions to the herb rather than dose-related problems. We do know from both animal and human experience that it takes very large amounts of valerian extract to cause significant side effects. An illustrative case is the young girl who tried to commit suicide by ingesting approximately 20 gm of valerian (20 to 40 times the recommended dose). She reported mild stomach cramps, chest tightness, fatigue, lightheadedness, and tremors of the hands and feet. All these symptoms resolved after two doses of activated charcoal and 24 hours of observation.

Although many trials have failed to demonstrate any morning grogginess or motor or concentration impairment, there are reports of acute motor impairment within a short time of taking valerian supplements. Patients should be warned not to drive or operate machinery for at least a few hours after ingestion.

There have been no reports of drug interactions with valerian, but it makes sense not to mix it with alcohol or other central nervous system depressants, such as benzodiazepines. As with goldenseal, some very preliminary evidence suggests that valerian might inhibit cytochrome P450 3A4 and thus increase the circulating levels of other medicines such as the statins, antifungals, erythromycin, and many others. Valerian has not been established as safe for use in children, pregnant women, or breastfeeding mothers.

REGULATION OF HERBAL AND DIETARY SUPPLEMENTS

In the three parts of this article, I have reviewed recent findings about the effectiveness of the most popular remedies. While it may be easy enough to discount the merits of this or that small study on one herb or another, even the most skeptical among us must recognize the growing amount of literature with which we are presented—particularly in the form of meta-analyses of multiple studies and systematic reviews.

Much of the fervor demonstrated by the public for St. John's wort in 1998—a year in which sales of that herb increased by 2800%—was created by press reports of a meta-analysis of 23 trials involving 1757 patients that showed the herb was as effective as conventional antidepressants in treating mild to moderate depression. Since that article, at least 12 more randomized trials have confirmed the herb's efficacy. An exception was the study recently published in JAMA (April 10, 2002), but it found no evidence of efficacy for sertraline, either, and the authors acknowledge the possibility of a problem with low assay sensitivity. Equally if not more questionable is that the median daily dose of hypericin that these patients with "moderately severe" major depression received was about the same as in most studies of patients with mild depression, and the lowest dose was lower.

Similar positive results have been found with a number of herbal preparations in other meta-analyses. A review of Ginkgo biloba covered nine placebo-controlled, double-blind studies involving 1497 patients that showed it was more effective than placebo in delaying the clinical course of dementia. A meta-analysis of 18 randomized, placebo-controlled trials of saw palmetto extract with 2939 patients showed improvement in signs and symptoms of benign prostatic hyperplasia superior to placebo.

Yet with all this mounting evidence of efficacy, are the benefits going to outweigh the risks? Most supplements in the United States and the United Kingdom are basically unregulated. In the United States, this situation is the result of the Dietary Supplement Health and Education Act of 1994 (DSHEA), which substantially broadened the definition of dietary supplements. The classification formerly included only the "essential" nutrients, but now, "supplement" may mean a vitamin, a mineral, an herb or other botanical, an amino acid, a substance intended to augment total dietary intake, or a concentrate, metabolite, constituent, extract, or combination of any ingredient described in the foregoing. Obviously, this is quite a broad definition.

In some countries, such as Germany, many botanical supplements are regulated as drugs and are subject to quality, safety, and efficacy parameters. But in the United States, they are distinguished from drugs and food additives and governed by regulations similar to those for food. In addition, review and approval by the Food and Drug Administration (FDA) of the ingredients of supplements is not required before marketing as would be the case with drugs or food additives. Food industry good manufacturing practices are expected to be followed by the producers of nutritional supplements, but as yet, the government has no specific guidelines in place.

Currently, the FDA is working with several trade organizations to develop guidelines (see box below), and some manufacturers have devised their own parameters for quality control. All of these organizations employ third-party inspectors and quality control measures to assure laboratory standards for quality and consistency. They are the beginnings of the industry's effort to police itself and show good quality control before the government steps in and does it for them. The fact remains, though, that unlike drugs and food additives, which must undergo rigorous testing and clinical or safety trials, supplements must be proved unsafe before the FDA can make a move to restrict their use. Many medical professionals and some consumers are uncomfortable with that and are calling for better regulation of the definition and implementation of quality standards for supplement makers, and the trade organizations' efforts may or may not ultimately satisfy their concerns.

Another consequence of DSHEA and subsequent amendments was the impact of new labeling restrictions on dietary supplements. Nutrition and ingredient labeling became mandatory and limits were set on health claims. Only six health claims have been approved for use on both food and dietary supplement labels: calcium for osteoporosis; folate for neural tube defects; sugar alcohol for cavities; and oat fiber, psyllium seed fiber, and soy protein for coronary heart disease. But it is permissible to state that the product provides nutrient support to a bodily structure or function. An example might be: "...supports a healthy cardiovascular system." Statements of this type must be reported to the FDA within 30 days of marketing the supplement, and the statements must be accompanied by the following disclaimer: "This product is not intended to diagnose, treat, cure, or prevent any disease."

These limitations apply to labeling only. As all of us know, claims—some unsubstantiated—about the health benefits of supplements are regularly made on TV, in books and magazines, and on the many Web sites where dietary supplements are sold. Patients are apt to be misled by these and to be unaware that dietary supplements are regulated more like foods than drugs, believing that their production and manufacture are under the auspices of the FDA. While it is apparent to health professionals that the lack of regulation of supplements creates the potential for some significant problems, our patients may feel much safer than they should. It's a good idea to perform a "reality check" with each patient and make sure he or she realizes that until the regulatory situation changes, the age-old adage "buyer beware" holds for the purchase of herbal supplements. For other points to discuss with patients about herbal medicine, see the sidebar below.

KEEPING UP WITH THE FIELD

It is extremely difficult to keep up with all the areas of medicine that are constantly changing: new drugs, new procedures, new therapies—to say nothing of the financial challenges facing all of us—and now, complementary and alternative medicine (CAM). Fortunately, as resources and options proliferate, it is getting easier to educate ourselves about CAM. The number of conferences, journals, newsletters, publications, Internet sites, and CD-ROMs continues to grow by leaps and bounds. There are more than 425 titles under the "Alternative Medicine" heading in the 2001 edition of Medical and Health Care Books and Serials in Print.

How does a busy physician begin to wade through all of the material dealing with complementary therapies? One possible starting point is an indispensable resource paid for with our tax dollars: the International Bibliographic Information on Dietary Supplements (IBIDS) database. This is a large, user-friendly, international collection of published scientific literature on dietary supplements, including vitamins, minerals, and botanicals, updated quarterly. Produced by the Office of Dietary Supplements at the National Institutes of Health, the IBIDS database was designed to assist all people in locating credible, scientific information on dietary supplements.

The IBIDS database currently contains more than 460,000 scientific citations and abstracts with links to more than 1600 journal Web sites where full-text articles are available online. The database can be accessed through public or university libraries or directly by going to http://ods.od.nih.gov/databases/ibids.html.

Beyond IBIDS, there is a wealth of information available to those who desire to continue to learn; for more educational resources, see the sidebar below.

As the tide of interest in herbal and nutritional therapies continues to rise, clinicians need to re-examine negative attitudes toward these methods in light of the abundance of information gleaned from recent clinical trials. Many surveys have shown that patients would rather get their health care information from their doctor than from anyone else. However, physicians have felt ill equipped to answer many of their patients' questions about herbal medicine. It is my hope that this article may help to build a bridge of communication between the two groups.

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