Update on Common Dietary Supplements

Emerg Med 37(3):18-28, 2005

What do we know about echinacea, ginkgo, saw palmetto, glucosamine, and black cohosh? Why are patients taking them, and what should their expectations and concerns be? The author describes patterns of use and highlights key research findings on these five popular supplements.

By Katherine Gundling, MD

Medicinal herbs and dietary supplements have become a common topic of conversation between patients and physicians, and medical journals devote increasing attention to their safety and efficacy. This article reviews several of the most commonly consumed herbs and supplements, based on consumer sales data for 2002, and identifies resources for reliable information about these products and their use (see box below).

DEFINITION OF A DIETARY SUPPLEMENT

For most of us the term "dietary supplement" brings to mind vitamins and minerals. Since the passage of the Dietary Supplement Health and Education Act (DSHEA) of 1994, however, the definition has encompassed botanical agents, various amino acids, natural hormone products, and a host of other substances that can be sold individually or in combination.

Physicians need to be familiar with dietary supplements for several reasons. One is that although the DSHEA stipulates that claims made for these products may pertain only to structure and function (as in "to support healthy prostate function"), some sellers continue to make claims that may engender unrealistic patient expectations about anything from baldness to cancer.

Another concern for physicians is the potency of these supplements. While many have little to nothing of consequence in them, others are high-quality, pharmaceutical-grade preparations designed to have specific physiologic effect. St. John's wort, the popular herbal product used for mild to moderate depression, is a good example of why physicians cannot assume that botanical agents are physiologically inert. Once one of the top-selling supplements, this agent was implicated in serious herb-drug interactions resulting in significant patient morbidity. Although its sales have declined, St. John's wort is still a popular remedy for those who self-diagnose or desire a "natural" treatment for depression.

On the other hand, there is increasing evidence that men with troublesome symptoms of benign prostatic hypertrophy (BPH) can obtain benefit from using saw palmetto, a botanical agent with a good safety profile.

Physicians can help their patients by staying up to date regarding the safety and efficacy of dietary supplements. Such information will allow doctors to offer new therapies while avoiding preventable adverse effects.

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ECHINACEA

Echinacea (Echinacea purpurea and others) remains one of the most commonly consumed botanical agents (see table for summary). Most people take it in hopes of enhancing immune function and thereby preventing or treating upper respiratory and other infections. Extracts have been prepared from roots, flowers, and leaves.

The most recent complete Cochrane Database Systematic Review, in 2000, noted that most studies of echinacea for prevention and treatment of viral upper respiratory infection (URI) reported positive results, but that there was not enough evidence to recommend one or more specific echinacea products. Subsequent studies have had mixed results. Schulten and colleagues found that a preparation of Echinacea purpurea was more effective than placebo and well tolerated in the alleviation of symptoms of the common cold in 80 adult men and women. Goel and colleagues were concerned that the variable results of clinical trials might have to do with inconsistency of the quality of echinacea preparations tested. They enrolled 282 adults in a trial that used a highly standardized, freshly harvested proprietary formulation. Upper respiratory infections developed in 128 patients, and, in comparison with subjects in the placebo group, those in the echinacea group (who followed all elements of the protocol) had lower total daily symptom scores. The real-world applicability of this protocol is uncertain.

On the other hand, Barrett and colleagues found no improvement over placebo in the severity or duration of self-reported symptoms of the common cold in 148 students who consumed a combination of E. purpurea and E. angustifolia. Yale and colleagues found no difference in total symptom scores, mean individual symptom scores, or time to resolution of URI in 128 adults who took placebo or 100 mg E. purpurea (freeze-dried pressed juice from the aerial portion of the plant) within 24 hours of the onset of symptoms. In another study with negative results, Taylor evaluated whether the consumption of E. purpurea in children could reduce the duration or severity of symptoms of URI. No significant difference was found in the evaluation of 707 URIs that occurred in 407 children. Notably, there was a higher incidence of rash in the echinacea group than in the placebo group.

Due to the variety of organisms that can cause symptoms of URI, Sperber attempted to study the effects of echinacea in a more tightly controlled environment. Forty-eight patients were given E. purpurea or placebo seven days before and after nasal inoculation with rhinovirus type 39. Almost all patients in both groups were infected with the virus. Clinical symptoms developed in 58% of the echinacea group and 82% of the placebo group, but this difference was not statistically significant. The question was raised whether the study was sufficiently powered to detect a significant difference.

What are the immunomodulatory properties of echinacea? Many in vitro and a few in vivo studies have been performed to investigate this question. In vitro studies, in particular, have shown enhanced macrophage activation with cytokine production, and in a smaller number of analyses, increased natural killer cell activity. Just how (or whether) these observations translate to clinical effect is not clear. The immunomodulatory effect of echinacea in humans has also not been demonstrated in the laboratory in a clear and consistent manner.

The challenges of studying echinacea are reflective of the study of botanical medicine in general. What part of the plant should be used? What is the difference between use of the root and use of the aerial parts? How does each commercial product (liquid, powder, capsule, tablet) vary in quantity and quality of active ingredients, and what are the differences among species of echinacea?

With respect to product quality, a recent study of 11 echinacea products purchased over the counter showed that five products failed the minimal requirements for product purity and quantity of active ingredients. One brand failed due to excessive lead content and the other four due to inadequate levels of active ingredients.

Short-term use of echinacea is probably safe for most healthy people, although, as previously noted, increased incidence of rash compared to placebo has been observed in children. Additionally, patients with autoimmune disorders, or any predisposition to them, should not use echinacea without express permission from a physician. Significant herb-drug interactions are not obvious and profound effects on the cytochrome P450 system have not been observed, although further investigation is warranted.

In summary, recent studies have not helped to clarify the true effects of echinacea in the prevention or treatment of the common cold. The more modern studies that have been well designed have shown conflicting results. Currently under way is a clinical trial sponsored by the National Institutes of Health (NIH), expected to enroll 800 subjects and to be completed in 2006. Importantly, it is difficult to compare results of clinical trials of echinacea because of the variety of preparations used and the different clinical outcomes measured. Consistency of quality is a problem with echinacea, as well as other herbal and nutritional preparations, in the United States.
 

GINKGO

Ginkgo (Ginkgo biloba) has remained at the top of the list of popular botanical agents (see table for summary). It is usually taken to improve memory or treat memory disorders, to treat vascular insufficiency, or to relieve tinnitus. It is one of the most commonly prescribed agents, pharmaceutical or herbal, in Germany. Most preparations are made from a leaf extract. Strictly speaking, ginkgo is a tree, not an herb, and can be found in many areas of the United States. Its vivid, yellow fall foliage and bilobed leaf shape make it easily recognizable.

The potential of Ginkgo biloba to help with memory disorders became widely known in the United States with the publication of the clinical trial by Lebars and colleagues. Although trials with demented patients are fraught with hazards, the investigators found improved cognitive performance and social function compared to placebo in a significant proportion of patients with dementia. Ginkgo also had a good safety profile.

Two well-designed recent studies add to the database of clinical information. In a study of adults with existing healthy cognitive function, Solomon and colleagues found no improvement in memory or related cognitive function with ginkgo compared to placebo. Ginkgo also had a good safety record in that trial. In a study of cognitively intact older adults, Mix and colleagues showed improvement in a number of neuropsychological parameters compared with placebo, and no significant adverse effects. This study was sponsored by the manufacturer of the study product.

The most recent substantive Cochrane review amendment, from November 2003, concluded that there was overall "promising evidence" of improvement in cognition and function with ginkgo. A large NIH-sponsored clinical trial is underway to determine whether Ginkgo biloba can delay or prevent the development of dementia in healthy elderly patients and, secondarily, whether it is associated with a difference in the incidence of cardiovascular disease.

Investigative interest in ginkgo has been largely related to treatment of existing vascular disease. The notion that ginkgo can improve memory in otherwise healthy young people has been mostly commercial hype. With respect to product quality, an independent review of ginkgo products purchased in April 2003 found that seven of nine brands were found to lack one or more of the necessary active constituents.

Most physicians are aware of case reports that associate ginkgo with increased incidence or severity of bleeding. This concern has not been supported by the aggregate data from clinical trials, however, which have not shown problems with excessive bleeding. The ongoing NIH trial of ginkgo for prevention of dementia has four years of clinical data regarding use of the agent in 3000 patients over the age of 75, many of whom are on antiplatelet agents (but not warfarin). The Data Safety and Monitoring Board has thus far not altered the trial due to problems of excessive bleeding in this elderly, high-risk population.

Some constituents of Ginkgo biloba are inhibitors of the cytochrome P450 system. The clinical significance of this finding, however, does not appear to be great, and probably depends on the active ingredients of the individual product.

In summary, Ginkgo biloba has shown promise in its ability to enhance cognitive function in people with dementia, but more information is needed to define its use in the general patient population. Many early trials used unsatisfactory methodology and several more modern trials show inconsistent results. It has a good safety record in trials to date, although product quality is, as usual, a concern.

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SAW PALMETTO

This botanical agent is an extract of the date palm, which is found most frequently in the southeastern United States and nearby islands. The most common use is for the prevention and treatment of BPH. Although it is by no means a miracle drug, saw palmetto (Serenoa repens) is gaining respect for the accumulating clinical and histologic evidence of its benefit.

The state of knowledge regarding saw palmetto for treatment of BPH was summarized by Gerber in a recent major urology journal (see Suggested Reading). The author wrote, "A significant limiting factor to our understanding of the use and effectiveness of phytotherapy is the lack of standardization of these products. Despite this lack of standardization and the variation in results that may be seen with herbal products, there is growing evidence from well-conducted clinical trials that phytotherapeutic agents may lead to subjective and objective symptom improvement beyond a placebo effect in men with BPH. In addition, histologic evidence has been presented demonstrating that saw palmetto causes atrophy and epithelial contraction within the prostate gland. Overall, it is likely that herbal therapy will continue to be used by a growing number of Americans to treat a variety of ailments. Physicians should attempt to remain open-minded regarding alternative approaches and educate themselves so that they may counsel patients in an informed and credible fashion."

A Cochrane review from 2002 concluded that the evidence suggests that saw palmetto provides mild to moderate improvement in urinary symptoms and flow measures, comparable to finasteride, with fewer adverse effects.

In an effort to clarify potential drug interactions, Markowitz and colleagues looked for effects of saw palmetto on the cytochrome P450 system and found no significant interaction. With respect to the quality of commercially available products, ConsumerLab purchased and tested 14 different products in 2003. Two brands failed testing due to fatty acid content that fell short of label claims, and two products contained only half the dose of saw palmetto that was found effective in clinical trials. Of the remaining 10 products, 9 passed; the 10th was found likely to contain undisclosed oils. Prices ranged from $4 to $20 for a one-month supply. Contrary to the usual situation, the cheapest supplement passed the test while the most expensive one did not.

In summary, saw palmetto may be worth recommending to patients with mild to moderate symptoms of BPH, keeping in mind the limited data regarding the risk-benefit ratio of long-term use. As with all supplements, product quality is unfortunately variable.
 

BLACK COHOSH

Black cohosh (Cimicifuga racemosa or Actaea racemosa) is a plant native to the Americas that was used by indigenous people as a remedy for problems with menstruation and menopause. Ironically, it has been used more in Europe than the United States since the original European settlers sent it back to family and friends in the places they left behind. Annual sales in the United States surpass $30 million. It grows best in the mountainous areas of the southeastern United States, and overharvesting is beginning to threaten its existence in the wild. Although it has been available in specialty stores for many years, it can be found almost everywhere now that hormone replacement therapy (HRT) has fallen out of favor, and it is addressed here because of the increased interest in it as an alternative to HRT.

Recent studies have begun to define the physiologic mechanism of black cohosh. Rather than having discrete effects on estrogen receptors, it may act centrally by way of the dopaminergic system. In fact, significant estrogenic effects of the plant have not been found. Clinical evidence for the use of black cohosh for treatment of menopausal symptoms has been promising, but trials have been limited by inadequate methodology, and no firm conclusions can be drawn. The typical dose is about 40 mg per day. Most clinical trials have been conducted with the same product and, as with all plant products, it is unclear whether results from one product are applicable to another.

Mild adverse effects, especially headache, have been seen with short-term use. Long-term safety is not known. Significant drug interactions have not been described. The North American Menopause Society currently recommends dietary and lifestyle changes as first-line treatment for vasomotor symptoms, with the addition of black cohosh, if desired, for mild symptoms.

In summary, evidence for the benefit of black cohosh to treat menopausal symptoms is promising but limited by the inadequate methodology of the clinical trials. Significant estrogenic activity has not been found. Mild adverse effects (especially headache) have been seen with short-term use; long-term safety is not known. There have been case reports of liver failure with black cohosh, but a clear association has not been established.
 

GLUCOSAMINE

Glucosamine is a nonbotanical dietary supplement that is commonly used for joint pain and dysfunction. It is a relatively simple molecule that is usually derived from the shells of crabs. It occurs naturally in human tissue, and supplementation seems to stimulate synthesis of glycosaminoglycan, proteoglycan, and hyaluronic acid. The relative potency of different oral preparations is unclear. Many preparations come in a combination form with chondroitin, which is often derived from cow, pig, or chicken cartilage. A typical dose of glucosamine is 500 mg by mouth three times a day, although it has been used successfully in clinical trials at 750 mg twice a day.

There is mounting evidence that glucosamine is of benefit for symptoms of osteoarthritis. There are also reports that glucosamine has disease-modifying effects. Two meta-analyses have summarized the existing data. Towheed and colleagues reviewed 16 randomized, controlled trials and concluded that glucosamine is both effective and safe in osteoarthritis. A meta-analysis by Richy and colleagues concluded that glucosamine has structural efficacy and both glucosamine and chondroitin have symptomatic efficacy. There were almost no data from which to draw conclusions about any structural efficacy of chondroitin.

Most recently a randomized, double-blinded, placebo-controlled trial involving several hundred postmenopausal women with osteoarthritis of the knee showed that in an intention-to-treat analysis over three years, glucosamine was associated with significant disease-modifying effects compared with placebo. There is an unfortunate paucity of data to compare glucosamine with nonsteroidal anti-inflammatory drugs (NSAIDs) for treatment of osteoarthritis. Preliminary information indicates that glucosamine is as effective as NSAIDs for pain control, but that NSAIDs act more quickly. On the other hand, NSAIDs do not have disease-modifying effects, which may explain why the improvement associated with NSAIDs is short-lived, whereas glucosamine has longer-lasting effects. The NSAIDs are also associated with a higher incidence of gastrointestinal distress. Glucosamine has been found to have no inhibitory effect on cyclo-oxygenase (COX) 1 or COX-2.

In general, glucosamine has been associated with no significant adverse effects. Questions have been raised about whether people with shellfish allergy are at increased risk of adverse reactions. Only one case of possible angioedema has been reported, and causality was not clear. Patients with shellfish allergy are typically sensitive to the troponin in muscle, whereas glucosamine supplements are made from the shell exclusively.

Is glucosamine hazardous to patients with type 2 diabetes mellitus? A recent study evaluated glycosylated hemoglobin levels in 38 patients after they took either glucosamine or placebo for 90 days. No difference between the two groups was found. One other recent study of less conclusive design found no evidence of induction of glucose intolerance in healthy volunteers who consumed glucosamine.

An independent testing laboratory found that the contents of most glucosamine products it evaluated were generally consistent with the labels. However, the report warned that the chondroitin level in a number of the combination products ranged from low to none. Products with the word "complex" in their name tended to have less of the active ingredient or ingredients.

A second independent analysis of glucosamine products, however, found that of 14 commercially available products tested, there was a variability in glucosamine content from 59% to 138% even in the sulfated form.

In summary, glucosamine and chondroitin appear to be efficacious and safe for the symptoms and possibly the structural changes of osteoarthritis. Products, especially those containing chondroitin, are of variable quality, and there is not much experience with long-term human use.
 

PRODUCT QUALITY

In addition to the references to product quality noted above, a recent article adds more insight into the confusing array of commercial products with potentially significant physiologic effect. The authors analyzed multiple brands of the 10 most commonly purchased botanical products of 1998 and concluded that price per daily dose was the best predictor of consistency in quality benchmarks—the higher, the better. Interestingly, store type was not a predictor of product quality.

Product quality is important not only from the standpoint of active ingredients, but also with regard to potential contaminants or adulterants. Contaminants are agents such as heavy metals that are naturally present in the soil where the plant is grown. Adulterants are substances that are intentionally placed in supplements without being listed on the label. Poor product quality might mislead a patient to think that a potentially helpful supplement is of no benefit. Equally disturbing is the possibility that contaminants or adulterants could make a patient ill.

Three points can be made in summary: More expensive brands are likely to reflect higher quality; patients and physicians should always consider the possibility of contamination or adulteration of supplements; and resources listed in this article can assist with the identification of high-quality brands.

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