Plant Alkaloids Toxicity

Etiology

Plant alkaloid toxicity results from over-exposure to plants harboring these phytochemicals, including seeds, flowers, or weeds, in the form of extracts, tinctures, herbal teas, or as contaminants of food products. Utilization may be inadvertent or deliberate- recreational or for self-harm. Contact may be direct or indirect through inhalation, ingestion, transdermal, or vertical transmission. Nicotine toxicity can result after ingestion of Nicotiana tabacum leaves, insecticidal products, electronic cigarette refills, cigarettes, and transdermal, as in green tobacco sickness affecting farm workers who harvest tobacco. Pyrrolizidine alkaloid toxicity may occur secondary to ingestion of parent plants for medicinal purposes or via consumption of food grain contaminated with the seeds of such plants.[5] 

Maternal consumption of plant products comprising pyridine or quinolizidine alkaloids has been linked to developmental defects in humans and animals. Through alkaloid-mediated desensitization of fetal muscle-type nicotinic acetylcholine receptors, fetal movement is arrested and leads to skeletal flexure defects like kyphosis, lordosis, scoliosis, and torticollis.[6] Cases of unintentional anticholinergic poisoning have resulted from tropane alkaloid contaminants in foods such as hamburgers, honey, millet used to make porridge, homemade wine, and Paraguay tea derived from Ilex paraguariensis. In 1995, an epidemic beginning in New York City ensued from the use of heroin adulterated with scopolamine, causing severe anticholinergic toxicity and affecting at least 300 unassuming individuals.[7] 

In many instances, as in the case of nicotinic toxicity, only small concentrations of a toxin may be required to cause illness. Poison hemlock has been unintentionally ingested by foragers searching for wild carrots due to the similar appearance of the two plants. Cytisine, another nicotine-like alkaloid found in Cytisus laburnum, has been held responsible for the mass poisoning of children and adults who consumed as little as 0.5 milligrams (mg) per kilogram (kg) body weight.

Epidemiology

Although the data related to alkaloid-specific exposures are limited, those involving general plant exposures are well-documented. In the United States, plant-related toxic exposures exceed one-hundred-thousand cases annually and account for about 3 to 5% of human exposures described to poison control centers. The most common route of exposure is ingestion, with approximately 98% of these being unintentional. Nearly 80% of reported plant-related poisonings involve children under six years of age. Most of the plants responsible for these events have limited toxicity, and most exposures are benign. Moreover, pediatric ingestions tend to be benign owing to the small quantities consumed.[8]

The more serious toxicities tend to involve adults who may mistake the plant in question as edible or intentionally ingest it for its homeopathic or toxic properties. Fortunately, only about 7% of individuals require medical evaluation, less than 20% report mild to moderate symptoms, and over 80% are asymptomatic. The fatality rate of such exposures in the United States, largely unintentional, is less than 0.001%. In other parts of the world where health care is less accessible, however, plant exposures pose a greater risk and public health burden. Between 1983 and 2009, only 45 fatalities were recorded, with Datura and Cicuta species accounting for 35.5% of these. Between 2000 and 2009, 52.2% of toxic plant ingestions involved males, and over 60% of such cases resulted in moderate to severe outcomes.[9]

History and Physical

As for all undifferentiated patient presentations, a thorough history and physical exam are key for minimizing diagnostic uncertainty. It is essential to obtain a complete past medical history, medication history, and detailed description (ideally a sample, if possible) of the toxicant, route, amount, and exposure time. Equally important is to understand the reason for consumption (e.g., accidental, intentional) and the presence of co-ingestions such as alcohol or illicit drugs. Plant alkaloid toxicities may produce a variety of major toxidromes, which are discussed below.  

The tropane alkaloids atropine, hyoscyamine, and scopolamine, also known as the belladonna alkaloids, are known to cause classic anticholinergic syndrome via their potent antimuscarinic effects. Clinical effects can be seen between 1 to 4 hours post-ingestion. Initially, these are characterized by blurred vision, photophobia, mydriasis, tachycardia, urinary retention, dry mucous membranes and skin, and reduced bowel sounds. These early signs and symptoms may be followed by hyperthermia as well as alterations in mental status, including confusion, agitation, combativeness, coma, and even death in severe cases.

Commonly, patients will experience amnesia to events following ingestion. Important to note is that not all characteristics of this toxidrome will necessarily be present in every case. These plant metabolites have been exploited for their hallucinogenic properties recreationally via the consumption of brewed teas and seeds. Plants containing these phytochemicals from the family Solanaceae may also be smoked. Datura stramonium (jimsonweed), the chief source of such seeds, is found in the United States and Southern Canada, and poisoning may lead to acute anticholinergic poisoning and death in both children and adults. Recreational ingestions exceed unintentional ingestions as the main cause of toxicity. The duration of the effect of belladonna poisoning may last from a few hours to days, depending on the dose of exposure.[10]

The widely distributed pyrrolizidine alkaloids found in food and phytomedicine vary considerably in their toxic potencies. Approximately one-half of the pyrrolizidines characterized thus far are toxic when ingested, with hepatotoxic, genotoxic, tumorigenic, and teratogenic effects. Prenatal exposure can lead to fetal pulmonary and hepatic defects. They may also be transmitted through breast milk. Acute hepatocellular necrosis can occur after ingestion of 10 to 20 mg of the alkaloid, likely caused by an oxidant effect. Liver damage can be induced by hepato-sinusoidal obstruction syndrome or veno-occlusive disease. Consumption of herbal medicines containing these phytochemicals has also been shown to upregulate ethanol-induced hepatotoxicity via enhancement of the apoptotic effects of ethanol.[11]

Arecoline, pilocarpine, and physostigmine represent the cholinergic alkaloids whose acute toxicity is caused by the accumulation of excessive levels of acetylcholine, which may lead to characteristic features of the cholinergic toxidrome: lacrimation, vomiting, and diarrhea. Severe toxicity may lead to bradycardia, bronchospasm, bronchorrhea, convulsions, coma, respiratory depression, and death. Chronic exposure to arecoline, which represents the major oxidative alkaloid in the seeds of Areca catechu, also known as areca (betel) nuts, has also been associated with oral cancer.[12]

Pilocarpine, used to treat glaucoma, is a stimulator of ocular muscarinic receptors. Physostigmine, derived from the Calabar bean (Physostigma venenosum), is a reversible acetylcholinesterase inhibitor that was used both diagnostically and therapeutically in anticholinergic overdose. It is not currently available.

Nicotinic toxicity can be caused by several alkaloids, which, in addition to nicotine, include sparteine, lobeline, cytisine, and the active agent in poison hemlock, coniine. The hallmark presentation of early nicotinic toxicity is vomiting. At sufficient doses, excessive stimulation of both pre-ganglionic and post-ganglionic nicotinic acetylcholine receptors leads to a toxidrome with features of both sympathomimetic toxicity and cholinergic toxicity. Severe nicotine poisoning can result in fasciculations, mydriasis, tachycardia, hyperthermia, hypertension, seizures, respiratory depression, and death. Hepatitis, rhabdomyolysis, and acute tubular necrosis have also been observed.

The psychotropic plant alkaloids mescaline and lysergic acid act upon serotonin receptors to generate hallucinogenic effects. The peyote cactus (Lophophora williamsii) found in northern Mexico and the southwestern United States serves as a source of the phenethylamine mescaline. Consumption of morning glory (Ipomoea spp) seeds can induce intoxicating effects via the tryptamine lysergic acid, another serotonergic hallucinogen.[13]

Opioids are derived from the poppy plant (Papaver spp.) and represent the alkaloidal central nervous system depressants with notable clinical utility for analgesia. Toxic amounts of these substances may lead to respiratory depression, miosis, and in severe cases, death. On the other hand, alkaloidal central nervous system stimulants include ephedrine, synephrine, and cathinone. Ephedrine from the Ephedra spp. and certain Sida cordifolia spp. was banned in the US by the FDA in 2004 due to adverse cardiovascular events and death, even among those without pre-existing cardiovascular disease.[14]

Isoquinoline alkaloids include structurally similar sanguinarine, hydrastine, and berberine. Berberine has demonstrated cardiac and respiratory depression, smooth muscle contraction, and uterine contraction. A mass sanguinarine poisoning from the consumption of a Mexican prickly poppy (Argemone mexicana) resulted in gastrointestinal symptoms, hepatomegaly, anemia, skin darkening and lesions, erythema, and peripheral edema. On the severe end, affected individuals may experience ascites, congestive heart failure, and myocarditis. Hydrastine ingestion has been reported to cause movement disorders that resemble poisoning by a non-isoquinoline alkaloid, strychnine, found in Strychnos nux-vomica. Poisoning from these alkaloids is associated with muscle spasms, weakness, rigidity, and death via respiratory muscle involvement.

Both hydrastine and strychnine inhibit the central nervous system glycine receptor and can also mimic acute tetanus toxicity. In contrast to tetanus toxicity, however, a poisoned individual may exhibit periods of muscle weakness or flaccidity. Sources of strychnine include rodenticides, contaminated heroin or cocaine, and an herbal remedy for arthritis called “maqianzi.”[15]

Swainsonine is an indolizidine alkaloid known to cause a lysosomal storage disease by inhibiting glycoprotein glycosylation. It is a known teratogen, and toxicity includes pancreatic and hepatic disease, respiratory depression, and chronic neurologic disease with weakness and failure to thrive.[16]

Evaluation

The evaluation of the patient with a suspected plant alkaloid toxic exposure centers on plant identification and consultation with a medical toxicologist or poison control center. Identifying the plant species based on characteristic features and consultation with a poison expert can be diagnostic. The now decommissioned Federal Drug Administration-managed PLANTOX database can be utilized for comparison.

As analytical science methods continue to advance, confirmatory DNA analysis of plant material may become more widespread. The diagnosis is generally clinical, and laboratory studies may be of limited diagnostic utility. In the case of cocaine toxicity, urine assays detect its primary metabolite, benzoylecgonine, within four hours of cocaine use and up to 10 days after use.[17] 

Laboratory evaluation should investigate possible co-ingestions, and an electrocardiogram should be performed to evaluate for dysrhythmias or conduction abnormalities. The remainder of the workup should be dictated by the history and physical examination. For patients with altered mental status, it is prudent to broaden the differential and workup to other medical causes, including but not limited to infectious or structural, as appropriate. Anticholinergic toxicity is identified based on presentation, although clinical specimens can be tested for atropine and scopolamine.

Treatment / Management

Management of these toxicities should focus on prevention, early identification, decontamination, close hemodynamic monitoring and observation, and supportive care. Early administration of activated charcoal within the first few hours of exposure to limit may benefit via the adsorption of toxins and reduced gastrointestinal absorption, but it is contraindicated in cases of an unprotected airway or decreased intestinal motility, as it may cause aspiration or bowel obstruction.[18] 

Benzodiazepines are first-line agents for acute agitation and seizures. For severe anticholinergic poisoning, the administration of a reversible anticholinesterase inhibitor should be considered. Classically, physostigmine was used, but it is not currently available. Rivastigmine and pyridostigmine have been proposed as alternatives but are not approved for this indication. Conversely, atropine is given as the antidote to reverse the cholinergic toxidrome.

In acute cocaine toxicity, beta-blockers should be avoided to prevent potential unopposed alpha-adrenergic stimulation. Sodium bicarbonate should be considered for wide-complex dysrhythmias. In opioid toxicity leading to respiratory depression, naloxone is indicated in addition to supportive care measures and close monitoring.

Differential Diagnosis

The differential diagnosis for plant alkaloid toxicity is broad and complex, given the variety of potential presentations. Some of the diagnoses clinicians should consider include the following:

• Hypoglycemia
• Acute tetanus
• Amphetamine toxicity
• Antidepressant toxicity
• Antidysrhythmic toxicity
• Cardiac glycoside plant poisoning
• Phencyclidine toxicity
• Hallucinogenic mushroom toxicity
• Hyperthyroidism, thyroid storm, and Graves disease
• Meningoencephalitis
• Status epilepticus
• Antihistamine overdose
• Alcohol withdrawal

Prognosis

While the data on specific toxicities and their outcome are limited, these poisonings are largely benign with a favorable prognosis. Outcomes depend upon the type, dose, and route of exposure, the presence of co-ingestions, early identification, and excellent supportive care.

Complications

Complications of plant alkaloid toxicity may be acute or chronic. Each of the toxidromes reviewed entails the potential to produce grave consequences if not identified or managed appropriately. The anticholinergic toxidrome that may result from belladonna alkaloid poisoning may be complicated by seizures or agitated delirium. Cardiac dysrhythmias that result may deteriorate into fatal dysrhythmias. Ingestion of one-hundred jimsonweed (Datura stramonium) seeds, which delivers about 6 mg of atropine, can prove fatal. Synephrine is a plant-derived alkaloid chemically related to ephedrine found in bitter orange (Citrus aurantium) that can also produce central nervous system stimulant activity. Like ephedrine, this toxin has been linked to deaths and drug interactions.[19]

The pyrrolizidine alkaloids are converted to highly reactive pyrroles by the hepatic cytochrome P450 enzymes, which result in hepatocellular toxicity in the acute setting. In about 30% of acute poisonings, a pyrrolizidine-alkaloid-induced proliferation of the hepatic vasculature intima leads to veno-occlusive disease. Death occurs in approximately 2 out of 10 cases. Toxicity with opioids and coniine may lead to respiratory depression, failure, and arrest. Berberine, derived from goldenseal (Hydrastis canadensis) and barberry (Berberis spp), has produced both respiratory and myocardial depressant effects.[20] 

The muscle spasms, rigidity, and weakness produced by strychnine may lead to respiratory failure and death. Consumption of sanguinarine may induce heart failure and myocarditis.[21] Chronic exposure to arecoline via betel nut (Areca catechu) chewing has been shown to lead to genotoxicity, oral submucous fibrosis, and head and neck cancer. Chronic dependence may result from prolonged and excessive use of opioids, cocaine, and the psychotropic alkaloids lysergic acid diethylamide and mescaline. Personality changes, mood lability, psychosis, rage reactions, and even suicidal or homicidal ideations may occur with the overuse of the latter three phytochemicals.