More threads by David Baxter PhD

David Baxter PhD

Late Founder
Top Herbal Products: Efficacy and Safety Concerns
by Darrell T. Hulisz, PharmD

A recent survey estimated that more than 38 million adults in the United States used herbal products and dietary supplements in 2002.[1] More than half of those users said that these products were important to their health and well-being, yet only one third told a conventional healthcare provider about their use.

Other reports have estimated that 25% of patients who seek medical attention for a serious medical problem are using "unconventional" therapies, and 70% of those patients do not disclose those practices to their physician.[2,3] One survey estimated that about 18% of the US population uses herbal therapy on a regular basis.[4]

Herbal products and dietary supplements are widely available in supermarkets and other retail outlets, as well as by mail order. In fact, only a small percentage of these products (4.5%) are actually sold in pharmacies.[5] Many patients believe they derive health benefits from these herbal preparations, yet some remain skeptical and may seek advice from health professionals prior to use. Thus, it is important for all health professionals to be informed about available products and to be aware of any potential problems associated with their use.

Concerns About Herbal Products and Dietary Supplements
Unlike prescription and over-the-counter drugs, herbal products are not regulated by the US Food and Drug Administration (FDA) to determine purity or potency.[6] In fact, some products may contain contaminants, and their potency is dependent on many factors, such as the climate and soil conditions where they are grown, harvested, and stored.[7] Some herbal preparations have even been found to contain prescription drugs and heavy metals as unlabeled ingredients, and in some cases, these contaminants have resulted in toxicities.[8-17]

The labeling of herbal products is regulated by the Dietary Supplement Health and Education Act of 1994 (DSHEA).[18] Under this law, manufacturers may only make general claims about a supplement's effect on the structure or function of the human body (e.g., "supports the immune system"). They must include the following statement in their labeling: "This product is not intended to diagnose, treat, cure, or prevent any disease."

The labels on herbal products are designed to promote product use and not necessarily to inform the consumer, so health professionals should be equipped with a general understanding of popular herbs and supplements, including knowledge of efficacy, common side effects, risks, and interactions. In addition, they should prospectively seek information regarding their patients' use of unconventional medicines to avoid adverse consequences.

Consumers should be advised that manufacturers of herbal supplements are not required to demonstrate safety or efficacy prior to marketing. Before the FDA can remove a product from the market, the agency must prove that the product is unsafe or ineffective. Recent examples of this include the ban on products containing ephedra due to adverse cardiovascular effects,[19] and the prohibition of kava amid concerns about hepatotoxicity.[20]

Patients with medical illness should not use herbs and dietary supplements without medical supervision. As will be discussed, some herbal products have adverse effects and may interact with prescribed medications. Furthermore, many conditions that patients try to diagnose or treat themselves may be serious, requiring a careful history and examination by a healthcare professional. For example, unsupervised use of saw palmetto for urinary symptoms may delay a diagnosis of prostate cancer.[21] Similarly, patients with symptoms such as chronic insomnia, anxiety, and depressed mood should see their health provider. Patients with cardiovascular disease, hypertension, heart failure, and hyperlipidemia should be under a healthcare professional's care and receive appropriate prescription drugs.

The following is an overview of some of the most commonly used herbal products, including important clinical considerations in the use of these products.

Echinacea for Fighting Cold Symptoms, Boosting Immunity
Echinacea is one of the most popular herbs in the United States, extracted from the purple coneflower that is native to North America. Species include Echinacea purpurea, Echinacea angustifolia, and Echinacea pallida. It has been studied as an adjunct therapy to enhance the immune system, mostly in upper respiratory tract infections, and these studies have produced mixed results.[22,23]

A recent meta-analysis concluded that standardized extracts of echinacea were effective in the prevention of common cold symptoms after clinical inoculation, when compared with placebo.[23] The authors of that study concluded that the likelihood of experiencing a cold was 55% higher with placebo than with echinacea (P < .043).

Some antiviral and bacteriostatic properties have been demonstrated in vitro, and the herb also appears to stimulate the production of cytokines (interferon, tumor necrosis factor, and interleukins).[24] Animal studies have revealed probable mechanisms of echinacea-induced immune enhancement, such as increasing the number of circulating white blood cells.[25]

Common side effects of echinacea supplements include unpleasant taste and allergic reactions. Because the flower is related to ragweed, cross allergenicity may occur in individuals allergic to ragweed.[26,27]

Echinacea is not recommended in patients with progressive or autoimmune disorders, including acquired immunodeficiency syndrome, tuberculosis, multiple sclerosis, collagen disorders, and diabetes mellitus. Theoretically, since echinacea alters the immune system, these disorders may be exacerbated.[28,29] Persistent use of echinacea has been associated with hepatotoxicity, so it should not be taken by patients who are taking other known hepatotoxins such as anabolic steroids, amiodarone, methotrexate, or ketoconazole.[30]

While not all randomized controlled trials performed to date have shown benefit for Echinacea over placebo,[22,31] a Cochrane review in 2006 concluded that the aerial parts of Echinacea purpurea might be effective for early treatment of colds in adults.[32]

Unfortunately, the optimal dose of echinacea is unknown, and multiple formulations exist, such as capsules, tinctures, teas, and extracted plant juice. Recommended dosages vary widely; for instance, capsules of Echinacea purpurea extract range from 100 to 500 mg, with manufacturers' suggested use ranging from 1 to 4 times daily for common cold prevention.

Take-home message: Clinicians should inform patients that a wide variety of Echinacea preparations and doses have been studied and results are inconsistent, making it difficult to recommend specific products. However, E. purpurea seems to be modestly effective for preventing the common cold in those at risk (eg, sick contacts). Evidence that the herb may reduce the duration of cold symptoms has been mixed. Patients allergic to ragweed, with progressive autoimmune disorders, and on hepatotoxic drugs should avoid echinacea.

Garlic: Warding Off Cardiovascular Disease?
Allium sativum, commonly known as garlic, has been used for centuries in cooking because of its flavoring properties. Today, it is used therapeutically by many consumers to prevent heart disease by controlling high cholesterol and high blood pressure. The suggested active ingredients are allicin and alliin.Numerous studies, however, have produced conflicting results regarding garlic's ability to lower lipids.[33-40] Positive findings in 3 trials exhibited a lowering of cholesterol in the range of 6.1% to 11.5%, primarily due to the lowering of low-density lipoproteins.[33-36] Other studies have yielded neutral or conflicting results.[37-39] One 12-week study tested the use of garlic powder in ambulatory patients, finding a 14% reduction of serum cholesterol.[40]

Garlic may have modest antihypertensive effects. Studies have documented either a small decline in arterial pressure (5% to 7% mm Hg) or no change at all.[41] A meta-analysis of 8 trials revealed 3 studies that concluded garlic significantly reduced systolic blood pressure, and 4 studies that found reductions in diastolic blood pressure in patients with mild hypertension.[42]

With regard to potential adverse effects, garlic has been shown to inhibit platelet aggregation in vitro[43-45] and in vivo[46]; thus, it should be used with great caution in individuals with bleeding disorders or in those who are receiving antiplatelet therapy.[47] There has been 1 report of a spontaneous epidural hematoma occurring with garlic supplementation, but this appears to be an isolated case.[48]

Garlic may also decrease warfarin concentrations.[49-51] Studies to date have not confirmed this interaction[52,53]; but particularly close monitoring of the international normalization ratio (INR) for patients taking both garlic and warfarin is prudent. Patients taking garlic supplements should discontinue use 7 to 10 days prior to having surgical procedures to avoid the potential for prolonged bleeding.[54]

The most prominent side effect of garlic supplementation is malodorous breath and garlic-like body odor.

Take-home message: Garlic should be used cautiously in individuals receiving antihypertensive medications, and blood pressure should be monitored carefully; orthostatic hypotension is a rare complication for those on antihypertensives.[55] Also, garlic should be avoided in those with a history of orthostasis or unexplained dizziness as well as in patients taking drugs that can increase bleeding, such as aspirin, warfarin and ibuprofen. A lack of standardization of garlic products and formulations makes it difficult to recommend a dose or specific product. For dyslipidemia, patients may benefit from taking 600 to 1200 mg of garlic powder daily in divided doses, or up to 4 g of raw garlic daily.

Ginkgo Biloba for Enhancing Memory, Combating Alzheimer's Disease
Ginkgo biloba is one of the oldest species of living trees, and ginkgo supplements are derived from the tree's leaves. This herbal remedy is marketed to improve memory, particularly in elderly individuals. While its mechanism of action is not fully understood, ginkgo contains flavonoids, terpenoids, and organic acids that are believed to act as free radical scavengers. These constituents have been shown to:

  • Inhibit platelet activation factor (reducing thrombosis);
  • Dilate arteries and capillaries; and
  • Block the release of chemotactic factors and inflammatory mediators.
Studies in the United States have found that ginkgo stabilized -- and in some cases improved -- cognitive function and socialization in patients with Alzheimer's disease, although the clinical significance of the improvement was not known.[56,57] LeBars and colleagues[56] reviewed 2020 patients in an intention-to-treat analysis that resulted in a 1.4-point advantage over placebo in the Alzheimer's Disease Assessment Scale-Cognitive subscale.

In addition, studies have also demonstrated that the standardized extract of ginkgo biloba (EgB) 761, is effective in reducing symptoms of claudication, giving patients a 50% increase in pain-free walking distance.[58]

In contrast, a recent clinical trial failed to demonstrate any improvement in cognitive function or in the quality of life in cognitively intact, older individuals.[59]

Ginkgo is considered relatively safe, although the leaves have been associated with mild gastrointestinal side effects and headache. Ingestion of ginkgo seeds may result in serious neurologic and allergic reactions; therefore, they are not used for medical purposes.[60,61] Ingestion of leaf-based extracts has been associated with a spontaneous hyphema (blood in the anterior chamber of the eye) in an elderly man,[62] and with spontaneous subdural hematomas.[63] However, while some isolated adverse events such as these exist, it is considered safe when used as directed.

Ginkgolide B, an active component of ginkgo biloba, is a potent inhibitor of platelet-activating factor, which is necessary for normal platelet aggregation. As with garlic, it should be avoided in patients using anticoagulants or antiplatelet therapy, or in those who have active bleeding such as peptic ulcer disease. Based on case reports, ginkgo is not recommended in patients with seizure disorders.[64-67]

Standardization of product and recommended dosing is lacking, but a typical dose is 40 mg to 80 mg taken 3 times daily, standardized to 24% to 27% ginkgo flavone glycosides and 6% to 7% triterpines per dose. A dose of ginkgo extract EGb 761 at 160 mg daily has shown equivalent efficacy compared with donepezil 5 mg daily for the treatment of Alzheimer's disease.[68]

Take-home message: Ginkgo is a reasonable therapeutic option in patients with Alzheimer's disease who are also receiving medical care, but providers should remember that the herb has antiplatelet activity and thus may not be appropriate for patients with bleeding disorder or on antiplatelet or anticoagulation agents.

St. John's Wort Used for Depression
This yellow flowering plant (Hypericum perforatum) is named after St. John the Baptist. Extracts of the flower have been used for centuries to treat mental illnesses. The herbal product has 10 constituents, of which hypericin is believed to be the most active ingredient in treating depression. St. John's wort has a high affinity for gamma-aminobutyric acid, which, when stimulated, produces an antidepressant effect.[69] Hypericin also appears to activate dopamine receptors and inhibit serotonin receptor expression. In vitro, it has been shown to block reuptake of serotonin and norepinephrine.[70] These mechanisms may explain the lag time associated with the effectiveness of the herb.

A number of studies have examined the effectiveness of St. John's wort in depression.[71,72] A meta-analysis of 23 controlled trials concluded that it was more effective than placebo in treating mild-to-moderate depression.[72] In a 12-week study of 135 depressed patients, the herbal extract (900 mg per day) was found to be more effective than fluoxetine (20 mg per day).[73] Other investigators have confirmed the herb's efficacy over placebo in mild-to-moderate depression.[74]

Because of its pharmacology, St. John's Wort should not be taken with prescription serotonin uptake inhibitors, as symptoms of serotonin syndrome have been observed with co-administration (headache, sweating, dizziness, and agitation).[75-77, 85]

In terms of other contraindications, St. John's wort should be avoided during pregnancy.[78,79] It has been associated with photosensitivity.[80] Studies have shown that the herbal product can reduce plasma concentrations of digoxin[77,81] and indinavir.[77,82,83] There have been cases of heart transplant rejection associated with the use of St. John's Wort that resulted from a reduction in cyclosporine plasma concentrations.[84,85] Breakthrough bleeding and unwanted pregnancies have been reported in women on concomitant therapy of oral contraceptives and St. John's Wort extract.[85,86] This is likely a result of St John's Wort-induced decreases in ethinyl estradiol or metabolite concentrations due to the herb's ability to induce cytochrome P450 (CYP450)-3A4 isoenzyme.

Take-home message: Patients who are depressed should not take this herb without medical supervision. St. John's Wort should be reserved for the mildly depressed patient with an aversion to prescription medication. Clinicians who recommend this botanical should be mindful of the numerous potential drug interactions arising from enzyme induction. The most commonly studied dose for depression is 300 mg taken 3 times a day, standardized to 0.3% to 0.5% hypericin per dose.

Valerian, Chamomile, Ginger: Calming Agents

Valerian root (Valeriana officinalis) has been used for centuries for its calming effects. Medics gave it to soldiers during World War I for the treatment of shell shock.[87,88] The active ingredients appear to be valepotriates (thought to be responsible for the sedative effects) and valeric acid, both of which mediate the release of gamma-aminobutyric acid. Randomized clinical trials have demonstrated efficacy of valerian root extract for treating insomnia.[89,90]

Mild side effects have included paradoxical stimulation (restlessness and palpitations), especially with long-term use. Valerian should not be used in pregnancy. This herb may have an additive effect with other central nervous system depressants. Patients should be cautioned regarding the operation of machinery when initiating therapy until they are accustomed to the effects. Other potential side effects include headaches, excitability, and uneasiness. Typical dosages for insomnia are 200-400 mg (standardized to 0.8%-1% valeric acids per dose) at bedtime.

Few human studies have been published on the use of chamomile (Matricaria recutita), yet it is cultivated worldwide for its sedating and calming properties. The active component apigenin has been shown to bind the same receptors as benzodiazepines, to exert an anxiolytic and mild sedative effect in mice.[91] Chamomile also has moderate antioxidant, antimicrobial, and antiplatelet activity in vitro.[92]

Chamomile is considered safe by the FDA, but it should be used with caution in individuals who are allergic to ragweed, as cross-allergenicity may occur. Allergic symptoms include tongue thickness, tight sensation in throat, angioedema of lips and eyes, diffuse pruritis, urticaria, and pharyngeal edema.[93,94] Because of its sedative effects, chamomile should be used with caution when taken in conjunction with medications that have also sedative side effects, or with alcohol. Oral doses vary from 400 to 1600 mg per day (standardized to 1.2% apigenin per dose). Chamomile is often brewed as a tea; 1 heaping teaspoon of dried flowers steeped in hot water for 10 minutes may be drunk up to 3 times a day.

Ginger (Zingiber officinale) is cultivated in Asia, Africa, and the Caribbean. It has been used for centuries as a flavoring agent and for its antiemetic properties. The root produces a volatile oil containing shogaol and gingerol.[95] Gingerol and shogaol have demonstrated analgesic, anti-inflammatory, sedative, antipyretic, and antitussive properties in vitro and in animals, as well as antioxidant antimicrobial, antifungal, antineoplastic, and antihypertensive benefits; many of these effects have yet to be tested in people, however.[96] Human studies have shown a significant reduction in nausea in patients with hyperemesis gravidarum taking doses of 250 mg 4 times a day,[96-98] and in patients with perioperative nausea and vomiting taking doses of 1 g prior to surgery.[99,100] A study comparing ginger with 100 mg dimenhydrinate and with placebo found that ginger was superior to both when patients were subjected to a revolving chair designed to produce motion sickness.[101]

Ginger has exhibited inhibition of thromboxane synthetase that resulted in prolonged bleeding.[102] Therefore, it is prudent for those taking anticoagulants to have their International Normalized Ratio (INR) monitored closely. Ginger can also cause mild gastrointestinal (GI) upset including heartburn, diarrhea, and mouth irritation.[96]

Take-home message: Valerian, chamomile, and ginger can be safely recommended in the majority of patients. These agents have shown modest efficacy for their primary uses. However, patients with chronic anxiety and insomnia should be under the care of a healthcare professional and thus should not attempt self-medication with botanicals.

Ginseng: A Natural Energy Booster
The term ginseng (Panax ginseng, Panax quinquefolius) means "man-root," and the ancient Chinese believed it could benefit all aspects of the human body; today, it is mostly used as an energy booster.[103] "Siberian ginseng" is derived from the Eleutherococcus senticosos shrub and has different properties than ginseng from the Panax family[104]; in fact, federal regulation now requires that this product be referred to as eleuthero to distinguish the 2 herbs.[105]

Derived from the root of the plant, the ginsenosides found in ginseng are a compilation of more than 20 saponin triterpenes and are thought to be the active ingredients.[106] Animal studies suggest that these steroid-like compounds work by stimulating the secretion of adrenocorticotropic hormone, resulting in increased production of cortisol.[107] The herb may also play a role in stimulating the production of adrenal hormone precursors.

Ginseng is considered by many to enhance physical, sexual, and mental performance, as well as increase resistance to stress. Because these potential benefits are somewhat subjective, however, controlled clinical trials are difficult to interpret. Generally speaking, results from clinical trials have been equivocal.[103]

Although it is much too early to tell how this may affect people with diabetes, animal studies suggest that ginseng may reduce glucose levels in obese, diabetic mice.[108,109]

Because it can have a mild stimulant effect, it should be avoided by patients with cardiovascular disease who are taking other stimulants. Ginseng has also been associated with reversible mastalgia and postmenopausal bleeding, although this appears to be a rare side effect.[110] Overuse of ginseng may be associated with diarrhea, hypertension, nervousness, dermatologic eruptions, and insomnia. This herb has also been associated with a reduction in the INR of warfarin-treated patients.[111] In addition, ginseng has been associated with altered hemostasis and is therefore contraindicated in patients with active bleeding; patients receiving anticoagulant and/or antiplatelet medications should be cautioned against using ginseng.[112]

As with many other herbs, ginseng formulations have not been standardized, nor have optimal doses been determined, but common regimens involve 100-600 mg per day in divided doses.

Take-home message: Historically, many claims have been made by supporters of Panax ginseng formulations; however, robust clinical trials are lacking. Patients who use ginseng should be cautioned not to exceed the labeled dosage since adverse effects may occur. Clinicians should discourage use in patients who are anticoagulated, and those with cardiovascular or metabolic disease, such as hypertension and diabetes.

Saw Palmetto: Effective for Benign Prostatic Hyperplasia?
The extract for saw palmetto (Serenoa repens) comes from the fruit of the palm tree and is often used to treat benign prostatic hyperplasia (BPH). Saw Palmetto extract is thought to inhibit 5-alpha reductase and thus block the conversion of testosterone to dihydrotestosterone, which is responsible for stimulating growth of the prostate gland.[113] It also blocks the uptake of both hormones by the prostate. Saw palmetto may exhibit some anti-inflammatory effects, presumably by inhibiting cyclooxygenase pathways.[114]

While early clinical studies suggested a modest benefit of saw palmetto in BPH, more recent studies are less consistent, and the precise clinical value of saw palmetto for treating urinary symptoms remains undefined.[115,116] In a recent randomized, double-blind, placebo-controlled trial, 225 men were given either standardized saw palmetto 160 mg twice daily or placebo for 1 year.[116] There was no significant difference between the 2 groups in the change in objective urologic symptom scores, maximal urinary flow rate, prostate size, residual volume after voiding, quality of life, or serum prostate-specific antigen levels. The incidence of side effects was similar in the 2 groups.

Side effects are uncommon with saw palmetto, but they may include headache and GI upset. There are no known important drug interactions with this herb.[113] The most commonly used dose for treating BPH is 160 mg twice daily.

Take-home message: Men with obstructive urinary symptoms should not self-medicate with saw palmetto. Such patients should be under medical supervision, because the symptoms of BPH can mimic other, more serious disorders, such as prostate cancer and prostatitis. This herb should be reserved for men with mild BPH symptoms who have an aversion to prescription drugs and are also under medical care.

Black Cohosh Used to Ease Hot Flashes
Black cohosh (Cimicifuga racemosa) is a plant native to Eastern North America. It contains a group of chemicals referred to as phytoestrogens because they mimic the effects of estrogens. For this reason it was a common remedy used by Native Americans for the treatment of painful menses (known as squawroot).

Recent clinical trials indicate that black cohosh is somewhat efficacious in relieving menopause symptoms.[117-121] The majority of the trials used the isopropranolic extract of black cohosh at a total dose of 40-80 mg daily. Most studies were only conducted for a short duration of either 3 or 6 months. Thus, further clinical trials are needed to assess efficacy of black cohosh beyond 6 months. Recent investigations do not support the earlier estrogen-receptor mediated theory as a plausible mechanism of action of black cohosh including a randomized, placebo-controlled, 1-year study of 351 women with menopausal symptoms failed to confirm efficacy of black cohosh.[122]

Black cohosh is generally considered safe without any major life-threatening adverse events.[121] Some patients may experience mild side effects including rash or GI upset. It should not be used in lactating or pregnant women. Since there is still speculation of an estrogen-like effect, black cohosh use should be avoided in women with a history of estrogen-dependent tumors or endometrial cancer. Most authorities suggest limiting its use to 6 months because no long-term trials have been conducted. Black cohosh offers an alternative to estrogen for symptoms of menopause, the most widely studied dose is 20-40 mg twice daily standardized to 1 mg triterpene glycosides.

Take-home message: Clinical trials using black cohosh to relieve menopausal symptoms have yielded conflicting results. However, some women experience benefits with the herb without apparent side effects. It appears to be safe, but use should be limited to no more than 6 months and should not be used in those with a history of estrogen-dependent tumors.

Consumers with serious or chronic health complaints will often self-diagnose and self-treat with herbs and supplements. This is not ideal, because many of these patients need supervised medical care, especially those with depression, prostate disease, dementia, or chronic insomnia.

Health professionals generally should advise against the use of herbs or supplements during pregnancy or lactation, because the effects on fetal development and breast milk excretion are unknown. Similarly, use in infants and younger children should be discouraged.

Patients should be advised to take the same dosages that have been studied in clinical trials, and not to exceed labeled amounts. Generally, herbs should be consumed only for a limited time. Patients should avoid products with labels that fail to specify the exact amount of the herb contained per dosage unit.

Health professionals should elicit a careful history from patients regarding any plant allergies, especially to ragweed and daisies, recalling that many patients with allergic rhinitis may not know what allergens trigger their attacks. Patients who are allergic to ragweed and flowers in the daisy family (asters, chrysanthemums) may have allergic reactions to products containing echinacea and chamomile. Some herbs are photosensitizing (eg, St. John's wort), and patients should be cautioned appropriately (especially fair-skinned individuals).

Patients anticipating surgical procedures should discontinue use of herbs at least 2 weeks prior to surgery, and should notify the anesthesiologist of any routine herb usage.[54] As discussed, some herbals may interfere with normal blood coagulation, predisposing patients to prolonged bleeding and interactions with warfarin (e.g., garlic, ginkgo, ginseng, and ginger).

David Baxter PhD

Late Founder

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