html xmlns=”http://www.w3.org/1999/xhtml” xml:lang=”en” style=”font-size:1.250rem;”> 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. 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. 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 • Reduces stress and frustration 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. 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?” 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. 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. 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. 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. 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. 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 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. 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. 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). 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). 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. 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. 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. 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 (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. 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. 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. 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.) 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 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 (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. 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). CoQ-10 is a potent antioxidant. It participates in many metabolic pathways, most notably production of adenosine triphosphate (ATP). 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. 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.
Complementary and Alternative Therapy
Regulation of Dietary Supplements
Dietary Supplement Health and Education Act of 1994
Core Provisions
Package Labeling
Adverse Effects
Impurities, Adulterants, and Variability
Current Good Manufacturing Practices Ruling
Dietary Supplement and Nonprescription Drug Consumer Protection Act
A Comment on the Regulatory Status of Dietary Supplements
Private Quality Certification Programs
Standardization of Herbal Products
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
Adverse Interactions With Conventional Drugs
Some Commonly Used Dietary Supplements
Black Cohosh
Uses
Actions
Effectiveness
Adverse Effects
Interactions With Conventional Drugs
Comments
Butterbur
Uses
Actions
Effectiveness
Adverse Effects
Interactions With Conventional Drugs
Coenzyme Q-10
Uses
Actions
Effectiveness
Adverse Effects
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Complementary and Alternative Therapy
Chapter 67
