AUTHOR INFORMATION

Section 1 of 11

Authored by Fermin Barrueto, Jr, MD, Assistant Professor, Department of Emergency Medicine, University of Maryland

Coauthored by Jon Mark Hirshon, MD, MPH, Associate Professor, Department of Emergency Medicine, University of Maryland School of Medicine

Fermin Barrueto, Jr, MD, is a member of the following medical societies: American Academy of Clinical Toxicology, American Academy of Emergency Medicine, American College of Emergency Physicians, American College of Medical Toxicology, and Society for Academic Emergency Medicine

Edited by B Zane Horowitz, MD, Medical Director, Oregon Poison Center; Professor, Department of Emergency Medicine, Oregon Health Sciences University; John T VanDeVoort, PharmD, Clinical Assistant Professor, College of Pharmacy, University of Minnesota; Michael Hodgman, MD, Assistant Clinical Professor of Medicine, Department of Emergency Medicine, Bassett Healthcare; John Halamka, MD, Chief Information Officer, CareGroup Healthcare System, Assistant Professor of Medicine, Department of Emergency Medicine, Beth Israel Deaconess Medical Center; Assistant Professor of Medicine, Harvard Medical School; and Asim Tarabar, MD, Assistant Clinical Professor of Emergency Medicine, Yale University School of Medicine; Consulting Staff, Department of Emergency Medicine, Yale-New Haven Hospital

Author's Email:	Fermin Barrueto, Jr, MD
Editor's Email:	B Zane Horowitz, MD

eMedicine Journal, October 10 2006, VOLUME 7, Number 10

INTRODUCTION

Section 2 of 11

Background: Although most plant exposures are unintentional, many adults ingest herbal products for self-treatment of illness and health maintenance. What constitutes an herbal product is generally ill defined. This article discusses several plants and plant products commonly used to improve health or to treat illness as herbs and herbal 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 adulterated 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 efficacious or safe prior to marketing. The Food and Drug Administration (FDA) has little control over which herbal products are marketed, but it 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; prohibition of an herbal product generally occurs after marketing and extensive distribution to the public. The burden of proof lies with the FDA and consumer reporting.

Previous case reports and studies reveal that herbal products may contain ingredients, sometimes toxic, not listed on the label; also, quantities of ingredients listed on the label can vary greatly, hindering definition of toxic ingredients and unsafe products for public consumption.

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 organs systems, including the nervous, cardiovascular, GI, hepatic, renal, and hematologic systems. The following herbal products are divided into specific toxic plants by the system most severely affected.

Central nervous system

Anticholinergic toxicity may be seen. 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 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 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. 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. An outbreak of digoxinlike deaths occurred in New York City when a Chinese aphrodisiac called Chan-Su was sold. The labeling was in Chinese and stated that the product was meant to be applied topically, but several people ingested it. This product contained an extract from the venom of Bufo toads, which caused the deaths. These types of ingestions can be treated with digoxin-specific Fab.

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 have enabled the FDA to ban ephedra products from the United States.

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. These herbal products include Heliotropium (heliotrope), Senecio (gordolobo), Crotalaria, and Symphytum (comfrey). Senecio and Crotalaria have been used in Jamaica to make bush tea. Toxicity can affect the fetus as well.

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 and kava 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 may have varying compositions, but some preparations have caused fatal hepatic injury. Other preparations have caused severe bradycardia.

Syo-saiko-to (a mixture of 7 herbs) has been associated with toxic hepatitis.

Dai-saiko-to has reportedly produced an autoimmune hepatitis.

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.

Renal system

Aristolochia species (eg, birthwort, heartwort, fangji) can cause interstitial renal fibrosis due to aristolochic acid, a known nephrotoxin.

Licorice root may cause profound renal potassium loss (see Plant Poisoning, Licorice).

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 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.

Other systems

Echinacea and chamomile tea can cause anaphylaxis.

Royal jelly and yohimbine can cause allergic reactions.

Shiitake mushrooms can cause severe dermatitis.

Garlic, chamomile tea, and capsicum may produce contact dermatitis.

Some herbal products contain high concentrations of heavy metals, such as lead, mercury, and arsenic (also found in kelp); they can cause heavy metal toxicity. (Use of ayurvedic medications should arouse suspicion of heavy metal contamination).

Some herbal preparations are adulterated with undeclared ingredients (eg, caffeine, acetaminophen, indomethacin, hydrochlorothiazide, ephedrine, chlorpheniramine, methyltestosterone, prednisolone, phenacetin). Adulteration with mefenamic acid and cadmium has resulted in acute renal failure. Adulteration with dipyrone and phenylbutazone has resulted in agranulocytosis.

Some herbal products have potentially dangerous endocrine effects, despite claims to the contrary, such as the estrogenic PC-SPES (a combination of 8 herbs). Recent incidence of toxicity due to herbal medication with oral sulfonylureas has been reported.

Frequency:

• In the US: According to a rural Mississippi study, almost three fourths of respondents had used plant-derived remedies during the preceding year. Another study found that one third of US citizens have used herbal medicines. One survey in an urban hospital showed herbal use to be 27% and highest (36%) among the Asian population. A national survey examining trends in alternative medicine found that use of at least 1 of 16 alternative therapies increased from 33.8% in 1990 to 42.1% in 1997.

• Internationally: The World Health Organization (WHO) has estimated that herbal and other plant-derived remedies are the most frequently used therapies worldwide. WHO estimates that 4 billion people, 80% of the world population, use herbal preparations for primary healthcare. One South Australian survey found that 48.5% of respondents used at least one nonmedically prescribed alternative medicine (including vitamins).

Mortality/Morbidity: The FDA noted 2621 adverse drug reactions and 184 deaths due to herbal products over a 5-year period. However, the report relied on voluntary physician reporting, which may substantially underestimate total incidence. Actual mortality and morbidity are difficult to assess due to underreporting.

Race: Some ethnic groups are more likely to utilize herbal preparations. One survey in a New York urban hospital showed overall herbal use to be 27% and highest (36%) among the Asian population.

CLINICAL

Section 3 of 11

History: The following questions are necessary to ascertain specific history:

• Was the herbal preparation collected or purchased? Where?

• What does the product purportedly contain? Is there a container, label, or picture of the product?

• Were other individuals exposed and affected?

• How recently and for what duration has the product been used by the patient?

• For what purpose was the herbal product acquired? To treat what condition?

Physical: Evaluate the patient for possible toxidromes such as anticholinergic syndromes or those consistent with cardiac glycosides or heavy metal poisonings.

• Anticholinergic syndromes (ie, mydriasis, dry mucous membranes and axilla, urinary retention, tachycardia, disorientation, hallucinations)

• Cardiac dysrhythmias (suspect cardiac glycoside or aconite toxicity)

• Hepatomegaly and jaundice (suspect pyrrolizidine alkaloids and herbal teas)

Causes: Adverse effects from herbal preparations can be categorized by type.

• One schema divides reactions into the following 4 types:

• Type A - Pharmacologically predictable, dose dependent, and preventable by dose reduction

• Type B - Idiosyncratic, pharmacologically unpredictable, toxicity not correlated with dose, often immunologically mediated, often serious and potentially fatal

• Type C - Developed over long-term therapy, well-described, and may be anticipated

• Type D - Delayed effects (eg, carcinogenicity, teratogenicity)

• Another schema divides reactions as follows:

• Allergic reactions

• Toxic reactions

• Adverse effects related to desired pharmacologic actions

• Mutagenic effects

• Drug interactions

• Contamination

• Mistaken plants

DIFFERENTIALS

Section 4 of 11

Anaphylaxis
Cholangitis
Cholecystitis and Biliary Colic
Cholelithiasis
Depression and Suicide
Encephalitis
Gastroenteritis
Glomerulonephritis, Acute
Heart Block, First Degree
Heart Block, Second Degree
Heart Block, Third Degree
Hepatitis
Hyperkalemia
Hypertensive Emergencies
Hypokalemia
Idiopathic Thrombocytopenic Purpura
Meningitis
Munchausen Syndrome
Munchausen Syndrome by Proxy
Pediatrics, Anaphylaxis
Pediatrics, Child Abuse
Pediatrics, Gastroenteritis
Pediatrics, Meningitis and Encephalitis
Pediatrics, Reactive Airway Disease
Pediatrics, Reye Syndrome
Pediatrics, Sudden Infant Death Syndrome
Plant Poisoning, Glycosides - Cardiac
Plant Poisoning, Glycosides - Coumarin
Plant Poisoning, Hypoglycemics
Plant Poisoning, Licorice
Plant Poisoning, Oxalates
Plant Poisoning, Phytophototoxins
Premature Ventricular Contraction
Renal Failure, Acute
Rhabdomyolysis
Toxicity, Mushroom - Amatoxin
Toxicity, Mushroom - Gyromitra Toxin
Toxicity, Mushroom - Hallucinogens
Toxicity, Mushroom - Orellanine

WORKUP

Section 5 of 11

Lab Studies:

• 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:

• Complete blood count (CBC)

• Electrolyte level

• Blood urea nitrogen (BUN) level

• Creatinine level

• Glucose level

• Liver function tests (LFTs)

• Electrocardiogram (ECG)

• Urinalysis

• Urine and serum toxicologic screens (including aspirin and acetaminophen levels)

• Pregnancy tests

• Evaluate serum digoxin levels with exposure to plants containing cardiac glycosides, such as Digitalis lanata. Serum digoxin levels in these circumstances only reflect exposure and do not correlate with toxicity (see Plant Poisoning, Glycosides - Cardiac).

• A proper history of which herbal products the patient takes is also vital if performing therapeutic drug monitoring (ie, checking digoxin levels to determine if 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 (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 Toxicity, Lead; Toxicity, Arsenic; Toxicity, Mercury; Toxicity, Heavy Metals).

Imaging Studies:

• 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.

Procedures:

• Consider a lumbar puncture for patients with altered mental status of unclear etiology, especially if febrile or with nuchal rigidity.

• Consider endotracheal intubation for airway protection.

TREATMENT

Section 6 of 11

Prehospital Care:

• Supportive care, with consideration to airway, breathing, and circulation, is essential.

• Stabilize airway, assess for respirations, and initiate respiratory assistance as needed.

• Assess blood pressure and pulse; initiate advanced cardiac life support (ACLS) resuscitation if needed.

Emergency Department Care:

• Supportive care, ACLS, and decontamination protocols are recommended.

• Specific treatments depend on the substance or substances ingested but can include specific antidotes for suspected cardiac glycoside toxicity (see Plant Poisoning, Glycosides - Cardiac), N-acetylcysteine (ie, Mucomyst) for hepatotoxicity from pennyroyal oil, or specific agents for heavy metal poisonings (see Toxicity, Lead; Toxicity, Arsenic; Toxicity, Mercury; Toxicity, Heavy Metals).

Consultations: Consider consultation with a poison control center and medical toxicologist. They may know of recent similar case presentations in the area and assist with management.

MEDICATION

Section 7 of 11

For toxic ingestions in general, consider activated charcoal. Other care should be based on patient's symptomatology.

Drug Category: GI decontamination -- These agents are used empirically to adsorb toxin in GI tract, thereby limiting systemic absorption. They are 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 and remove it from the body.

Drug Name	Activated charcoal (Liqui-Char) -- Emergency treatment in poisoning caused by drugs and chemicals. Network of pores present in activated charcoal adsorbs 100-1000 mg of drug per gram of charcoal. Does not dissolve in water. For maximum effect, administer within 30 min of ingesting poison. Avoid sorbitol-containing products in pediatric patients, since electrolyte and fluid disturbances may occur.
Adult Dose	1 g/kg PO; 240 mL of diluent/30 g
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity; poisoning or overdosage of mineral acids and alkalies
Interactions	May inactivate ipecac syrup if used concomitantly; effectiveness of other medications decreases with coadministration; do not mix charcoal with sherbet, milk, or ice cream (decreases adsorptive properties)
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Not very effective in poisonings of ethanol, methanol, and iron salts; do not induce emesis before administering; emesis with ipecac is not necessary, patient may not tolerate activated charcoal for 1-2 h; can administer in early stages of gastric lavage; without sorbitol, gastric lavage returns are black; aspiration risk; monitor for presence of bowel sounds before administration to minimize risk of charcoal ileus; consider NG tube and ET airway protection in decreased mental status

FOLLOW-UP

Section 8 of 11

Further Inpatient Care:

• Further follow-up care depends on the material ingestion, amount of ingestion, and effects on the individual.

Patient Education:

• Educate patients on risks of various herbal products.

• For excellent patient education resources, visit eMedicine's Poisoning Center and Poisoning - First Aid and Emergency Center. Also, see eMedicine's patient education articles Food Poisoning, Wilderness: Poisons, and Activated Charcoal.

MISCELLANEOUS

Section 9 of 11

Medical/Legal Pitfalls:

• Failure to ask patients about use of herbs and herbal products

• Failure to report drug interactions or any herbal poisonings to the FDA for further investigation. (The Web site can be viewed at MedWatch. Their telephone number is 1-800-FDA-1088.)

• Failure to consult the local poison control center or medical toxicologist when dealing with a poisoning or exposure.

TEST QUESTIONS

Section 10 of 11

CME Question 1: Which of the following may be responsible for harmful effects of herbal preparations?

A: Allergic reaction to an ingredient of the preparation
B: Ingestion of a mistaken plant
C: Contamination of herbal preparation with a toxic substance
D: Interaction of herbal preparation with other medications
E: All of the above are correct.

The correct answer is E: Adverse effects of herbal preparations can be due to allergic reactions, toxic reactions, mutagenic effects, ingestion of mistaken plants, drug interactions, and contaminants.

CME Question 2: Which of the following questions should be considered when evaluating an individual with a possible reaction to an herbal preparation?

A: Where did you obtain the product?
B: How recently and for how long have you taken this product?
C: Do you have a sample of the substance for evaluation?
D: Were other individuals exposed and affected?
E: All of the above are correct.

The correct answer is E: All of the above questions should be considered when evaluating an individual with a possible reaction to an herbal preparation.

Pearl Question 1 (T/F): Herbal preparations are homogenous substances.

The correct answer is False: Generally many different plants and other substances can be found in herbal products. Substances found in the product may differ from ingredients listed on the container.

Pearl Question 2 (T/F): Reactions to an herbal product can be life threatening.

The correct answer is True: Both immediate and delayed reactions may be life threatening. Herbal products can cause significant allergic reactions, toxic reactions, and pharmacologic reactions.

Pearl Question 3 (T/F): Acute liver failure is associated with germander.

The correct answer is True: Germander has been used as a slimming aid in France and Canada and has resulted in significant hepatic toxicity.

Pearl Question 4 (T/F): Herbal and other plant-derived remedies are frequently used.

The correct answer is True: The World Health Organization estimates that herbal and other plant-derived remedies are the most frequently used therapies worldwide.

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Section 11 of 11

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