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Complementary and Alternative Therapy
Jacqueline Rosenjack Burchum DNSc, FNP-BC, CNE
The National Center for Complementary and Integrative Health (NCCIH) defines complementary health approaches as “a nonmainstream practice used together with conventional medicine” and alternative health approaches as “a nonmainstream practice that is used in place of conventional medicine.” Examples include both products (e.g., herbs, probiotics, and vitamins) and practices (e.g., meditation, acupuncture, and therapeutic touch). According to the National Health Statistics Reports published in 2015, 32.3% of adults in the United States used some form of complementary and alternative medicine (CAM) in 2012 (the year of the most recent national study).
Dietary supplements are the most common form of CAM. Dietary supplements are defined by the U.S. Food and Drug Administration (FDA) as “a product intended for ingestion that contains a ‘dietary ingredient’ intended to add further nutritional value to (supplement) the diet. A ‘dietary ingredient’ may be one, or any combination, of the following substances: a vitamin, a mineral, an herb or other botanical, an amino acid, a dietary substance for use by people to supplement the diet by increasing the total dietary intake, a concentrate, metabolite, constituent, or extract.”
The popularity of supplements may be explained by several factors (Box 67.1). Some people like the sense of empowerment that comes from self-diagnosis and self-prescribing. Others may turn to supplements out of anger or frustration with their health care providers. Still others may distrust conventional medicine or may feel it has failed them. In addition, supplements may be a way to save money: because these products are available without prescription, they can be purchased without the cost of visiting a prescriber. In fact, according to the National Health Interview Survey (NHIS), there is a clear relationship between concern about the costs of conventional care and the likelihood of turning to CAM. However, perhaps the strongest force driving the demand for nutritional supplements is aggressive marketing.
Our understanding of CAM is far from adequate. To advance our knowledge, the National Institutes of Health (NIH) created the National Center for Complementary and Alternative Medicine (NCCAM) in the late 1990s. This organization (renamed the National Center for Complementary and Integrative Health [NCCIH] in 2014) is charged with promoting and funding basic research and clinical trials designed to address open questions on the safety and efficacy of CAM. The NCCIH website, which provides a wealth of information on CAM, is available at https://nccih.nih.gov.
Regulation of Dietary Supplements
Dietary Supplement Health and Education Act of 1994
Core Provisions
In 1994, after intensive lobbying efforts from the multibillion-dollar dietary supplement industry aimed at minimizing FDA oversight, Congress passed the Dietary Supplement Health and Education Act of 1994 (DSHEA). The Food, Drug, and Cosmetic Act requires that conventional drugs—both prescription and over-the-counter agents—undergo rigorous evaluation of safety and efficacy before receiving FDA approval for marketing. The DSHEA categorizes botanical products (herbal supplements), vitamins, and minerals as dietary (food) supplements rather than as drugs. By classifying products as dietary supplements, the DSHEA exempts them from undergoing FDA scrutiny and approval before marketing. In fact, dietary supplements can be manufactured and marketed without giving the FDA any proof they are safe or effective. All the manufacturer must do is notify the FDA of efficacy claims. If a product eventually proves harmful or makes false claims, the FDA does have the authority to intervene—but only after the product had been released for marketing. Furthermore, to challenge a claim of efficacy, the FDA must file suit in court; the challenge cannot be made through a simple administrative procedure.
Package Labeling
The DSHEA does impose some restrictions on labeling. All herbal products must be labeled as dietary supplements. In addition, the label must not claim that the product can be used to diagnose, prevent, treat, or cure a disease. In fact, it must state the opposite: this product is not intended to diagnose, treat, cure, or prevent any disease. However, the label is allowed to make claims about the product’s ability to favorably influence body structure or function. Put another way, the label can insinuate specific benefits but can’t make overt claims. By way of illustration, labels can bear statements such as these:
• Helps promote urinary tract health
• Helps maintain cardiovascular function
But labels can’t bear statements or terms such as these:
• Reduces pain and stiffness of arthritis
• Supports the body’s antiviral capabilities
• Improves symptoms of Alzheimer disease
• Relieves menopausal hot flashes
• “Antibiotic,” “antiseptic,” “antidepressant,” “laxative,” or “diuretic”
If all of this sounds like semantic hair splitting—it largely is. Furthermore, regardless of what the label says, common sense assumes that people will take herbal products with the intent to prevent or treat disease.
Under the provisions of the DSHEA, there is no assurance that a product actually contains what the label proclaims: the package may contain ingredients that are not listed, or it may lack ingredients that are listed. These shortcomings and others have been addressed by the Current Good Manufacturing Practices (CGMPs) ruling, issued by the FDA in 2007.
Adverse Effects
With dietary supplements, as with conventional drugs, the manufacturer is responsible for safety. However, the similarity ends there. Under the DSHEA, a product is presumed safe until proved hazardous. Furthermore, the burden for proving danger lies with the consumer and the FDA. With conventional drugs, opposite logic and regulations apply: drugs are presumed dangerous until rigorous testing by the manufacturer reveals an absence of serious adverse effects. Because of this system, the number of dangerous drugs that reach the market is kept to a minimum. Ask yourself, “Which product would I be more comfortable using—one that has been tested for adverse effects before I take it, or one that is evaluated for adverse effects only after it caused me harm?”
Impurities, Adulterants, and Variability
The DSHEA does not address the issues of impurities, adulterants, or variability. As a result, dangerous products have been allowed to reach consumers. A few examples illustrate the problem:
• A combination product used to “cleanse the bowel” caused life-threatening heart block. Analysis revealed contamination with Digitalis lanata, a plant with powerful effects on the heart.
• Among 125 ephedra products analyzed by the FDA, ephedrine content per dose ranged from undetectable to 110 mg. Also, some products had 6 to 20 additional ingredients.
• Testing of 10 brands of ginseng products revealed a 20-fold variation in ginsenoside content.
• When the California Department of Health Sciences analyzed 243 Asian patent medicines, they found 24 containing lead, 35 containing mercury, and 36 containing arsenic—all in levels above those permitted in drugs. Of these products, 7% were adulterated with undeclared pharmaceuticals, including ephedrine, chlorpheniramine, methyltestosterone, and phenacetin.
As discussed later, the CGMPs ruling, issued by the FDA in 2007, should prevent the sale of such products in the future.
Current Good Manufacturing Practices Ruling
In June 2007, the FDA issued a set of standards to regulate manufacturing and labeling of dietary supplements. These standards, referred to as Current Good Manufacturing Practices, are designed to ensure that dietary supplements be devoid of adulterants, contaminants, and impurities, and that package labels accurately reflect the identity, purity, quality, and strength of what’s inside. In addition, the label should indicate not only active ingredients but also inactive ingredients. The CGMPs also mandate that manufacturers establish quality-control procedures, with the objective of preventing mislabeled, underfilled, or overfilled formulations; variations in tablet size, color, or potency; and contamination with drugs, bacteria, pesticides, glass, lead, and other potential contaminants. Unfortunately, even with the new standards and rules, there is still no assurance that dietary supplements will be either safe or effective—but at least we will have improved confidence regarding package contents.
Dietary Supplement and Nonprescription Drug Consumer Protection Act
The Dietary Supplement and Nonprescription Drug Consumer Protection Act, passed in 2006, mandates reporting of serious adverse events for nonprescription drugs and dietary supplements. The following events should be reported: deaths, hospitalizations, life-threatening experiences, persistent or significant disabilities, and birth defects. Manufacturers and distributors must report these to the FDA within 15 days. Reports can be filed by telephone or by mail, or through the MEDWATCH program at http://www.fda.gov/Safety/MedWatch.
A Comment on the Regulatory Status of Dietary Supplements
Although herbal products and other dietary supplements are not regulated for either safety or efficacy, many of these products have components that can produce profound beneficial and adverse pharmacologic effects. Nonetheless, reliable information on clinical effects is largely lacking. Many of those working in the fields of pharmacy, medicine, and nursing are concerned that the exceptions made for dietary supplements are both irrational and dangerous.
Private Quality Certification Programs
Four private organizations—the U.S. Pharmacopeia (USP), ConsumerLab, the Natural Products Association, and NSF International (formerly known as the National Sanitation Foundation)—test dietary supplements for quality. A “seal of approval” is given to products that meet their standards, which are very similar to the CGMPs described previously. The USP standards are enforceable by the FDA. All four organizations require manufacturers to pay for the tests, and all four report on the following:
In addition, two organizations—the USP and ConsumerLab—report on postapproval surveillance.
Standardization of Herbal Products
With herbal products, there is often uncertainty about the amounts of active ingredients. The concentration of active ingredients in herbal crops can vary from year to year and from place to place. Reasons include differences in sunshine, rainfall, temperature, and soil nutrients. As a result, the potency of herbal products can vary widely.
Variability can be reduced through standardization, a three-step process in which the manufacturer (1) prepares an extract of plant parts, (2) analyzes the extract for one or two known active ingredients, and (3) dilutes or concentrates the extract such that the final product contains a predetermined amount of the active ingredients. The objective is to achieve therapeutic equivalence from batch to batch made by the same manufacturer, and among batches made by different manufacturers. Table 67.1 lists the concentrations of active ingredients in some standardized preparations.
TABLE 67.1
Concentrations of Active Agents in Some Standardized Herbal Preparations
| Herb | Amount of Active Agent |
| Black cohosh | 2.5% Triterpene glycosides |
| Echinacea | 4% Phenolic compounds |
| Feverfew | 0.2% Parthenolide |
| Ginkgo biloba | 24% Ginkgo flavonoids, 6% terpenoids |
| St. John’s wort | 0.3% Hypericin |
| Valerian root | 1% Valerianic acid |
Standardization has two important benefits. First, it permits accurate dosing. Second, it permits extrapolation of data obtained in clinical trials to the public in general.
Unfortunately, standardization also has drawbacks. The extraction process might destroy active compounds. Furthermore, the process may fail to extract as-yet unidentified active agents, and hence the extract may have a different spectrum of effects than the intact plant. To the extent this is true, historical data obtained with whole plants will lose some value as a basis for helping us understand clinical responses to the standardized extract.
Adverse Interactions With Conventional Drugs
Herbal products and other dietary supplements can interact with conventional drugs, sometimes with significant harmful results. The principal concerns are increased toxicity and decreased therapeutic effects. Clinicians and consumers should be alert to these possibilities. Unfortunately, with many supplements, reliable information on adverse interactions is lacking—in large part because potential interactions have not been systematically studied. Hence, if a patient is taking a conventional medication and a dietary supplement, and therapeutic effects are lost or toxicity appears, it may be impossible to say for sure that the supplement was (or was not) responsible.
A few important interactions have been identified, including the following:
• St. John’s wort can induce CYP3A4 (the 3A4 isoenzyme of cytochrome P450) and can thereby accelerate the metabolism of many drugs, causing a loss of therapeutic effects.
• Several herbal products, including Ginkgo biloba, feverfew, and garlic, suppress platelet aggregation and hence can increase the risk for bleeding in patients receiving antiplatelet drugs (e.g., aspirin) or anticoagulants (e.g., warfarin, heparin).
• Ma huang (ephedra) contains ephedrine, a compound that can elevate blood pressure and stimulate the heart and central nervous system (CNS). Accordingly, ephedra can intensify the effects of pressor agents, cardiac stimulants, and CNS stimulants, and counteract the beneficial effects of antihypertensive drugs and CNS depressants.
These interactions, at least, can be avoided—provided the prescriber is aware of them, and provided the patient informs the prescriber about supplement use. Unfortunately, up to 70% of patients neglect to do so.
Some Commonly Used Dietary Supplements
Black Cohosh
Uses
Black cohosh has a long history in America. The herb was used by Native Americans and later by American colonists. Between 1820 and 1926, it was listed as an official drug in the USP.
Black cohosh (Cimicifuga racemosa) is used for treating symptoms of menopause, including hot flashes, vaginal dryness, palpitations, depression, irritability, and sleep disturbance. The preparation should not be used to reduce hot flashes caused by tamoxifen and other selective estrogen receptor modulators (SERMs).
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How black cohosh works is unknown. At one time, we believed it suppressed release of luteinizing hormone (LH). However, clinical studies have failed so show an effect on female hormones, including LH, estradiol, prolactin, and follicle-stimulating hormone. In laboratory studies, black cohosh does not interact with estrogen receptors: it doesn’t bind to these receptors, upregulate estrogen-dependent genes, or promote growth of estrogen-dependent tumors (at least in animals).
Effectiveness
Early studies carried out in Germany supported the ability of black cohosh to effectively relieve menopausal symptoms. In 2012, however, a Cochrane meta-analysis of 16 randomized controlled trials involving more than 2000 women concluded that there was insufficient evidence to support black cohosh for management of menopausal symptoms. After a review of the evidence, the NCCIH concluded, “[T]here is overall insufficient evidence to support the use of black cohosh for menopausal symptoms.” These conclusions were echoed by the American College of Obstetricians and Gynecologists (ACOG) when they updated their clinical guidelines for management of menopausal symptoms in 2014. Conversely, at the time of this writing, the North American Menopause Society continues to include black cohosh among the natural remedies for hot flashes listed on its website.
Adverse Effects
Some women taking black cohosh have developed liver inflammation. In some instances, this has led to liver failure. The association is tenuous, however, because the occurrence has been rare, and a distinction from other possible causes of liver injury has not been ruled out.
Less serious and more common adverse effects include rash, headache, dizziness, and abdominal discomfort. Safety in pregnancy and breastfeeding has not been established; however, for those taking black cohosh for menopausal benefit, this would only be a concern in rare circumstances. One caveat acknowledged almost universally is the need to limit the use of black cohosh to 6 months because long-term studies have not been conducted.
Interactions With Conventional Drugs
Black cohosh may potentiate the hypotensive effects of antihypertensive drugs as well as the hypoglycemic effects of insulin and other drugs for diabetes. Black cohosh may potentiate the effects of estrogens used for hormone therapy. Black cohosh should be used with caution in patients taking other drugs that may harm the liver.
Comments
Users must not confuse black cohosh with blue cohosh (Caulophyllum thalictroides). Although blue cohosh has legitimate uses, including promotion of menstruation and labor, it is very different from black cohosh and potentially more dangerous. Blue cohosh can elevate blood pressure, increase intestinal motility, and accelerate respiration. It can also induce uterine contractions and hence should be avoided during pregnancy. Some commercial products contain both black cohosh and blue cohosh. Women who want only black cohosh should avoid these products.
Butterbur
Butterbur (Petasites hybridus) is a bush that grows in marshy areas across North America. Products are made from the rhizomes and roots as well as the stems of this plant.
Uses
Butterbur is most commonly taken for migraine headaches, allergies, and asthma. It is one of the few botanicals recommended as a drug of first choice based on outcomes of randomized controlled trials.
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Butterbur has antiinflammatory, antispasmodic, and vasodilatory effects. As with many herbal products, the exact mechanism of action is unknown. Some believe that butterbur works as a calcium channel blocker. Laboratory studies point to inhibition of lipoxygenase, an enzyme which contributes to the synthesis of leukotrienes and other proinflammatory substances.
Effectiveness
Although evidence remains lacking for the efficacy of butterbur in the treatment of skin allergies and asthma, substantial evidence supports other uses. According to the NCCIH:
• A sponsored literature review found that butterbur is just as effective as an antihistamine for allergy symptoms.
• Butterbur appears to relieve nasal allergy symptoms.
• Research findings indicate that butterbur can be effective in treating migraine headache.
The American Academy of Neurology (AAN) and the American Headache Society (AHA) also noted the effects of butterbur on preventing migraine headache. In 2012 they published a joint report in which they not only pronounced that butterbur was effective in decreasing migraine headache frequency, but also gave it the highest (Level A) rating. Their conclusion? “Petasites (butterbur) is effective for migraine prevention and should be offered to patients with migraine to reduce the frequency and severity of migraine attacks.” For this purpose, the AAN recommends 50 to 75 mg twice a day. (See the AAN 2014 report Headache: Quality Measurement Set available through http://www.aan.com.)
Adverse Effects
Long-term safety has not been established; however, butterbur appears to be safe for short-term use of less than 4 months’ duration when taken at recommended doses. The most common adverse effects are eructation (belching), headache, and fatigue. Those who have allergies to ragweed, daisies, marigolds, and chrysanthemums may have allergic reactions to butterbur.
With the increased use of butterbur, the concern has arisen regarding new reports of liver injury. According to the NCCIH, this can be the result of pyrrolizidine alkaloids (PAs) found in butterbur. The NCCIH recommends using only butterbur products where these have been removed and are certified as PA-free. Whether this type of product was taken by those who developed liver injury is unknown.
Interactions With Conventional Drugs
Interactions can occur if butterbur is given with drugs that induce CYP3A4 isoenzymes. Examples include not only drugs such as carbamazepine, phenobarbital, and phenytoin but also dietary supplements such as echinacea, garlic, and St. John’s wort. The greatest concern comes when a non-PA-free form of butterbur is used because PAs are substrates of CYP3A4 isoenzymes; metabolism converts these to their toxic metabolites.
Coenzyme Q-10
Coenzyme Q-10 (ubiquinone, CoQ-10) is an antioxidant that serves a vital role in cellular energy production. As we age, CoQ-10 levels decrease. This has led to increased interest in the use of CoQ-10 in treatment of conditions associated with aging and with cellular energy production.
Uses
CoQ-10 is used to treat heart failure, muscle injury caused by HMG-CoA reductase inhibitors (statins), and mitochondrial encephalomyopathies (i.e., muscle and nervous system injury caused by deranged mitochondrial metabolism).
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CoQ-10 is a potent antioxidant. It participates in many metabolic pathways, most notably production of adenosine triphosphate (ATP).
Effectiveness
In patients with documented CoQ-10 deficiency, replacement therapy with CoQ-10 offers clear benefits. Although some study findings have been mixed, the NCCIH reports a number of positive outcomes associated with the use of CoQ-10.
• Patients with heart failure who took CoQ-10 had improved cardiac function.
• Patients who took CoQ-10 after cardiac surgery had faster recovery.
• CoQ-10 may improve sperm count and semen quality; however, further studies are needed to identify an improvement in conception.
Research studies that examined the effect of CoQ-10 on statin-associated muscle injury, cancer prevention and treatment, and hypertension were inconclusive.
Adverse Effects
CoQ-10 is well tolerated. High doses may produce gastrointestinal (GI) disturbances, including gastritis, reduced appetite, nausea, and diarrhea. Liver enzymes may increase, although no reports of actual liver injury have been made. Women who are pregnant or breastfeeding should not take CoQ-10 because safety has not been established.
Interactions With Conventional Drugs
CoQ-10 is structurally similar to vitamin K2 and hence may antagonize the effects of warfarin.
Biosynthesis of CoQ-10 shares a common pathway with cholesterol. As a result, drugs such as the statins, which inhibit synthesis of cholesterol, can also inhibit synthesis of CoQ-10, causing levels of endogenous CoQ-10 to decline. (Statin-induced reductions in CoQ-10 may explain why statins cause muscle injury.)
Cranberry Juice
Uses
Cranberry juice is used to prevent urinary tract infections (UTIs) and to decrease urine odor in patients with urinary incontinence.
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Benefits derive from the presence of proanthocyanidins, a group of compounds that prevent bacteria from adhering to the urinary tract wall. Bacteria that have already attached themselves are not affected. Cranberry juice does not acidify the urine as previously thought.
Effectiveness
Daily consumption of cranberry juice can prevent recurrent UTIs, but this has been demonstrated only in certain age groups. Specifically, it appears to benefit older-adult women and women in their teens or 20s, but not middle-aged adults or young girls. Furthermore, although cranberry juice can prevent UTIs, it is not effective as treatment for an established infection. In patients with urinary incontinence, cranberry juice can reduce unpleasant odor. Little is known about the efficacy of cranberry-extract capsules. Accordingly, cranberry juice itself is the preferred formulation.
Adverse Effects
Drinking more than 1 L/day may increase the risk for GI upset and formation of kidney stones.
Interactions With Conventional Drugs
There is some evidence that cranberry juice may increase the risk for bleeding in patients taking warfarin. Accordingly, these patients should be monitored closely.
Echinacea
Echinacea is the scientific name of the coneflower plant which is native to the United States and parts of Canada. Echinacea was listed in the National Formulary from 1916 to 1950, but fell from favor owing to development of antibiotics and a lack of scientific data to support its use.
Uses
Echinacea (Echinacea angustifolia, E. purpurea, E. pallida) is administered orally and topically. Oral echinacea is taken to stimulate immune function, suppress inflammation, and treat viral infections, including influenza and the common cold. Topical echinacea is used to treat wounds, burns, eczema, psoriasis, and herpes simplex infections.
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Active ingredients in echinacea preparations include cichoric acid, polysaccharides, flavonoids, and essential oils. These ingredients have been thought to produce antiviral, antiinflammatory, and immunostimulant effects through a combination of actions, including mobilization of phagocytes, stimulation of T-lymphocyte proliferation, stimulation of interferon and tumor necrosis factor production, and inhibition of hyaluronidase, a proinflammatory enzyme.
Effectiveness
Although echinacea is taken widely to prevent and treat colds, its efficacy is highly questionable. Recent randomized, placebo-controlled trials designed to evaluate the ability of echinacea to prevent colds found no effect on (1) the time to developing an upper respiratory tract infection (URI); (2) the incidence, duration, or severity of URIs that did develop; or (3) development of experimentally induced URIs. Other recent trials conducted on adults and children who already had a URI found echinacea no better than placebo at reducing either the duration or severity of symptoms. The NCCIH continues to support research for its effects on the immune system.
Adverse Effects
Very few adverse effects have been reported. The most common complaint is unpleasant taste. Fever, nausea, and vomiting occur infrequently.
Rarely, echinacea causes allergic reactions, including acute asthma, urticaria, angioedema, and anaphylaxis. Echinacea belongs to the daisy family of plants, whose members include ragweed, asters, chamomile, and chrysanthemums. People allergic to any of these plants are at increased risk for reacting to echinacea. Individuals with atopy (a genetic tendency toward allergic conditions) appear at increased risk for reacting to echinacea.
Until echinacea’s effects on the immune system are fully known, it would be prudent to avoid the drug in patients with autoimmune diseases, such as lupus erythematosus or rheumatoid arthritis. Although short-term exposure to echinacea may stimulate immune function, there is concern that long-term exposure can suppress immune function. Accordingly, long-term therapy should be avoided in immunocompromised patients, including those with HIV infection. In addition, prolonged therapy should be avoided in people with tuberculosis and other chronic infections that require optimal immune function for cure.
Interactions With Conventional Drugs
By stimulating the immune system, echinacea can oppose the effects of immunosuppressant drugs. Conversely, by suppressing immune function (in response to long-term use), echinacea can compromise drug therapy of tuberculosis, cancer, and HIV infection.
Feverfew
Feverfew (Tanacetum parthenium) is a bushy plaint with small daisy-like flowers that grows throughout North and South America and Europe. Supplements are made from the dried leaves, although sometimes the flowers and stems are included.
Uses
Feverfew is used primarily for prophylaxis of migraine. It is also taken for a number of conditions associated with hypersensitivity and altered immune responses such as allergies, asthma, rheumatoid arthritis, and psoriasis.
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The principal active agent in feverfew is parthenolide, a compound found in feverfew leaves. How parthenolide suppresses migraine is poorly understood. Possibilities include inhibition of vasoconstriction in the brain, suppression of serotonin release from platelets and leukocytes, and suppression of inflammation secondary to inhibition of arachidonic acid release.
Effectiveness
Clinical studies on feverfew’s effect on migraine headaches have had mixed results. Some findings suggest that, when taken prophylactically, the herb can reduce the frequency of attacks and the severity of symptoms (nausea, photophobia, phonophobia, and pain). Feverfew was found less effective when taken to abort an ongoing attack, however. Furthermore, the doses required are much higher than those for prophylaxis.
In 2012, the AAN and the AHS published a joint report on the evidence for CAM on episodic migraine prophylaxis. Their conclusion was that feverfew was probably effective for this purpose. (See earlier section “Butterbur.”) The AAN recommends dosing at 50 to 300 mg to be taken twice a day for migraine prophylaxis.
What about the other purposes for which people use feverfew? Unfortunately, there is no reliable evidence that feverfew can benefit patients with rheumatoid arthritis or other inflammatory conditions.
Adverse Effects
Feverfew is very well tolerated. No serious adverse effects have been reported, although long-term studies of safety are lacking. Mild reactions include abdominal pain, indigestion, diarrhea, flatulence, nausea, and vomiting. Chewing feverfew leaves, a rare practice today, can cause oral ulceration, tongue irritation, and swollen lips. Some patients develop postfeverfew syndrome, characterized by nervousness, fatigue, insomnia, tension headache, and joint pain or stiffness.
Feverfew belongs to the same plant family as echinacea. Accordingly, individuals allergic to ragweed, chrysanthemums, daisies, and marigolds may also be allergic to feverfew. By suppressing release of arachidonic acid in platelets, feverfew can decrease platelet aggregation and may thereby pose a risk for bleeding. Accordingly, the product should be discontinued 2 weeks before elective surgery.
Some reports suggest that feverfew may cause uterine contractions. For this reason, women who are pregnant should not take this drug. Safety regarding breastfeeding has not been established.
Interactions With Conventional Drugs
By suppressing platelet aggregation, feverfew can increase the risk for bleeding in patients taking antiplatelet drugs (e.g., aspirin) or anticoagulants (e.g., warfarin, heparin).
Comments
There is great variability in feverfew products. Some contain little or no active ingredient.
Flaxseed
Flaxseeds are small seeds of the flax plant that grows in the Northwest United States and Canada. They may be processed in various products or added whole to cereals and other food products.
Uses
Flaxseed powders are used to treat constipation and dyslipidemias. Because it is a phytoestrogen, some women take it to combat hot flashes associated with menopause. Flaxseed also represents a vegetarian source of omega-3 fatty acids.
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Ground flaxseed provides soluble plant fiber and alpha-linolenic acid. Like other high-fiber products, flaxseed can reduce serum cholesterol.
Flaxseed is an important food source of phytoestrogens called lignans. In the colon, bacteria convert these lignans into enterolactone and enterodial, compounds that have both mild estrogenic and antiestrogenic actions. The antiestrogenic actions can decrease cellular proliferation in breast tissue.
Effectiveness
Like other fiber products, flaxseed has the potential to decrease plasma levels of total cholesterol and low-density lipoprotein (LDL) cholesterol but does not affect high-density lipoprotein (HDL) cholesterol or triglycerides. These effects occur predominantly among people with high cholesterol levels and in women who are postmenopausal. In contrast, defatted flaxseed may increase triglyceride levels, so it should be avoided by patients with hypertriglyceridemia.
Owing to its soluble fiber content, flaxseed acts like a bulk-forming laxative to relieve constipation. As with any bulk-forming laxative, adequate fluid intake is an important component of therapy.
Other than for management of hypercholesterolemia, current studies do not support the use of flaxseed for cardiovascular disease. They also do not support its use for relief of menopausal symptoms or cancer prevention. However, NCCIH funding of flaxseed research is ongoing.
Adverse Effects
Like other sources of dietary fiber, flaxseed can cause GI effects, including bloating, flatulence, and abdominal discomfort.
Interactions With Conventional Drugs
Flaxseed may reduce the absorption of conventional medications. Hence, it should be taken 1 hour before or 2 hours after these drugs.
Garlic
Garlic (Allium sativum) is a common plant known for its edible bulb. It has been used throughout history for a myriad of uses and remains one of the most popular dietary supplements in use today.
Uses
Garlic is used primarily for effects on the cardiovascular system. The herb is taken to reduce levels of triglycerides and LDL cholesterol and to raise levels of HDL cholesterol. Garlic is also employed to reduce blood pressure, suppress platelet aggregation, increase arterial elasticity, and decrease formation of atherosclerotic plaque. In addition, garlic has been used for antimicrobial and anticancer effects.
Actions
Beneficial effects are presumed to result from the actions of sulfides in garlic oil. Intact garlic cells contain alliin, an odorless amino acid. When garlic cells are crushed, they release allinase, an enzyme that converts alliin into allicin. Allicin is the major active agent in garlic oil and the compound that gives garlic its distinctive aroma. In addition to allicin, garlic oil contains ajoenes (pronounced AH-ho-weens), biologically active compounds that contribute to beneficial effects.
Garlic is thought to reduce cholesterol levels by interfering with cholesterol synthesis in the liver. There is conflicting evidence regarding inhibition of HMG-CoA reductase, the rate-limiting enzyme in cholesterol synthesis and the enzyme that “statin” drugs inhibit.
Antiplatelet effects, which are well documented, result in part from inhibiting thromboxane synthesis. Methylallyltrisulfide is the chemical in garlic believed responsible. In addition, garlic may suppress platelet aggregation by disrupting calcium-dependent processes. Coagulation is also affected by the ajoenes, which have antithrombotic actions and may also stimulate fibrinolysis.
Lowering of blood pressure may be explained by garlic’s ability to increase the activity of nitric oxide synthase, the enzyme in blood vessels that makes nitric oxide. Nitric oxide, also known as endothelium-derived relaxant factor, is a powerful vasodilator.
Effectiveness
As with many dietary supplements, research findings regarding garlic have been mixed. Outcomes of small trials in the 1990s demonstrated that garlic can produce favorable effects on plasma lipids. More recent and larger studies, however, have cast doubt on those findings.
After reviewing the scientific research, the NCCIH has concluded the following, for now:
• Garlic does not appear to lower LDL cholesterol.
• Garlic may lower blood pressure, but any benefit appears modest, at best.
• Garlic may decrease the rate of atherosclerosis development.
Regarding the effect of garlic on cancer prevention, at this time, the National Cancer Institute recognizes that garlic may have a role in cancer prevention but, in the absence of adequate reliable data, does not recommend it.
Adverse Effects
Garlic is generally well tolerated. The most common side effects are bad breath and body odor. (This occurs because a product of garlic metabolism is allyl methyl sulfide, a sulfur compound that is excreted through respiration and skin pores.) Rarely, garlic causes heartburn, flatulence, nausea, vomiting, diarrhea, and a burning sensation in the mouth. These effects are most pronounced with raw garlic and in people who don’t eat garlic often. Patients suffering from infectious or inflammatory GI disorders should avoid garlic owing to its potential for GI irritation.
Interactions With Conventional Drugs
Garlic has significant antiplatelet effects. Accordingly, it can increase the risk for bleeding in patients taking antiplatelet drugs (e.g., aspirin) or anticoagulants (e.g., warfarin, heparin). Garlic can reduce levels of at least two drugs: cyclosporine (an immunosuppressant) and saquinavir (a protease inhibitor used to treat HIV infection).
Ginger Root
Ginger grows primarily in the tropics. Its root, actually a rhizome, is the source of the ginger root used in CAM.
Uses
Ginger root (Zingiber officinale) is used primarily to treat vertigo and to suppress nausea and vomiting associated with motion sickness, morning sickness, seasickness, and general anesthesia. In addition, ginger has antiinflammatory and analgesic properties that may help people with arthritis and other chronic inflammatory conditions. Some practitioners use ginger for URIs, although proof of efficacy is lacking.
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The mechanism by which ginger suppresses nausea and vomiting is unclear. A good possibility is blockade of serotonin (5-hydroxytryptamine3, or 5-HT3) receptors located in the chemoreceptor trigger zone of the medulla and on afferent vagal neurons in the GI tract. Activation of these receptors triggers emesis. Conversely, blockade of these receptors suppresses emesis. In fact, drugs that block 5-HT3 receptors (e.g., ondansetron [Zofran]) are the most effective antiemetics available. Galanolactone, a major constituent of ginger, can block 5-HT3 receptors in vitro, suggesting that receptor blockade may underlie antiemetic effects. Other actions that may contribute to beneficial effects include stimulation of intestinal motility, salivation, and gastric mucus production and suppression of GI spasm secondary to anticholinergic and antihistaminic actions.
The antiinflammatory effects of ginger have been attributed to inhibiting synthesis of prostaglandins and leukotrienes, which are powerful inflammatory mediators.
How ginger may reduce vertigo is unknown.
Effectiveness
There is good evidence supporting the benefits of ginger root for prevention and treatment of morning sickness. A 2014 meta-analysis of the evidence demonstrated a decrease in nausea but not in episodes of vomiting. Unfortunately, studies focused on nausea due to motion sickness and postoperative nausea and vomiting (in the absence of opioids) have had conflicting results.
In patients with rheumatoid arthritis, ginger root appears to reduce pain, improve joint mobility, and decrease swelling and morning stiffness. These studies are inconclusive, however, and further research is ongoing.
Adverse Effects
Ginger is very well tolerated. Severe toxicity has not been reported—although excessive doses (above 5 g/day) have the potential to cause CNS depression and cardiac dysrhythmias. Huge doses may also cause GI disturbances.
Although ginger has effectiveness in relieving morning sickness, it should be used with caution during pregnancy because safety in pregnancy has not been proved. High-dose ginger is believed to stimulate the uterus and thus may theoretically cause spontaneous abortion, although there are no reports of this ever happening. A 2012 population study of women in Norway included data on 1020 women who used ginger during pregnancy. Research findings showed no increased risk for malformations, spontaneous abortion, or other complications compared with women who did not take ginger.
Interactions With Conventional Drugs
Ginger can inhibit production of thromboxane by platelets and can thereby suppress platelet aggregation. Accordingly, ginger can increase the risk for bleeding in patients receiving antiplatelet drugs (e.g., aspirin) or anticoagulants (e.g., warfarin, heparin). Ginger can lower blood sugar and hence may potentiate the hypoglycemic effects of insulin and other drugs for diabetes.
Ginkgo biloba
Medicinal ginkgo is prepared by acetone extraction of leaves from the Ginkgo biloba tree. These leaves contain two classes of active compounds: flavonoids (ginkgoflavone glycosides) and terpenoids (ginkgolides, bilobalide). Ginkgo biloba extracts (GBEs) are standardized to contain 24% flavonoids and 6% terpenoids. Daily oral doses of standardized GBE range from 60 to 240 mg.
Uses
Ginkgo (Ginkgo biloba) is used primarily to improve memory, to halt progression of dementia, and to decrease intermittent claudication. Less common uses include treatment of erectile dysfunction and other conditions associated with decreased perfusion.
Actions
Any benefits are believed to derive from improved blood flow secondary to ginkgo-induced vasodilation. GBEs also suppress production of platelet-activating factor (PAF), a mediator of platelet aggregation, bronchospasm, and other processes. Reduced PAF production may help protect against thrombosis as well as bronchospasm and other allergic disorders.
Effectiveness
Gingko is one of the most studied of the herbal products. As with many of these, early studies showed promising findings that conflicted with more recent and rigorous clinical trials.
Studies that examine the effects of gingko on intermittent claudication have had mixed results. Most have not demonstrated a significant benefit. In those in which improvement was noted, the degree of improvement was small.
What about benefits in dementia? In a large placebo-controlled trial—the Ginkgo Evaluation of Memory (GEM) study, sponsored by the NIH—GBE failed to prevent dementia of any sort, including Alzheimer disease. This study enrolled more than 3000 participants 75 years or older. Half received a GBE formulation (120 mg twice daily), and the other half received a placebo. The result? After 6 years of treatment, the incidence of dementia was nearly identical in both groups.
The NCCIH is currently studying ginkgo effects in multiple sclerosis, sexual dysfunction caused by antidepressants, insulin resistance, and memory loss due to electroconvulsive therapy. Additional studies continue for intermittent claudication and dementia.
Adverse Effects
Ginkgo is generally well tolerated. In some patients, it causes stomach upset, headache, dizziness, or vertigo, all of which can be minimized by avoiding rapid increases in dosage. There have been case reports of spontaneous bleeding, although no bleeding was observed in the GEM study.
There have been reports of people eating raw or roasted ginkgo seeds. Unlike ginkgo leaves, the seeds contain significant amounts of toxins. Seizures and fatalities have occurred after ingestion.
Interactions With Conventional Drugs
Ginkgo may suppress coagulation. Accordingly, it should be used with caution in patients taking antiplatelet drugs (e.g., aspirin) or anticoagulants (e.g., warfarin, heparin).
There is concern that ginkgo may promote seizures. Accordingly, the herb should be avoided by patients at risk for seizures, including those taking drugs that can lower the seizure threshold, including some antipsychotics, antidepressants, cholinesterase inhibitors, decongestants, first-generation antihistamines, and systemic glucocorticoids.
Glucosamine and Chondroitin
Glucosamine and chondroitin are individual products that are usually administered together. Both are innate substances in the body that serve as essential components of cartilage. Products containing these substances can come from natural sources (e.g., animal cartilage) or may be manufactured in a laboratory.
Uses
These agents are used widely to treat osteoarthritis. Osteoarthritis primarily affects the knee, hip, and wrist joints.
Actions
Glucosamine is employed by the body in the synthesis of cartilage and synovial fluid. Chondroitin helps to keep cartilage hydrated. When given to people with osteoarthritis, glucosamine may help in several ways. First, it can act as a substrate for making cartilage and synovial fluid. Second, it can stimulate the activity of chondrocytes, the cells in joints that make cartilage and synovial fluid. And third, it can suppress production of cytokines that mediate joint inflammation and cartilage degradation. Chondroitin has a role in maintaining cartilage integrity.
Effectiveness
Studies on the efficacy of glucosamine and chondroitin in osteoarthritis have yielded mixed results. Most studies do not show improvement in pain relief; however, some studies have demonstrated a modest improvement in joint structure.
In 2012, the American College of Rheumatology updated their recommendations for the management for osteoarthritis. After an examination of the evidence, the expert panel advised providers not to use glucosamine and chondroitin for osteoarthritis management.
Adverse Effects
The most common side effects are GI disturbances, such as nausea and heartburn. Because commercial glucosamine is produced from the exoskeletons of shellfish (shrimp), glucosamine should be used with caution in patients with shellfish allergy. In theory, glucosamine can raise blood levels of glucose, but this has not been observed in clinical trials.
Interactions With Conventional Drugs
Several case reports suggest glucosamine may increase the risk for bleeding. Accordingly, patients taking antiplatelet drugs (e.g., aspirin) or anticoagulants (e.g., warfarin, heparin) should probably avoid this product.
Green Tea
Green tea is produced from the Camellia sinensis plant. This is the same plant used to produce black tea and oolong tea. The differences lie in the method of production.
Uses
Green tea and green tea extracts have been used to lose weight, improve mental clarity, and prevent and treat cancers of the stomach, skin, bladder, and breast.
Actions
The mechanism underlying beneficial effects is poorly understood and probably multifactorial. Polyphenols in green tea may underlie antiinflammatory, chemoprotective, and antioxidant effects. Chemoprotection may also stem from epigallocatechin-3-gallate (EGCG), a compound in green tea extracts. The caffeine in green tea may be responsible for weight loss and improved mental clarity.
Effectiveness
Data on green tea efficacy are limited. There is evidence that drinking green tea throughout the day can improve mental clarity and may help with weight loss. In both cases, any benefits are probably due to caffeine and not a substance unique to green tea.
Studies done in animals and cultured cancer cells have shown that green tea and EGCG may prevent or slow the growth of certain cancers. Also, there is a small body of evidence indicating that drinking green tea may help prevent recurrence after treatment of early-stage breast cancer. These studies have shown mixed results; however, research is ongoing.
Adverse Effects
Moderate consumption appears to be safe. As with other caffeine-containing products, overconsumption may result in headache, nausea, anxiety, insomnia, increased heart rate, and increased urination. Hepatotoxicity has been reported, primarily in people using concentrated green tea extracts. The mechanism of the hepatotoxicity remains unknown.
Interactions With Conventional Drugs
There is a long list of potential drug interactions. Green tea should be consumed with caution by patients taking vasodilators, stimulants and other psychoactive medications, and medications with a known risk for liver damage. Green tea contains a small amount of vitamin K, which may decrease the anticoagulant effects of warfarin.
Peppermint
Peppermint (Mentha piperita) is a common herb in North America as well as Europe and the Middle East. It is often found in near streams, especially in partially shaded areas.
Uses
Peppermint is best known as a culinary flavoring. Peppermint tea is a popular drink in some regions. When used as a medicinal preparation, peppermint oil is the form most commonly used. It is available over the counter in gel tablets or capsules.
Randomized controlled trials (RCTs) have demonstrated a beneficial effect of peppermint oil for management of irritable bowel syndrome (IBS). In their 2014 Monograph on the Management of Irritable Bowel Syndrome and Chronic Idiopathic Constipation (available at http://gi.org/wp-content/uploads/2014/08/IBS_CIC_Monograph_AJG_Aug_2014.pdf), the American College of Gastroenterology included peppermint oil among their recommendations for IBS management.
Peppermint oil is also gaining recognition as therapy for small intestine bacterial overgrowth (SIBO). SIBO is a condition that has become increasingly common as a result of increases in over-the-counter proton pump inhibitor use as well as following certain bariatric surgeries such as the Roux-en-Y gastric bypass. As bacteria break down carbohydrates and other substances, excessive gas forms. This results in severe abdominal cramps and low volume diarrhea. SIBO is typically treated with antibiotics; therefore, the antibiotic properties of peppermint oil are beneficial in this regard.
Small studies have also supported the use of peppermint oil to manage esophageal spasms in adults and functional abdominal pain in children. Numerous anecdotal reports suggest topical use of peppermint oil applied to the temples may help ease tension headaches. This is supported by two small trials comparing peppermint oil to a placebo and peppermint oil to acetaminophen. In these, peppermint oil was significantly more effective than the placebo and equal in effectiveness compared to acetaminophen.
Actions
Peppermint oil inhibits smooth muscle activity in the gastrointestinal tract. The exact mechanism is unclear; however, animal studies have indicated a possible relationship to blocking of calcium channels in the GI system.
Antibacterial properties of peppermint may come, in part, from menthol and other volatile oils. Research has demonstrated that peppermint oil has a bacteriostatic effect against 22 strains of both gram positive and gram negative bacteria and bactericidal activity against Escherichia coli, Helicobacter pylori, and Salmonella enteritidis.
It has been theorized that peppermint activates opioid receptors. Recent studies point to a different mechanism for pain relief: stimulation of transient receptor potential ion channel melastatin subtype 8 (TRPM8) in gastrointestinal pathways. TRPM8 receptors are activated by cold temperatures and by cooling agents such as menthol, which is a component of peppermint,
Effectiveness
Numerous studies demonstrate that peppermint oil is significantly superior to a placebo for management of IBS. Smaller studies support its use for SIBO, functional abdominal pain, and tension headache.
Adverse Effects
Peppermint can lower esophageal sphincter pressure leading to gastroesophageal reflux. This is more likely to occur with peppermint teas. Peppermint gels do not usually cause such problems because their enteric coating allows them to pass through the stomach intact.
Allergic reactions have been reported. Perianal burning has been reported following high doses. Excessive doses have also been tied to renal problems. At standard doses, peppermint oil appears to be devoid of serious adverse effects.
Interactions With Conventional Drugs
Over a decade ago, questions were raised regarding CYP1A2 inhibition by peppermint oil; however, this has not been demonstrated in humans. Peppermint oil may have an additive effect when administered with antispasmodics.
Probiotics
Probiotics are dietary supplements composed of potentially beneficial bacteria or yeasts. These preparations typically contain two types of bacteria—lactobacilli and bifidobacteria—as well as Saccharomyces boulardii, a specific strain of yeast. All of these microorganisms are normal components of our gut flora.
Uses
The bacteria in probiotics may help treat irritable bowel syndrome (IBS), ulcerative colitis, Clostridium difficile–associated diarrhea (CDAD), and, in children, rotavirus diarrhea. Products containing S. boulardii are used for CDAD.
Actions
Normal intestinal and colonic bacteria play several important roles: they help metabolize foods and some drugs; they promote nutrient absorption; and they reduce colonization of the gut by pathogenic bacteria. Lactobacillus and Bifidobacterium species adhere to the intestinal wall and thereby prevent attachment of bacterial pathogens. They also control bacterial overgrowth by producing lactic acid and to some degree by producing hydrogen peroxide. Benefits may also derive from increasing nonspecific cellular and humeral immunity. The yeast S. boulardii produces proteases that can degrade toxins produced by C. difficile. Benefits of S. boulardii in Crohn disease derive in part from increasing intestinal secretion of immunoglobulin A.
Effectiveness
According to information available at NCCIH (https://nccih.nih.gov/health/probiotics), studies on probiotics have yielded conflicting results. Larger and more rigorous research studies are needed. There is some evidence that Lactobacillus species may reduce the duration of diarrhea in patients with rotavirus infection and other GI conditions. Effectiveness appears to vary among Lactobacillus species. VSL#3, a product composed of lactobacilli, bifidobacteria, Streptococcus thermophilus, and other bacteria, appears to have a role in inducing remission of ulcerative colitis, perhaps in as many as 50% of patients. In patients with IBS, VSL#3 may reduce bloating and abdominal pain. However, the product does not improve bowel movement frequency or consistency. Additional testing is needed.
Adverse Effects
Probiotics are generally well tolerated. Flatulence and bloating are the most common adverse effects. Infection of the blood with lactobacilli and fungi has been reported after ingestion of yogurt, but only in severely ill, immunocompromised patients taking broad-spectrum antibiotics long term. Fungemia has occurred most often when packets of S. boulardii [Florastor] have been opened at the bedside in the intensive care unit. Florastor is contraindicated in patients who have central lines.
Interactions With Conventional Drugs
Antibacterial and antifungal drugs can kill the bacteria and yeasts in probiotic products. Accordingly, to help preserve probiotic activity, these preparations should be administered no sooner than 2 hours after dosing with antibacterial or antifungal drugs.
Resveratrol
Resveratrol is a chemical found in grapes (mainly the skin), red wine, purple grape juice, blueberries, cranberries, and peanuts. Resveratrol content of dietary supplements ranges from 16 to 600 mg per tablet or capsule. The amount in red wine is quite low, only 0.3 to 1.9 mg per 150-mL serving.
Uses
Resveratrol is an antioxidant promoted for antiaging effects and for protection against chronic diseases. Owing to the presence of resveratrol in red wine, researchers thought it might explain the French paradox: how can it be that French people have a relatively low incidence of coronary heart disease, despite having a diet relatively high in saturated fats? However, the amount of resveratrol in red wine seems much too low for significant cardioprotectant effects.
Recent research findings have opened the door to the potential for resveratrol to improve outcomes in a number of conditions. Research is ongoing to determine resveratrol’s role in management of heart disease, diabetes, obesity, and Alzheimer disease.
Actions
In 2012, a breakthough NIH study of resveratrol identified the mechanism of action, heretofore believed to be due to direct interaction with sirtuin enzymes. Resveratrol inhibits phosphodiesterases (PDEs). This, in turn, increases levels of cyclic adenosine monophosphate (AMP) and activation of AMP-dependent kinase. This is important because PDEs play a role in many chronic conditions (e.g., heart disease, diabetes, chronic obstructive pulmonary disease), and PDE inhibitors are proving to be important drugs in managing these.
Effectiveness
Resveratrol has produced clear benefits in animal studies. In middle-aged mice on a high-calorie diet, resveratrol increased insulin sensitivity and reduced mortality. In normal-weight mice, resveratrol failed to reduce mortality, but did improve cardiovascular function, bone density, and motor coordination, and delayed formation of cataracts. In rodent models of human cancers, resveratrol suppressed tumor growth, including tumors of the lung, skin, breast, and prostate. In diabetic rats, resveratrol lowered blood glucose, and in human cells grown in culture, resveratrol increased glucose uptake. In one human study, resveratrol suppressed production of tumor necrosis factor and free radicals; both actions could reduce blood vessel inflammation and subsequent atherosclerosis.
Although studies done in cell cultures and animals have been encouraging, very little is known about the long-term benefits of resveratrol in humans. In fact, we have no data at all showing that resveratrol either slows aging or reduces the incidence or severity of any disease.
Adverse Effects and Interactions With Conventional Drugs
Information on adverse effects is limited. We do know that resveratrol has antiplatelet actions, which might intensify the effects of anticoagulants and antiplatelet drugs. Also, resveratrol can mimic the effects of estrogen and hence is not recommended for women with estrogen-dependent breast cancer. In addition, resveratrol may increase insulin sensitivity and hence should be used with caution by patients taking antidiabetic agents.
Saw Palmetto
The American saw palmetto (Serenoa repens, Sabal serrulata) is a small palm tree that grows in the eastern United States. The product employed clinically is an extract made from its berries.
Uses
Saw palmetto is taken to relieve urinary symptoms associated with benign prostatic hyperplasia (BPH). No other use has been identified.
Actions
How does saw palmetto affect prostate function? Some have postulated that it causes blockade of testosterone receptors, blockade of alpha-adrenergic receptors, and suppression of inflammation. Contrary to prior belief, the preparation does not seem to inhibit 5-alpha-reductase, the enzyme that converts testosterone into dihydrotestosterone (DHT), the active form of testosterone in the prostate. Saw palmetto does not reduce prostate size or serum levels of testosterone, DHT, or prostate-specific antigen (PSA).
Effectiveness
At this time, there is insufficient evidence to support using saw palmetto for BPH or any other condition. Although early studies suggested that saw palmetto might reduce symptoms of BPH, these results have not been confirmed by more rigorous studies. Two clinical trials funded by the NIH showed that saw palmetto extract is no more effective than placebo at reducing symptoms of BPH. A 2012 Cochrane review of 32 RCTs involving 5666 men found no significant difference between saw palmetto and a placebo. It continues to be widely used, however, and promoted in nonprofessional magazines and other resources.
Adverse Effects
Saw palmetto is very well tolerated. Significant adverse effects have not been reported. Rarely, saw palmetto causes nausea or headache. Although antiandrogenic effects (e.g., gynecomastia) have not been reported, it may be wise to monitor for them. Saw palmetto may have antiplatelet actions, but increased bleeding has not been reported.
Because of its antiandrogenic effects, saw palmetto represents a danger to the developing fetus. Pregnant women should not ingest this herb, but then we would hope that women would not anticipate needing a preparation whose only indication is treatment of BPH.
Interactions with Conventional Drugs
Because of its antiplatelet effects, saw palmetto should be used with caution in patients taking antiplatelet drugs (e.g., aspirin) or anticoagulants (e.g., warfarin, heparin).
Soy
Soy is a member of the pea (legume) family. Although it is processed in tablets and capsules for CAM, it has become a common staple in American diets both in its original form (edamame) and in processed foods such as soy sauce and tofu.
Uses
Soy protein and soy isoflavones have several uses, including prevention of breast cancer and, in postmenopausal women, treatment of vasomotor symptoms (hot flashes) and prevention of osteoporosis.
Actions
Soy’s major active components are phytoestrogens (isoflavones and lignans) and phytosterols (betasitosterol). Two isoflavones—genistein and daidzein—undergo enzymatic conversion to equol, a compound with estrogenic actions. Soy isoflavones are structurally similar to estradiol (the major endogenous estrogen) and can bind with estrogen receptors. However, like the SERMs, isoflavones exert mixed estrogenic and antiestrogenic actions. In women with normal estrogen levels, soy isoflavones appear to antagonize endogenous estrogen. By contrast, in postmenopausal women, soy isoflavones act as estrogen agonists.
Effectiveness
Clinical trials using soy-derived phytoestrogens to relieve menopausal hot flashes have yielded mixed results. Overall, the studies lean toward a reduction in hot flashes.
Several epidemiologic studies infer that soy consumption may reduce the risk for developing breast cancer. In particular, population studies have documented that Asian women who eat a diet high in soy are at reduced risk. However, clinical trials confirming this benefit are lacking.
Several early studies suggested that isoflavones either increase bone mineral density or slow the progression of osteoporosis in perimenopausal and postmenopausal women. However, with one exception, several meta-analyses of studies published between 2010 and 2015 do not demonstrate significant improvement in bone mineral density. The exception? A meta-analysis on the effects of phytoestrogens on osteoporosis in ovariectomized rats.
Adverse Effects
Soy and soy extracts are very well tolerated. Gastrointestinal effects—bloating, nausea, constipation or diarrhea—are most common. Rarely, soy can cause migraine, probably because of its estrogenic effects. Large amounts of soy products may increase the risk for oxalate kidney stones. There have been several cases of goiter and hypothyroidism in infants who drank soy-based formula. Concerns that soy formulas might cause feminization of male infants were dispelled by a 2008 review from the American Academy of Pediatrics.
Interactions With Conventional Drugs
Soy should not be combined with tamoxifen and other drugs that can block estrogen receptors. By killing intestinal flora, antibiotics may reduce conversion of isoflavones to their active form, thus decreasing any potential positive effects of soy.
St. John’s Wort
St. John’s wort (Hypericum perforatum) is a plant that grows wild in the western United States and parts of Canada. Its yellow flowers are used in the preparation of extracts and other preparations.
Uses
St. John’s wort is used primarily for oral therapy of mild to moderate depression. The herb has also been used topically to manage local infection and orally to relieve pain and inflammation.
Actions
Benefits of St. John’s wort appear to derive from two compounds—hyperforin and hypericin—that are extracted from flowers of the plant. These compounds can decrease reuptake of three neurotransmitters: serotonin, norepinephrine (NE), and dopamine. Blockade of serotonin and NE uptake mimics the actions of some conventional antidepressants. Early research attributed antidepressant effects to inhibition of monoamine oxidase (MAO). However, we now know that the degree of MAO inhibition is too small to explain clinical effects.
Effectiveness
How effective is St. John’s wort? At this time, it’s hard to say. Although numerous studies have been conducted, evidence for efficacy is mixed, owing to poor study design, heterogeneous study populations, and variable hypericin content of the preparations used, as well as other confounding factors. The bottom line? For patients with mild to moderate major depression, St. John’s wort appears superior to placebo and equal to tricyclic antidepressants. For patients with severe depression, there is no convincing proof of efficacy.
Adverse Effects
St. John’s wort is generally well tolerated. Allergic skin reactions may occur, especially in people allergic to ragweed and daisies. In addition, the herb may cause CNS effects (e.g., insomnia, vivid dreams, restlessness, anxiety, agitation, and irritability) as well as GI discomfort, fatigue, dry mouth, and headache. High-dose therapy may pose a risk for phototoxicity. To reduce this risk, patients should minimize exposure to sunlight, wear protective clothing, and apply a sunscreen to exposed skin.
Interactions With Conventional Drugs
St. John’s wort is known to interact adversely with many drugs—and the list continues to grow. Three mechanisms are involved: induction of cytochrome P450 enzymes, induction of P-glycoprotein, and intensification of serotonin effects. Let’s consider these one by one:
• Induction of 3A4 isoenzymes of cytochrome P450 can accelerate the metabolism of many drugs, thereby decreasing their effects. This mechanism appears responsible for breakthrough bleeding and unintended pregnancy in women taking oral contraceptives, transplant rejection in patients taking cyclosporine (an immunosuppressant), reduced anticoagulation in patients taking warfarin, and reduced antiretroviral effects in patients taking protease inhibitors or nonnucleoside reverse transcriptase inhibitors.
• P-glycoprotein is a transport protein found in cells that line the intestine and renal tubules. In the intestine, P-glycoprotein transports drugs out of cells into the intestinal lumen; in renal tubules, P-glycoprotein transports drugs out of tubular cells into the urine. Hence, by increasing P-glycoprotein synthesis, St. John’s wort can accelerate elimination of drugs and can thereby reduce their effects. This is the mechanism by which St. John’s wort greatly reduces levels of digoxin, a drug for heart failure. Other drugs whose levels can probably be reduced by this mechanism include calcium channel blockers, steroid hormones, protease inhibitors, and certain anticancer drugs (e.g., etoposide, paclitaxel, vinblastine, vincristine).
• Combining St. John’s wort with certain drugs can intensify serotonergic transmission to a degree sufficient to cause potentially fatal serotonin syndrome. Although St. John’s wort can enhance serotonergic transmission by itself, its effect is relatively weak. Hence, when used alone, the herb poses little risk. However, if St. John’s wort is combined with other serotonin-enhancing agents, the risk is greatly increased, and hence St. John’s wort should not be combined with such drugs. Among these are amphetamine, cocaine, and many antidepressants, including MAO inhibitors, selective serotonin reuptake inhibitors, certain tricyclic agents (e.g., amitriptyline, clomipramine), and duloxetine, nefazodone, and venlafaxine.
Because St. John’s wort has a variety of known adverse interactions—and is likely to have more that are as yet unknown—caution is clearly advised. St. John’s wort is not recommended for treating depression in patients taking other medications.
Valerian
Valerian (Valeriana officinalis), also known as garden heliotrope, is a common plant in Europe and Asia, although it is grown in some areas of North America. The plant’s rhizomes and roots are used in the preparation of medicinal products.
Uses
Valerian root is a sedative preparation used primarily to promote sleep. In addition, some people take it to reduce anxiety-associated restlessness.
Actions
Valerian may work by increasing the availability of gamma-aminobutyric acid (GABA, an inhibitory neurotransmitter) at synapses in the CNS. (Benzodiazepines and benzodiazepine-like drugs, which are the major conventional hypnotics, act by potentiating the actions of GABA.) In addition, valerian may act as a direct GABA agonist. The active ingredients in valerian have not been identified.
Effectiveness
Although valerian has been used for centuries in Europe, China, and other countries, objective evidence of efficacy is lacking. According to the NCCIH at https://nccih.nih.gov/health/providers/digest/sleep-disorders-science, “Various herbs such as valerian, chamomile, and kava, and homeopathic medicines sometimes used as sleep aids have not been shown to be effective for insomnia.” Even so, some suggest it may still have mild sedative effects that may be useful for anxiety.
Adverse Effects
Valerian is generally very well tolerated. The FDA has given valerian a Generally Recognized as Safe (GRAS) rating when the product is consumed in amounts commonly used in food. Possible side effects include daytime drowsiness, dizziness, depression, dyspepsia, and pruritus. Prolonged use may cause headache, nervousness, or cardiac abnormalities. Because valerian can reduce alertness, users should exercise caution when performing dangerous activities, such as driving or operating dangerous machinery. In addition, valerian should be used with caution by people with psychiatric illnesses (e.g., depression, dementia). As with benzodiazepines, there may be a risk for paradoxical excitation and physical dependence. We do not know if valerian enters breast milk or harms the developing fetus. Until more is known, valerian should be avoided by women who are pregnant or breastfeeding.
Interactions With Conventional Drugs
In theory, valerian can potentiate the actions of other drugs with CNS-depressant actions. Among these are alcohol, benzodiazepines, barbiturates, opioids, antihistamines, and centrally acting skeletal muscle relaxants. These combinations should be used with caution.
Harmful Supplements to Avoid
To help protect the public from dangerous botanical products, the FDA and the Federal Trade Commission are monitoring adverse event data and issuing warnings to consumers and manufacturers. Three potentially harmful products—comfrey, kava, and Ma huang—are discussed here.
Comfrey
Comfrey (Symphytum officinale) is an herbal supplement used topically and orally. Topical use appears safe. Oral use is not. Why? Because comfrey contains pyrrolizidine alkaloids, which can cause venoocclusive disease (VOD) in animals and hepatic VOD in humans. Hepatic VOD can result in severe liver damage. In addition to causing VOD, pyrrolizidine alkaloids may also be carcinogenic. Accordingly, in July of 2001, the FDA issued a letter to dietary supplement manufacturers advising them to remove comfrey from the market. They urged manufacturers to discontinue production, pull existing product off the shelves, and to warn consumers of the possible dangers; however, comfrey remains widely available for sale on the Internet and elsewhere.
Kava
Kava (Piper methysticum), also known as kava-kava or awa, is used to relieve anxiety, promote sleep, and relax muscles. In the United States the herb has been promoted as a natural alternative to benzodiazepines (e.g., diazepam [Valium]) for treating anxiety and stress. Unfortunately, kava can cause severe liver injury, leading the FDA to issue a public warning in March 2002. Later that year, the Centers for Disease Control and Prevention issued a report on kava-related hepatotoxicity. In the report, they discussed 11 cases of hepatotoxicity from the United States and Europe in which the victims required a liver transplant owing to severe liver failure. Because of concerns over hepatotoxicity, kava sales have been restricted in Germany, Canada, Switzerland, France, and Australia—but not yet in the United States.
Ma Huang (Ephedra)
Ma huang (ephedra) contains ephedrine, a compound that can elevate blood pressure and stimulate the heart and CNS. High-dose ephedra has been associated with stroke, myocardial infarction, and death. To date, more than 17,000 adverse events have been reported, and at least 155 users have died. In 2004 the FDA banned U.S. sales of all ephedra products, marking the first time that a dietary supplement has been ordered off the market. The ban was challenged by an ephedra producer and, in 2005, was partially reversed: a federal court upheld the ban for ephedra products that contain more than 10 mg/dose, but reversed the ban for products that contain 10 mg or less, arguing that there are insufficient data to prove that low doses pose a “significant or unreasonable risk.” In 2006, a federal appeals court upheld the FDA ban of ephedra. This ban was challenged again in 2007, but the U.S. Court of Appeals denied the petition for rehearing. At this time, the FDA ban does not apply to ephedra in traditional Asian medicines or in herbal teas, which are not marketed as dietary supplements.
