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CHAPTER 164 Plants, Mushrooms, and Herbal Medications Richard D. Shih PERSPECTIVE BOTANICAL IDENTIFICATION Botanicals such as plants, herbal products, and mushrooms have a long-standing and important place in medical history. Their use as therapeutic agents has been documented in the earliest of medical writings. The extraction of alkaloids from the opium poppy in the 1800s was a forerunner of modern pharmacology. The general public increasingly is using herbal products for medicinal purposes. Despite the tremendous growth in popularity of herbal products, data on herbal efficacy and toxicity are limited. This chapter focuses not on the medicinal use of natural products but rather on the toxicology related to their exposure or utility. Identification of the botanical in question is most useful, but most patients and medical professionals do not have enough knowledge of botany or plant identification. The name of the plant or mushroom is often confusing because the scientific name is not typically known, and common names often overlap. Most emergency department personnel cannot identify common plants, such as mistletoe, holly berries, philodendron, and others. Several resources may be helpful, including plant atlases, CD-ROM plant databases, a local botanical expert, botanical garden personnel, or a poison center. Alternatively, a digital photograph of the plant or mushroom in question can be quickly e-mailed to a local expert to aid in identification.5 With herbal products, the product name or herbal plant may be known. Because of the limited Food and Drug Administration (FDA) regulation, however, the purported herb might have been harvested from the wrong plant or contaminated with other toxic material. Epidemiology Although plants, mushrooms, and herbal products are derived naturally, they have different but predictable exposure patterns and epidemiology. Ingestions fall into three common exposure patterns. Unintentional Childhood Exposure Unintentional childhood exposure occurs most commonly with plants. Approximately 5% of all poison center calls involve plants. Of these, about 80% involve children younger than 5 years. Most of these cases involve household plants with a limited amount of plant material or toxin ingested, resulting in little or no toxicity.1,2 Misidentification of Botanical Natural plant and mushroom gathering for personal food ingestion is a popular activity. Mistakes while foraging commonly occur, with the potential for serious toxicity and death. In contrast to unintentional childhood exposures, foraging accidents by adults usually involve the eating of plants or mushrooms and are associated with a much larger toxin burden because a larger quantity of the botanical is ingested. Another type of botanical misidentification occurs with herbal products when plants used for herbal manufacture are misidentified by the manufacturer and incorrectly packaged and marketed. Plants as Drugs of Abuse Many plants, mushrooms, and herbals are used and abused for their mind-altering potential. These include hallucinogenic mushrooms, peyote, kava kava, and anticholinergic plants such as jimsonweed.3,4 2066 Plants Among more than 60,000 plant exposures reported to U.S. poison centers annually, most plant exposures occur in children (younger than 5 years) and involve household plants. Hospitalization for plant poisoning is rare, and fatalities occur in less than one in 10,000 exposures. Of thousands of different plant species, only a few are dangerously toxic.1,2,6 Following is a more detailed discussion of specific plants focusing on plants that are most poisonous or most commonly implicated in human exposures.1,6 Abrus precatorius Abrus precatorius (Fig. 164-1), known by several different common names (jequirity pea, rosary pea, prayer bean, Seminole bean, Indian bean, and crab’s eye), contains the toxin abrin, which affects protein synthesis, leading to cell death. The toxin is found in highest concentration in the seeds, which are used in jewelry or decoration. Because of their attractiveness, the seeds are often ingested by children. The hard, shiny coat causes most seeds to pass through the gastrointestinal tract without being digested. If the seeds are chewed or do not pass through the bowel rapidly and become digested, abrin is released, causing nausea, vomiting, and abdominal pain, which can be severe, and fluid and electrolyte balance is disturbed.7-11 Systemic absorption of the toxin is limited because the protein is enzymatically digested in the gastrointestinal tract. Rare parenteral exposure of small amounts is associated with severe toxicity and possible death. Treatment is supportive, with attention to fluid rehydration and electrolytes. Symptomatic Chapter 164 / Plants, Mushrooms, and Herbal Medications 2067 Figure 164-2. Cicuta maculata (water hemlock). (Courtesy Steven Setzer.) Figure 164-1. Abrus precatorius (jequirity pea or rosary pea). (Courtesy Steven Setzer.) patients should be given activated charcoal to absorb leaking abrin, and whole-bowel irrigation has not been studied but may help in moving numerous seeds more rapidly through the gastrointestinal tract. Brassaia The Brassaia is a popular indoor plant known as schefflera, umbrella tree, Australian umbrella tree, dwarf schefflera, rubber tree, and starleaf. This plant contains calcium oxalate crystals, which can cause mouth pain, but most ingestions cause mild or no symptoms. Capsicum annum Capsicum annum includes many types of peppers (e.g., chili pepper, red pepper, bell pepper) and contains the active toxin capsaicin. This alkaloid releases and depletes selected nerve terminals of substance P, causing a severe local inflammatory response manifested by swelling, fluid exudation, and pain, which resolves rapidly as capsaicin depletes substance P. Capsaicin is not absorbed well through intact skin, but rarely symptoms can occur with prolonged and intense exposure.12 Ingestions often cause gastrointestinal symptoms, depending on the amount of toxin exposure. Most capsaicin exposures are from a pepper spray product, causing chemical conjunctivitis. Keratitis can occur and is assessed with fluorescein. Treatment consists of local irrigation and analgesics. Despite their often dramatic appearance, cases resolve rapidly during several hours without sequelae.13-15 Use of topical antacids may be effective for dermal exposures. Inhalation of capsaicincontaining powders is less common but can cause severe pulmonary exudation, potential acute respiratory distress syndrome, and death.16 Treatment is supportive, but extracorporeal membrane oxygenation has been used in children who have acute respiratory distress syndrome. Cicuta maculata Cicuta maculata (Fig. 164-2), commonly known as water hemlock, contains the potent neurotoxin cicutoxin.17 Deaths from water hemlock are among the most commonly reported plant fatalities in the United States. Water hemlock has small white flowers at the ends of umbrella-like stems. They resemble Daucus carota (Queen Anne’s lace) and Heracleum lanatum (cow parsnip). The mistaking of water hemlock for one of these edible plants is a common cause of exposure.18 Ingestion of any part of the plant can lead to nausea, vomiting, and abdominal cramping. Severe toxicity is manifested by seizures occurring within the first hour, which often are intractable and are a common cause of death. The toxic mechanism may be due to γ-aminobutyric acid (GABA) receptor antagonism. The ingestion is highly toxic and may be fatal. Seizures are common and are initially treated with benzodiazepines (i.e., lorazepam, 1-2 mg intravenously). If response is poor, treatment is as described for status epilepticus in Chapter 102. Because of the severe toxicity and lack of effective antidote, activated charcoal may be useful. Consultation with a regional poison center may be useful in individual cases. Conium maculatum Conium maculatum (Fig. 164-3), or poison hemlock, was purported to be used in the execution of Socrates. It is mistaken for several edible plants, such as Daucus carota (Queen Anne’s lace), Foeniculum vulgare (sweet fennel), and Heracleum lanatum (cow parsnip).19 Poison hemlock contains the toxin coniine, which is similar to nicotine in structure and toxicity. The clinical picture and management resemble those of tobacco poisoning (see section on Nicotiana tabacum).20,21 Datura stramonium Datura stramonium (jimsonweed) (Fig. 164-4) is one of numerous plants with alkaloids that have anticholinergic effects (see Chapter 150). The fruit is spiny and when opened contains 50 to 100 black seeds. All parts (including the seeds) contain the toxins atropine, hyoscyamine, and scopolamine, which are potent anticholinergic agents.22,23 One hundred seeds approximate 6 mg of atropine. 2068 PART IV ◆ Environment and Toxicology / Section Two • Toxicology Figure 164-3. Conium maculatum (poison hemlock). (Courtesy Steven Setzer.) Figure 164-5. Dieffenbachia. (Courtesy Steven Setzer.) plant parts are chewed.33,34 Because of the immediate pain, further exposure typically is limited. Treatment is aimed at pain relief and local supportive measures, typified by feeding of ice cream to a symptomatic infant. Analgesics such as nonsteroidal antiinflammatory drugs or opioids may be needed for pain. Epipremnum aureum Epipremnum aureum is a common household plant also known as pothos ivy, devil’s ivy, hunter’s robe, and golden pothos. Toxicity is due to calcium oxalate crystals,6 the same toxin found in the Dieffenbachia, and the toxicity and treatment are similar. Figure 164-4. Datura stramonium (jimsonweed). (Courtesy Steven Setzer.) Exposures are most commonly a result of abuse for hallucinogenic effects, usually by smoking of dried leaves or ingestion of the seeds.24-26 The clinical picture is that of the anticholinergic toxidrome.27,28 The symptoms can last for several days if the overdose is due to ingestion of seeds. It is unclear if activated charcoal and gastric emptying measures are effective at decreasing the course of toxicity and are not routinely recommended. Consultation with a regional poison center may be useful in individual cases.24 Treatment is as for anticholinergic poisoning29,30 (see Chapter 150). Dieffenbachia Dieffenbachia (Fig. 164-5) has more than 30 different common names, including dumb cane, mother-in-law’s tongue, dumb plant, and tuft root. Some of these names refer to the inability to talk that can occur after biting into parts of this plant. Typically, the mucous membranes of the mouth are affected immediately with severe pain, swelling, and the sensation of biting into glass. Most cases are limited to the mucous membranes of the oropharynx, but rare cases of airway compromise have been reported.31 The local effects are due to calcium oxalate crystals, packaged into bundles called raphides, that are found in cellular structures called idioblasts.32 These idioblasts also contain proteolytic enzymes that are ejected out of the idioblasts with the oxalate crystals when Eucalyptus Eucalyptus plants have common names, such as the silver dollar, lemon-scented gum, cider gum, and blue gum. These plants are not toxic but are implicated in frequent plant exposures.35 The plants are used, however, to produce concentrated (approximately 70%) eucalyptus oil. Ingestion of small amounts (1-3 mL) has been reported to cause severe toxicity.36 The predominant symptoms are neurologic, including mental status alteration, headache, ataxia, and seizures. Treatment of severe toxicity is symptomatic supportive, except for seizures, which are treated as described in Chapter 102. Euphorbia pulcherrima Euphorbia pulcherrima (poinsettia) is a popular ornamental plant that is frequently implicated in plant exposures. It has a false reputation for being extremely poisonous. Ingestions are benign or cause minimal toxicity. However, contact dermatitis is relatively common with skin exposure and can be treated with steroids or antihistamines. Further discussion is found in Chapter 120. Ilex Ilex (holly) contains more than 400 different species and is frequently implicated in plant exposures. The plant’s red and black berries are attractive to children and contain numerous toxins that are potent gastrointestinal irritants. Symptoms include nausea, vomiting, abdominal cramping, and diarrhea. Treatment is supportive and may require intravenous fluids and antiemetics. Chapter 164 / Plants, Mushrooms, and Herbal Medications 2069 Figure 164-6. Nerium oleander. (Courtesy of Steven Setzer.) Figure 164-7. Phytolacca americana (pokeweed). (Courtesy Steven Setzer.) Nerium oleander Nerium oleander (Fig. 164-6), or oleander, is one of many plants that contain toxic cardiac glycosides37,38 structurally similar to digoxin. Ingestion of several leaves is unlikely to cause serious symptoms.39,40 Large exposures from suicide attempts or misidentification of plants used for teas or herbal products can lead to severe toxicity or death. The cardiac glycosides are potent sodiumpotassium–adenosine triphosphatase inhibitors, and the symptoms they cause are similar to those of digoxin poisoning (see Chapter 152). Measurement of an abnormal digoxin level is only qualitative proof of exposure because the serum digoxin test can falsely measure nondigoxin cardiac glycosides. Conversely, a normal digoxin measurement does not rule out exposure because the level of cardiac glycoside cross-reactivity varies. Treatment of dysrhythmias and hypotension includes multidose activated charcoal (50 g every 6 hours for 3 days) and digoxin-specific Fab antibodies (see Chapter 152).39-44 However, larger doses of Fab fragments generally are needed than for comparable digoxin poisonings. The initial empirical dose of digoxin-specific Fab fragments is 10 vials. If response to therapy is poor, repeated administration of an additional 10 vials is recommended. Nicotiana tabacum Nicotiana tabacum is widely grown in the southeastern United States as a source for cigarette and cigar tobacco. Several Nicotiana species contain nicotine as their major toxin, which activates and subsequently blocks acetylcholine receptors in the central nervous system (CNS) and peripheral autonomic nervous system. Most exposures are the ingestion of cigarettes or cigars by young children. Dermal exposure to workers harvesting plants and ingestion of wild plants mistaken for edible plants also have led to poisoning.45,46 The ingestion of one or two cigarettes has the potential to cause moderate poisoning in children, but most children ingesting cigarettes do not manifest toxicity. Patients without nausea and vomiting do not seem to progress to more severe toxicity.47 Dermal exposure in tobacco workers has been called green tobacco sickness.48 Nicotine is absorbed through the skin and occurs most severely when the skin or plant is wet. Exposure can be avoided by wearing of proper protective equipment. Symptoms begin shortly after absorption. Nausea, vomiting, salivation, lacrimation, diarrhea, hypertension, tachycardia, diaphoresis, agitation, and fasciculation are seen initially. More severe toxicity is manifested by seizures, respiratory depression (muscle weakness), and hyperthermia.49 Activated charcoal may be useful to limit absorption. Other treatments are supportive in nature because no specific antidote for nicotine is available. If seizures occur, initial treatment is with a benzodiazepine (i.e., lorazepam, 1-2 mg intravenously). If response is poor, treatment is as described for status epilepticus in Chapter 102. If severe salivation and lacrimation occur, atropine in 1-mg doses may be repeated until symptoms improve. Phytolacca americana Found in the eastern United States, Phytolacca americana (Fig. 164-7) is commonly known as pokeweed, poke, pokeberry, inkberry, scoke, American cancer, garget, phytolacca, and pigeonberry. Although the plant is poisonous, it can be detoxified by boiling it in water twice before use in salads or other recipes. Toxicity is seen when the plant is inadequately detoxified or raw parts of the plant are eaten.50 Symptoms begin shortly after ingestion and include severe nausea, vomiting, abdominal cramping, and diarrhea. Treatment is supportive. Pyracantha Pyracantha, commonly known as the firethorn, has small red, orange, or yellow fruit attractive to and commonly ingested by children. The plant is not toxic, but the thorny parts can penetrate skin deeply and may be difficult to remove. Rhododendron Rhododendron includes more than 1000 species of azaleas and rhododendrons, including mountain laurel, dwarf laurel, rose bay, western Labrador tea, and Japanese pieris. Numerous structurally related toxins (diterpene polyalcohols) have been identified from these plants, including grayanotoxin, rhodojaponin, asebotoxin, and others.51-53 These toxins bind to sodium channels and increase 2070 PART IV ◆ Environment and Toxicology / Section Two • Toxicology Figure 164-8. Taxus (yew). (Courtesy Steven Setzer.) permeability (sodium channel openers), causing cardiovascular (e.g., bradycardia and hypotension) and gastrointestinal (e.g., nausea, vomiting, and abdominal pain) effects. Although ingestion of a few leaves is unlikely to cause symptoms, larger exposures can cause severe toxicity. In addition, these plant toxins can be concentrated in honey, so large honey ingestions, “mad honey,” can also lead to toxicity.52,54 However, no deaths have been reported. Treatment is supportive; atropine and cardiac pacing are used for bradycardia. For ventricular dysrhythmias, sodium channel– blocking agents, such as quinidine and procainamide, are used. However, limited efficacy data are available for these therapies. If response is poor, treatment with standard advanced cardiovascular life support (ACLS) protocol is warranted. Spathiphyllum Spathiphyllum includes the peace lily, Mauna Loa, white anthurium, and snowflower. These plants contain calcium oxalates and have toxicity and treatment similar to those of Dieffenbachia. Taxus Taxus (yew trees) (Fig. 164-8) have a hard seed surrounded by a fleshy red cup (the aril). The aril portion is not poisonous, and the seed has a hard coat that limits toxin release in the gastrointestinal tract so that most ingestions are nontoxic. If the seed is chewed or leaves are ingested, cardiac (e.g., bradycardia and hypotension) and gastrointestinal (e.g., nausea, vomiting, and abdominal pain) symptoms may occur. Deaths from this plant have been reported, usually in the setting of a suicide and secondary to cardiac manifestations. Bradycardia is treated with atropine. Wide-complex tachydysrhythmias are not responsive to sodium bicarbonate and should be treated per standard ACLS guidelines.55,56 HERBAL MEDICINES Herbal products have gained an extraordinary amount of popularity in the past several decades. Although the highest use is among immigrants and patients with difficult-to-treat diseases, such as advanced cancer and acquired immunodeficiency syndrome (AIDS), these products are used by approximately 30% of the general population.57-59 Consumers often perceive herbals as more “natural” and thus “safer” and “harmless” despite many examples of toxicity associated with their use. This is coupled with medical practitioners’ having limited knowledge about herbal medications. In addition, herbals are widely marketed as safe and effective, especially on the Internet.60 One study of pregnant patients documented 45% herbal medicine use during some point of the pregnancy.61 Emergency department patients are also frequent users of herbal products.62-64 Herbal products are classified as dietary supplements and are not regulated as medications, even though they are used for their medicinal value.58,64,65 Regulation of dietary supplements is limited. Safety, quality, and efficacy for medicines are the responsibility of manufacturers. For herbal products used as dietary supplements, of which there are thousands to hundreds of thousands of potential products, the burden of proving efficacy and safety lies with the FDA.65-68 Studies looking at the efficacy of herbal products are limited, with few randomized, controlled studies. The National Institutes of Health sponsored several high-profile randomized placebocontrolled studies assessing the efficacy of several well-known herbals: St. John’s wort for depression, hawthorne extract for congestive heart failure, echinacea for the common cold, glucosamine– chondroitin sulfate for arthritis of the knee, saw palmetto for benign prostatic hypertrophy, and ginko biloba for dementia onset. Unfortunately, none of these trials has shown the herbal treatment to be effective.69-74 In addition, herbal manufacturers are not required to conduct efficacy studies. Studies evaluating side effects, drug interactions, and toxicity are even less available. Most herbal products have some direct pharmacologic action. The potency of these agents is usually limited, however. As a result, toxicity and side effects from the direct actions of herbal products are relatively uncommon.69-76 The lack of manufacturing quality control accounts for most toxicologic problems associated with their use. Four major types of toxicologic problems are associated with herbal product use: the misidentification of an herbal plant and toxicity resulting from a substituted plant, contamination with nonherbal toxic material, direct toxicity or overdose of the herbal product (Table 164-1), and drug-herbal interaction (Table 164-2).77 Misidentification of Herbal Plants Incorrect plant identification and subsequent use in the production of herbal products have occurred on numerous occasions, leading to epidemic exposures with tragic outcomes. The following examples illustrate this problem. Herbal Slimming Regimen, 1992 During the early 1990s, the Chinese herb Stephania tetrandra was used for weight loss in Belgium. More than 100 cases of renal failure and many cases of urethral dysplasia resulted from toxicity of this herbal regimen. It was discovered that Aristolochia fangchi, which contains the nephrotoxin aristolochic acid, was mistakenly used instead of S. tetrandra.78-81 Paraguay Tea, 1994 The South American herbal tea Paraguay tea is made from Ilex paraguariensis, used for urinary tract infections, cardiac insufficiency, and “lack of stamina.” In 1994, several individuals had anticholinergic poisoning from Paraguay tea after the manufacturer had purchased and mistakenly used other plant materials containing the belladonna alkaloids atropine, scopolamine, and hyoscyamine directly from farmers before packaging.82 Digitalis lanata, 1997 An herbal dietary supplement used for “internal cleansing” contained 14 herbal ingredients. Two patients had complete heart Chapter 164 / Plants, Mushrooms, and Herbal Medications 2071 Table 164-1 Common Herbal Medications and Adverse Effects HERBAL NAME BOTANICAL NAME USES ADVERSE EFFECT Bee pollen Apis mellifera General tonic Allergic reactions Betel nut Areca catechu Stimulant Bronchospasm Blue cohosh Caulophyllum thalictroides Menstrual cramps Nicotinic effects Astringent, wounds Dermatitis, GI, hepatic, renal, CNS Boron Buckthorn Rhamnus frangula Laxative Diarrhea Cantharidin Cantharis Aphrodisiac GI, dermatitis, renal Cat’s claw Uncaria tomentosa AIDS, cancer, arthritis None reported Chamomile Matricaria chamomilla Fever, cough, colds, wounds Allergic reactions Chaparral Larrea tridentata Cancer, aging, general tonic Hepatotoxicity Comfrey Symphytum officinale Contusions and sprains Hepatotoxicity Compound Q Trichosanthes kirilowii AIDS Pulmonary, CNS Dandelion Taraxacum officinale Diuretic, appetite stimulant None reported Dong quai Angelica polymorpha Blood purifier, increase circulation Anticoagulation, dermatitis Echinacea Echinacea purpurea Common cold Fever, nausea and vomiting Ephedra Ephedra spp. Stimulant, asthma Hypertension, tachycardia, CNS, MI Fennel Foeniculum vulgare GI illnesses, cough Allergic reactions Fenugreek Trigonella foenumgraecum Expectorant, anti-inflammatory None reported Feverfew Tanacetum parthenium Migraines, antipyretic Post-feverfew syndrome, rebound migraine Garlic Allium sativum Infection, CAD, hypertension Dermatitis, GI Germander Teucrium chamaedrys Gout, fever, dietary aid Hepatotoxicity Ginger Zingiber officinale Motion sickness, GI illness None reported Ginkgo Ginkgo biloba General tonic, depression, anxiety, memory GI effects, bleeding effects, drug interactions Ginseng Panax ginseng General tonic, depression, stress, anxiety, fatigue Ginseng abuse syndrome Arthritis None reported Glucosamine Goldenseal Hydrastis canadensis Cutaneous wounds GI, CNS, and pulmonary effects in overdose Gordolobo yerba Senecio longiloba URI, fever Budd-Chiari syndrome Henbane Hyoscyamus niger Sedative, GI discomfort Anticholinergic toxicity Jimsonweed Datura stramonium Asthma Anticholinergic toxicity Juniper Juniperus communis UTI, kidney stones, appetite Renal toxicity Kava kava Piper methysticum Sedative, aphrodisiac Euphoria, CNS Kumbucha Cancer, memory loss None reported Larkspur Delphinium consolida Diuretic, sedative Lethargy, muscle paralysis Licorice Glycyrrhiza glabra Cough, GI illnesses Hypokalemia, drug interactions Ma huang Ephedra sinica General tonic, common cold Sympathomimetic Mate Ilex paraguayensis Stimulant None reported Milk thistle Silybum marinum General tonic, GI disorders None reported Mistletoe Viscum album GI illness, cancer, HIV infection GI, bradycardia, CNS Nutmeg Myristica fragrans Aphrodisiac, hallucinogen CNS, GI Parsley Petroselinum crispum UTI, kidney stones Contact dermatitis Pennyroyal Mentha pulegium Abortifacient, GI illnesses Hepatotoxicity Rose hips Rosa canina URI, vitamin C None reported Rue Ruta graveolens Menstrual disorders Contact dermatitis, GI and CNS effects in overdose Sage Salvia officinalis Antiseptic, wounds Absinthism St. John’s Wort Hypericum perforatum Depression, anxiety Drug interactions Sassafras Sassafras albidum GI stimulant Liver, carcinogen Saw palmetto Serenoa repens Benign prostatic hypertrophy GI effects Continued 2072 PART IV ◆ Environment and Toxicology / Section Two • Toxicology Table 164-1 Common Herbal Medications and Adverse Effects—cont’d HERBAL NAME BOTANICAL NAME USES ADVERSE EFFECT Scullcap Scutellaria lateriflora Nervous disorders, bitter tonic Hepatotoxicity Shepherd’s purse Capsella bursa pastoris Hypertension, CHF, headaches, menstrual disorders None reported Siberian ginseng Eleutherococcus senticosus General tonic None reported Soy Glycine max Menopause, CAD Carcinogen Tonka bean Dipteryx odorata Whooping cough Anticoagulant effect T’u-san-chi Gynura segetum Stimulant tea Budd-Chiari syndrome Valerian Valeriana officinalis Sleep, anxiety, general tonic Hepatotoxicity Woodruff Galium odorata Diuretic, anxiety, menstrual disorders Anticoagulant effect, CNS effects, hepatotoxicity Wormwood Artemisia cina Worm infection, anxiety Seizures, CNS effects Yarrow Achillea millefolium Poor appetite, GI illnesses Allergic reactions Yew Taxus baccata GI illness, cancer Dizziness, bradycardia Yohimbine Pausinystalia yohimbe Sexual disorders, aphrodisiac Hypertension, agitation, CNS effects CAD, coronary artery disease; CHF, congestive heart failure; CNS, central nervous system; GI, gastrointestinal; MI, myocardial infarction; URI, upper respiratory infection; UTI, urinary tract infection. Table 164-2 Common Herbal-Drug Interactions HERBAL DRUG TYPE OF INTERACTION Betel nut Fluphenazine Prednisone and salbutamol Extrapyramidal effects Bronchospasm Boldo Warfarin Increased INR Chili pepper ACE inhibitors Theophylline Cough Increased drug absorption Curbicin Warfarin Increased INR D-400 Oral hypoglycemics Increased drug concentration and decreased serum glucose Danshen Warfarin Increased INR Devil’s claw Warfarin Increased INR Dong quai Warfarin Increased INR Fenugreek Warfarin Increased INR Garlic Warfarin Increased INR Ginkgo Aspirin Blood thinners Thiazide diuretics Warfarin Increased platelet inhibition Bleeding side effects Hypertension Increased INR Ginseng Warfarin Ethanol Decreased INR Increased ethanol clearance Green tea Warfarin Decreased INR Guar gum Many drugs Digoxin Decreased absorption of drug Decreased drug concentration Karela Chlorpropamide Decreased serum glucose Licorice Oral contraceptives Prednisolone Antihypertensives Hypertension, edema, hypokalemia Alteration of pharmacokinetics Hypokalemia Lycium Warfarin Increased INR Ma huang Guanethidine MAO inhibitors Sympathomimetic effects Sympathomimetic effects Mango Warfarin Increased INR Oat bran Lovastatin Decreased drug concentration Papaya Warfarin Increased INR Chapter 164 / Plants, Mushrooms, and Herbal Medications 2073 Table 164-2 Common Herbal-Drug Interactions—cont’d HERBAL DRUG TYPE OF INTERACTION PC-SPES Warfarin Increased INR Pectin Lovastatin Decreased drug concentration Psyllium Lithium Decreased drug concentration St. John’s wort Selective serotonin reuptake inhibitors Theophylline Digoxin Cyclosporine Indinavir Irinotecan Nevirapine Oral contraceptives Simvastatin Warfarin Serotonin syndrome Decreased drug concentration Decreased drug concentration Decreased drug concentration Decreased drug concentration Decreased drug concentration Decreased drug concentration Decreased drug concentration Decreased drug concentration Decreased INR Siberian ginseng Digoxin Increased digoxin levels Soy Warfarin Decreased INR Tamarind Aspirin Increased drug absorption Wheat bran Digoxin Decreased drug concentration Yohimbine Tricyclic antidepressants Hypertension ACE, angiotensin-converting enzyme; INR, international normalized ratio; MAO, monoamine oxidase. block because one of the herbal ingredients, plantain, contained Digitalis lanata (a cardiac glycoside–containing plant).83 Dandelion Salad, 2004 Dandelion is a commonly ingested herb used as an appetite stimulant and diuretic. Many users grow and harvest their own plants. A 53-year-old woman who had ingested some home-grown dandelion had persistent nausea, vomiting, and bradycardia with a heart rate between 30 and 40 beats/minute. Her bradycardia persisted for several days and had associated syncope. Her diagnosis was unclear until it was discovered that she had mistakenly harvested and ingested foxglove instead of dandelion.84 Contamination with Nonherbal Toxic Material Contamination with nonherbal toxic material as a mechanism of herbal toxicity may be due to contamination of the products at the time of manufacture or consumer fraud. Because of the limited FDA regulation of herbal manufacturers, one of the major risks of herbal use is the use of a product contaminated with a toxic substance. A study of Asian herbal patent medications sold in California found that 32% of these products were contaminated with heavy metals or undeclared pharmaceuticals.85 Lead, mercury, arsenic, cadmium, aluminum, tin, zinc, and copper have been found in herbal products.86-89 The most common undeclared pharmaceuticals include ephedrine, chlorpheniramine, methyltestosterone, and phenacetin.90 Metal shavings have been added to herbal preparations to increase selling price when the herbals are sold by weight. Some herbal products use the metal as an active ingredient with a purported medicinal benefit (e.g., lead in azarcon or mercury in cinnabar). Other cases involve contamination with the metals during the manufacturing process.89-91 Consumer fraud in the herbal industry has been well documented on numerous occasions. Typically, an FDA-controlled pharmaceutical product is mixed in with an herbal product, or the label did not list the pharmaceutical agent. Chuifong toukuwan, an herbal preparation, was associated with several cases of agranulocytosis. Analysis revealed that it contained phenylbutazone, indomethacin, and aminopyrine.92 Gan mao tong, an herbal product found to contain phenylbutazone, caused aplastic anemia.93 An undefined herbal preparation that was used “to avoid taking other medicine” was found to contain triamcinolone. A patient using the product for more than 1 year had several manifestations of steroid excess: thoracic compression fractures, proximal muscle weakness, and osteoporosis.94 Tung shueh, an herbal product that was found to contain mefenamic acid and diazepam, caused gastrointestinal bleeding and acute interstitial nephritis.95 Another herbal product was found to contain mefenamic acid, which caused acute renal failure necessitating hemodialysis. Dr. Tong Shap Yee’s asthma pills were found to contain theophylline.96 Leng Pui Kee herbal cough remedy was found to contain bromhexine.96 Direct Toxicity of Herbals and Herbal-Drug Interactions Some herbal preparations can cause allergic reactions ranging from contact dermatitis to anaphylactic shock (Box 164-1).97,98 Other herbal products are associated with uncommon idiosyncratic reactions, particularly hepatic toxicity (see Table 164-1).99-104 Herbal products are often taken in overdose. Not controlled by a prescription system, herbal medicines are seen as natural and safe so that “if one is good, then two or three is better.” Direct toxicity is often due to this overuse. Herbs associated with specific toxicities and side effects are listed in Table 164-1.89,96,98,105-107 Concurrent herbal and pharmaceutical use is common and can cause drug interactions. Of U.S. adults, 18% who take prescription medications also use an herbal or mineral supplement, and 60% who use alternative therapies are unlikely to report this to their physicians.108 Individuals often do not consider that herbs can potentially interact with conventional medicines, and serious drug reactions associated with an herbal product are less likely to be reported than are reactions that occur with a conventional medicine. Common herbal-drug interactions are listed in Table 164-2.109,110 2074 PART IV ◆ Environment and Toxicology / Section Two • Toxicology BOX 164-1 Herbals Associated with Allergic Reactions Agnus castus Angelica Aniseed Apricot Aristochol Arnica Artichoke Asafetida Balxum of Peru Bee pollen Bee venom Black cumin oil Boneset Camphor Capsaicin Cassia Cedar wood oil Celery Chamomile Chrysanthemum Cinnamon Cowslip Curcumin Dandelion Echinacea Elecampane Euphorbia Fennel Feverfew French marigold Fucus Garlic Gingko Gravel root Guaiacum Holy thistle Hops Hydrangea Hydrocotyle Inula helenium Jasmine Juniper Kava Lady’s slipper Lavender Mai-Men-Dong-Tang Meadowsweet Motherwort Paprika Parsley Peppermint oil Pilewort Plantain Pulsatilla Rosemary Rosewood Royal jelly Rue Slippery elm Tansy Tea tree oil Tung seed Wild carrot Yarrow Ylang-ylang Table 164-3 Mushroom Groups GROUP/TOXIN REPRESENTATIVE EXAMPLE CLINICAL EFFECTS Early Onset of Symptoms Coprine Coprinus atramentarius Disulfiram reaction with alcohol GI toxin Many species Nausea, vomiting, diarrhea, abdominal pain Ibotenic acid and muscimol Amanita muscaria Diverse CNS effects, including hallucinations, seizures, delirium, coma, agitation Muscarine Clitocybe dealbata Peripheral cholinergic toxidrome Psilocybin Psilocybe cubensis CNS effects, including hallucinations and euphoria Late Onset of Symptoms Cyclopeptides Amanita phalloides GI effects followed by hepatotoxicity Gyromitrin Gyromitra esculenta GI effects followed by seizures Orellanine Cortinarius orellanus GI effects followed by renal toxicity Allenic norleucine Amanita smithiana GI effects followed by renal toxicity CNS, central nervous system; GI, gastrointestinal. and management is most often used to identify the highest risk ingestions. MUSHROOMS Mushroom Groups U.S. poison center data estimate that five exposures take place for every 100,000 population per year. These exposures occur in three types of situations: ingestion of wild mushrooms by young children playing outdoors (which usually results in a small exposure), mistaken selection of poisonous mushrooms while foraging for edible wild mushrooms intended for a meal (which leads to a larger toxin exposure and most of the severe cases of mushroom poisoning, including deaths), and abuse of certain mushrooms for their mind-altering potential.3,4 Mushrooms of abuse typically involve a young population that often abuses other drugs. Most of these cases do not come to medical attention and often involve other substances added to the mushrooms. Despite the potential for severe toxicity and death, most exposures are relatively benign.2,111,112 Approximately 5% result in moderate poisoning, with only a few deaths reported per year. Ten general groupings have been found to be useful for clinical management (Table 164-3). These groups can be classified into mushrooms with early onset of symptoms (0-4 hours after ingestion), late onset of symptoms (<6 hours after ingestion), or no symptoms (edible). Mushrooms with serious toxicity and potential for death have late onset of symptoms. Particular attention should be paid to the timing of initial symptoms.113-115 Mushroom species often grow together, and foragers frequently pick and eat more than one species of mushroom so that the onset of early symptoms does not preclude the diagnosis of a more serious poisoning. Management of Mushroom Exposure The prognosis depends on the specific species. Identification of the mushroom is the most helpful factor in deciding on a treatment plan. Techniques for mushroom identification are described in most mycology and toxicology textbooks. Local mycologists or a poison center may be helpful. If a specimen is available, it can be stored in a paper bag at room temperature for delivery. Alternatively, a digital picture can be taken and e-mailed.5 Vomitus can be collected because mushroom parts may be recovered. Despite these measures, the species is unknown in more than 90% of ingestions. Because Amanita species are responsible for most deaths, a clinical strategy or algorithm for differential diagnosis Early Onset of Symptoms Gastrointestinal symptoms of nausea, vomiting, diarrhea, and abdominal cramps are common among many of the mushroom groupings (see Table 164-3). These symptoms are most predominant, however, in the gastrointestinal toxin group. This group contains numerous diverse mushrooms, many with unknown toxins. They cause symptoms rapidly (0.5-3 hours) after ingestion, and symptoms typically last 24 hours. Treatment is supportive, with good outcome expected. CNS effects are associated with two groups of mushrooms, ibotenic acid–muscimol and psilocybin.113,114 Psilocybin is structurally related to serotonin and lysergic acid diethylamide (LSD). Similar to LSD, hallucinations and CNS effects are prominent. This mushroom is most often used as a drug of abuse and is often obtained from Internet sources.3,4,116 Ibotenic acid and muscimol are toxins that are structurally related to glutamic acid and GABA. Chapter 164 / Plants, Mushrooms, and Herbal Medications 2075 Glutamic acid is an excitatory neurotransmitter, whereas GABA is an inhibitory one. Lethargy, hallucinations, seizures, or severe agitation begins within 1 to 2 hours after ingestion. Treatment of seizures and supportive care produce a good outcome. The cholinergic toxidrome is associated with muscarinecontaining mushrooms. Muscarine is structurally related to acetylcholine. Because of muscarine’s quaternary structure, it does not cross the blood-brain barrier. Symptoms include salivation, lacrimation, urination, defecation, gastroenteritis, and emesis (SLUDGE). Atropine can be used for severe symptoms. Pralidoxime is not indicated because acetylcholinesterase inhibition is not involved.117 The final mushroom group causes early onset of symptoms only with simultaneous ingestion of ethanol.118 These coprinecontaining mushrooms cause a disulfiram-like reaction by blocking acetaldehyde dehydrogenase. The symptoms include flushing, nausea, vomiting, and headache. The onset of this reaction associated with ethanol can occur 30 minutes to several days after mushroom ingestion. Treatment is supportive and similar to that of disulfiram reactions from other causes. Late Onset of Symptoms Four groups of mushrooms cause late onset of symptoms (>6 hours after ingestion): cyclopeptide, gyromitrin, orelline/ orellanine, and allenic norleucine. The orelline/orellanine-containing mushrooms are infrequently found in the United States, and there have not been any reported cases of toxicity in North America. The allenic norleucine–containing mushrooms have involved the Amanita smithiana mushroom located in the Pacific Northwest. Only a few cases (<20 total cases) have been reported and have typically involved individuals foraging from that area of the United States for the edible matsutake or pine mushroom (Tricholoma magnivelare). The main toxicity is delayed-onset renal failure. Gastrointestinal symptoms are frequently present and may be manifested early after ingestion. These symptoms typically subside, and patients present with renal symptoms 3 to 4 days after ingestion.119 The cyclopeptide group is responsible for most mushroom-related deaths in the United States. The cyclopeptide mushrooms contain many species, of which Amanita phalloides is the most well known.120 Several cyclopeptide toxins have been identified (e.g., amatoxins, virotoxins, phallotoxins) that are thought to be responsible for toxicity.121,122 Initial manifestations, such as severe nausea, vomiting, diarrhea, and abdominal cramping, begin 6 to 24 hours after ingestion. Hydration and supportive care often lead to initial relief of symptoms and a relatively quiescent period. Hepatic toxicity followed by other end-organ involvement may ensue in the next several days to weeks. Progressive elevation of hepatic transaminases, jaundice, and hepatic encephalopathy can lead to death.121 Many cases are misdiagnosed as gastroenteritis. Numerous noninvasive therapies have been suggested, including silibinin, silybin, thioctic acid, activated charcoal, high-dose penicillin, dexamethasone, vitamin C, cytochrome c, cimetidine, N-acetylcysteine, kutkin, and aucubin.122,123 None of these therapies has been rigorously tested in human-controlled studies. Multidose administration of activated charcoal seems to be reasonable because of its ability to bind the toxins and its availability and relative safety; however, its effectiveness is unclear. Numerous invasive therapies also have been proposed for use in cyclopeptide poisoning, including forced diuresis, hemodialysis, hemoperfusion, hemofiltration, plasmapheresis, and hepatic transplantation.124-127 Similar to the noninvasive modalities, it is not clear if any of these therapies are effective. There have been several reports of successful transplantation in severe cases of poisoning124-127; however, it is uncertain what criteria should be used for selection of candidates.127-130 Patients with severe hepatic signs and symptoms should be considered for transfer to a transplant center. Gyromitrin-containing mushrooms commonly are mistaken for edible mushrooms as they look like Morchella species (morel) mushrooms.131 The metabolites of this toxin cause GABA neurotransmitter depletion similar to isoniazid toxicity, leading to excitatory CNS effects, such as headaches, agitation, and seizures. Effects also include nausea, vomiting, and possible hepatotoxicity. The onset of symptoms is at least 6 hours after ingestion. Because of its similarity to isoniazid toxicity, pyridoxine has been proposed as an antidote. It is unclear how effective this antidote is, but it is useful for gyromitrin-induced CNS effects because of its availability and safety profile. Orelline/orellanine-containing mushrooms (Cortinarius genus) have been found in North America. There have been no reports of toxicity associated with cases in the United States, however, with most reported cases in Europe. Symptoms begin 1 to 2 days after ingestion, with nausea, vomiting, abdominal pain, and headache. Renal toxicity is manifested days to weeks after these initial symptoms and can progress to chronic renal failure.132,133 Disposition Initial management is aimed at ruling out of mushroom groups associated with early onset of symptoms. If the patient remains asymptomatic after a 3-hour period of observation, the patient should be discharged with instructions to return if any symptoms are manifested during the next 72 hours. KEY CONCEPTS ■ Plant exposures occur commonly in children and most commonly involve household plants. Most exposures cause little or no toxicity. ■ Plants and mushrooms are often ingested for their mindaltering properties. ■ Misidentification of plants and herbal products is a common cause of plant-induced and herbal product–induced toxicity. ■ Natural plant and mushroom gathering for personal ingestion is a popular activity. Mistakes while foraging occur commonly, with the potential for serious toxicity and numerous fatalities. ■ Herbal medicines increasingly are being used by the general public. Limited information is available about the efficacy and toxicity of these products. ■ In the assessment of a patient exposed to a mushroom, the timing of initial symptoms and the assessment for associated symptoms constitute the most important data needed to make a differential diagnosis. ■ A patient who has eaten or been exposed to a wild mushroom may have another medical condition actually responsible for the symptoms. 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