45: Herbal Preparations

Although there is increased awareness of the widespread use of herbal ­preparations in the United States, physicians frequently seek information about their usage only after the patient demonstrates toxicity.

Since ancient times and perhaps since prehistoric times, people of all cultures have used herbal preparations to treat disease and promote health.⁴⁰ A 60,000 year-old Iraqi burial site contained eight different medicinal plants, suggesting very early historical usage.¹⁴² The earliest surviving written account of medicinal plants is the Egyptian Ebers papyrus, circa 1500 b.c., which lists dozens of medicinal plants and their intended uses. In India, the Vedas, epic poems written in approximately 1500 b.c., contain references to herbal preparations of the time. In China, the Divine Husbandman’s Classic, written in the first century a.d., lists 252 herbal preparations. In ancient Europe, herbal medicines were the mainstay of healing. In the first century, the Greek physician Dioscorides wrote one of the first European herbal books, De Materia Medica, which listed 600 herbals and was translated into many languages. Shamans and folk healers from the Americas, Africa, Australia, and Asia continue to include herbals for spiritual and medicinal purposes based on oral traditions passed from generation to generation.

During the Scientific Revolution, European scientists began to isolate purified extracts of plant products for use as medicinal agents. In 1804 and 1832, morphine and codeine were isolated from the sap of the poppy plant Papaver somniferum.⁷³ In the mid-eighteenth century, Edward Stone described in a letter to the president of the Royal Society of Medicine the successful use of the bark of the willow tree in curing “agues” (fever).²⁰ In 1829, salicin, the active ingredient of the willow bark, was identified. Its derivative sodium salicylate was marketed in 1875 as a treatment for rheumatic fever and as an antipyretic. The enormous success of this drug led to the synthesis of acetylsalicylic acid in 1899. The original name, aspirin (a cetyl-spiric acid), is said to have been derived from Spiraea, the plant genus from which salicylic acid once was prepared. Even today, plant preparations still are being investigated for the development of modern drugs. Sweet wormwood (Artemisia annua, qing hao) was first described as a treatment for malaria in China in 168 b.c.⁸⁸ In 1971, the active parent compound artemisinin was first isolated by Chinese investigators. Artemisinin, when used in combination with other antimalarials, is considered the best ­treatment for falcipararum-resistant malaria.^85,107,134 Prescriptions from plant-derived medicines currently represent approximately 25% of prescriptions dispensed in the United States^2,163 and at least 60% of nonprescription medications contain one or more natural products as ingredients.⁴⁸

Herbal preparations continue to be the dominant form of healing in the developing world because of the high cost of “Western” medical treatment and the scarcity of “Western”-trained medical personnel.^47,92,95,108 The World Health Organization estimates that 4 billion people, up to 80% of the world population, use herbal preparations for some aspect of primary health care.^2,166

Herbal preparations and other dietary supplements are not only sold exclusively in health food stores but are readily available for sale in mainstream retail outlets such as grocery stores, drug stores, complementary medicine practitioners, offices, mail order companies, the Internet, and gasoline stations. US pharmaceutical companies have also entered the herbal market. US herbal dietary supplement sales were estimated at $5.3 billion in 2011, representing direct sales of $2.6 billion, natural and health food sales of $1.8 billion, and $1 billion from mass-market retailers. Over the last 4 years, sales have continued to increase: 4.5% in 2011, 0.2% increase in 2010, 4.8% in 2009, and 0.9% in 2008.¹⁴ Similarly, worldwide herbal preparation usage continues to grow. The current global herbal supplements and remedies market is valued at $62 billion and it is predicted to reach $107 billion by 2017.⁶⁷

Although they often are used by consumers in the hope of preventing or treating medical illness, herbals are not classified as medications; therefore, despite reports of toxicity associated with their usage, no systematic evaluation of herbal efficacy or safety is required. Additionally problematic is that patients often do not consider herbal preparations as medications and may not provide a history of usage unless questioned specifically about herbal usage.

Unfortunately, the medical profession’s response to the widespread usage of herbal preparations appears to be inconsistent, with one study suggesting that the medical practitioner’s knowledge of current herbal preparation regulations is grossly inadequate.⁶ Several studies have attempted to determine how US hospitals regulate herbal preparation use in their facilities.^4,9,43,63 Depending on the study, only 31% to 79% of respondents reported having formal policies governing the usage of herbal preparations in their facilities. Herbal preparation use was completely banned in 11% to 22% of facilities. However, the majority of facilities did allow the use of herbal preparations if they were ordered by an authorized prescriber. Identified ­concerns addressed in these studies included difficulties in identifying products (particularly “home supply” products), and concerns for appropriate dosing, efficacy, safety, and consistency. The conflicting approaches have been attributed to health care facilities attempting to balance patient-centered care with their legal, medical, and ethical concerns about these products.^17,63

In 1998, Congress established the National Center for Complementary and Alternative Medicine (NCCAM) at the National Institutes of Health to stimulate, develop, and support research in complementary and alternative medicines.¹⁰⁵ So far, NCCAM-funded studies have failed to demonstrate any clinical benefit for using St. John’s wort for depression,⁸¹ hawthorne for congestive heart failure,¹⁷⁰ echinacea for the common cold,¹⁵² glucosamine and chondroitin sulfate for osteoarthritis,⁴² saw palmetto for benign prostatic hypertrophy,¹¹Gingko biloba for dementia,⁵² shark cartilage for lung cancer,¹⁰⁰ and cranberry juice for recurrent urinary tract infections.⁴¹

The botanical definition of the term herb is specific for certain leafy plants without woody stems. However, the term herbal preparations often includes non-herb plant materials, even animal and mineral products. Thus, in a broad sense, the term herbals includes any “natural” or “traditional” remedy, but these terms also are poorly defined. Although these xenobiotics are often also called medications, this terminology may be inaccurate and misleading. Many herbal preparations purportedly are used for their nonspecific “adaptogenic” properties by permitting the body to return to a normal state by resisting stress, but they lack any specific medicinal effects. Because many herbal users and herbalists do not consider herbal preparations medications, use of the term herbal medicine by the clinician may convey a different, and perhaps unintended, meaning. For these reasons, it may be inappropriate and without benefit to refer to these products as medication, but they are xenobiotics.

Herbal preparations are considered to be a subset of “alternative therapies.” These therapies are defined as interventions that are neither widely taught in US medical schools nor generally available in US hospitals.⁵⁴ When these alternative therapies are used in conjunction with conventional medical therapies, they are also known as complementary and alternative medicine (CAM).¹¹⁷ The NCCAM groups CAM into five domains: whole medical systems (eg, Ayurveda, homeopathy), mind–body medicine (eg, prayer, hypnosis), biologically based practices (eg, herbal preparations, dietary supplements), manipulative and body-based practices (eg, acupressure, acupuncture, chiropractic, massage), and energy medicine (eg, therapeutic touch).¹¹⁷

The study of herbal preparations is complicated by the lack of standardized nomenclature, while the diversity of common, proprietary, and botanical names may increase the confusion. A single plant preparation may have many common names, in addition to its botanical name. For example, Datura stramonium is also known as jimson weed, Angel’s trumpet, apple of Peru, Jamestown weed, thornapple, and tolguacha. Likewise, a common name for a plant, such as gordolobo, may refer to several plants, such as Verbascum thapsus and Gnaphalium macounii.⁸⁰ The mandrake refers not only to the belladonna-alkaloid–containing Mandragora officinarum but also the podophyllum-containing Podophyllum peltatum. Thus, accurate classification of herbal preparations is very difficult, which limits effective study and increases the risk of adverse effects.

For regulatory purposes the US government classifies herbal preparations as a type of dietary supplement, which means that the US Food and Drug Administration (FDA) classifies them as nutrients with nondrug status.⁴⁵ However, many nonherbals, such as vitamins, minerals, nutritional supplements, and food additives, are also dietary supplements (Chaps. 42, 46, and 47).

In the United States, herbal preparations are not subjected to the same standards as drugs. The FDA has gradually assumed an increased role in its vigilance over the manufacturing, marketing, and sales of herbal preparations. In 1994, Congress passed the Dietary Supplement Health and Education Act, which reduced the oversight by the FDA of products categorized as dietary supplements.⁵⁷ Dietary supplements include vitamins, minerals, herbals, amino acids, and any product that had been sold as a “supplement” before October 15, 1994.⁴⁵ After October 15, 1994, any new ingredient intended for use in dietary supplements requires notification and approval by the FDA at least 75 days in advance of marketing. The FDA must review and determine whether the proposed ingredient is expected to be safe under the intended conditions for use. However, because most ingredients contained in dietary supplements were in use prior to 1994, the vast majority of dietary supplements are not subject to even this weakened premarket safety evaluation. After marketing, if the FDA determines that a manufactured dietary supplement is unsafe, the agency can warn the public, suggest changes to make the supplement safer, urge the manufacturer to recall the product, recall the product, or ban the product.

On several occasions the FDA has urged manufacturers to stop producing dietary supplements containing unsafe products. In July 2001, the FDA warned dietary supplement manufacturers to stop marketing products containing aristolochic acid because of nephrotoxicity and to remove comfrey products from the market because of hepatotoxicity. In November 2001, the FDA warned the manufacturer of LipoKinetix (containing phenylpropanolamine, caffeine, yohimbine, diiodothyronine, usnic acid) to remove the supplement from the marketplace because of reports of associated hepatotoxicity. In 2002, the FDA warned consumers and health care professionals of the risk of hepatotoxicity associated with the use of kava-containing products.¹⁵⁷ However, the FDA did not ban the development of kava-­containing products or ban their sale in the United States. In March 2004, the FDA warned dietary supplement manufacturers to stop manufacturing androstenedione or face enforcement actions.¹⁵⁶ To ban a dietary supplement from the marketplace, the FDA must prove that the product is unsafe. In April 2004, the FDA banned all sales of dietary supplements containing ephedra. This was the first FDA prohibition of a supplement since 1994.¹⁵⁵ In April 2012, FDA warned manufacturers that the stimulant used in some fitness supplements, dimethylamylamine, did not qualify as a legal dietary supplement. One year later, the FDA issued a consumer warning that dimethylamylamine usage is associated with cardiovascular complications with 86 reported illnesses and deaths.¹⁵⁸

Because the law requires the FDA to consider dietary supplements as food products, quality control issues and production methods are governed by the Current Good Manufacturing Practices regulations for foods.¹⁵⁴ However, these regulations only ensure that foods, and thus dietary supplements, are produced under sanitary conditions; they do not guarantee the safety, efficacy, or quality of the product, as is required for pharmaceuticals. Two studies suggest that many herbal preparations do not even contain appreciable quantities of the listed herb. In one study of 54 ginseng products, 60% of those analyzed contained pharmacologically insignificant amounts of ginseng and 25% contained no ginsenosides.⁹⁷ A study of echinacea preparations determined that 10% of preparations contained no measurable echinacea, the assayed species was consistent with labeled content in 52% of the sample, and only 43% met the quality standard described by the label.⁶⁵ From 2004 to 2008, the FDA investigated online sales of dietary supplements purported to treat erectile dysfunction or enhance sexual performance by purchasing and analyzing the ingredients of these products.¹⁵³ One-third of the purchased dietary supplements (six out of 17) contained undisclosed prescription drug ingredients such as sildenafil, vardenafil, or related substances.¹⁵³ In a 2010 press announcement, the FDA revealed that the three most common categories of tainted products marketed as dietary supplements are weight loss products containing active ingredients such as sibutramine, body-building products containing anabolic steroids or steroid analogs, and sexual enhancement products that contain phosphodiesterase type 5 inhibitors such as sildenafil.⁵⁹

Herbal products can be initially marketed without any proof of testing for efficacy or safety. Although packaging that claims to cure or prevent a specific disease is not permitted unless approved by the FDA, claims detailing how a product affects the “body’s structure or function” are permissible. Substantiation of these claims is required only if challenged by regulators,¹⁵⁴ but the methodology and requirements for this substantiation are not well defined.

These findings were corroborated by a study evaluating herbal advertising on the Internet. The study determined that 81% of Web sites marketing dietary supplements made one or more health claims without approval from the FDA, and of these sites, 55% made specific claim to treat, prevent, or cure a specific disease.¹¹³

In March 1999, the FDA implemented new dietary supplement labeling rules. All dietary supplement labels must provide a statement of identity (eg, ginseng), net quantity of contents (eg, 60 capsules), structure–function claims with disclaimers that the product has not been evaluated by the FDA; directions for use; supplements fact panel (list of serving size, amount, and active ingredients), other ingredients list, and name and place of business of manufacturer, packer, or distributor. The Dietary Supplement and Nonprescription Drug Consumer Protection Act was signed into law in December 2006.⁵¹ Under this law, manufacturers, packers, or distributors of nutritional supplements are required to notify the FDA about serious adverse events related to their products. In 2007, the FDA issued its current good manufacturing practices final rule, effective in June 2008. The final rule is more stringent than previous regulations and it contains sections similar to current good manufacturing practices for drugs. Manufacturers are required to evaluate the identity, purity, strength, and composition of their dietary supplements. Yet, unlike the FDA regulations for drugs, the final rule still does not require any proof of efficacy or safety. In essence, the FDA, through its regulations, has gradually shifted dietary supplements from a poorly regulated food product into a unique category between a conventional food product and a drug. This has served to fuel the debate on both sides: those who view dietary supplements as more similar to food groups (eg, chamomile tea) and want less government regulation, and others who argue that herbs contain pharmacologically active drugs (eg, ephedra) that require greater regulation.^106,114

The FDA recently released data suggesting that its regulations alone are insufficient in ensuring the safety of dietary supplements sold in the United States. Since it began assessing good manufacturing practice compliance in 2008, the FDA has found violations of manufacturing rules in nearly one-half of the 450 dietary supplement firms it has inspected. One in four inspected companies had violations serious enough to warrant release of an FDA warning letter that could result in a significant enforcement action such as halting production and distribution. The FDA also believes that adverse events associated with dietary supplements are significantly underreported by manufacturers even though it is required by law. For the first 10 months of 2008, the FDA received approximately 950 reports of adverse events, but the agency estimates the true annual number of adverse events is much higher at 50,000.^102,151 In 2009, the US Government Accountability Office issued a report to Congress that provided four recommendations highlighting the difficulties the FDA had in ensuring the safety of dietary supplements sold in the United States.¹⁵⁹ First, the FDA should be given the authority to require dietary supplement companies to identify themselves as a dietary supplement company, to provide a list of all dietary supplement products they sell, and to report all adverse events related to dietary supplements. Second, the FDA should issue guidance to clarify when an ingredient is considered a new dietary ingredient, the evidence needed to document the safety of a new dietary ingredient, and appropriate methods to establish ingredient identity. Third, the FDA should provide guidance to the industry to clarify when products should be marketed as either dietary supplements or conventional food formulated with added dietary ingredients. Fourth, the FDA should coordinate with consumer outreach to educate consumers about the safety and efficacy of dietary supplements and to assess the effectiveness in improving consumer understanding about dietary supplement. In 2010, the US Government Accountability Office also conducted an investigation to determine whether storefront and mail-order retailers of herbal preparations are using deceptive or questionable marketing practices and whether herbal dietary supplements are contaminated with harmful substances.¹⁶⁰ The investigation found that many herbal dietary supplement retailers were making improper health claims and in some cases were giving potentially harmful medical advice. The study also found that many herbal dietary supplements contain contaminants. In 37 of the 40 herbal dietary supplements tested, trace contaminants were identified (metals or pesticides), although none were identified in quantities considered to be acutely toxic.

The pharmacologic activity of herbal preparations (plant containing or derived) can be classified by five active constituent classes: volatile oils, resins, alkaloids, glycosides, and fixed oils.¹⁴⁴

• Volatile oils are aromatic plant ingredients. They are also called ethereal or essential oils, because they evaporate at room temperatures. Many are mucous membrane irritants and have central nervous system (CNS) activity. Examples of herbs containing volatile oils include pennyroyal oil (Mentha pulegium), catnip (Nepeta cataria), chamomile (Chamomilla recutita), and garlic (Allium sativum; Chap. 43).

• Resins are complex chemical mixtures of acrid resins, resin alcohols, resinol, tannols, esters, and resenes. These substances are often strong gastrointestinal (GI) irritants. Examples of resin-containing herbs include dandelion (Taraxacum officinale), elder (Sambucus spp), and black cohosh root (Cimicifuga racemosa).

• Alkaloids are a heterogeneous group of alkaline and nitrogenous compounds. The alkaloid compound usually is found throughout the plant. This class consists of many pharmacologically active and toxic compounds. Examples of alkaloid-containing herbs include aconitum (Aconitum napellus), goldenseal (Hydrastis canadensis), and Jimson weed (Datura stramonium).

• Glycosides are esters that contain a sugar component (glycol) and a nonsugar (aglycone), which yields one or more sugars during hydrolysis. They include the anthraquinones, saponins, cyanogenic glycosides, and lactone glycosides. The anthraquinones (senna {Cassia acutifolia} and aloe {Aloe vera}) are irritant cathartics. Saponins (licorice {Glycyrrhiza lepidota} and ginseng {Panax ginseng and P. quinquefolius}) are mucous membrane irritants, cause hemolysis, and have steroid activity. Cyanogenic glycosides found in apricot, cherry, and peach pits release cyanide. Lactone glycosides (tonka beans {Dipteryx odorata}) have anticoagulant activities. Cardiac glycosides defined as cardioactive steroids (Chap. 65) are found in foxglove (Digitalis spp) and oleander (Nerium oleander).

• Fixed oils are esters of long-chain fatty acids and alcohols. Herbs containing fixed oils are generally used as emollients, demulcents, and bases for other products. Generally, they are the least active and least dangerous of all herbal preparations. Examples include olive (Olea europaea) and peanut (Arachis hypogaea) oils.

Factors Contributing to Herbal Toxicity

The toxicity of a plant may vary widely and depends on conditions such as the time of year and developmental stage at which the plant is collected.⁸⁰ The pyrrolizidine alkaloid content of Senecio leaves varies widely from month to month and year to year.⁸⁰ In some cases, only selective parts of a plant used to prepare an herbal preparation are responsible for its toxicity. For example, the pyrrolizidine content of comfrey–pepsin capsules varies from 270 to 2900 mg/kg, depending on whether the leaves or roots were used in the preparation.⁷⁹ The geographical area in which the plant is collected may affect its toxicity. Senecio longilobus from Gardner Canyon, Arizona, may contain up to 18% pyrrolizidine alkaloids by dry weight, the highest concentration/amount recorded for any Senecio plant species (normal concentration is 0.5%). Finally, conditions and duration of storage may affect its toxicity. The toxicity of Crotalaria decreases with storage because of the breakdown of pyrrolizidines.

Few poisonings result from the inherent toxicity of the herbal, because of the low concentration of active ingredient and the known safety of the chosen herb (Table 45–1). Instead, poisonings tend to result from the misuse, overuse (including increased concentration in some commercial derivative products), misidentification, misrepresentation, or contamination of the product. Metal and mineral poisonings from lead, cadmium, mercury, copper, selenium, zinc, and arsenic are associated with herbal preparation usage.^{28,36,46,50,53,121,125,130} High concentrations of these salts sometimes result from contamination during the manufacturing process of some herbal or patent medications (ready-made preparations used by traditional Chinese herbalists). In some cases, as with cinnabar (mercuric sulfide) and calomel (mercurous chloride), these ingredients are intentionally included for purported medicinal benefit.⁸⁶ Patent medications may also contain pharmaceutical medications, such as acetaminophen, aspirin, antihistamines, or corticosteroids.^37,50 Many of these medicines are not listed on the packaging and may not even be approved for use in the United States. For example, four cases of agranulocytosis followed consumption of Chui Fong Tou Ku Wan, a preparation that contains both aminopyrine (which is not approved for nonprescription sales in the United States) and phenylbutazone (which was withdrawn from the US market in the 1980s), neither of which are listed on the packaging.¹³² Both aminopyrine and phenylbutazone are associated with agranulocytosis.

Herbal preparations are associated with a wide variety of toxicologic manifestations (Table 45–2). In addition, many individual herbal preparations are associated with multiple toxicologic effects. To better understand these effects, it is useful to organize herbal toxicity into several general categories.⁵⁹

Direct Health Risks

Direct health risks include pharmacologically predictable and dose-dependent toxic reactions, idiosyncratic toxic reactions, long-term toxic effects, and delayed toxic effects. For example, ingestion of aconite tea, in the suggested dose, causes tachydysrhythmias and hypotension. Idiosyncratic toxic reactions cannot be predicted on the basis of principal pharmacologic properties. For example, ingestion of chamomile tea results in anaphylaxis in a small subset of patients with probable allergies to the Compositae family. Long-term toxic effects occur only after chronic usage. For example, chronic use of herbal anthranoid laxatives results in muscular weakness from hypokalemia. Delayed toxic effects include carcinogenicity and teratogenicity. Another example is urothelial cancers in humans as a result of prolonged consumption of Aristolochia.¹¹⁹

Indirect Health Risks

Herbal use may adversely impact health by altering previous conventional prescription medication therapy. A patient may discontinue or become less compliant with previous therapy, with untoward consequences. Alternatively, the addition of an herbal preparation may affect the pharmacologic effect, principally by altering the bioavailability or clearance of concurrently used medications. Coadministration of St. John wort, an inducer of CYP3A4, with the protease inhibitor indinavir, which is metabolized by this enzyme, may result in decreased plasma indinavir concentrations and potentially decreased antiretroviral activity.¹²⁸

Most Widely Used Herbal Supplements

The most popular herbal supplements (food, drug, and mass-market retail outlets {excluding warehouse buying clubs and convenience store sales}) in the United States in 2011 are listed below in order of sales.¹⁴ The top five represent more than $100 million of sales.¹⁴

1. Cranberry(Vaccinium macrocarpon)—Cranberry is a popular remedy for treatment of urinary tract infections, but it appears to be ineffective in preventing recurrent urinary tract infections.⁴¹ Cranberry appears to be safe in appropriate doses.⁷

2. Soy(Glycine max)—Soy contains two popularly advertised ingredients: protein and isoflavones. Diets high in soy protein are associated with decreased cholesterol and low-density lipoprotein concentrations. Soy isoflavone supplements (genisten, daidzen) are phytoestrogens (plant estrogens) that currently are suggested as alternative remedies for treatment of menopausal symptoms. There is current concern regarding the effect of high concentrations of isoflavones on the risk of developing breast cancer in postmenopausal women and breast cancer survivors.

3. Saw palmetto(Serenoa repens)—Saw palmetto is a popular remedy for benign prostatic hypertrophy. Saw palmetto inhibits 5-α-reductase. However, a recent study observed that saw palmetto did not improve symptoms or objective measures of benign prostatic hypertrophy.¹¹ Saw palmetto appears to be safe in appropriate doses.^110,122

4. Garlic(Allium sativum)—Garlic has been used as a food and a medicine since ancient times. As a herb, it is used for treatment of infections, hypertension, colic, and cancer.⁶⁴ The intact cells of garlic contain the odorless, sulfur-containing amino acid derivative (+)-S-allyl-l-cysteine sulfoxide, also known as alliin. When crushed, alliin is converted to allicin (diallyl thiosulfinate), which has antibacterial and antioxidant activity and gives the herb its characteristic odor and flavor. Adverse effects of garlic extracts include contact dermatitis, gastroenteritis, nausea, and vomiting. Several constituents of garlic, such as ajoene, possess antiplatelet effects. Consequently, garlic may increase the risk of bleeding in individuals who are also taking antithrombotics.⁶⁴

5. Ginkgo(Ginkgo biloba)—This herb contains ginkgo flavone glycosides, known as ginkgolides, that are reputed to have antioxidant properties, inhibit platelet aggregation, and increase circulation. It is popularly used to treat or prevent both Alzheimer disease and peripheral vascular disease. However, two studies in 2002 and 2008 failed to demonstrate any improvement in cognitive function in healthy elderly subjects without cognitive impairment.^52,143 In appropriate doses ginkgo appears to be safe, although it may increase the risk of bleeding in individuals who are also taking antithrombotics or anticoagulants.^61,110,122

6. Milk thistle(Silybum marianum)—Milk thistle contains silymarin and silibinin, and is a popular remedy for treatment of liver dysfunction. It is also an investigational antidote for Amanita mushroom poisoning. It appears to be safe (Antidotes in Depth: A36).

7. Echinacea(Echinacea purpurea, angustifolia)—Echinacea is a reputed immunostimulant and is a popular herbal remedy for cold symptoms. However, an NCCAM-funded study was unable to detect any improvement in preventing these symptoms.¹⁵² Echinacea appears to be safe in appropriate doses.⁷¹ Rare individuals develop allergic reactions when taking echinacea.¹¹⁵

8. Black cohosh(Cimicifuga racemosa)—Black cohosh is used for the treatment of premenstrual syndrome and as alternative estrogen replacement therapy for relief of perimenopausal symptoms. It also is used as a treatment for arthritis and as a mild sedative. Black cohosh appears to be safe in appropriate doses.^13,78

9. St. John wort(Hypericum perforatum)—St. John wort is used to treat depression and is also used as a topical remedy for cuts, bruises, and wounds.¹³⁵ It has lost its popularity as an AIDS treatment because of the lack of clinical efficacy.⁷² The active ingredients are hyperforin and hypericin. Its antidepressant properties likely derive from the ability of hyperforin to inhibit the reuptake of serotonin, dopamine, norepinephrine, γ-aminobutyric acid, and glutamate.²² A major study in 2002 demonstrated that St. John wort is ineffective in treating depression.⁸¹ Acute toxicity appears limited to photosensitization reactions. St. John wort induces CYP3A4 and may interact with medications metabolized by this enzyme (eg, indinavir, oral contraceptives, cycloserine).^103,128 Hyperforin is a weak monoamine oxidase inhibitor, raising concerns about interactions with the selective serotonin reuptake inhibitors.¹²⁸

10. Ginseng(Panax ginseng)—Ginseng is the common name for deciduous, perennial plants of the genus Panax. Panax ginseng is native to Korea, China, Japan, and Russia. Panax quinquefolius is the common ginseng species in North America and grows abundantly throughout the central and eastern regions of Canada and the United States. Ginseng preparations have been used in China for treatment of respiratory illnesses, GI disorders, impotence, fatigue, and stress (“adaptogenic effect”). It is regarded as a tonic and panacea (hence the name Panax, meaning “all healing”). Its only recognized use in the United States is as an external demulcent.^66,96,111 Ginseng provides a good example of the complexity of the biochemistry and pharmacologic effects of herbs. The active components of ginseng are called ginsenosides and include panaxin, panax acid, panaquilin, panacen, sapogenin, and ginsenin. Its general metabolic effects include decreasing serum glucose and serum cholesterol concentrations; increasing erythropoiesis, hemoglobin production, and iron absorption from the GI tract; increasing blood pressure and heart rate; GI motility; and CNS stimulation. Ginseng abuse syndrome, which consists of hypertension, nervousness, sleeplessness, and morning diarrhea, has been described following long-term use of ginseng.^66,139,140 Ginseng use may reduce the anticoagulant effect of warfarin.^82,169

11. Valerian(Valeriana officinalis)—Valerian is a popular remedy for treatment of anxiety and is also used as a sleeping aid. Valerian appears to be safe in appropriate doses. Valerian may potentiate sedation in patients taking sedative-hypnotics.¹²²

12. Green tea—Green tea is a popular antioxidant used to prevent chronic disease as well as for weight reduction. It is also touted to protect against cancer and decrease cholesterol concentrations. A 2006 study in Japan observed that green tea consumption was associated with a decreased mortality from all causes of cardiovascular disease.⁹¹ Polyphenols contained in green tea including catechins and epigallocatechin gallate are responsible for its antioxidant properties. Although green tea consumption is considered to be safe, recent case reports describing the development of acute hepatitis following ingestion of green tea extracts or infusions suggest that idiosyncratic hepatotoxicity may occur in rare individuals.^{12,15,62,68,83,84}

13. Evening primrose(Oenothera biennis)—Evening primrose contain cis-γ-linoleic acid, a prostaglandin E₁ precursor. This herb is a popular remedy for treatment of premenstrual syndrome, diabetes, eczema, and rheumatoid arthritis. Evening primrose appears to be safe in appropriate doses. This herb may lower the seizure threshold in epilepsy.

Cardiovascular Toxins

Aconite.

Aconites (caowu, chuanwu, and fuzi) are the dried root stocks of the Aconitum plant.¹⁴⁶ In China, aconite usually is derived from Aconitum carmichaelii (chuan wu) or A. kuznezoffii (caowu). In Europe and the United States, aconite is derived from A. napellus, commonly known as monkshood or wolfsbane. The tubers are the most toxic part of the plant. When ingested, both cardiac and neurologic toxicity occur. Aconite poisoning is far more common in Asia, especially China.³⁹ In Hong Kong, it is responsible for the majority of serious poisonings from Chinese herbal preparations.^35,37,39

Aconite toxicity is caused by C19 diterpenoid-ester alkaloids, including aconitine, mesaconitine, and hypaconitine.²¹ Aconitine increases sodium influx through the sodium channel, increasing inotropy while delaying the final repolarization phase of the action potential and promoting premature excitation.⁷⁶ Sinus bradycardia and ventricular dysrhythmias can occur.³⁸ Symptoms can occur from 5 minutes to 4 hours after ingestion. Paresthesias of the oral mucosa and entire body may be followed by nausea, vomiting, diarrhea, and hypersalivation, and then by progressive skeletal muscle weakness. Fatalities may occur with doses as low as 5 mL aconite tincture, 2 mg pure aconite, or 1 g dried plant. Atropine may be of value in treating bradycardia or hypersalivation.¹⁴⁷ Although no antidote is available, anecdotal reports suggest the use of amiodarone, flecainide, lidocaine, and procainamide for ventricular tachydysrhythmias.^147,168 Pharmacologic principles support the use of these sodium channel blockers. One case of aconite-induced refractory tachydysrhythmias was successfully managed with a ventricular assist device.⁵⁶ In a case series of two aconite-poisoned patients, reversal of aconite-induced ventricular dysrhythmias was attributed to the use of charcoal hemoperfusion for aconitine removal.^98,99

Ch’an Su.

Ch’an Su is a traditional herbal remedy derived from the secretions of the parotid and sebaceous glands of the toad Bufo bufo gargarizans or Bufo melanosticus. This remedy is traditionally used as a treatment for congestive heart failure.⁸⁹ Ch’an Su contains two groups of toxic compounds: digoxinlike cardioactive steroids consisting of bufadienolides and the alkaloid bufotenin. Clinical findings following ingestion are similar to cardioactive steroid poisoning, including gastrointestinal symptoms and dysrhythmias. It was also marketed as an aphrodisiac for its purported topical anesthetic effects and sold under names such as “Stone,” “Love Stone,” “Black Stone,” and “Rock Hard.” Between 1993 and 1996 in New York City, several fatalities were associated with the ingestion of Ch’an Su marketed as a topical aphrodisiac.²⁵ Severe toxic reactions and death are reported after mouthing toads, “toad licking,” or eating an entire toad, or ingesting toad soup, or toad eggs.¹⁸ Assays for serum digoxin unpredictably cross-react with bufadienolides, but may qualitatively assist in making a presumptive diagnosis (Table 45–1). Digoxin-specific Fab was successfully used to treat Ch’an Su poisoning and should be empirically administered for any suspected case of cardiotoxicity from Ch’an Su or other cardioactive steroid^18,141 (Chap. 65).

Central Nervous System Toxins

Absinthe.

Wormwood (Artemisia absinthium) extract is the main ingredient in absinthe, a toxic liquor that was outlawed in the United States in 1912. This volatile oil is a mixture of α- and β-thujone (Table 45–3).¹⁶⁷ Chronic absinthe use caused “absinthism,” characterized by psychosis, hallucinations, intellectual deterioration, and seizures. The most famous victim of absinthism may have been Vincent Van Gogh, who is thought to have suffered from this disorder in the later part of his life.⁵ A thujone-free wormwood extract now is used for flavoring vermouth and pastis. A case of wormwood-induced seizures, rhabdomyolysis, and acute kidney failure was described involving a patient who purchased from the Internet and consumed approximately 10 mL essential oil of wormwood, assuming it was absinthe liquor.¹⁶⁴ Treatment remains supportive.

Anticholinergics: Henbane, Jimson Weed, Mandrake.

Many plants contain the belladonna alkaloids atropine (d,l-hyoscyamine), hyoscyamine, and scopolamine (l-hyoscine). They may still be used therapeutically for treatment of asthma and occasionally are mistakenly included in herbal teas.³⁴ Signs and symptoms of anticholinergic poisoning include mydriasis, diminished bowel sounds, urinary retention, dry mouth, flushed skin, tachycardia, and agitation. Mildly poisoned patients usually require only supportive care and sedation with intravenous benzodiazepines. Intravenous physostigmine reverses anticholinergic poisoning; however, its use should be limited to treatment of moderately to severely symptomatic patients because inappropriate use may cause seizures and dysrhythmias (Antidotes in Depth: A9).

Ephedra.

Members of the genus Ephedra generally consist of erect evergreen plants resembling small shrubs.¹⁵⁰ Common names include sea grape, ma-huang, yellow horse, desert tea, squaw tea, and Mormon tea. Ephedra species have a long history of use as stimulants and for management of bronchospasm. They contain the alkaloids ephedrine and, in some species, pseudoephedrine.^132,150 In large doses, ephedrine causes nervousness, headache, insomnia, dizziness, palpitations, skin flushing, tingling, vomiting, anxiety, restlessness, mania, and psychosis. The treatment is similar to that for other CNS stimulants (Chap. 76). In a published review of 140 reports of adverse events associated with ephedra use submitted to the FDA, 62% of cases (82) were considered “probable” or “possibly” related to ephedra use. Hypertension was the most commonly reported adverse effect (17 cases), followed by palpitations or tachycardia (13 cases), strokes (10 cases), and seizures (seven cases). Ten reported cases resulted in death. Thirteen cases resulted in permanent disability.⁷⁴ In 2002, the FDA banned the sale of ephedra-containing dietary supplements.¹⁵⁵ However, other herbal preparations, such as bitter orange (Citrus aurantia), contain ephedralike alkaloids (synephrine) and are still widely available.^115,121 Exposures may result in cardiovascular toxicity.^116,121

Nicotinics: Betel Nut, Blue Cohosh, Broom, Chestnut, Lobelia, Tobacco.

Betel (Areca catechu) is chewed by an estimated 200 million people worldwide for its euphoric effect. As an herb, it used as a digestive aid and as a treatment for cough and sore throat. Its active ingredient is arecoline, a direct-acting nicotinic agonist. The betel leaf also contains a phenolic volatile oil and an alkaloid capable of producing sympathomimetic reactions. Arecoline is a bronchoconstrictor, although weaker than methacholine, and may exacerbate bronchospasm in asthmatic patients chewing betel nut.¹⁴⁹ Treatment for betel nut toxicity is supportive. Long-term use of betel nut is associated with leukoplakia and squamous cell carcinoma of the oral mucosa.¹²⁰

Many other herbal preparations have nicotinic effects. Examples of plants and their nicotinic ingredient include blue cohosh¹³, methylcytisine, broom, l-sparteine, chestnut, esculin, lobelia, lobeline, and tobacco/nicotine (Chap. 85).

Other herbs that have CNS activity include valerian (sedation), kava kava (sedation), Japanese star anise (seizures), nutmeg (hallucinations),¹⁶⁵ mace (hallucinations), and iboga (hallucinations).

Gastrointestinal Toxins

Goldenseal.

Goldenseal (Hydrastis canadensis) originally was used by the Cherokees and other Native Americans as a dye and an internal remedy.⁶⁹ Today, it is used as an astringent, as a remedy for mucous membranes or GI tract disorders, and as treatment for menorrhagia. Goldenseal is reputed to mask the presence of illicit drugs on urinary drug screens, although multiple studies indicate goldenseal does not affect the results of urinary drug screens.^44,118,124 This myth originated in the murder-mystery Stringtown on the Pike (1900), which was written by the internationally known plant pharmacist Uri Lloyd. In this novel, one of the major characters is accused of murder by poisoning with strychnine but is posthumously exonerated with evidence that hydrastine (the active alkaloid in goldenseal) and morphine cross-react to produce a positive color assay for strychnine.⁶⁰ Appropriate usage of this herb is thought to be safe, but ingestion of large amounts can cause vomiting, diarrhea, convulsions, paralysis, and respiratory failure. In cases of large ingestions, the patient should receive supportive and symptomatic care.

Hepatotoxins

Pennyroyal.

Pennyroyal oil is a volatile oil extract from the leaves of Mentha pulegium and Hedeoma pulegioides plants. Herbalists use pennyroyal oil as an abortifacient and to regulate menstruation. It is also used as a flea/mosquito repellant and as a fragrance. The abortive effect is thought to be caused by irritation and contraction of the uterus.¹⁴⁶ Pennyroyal usually is ingested as a strong tea prepared from the leaves or as the oil itself. It is cited as causative in several well-documented cases of hepatic failure following ingestion of as little as 15 mL of the oil.^3,8 The postulated mechanism is direct hepatotoxicity following glutathione depletion from the cyclohexanone pulegone and its cytochrome P450 (CYP1A2, CYP2E1, CYP2C19)-dependent toxic metabolites that include menthofuran.⁸⁷ On autopsy, vacuolization of the white matter of the midbrain was reported in both a fatal human exposure and in animal models.^7,123 Because pulegone depletes hepatic glutathione stores, N-acetylcysteine treatment may be beneficial^3,19 (Antidotes in Depth: A3). In an animal model, pretreatment with cytochrome P450 inhibitors cimetidine (CYP1A2, CYP2C19) and disulfiram (CYP2E1) reduced pulegone-induced hepatotoxicity.¹⁴⁵ It may be reasonable to consider use of cytochrome P450 inhibitors in the treatment of pennyroyal-poisoned patients; however, evidence of clinical benefit in humans currently is lacking.

Pyrrolizidine Alkaloids.

Pyrrolizidine alkaloids are hepatotoxins found in many plants, including heliotrope (Heliotropium), ragwort or groundsel (Senecio), rattlebox (Crotalaria), and comfrey (Symphytum).^127,131 Examples of other plants and products containing pyrrolizidine alkaloids include borage (Borago officinalis), coltsfoot (Tussilago farfara), and T’u-san-chi’i (Gynura segetum).^79,90,132 The alkaloids undergo metabolism to pyrroles, which serve as biologic alkylating agents.⁷⁹ The pyrroles cause hepatic sinusoidal hypertrophy and venous occlusion, resulting in hepatic veno-occlusive disease, hepatomegaly, cirrhosis, and possibly hepatic carcinoma. Chronic low dose exposure may cause pulmonary toxicity resulting in pulmonary artery hypertension and right ventricular hypertrophy. Consumption of “bush” tea, prepared from the leaves of the Crotalaria plant, is considered an endemic problem in Jamaica. Epidemics have also occurred in Afghanistan and India, where ingestion of contaminated cereals containing Heliotropium and Crotalaria seeds resulted in reports of 1632 and 60 cases of venoocclusive disease, respectively.^112,148 In Western countries, ingestion of herbal products containing Senecio and comfrey have led to several cases of hepatic venoocclusive disease.¹²⁷ Treatment of hepatic venoocclusive disease is supportive but may require liver transplantation in severe cases.

Several other herbal preparations are associated with hepatotoxicity.⁹³ These preparations include chaparral (Larrea tridentata),^24,70 germander(Teucrium chamaedrys),⁹⁴ impilia (Callilepsis laureola),⁹⁰ atractylis (Atractylis gummifera), sassafras (Sassafras albidum),¹³⁹ and kava kava (Piper methysticum).¹⁵⁷

Metals

Poisonings by metallic salts, including arsenic, cadmium, lead, and mercury, may occur following consumption of various types of herbal preparations^27,30,46,132 (Chaps. 89, 91, 96, and 98). Treatment consists of ceasing consumption of the herbal product and use of an appropriate ­chelator when indicated.

Hai-ge-ten (clamshell powder) contamination with copper, chromium, arsenic, or lead is described in several case reports.^75,104 Pay-loo-ah, a red and orange powder used by the Hmong people as a fever and rash remedy, was contaminated with lead.²⁶ Ayurvedic remedies are either herbal only or rasa shastra, which, based upon ancient traditional healing of India, deliberately combines metals such as gold, silver, copper, zinc, iron, lead, tin, and mercury and are used by the majority of the Indian population.^{28,129,130,137} Ghasard, Bola Goli, Kandu, and Moha Yogran Guggulu, traditional Indian remedies for abdominal pain, are associated with lead poisoning.^27,138 One fatality from lead poisoning from Ghasard, Bola Goli, and Kandu is reported from the United States.²⁷ In one study, 20% of surveyed Ayurvedic products produced in South Asia and sold on a nonprescription basis in stores in the Boston area contained potentially harmful concentrations of lead, mercury, or arsenic.¹³⁶ A follow-up study determined that a similar 21% of Ayurvedic products sold through the Internet also contained potentially harmful concentrations of lead, mercury, or arsenic irrespective of whether manufacture occurred in the United States or India.¹³⁷

These same investigators recently studied the lead, mercury, and arsenic concentrations in the United States and Indian manufactured Ayurvedic medicines sold via the Internet demonstrating that 20% of these were contaminated with one of these metals, all exceeding one or more standards for acceptable daily intake of a toxic metal.¹³⁷ Azarcon (lead tetroxide) and greta (lead oxide) are used by an estimated 7.2% to 12.1% of Mexican-Hispanic families for treatment of empacho. In Spanish, empach o means “blocked intestine,” but it refers to any type of chronic digestive problem, including such diverse symptoms as constipation, diarrhea, nausea, vomiting, anorexia, apathy, and lethargy.^31,33 Azarcon and greta are fine powders with total lead contents varying from 70% to more than 90%.^16,32

Herbal balls, hand-rolled mixtures of herbs and honey produced in China, are often associated with arsenic and mercury contamination.⁵⁵ Examples include An Gong Niu Huang Wan, Da Huo Luo Wan, and Niu Huang Chiang Ya Wan.

Renal Toxins

Aristolochia.

An epidemic of renal failure in Belgium was linked to the substitution of Aristolochia fangchi, also known as birthwort, heart-wort, and fangchi, for another Chinese herbal, Stephania tetranda, in the formulation of a weight-loss regimen.^161,162 Of 70 identified cases of renal fibrosis, 30 patients developed chronic renal failure. Aristolochic acid in Aristolochia causes renal fibrosis, which typically becomes clinically apparent 12 to 24 months after the initial injury. Patients with Aristolochia-induced nephropathy also have an increased risk for developing urothelial cancer.¹¹⁹

Miscellaneous

Chamomile Tea.

Chamomile tea is a popular herbal drink made from chamomile flower heads. Anaphylactic reactions can occur in patients allergic to ragweed, asters, chrysanthemums, or other members of the Compositae family.^10,23 Such reactions are rare but can be life threatening. The patient need not have severe allergies or be highly atopic to experience a cross-reaction.

Chinese Patent Medicines

Chinese patent medicines, a component of traditional Chinese medicine (TCM), contain traditional herbals, formulated into tablets, capsules, syrups, powders, ointments, and plasters, for easy use. They are produced by poorly regulated Chinese pharmaceutical agencies and are highly susceptible to adulteration (intentional) or contamination (inadvertent). They are often sold by nonherbalists at convenience stores in packages with incomplete documentation of ingredients and often are not labeled in English. Many contain undocumented pharmaceuticals, like to increase their effectiveness, and improve sales among non–TCM users in Western nations. For example, in 2007, 90 Chinese patent medicines randomly purchased in New York City’s Chinatown identified five samples containing nine undisclosed Western medications, including chlormethiazole, chlorpheniramine, diclofenac, chlordiazepoxide, hydrochlorothiazide, triamterene, diphenhydramine, and sildenafil citrate.¹⁰⁹

Treatment

A specific treatment strategy should emphasize identification of the specific herbal preparation(s) used by the patient, concurrent medication(s), and medical illness(es). Because herbal preparation toxicity varies greatly depending on the preparation used, careful examination may be aided by knowledge of the herbal preparation. In most cases, supportive care and discontinuation of the herbal preparation(s) are sufficient. Some herbal toxicities require specific laboratory analysis and therapy (Table 45–1).

All adverse events associated with herbal preparations should be reported to the local poison control center or to FDA MedWatch by phone at 1-800-FDA-1088 or online at https://www.fda.gov/medwatch.

• Although most herbal preparation users will experience no ill effects, both herb users and clinicians should be aware that these preparations are pharmacologically active, have the potential for toxicity, and are not as closely regulated by the FDA (or any governmental agency) as pharmaceuticals.

• Herbal preparation users should be aware that these preparations are poorly studied with scientific proof of efficacy lacking for most preparations. No standards exist for their manufacture, quality, or control and many herbal products do not contain the purported amount of the active ingredient. Some herbal products do not even contain the specified active ingredient.

• Many herbal stores are staffed by untrained personnel who may dispense incorrect medical advice and unfounded claims concerning their products.^126,160

• Clinicians should be familiar with herbal preparations and their potential for drug interactions and adverse events.

Acknowledgment

Mary Ann Howland, PharmD, and Neal A. Lewin, MD, contributed to this chapter in previous editions.

References

Bibliography