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Home , Coniine, Conium maculatum

The in the cup

Hemlock , maculatum. Illustration by Jim M’Guinness.

26 The Pharos/Spring 2011 Horton A. Johnson, MD The author (AΩA, Tulane University 1979), was formerly active ingredient could be isolated, how it functioned physi- director of Pathology, St. Luke’s/Roosevelt Hospital and ologically, and whether it might be another plant like Professor of Pathology, Columbia University College of , strychnine, and quinine, which had just recently Physicians and Surgeons. A previous contributor to The been isolated. The winner of the prize, August Ludwig Gieseke Pharos, he is a docent at The Metropolitan Museum of Art. (Giseke), had received from a colleague an ample quantity of seeds of the spotted hemlock and decided to use that as the robably the best-known image of the death of subject of his investigations. is the painting by Jacques-Louis David now in the His report of his work3 recalls the fact that it took place Metropolitan Museum of Art. David followed, more just thirty-six years after Lavoisier’s Traité had given birth to Por less, the eyewitness account of Phaedo as recorded by modern inorganic chemistry. Organic chemistry was still in its .1 Socrates, in prison, shackles removed, discoursing on infancy, just emerging from the shadowy worlds of alchemy the after-life, is about to accept the poison. Having followed and herbalism. The litmus test was available from the alche- Zeus’s command in a dream to “make music and work at mists, but otherwise organic substances were characterized it,” his lyre is at his side. Crito clutches his master’s leg and chiefly by odor and taste. Gieseke had no thought of atoms Apollodoros weeps. In the background Socrates’s wife is being or molecules. led away at his request. At the foot of the couch, facing away Gieseke planned to separate various fractions of the hem- from Socrates and the grief-stricken disciples, sits the ghost lock juice on the basis of volatility, solubility, and crystalliza- of Plato, a gray figure, head bowed in thought, scroll, pen, tion. The various components would then be tested in rabbits and ink at his side. Plato was, by his own admission, absent to determine which contained the active principle, the poison. because of illness, but David has placed him there in spirit. He would follow closely on the work of the Swiss apothecary The centerpiece of the painting is the cup of poison, offered chemist Jacques Peschier, who in 1821 had separated the juice by the distraught jailer and calmly accepted by Socrates as he of the hemlock into several components. One of these, ob- continues his discourse. It has been assumed that the poison tained after treatment with magnesium hydroxide and ether was the juice of the spotted hemlock, L, extraction, yielded a mere one-half gram of an alkaline mate- a member of the parsley family and unrelated to the hemlock rial, not enough for further investigation. Peschier had named tree. The Greeks had a specific word for the poisonous hem- the substance after the Latin for hemlock.3 lock, κώνειον (hence the Latin conium), but Plato never called Gieseke’s first attempt failed rather badly. He began by it that. Instead he used the general term, φάρμακον, simply mashing hemlock seeds in wine spirits (ethyl ) and fil- meaning a drug or poison. Since the juice of hemlock or tering out the solid material. He then evaporated the alcohol seeds was, at that time, commonly used to execute criminals, and dissolved the residue in water. Following Peschier’s lead, and since it was repeatedly referenced by ancient authors in the aqueous solution was heated and mixed with magnesium connection with the death of Socrates, and given Phaedo’s de- hydroxide. As he did this, an intolerable odor spread not only scription of the mode of death, it seems reasonable to assume through his laboratory but throughout the entire building. that Socrates did, in fact, drink juice of hemlock.2 One won- Fearing for his health and that of others, he quickly brought ders, then, just what was the poisonous substance in that cup? the procedure to an end. Starting over, he heated the aqueous hemlock extract In 1824 the medical faculty of the University of Halle, with magnesium hydroxide again, but this time in a retort, Germany, offered a prize for the investigation of any of the capturing the noxious fumes by condensing them along with local poisonous . The study was to determine how the the steam in the neck of the retort. The residual material

The Pharos/Spring 2011 27 The poison in the cup

Phaedo recalled that Socrates’s jailer, who must have wit- nessed many deaths by hemlock poisoning, said that a “cold- ness [lifelessness?] and congealing” would travel from the legs up the body until it reached the heart, causing death. The experienced executioner tested the progress by pinching hard first the feet, then calves, and so on. Although he appeared to be testing for sensory loss, it may have been for motor loss, loss of pain-withdrawal reflex. If the cup really contained the juice of Conium maculatum, a flaccid paralysis moved up Socrates’s body until it affected the muscles of respiration, causing asphyxia. In theory, he could have been saved by arti- ficial respiration until the effects of the poison wore off. Gieseke made several speculations that would be proven correct. He suggested that any basic substance, not just mag- nesium hydroxide, might somehow drive the poison out of The coniine molecule. the hot water solution and that addition of any acid might draw it back into solution. Actually, coniine, the most impor- remaining in the retort was saved and further separated to tant of several in the hemlock plant, was present in make two fractions that would eventually prove to be innocu- the form of stable, water-soluble, acid salts. As he heated the ous to the rabbits. The distillate, a slightly yellow, turbid, crude aqueous extract and made it basic by adding magne- aqueous solution, had oily droplets floating on its surface. sium hydroxide, Gieseke was liberating the free, basic, poorly It had a very bitter, ammonia-like taste, an odor much like soluble, and volatile coniine from its acid salts and into the the spirits of hartshorn, and a strongly alkaline reaction with atmosphere. A century and a half before the scourge of “crack litmus. It was neutralized with and then evapo- ,” Gieseke was “free-basing” another plant alkaloid, rated to obtain needle-like crystals. These were dissolved coniine. Adding acid reversed the process, recapturing the in alcohol to produce a fraction that was lethal to rabbits. coniine into acid salts. Gieseke had, with this simple procedure, isolated from the As he worked with the poison, there was always a smell of crude hemlock extract the active principle of hemlock in pure ammonia about. He speculated that traces of ammonia were crystalline form, probably as coniine sulfate. Interestingly, he being released from the poison itself, that ammonia might be never used Peschier’s term, coniine, but simply referred to it a part of the poison. Coniine can, in fact, be reduced to release as Schierlinggift, hemlock poison. ammonia, leaving a straight carbon chain, ordinary octane. The dried material was dissolved in water and given (route Gieseke suggested, as had others before him, that it might be not specified, probably by mouth) to two young rabbits, one an ammonia component that gave the plant alkaloids their grain (65 mg) to one and 5 grains to the other. The rabbit given basic or alkaloid character. It is indeed the nitrogen atom with the larger dose died within two minutes. The other, however, its lone pair of electrons that makes coniine “alkaloid.” died slowly, allowing Gieseke to describe what would become Alkaloid chemistry moved ahead swiftly in the following known as the typical syndrome of hemlock poisoning: as- years. In 1881, the great A. W. Hofmann determined the em- cending flaccid paralysis, not unlike the death of Socrates as pirical formula of coniine, C8H17N, and deduced its structural described by Phaedo. Within fifteen minutes the animal began formula, a ring with a propyl group at the 2 posi- to hop around anxiously. Soon the hind legs became paralyzed tion.4 By century’s end, dozens of plant alkaloids had been and stretched out on the table. The animal struggled to sup- isolated and characterized, including morphine, codeine, port itself upright with its forelegs. After twenty minutes the , , cocaine, quinine, strychnine, and caffeine.5 forelegs collapsed, and the animal tried to support itself off the Coniine, the simplest of all the plant alkaloids, was the first table with its head. After thirty minutes it lay down on its side. to be synthesized in 1885 by Ladenberg6 who, in his compre- Clonic spasms began. Eyes became fixed. After fifty-five min- hensive History of the Development of Chemistry,7 made no utes the animal was dead. Autopsies of these animals showed mention of Gieseke and his primitive experiments. no significant pathological changes. It has since been shown that coniine blocks the neuro- The Metropolitan Museum of Art bought David’s painting muscular junctions of skeletal muscles, but Gieseke, knowing in 1931. Within a few years millions of visitors to the museum nothing of neuromuscular junctions or lower motor neurons, had witnessed Socrates accepting the cup of hemlock with attributed the deaths to poisoning of the spinal cord and its coniine. Those who knew the story could foresee Socrates brain. His rabbits actually died of paralysis of the muscles of drinking the poison cheerfully and arising to walk about until respiration. he felt a heaviness in his legs. They would remember how he

28 The Pharos/Spring 2011 Jacques-Louis David (French, 1748-1825), The Death of Socrates, 1887, oil on canvas, 51 x 77¼ in. The Metropolitan Museum of Art, Catharine Lorillard Wolfe Collection, Wolfe Fund, 1932(31.45). Image © The Metropolitan Museum of Art.

lay on his back as the chill of death traveled upward toward Did Plato Tell the Truth? In: The Trial and Execution of Socrates: his abdomen, and how he spoke his last words, “Crito, we Sources and Controversies. Brickhouse TC, Smith ND, editors. New owe a cock to Asclepius. Pay it, and do not neglect it.” After a York: Oxford Press; 2002: 255–76. while he moved a bit. Then his eyes became fixed. Crito closed 3. Gieseke AL. Über die wirksame Princip des Schierlings, Co- his eyes and mouth. “Such was the end,” said Phaedo, “of our nium maculatum. Arch Pharm 1827; 20: 97–111. friend, who was, as we may say, of all those of his time whom 4. Hofmann, AW. Einwirken der Wärme auf die Ammonium- we have known, the best and wisest and most righteous man.” basen. Ber dtsch chem Ges 1881; 14: 705–13. In 1942, long after the painting had become an icon of the 5. Pictet A. The Vegetable Alkaloids. With Particular Reference Phaedo, the brilliant Belgian sleuth, Hercule Poirot, became to Their Chemical Constitution. Biddle HC, translator. New York: acquainted with a landed English gentleman who distilled John Wiley and Sons; 1913. coniine in his home laboratory, evidently following, more or 6. Ladenburg A. Über die imine. Ber dtsch chem Ges 1885; 18: less, the method of Gieseke. The amateur chemist enjoyed 2956–61. demonstrating the procedure to friends and neighbors, after 7. Ladenburg A. Lectures on the History of the Development of which he led them into the library for a reading of the death Chemistry since the Time of Lavoisier. Dobbin L, translator. Edin- of Socrates in Plato’s Phaedo.8 One cannot help but wonder to burgh: The Alembic Club; 1900. what extent Dame Agatha may have been inspired by David’s 8. Christie A. Five Little Pigs. New York: Dodd, Mead and Com- The Death of Socrates. pany; 1942: 35–36, 141.

References The author’s address is: 1. Plato. Phaedo. Fowler HN, translator.  London: William 160 West 66th Street #47C Heinemann; 1928. New York, New York 10023 2. Bloch E. Hemlock poisoning and the death of Socrates: E-mail: [email protected]

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