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.
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.
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. Concern has been raised regarding initiation of hyperadrenergic MAOI reactions by mixing adrenergic preparations, such as ephedra and ephedrine-containing preparations, with St. John's wort; however, no cases of serotonin syndrome or MAOI crisis have been linked to the use of St. John's wort. 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.
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]
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. However, ephedra is available for sale as an asthma preparation and should still be considered for abuse. It is still promoted in body-building circles.
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 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.
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 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.[3] 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.[4]
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.[5]
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 reported.[6]
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.[7] However, a comprehensive review estimated that the incidence rate of hepatotoxicity from kava-kava is one in 60-125 million users.[8] 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.[9]
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 has been contaminated with a by-product and associated with 38 deaths. Numerous chronic pulmonary effects are known collectively as eosinophilia-myalgia syndrome. Elevated eosinophil levels are characteristic of the syndrome.
Adverse effects of herbal preparations may also include the following:
Some herbal products contain high concentrations of heavy metals, such as lead, mercury, and arsenic (also found in kelp). Use of ayurvedic medications should arouse suspicion of lead contamination.) Chinese herbal medications have been an incredible 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%).
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.[12]
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.[13] Other drugs that have been found in herbal preparations include the following:
Adulteration with mefenamic acid and cadmium has resulted in acute kidney injury. Adulteration with dipyrone and phenylbutazone has resulted in agranulocytosis.
Adverse effects from herbal preparations can be categorized by type. One schema divides reactions into the following 4 types:
Another schema divides reactions as follows:
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.[14] The 2017 annual report of the American Association of Poison Control Centers' National Poison Data System documented 42,645 single exposures for dietary supplements/herbals/homeopathic substances with the majority of exposures (32,000) in children younger than 6 years. Of the 6187 exposures treated in health care facilities, 46 were reported to have major adverse outcomes and 3 deaths were noted.[15]
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.[16, 17]
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.[18]
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.
The following questions are necessary to ascertain specific history:
Evaluate the patient for possible toxidromes such as anticholinergic syndromes or those consistent with cardiac glycosides or heavy metal poisonings, as follows:
When evaluating critically ill patients with unknown ingestions, a number of laboratory tests should be considered to help identify the possible toxic effects and severity of illness caused by the material ingested. Laboratory tests can include the following:
Evaluate serum digoxin levels with exposure to plants containing cardiac glycosides, such as Digitalis lanata. Serum digoxin levels in these circumstances reflect exposure only and do not correlate with toxicity (see Cardiac Glycoside Plant Poisoning).
A proper history of which herbal products the patient takes is also vital for guiding therapeutic drug monitoring (eg, checking digoxin levels to determine whether the patient is taking the appropriate dose). Multiple herbal products may interfere with the assay and give either falsely elevated or decreased digoxin serum concentrations because of interference with the digoxin assay.
Use urine drug screens to detect adulterants (eg, thin-layer chromatography, gas chromatography, mass spectrometry). Ephedra use may be detected as phenylpropanolamine (which was recalled from US market) or may turn the amphetamine screen on a urine drug screening test positive.
Heavy metal screens may be appropriate with specific clinical presentations. See the following:
Consider computed tomography scan of the brain for patients with altered mental status. Radiographs can assist with diagnosing heavy metal exposure if opacities are seen with the gastrointestinal tract. Even a radiograph of the herbal product itself may reveal the presence of a heavy metal.
Consider a lumbar puncture for patients with altered mental status of unclear etiology, especially if fever and/or nuchal rigidity is present.
Prehospital care is supportive. Emergency personnel should do the following, as needed:
Emergency department care consists of supportive care, ACLS, and decontamination protocols. Specific treatments depend on the substance or substances ingested but can include agents such as the following:
Consider consultation with the local poison control center and medical toxicologist. They may know of recent similar case presentations in the area and assist with management.
Information on adverse reactions (eg, product recalls because of contamination) can be obtained at the US Food and Drug Administration (FDA) Safety Information and Adverse Event Reporting Program Report (MedWatch). Serious drug interactions or toxicity from herbal preparations should also be reported to MedWatch for further investigation. The telephone number for reporting is 1-800-FDA-1088.
For toxic ingestions in general, consider activated charcoal, provided that airway control is ensured. Other care should be based on the patient's signs and symptoms.
Clinical Context: Activated charcoal is used in emergency treatment for poisoning caused by drugs and chemicals. A network of pores adsorbs 100-1000 mg of drug per gram. Activated charcoal does not dissolve in water. Administer it as soon as possible after poison ingestion. Repeated doses may help to lower systemic levels of ingested compounds. Activated charcoal is usually administered with sorbitol in alternating doses.
Activated charcoal adsorbs ingested medication remaining in the gastrointestinal tract and creates a concentration gradient to "pull back" medication circulating in the bloodstream. It is most effective if administered within 1 hour of ingestion. In selected cases, repeated doses may be beneficial if the toxin is entero-hepatically metabolized, allowing a second opportunity to bind it and remove it from the body.