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Overview of herbal medicine and dietary supplements

Overview of herbal medicine and dietary supplements
Literature review current through: Jan 2024.
This topic last updated: Oct 23, 2023.

INTRODUCTION — Herbal medicine and dietary supplements are commonly used by patients. This topic will address the general issues of regulation and safety of these preparations. The use, indications, safety, and efficacy of specific herbal preparations and complementary medicines can be found in other UpToDate topics:

(See "Clinical use of St. John's wort".)

(See "Clinical use of saw palmetto".)

(See "Clinical use of ginkgo biloba".)

(See "Chinese herbal medicine for the treatment of allergic diseases".)

(See "Complementary and alternative treatments for anxiety symptoms and disorders: Herbs and medications".)

Specific toxicities related to the use of herbal and dietary supplements are reviewed elsewhere:

(See "Hepatotoxicity due to herbal medications and dietary supplements".)

(See "Nephropathy induced by aristolochic acid (AA) containing herbs".)

BACKGROUND — Plants have been used for medicinal purposes for thousands of years. The fruit of the Fomitopsis betulina fungus was likely used as an antiparasitic and laxative by the "Ice Man" who lived 5300 years ago [1]. Further, St. John's wort was used for a variety of ailments by Greek herbalists such as Hippocrates and Galen from fifth century BCE to second century AD [2]. The Inner Classic of the Yellow Emperor around 100 BCE describes complex traditional Chinese herbs [3]. Herbal medicines flourished in Europe in the 17th century [4], then showed a decline with the Scientific Revolution [5]. European immigrants brought their own herbal medicine traditions to North America and learned many others from Native Americans. Two-thirds of entries in the first edition of the United States Pharmacopoeia (USP) published in 1820 were botanical substances [6].

After about 1920, standardized pharmaceutical drugs increasingly replaced herbal therapies in the United States. Many conventionally used pharmaceuticals, however, are derived from plant species (table 1).

Commonly used herbs and supplements — A list of commonly used herbs and supplements is provided below with links to more information about use, efficacy, and safety elsewhere in UpToDate and from the US National Library of Medicine (NLM) and National Institutes of Health (NIH) websites. General concerns about quality and safety are reviewed below. (See 'Quality and efficacy' below and 'Safety' below.)

Black cohosh (Actaea racemosa, Cimicifuga racemosa) (see "Menopausal hot flashes", section on 'Role of complementary and alternative therapies') – NLM MedlinePlus and NCCIH.

Chamomile (Matricaria recutita) (see "Infantile colic: Management and outcome", section on 'Herbal remedies') NCCIH

Capsicum pepper, cayenne (Capsicum frutescens, Capsicum annuum) (see "Complementary and alternative therapies for allergic rhinitis and conjunctivitis", section on 'Capsaicin (Capsicum annum)' and "Cancer pain management: Role of adjuvant analgesics (coanalgesics)", section on 'Local anesthetics' and "Management of knee osteoarthritis", section on 'Topical capsaicin')

Coenzyme Q10 (Ubiquinol, Ubiquinone, Ubidecarenone) (see "Mitochondrial disorders: Treatment", section on 'CoQ10 deficiency' and "Statin muscle-related adverse events", section on 'Coenzyme Q10' and "Investigational therapies for management of heart failure", section on 'Coenzyme Q10') – National Cancer Institute (NCI)

Cranberry (Vaccinium macrocarpon, Vaccinium oxycoccos) (see "Recurrent simple cystitis in women", section on 'Cranberry products' and "Urinary tract infections in children: Long-term management and prevention", section on 'Cranberry juice') – NCCIH

Creatine (see "Unipolar depression in adults: Investigational and nonstandard treatment", section on 'Creatine' and "Nutritional and non-medication supplements permitted for performance enhancement", section on 'Creatine') – NLM MedlinePlus

DHEA (Dehydroepiandrosterone) (see "Treatment of adrenal insufficiency in adults", section on 'Androgen replacement therapy for selected females') – NLM MedlinePlus

Echinacea (Echinacea angustifolia) (see "Clinical use of echinacea") – NCCIH

Evening primrose oil (Oenothera biennis) (see "Menopausal hot flashes", section on 'Role of complementary and alternative therapies' and "Treatment of atopic dermatitis (eczema)", section on 'Dietary supplements') – NCCIH

Feverfew (Tanacetum parthenium) (see "Preventive treatment of episodic migraine in adults") – NCCIH

Fish oil (see "Fish oil: Physiologic effects and administration" and "Lipid management with diet or dietary supplements")

Flax, flaxseed oil, linseed (Linum usitatissimum) (see "Lipid management with diet or dietary supplements") – NCCIH

Garlic (Allium sativum) (see "Lipid management with diet or dietary supplements", section on 'Supplements that we do not recommend' and "Epidemiology and risk factors for colorectal cancer", section on 'Garlic') – NCCIH

Ginkgo biloba (see "Clinical use of ginkgo biloba") – NCCIH

Ginseng (Panax quinquefolius, Panax ginseng, Eleutherococcus senticosus) (see "Chinese herbal medicine for the treatment of allergic diseases", section on 'Modified Mai Men Dong Tang (mMMDT) formula') – NLM MedlinePlus (American and Siberian)

Glucosamine and chondroitin (see "Management of knee osteoarthritis", section on 'Nutritional supplements' and "Subacute and chronic low back pain: Nonpharmacologic and pharmacologic treatment", section on 'Pharmacologic therapies') – NLM MedlinePlus (glucosamine sulfate and chondroitin sulfate)

Green tea (Camellia sinensis) (see "Benefits and risks of caffeine and caffeinated beverages", section on 'Consumption' and "Lipid management with diet or dietary supplements", section on 'Omega-3 fatty acids') – NCCIH

Hawthorn (Crataegus monogyna) (see "Investigational therapies for management of heart failure", section on 'Hawthorn extract') – NCCIH

Horse chestnut seed extract (Escin, Aesculus hippocastanum) – NCCIH

Kava (Piper methysticum) (see "Hepatotoxicity due to herbal medications and dietary supplements", section on 'Kava-kava' and "Generalized anxiety disorder in adults: Management") – NCCIH

Melatonin (see "Pharmacotherapy for insomnia in adults", section on 'Melatonin')

Methylfolate-methylcobalamin-acetylcysteine (see 'Regulation in the United States' below) – NIH dietary supplement label database; marketed as a "medical food"

Milk thistle (Silymarin, Silybum marianum) – NCI and NCCIH

Omega-3 fatty acids (see "Fish oil: Physiologic effects and administration" and "Lipid management with diet or dietary supplements", section on 'Omega-3 fatty acids')

Probiotics (see "Probiotics for gastrointestinal diseases") – NCCIH

S-adenosylmethionine (SAMe) (see "Management of alcohol-associated steatosis and alcohol-associated cirrhosis", section on 'Therapies of uncertain or no benefit')

Saw palmetto (Serenoa repens) (see "Clinical use of saw palmetto") – NCCIH

Soy isoflavones (Glycine max) (see "Lipid management with diet or dietary supplements", section on 'Supplements that we do not recommend' and "Overview of the management of low bone mass and osteoporosis in postmenopausal women", section on 'Therapies not recommended')

St. John's wort (Hypericum perforatum) (see "Clinical use of St. John's wort") – NCCIH

Turmeric (curcumin, Curcuma longa) (see "Management of knee osteoarthritis", section on 'Nutritional supplements')

Valerian (Valeriana officinalis) (see "Pharmacotherapy for insomnia in adults", section on 'Others') – NCCIH

UNITED STATES

Epidemiology — A 1990 national telephone survey of complementary and alternative medicine use by United States adults demonstrated that 2.5 percent of respondents used herbal medicines [7]. A follow-up 1997 national survey showed almost a fivefold increase, with 12.1 percent of United States adults reporting herbal medicine use in the previous year [8]. One factor contributing to this dramatic increase was congressional passage of the Dietary Supplement Health and Education Act (DSHEA) in 1994. DSHEA allowed manufacturers to market their herbal products without prior demonstration of safety or efficacy. (See 'Regulation in the United States' below.)

Data from the 2012 National Health Interview Survey (NHIS) Alternative Medicine Supplement showed that 17.7 percent of United States adults had used natural products in the previous year, including herbs and other naturally occurring nonbotanical supplements such as glucosamine sulfate (derived from crustacean shells) and fish oils [9]. The following natural products were the 10 most commonly used by United States adults in the NHIS survey (percentages are the rate of use among United States adults):

Fish oil (7.8 percent)

Glucosamine or chondroitin (2.6 percent)

Probiotics or prebiotics (1.6 percent)

Melatonin (1.3 percent)

Coenzyme Q-10 (1.3 percent)

Echinacea (0.9 percent)

Cranberry (0.8 percent)

Garlic (0.8 percent)

Ginseng (0.7 percent)

Ginkgo biloba (0.7 percent)

National Health and Nutrition Examination Survey (NHANES) data show that use of supplements (including vitamins, minerals, and non-vitamin, non-mineral supplements) by noninstitutionalized adults in the United States remained stable from 1999 to 2012, with 52 percent of United States adults reporting use from 2011 to 2012 [10]. Use of supplements other than multivitamin products was reported by 34 to 39 percent.

Market sales — Herbal sales have shown slow growth since 2004. Obtaining accurate market data that capture all of United States herbal sales is difficult. This is due in part to the multiple channels available for purchasing supplements such as drug stores, supermarkets, warehouse buying clubs, natural food stores, multilevel marketing, health professionals, and the Internet. Nonetheless, using multiple survey methods, total sales of herbal and dietary supplements in the United States were estimated to be USD $8.8 billion for 2018 [11].

Reasons for use — Americans reported that their top reasons for using herbs and supplements were enhancing health and helping with common chronic symptoms or diseases such as memory loss, arthritis, and fatigue [12]. In this way, herbs are similar to other complementary and alternative medicines in that they are frequently used for chronic conditions for which conventional medicine does not offer straightforward answers or cures.

Herbs are also appealing to those who perceive nature as benevolent and healing [13]. Associated with this is the mistaken perception that a naturally derived product is always safe.

Regulation in the United States — In the first half of the 20th century, medicinal herbs were included in the United States National Formulary and the United States Pharmacopoeia (USP). In 1962, outrage over limb defects from thalidomide prompted Congress to pass the Kefauver-Harris Drug Amendment. This required proof of safety and efficacy for all prescription and over-the-counter drugs and reassigned herbal medicines to the category of food supplements which have a lower threshold of required evidence for safety [14].

A campaign by consumers, supplement manufacturers, and political advocates resulted in a 1994 bill passed by Congress called the Dietary Supplement Health and Education Act (DSHEA). DSHEA defined dietary supplements as a product containing one or more of the following: a vitamin, mineral, amino acid, herb, other botanical, concentrate, metabolite, constituent, or extract [14]. DSHEA placed dietary supplements in a distinct category from drugs. Labels of dietary supplements are required to state: "this product in not intended to diagnose, treat, cure, or prevent any disease." Supplement manufacturers are prohibited from making direct claims about treating specific diseases. However, product labels are allowed to make health claims, such as "promotes prostate health" or "supports the circulatory system."

Supplements can also be sold as "medical foods," which are defined in the applicable regulation as foods to be consumed or administered enterally under clinician supervision for dietary management of a disease or condition with distinctive nutritional requirements [15]. Medical foods are not subject to any regulatory requirements applicable to drugs. Product labels are allowed to make health claims similar to supplements.

Importantly, makers of dietary supplements and medical foods are not required to prove efficacy, safety, or quality of a product prior to marketing. Supplement manufacturers are also not obligated to report postmarketing adverse events to the FDA. DSHEA therefore moved the burden of proving that a product is unsafe or ineffective to the FDA. The FDA has removed many dietary supplement products from market, most notably PC-SPES, and products containing ephedra and androstenedione. Often, however, the Federal Trade Commission (FTC) and local attorneys general, prosecuting advertising fraud, are the only means by which supplement manufacturers can be held to comply with regulations about claims for their products.

Increasing research, case reports, and publicity of adverse effects and harmful drug-herb interactions have prompted many clinicians, physician organizations such as the National Academy of Medicine, and consumer groups such as the Center for Science in the Public Interest to call for reform of DSHEA [16-18]. National surveys found that 81 percent of Americans believed evidence of safety should be required before allowing the sale of a supplement [19]. However, more than half did not understand that current regulations did not require such evidence. Thus, the public appears to be sensitive to safety issues and supportive of greater regulation.

In 2007, the FDA issued new rules requiring Good Manufacturing Practices (GMPs) for dietary supplements [20]. The GMPs require dietary supplements be properly labeled, free of adulterants, and manufactured according to specified standards for personnel and equipment. However, the rules allow manufacturers, in particular smaller companies, significant flexibility to specify the quality criteria they will follow. As an example, there are no specified maximum acceptable concentrations or daily dose limits for heavy metals such as lead [20]. There is concern whether the GMPs are being uniformly followed. For example, from 2010 to 2013, 71 percent of 626 FDA inspections of supplement manufacturers resulted in citations for not following the new standards; on average, each company was cited for seven deviations [21]. Furthermore, one study found that many supplements recalled due to adulteration with pharmaceutical ingredients were still available for purchase six months after the recall [22]. (See 'Purity and adulteration' below.)

INTERNATIONAL

Epidemiology — Herbs are commonly used for medicinal purposes throughout the world. Data on this usage come from convenience samples, national surveys, ethnographic studies, market data, and toxicity reports from Canada, Europe, Asia, Australia, the Caribbean, South and Central America, and Africa [23-37].

Europe — In Europe, herbal medicine is frequently referred to as phytotherapy and is commonly integrated with conventional medicine in many countries within the European Union. Sales of herbal medicines and dietary supplements in Europe in 2009 were nearly EUR €7 billion.

Herbal products are often used as a first-line therapy for conditions such as benign prostatic hyperplasia in Germany, Italy, and elsewhere.

Other studies of use include:

A nationally representative survey of the German general public found that 65 percent used herbal medicines [38]. German clinicians receive medical school training in medicinal herbs and must pass a test on herbal medicine to become licensed. Approximately 80 percent of German clinicians regularly prescribe herbs.

A survey of 21,923 adults in the Northwest region of England found 12.8 percent used one or more herbs [24].

Half of Danish preoperative patients reported taking herbal medicines, including ginkgo and echinacea [25].

Twenty-seven percent of outpatients in a Spanish gastroenterology clinic had used herbs in the previous year [26].

Asia — Alongside acupuncture and massage, herbs play a significant role in traditional Chinese medicine [39]. Ayurveda, the most common traditional medicine practiced in India, uses over 6000 herbal combinations in its pharmacopoeia [37]. Vietnam, Malaysia, Korea, and other Southeast Asian countries have their own systems of traditional medicine. (See "Chinese herbal medicine for the treatment of allergic diseases".)

Developing world — In developing countries, herbal medicines are often less expensive and more accessible than conventional pharmaceuticals. As an example, 78 percent of households in a low-income neighborhood of Managua, Nicaragua reported herbal use [30]. Almost two-thirds of respondents from Brazilian urban primary care clinics reported use of herbal therapies, often due to inability to obtain conventional medicines [31].

Recommendations for herbal use are often given by family members, community elders, village health workers, midwives, or healers. Herbal formulations are often prepared individually for the patient from raw plant materials, instead of being commercially available.

In many developing countries, the administering of traditional medicines is often part of an elaborate healing ritual with spiritual or supernatural components [40].

International regulation — In general, regulation of the quality of herbal products is greater in the European Union than in the United States. A 2004 European Union directive requires manufacturers of all over-the-counter herbal products to register and license the product with the European Agency for the Evaluation of Medicinal Products. A premarket evaluation of quality and safety of the product is required. Companies need to carry out post-marketing surveillance and report serious adverse events. Indications for these over-the-counter herbal products are for minor conditions not usually requiring a clinician's care. Instead of requiring new rigorous efficacy studies to market a new product, documentation from the medical literature of safety for the relevant condition and reasonable plausibility of efficacy is needed. In countries such as Germany and France herbal medicines are partially or fully reimbursed.

In a 2005 report, the World Health Organization (WHO) assessed the policies and regulatory status regarding the use of herbal medicines based upon surveys distributed to 191 member states, of which 141 nations responded [41]. 37 percent of responding nations had herbal medicine regulations in place, and approximately half of the remaining countries were considering implementing regulations. Over two-thirds of countries sold herbal medicines without requiring a prescription, with only a few herbal medicines available by prescription only (eg, saw palmetto, ginkgo, St. John's wort).

In 2013, WHO published an updated global Traditional Medicine Strategy to develop strategies and solutions to promote the safe and effective use of complementary medicine with traditional medical practices, and for the integration of complementary methods into traditional medical practice into national health care systems where appropriate [42].

QUALITY AND EFFICACY — Given the regulatory structure for herbal medicines, there is substantial variation in the quality of commercially available products in the United States and elsewhere. Variability in product quality can impact the product's efficacy, safety, and therefore clinical usefulness.

Quality — There are multiple determinants of the quality of an herbal product. These factors all impact the ability to insure consistency and standardization of herbal products.

Plant species used — Several common herbal products are drawn from closely related species. As an example, studies of echinacea for the treatment and prevention of the common cold utilize Echinacea purpurea, E. pallida, and/or E. angustifolia. The relative pharmacologic activity of these different species is unclear. Serious injury also has resulted from the misidentification of other plant species and subsequent mislabeling [43].

Plant parts used — Different plant parts from the same species may have different pharmacologic activity. As an example, echinacea products vary according to the proportion of root and aerial parts used. The relative activities of these different parts of the same plant are uncertain. Other inherent problems involve contamination by plant parts not normally utilized [44].

Harvesting and storage conditions — The strength of a plant's pharmacologic activity may also vary according to where it was raised, when it was harvested, and the length of time it was stored [45]. Plant products and their active constituents can vary from year to year due to climatic changes involving rainfall, sunlight, and even genetic composition [46]. Problems with prolonged storage may also lead to microbial contamination.

Processing — Herbs can be processed and formulated multiple ways. Whole herbs can be homogenized and extracted using solvents (eg, alcohol, glycerol, acetone, water). These extracts can be dried and encapsulated or made into liquid tinctures. Whole herbs can also be eaten or consumed as teas. Topical applications can be made using poultices or creams. Different processing techniques can result in different chemical composition of the final product.

Standardization — Herbs are complex substances with dozens or hundreds of chemical constituents. Often it is unclear which of these chemicals play an important role in the herb's pharmacologic activity. Some herbal products are standardized to contain a specified amount of one or two chemicals or chemical groups thought to be the active ingredients for the herb. Examples include ginkgo extracts standardized to 24 percent flavonoid glycosides and 6 percent terpenoids, and St. John's wort standardized to 0.3 percent hypericin. The latter is an example of a product standardized to a component that many experts believe is not the most important component for antidepressant activity [47,48]. (See "Clinical use of St. John's wort".)

Even when herbal preparations are labeled "standardized," there may be significant variation. One study of echinacea found that the content did not match the labeling in 47 percent of samples labeled "standardized" [49].

Accuracy of labeling — Multiple reports of inaccurate herb labeling have been documented. As an example, a study of commercially available Asian ginseng products showed that, among products with a labeled concentration of ginsenosides, the actual measured ginsenoside varied from zero to over 300 percent of labeled concentrations [50]. Similarly, in a study of valerian products, 4 out of 17 products tested had no detectable levels of the expected valerenic acids, while another four had only one-half the expected amount [51].

Similarly, another study examining herbal products available in North America found that 32 percent contained a different plant species and did not contain any of the labeled product and, of those that did contain the specified product, 33 percent contained an additional plant species as well [52].

In addition, many brands of the same herb have labeling recommendations that vary greatly [53]. Among 880 commercial products of the 10 most commonly purchased herbs, only 43 percent were consistent with generally accepted benchmarks; 37 percent were inconsistent with accepted benchmarks or were insufficiently labeled to determine whether or not they were consistent with accepted benchmarks.

Purity and adulteration — There are frequent occurrences of herbal medicines and supplements containing active pharmaceuticals or other bioactive agents that are not identified on the label [54-56]. Examples include:

PC-SPES, a patented supplement used for prostate cancer and since recalled by the FDA, was found to contain diethylstilbestrol (DES), warfarin, and indomethacin [54].

Multiple brands of adrenal support supplements were found to contain small amounts of thyroid hormone and at least one steroid hormone [55].

Supplements marketed for sexual enhancement have been found to contain varying quantities of phosphodiesterase-5 inhibitors, most frequently sildenafil [56].

Sibutramine and the laxative phenolphthalein, two drugs previously recalled by the FDA, have been found in weight-loss supplements [56].

Anabolic steroids and their analogues have been identified in muscle building supplements [56].

Reports of lead, mercury, and arsenic contamination in imported traditional Chinese [57] and Indian [58-62] herbal products have also occurred. (See "Lead exposure, toxicity, and poisoning in adults" and "Arsenic exposure and chronic poisoning".)

Efficacy — Prior to 2000, a number of predominantly European studies suggested efficacy for common herbs such as echinacea for upper respiratory infection, saw palmetto for benign prostatic hyperplasia, ginkgo for dementia, and St. John's wort for depression. However, more recent adequately powered, rigorous, double-blind, placebo-controlled trials of standardized well-defined preparations suggest the contrary. (See "Clinical use of echinacea" and "Clinical use of St. John's wort" and "Clinical use of saw palmetto" and "Clinical use of ginkgo biloba".)

Several herbal medicines and dietary supplements evaluated in controlled trials show therapeutic promise. Larger, well-designed studies with standardized preparations are needed, and practitioners should consider the quality of the evidence for efficacy and safety prior to recommending these:

Soy products (Glycine max) for treating hypercholesterolemia. (See "Lipid management with diet or dietary supplements" and "Lipid management with diet or dietary supplements", section on 'Soy'.)

Ginger (Zingiber officinale) for antiemetic efficacy in various situations that can produce nausea and vomiting (eg, postoperative, chemotherapy, motion sickness, pregnancy). The majority of studies show ginger to be more effective than placebo, although safety in pregnancy has not been adequately proven. (See "Nausea and vomiting of pregnancy: Treatment and outcome", section on 'Ginger supplements' and "Management of poorly controlled or breakthrough chemotherapy-induced nausea and vomiting in adults", section on 'Complementary therapies'.)

Probiotics for various gastrointestinal conditions such as ulcerative colitis, pouchitis, infectious diarrhea, and irritable bowel syndrome. (See "Probiotics for gastrointestinal diseases".)

Fish oils containing omega-3 fatty acids such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) for reduction in cardiovascular risk. (See "Fish oil: Physiologic effects and administration".)

SAFETY — Safety issues for herbs include adverse effects and drug-herb interactions. Asking patients about herbal medicine use and potential side effects will improve their recognition by patients and clinicians. In the United States, adverse events related to herbal products can be reported to the US Food and Drug Administration (FDA) MedWatch program online, by fax (800-FDA-0178), or by mail.

Adverse effects — Our knowledge about adverse effects of herbs comes predominantly from case reports and clinical trials. Few systematic studies of safety have been completed. Several tables are prepared, reviewing the effects of commonly used herbal medications on glucose metabolism (table 2), lipids (table 3), hormones (table 4), blood pressure (table 5), and the heart (table 6).

Notable examples of adverse effects include:

Ephedra alkaloids (derived from Ephedra sinica or Ma huang) have been commonly combined with caffeine and marketed for weight loss and athletic enhancement [63]. A review of adverse events possibly associated with ephedra use between 1997 and 1999 found episodes of hypertension, arrhythmias, myocardial infarction, stroke, and seizures [64]. Ten events led to death and 13 to permanent disability. Of these 23 reports, nine occurred at recommended ephedra doses in individuals without significant preexisting cardiovascular or neurologic risk factors. Although double-blind, randomized, controlled trials of ephedra-caffeine combinations have shown modest efficacy over placebo for weight loss [65,66], data from 50 ephedra trials showed an estimated 2.2- to 3.6-fold increase in the odds of psychiatric, autonomic, cardiovascular, and gastrointestinal symptoms [67]. There have also been case reports of heart failure in patients taking ephedra [68].

Despite ephedra products comprising only 0.8 percent of all dietary supplement sales in 2001, they were responsible for 64 percent of all herb-related adverse events reported to US Poison Control Centers during the same year [69]. In part based upon these data, the FDA on April 12, 2004 banned manufacturers from the sale of products containing ephedra [70,71]. Some manufacturers subsequently substituted bitter orange (Citrus aurantium) for ephedra in weight-loss products. C. aurantium contains synephrine, an adrenergic agonist similar to phenylephrine and ephedrine, that has been associated with serious cardiovascular and neurologic side effects [71,72].

Plants containing pyrrolizidine alkaloid constituents can lead to liver toxicity secondary to veno-occlusive lesions, resulting in parenchymal necrosis, fibrosis, and even cirrhosis (table 7) [73]. The precise mechanism of hepatic injury is unknown but appears to result from the accumulation of toxic metabolites produced via the cytochrome system [74]. The increased concentration of cytochrome P450 enzymes in the centrilobular region of the liver correlates with the changes seen pathologically. (See "Hepatotoxicity due to herbal medications and dietary supplements".)

Consumption of kratom (Mitragyna speciosa), an herb promoted for self-treatment of opioid withdrawal, has been the subject of FDA warnings against its use; there have been concerns about overdose-related deaths, risks of addiction, abuse, and dependence as well as a mandatory product recall due to contamination with salmonella [75-80]. Kratom use can also lead to respiratory depression, anorexia, depression, psychosis, and seizures. (See "Opioid withdrawal: Medically supervised withdrawal during treatment for opioid use disorder" and "Opioid withdrawal: Medically supervised withdrawal during treatment for opioid use disorder", section on 'Kratom'.)

Some herbal treatments are known to be nephrotoxic and should be avoided. As an example, Aristolochia, a Chinese herb included in some weight-loss herbal formulas, is associated with nephropathy; it is also a probable human carcinogen associated with urothelial cancers [81]. (See "Nephropathy induced by aristolochic acid (AA) containing herbs".)

Herbal products can contain harmful contaminants including heavy metals (see 'Purity and adulteration' above). These may be incidental contaminants from plant raw materials or the manufacturing process. However, they may be sometimes intended constituents of the product, since several non-Western healing traditions such as traditional Indian (Ayurvedic) and Chinese medicine systems intentionally use heavy metals, including lead, for their purported therapeutic efficacy [57,58]. Use of Ayurvedic and/or traditional Chinese medicine herbs, as well as St. John's wort, has been associated with higher blood lead levels among women [82]. At least 120 cases of heavy metal toxicity have been reported from traditional Indian (Ayurvedic) herbal medicine products that contain lead, mercury, and arsenic [58,83-85]. Most of these cases involve lead and products manufactured outside of the United States. Lead toxicity from Ayurvedic medicine products has been linked to anemia and other clinical manifestations [61,62,86]. (See "Lead exposure, toxicity, and poisoning in adults" and "Arsenic exposure and chronic poisoning".)

The belief among some patients that "more is better" leads to significant side effects and potential harm from ingesting large quantities of herbal products [87]. Toxicities due to overuse have been documented with ginseng and licorice [88].

Herb-drug interactions — Increasing data show the potential for herbal medicines to interact with prescription and nonprescription pharmaceuticals [89]. Several of these interactions have been documented to occur through case reports. Other interactions have been theorized through in vitro studies but not documented with case reports.

Specific interactions of natural and alternative drugs with other medications may be determined using the drug interactions program included with UpToDate. This can be accessed from the UpToDate online new search tab or through the individual drug information topics, section on Drug interactions.

Several systematic reviews identified herb-drug pairs that have been reported to interact based on clinical data or in vitro studies [90,91]. Warfarin was the most frequent pharmaceutical implicated and St. John's wort had the most drug-herb interactions [91]. Herb-induced alteration in the metabolism of cytochrome P450 enzymes was the most common mechanism implicated in herb-drug interactions.

Specific examples of documented herb-drug interactions include:

The hyperforin component of St. John's wort induces the cytochrome P450 3A4 (CYP3A4) system, which metabolizes a number of drugs including protease inhibitors, cyclosporine, oral contraceptives, irinotecan, warfarin, and digoxin. Failure of antiretroviral therapy, transplant rejection, and contraceptive failure have been reported. In addition, St. John's wort may produce the serotonin syndrome when taken with other serotonergic medications. (See "Clinical use of St. John's wort", section on 'Drug interactions'.)

Ginkgo biloba has antiplatelet and antithrombotic effects and therefore has the potential to interact with anticoagulants such as warfarin, nonsteroidal anti-inflammatory drugs (NSAIDs), and aspirin, leading to an increased risk for spontaneous hemorrhage and bleeding. (See "Clinical use of ginkgo biloba", section on 'Potential interactions'.)

Concomitant ingestion of grapefruit juice and certain dihydropyridine calcium channel blockers may elevate the plasma concentration of the latter, possibly leading to hypotension [92]. Grapefruit juice increases the bioavailability of certain calcium channel blockers and HMG-CoA reductase inhibitors by inhibiting the CYP3A4 isoenzyme found in the liver and gut wall [93]. The result of this inhibition is that more drug is absorbed and plasma concentrations increase.

INTERNET EVIDENCE-BASED RESOURCES — There are a number of web-based resources aimed at providing health care practitioners and consumers with evidence-based information on herbal medicine.

Natural Medicines

Consumer Lab

NIH National Center for Complementary and Integrative Health Herb Fact Sheets

NIH MedlinePlus Herbs and Supplements Directory

NIH Office of Dietary Supplements

NIH Office of Dietary Supplements Dietary Supplement Label Database

COUNSELING PATIENTS

Asking about use — Surveys have found that one-fourth of patients who use herbal medicines did not disclose this to their health care providers [94]. Patients cited "it wasn't important for my doctor to know" and "the doctor never asked" as reasons for not disclosing this information.

There are several important reasons for asking patients about the use of herbal medicines:

Herbs are pharmacologically active and therefore can positively and negatively impact patient health. Positive effects may include improvement of disease-specific outcomes. Negative effects may include adverse effects and drug-herb interactions. For these reasons, The Joint Commission in the United States now requires that herb and supplement use be recorded and reconciled as part of the medication list in the hospital medical record [95]. In a study of hospitalized medical patients, however, only 36 percent of patients who used dietary supplements had appropriate documentation in the medical record [96].

Discussion of herbal medicine use may open dialogue about patient concerns that may be amenable to management with well-studied conventional therapies. For example, further questioning of a patient who uses multiple supplements such as garlic, Vitamin E, and Coenzyme Q-10 might reveal anxiety of myocardial infarction due to a family history of premature heart disease. Measuring cardiovascular risk markers and educating the patient about conventional cardiac risk factor reduction and therapy could then be initiated.

Providers may need to consider herb-drug interactions when prescribing and dosing conventional medications.

Asking about herb use can be done during the medication history by asking: "What prescription medications, over-the-counter medicines, vitamins, herbs, or supplements do you use?"

This encourages communication by demonstrating the practitioner's interest in the information and willingness to discuss herb and supplement use. It is also appropriate to put a question like this into medical intake questionnaires filled out prior to the appointment.

When the labeled ingredients of a commercial herbal product are unknown, practitioners can consult the Dietary Supplement Labels Database or the product's website.

Patients who use herbs should be asked about their reasons for use. Motivation for herb use is often not based upon scientific data [19]. Of herbal users surveyed, 72 percent stated they would continue using supplements despite a negative government scientific study. Instead, patients often get their information about herbs from family, friends, advertisements, and the Internet. Patients can be directed to MedlinePlus for free evidence-based information about many herbal products.

Advising patients — The schema in the table (table 8) can be used to develop an approach to advising patients about an herbal product based upon the evidence for that product's quality, efficacy, and safety [54,63].

If there is strong evidence for a dietary supplement's quality, safety, and efficacy, it may be reasonable to proactively recommend that product and closely monitor the patient. Given frequent uncertainty in supplement quality, however, few products meet these criteria.

Further, it is appropriate to discourage use of products when there is evidence for inefficacy, potential risk of harm, or lack of product quality. Examples of products with risk of harm include herbal medicines known to contain toxic heavy metals from South Asia (eg, mahayograj guggulu, ekangavir ras, shilajit) and East Asia [56,58], St. John's wort when taken with medicines metabolized by cytochrome P450 3A4 (CYP3A4), and ephedra-related products [67].

Because evidence regarding quality, efficacy, and/or safety for most supplements is uncertain, insufficient, or contradictory, practitioners should provide careful guidance for their patients. For products without good evidence, clinicians should counsel and caution patients regarding the uncertainty of the evidence, and the impact of uncertain quality on efficacy and safety should be emphasized. If the patient chooses to proceed with an herbal product, a plan should be agreed upon for ongoing monitoring for both benefits and adverse effects. These discussions should be documented clearly in the medical record.

Clinicians need to take into account patients' individual health conditions, concerns, values, and preferences [97]. Patients seeking or already using herbal treatments should have an appropriate evaluation for their condition; clinicians should consider the patient's query as an opportunity to explore a health concern that might not have otherwise been disclosed, and proven conventional treatments can be offered as possible treatment.

For the patient who decides to use an herbal product against the counsel of their clinician, a nonjudgmental attitude will allow channels of communication to remain open and allow for monitoring and ongoing discussion.

Choice of brand — Patients who use herbs often ask their providers what brand should be used, but lack of regulatory reform in the herbal industry makes it difficult to provide an informed response. One option is to suggest only the use of brands that have been tested by independent sources, found to meet minimum quality criteria, and display a seal of approval. Three independent organizations offer quality testing: US Pharmacopeia, ConsumerLab.com, and NSF International. Manufacturers voluntarily submit and pay for their products to be independently evaluated by these organizations for good manufacturing practices, accurate labeling of ingredients, and absence of harmful levels of contaminants. The seal, however, does not assure that a supplement is effective for the condition it purports to treat or safe for all patients. For ethical reasons, selling supplements through practitioners' offices or multilevel marketing plans should be discouraged.

Special populations

Pregnancy and nursing — Few animal or human studies have been conducted on the safety of herbal medicines in pregnancy or while nursing. Given the paucity of data for these populations as well as the uncertainty in product quality, women who are pregnant, contemplating pregnancy, or lactating should generally be discouraged from using herbal treatments.

Infants and children — Parents should be cautioned about the relative lack of studies demonstrating efficacy and safety of herbal medicines in infants and children. Additional concerns are proper dosing in this age group, greater susceptibility to potential contaminants, and uncertainty of product quality.

Older adults — Caution should be exercised in the use of herbs in older adults due to possible decreased renal and hepatic clearance of herb and drug metabolites. Additionally, for older individuals taking multiple medications, there is a greater potential for herb-drug interactions [45].

Surgical patients — No large prospective study of the impact of perioperative herb use on surgical outcomes has been completed. Herbs may impact surgery through altered coagulation (eg, ginkgo, ginseng, garlic), cardiovascular stability (eg, ephedra), glucose control (ginseng), anesthesia (eg, valerian, kava), and increased metabolism of perioperative medication (eg, St. John's wort). Case reports of perioperative bleeding associated with Ginkgo biloba [98] and saw palmetto [99] have been reported. Authors have recommended avoiding herbs for at least two to three weeks prior to surgery [100,101].

SUMMARY AND RECOMMENDATIONS — Natural products are widely used by patients in the United States and elsewhere. They have the potential for both benefit and harm. (See 'Commonly used herbs and supplements' above.)

Patients and clinicians should be aware of frequent occurrences of both inaccurate herb labeling and of supplements containing active pharmaceuticals or other bioactive agents that are not identified on the label. (See 'Accuracy of labeling' above and 'Purity and adulteration' above.)

Patients should be asked about use of dietary supplements in a nonjudgmental manner as part of the medication history. (See 'Asking about use' above.)

Patients can be advised about dietary supplement use or avoidance based upon a product's quality, efficacy, and safety (table 8). (See 'Advising patients' above.)

Uncertainty in quality and the relatively few well-designed studies make it difficult for clinicians to recommend dietary supplements for most patients. (See 'Advising patients' above.)

When patients decide to use dietary supplements, they should be monitored for evidence of benefits and harmful effects, including side effects. (See 'Advising patients' above.)

We suggest that pregnant and nursing patients be advised to avoid dietary supplements (Grade 2C). (See 'Pregnancy and nursing' above.)

An option for counseling patients who seek advice about what brand of dietary supplement to use is to suggest products that have been tested by independent sources. (See 'Choice of brand' above.)

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Topic 1392 Version 83.0

References

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