Alkaloids

Alkaloids are nitrogen-containing organic compounds that act as bases and form salts with acids. Plant alkaloids are soluble organic acid–alkaloid salts that contain nitrogen in a ring structure that is heterocyclic or aromatic, or both. Alkaloids are generally distributed throughout a given plant, so all ingested parts are toxic. Further subdivision into chemical groups is based on ring structure (Table 64-2).

TABLE 64-2 Plant Alkaloids and Their Structures

Alkaloid Type	Alkaloid Structure	Examples
Indole		Ergonovine (ergots)
		Strychnine
		Physostigmine (calabar beans)
		Rauwolfia alkaloids (reserpine)
Isoquinoline		Opium alkaloids
		Emetine (ipecac)
Pyridine/piperidine		Nicotine (tobacco)
		Arecoline (betel nut)
		Lobeline (Indian tobacco)
Purine		Caffeine
		Theobromine (cacao)
Quinoline		Cinchona alkaloids (quinidine)
Steroid		Veratrum alkaloids (false hellebore) Aconite (monkshood)
Tropane		Atropine (belladonna)
		Hyoscyamine
		Hyoscine (scopolamine)

Glycosides

Sugars in the form of acetals are called glycosides. In glycosides, a glycosyl group replaces an alcohol or a hydroxyl group. On hydrolysis, glycosides yield sugars (glycones) and aglycone compounds. The aglycone moiety accounts for most of the toxicity, although the sugar may enhance solubility and absorption (Figure 64-1, online). Glycoside-producing plants include cardioactive, cyanogenic, saponin, anthraquinone, and coumarin glycoside compounds.

FIGURE 64-1 Hydrolysis of amygdalin, with its toxic aglycone group, yields hydrogen cyanide. The enzyme β-glucosidase, called emulsin, contained in plants can catalyze amygdalin hydrolysis.

Resins

Resins are highly toxic compounds of diverse chemical and plant origin united by the physical characteristics of insolubility in water, absence of nitrogen, and solid or semisolid state on extraction at room temperature. Resins are usually mixed with other compounds, such as volatile or essential oils (oleoresins), gum (gum resins), and sugars (glycoresins).

Oxalates

Oxalates occur naturally in plants as soluble (sodium or potassium) or insoluble (calcium) oxalates or acid oxalates. Oxalates have corrosive effects and bind serum calcium, causing hypocalcemia.

Phytotoxins

Phytotoxins, or toxalbumins, are among the most toxic substances of plant origin. They are composed of large protein molecules that resemble bacterial toxins in structure and in their ability to act as antigens (Figure 64-2, online).

FIGURE 64-2 The structures of ricin and abrin (phytotoxins isolated from the castor bean plant and the jequirity bean plant, respectively) are similar in structure to biologic toxins such as botulinum. These glycoproteins are composed of two peptide chains, designated A and B, connected by a disulfide bond.

Anticholinergic Syndrome

Toxicity may ensue after ingesting or smoking plant parts.⁴⁵ The tropane alkaloids competitively inhibit postsynaptic muscarinic receptors, producing the classic anticholinergic syndrome (Figure 64-3 and Box 64-1).^{104,113,203,209,230} A useful clinical sign of anticholinergic toxicity is lack of perspiration in the axillae. Anticholinergic findings suggestive of poisoning may be remembered using the following mnemonic:^209,240

FIGURE 64-3 Nicotinic and muscarinic receptors of the central nervous system, autonomic nervous system, and peripheral skeletal muscles. Anticholinergic toxins (e.g., tropane alkaloids) antagonize muscarinic receptors, causing confusion, agitation, abnormal movements, hallucinations, and coma centrally, and mydriasis, anhidrosis, tachycardia, urinary retention, and ileus peripherally. Direct nicotinic agonists (e.g., arecoline, coniine, cytisine, lobeline, nicotine) stimulate nicotinic receptors; however, prolonged depolarization at the receptor causes eventual blockade of nicotinic receptors. ACh, Acetylcholine; ANS, Autonomic nervous system; CNS, central nervous system; Epi, epinephrine; M, muscarinic receptor; NE, norepinephrine; N_M, nicotinic receptor at skeletal muscle; N_N, nicotinic receptor in nervous system.

Jimsonweed

Datura species are generally known as jimsonweed or thorn apple, and Brugmansia species are generally known as angel’s trumpet (Figure 64-4).^112,113,263 Young, thin, and tender stems of jimsonweed contain the highest concentration of tropane alkaloids.¹⁷⁹ However, the seeds also contain high concentrations of the alkaloids, and as little as one-half a teaspoonful of seeds may cause death from cardiopulmonary arrest. The word jimsonweed is thought to be derived from Jamestown, Virginia, where British troops reportedly behaved bizarrely after consuming Datura in 1676. D. stramonium has been reportedly used in Haitian zombification rituals.^{45,67,112,113} Jimsonweed has been used to treat asthma, heralding the current use of ipratropium bromide.

FIGURE 64-4 Jimsonweed (Datura species) is a bush with trumpet-like flowers (A) and thorny seedpods that contain numerous small kidney-shaped seeds (B). A nickel is shown for size comparison. Angel’s trumpet (Brugmansia species) is a tree (C) with trumpet-like flowers (D).

(Courtesy Kimberlie A. Graeme, MD, and Phillip Saba, MD.)

Reports of abuse of Datura and Brugmansia as hallucinogens continue to be reported in the United States and Europe.^{45,113,217,255} Clusters of poisonings among adolescents are typical.* Frequently, a tea of the plant parts is brewed.¹³⁸ Report of toxicity after using a homemade Datura toothpaste has also been reported.²⁰⁵ A mass poisoning occurred in Botswana after consumption of porridge made from sorghum flour contaminated with seeds of D. stramonium.¹⁹⁷ Symptoms may appear within minutes and may last for days.^68,203,255 Tachycardia, dry mouth, agitation, nausea, vomiting, incoherence, disorientation, auditory and visual hallucinations, mydriasis, decreased bowel sounds, slurred speech, hyperthermia, flushed skin, urinary retention, and hypertension have been reported.† Blurred vision and photophobia may be secondary to mydriasis. Isolated mydriasis and cycloplegia may be seen, including anisocoria, after topical contact to the eyes.^123,130,263 With severe toxicity, seizures, flaccid paralysis, and coma may ensue. Focal neurologic signs and posturing, as well as death, have also been reported.‡ Death may occur as a result of behavioral changes, leading to trauma, drowning, or environmental exposure associated with hyper- or hypothermia.¹³⁸ Autopsy has revealed edema of the brain and lungs with focal hemorrhages within the alveolar lumens, ischemic lesions and edema of the heart, and hyperemia of the sinusoidal tracts of the liver.³¹

Anticholinergic poisoning should be suspected when patients are observed to communicate with imaginary friends with mumbled speech, and to demonstrate repetitive picking behavior.^112,242 Symptoms generally begin 30 to 60 minutes after ingestion and continue for 24 to 48 hours, but they may begin within several minutes and persist for several days. Patients are generally amnestic of events during their poisoning. Studies may show leukocytosis, mild transient elevation of liver enzymes, elevated creatine phosphokinase (CPK) levels and other evidence of rhabdomyolysis, and changes on an electrocardiogram (ECG) that are consistent with tachycardia and dysrhythmias.^45,68,89,113

Deadly Nightshade

Ingestion of A. belladonna is less common than Datura and Brugmansia ingestion. All parts of deadly nightshade contain tropane alkaloids, but the highest concentrations are in the ripe fruit and green leaves; each berry may contain up to 2 mg of atropine. The berries may be mistaken for bilberries (hurtleberries). A family of eight had varying acute exposures to A. belladonna after eating both raw and cooked berries in a pie. The most severely poisoned patient had anticholinergic symptoms, with hypertonia, hyperthermia, respiratory failure, and coma requiring mechanical ventilation. Urine drug screens detected only atropine and not scopolamine, the latter which is present in much smaller quantities.^230,242 A review of 49 children with acute deadly nightshade intoxication found that children most commonly demonstrated meaningless speech, tachycardia, mydriasis, and flushing; lethargy and coma were seen in the more severely poisoned children.³⁷ A patient with seasonal chronic ingestion presented with recurrent tachycardia, mydriasis, inability to concentrate, visual hallucinations, delusions, inappropriate laughter, dizziness, and headache.¹⁴⁰

Treatment

Treatment of anticholinergic plant exposure consists primarily of decontamination and supportive care, including airway protection, intravenous (IV) fluids, and vasopressors for hypotension resistant to IV fluids. Hyperthermia should be assessed and treated if significant. Agitation can be treated with careful administration of benzodiazepines. Haloperidol and phenothiazines should not be used because these agents may enhance toxicity. Foley catheterization or nasogastric tube placement may be necessary if there is bladder distention or decreased gut motility, respectively.^{104,138,140,200,230}

Some recommend treating severe central anticholinergic syndrome with carefully titrated physostigmine, which is derived from the calabar bean of Physostigma venenosum. This cholinesterase inhibitor blocks acetylcholine degradation; the resultant accumulation of acetylcholine overcomes the competitive inhibition of atropinic agents, such as those found in jimsonweed. Rapid, though generally transient, reversal of peripheral and central nervous system (CNS) effects can ensue. However, bradycardia, asystole, ventricular arrhythmias, hypotension, bronchospasm, bronchorrhea, and seizures have been reported after rapid IV administration of physostigmine, limiting its routine use. Persons with cardiac conduction abnormalities are particularly susceptible to the cardiac complications. Use of physostigmine generally does not shorten the hospital stay.*

Most cases of anticholinergic poisoning can be managed safely and effectively with supportive care alone.²⁴⁰ Consultation with a toxicologist is recommended before using physostigmine. If physostigmine is used, the recipient should be on a cardiac monitor, with pulse oximetry, and a physician at the bedside should slowly administer graduated doses of the drug.^36,104,242

Tobacco Plants

Tobacco contains both nicotine and related alkaloids with similar pharmacologic properties, such as the alkaloid anabasine, which is found in Nicotiana glauca (wild tree tobacco) (Figure 64-5). N. glauca has been mistaken for Amaranthus hybridus (marog) and eaten with porridge in South Africa. Ingestion of N. glauca is generally fatal. Anabasine, an isomer of nicotine that appears to be more toxic than nicotine, probably accounts for much of the toxicity of N. glauca, N. debneyi, and N. rotundifolia. Anabasine concentrations can be particularly high in the roots of the plants. Although there are over 60 Nicotiana species, some other more common tobacco family members include N. rustica (Mapacho), N. tabacum (cultivated or common tobacco), N. trigonophylla (desert tobacco) (Figure 64-6), and N. attenuata (coyote tobacco). N. tabacum is the major source of commercial tobacco and contains between 0.5% and 9% nicotine. N. rustica (Mapacho) tends to contain higher concentrations of nicotine than does N. tabacum. Nicotine alkaloids are rapidly absorbed from the oral and GI tracts, the respiratory tract, and the skin. The kidneys excrete nicotine fairly rapidly after biotransformation in the liver and lungs. The half-life is 1 to 2 hours. Although the lethal dose of ingested nicotine is not well established, 2 to 5 mg may cause nausea, and 40 to 60 mg may be lethal in humans. One to two cigarettes, ingested and absorbed, could be lethal in a child.^{176,180,228,236,247}

FIGURE 64-5 Tree tobacco (Nicotiana glauca).

FIGURE 64-6 Nicotiana trigonophylla (desert tobacco) and other Nicotiana species are characterized by narrow tube-like flowers.

(Courtesy Kimberlie A. Graeme, MD.)

Nicotinic Syndrome

Peripherally, acetylcholine is a neurotransmitter for autonomic and somatic motor fibers. It is stored in vesicles within the presynaptic neuron and is released by calcium-dependent exocytosis into the synapse, where it binds to receptors and is eventually degraded by acetylcholinesterase. Acetylcholine can bind to two receptor types, nicotinic and muscarinic. Nicotinic receptors are located on postganglionic autonomic neurons (N_N receptors) and at skeletal neuromuscular junctions (N_M receptors). Direct nicotinic agonists (e.g., arecoline, coniine, cytisine, lobeline, nicotine) prolong depolarization at these receptors and eventually cause blockade of nicotinic receptors. Clinical evidence of stimulation followed by blockade is apparent. Hypertension, tachycardia, pallor, vomiting, diarrhea, abdominal pain, salivation, bronchorrhea, tachypnea, muscle fasciculations, spasms, confusion, agitation, tremor, and convulsions (the stimulation) are followed by hypotension, bradyarrhythmias (occasionally asystole), hyporeflexia, paralysis, coma, and respiratory failure (the blockade). When death occurs, it is generally due to respiratory paralysis (Box 64-2; see also Figure 64-3).*

Green tobacco sickness is a mild form of nicotine poisoning seen in tobacco-naive field workers with dermal exposure to leaves of green tobacco in wet environments. Nicotine, a water-soluble alkaloid, is absorbed dermally. The syndrome is characterized by weakness, salivation, nausea, vomiting, diarrhea, abdominal cramps, headache, dizziness, visual and hearing disturbances, respiratory depression, and occasionally fluctuations in blood pressure and heart rate. Neuromuscular blockade may result in death. A urinary nicotine metabolite, cotinine, may be helpful diagnostically.^{15,176,228,247}

Lobeline, derived from the Indian tobacco plant Lobelia inflata, is a high-affinity nicotinic ligand. It can cause nicotine-like effects, but is generally less toxic than is nicotine.⁶³

Poison Hemlock

C. maculatum (poison hemlock) (Figure 64-7), also known as spotted hemlock, California or Nebraska fern, stinkweed, fool’s parsley, and carrot weed, is often mistaken for an edible plant, such as parsley, parsnip, or anise; however, it has a mousy odor and an unpleasant bitter taste, and it burns the mouth and throat. The stem is hollow with purplish to reddish brown spots. Its long taproot is solid and parsnip-like. Although all plant parts are poisonous, the unripe fruit is especially toxic. Poisonings are more common in the spring and summer. Poisoning may also occur after eating birds that have consumed poison hemlock. Coniine and γ-coniceine, the principal alkaloids in C. maculatum, are pyridine derivatives similar to nicotine. Coniine is more toxic than is γ-coniceine. The alkaloid is volatile and susceptible to drying and heating.^{25,152,228,268,274}

FIGURE 64-7 Poison hemlock (Conium maculatum).

C. maculatum was used in ancient times for capital punishment and murder. The primary action of the toxic alkaloids is activation and then blockade of nicotinic acetylcholine receptors. Initially, stimulation causes sialorrhea, nausea, vomiting, diarrhea, abdominal cramping, tremor, ataxia, confusion, blurred vision, hypertension and tachycardia, followed by dry mucosae, GI hypotonia, lethargy, weakness, diminished cardiac contraction, hypotension, and bradycardia, as with nicotinic syndrome. Muscles rapidly swell and stiffen, with multifocal necrosis of myocytes and associated muscle pain. Muscle fasciculations may be followed by flaccid paralysis, including respiratory paralysis. Rhabdomyolysis and acute tubular necrosis with renal failure may occur. Elevated CPK and liver function tests (LFTs) may be noted. Death is usually from respiratory failure. Autopsy may reveal congestion of the lungs and liver.*

Betel Nut

Areca catechu (areca palm) (Figure 64-8) produces betel nut, a common masticatory drug in the Far East, Asia, India, and the South Pacific; it is also shipped elsewhere. An estimated 10% to 25% of the world’s population chews “betel quid.” It is generally chewed with slaked lime paste (calcium hydroxide) wrapped in leaves of betel pepper (Piper betel). known as “quid,” “punsupari,” and “pan masala.” Occasionally, tobacco is added. Quid is sucked in the lateral gingival pocket. Commercially, areca nut is marketed in the form of sweetened areca nut, known as “supari.” A. catechu contains arecoline and guvacoline, which are hydrolyzed to arecaidine and guvacine, respectively. These are strong inhibitors of gamma-aminobutyric acid (GABA) uptake. These arecal alkaloids also are nicotinic and muscarinic. Betel pepper leaves contain betel oil, which contains psychoactive phenols and cadinene. These possess cocaine-like properties. Clinical effects resemble nicotinic syndrome and cholinergic toxicity, including CNS effects (dizziness, euphoria, subjective arousal, altered mental status, hallucinations, psychosis, convulsions), cardiac effects (tachycardia, hypertension, palpitations, arrhythmias, bradycardia, hypotension, chest discomfort, and acute myocardial infarction in susceptible individuals), pulmonary effects (bronchospasm, tachypnea, dyspnea), GI effects (salivation, vomiting, diarrhea), urogenic effects (urinary incontinence), and musculoskeletal effects (weakness and paralysis). Use with calcium salts may result in hypercalcemia, hypokalemia, and metabolic acidosis with renal potassium wasting and renal insufficiency. Betel nut use is also associated with flushing, diaphoresis, warm sensations, red- or orange-stained oral mucosa and saliva, and teeth stained dark brown or black. Precancerous oral lesions may also occur with chronic use.†

FIGURE 64-8 Betel nut (Areca catechu).

(Courtesy Daniel Brooks, MD, and Tammy Tyree, NP.)

Blue Cohosh

Caulophyllum thalictroides is known as blue cohosh or squaw root. All parts of the plant contain the nicotinic alkaloid n-methylcytisine, which is much less potent than nicotine. Teas made from C. thalictroides have been used to induce labor and have resulted in newborn death and perinatal complications of stroke, congestive heart failure, respiratory failure, and circulatory collapse. The infant toxicity is thought to be due to the toxic saponins, caulosaponin and caulophyllosaponin.²²⁸

Golden Chain Tree

All parts of Laburnum anagyroides (golden chain tree) are toxic and contain the nicotinic alkaloids cytisine and n-methylcytisine. Cytisine is a quinolizidine alkaloid but is often classified with the pyridine and piperidine alkaloids. These alkaloids stimulate nicotinic ganglions. The toxins are concentrated in the seeds. Toxicity is generally only mild to moderate; however, an unusual fatality occurred in which 23 seedpods were found in the stomach of an adult at autopsy. Other plants that contain cytisine include Kentucky coffee tree (Gymnocladus dioica), necklace pod sophora (Sophora tomentosa), and mescal bean bush (Sophora secundiflora) (Figure 64-9) (see Hallucinogenic Plants, later). Structures follow:²²⁸

FIGURE 64-9 Mescal bean bush (Sophora secundiflora) (A) is characterized by bean pods that contain burnt-red seeds (B) and by purple blooms (C).

(Courtesy Phillip Saba, MD, and Kimberlie A. Graeme, MD.)

Treatment

Treatment of nicotinic syndromes consists of supportive care with particular attention to airway protection and ventilation. Administration of activated charcoal has been used because it adsorbs nicotine in vitro. However, nicotine and related alkaloids are absorbed rapidly and often produce vomiting, which may limit the usefulness of activated charcoal. These alkaloids may also induce altered mental status, which can increase the risks associated with activated charcoal. Benzodiazepines and barbiturates are given for seizures. Adequate urine output is maintained, with consideration of urine alkalinization. Treating initial excessive adrenergic stimulation with adrenergic antagonists is ill advised because this complicates the nicotinic blockade that typically follows. Symptomatic bradycardia is treated with atropine; hypotension can be treated with IV fluids and inotropic agents if needed. Atropine may also help to treat bronchorrhea.²²⁸

Ergot

The ergot alkaloids ergonovine and ergotamine are indole derivatives found in the fungus C. purpurea, which infects rye and other grains. The ergot alkaloids are serotonin agonists. Commercial grains are now inspected for the presence of ergot, and inadvertent poisoning is rare. An outbreak of ergotism occurred in Ethiopia in 1977. In the Middle Ages, epidemics of ergotism resulted from repeated ingestion of ergot-contaminated breads.

Ergotism has two forms, gangrenous and convulsive. Both begin similarly with a vague illness that may include GI symptoms, progressing to a sensation of ants crawling on the skin, primarily affecting the legs. Hallucinations can occur with both forms. Gangrenous ergotism, a vasospastic disease, was the cause of the ninth-century epidemic disease known as St Anthony’s fire, which consisted of burning limb pain and eventual loss of limb sensation, followed by gangrene and autoamputation of charcoal-black limbs. People migrated to St Anthony’s Order, a society of monks, and began to heal, once they received a diet free of ergot-contaminated grains. Convulsive ergotism is characterized by painful flexion of the fingers and wrists, flexion or extension of the ankles, double vision, altered mental state, hallucinations, and diaphoresis. With progression, the body becomes bent in spasm, appearing to roll up into a ball, or it becomes rigid in extension; this may be followed by seizures.*

Morning Glory

The active component of the naturally occurring hallucinogen found in the seeds of morning glory (Ipomoea violacea) (Figure 64-10) is ergine, or (+)-lysergic acid amide, an indole derivative.¹¹² About 300 seeds, or enough to fill a cupped hand, are equivalent to 200 to 300 mg of LSD, with similar systemic and hallucinatory effects. Ingestion of Hawaiian baby woodrose seeds (Argyrlia nervosa) has similar effects.¹⁰⁵

FIGURE 64-10 Morning glory (Ipomoea violacea).

Nutmeg

Myristica fragrans (Figure 64-11) is used to make the spices nutmeg and mace. Mature rinds of the fruit split, revealing a bright-red, fringed, fleshy coating on the outside of its seed. The coating contains mace, and the seed contains nutmeg. Nutmeg contains myristicin, which has an indole-like structure and is metabolized to amphetamine-like compounds. Other alkylbenzene derivatives, such as safrole and elemicin, are also found in nutmeg. Nutmeg has been abused for its alleged hallucinogenic effects. A person who ingested one grated nutmeg (7 g) had weakness, loss of coordination, vertigo, fainting, nausea, and paresthesias but no hallucinations.^238,265

FIGURE 64-11 Nutmeg (Myristica fragrans).

(Courtesy Daniel Brooks, MD, and Tammy Tyree, NP.)

Cannabis

Cannabis preparations are largely derived from the female Cannabis sativa plant. The primary psychoactive component is δ-9-tetrahydrocannabinol (THC), which is most concentrated in the flowering tops. Marijuana generally contains 0.5% to 5% THC; however, the Sinsemilla and Netherwood varieties may contain up to 20% THC, and hashish and hashish oils have higher concentrations. Cannabinoids can be smoked or ingested. A typical marijuana cigarette contains 0.5 to 1.0 g of cannabis, and the THC delivered varies from 20% to 70%, with a bioavailability of 5% to 24%. As little as 2 mg of available THC produces effects in occasional users.¹¹⁹

Cannabinoids bind to specific cannabinoid receptors in areas of the brain involved with cognition, memory reward, pain perception, and motor coordination. Cannabinoids act as neuromodulators in the release and action of neurotransmitters (e.g., acetylcholine, glutamate).^75,119 Endogenous ligands for these receptors are endocannabinoids. The first endocannabinoid identified was anandamide, named after the Sanskrit word ananda, which means “bliss.”

Desirable effects include mild mood-altering qualities, euphoria, alteration in perceptions, time distortion, and intensification of ordinary sensory experiences (e.g., gustatory, visual, and auditory sensations). Adverse effects include impairment of short-term memory and attention, mydriasis and slowly reactive pupils, impairment of motor skills and reaction times, nausea, vomiting, and anxiety. Psychotic symptoms have been reported in persons vulnerable to psychosis. Clinically, tachycardia may occur within minutes of THC exposure and may last a few hours. Minor changes in blood pressure may also occur. Exposed toddlers may present with lethargy, slurred speech, ataxia, and shaking.^27,119

Peyote

The hallucinogenic peyote cactus Lophophora williamsii (Figure 64-12) contains alkaloids that are phenylethylamines or isoquinolines rather than indoles. Mescaline (3,4,5-trimethoxy-β-phenylethylamine), the primary psychoactive component of peyote, is structurally similar to the neurotransmitters norepinephrine and epinephrine and to hallucinogenic amphetamines. Pharmacologically, however, mescaline is similar to hallucinogenic indoles. Mescaline may affect the action of norepinephrine and serotonin, evidenced clinically by sympathomimetic effects, followed by marked visual hallucinations. Mescaline produces slight rises in blood pressure and heart rate, tachypnea, hyperreflexia, mydriasis, ataxia, perspiration, flushing, salivation, and urination. No deaths have been reported from peyote poisoning. Type B botulism was associated with consumption of a ceremonial tea made from peyote that was stored in a jar by members of the Native American Church. Affected members had bilaterally symmetric, flaccid weakness in all extremities, dysphagia, nasal speech, and diplopia.^9,126

FIGURE 64-12 Peyote (Lophophora williamsii).

Mescal Bean Bush

The mescal bean bush or Texas mountain laurel (Sophora secundiflora) of the pea family (Fabaceae) produces hallucinogenic dark-red beans (mescal beans; see Figure 64-9). The beans contain the toxic alkaloid cytisine, which causes nausea, numbing sensations, hallucinations, unconsciousness, convulsions, and death through respiratory failure. The beans may be boiled in water and the mixture consumed, producing a delirium or “visionary trance.” The origin of mescalism in modern peyote religion is debated. Mescal beans are worn during some peyote ceremonies.⁹

Tabernanthe iboga

Tabernanthe iboga contains indole alkaloids, including ibogaine. The root of this plant is used in West Africa to communicate with ancestors, reportedly producing “visions” and “waking dreams.” It produces altered states of consciousness, delusions, hallucinations, mydriasis, tachycardia, tremor, and ataxia. Convulsions and lethal respiratory arrest have also been reported. A man was found dead after ingesting a powdered root bark of T. iboga shrub mixed with sweet concentrated milk. Autopsy revealed pulmonary edema with hemorrhagic alveolitis and vascular congestion.^39,151

Khat

The evergreen khat tree, Catha edulis, grows in East Africa and Arabia (Figure 64-13). Khat is also known as chat, qat, kat, kath, gat, eschat, miraa, murungu, qaad, and jaad. As early as 1237, khat was advocated in Arabic medical literature as a mood-elevating and hunger-suppressing agent. Khat leaves and bark continue to be chewed, with the juice of the masticated plant being swallowed for stimulatory effects. Khat contains cathinone (2-amino-1-phenyl-1-propanone), cathine (norpseudoephedrine), and norephedrine. Cathinone, a phenylalkylamine, is the major psychoactive constituent. Structurally, cathinone is similar to amphetamines, and khat has been referred to as a “natural” amphetamine. Like amphetamines, cathinone is an indirect sympathomimetic, inducing release of dopamine, serotonin, and norepinephrine.*

FIGURE 64-13 Khat (Catha edulis).

(Courtesy Daniel Brooks, MD, and Tammy Tyree, NP.)

The structures of methcathinone, cathinone, and ephedrine follow:

Cathinone in fresh plant material must be extracted by masticating laboriously; this results in gradual absorption. As the leaf wilts, cathinone content decreases and the leaf loses its potency as a psychostimulant. Because only fresh leaves produce the desired stimulatory effects, in the past, khat use was generally limited to countries where khat was produced (e.g., North Yemen, Ethiopia, Kenya); however, khat is now air-freighted to Europe and the United States, with a recent increase in use in upstate New York. Khat is transported damp, rolled in a banana leaf bundle called a marduff.

Desirable effects of khat include increased energy and alertness, feelings of increased endurance and self-esteem, enhanced imaginative ability, higher capacity to associate ideas, and euphoria. Cathinone has both positive chronotropic and inotropic effects. Tachycardia, increased blood pressure, tachypnea, and mydriasis are seen. Adverse effects include anorexia, hypomania, insomnia, delusions, paranoid psychosis, aggression, depression, anxiety, hyperthermia, stomatitis, oral lesions/cancers, gastritis, and endocrine disturbances. Khat use has also been associated with vasoconstriction, acute myocardial infarction, leukoencephalopathy and an increased incidence of acute cerebral infarction. Khat is known to be habit forming and has been classified as a substance of abuse by the World Health Organization. Cathinone is a Schedule I controlled substance under federal regulations in the United States.†

Treatment

Treatment of patients exposed to hallucinogenic plants is generally supportive. First-line treatment for agitation is generally benzodiazepines.

Poppy

Papaver somniferum flowers are large and white with purple stains at the base of each petal. They yield opium, a complex of more than 20 alkaloids, including morphine, codeine, and papaverine. Morphine was the first plant alkaloid isolated, by pharmacist Friederich Wilhelm Adam Serturner in 1806.¹¹⁷ Seeds of P. somniferum are used in various foods and beverages, including bagels, muffins, pastries, curry sauce, rice, and teas. Opiate toxicity from poppy seed exposure occurred in a 6-month-old infant given 75 mL of strained milk made with 200 g of poppy seeds in 500 mL milk, resulting in respiratory arrest requiring ventilation. Opiate toxicity has also occurred after ingestion of a boiled poppy plant and after ingestion of spaghetti with poppy seeds. Poppy dependence has also been described. Ingestion of poppy seeds can result in detectable levels of morphine and codeine by urine drug screen testing.^{146,158,204,262}

Yellow Jasmine

Gelsemium sempervirens (Carolina or yellow jessamine) is a woody perennial evergreen vine with fragrant yellow flowers. It contains multiple indole alkaloids, including gelsemine, gelseminine, and gelsemoidin. Gelsemine binds to acetylcholine receptors at the neuromuscular junction (peripheral nicotinic acetylcholine receptors) and, to a lesser extent, at muscarinic receptors. A toddler who ate the blossoms of G. sempervirens experienced neuromuscular blockade with ataxia, dysarthria, facial and extremity weakness, bilateral ptosis, and transient coma. The child recovered without sequelae.²⁶

Strychnine

Strychnine, an indole found in seeds of the tree Strychnos nux-vomica, is a powerful CNS stimulant. Poisoning may also occur after ingestion of rodent poisons containing strychnine, with the use of illicit drugs contaminated with strychnine, or with the use of herbal remedies contaminated with strychnine. Strychnine is especially concentrated in the seeds and roots of the plant. The bark of S. nux-vomica also contains the alkaloid brucine, which is less potent than strychnine, but produces similar toxicity when consumed. Strychnine is a selective, competitive antagonist of glycine, a major inhibitory neurotransmitter, at its postsynaptic receptors in the spinal cord and brainstem. Poisoning produces an excitatory state, with hyperreflexia, hypersensitivity to stimuli, migratory rippling movements of the muscles, twitching, rigidity, and spinal convulsions (generally, flexor spasm of the upper limbs, extensor spasm of the lower limbs, opisthotonic posturing, and spasms of the jaw muscles, all without loss of consciousness or postictal states). Minimal stimulation elicits diffuse muscle contractions. In between spasms, which last from 30 seconds to 2 minutes, muscles become completely relaxed. Respiratory and secondary cardiac failure may ensue during severe convulsions. Treatment consists of supportive care, benzodiazepines, and barbiturates. Chemical paralysis with a nondepolarizing agent, endotracheal intubation, and mechanical ventilation may be required for severely poisoned patients. Hyperthermia, rhabdomyolysis, renal failure, and acidosis may occur secondary to convulsions. These complications often require treatment. Occasionally, death ensues despite aggressive treatment.*

Some Strychnos species in Africa contain alkaloids that produce curare-like effects. These alkaloids act through nondepolarizing and competitive mechanisms at the neuromuscular junction, competing with acetylcholine for the receptor, hence blocking nerve-to-muscle transmission. This results in paralysis; however, paralysis is not seen after ingestion of these species, because the toxic alkaloids are not absorbed from the gastrointestinal tract.²⁰⁷

Wild Wisteria

The root of Securidacea longepedunculata (violet tree; wild wisteria) has been used as an intravaginal suicidal poison and an abortifacient. The distilled oil of the root is primarily methyl salicylate (discussed latter with essential oils); however, wild wisteria also contains the alkaloid securinine, a GABA-A receptor antagonist, which produces hyperreflexia, hypertonia, and seizures. Death can result within hours of placing the root intravaginally, and is generally preceded by vomiting, diarrhea, and dehydration.²⁴⁶

Water Hemlock

Water hemlock (Cicuta maculata) is one of the most toxic resin-containing plants. The resin of C. maculata, an unsaturated aliphatic alcohol called cicutoxin, has the following structure:

Species within the Umbelliferae (also called Apiaceae) family are divided into the Cicuta and Oenanthe genera. Nine subspecies of Cicuta of the Umbelliferae family are poisonous (Figure 64-14). C. virosa is common European water hemlock, whereas C. maculata and C. douglasii are found in North America. Oenanthe crocata, or hemlock water dropwort, is found in Europe and North America. Common names for Cicuta species include cowbane, five-finger root, snake weed, snake root, wild carrot, dead man’s fingers, death-of-man, poison parsnip, wild parsnip, beaver poison, children’s bane, muskrat weed, spotted hemlock, spotted cowbane, musquash root, false parsley, fever root, mock-eel root, wild dill, spotted parsley, and carotte à Moreau. Roots have a parsnip-like or carrot-like odor, and Cicuta species are often mistaken for edible plants, such as water parsnip. These plants have also been mistaken for pignut, sweet flag, wild carrot, wild celery, wild ginseng, and kvanne. Mature roots have air-filled chambers and are found on the ends of hollow stems. All parts of the plant are toxic, but the roots contain the highest concentration of cicutoxin. Ingestion of as little as 2 to 3 cm of the root may be fatal to an adult. The severity of poisoning and time until onset of symptoms is proportional to the amount of plant ingested. The plant is most toxic in the spring. The principal toxins, cicutoxin and oenanthotoxin, contained in these plants act as noncompetitive GABA antagonists in the central nervous system, resulting in unabated neuronal depolarization that manifiests as seizures, including status epilepticus.^{104,131,152,229}

FIGURE 64-14 Cicuta species have characteristic flowering tops, typical of the Umbelliferae family (A), and roots with air-filled chambers at the ends of hollow stems (B).

(Courtesy Steven Curry, MD.)

Water hemlock poisoning should be considered in any patient who presents with cholinergic-like poisoning and abrupt onset of seizures. Early symptoms include muscarinic effects and involve primarily the GI tract: abdominal pain, vomiting, and diarrhea. However, marked diaphoresis, salivation, and respiratory distress may also be seen. Nicotinic effects are less prominent (see Figure 64-3). Tachycardia and hypertension or bradycardia and hypotension may be seen. Dysrhythmias may occur. Ataxia, paresthesias, muscle spasms, weakness, and altered mental status have been reported. With severe poisoning, coma and epileptiform seizure activity, or spastic and tonic movements, including opisthotonus without electroencephalographic seizure activity, may occur. Rhabdomyolysis and renal failure have been reported. Deaths may be associated with persistent seizures, cerebral edema, ventricular fibrillation, pulmonary edema, cardiopulmonary arrest, and disseminated intravascular coagulation. Laboratory abnormalities include metabolic acidosis and elevated CPK and LFTs. Treatment includes securing an airway, ventilation, and treatment of seizures with benzodiazepines and barbiturates. Phenytoin is contraindicated because it is ineffective for seizure control. Anticholinergic agents are not recommended, because these agents do not reduce seizure activity. Continuous EEG monitoring is helpful. Treatment of hypoxia, acidosis, hyperthermia, rhabdomyolysis, and cerebral edema should be provided. Hypotension can be treated with intravenous fluids and vasopressors. Recovery can take up to 4 days, and some patients never completely recover. Although survival has improved with aggressive supportive care, death may still ensue. Autopsies reveal pulmonary and cerebral edema, brain hemorrhages and renal necrosis.^{104,131,152,229}

Myrtle-leaved Coriaria

Coriaria myrtifolia (also known as myrtle-leaved coriaria, Currier’s sumach, or Redoul sumach) grows in the western Mediterranean area. C. myrtifolia contains coriamyrtin, an analogue of picrotoxin. The toxin is found in high concentrations in the berries, which resemble blackberries. Ingestion of only a few fruits can produce significant toxicity. The leaves are also toxic. Rarely, individuals have become poisoned after eating snails acquired off the plant, after drinking the milk of goats that had been eating the plant, and after consuming honey contaminated by its nectar. The leaves have also been mistakenly eaten when thought to be the leaves of senna (Cassia senna L.). Initially, vomiting, abdominal pain and drunken intoxication are seen. This may be followed by twitching, seizures (including status epilepticus), coma and apnea. Death may occur. Treatment with benzodiazepines and barbiturates should be considered.⁶⁹

Other Convulsants

Anticholinergic and nicotinic plants may produce seizures, as discussed earlier. Ingestion of plants that produce hypoglycemia, such as ackee (B. sapida), wild yam (Dioscorea spp.), cocklebur (Xanthium spp.), bird-lime (Atractylis gummifera) and ox-eye daisy (Callilepis laureola) are associated with seizures and discussed later.

Foxglove

D. purpurea grows wild in parts of the United States and is cultivated as a garden ornamental plant. D. purpurea contains only digitoxin, not digoxin. Withering reported the medical use of extracts of D. purpurea based on a recipe for treating “dropsy.”^129,192 The leaves have been consumed in a risotto when they were mistaken for borage leaves, and in a salad when mistaken for dandelion leaves.^38,189 Toxicity has also been reported from consumption of contaminated field water with Digitalis plants growing nearby.¹⁸⁹ D. lanata was mistakenly substituted for plantain in herbal products, with resultant human cardiotoxicity.²³⁹ D. lanata contains lanatosides A, B, and C, which yield digoxin and digitoxin. Intentional overdoses also occur.^157,189

Oleander

All parts of N. oleander and T. peruviana are toxic, but the seeds contain more glycoside than do other parts of the plant. Yellow oleander (T. peruviana), a native plant of tropical America, grows abundantly in the United States. Ingestion of a couple of seeds of yellow oleander, known as “lucky nuts,” can result in death; however, the number of seeds ingested is a poor guide to the degree of poisoning. Yellow oleander contains the cardiac glycosides thevetin A and B, thevetoxin, neriifolin, peruvoside, ruvoside, and others. It is a popular suicidal agent in Sri Lanka and India. Of patients admitted with T. peruviana poisoning in Sri Lanka, 43% had arrhythmias, many requiring temporary pacing; 6% died shortly after admission. Common oleander (N. oleander), a native plant of the Mediterranean, grows abundantly in the United States. Common oleander contains the principal cardiac glycosides oleandrin and neriine, as well as folinerin and digitoxigenin. Severe toxicity has been reported after consumption of unprocessed common oleander leaves and prepared teas. Chronic toxicity has occurred with criminal intentional poisoning. Topical application of homemade N. oleander solutions onto psoriatic wounds has resulted in toxicity.*

Squill

U. maritima was used by ancient Egyptians and Romans as a diuretic, heart tonic, expectorant, emetic, and rat poison. Squill contains several cardiac glycosides, including scillaren A, glucoscillaren A, scillaridin A, and scilliroside.^86,260,271

Sea Mango

C. manghas (sea mango) is similar to C. odollam (pink-eyed cerbera, yellow-eyed cerbera, suicide tree). This tree grows in India, Vietnam, Cambodia, Sri Lanka, Burma (Myanmar), Madagascar, and Australia. The plant has large white flowers that smell like jasmine. When the fruit is still green, it looks like a small mango. The inner fruit (kernel) is white, but upon exposure to air turns violet, then dark grey, and then black. The crushed, white fleshy kernel is commonly consumed as a suicidal poison in India and Sri Lanka. The seeds are quite toxic. The leaves are less toxic. These plants contain the toxins cerberoside, cerberin, and odollin. After ingestion, death can occur within hours.^{83,107,168,259}

Clinical Presentation

The onset of symptoms and duration of action are well known for certain glycoside preparations, such as digoxin, digitoxin, and ouabain, but may vary considerably after plant ingestions. For example, oleandrin exhibits protracted binding times to cardiac myocardial tissues.¹⁶¹ Generally, cardiac glycoside toxicity produces nausea, vomiting, diarrhea, abdominal tenderness, visual changes (appearance of yellow and green colors, “halos,” geometric shapes, scintillations, photophobia), mental status changes (disorientation, psychosis, lethargy, stupor, dysarthria, weakness, dizziness, restlessness, seizures), cardiac disturbances (palpitations, premature ventricular beats, bradycardia, atrioventricular block, sinus node block, paroxysmal atrial tachycardia with block, junctional tachycardia, bidirectional ventricular tachycardia, ventricular arrhythmias, myocardial depression with cardiogenic shock, syncope), hyperkalemia, and death. When death occurs, it is generally caused by cardiotoxicity. The ECG may reveal nonspecific ST-segment and T-wave changes, similar to digoxin-induced changes.* Serum digoxin levels may be elevated after exposure to plants containing cardiac glycosides, because antibody-based digoxin assays cross-react nonquantitatively with many cardiac glycosides. Digoxin immunoassays predict only the presence of the glycoside, not the degree of toxicity.^{82,116,161,260} Conversely, the degree of hyperkalemia often correlates with severity of toxicity.^82,107