Practice Essentials
Although most plant exposures are unintentional, many adults ingest herbal products for self-treatment of illness and for health maintenance; indeed, the sale of herbal preparations has developed into a billion-dollar industry. What constitutes an herbal product is generally ill-defined and, though the term implies a leafy plant, herbal products may contain nonherb plant materials, animal products, and/or mineral products.
While many herbal products are innocuous or possess minimal toxicity, some contain toxic ingredients that may not be identified on the label. These unidentified ingredients may be unintentionally included in the product (eg, misidentification of a toxic plant as a desired nontoxic plant or contamination with pesticide residues or heavy metals) or adulterants introduced for increased effect (eg, addition of a pharmaceutical agent to an herbal preparation).
Dietary supplements, including herbal products, are regulated under the Dietary Supplement Health and Education Act (DSHEA) of 1994 as a food product. This Act does not require these products to be effective or safe prior to marketing.
The US Food and Drug Administration (FDA) has little control over the marketing of herbal products, but may prohibit sales of herbal products containing pharmaceutical agents. The FDA also may prohibit sale of an herbal product proven to have serious or unreasonable risk under conditions of use on the label or as commonly consumed. However, prohibition of an herbal product generally does not occur until after marketing and extensive distribution to the public. The burden of proof lies with the FDA and consumer reporting.
Case reports and studies have documented that herbal products may contain ingredients, sometimes toxic, not listed on the label. In addition, the quantities of ingredients listed on the label can vary greatly, hindering definition of toxic ingredients and unsafe products for public consumption.
This article discusses several plants and plant products commonly used to improve health or to treat illness as herbs and herbal products. Herbs and herbal products in this article are discussed because of their reported toxicity and increased use in the general patient population. Many herbal products continue to be available to the public with either ill-defined or unknown toxicity.
Pathophysiology
Herbal products are generally heterogeneous, may produce multiple effects, and may affect multiple organ systems, including the nervous, cardiovascular, gastrointestinal (GI), hepatic, renal, and hematologic systems. The following section discusses specific toxic plants, categorized by the system most severely affected.
Central nervous system
Several herbal products can produce anticholinergic symptoms. Atropa belladonna contaminated burdock root tea in the 1970s and 1980s, resulting in anticholinergic toxicity. Datura metel L fastuosa mistakenly has been used in place of Campsis and Paulownia species, producing anticholinergic poisoning.
Plants with anticholinergic activity include Datura stramonium (jimson weed), A belladonna (deadly nightshade), and Hyoscyamus niger (henbane). In the 1970s, ginseng contaminated with Mandragora officinarum (scopolamine-containing mandrake) produced anticholinergic toxicity.
Kava-kava (Piper methysticum) is an herbal preparation that may be brewed into a beverage and is especially popular among natives of the South Pacific islands. Methysticine and kawain (a local anesthetic) are its main constituents; however, primary effects of kava-kava are anxiolytic, myorelaxant, and sedation. This herbal preparation has also been associated with hepatotoxicity.
St. John's wort (Hypericum perforatum) is a weak monoamine oxidase inhibitor (MAOI) and serotonin agonist commonly used as an anti-depressant. St. John's wort is mildly serotonergic and combining it with other serotonergic medications (eg, a selective serotonin reuptake inhibitor [SSRI], bupropion) may result in serotonin syndrome. When taken in conjunction with other prescription medications, St. John's wort may decrease their systemic bioavailability.
Podophyllum emodi and Podophyllum peltatum (mandrake and mayapple, respectively) contaminated herbal preparations (eg, Gentiana and clematis) in the 1980s and 1990s. Podophyllin causes metaphase arrest at the cellular level and altered mental status, peripheral motor and sensory neuropathy, gastroenteritis, and multisystem organ failure.
Lobelia inflata and Nicotiana products can cause nicotine toxicity, with hypertension, fasciculations, and CNS excitation. Severe cases may progress to neuromuscular paralysis. Older versions of smoking-deterrent tablets contained Lobelia.
Strychnos nux-vomica (strychnine) has been found in imported herbal patent medicines and can cause abdominal distress. [1] Although frequently formulated in homeopathic doses, toxic amounts of strychnine cause profound metabolic acidosis, rhabdomyolysis, and generalized "spinal seizures" in fully alert patients.
Cardiovascular system
Cardiac glycosides and other cardioactive steroid contaminants may cause toxicity. Digitalis lanata was mistaken for plantain and caused severe cardiotoxicity (eg, complete heart block) in 1997 when consumed as an internal cleansing product. [2] Oleander (Nerium oleander) contains the cardiac glycoside oleandrin. Use of oleander extracts as anti-diabetic agents or anti-cancer treatment has been associated with cardiac glycoside toxcity, including death. [3]
Ephedra and ephedrine-containing products (eg, Ma Huang) may produce cardiac stimulation, hypertension, peripheral vasoconstriction, chest pain, myocardial infarctions, and intracerebral hemorrhage. Ma Huang (ephedra) may produce hypersensitivity myocarditis (case report) and vasculitis. A sufficient public outcry and data collected on adverse effects enabled the FDA to ban ephedra products for use in weight loss.
Aconitum species (ie, monkshood or wolfsbane) contain aconitine; Veratrum species contain Veratrum alkaloids. These toxins open sodium channels in cardiac myocytes, resulting in conduction blockade, bradycardia, ventricular dysrhythmias (especially bidirectional tachycardia), and refractory cardiovascular collapse. Aconitine-containing Chinese herbal medicine compounds have been used to treat chronic pain syndromes and unfortunately have also been associated with deaths in Asia and Australia.
Cinchona bark ingestion can cause quinine toxicity.
Hepatic system
Hepatic toxicity with Budd-Chiari syndrome has been reported with pyrrolizidine alkaloids, which are metabolized to alkylating agents that produce hepatic veno-occlusive disease, hepatomegaly, and cirrhosis. Toxicity can affect the fetus as well. Plants that contain these substances include Heliotropium (heliotrope), Senecio (gordolobo), Crotalaria, and Symphytum (comfrey). Senecio and Crotalaria have been used in Jamaica to make bush tea. Use of comfrey tea as a treatment for abdominal pain has resulted in hepatic veno-occlusive disease. [4]
Use of herbal preparations of greater celandine (Chelidonium majus) prescribed for gastric and biliary disorders has been associated with acute cholestatic hepatitis. [5]
Mentha pulegium (ie, pennyroyal oil, "squaw" mint) teas have been mistaken for other mint teas and have been used intentionally as abortifacients. These teas contain the hepatotoxin pulegone, which causes centrilobular hepatocellular necrosis. Pulegone toxicity can result in multisystem organ failure.
Germander (Teucrium chamaedrys) can cause centrilobular necrosis. In France, germander was marketed as a slimming agent in the 1990s; fatalities were reported.
Chaparral (ie, creosote bush, greasewood, hediondillo) can produce periportal injury, inflammatory changes, scarring, cholangitis, and cholestasis.
Jin Bu Huan is a Chinese herbal preparation with a long history of use as a sedative, analgesic and decongestant. The compositions of Jin Bu Huan may vary, but can include Lycopodium serratum, Panax, Pseudo ginseng, Polygala chinensis, and Stephania. [6] Some preparations have caused fatal hepatic injury. Other preparations have caused severe bradycardia.
A survey of worldwide cases of liver injury associated with herbal traditional Chinese medicine established causality for 28 different herbs or herbal mixtures: Bai Xian Pi, Bo He, Ci Wu Jia, Chuan Lian Zi, Da Huang, Gan Cao, Ge Gen, Ho Shou Wu, Huang Qin, Hwang Geun Cho, Ji Gu Cao, Ji Xue Cao, Jin Bu Huan, Jue Ming Zi, Jiguja, Kudzu, Ling Yang Qing Fei Keli, Lu Cha, Rhen Shen, Ma Huang, Shou Wu Pian, Shan Chi, Shen Min, Syo Saiko To, Xiao Chai Hu Tang, Yin Chen Hao, Zexie, and Zhen Chu Cao. [7]
Sho-saiko-to (a mixture of 7 herbs) is a Chinese preparation that is widely used as a prescription medicine in Japan, principally for treatment of hepatitis. Nevertheless, it has been associated with toxic hepatitis.
Artemisinin, which is found in the leaves of Artemisia annua, is a component of therapies for malaria that generally are considered safe, effective, and well tolerated. In addition, herbal supplements containing artemisinin are marketed for general health maintenance and for treatment of parasitic infections and cancers. A case of hepatitis associated with ingestion of an herbal supplement containing artemisinin has been reported, however. [8]
Dai-saiko-to is a traditional Japanese herbal medicine. A case of autoimmune hepatitis becoming clinically apparent in a patient using dai-saiko-to has been reported. [9]
Kombucha tea is a symbiotic mixture of yeast and bacteria brewed into tea. Case reports describe a syndrome characterized by hepatotoxicity, pulmonary edema, and disseminated intravascular coagulation (DIC) after ingestion.
Case reports of hepatotoxicity from kava-kava led to bans and regulations of its use in several countries. [10] However, a comprehensive review estimated that the incidence rate of hepatotoxicity from kava-kava is one in 60-125 million users. [11] In 2014, a German court overturned that country's ban on kava-kava, stating that risk from kava exposure had not been clearly demonstrated and did not appear unusually high. [12]
Hematologic system
Ginkgo biloba has been reported to increase bleeding times and may have contributed to intracranial hemorrhages. Yohimbine use has been associated with agranulocytosis (probably an idiosyncratic response) and priapism. Dysosma pleianthum (ie, bajiaolian) contains podophyllotoxin and causes thrombocytopenia and leukocytosis.
Jui, a Chinese herbal medication, has been associated with thrombocytopenia. A reaction may be triggered by repeat exposure because of sensitization from previous exposure or exposures. Jui contains Sinomeni caulis et rhizoma, Glycyrrhizae radix, Aralia elata, Glechomae herba, and Taxus cuspidata.
L-tryptophan contaminated with a by-product was responsible for a 1989 epidemic of eosinophilia-myalgia syndrome that was associated with 36 deaths; rare cases of the syndrome from other causes were subsequently reported. The syndrome is characterized by abrupt onset of peripheral eosinophilia, myalgia, and rash, edema, pulmonary involvement, and/or neuropathy.
Other systems
Adverse effects of herbal preparations may also include the following:
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Licorice root may cause profound renal potassium loss (see Licorice Poisoning)
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Echinacea and chamomile tea can cause anaphylaxis
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Royal jelly and yohimbine can cause allergic reactions
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Shiitake mushrooms can cause severe dermatitis
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Garlic, chamomile tea, and capsicum may produce contact dermatitis
Contamination and adulteration
Some herbal products contain high concentrations of heavy metals, such as lead, mercury, and arsenic (also found in kelp). Contamination with heavy metals—especially lead, but also arsenic and mercury—is well documented in the literature. [15, 16] Chinese herbal medications have been a remarkable source of contamination, with one study showing that, out of 247 traditional Chinese medicines investigated, a proportion were contaminated with arsenic (5-15%), lead (5%), and mercury (approximately 65%). [17]
In a study of 6,712 women aged 20 years or older, those using herbal supplements had lead levels that were 10% higher than nonusers. Blood lead levels were 24% higher in women using ayurvedic or traditional Chinese medicine herbs; 23% higher in those using St. John's wort, and 21% higher in those using kava, valerian, black cohosh, bee pollen, or nettle. [17]
Some herbal preparations have been found to be adulterated with undeclared ingredients. For example, the prostate cancer remedy PC-SPES was withdrawn from the market in 2002 after samples were found to contain warfarin, diethylstilbestrol, and indomethacin. [18] Other drugs that have been found in herbal preparations include the following:
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Caffeine
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Acetaminophen
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Hydrochlorothiazide
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Ephedrine
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Chlorpheniramine
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Methytestosterone
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Prednisolone
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Phenacetin
Adulteration with mefenamic acid and cadmium has resulted in acute kidney injury. Adulteration with dipyrone and phenylbutazone has resulted in agranulocytosis.
Etiology
Adverse effects from herbal preparations can be categorized by type. One schema divides reactions into the following 4 types:
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Type A - Pharmacologically predictable, dose dependent, and preventable by dose reduction
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Type B - Idiosyncratic, pharmacologically unpredictable, toxicity not correlated with dose, often immunologically mediated, often serious and potentially fatal
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Type C - Developed over long-term therapy, well-described, and may be anticipated
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Type D - Delayed effects (eg, carcinogenicity, teratogenicity)
Another schema divides reactions as follows:
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Allergic reactions
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Toxic reactions
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Adverse effects related to desired pharmacologic actions
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Mutagenic effects
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Drug interactions
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Contamination
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Mistaken plants
Epidemiology
An estimated 50 to 60% of adult Americans ingest an herbal or dietary supplement on a regular basis. One study reported that at least 23,000 emergency department visits in the United States each year are attributed to adverse events from dietary supplements. [19] The 2019 annual report of the American Association of Poison Control Centers' (AAPCC) National Poison Data System (NPDS) documented 69,618 human exposures for dietary supplements/herbals/homeopathic substances, which is the 11th most common substance category associated with human exposure. The AAPCC also reported that exposure to dietary supplements/herbals/homeopathic substances is on the rise over the past 10 years at a mean increase of 95 exposures per year, the 14th most rapidly increasing category of exposure.
The majority of dietary supplements/herbals/homeopathic substances exposures reported to the NPDS are in children under the age of 5—48,537 exposures occurred in 2019, making it the 5th most common category of exposure in children in that age range, whereas in adults age 20 years and older it is not in the top 25 categories of exposure. Of the 7053 exposures treated in health care facilities, 51 were reported to have major adverse outcomes and 2 deaths were noted. [20]
The National Center for Health Statistics reports that in 2007-2012, almost 4 out of 10 adults and over 1 in 10 children aged 4–17 years had used complementary and alternative medicine (CAM) therapy in the previous 12 months and that nonvitamin, nonmineral dietary supplements were the most commonly used, comprising approximately 18% of CAM therapies in adults and approximately 5% in children. [21, 22]
The World Health Organization (WHO) estimated that herbal and other plant-derived remedies are the most frequently used therapies worldwide. WHO estimated the output of Chinese materia medica was US $83.1 billion in 2012, an increase of more than 20% from the previous year. In the Republic of Korea, annual expenditures for traditional medicine products was US $7.4 billion in 2009 and spending for natural products in the United States was US $14.8 billion in 2008. [23]
Traditional Chinese herbal medications have been an ever-increasing source of contamination, either intentional or unintentional. Due to lack of transparency of reporting, however, the risk to the general population has been difficult to assess.
