Conium maculatum, poison hemlock, is one of the highly poisonous perennial herbaceous flowering plants of the family Apiaceae, native in temperate regions of Europe, West Asia, as well as North Africa, but has been introduced and naturalized in many other areas, including Asia, North America, Australia, and New Zealand. Upon drying the toxicity of the plant material is greatly reduced, although not gone completely, implying that the toxic principle might be a volatile one or unstable. Up to now ten volatile alkaloids have been identified of which coniine and γ-coniceine are generally the most abundant ones and they account for most of the plant’s acute and chronic toxicity. The latter, which is the first formed biosynthetically and is more toxic, often accompanies coniine, sometimes occurring in greater quantities.
General symptoms of hemlock poisoning include an initial stimulation of motor nerve endings and central nervous system, followed by paralysis and depression, respectively, problems in movement, slow and weak, then later, rapid pulse, hyperventilation, urination, and finally coma and death.
Conium maculatum contains piperidine alkaloids: coniine (2-propylpiperidine), N-methyl-coniine (1-methyl-2-propylpiperidine), conhydrine 2-(1-hydroxypropyl)-piperidine, pseudoconhydrine (5-hydroxypropyl)-piperidine (these are saturated piperidine alkaloids) and γ-coniceine (2n-propyl-1Δ-piperidine), a partially unsaturated one. Conhydrinone and N-methyl-pseudoconhydrine were later isolated.
The piperidine alkaloids (numbering several hundred) in general are derived biosynthetically from lysine, acetate or mevalonate as the precursor. The piperidine alkaloids found in Conium maculatum are acetate-derived. The results of chemical and biochemical investigations suggested, that Conium piperidine alkaloids are formed by the cyclisation of an eight-carbon chain derived from four acetate units. Nitrogen was incorporated at some stage in the pathway to give the piperidine nucleus. Experiments with N-labelled amino acids showed, that l-alanine provided the N in a transaminase catalysed enzymatic reaction (the presence of such a aminotransferase which produces γ-coniceine from 5-oxooctanal, was established). After the transamination, the 5-oxooctylamine is formed, there is a non-enzymatic cyclisation producing γ-coniceine. γ-Coniceine is the precursor of the other Conium alkaloids. The observation, that when the concentration of coniine was higher, the concentration of γ-coniceine was low, and vice versa supported the precursor role of γ-coniceine in the biosynthesis of coniine.
The interconversion of coniine and γ-coniceine in Conium plants indicated that these compounds are members of an oxidation-reduction system. The γ-coniceine was reduced to coniine by a γ-coniceine reductase but the reverse reaction also occurred. The reduction of γ-coniceine, however, is stochiometrically preferred.
MECHANISMS OF TOXICITY
Nicotine-like alkaloids act agonistically at nicotinic-type acetylcholine (cholinergic) receptors (nAChRs). These sodium-gated receptors exist widely in the central and autonomic nervous systems, and the neuromuscular junction; they can be present at either pre- or postsynaptic sites. Their autonomic sites include the adrenal medulla and autonomic ganglia; in the latter case the postsynaptic receptors are located on the commencement of the postganglionic autonomic neurons, whose junction with the end organs involves cholinergic (muscarinic type) or norepinephrine.
The nicotinic alkaloids act as agonists on the nAChRs, causing increased sodium ion influx through the channel, which leads to prolonged membrane depolarization and consequently enhanced action potential propagation. Increased ganglionic transmission to the postganglionic sympathetic fibers and catecholamine release from the adrenal gland may cause tachycardia and hypertension. Also, discharges directly from the spinal cord can cause muscle fasciculations and tremor. Furthermore, increased postganglionic parasympathetic fiber activity can also occur, with risk of miosis, salivation, lacrimation, and bronchospasm. However, nAChRs do not play a direct role at the neuroeffector junctions, where muscarinic cholinergic (and noradrenergic) receptors predominate. Indeed, because of the large number of different neuronal receptor types, the dose–response relationships of nicotine and related alkaloids are complicated.
Over a substantial dose range, increasing acute doses of these alkaloids result in proportionally more stimulation of the nAChRs, and thus greater associated adrenergic, somatic, cholinergic (and central) symptoms, as described above. However, paradoxically, at still greater doses and/or more sustained exposures, autonomic ganglionic blockade can occur, which, along with similar effects on central nicotinic receptors, can lead to hypotension, bradycardia, and respiratory depression.
A hemlock poisoning is recorded in humans who have mistakenly eaten the leaves of the plants for parsley (Petroselinum crispum) or the roots for parsnips (Pastinaca sativa), or the seeds for anise (Pimpinella anisum). The primary action on hemlock is on the central nervous system. The effect of the plant is similar to poisoning with nicotine. The symptoms of human poisoning are in general the same as of the animals, but the acute renal failure seems to be a symptom only of the human poisoning.
In the non-rapidly fatal cases they tested myoglobinuria, serum muscle enzymes and renal function. In the patients with acute renal failure were performed microscopic examination of kidney; immunohistochemistry was performed to identify myoglobin and actin in tubules. The alkaloid coniine was detected in urine, serum or tissues. Neurological features were presented in all of the cases coniine had a curare-like effect on the neuromuscular junction.
The mechanism of action of Conium alkaloids is twofold. The most problematical effect occurs at the neuromuscular junction where they act as non-depolarizing blockers, similar to curare. Death is usually caused by respiratory failure.
The Conium alkaloids produce a biphasic nicotine-like effect.
The initial stimulatory effects include nausea and vomiting, excessive salivation, diarrhea, and abdominal pain. Hypertension and tachycardia reflect increased adrenergic tone but may partly relate to constriction of coronary arteries; pallor from constriction of peripheral blood vessels is also common. Early neurological effects include ataxia, tremor, restlessness, headache, visual and hearing disturbances, confusion, dizziness, muscle fasciculations, miosis, and seizures; deep tendon reflexes may also be diminished. Additional early symptoms include diaphoresis and tachypnea.
After the initial stimulatory phase, a period of direct depressor effects can ensue, because of “paradoxical” inhibition of the nicotinic cholinergic receptors.
In this second phase circulatory effects can change to hypotension and sinus bradycardia, cardiac conduction abnormalities and dysrhythmias, block, atrial fibrillation, QT prolongation, and ventricular fibrillation. Central effects include central nervous system depression and coma. Mydriasis has also been reported, which may be due to autonomic factors. Increasing neuromuscular blockade can lead to ptosis, muscular weakness, and/or paralysis, with dyspnea or apnea, respiratory failure and central nervous system depression. Deaths have occurred, which appear to be due to severe respiratory depression caused by muscular paralysis or to cardiovascular collapse. Coniine can produce rhabdomyolysis by either a direct toxic effect on skeletal muscle or a strychnine-like pro-consulvant action on the central nervous system.
Ingestion of C. maculatum plant material may result in toxicity and death. Two adults died after ingesting an unknown amount of hemlock, which was prepared by boiling the leaves in water. An estimated lethal dose in a 3-year-old male has been reported to be approximately 142 g of leaf material. Intubation has been required 40 min after an adult ingested an unknown amount of C. maculatum plant matter.
Clinical spectrum of accidental hemlock poisoning, 1991
Poison hemlock-induced respiratory failure in a toddler, 2009
Poison hemlock intoxication does not seem to be a contraindication to organ donation, 2003
Acute renal failure due to tubular necrosis caused by wildfowl-mediated hemlock poisoning, 1993
C. maculatum’s effects have been studied also in animals, to which it’s poisonous too. In a short time the alkaloids produce a potentially fatal neuromuscular blockage when the respiratory muscles are affected. Acute toxicity, if not lethal, may resolve in the spontaneous recovery of the affected animals provided further exposure is avoided. It has been observed that poisoned animals tend to return to feed on this plant. Chronic toxicity affects only pregnant animals. When they are poisoned by C. maculatum during the fetus's organ formation period, the offspring is born with malformations, mainly palatoschisis and multiple congenital contractures (MCC; frequently described as arthrogryposis). Chronic because of the difficulty in associating malformations with the much earlier maternal poisoning. Toxicity is irreversible and although MCC can be surgically corrected in some cases, most of the malformed animals are lost. Since no specific antidote is available, prevention is the only way to deal with the production losses caused by the plant. Control with herbicides and grazing with less susceptible animals (such as sheep) have been suggested. C. maculatum alkaloids can enter the human food chain via milk and fowl. Such losses may be underestimated, at least in some regions.
Evaluation of developmental toxicity of coniine to rats and rabbits, 1993
Actions of piperidine alkaloid teratogens at fetal nicotinic acetylcholine receptors, 2010
Antinociceptive activity of coniine in mice, 2009
Historically, extracts of this species have been used as both a sedative and an antispasmodic. However, because of the plant toxicity, this usage was discontinued by the early twentieth century.
Activated charcoal adsorbs nicotine in vitro and prompt decontamination may assist in minimizing the full effects of intoxication. Although the efficacy of activated charcoal has not been formally assessed and symptoms may develop quickly, gastrointestinal decontamination with activated charcoal can be considered in patients with an intact or protected airway.
In symptomatic patients, general supportive measures including securing and stabilizing the airway along with assisted ventilation, seizure control, and hemodynamic stabilization should take precedence over decontamination.
Induction of emesis is also not recommended.
Supportive care is the mainstay of management with primary emphasis on cardiovascular and respiratory support.
Cardiovascular effects, including tachycardia and hypertension, are common early symptoms of toxicity; however, this period of initial adrenergic stimulation is typically brief and usually does not require any specific treatment. Therefore, treatment with adrenergic antagonists should be avoided as such therapy may worsen cardiovascular symptoms during the blockade phase, which could progress to shock with cardiovascular collapse. Hypotension should be treated with intravenous fluids; if this is unsuccessful, sympathomimetics such as dopamine or norepinephrine or other inotropic and/or vasopressor agents may be required to restore the circulation and an adequate blood pressure.
In the second phase, bradycardia is a common finding and if symptomatic, should be treated with atropine.
Respiratory muscle paralysis combined with bronchoconstriction and increased mucosal secretions can result in respiratory failure. Atropine should be used to control symptoms of excessive parasympathetic stimulation such as hypersalivation, bronchorrhea, or wheezing. In the case of deteriorating respiratory function, respiratory support with rapid sequence intubation and positive pressure ventilation are vital.
Gastrointestinal effects are caused by both central and peripheral actions. The central component of the vomiting response is stimulation of the emetic chemoreceptor trigger zone. Vomiting and diarrhea are common and may lead to fluid and electrolyte imbalances and hypovolemic hypotension. Management includes appropriate intravenous fluid and electrolyte replacement, and antiemetic medication. Atropine administration can often help to settle the gastrointestinal hyperactivity, which may be due to excess muscarinic parasympathetic stimulation.
Seizures are uncommon but may develop after the ingestion of large doses of nicotine or related alkaloids. Extreme agitation or seizures should be treated with a benzodiazepine; recommendations include lorazepam or diazepam. Longer-acting anticonvulsants are typically unnecessary, but may be required as second-line therapy if seizures are refractory to benzodiazepines. In this situation Phenobarbital should be infused. Use of benzodiazepines or barbiturates may lead to respiratory depression.
Rhabdomyolysis may be a further complication. Management includes adequate intravenous fluids to ensure good renal output, although urinary alkalinization might also help to minimize the risk of myoglobin-induced kidney damage. In severe cases subsequent renal failure may develop, requiring supportive management including hemodialysis.
Poisoning from nicotinic alkaloids is potentially completely reversible. Patients recovering from acute intoxication following effective symptomatic and supportive care are unlikely to have any long-term sequelae. However, prolonged untreated seizures or apnea may potentially lead to residual impairments secondary to the anoxic insult.
With the common name of cicuta other two species of plants are usually indicated, both inclused in different genres:
• Minor cicuta (Aethusa cynapium), also confused with parsley. The similarity between these plants has caused poisoning events.
• Water hemlock (Cicuta maculata) is substantially more toxic and contains a different class of toxic components. The alkaloid responsible of water hemlock’s effects is not coniine but cicutoxine. Although many symptoms overlap, differentiation is important; in severe poisoning C. maculatum causes respiratory paralysis, whereas C. maculate results in profound seizures and potentially status epilepticus. They can be distinguished, however, on the basis of their characteristic morphological properties: C. maculatum has a single tap root, purple and spotted stem, whereas C. maculata has branched root systems with tubules and an absence of purple spots.
Child poisoning after ingestion of a wild apiaceae, 2008
WHAT KILLED SOCRATES?
The most famous victim of hemlock poisoning is the philosopher Socrates. After being condemned to death for impiety in 399 BC, Socrates was given a potent infusion of the hemlock plant. Plato described Socrates' death in the Phaedo:
The man...laid his hands on him and after a while examined his feet and legs, then pinched his foot hard and asked if he felt it. He said "No"; then after that, his thighs; and passing upwards in this way he showed us that he was growing cold and rigid. And then again he touched him and said that when it reached his heart, he would be gone. The chill had now reached the region about the groin, and uncovering his face, which had been covered....
Although many have questioned whether this is a factual account, careful attention to Plato's words, modern and ancient medicine, and other ancient Greek sources point to the above account being consistent with Conium poisoning.
What killed Socrates? Toxicological considerations and questions, 2009
Hemlock Poisoning and the Death of Socrates: Did Plato Tell the Truth?, 2001