Selected herbal toxicities (Proceedings)

The regulation of herbs and other dietary supplements differs from most pharmaceutical drugs. In 1994, the Dietary Supplement and Health Education Act (DSHEA) was created. This act includes vitamins, minerals, neutraceuticals, and herbs. Under the DSHEA, supplement manufacturers are not required to prove efficacy, safety, and there are no mandated quality controls. The FDA can intervene if enough adverse reactions to a specific product occur, but the burden of proof is on the FDA to prove a particular product is harmful. Manufacturers are allowed to state what effect a product is expected to produce (such as the antidepressant effects produced by St. John's Wort) but the manufacturer can not claim a product specifically cures a stated effect. The label must include the statement that the claims have not been evaluated by the FDA.

Ma huang, Sida cordifolia, and citrus aurantium

Ma Huang is produced from Ephedra sinica, as well as other Ephedra species and herbs such as Sida cordifolia. Today, ma huang is frequently used as a weight-loss aid because of its stimulant properties and as a decongestant because it is vasoconstrictive. When used as a weight-loss aid, frequently caffeine-containing plants are included in the formulation, which can increase toxicity. Some formulations will list the quantity of ephedrine per unit of drug. Due to many recent reports of adverse effects of Ephedra species, more products are substituting Sida cordifolia and advertising the product as ephedrine free. Bitter orange usage is increasing in frequency as well, because it contains synephrine, instead of ephedrine.

The FDA has banned Ephedra containing substances, but did not specifically list the active constituents. Many people stockpiled their favorite products when the ban was announced, so Ephedra cases will continue. Products containing S. cordifolia and bitter orange cause the same clinical syndrome as those containing Ephedra.

Pharmacologically, ephedrine and pseudoephedrine are sympathomimetic alkaloids. The alkaloids stimulate alpha- and beta-adrenergic receptors, causing the release of endogenous catecholamines at synapses in the brain and heart. This stimulation results in peripheral vasoconstriction and cardiac stimulation. This results in increased blood pressure, tachycardia, ataxia, restlessness, tremors, and seizures.

Onset of clinical signs following ingestion of ephedrine or pseudoephedrine may be as early as 30 minutes or delayed several hours post ingestion. Once an animal becomes symptomatic, clinical signs may last for thirty-six to forty-eight hours. Pseudoephedrine is excreted in urine as an unchanged drug. In humans, the elimination half-life varies between 2-21 hours, depending on the urine pH.

Clinical signs have been seen in dogs at 5-6 mg/kg and deaths have occurred at 10-12 mg/kg. Dogs have a narrow margin of safety compared to other species. Toxicity can be increased if other sympathomimetic substances (such as phenylpropanolomine) are taken at the same time. Clinical signs of ma huang toxicosis in animals are comparable to those seen with overdoses of over-the-counter and prescription products containing pseudoephedrine. Effects are generally limited to the cardiovascular and central nervous systems. Initial signs usually begin with restlessness, pacing, and agitation. Vocalization may occur. Dogs may exhibit hallucinogenic behavior. On clinical examination, mydriasis, tachycardia, hypertension, muscle tremors, and seizures may be present. Death is usually due to cardiovascular collapse.

For a recent ingestion (fifteen minutes or less) in an asymptomatic animal, emesis may be induced. Administer activated charcoal and a cathartic. Tremors, seizures, and nervousness are best controlled by acepromazine maleate (0.05 to 1 mg/kg IV, IM, or SQ), chlorpromazine (0.5 to 1 mg/kg IV or IM), or a barbiturate such as phenobarbital (3 mg/kg IV to effect). For acepromazine and chlorpromazine, start at the low end of the dosage range and increase as needed. Dissociative effects of benzodiazepines are frequently exaggerated in dogs with pseudoephedrine toxicosis; dogs may actually become more agitated after the administration of diazepam. Propranolol (0.02 to 0.06 mg/kg slowly intravenously) or another beta-blocker can be used to control tachycardia. Administer intravenous fluids, and monitor the animal. Hypertension can cause pulmonary edema, although it is rare. Obtain baseline blood tests, including serum potassium and glucose concentrations.

Guarana

Guarana is the common name of Paullinia cupana, a plant containing high levels of caffeine. Guarana may contain 3% to 5% caffeine by dry weight compared to coffee beans (1-2 % caffeine) and tea (1-4 % caffeine). Common names include Brazilian cocoa and Zoom. Theobromine and theophylline have also been found in the plant. Historically, guarana was used to provide energy during fasting, as an aphrodisiac, and to prevent malaria and dysentery. Guarana is frequently found in herbal weight loss aids (with or without ma huang) and in products promising increased energy. Because guarana contains methylxanthines, it produces a clinical syndrome similar to chocolate, coffee, or over the counter stimulant products which contain caffeine.

Caffeine is a methylated xanthine. It increases cyclic AMP, releases catecholamines, and increases muscular contractility. The net effect is a positive inotropic and chronotropic effect on the heart, cerebral vasoconstriction, renal vasorelaxation, and smooth muscle relaxation in the gastrointestinal tract.

Caffeine is well absorbed orally. The plasma half-life in the dog is 4.5 hours. Caffeine is metabolized in the liver and undergoes enterohepatic recirculation. Caffeine is excreted through the urine. As with Ma huang, there are several medical conditions, which may enhance toxicity. These conditions include heart and kidney disease, and ulcers. Caffeine has caused birth defects in animals.

The LD50 of caffeine in dogs is reported to be 140 mg/kg. However, serious toxicity and death have been reported at doses much lower than the LD50. Signs of acute caffeine toxicity in humans appear at 15 to 30 mg/kg and the lethal dose is estimated to be 100 to 200 mg/kg. For combinations of ma huang and guarana, the minimum dose at which clinical signs were reported is 1.3 mg/kg ma huang and 4.4 mg/kg guarana. The minimum dose at which death was reported was 5.8 mg/kg ma huang and 19.1 mg/kg guarana. These doses were obtained from cases reported to the ASPCA Animal Poison Control Center. There are multiple drugs that can interact with caffeine. Besides pseudoephedrine and ma huang, monoamine oxidase inhibitors, aspirin, and cimetidine are commonly used medications that should not be combined with caffeine. The sedative effects of benzodiazepines may be decreased by caffeine.

Clinical signs include vomiting, restlessness and hyperactivity, polydipsia and polyuria. Tachycardia and other cardiac arrhythmias such as premature ventricular contractions (PVCs), are possible. Clinical signs progress to muscle tremors and seizures, and finally death.

Treatment consists of early decontamination. Induce emesis in an asymptomatic animal or perform gastric lavage. Because enterohepatic recirculation occurs in caffeine toxicosis, repeated doses of activated charcoal are beneficial. Cardiac function should be monitored. Tachycardia can be treated with a beta-blocker such as metoprolol or propranolol. The dose is the same as in ma huang toxicosis. Premature ventricular contractions can be treated with lidocaine. Lidocaine is dosed at an initial bolus of 2-4 mg/kg slowly intravenously, followed by an IV drip of a 0.1% solution at 30-50 mcg/kg/minute. Muscle tremors and seizures are treated with diazepam (0.5-1.0 mg/kg in increments of 5-10 mg, to effect) or a barbiturate can be used (dose as per ma huang). IV fluids potentially enhance excretion. A urinary catheter should be placed because methylxanthines can be absorbed through the bladder wall.

Griffonia simplicifolia

Griffonia simplicifolia seeds are used as a source of 5-hydroxytryptophan (5-HTP). This extract is generally used to treat depression, headaches, obesity and insomnia in humans. 5-HTP is reported to increase serotonin in the CNS. Label information may list 5-HTP, 5-hydroxytryptophan, or griffonia seed extract as an ingredient. Drug interactions with MAO inhibitors, antidepressants, and herbs such as St. John's Wort can occur.

5-HTP is rapidly and well absorbed from the gastrointestinal tract. 5-HTP readily crossed the blood-brain barrier. Once target cells are reached, 5-HTP is converted to serotonin (5-hydroxytryptamine). Serotonin is important in the regulation of sleep, cognition, behavior, temperature regulation, and other functions.

In dogs, the minimum toxic dose reported is 23.6 mg/kg and the minimum lethal dose reported in dogs is 128 mg/kg. There is not necessarily a good correlation between severity of signs and dose ingested. Signs have been reported from 10 minutes up to four hours post ingestion. Signs can last up to 36 hours.

Clinical signs resemble serotonin syndrome in humans. Signs include seizures and tremors, depression, ataxia, and hyperesthesia. Gastrointestinal effects including vomiting, diarrhea, and drooling are common. Severe hyperthermia and blindness have been reported.

Treatment includes early decontamination. Seizures, tremors, and other neurologic signs usually respond well to diazepam (0.2 to 1 mg/kg, IV to effect) or barbiturates. Fluid therapy should be initiated. Hyperthermia can be managed with cool water baths and fans. Baseline blood and chemistry panels should be obtained. Cyproheptadine is a serotonin antagonist and can be used at 1.1 mg/kg PO or rectally until signs resolved.

Yohimbine

Yohimbine is derived from the bark of Pausinystalia yohimbe. It has long been considered an aphrodisiac, and the bark was smoked as a hallucinogen. In traditional medicine, angina and hypertension were treated with yohimbine. Today, it is mostly used as a sexual stimulant, and is frequently marketed as herbal Viagra.

Pharmacologically, yohimbine is classed as an alpha 2-adrenergic blocking agent. In large doses, severe and life threatening clinical signs can be seen. Clinical effects are related to the alpha 2 blockade and subsequent CNS and cardiovascular stimulation. Clinical signs include hyperactivity, agitation, tremors, seizures, vomiting, diarrhea, abdominal pain, hypertension initially followed by a profound hypotension.

Treatment includes early decontamination. Control tremors and seizures with diazepam or a barbiturate. Monitor blood pressure, body temperature, and oxygen saturation. IV fluids should be given. Monitor blood glucose. Do not use epinephrine and dopamine for treatment of hypotension. Dopamine has been associated with fatal cardiac arrest when given in association with other alpha 2-adrenergic blocking agents in people. The FDA has warned that several products listed as containing yohimbine and other drugs actually contain tadalafil, a prescription drug labeled for erectile dysfunction. Clinical signs and treatment may vary if labeling information is incorrect.

Alpha lipoic acid

Alpha lipoic acid is a fat-soluble, sulfur-containing antioxidant. A variety of synonyms exist including lipoic acid, thioctic acid, acetate replacing factor, biletan, lipoicin, thioctaid and thioctan. In toxicology, alpha lipoic acid is useful in treating amanita mushroom poisoning. In veterinary medicine, it is used to treat diabetic polyneuropathy, cataracts, glaucoma, and ischemia-reperfusion injury.

Alpha lipoic acid is readily absorbed orally. Alpha lipoic acid is synergistic with insulin, causing decreased blood sugar and increasing liver glycogenesis, and facilitates glucose uptake into cells. At this time, based on ASPCA Animal Poison Control Center data, the minimum lethal dose in dogs is 331.12 mg/kg, with the potential for deaths to occur at much lower doses. Cats are about 10X more sensitive than dogs, rats, or humans. The minimum toxic dose for cats is 13 mg/kg. At 30 mg/kg, neurologic signs and mild hepatocellular damage can occur. Reported therapeutic doses for cats are 1-5 mg/kg, with a maximum dose of 25 mg/day. A therapeutic dose for dogs is up to 200 mg/day, or 150 ppm in the diet.

Clinical signs of toxicity include vomiting, ataxia, hypersalivation, tremors and hypoglycemia. Seizures can occur and symptomatic animals should be monitored for acute renal failure. Clinical signs can occur 30 minutes to several hours post-ingestion.

Decontamination should be performed within an hour of ingestion. For cats, decontaminate any dose >5 mg/kg. Dogs should be decontaminated at doses >50 mg/kg. If a dose is between 30-50 mg/kg, the decision to decontaminate should be made on an individual basis. Baseline laboratory values for blood glucose, liver enzymes, BUN, creatine and electrolytes should be obtained. Treatment is primarily symptomatic: control hypoglycemia, support liver function, correct dehydration if present, control vomiting, tremors and seizures. Fluid diuresis can be helpful.

Echinacea purpurea

Echinacea purpurea is one of the most popular herbal supplements in use today. The common names of Echinacea include purple coneflower, comb flower, scurvy root, and others. Historically, echinacea was used by Native Americans and adopted by settlers. Uses ranged from "blood purifiers" to dizziness to rattlesnake bites. Echinacea contains essential oils, as well as glyco-proteins, alkamides, and flavonoids. All parts of the plant are used in various herbal preparations. A small ingestion of Echinacea generally does not require medical intervention. Any gastrointestinal upset is generally self-limiting and the pet owner will be able to treat with supportive care (NPO, kaolin/pectin 1-2 ml/kg QID prn). It is imperative to determine if the animal ingested other herbal products or medications. Large recent ingestions can be treated with gastric decontamination. If an animal develops severe vomiting, symptomatic treatment with IV fluids and other supportive care should be initiated.

Chamomile

Chamomile refers to both German chamomile (Matricaria recutita) and Roman chamomile (Chamaemelum nobile). In folk medicine, chamomile is used for rheumatism and intestinal parasitism. In veterinary medicine, the most common uses are as a natural wormer, sedative, and as a treatment for aggression.

Chamomile contains essential oils, flavanoids, and hydroxycoumarins. The ASPCA Animal Poison Control Center has reports of 6 cases of ingestion in cats. Three cases involved gastrointestinal upset (vomiting and/or diarrhea), 4 cases reported depression and lethargy, and 2 cases reported epistaxis. Of the two cats with epistaxis, one also developed hematomas. Epistaxis and hematoma development is probably due to hydroxycoumarin content. One cat developed no clinical signs. The majority of dogs developed no clinical signs. Vomiting and hypersalivation were the most commonly reported clinical signs in dogs.

Management of recent ingestions includes gastric decontamination. In cases of large ingestions, activated charcoal can be given. Treatment for gastric irritation is symptomatic and supportive (NPO, gastrointestinal protectants, fluid therapy if severe vomiting or dehydration occurs). If anaphylaxis occurs, standard therapy with epinephrine, steroids, and antihistamines should be initiated. For animals with bleeding disorders such as von Willebrand's, or cats, a packed cell volume and activated clotting time or coagulation profile may be required. If necessary, a blood transfusion could be administered.

Valerian root

Valerian root (Valeriana officianalis) is one of the most popular herbs on the market. Common names include all-heal, heliotrope, Vandal root, and Capon's tale. It is an herbaceous perennial found widely over the United States.

The primary active ingredients are volatile oils, alkaloids, and most importantly, valepotriates. Valerian is used primarily as a sedative, and as a sleeping aid. It has also been used in epilepsy, headaches, colic, and numerous other minor ailments. Valerian increases the length of sedation induced by pentobarbital and length of anesthesia produced by thiopental. Most reports of adverse effects of valerian in human literature occur after chronic use. Acute exposures in dogs and cats are expected to cause no more than mild vomiting and/or sedation.

Generally, significant treatment would be unnecessary. The sedative effects are generally short-lived and can be managed by an owner at home.

Essential oils

Essential oils are produced by a large number of plants. The oils are a mixture of terpenes and other chemicals. Essential oils are used from food flavorings to perfumes to medications. The most commonly used essential oils in veterinary medicine include Melaleuca or tea tree oil (Melaleuca alternifolia), pennyroyal oil (Mentha pulegium), D-limonene and linalool (Citrus spp.), Citronella (Cymbopgum nardus), Thuja (Thuja occidentalis), and wormwood or absinthe (Artemisia absinthium). In veterinary medicine, essential oils are most commonly used to treat flea infestations, hot spots or other dermatological conditions, or as wormers. Oils may be found in shampoos, dips, liniments, teas, tinctures, syrups, or other formulations.

Essential oils are rapidly absorbed both orally and dermally. They are metabolized by the liver to glucuronide and glycine conjugates. Cats appear to be more sensitive to essential oils than dogs. The acute LD50 varies significantly between various essential oils.

The most common clinical signs after dermal exposures include ataxia, muscle weakness, depression, and behavioral abnormalities. Severe hypothermia and collapse have occurred in cats. A transient paresis can occur in small breed dogs when melaleuca oil is applied down the spine as a topical flea treatment. Cats have developed scrotal dermatitis after exposure to D-limonene or linalool. Liver failure is associated with essential oils, especially pennyroyal and melaleuca. Oral ingestions cause vomiting and diarrhea. Central nervous system depression may occur, and seizures are possible with large doses. Aspiration pneumonia can occur when essential oils are inhaled. Death can occur with sufficient doses. Signs usually develop from almost immediately up to eight hours post exposure.

Recent dermal exposures should be treated by bathing. Activated charcoal is effective in oral exposures. Do not induce emesis because of the potential for aspiration pneumonia. Regulate body temperature. IV fluids help correct hypotension and aids in renal elimination. Monitor electrolytes, cardiac, and respiratory function. Seizures and tremors usually respond to diazepam. Aspiration pneumonia may require oxygen and broad-spectrum antibiotics. Hepatic damage usually responds to good supportive care, although N-acetylcysteine has been used experimentally in humans diagnosed with pennyroyal toxicosis. N-acetylcysteine has a loading dose of 140mg/kg and a maintenance dose of 70 mg/kg QID. Signs usually resolve over a few hours up to a few days. Most animals do have a good prognosis with appropriate treatment. Many mild cases require only mild home treatment and observation.

Grapefruit seed extract

Grapefruit seed extract (GSE) is being touted as a disinfectant, to cure fungal disease, external parasites, and many other conditions. GSE is acidic, and contains quaternary compounds similar to cationic detergents. When the product is not diluted properly, clinical manifestations can occur.

Severity of injury typically depends on the concentration of the product and the duration of the contact. Primary clinical signs include hypersalivation, vomiting with possible hematemesis, muscular weakness. Fasciculations and CNS depression may occur. Diarrhea, dermal necrosis or dermatitis, pulmonary edema, and hypotension are possible. Corrosive burns can occur in the mouth, especially on the tip and sides of the tongue, pharynx and the esophagus. Hyperthermia is common in cats.

If a dermal exposure has occurred, bathe and rinse thoroughly. Flush eyes if an ocular exposure occurred. In oral exposures, do not induce vomiting because of potential corrosive effects. Activated charcoal will not bind a cationic detergent. Do give milk or water for oral dilution. If GI signs or oral lesions develop, sucralfate slurries and an H2 blocker can be used to treat ulcerations. A broad spectrum antibiotic is recommended to prevent secondary bacterial infection. Pain management should be administered as needed. Corticosteroid use is controversial but can be used to reduce the inflammatory response for one or two days. Animals should be on an antibiotic if a steroid is used. Maintain hydration, and provide nutritional support as needed. In severe cases, esophageal stricture may develop as a sequellae.