Strychnos, Ipecac and the Plants Behind Magendie's Medicines

Table of Contents

1. 1. The Strychnos Family of Poison Plants
2. 2. Upas: The Arrow Poison of Java
3. 3. Strychnine and Brucine
4. 4. How Strychnine Acts: The Glycine Receptor
5. 5. Strychnine in Nineteenth-Century Medicine
6. 6. Ipecacuanha Root and Emetine
7. 7. Emetine and Amoebic Dysentery
8. 8. Opium, Cinchona and Hellebore in the Formulaire
9. 9. Iodine, Bromine and Prussic Acid
10. 10. Why a Pure Alkaloid Is Predictable
11. Key Research Papers
12. Connections

1. The Strychnos Family of Poison Plants

Strychnos is a large genus of tropical trees, shrubs and woody climbers found across Asia, Africa and the Americas. Many of its members are intensely bitter, and several are among the most poisonous plants known. In Magendie’s day two Asian species were already familiar in European pharmacies. The first was nux vomica, the seed of Strychnos nux-vomica, a tree of India and Southeast Asia. Its seeds are flat grey discs covered in fine silky hairs, sitting in the pulp of an orange fruit. The second was the Saint-Ignatius bean, the seed of Strychnos ignatii, a climbing plant of the Philippines whose name recalls the Jesuit missionaries who sent it to Europe.

Both seeds had long been traded as drugs and as poisons for vermin. What made them scientifically important was the observation Magendie made with the botanist and physician Alire Raffeneau-Delile in 1809. In the second edition of his Formulaire (1822), Magendie summed up that work in a single sentence: it had shown “qu’une famille entière de végétaux (les strychnos amers) a la propriété singulière d’exciter fortement la moelle épinière sans intéresser, autrement que d’une manière indirecte, les fonctions du cerveau” — that a whole family of plants, the bitter strychnos, has the singular property of strongly exciting the spinal cord while touching the functions of the brain only indirectly.

That sentence carries a new way of thinking. Plants of different species, from different countries, produced the same effect on the same part of the body. To Magendie this pointed to a shared chemical principle inside them, not to some special virtue of each plant. Historians of science count this comparison as the first experimental comparison of similar drug effects produced by plants of different botanical origin, and as one of the starting points of modern pharmacology. The story of those experiments is told on the Formulaire page of this wing.

The genus has a second famous face. In South America other Strychnos species are among the plants that went into some forms of curare, the arrow poison that paralyses rather than convulses. Its study became one of the great achievements of Magendie’s pupil Claude Bernard, described on the Claude Bernard curare page. One family of plants thus produced both the convulsant poisons Magendie studied and part of the paralysing poison his student made famous.

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2. Upas: The Arrow Poison of Java

The 1809 experiments began not with nux vomica but with a poison from Java called upas. Travellers’ tales had made the “upas tree” a legend in Europe — a tree said to kill everything that came near it — and real samples of Javanese arrow poison reached French naturalists in the early nineteenth century. Raffeneau-Delile’s own medical thesis of 1809 was titled Sur les effets d’un poison de Java appelé l’upas tieuté, et sur les différentes espèces de strychnos — on the effects of a Java poison called upas tieuté, and on the different species of strychnos.

The word “upas” covered more than one poison, and this matters for the history. Upas tieuté was prepared from a Strychnos climber and, like nux vomica, caused violent convulsions. Upas antiar came from an entirely different tree, Antiaris toxicaria, a member of the fig and mulberry family; its poison acts mainly on the heart, in the manner of the cardiac glycosides found in foxglove. Delile’s thesis title names upas tieuté, the Strychnos poison, and that fits the convulsions he and Magendie recorded.

Magendie explained in the Formulaire why the work moved on from upas. The Javanese poison was not available in commerce, so the two men looked for something with the same action that could be bought in Paris — and found it in nux vomica and Saint-Ignatius bean. That practical step tied a rare exotic arrow poison to two ordinary pharmacy seeds, and pointed straight toward the hidden substance they shared.

Arrow poisons remained a thread through French physiology. Claude Bernard’s unpublished notes on curare, upas, strychnine and other arrow poisons were later edited and published by the historian Mirko Grmek, showing how directly the pupil carried on the teacher’s questions.

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3. Strychnine and Brucine

As early as 1809 Magendie suspected that the bitter strychnos seeds owed their action to a definite chemical substance. Within a decade chemists found it. The Paris pharmacists Pierre-Joseph Pelletier and Joseph-Bienaimé Caventou isolated strychnine from Saint-Ignatius bean and nux vomica, finding it in 1818 and publishing their memoir in 1819. In 1819 they described a second, closely related alkaloid, brucine, from “false angostura” bark — bark later shown to come from the nux vomica tree itself; the name recalls the genus Brucea, from which the bark was wrongly believed to come. Their wider work, including quinine, is told in the Pelletier and Caventou plant-alkaloid page.

An alkaloid is a nitrogen-containing plant substance that behaves chemically as a base: it combines with acids to form salts. That property was what let chemists pull these substances out of plant material and crystallise them, and it is why the early pure medicines were often given as salts. Morphine, isolated by Friedrich Sertürner, had shown the way; strychnine, brucine, emetine, quinine and veratrine followed in quick succession in Paris.

Strychnine and brucine are chemical cousins. Brucine carries two extra methoxy groups on the same complex ring skeleton and is far weaker as a convulsant. Strychnine itself is an unusually complicated molecule of seven interlocking rings. Its full structure took chemists more than a century to work out, and its first laboratory synthesis, by Robert Burns Woodward in 1954, became a landmark of organic chemistry.

For Magendie the important thing was simpler. Once strychnine existed as a white crystalline powder, the effect he had seen with whole seeds could be reproduced with a weighed amount of one substance. The 1822 Formulaire has separate chapters on the resin of nux vomica and on strychnine, recording this step from crude plant to pure principle.

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4. How Strychnine Acts: The Glycine Receptor

Magendie showed by experiment that the strychnos poisons act on the spinal cord: cutting the cord from the brain did not stop the convulsions, but destroying the cord abolished them. He could not know why. The answer came 164 years later, from the science of nerve chemistry.

The spinal cord is constantly balancing “go” and “stop” signals. When a muscle contracts, nerve cells in the cord also send braking signals that relax the opposing muscle and keep the reflex in proportion. In the spinal cord and brainstem one of the main braking messengers is the amino acid glycine. Glycine released at a synapse opens chloride channels on the receiving nerve cell — the glycine receptors — and makes that cell less likely to fire.

In 1973 Anne B. Young and Solomon H. Snyder, at Johns Hopkins, reported in the Proceedings of the National Academy of Sciences that radioactively labelled strychnine binds to synaptic membranes of the spinal cord at sites that behave as postsynaptic glycine receptors. Strychnine sits in the receptor and stops glycine from acting. With the brakes removed, every small stimulus — a sound, a touch, a draught — spreads through the cord unchecked, and opposing muscles contract together in powerful spasms.

The modern explanation fits Magendie’s 1809 finding closely. The poison acts at the level of the spinal cord, and in strychnine poisoning consciousness is typically preserved during the spasms, matching his remark that the brain is affected only indirectly. Strychnine has since become a standard laboratory tool for identifying glycine receptors, so the poison Magendie studied in whole seeds helped map one of the nervous system’s own messenger systems.

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5. Strychnine in Nineteenth-Century Medicine

Once strychnine could be obtained pure, physicians began to use it, and Magendie’s Formulaire was one of the routes by which it entered practice. In the 1822 edition he credited the physician Pierre Fouquier with publishing cases of paralysis treated with nux vomica before him, and said that he had obtained similar results himself. That is reported here as his own account of the time; the idea behind it was that a substance which so strongly excites the spinal cord might restore movement to paralysed limbs.

Over the following decades strychnine settled into the nineteenth-century materia medica as a “tonic” and stimulant. The historian John S. Haller Jr. traced this long career in his 1973 history of strychnine in nineteenth-century medicine. Strychnine appeared in tonics for weakness, poor appetite and convalescence, and in remedies aimed at the heart, the breathing and the nerves. The theory of the period held that tiny amounts would “tone up” a tired nervous system.

The same substance was at the same time one of the best-known poisons of the age. It was sold to kill rats and other animals, and it featured in accidental poisonings and in notorious criminal cases. Its effects were clear to physicians: muscle stiffening, spasms triggered by slight stimuli, an arched back, and death from exhaustion and failure of breathing. The narrow margin between the amounts used in medicine and the amounts that caused poisoning was a recurring theme in the medical literature of the period.

In the twentieth century, as pharmacology moved from tradition to measured evidence, strychnine lost its place as a medicine. The research of later decades did not support the old “tonic” claims, and its toxicity weighed against any use. It survives today mainly as a research tool and, in some countries, as a regulated poison for vermin control — a reminder that the purity which made it predictable also made it dangerous.

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6. Ipecacuanha Root and Emetine

Ipecacuanha is the root of a small shrub of the Brazilian rainforest, known botanically as Carapichea ipecacuanha (older names Cephaelis ipecacuanha and Psychotria ipecacuanha). Indigenous peoples of Brazil used the root, and Portuguese writers described it in the seventeenth century. It reached Europe as a remedy for “fluxes” and dysentery, and above all as a reliable means of causing vomiting. A traditional account credits the physician Jean-Adrien Helvétius with making it famous in France in the late seventeenth century after treating members of the court of Louis XIV.

Magendie had his own interest in vomiting. In 1813 he presented a memoir on the mechanism of vomiting, and among his works listed in the 1822 Formulaire is a study of the effects of emetics on humans and animals. In 1817 he and Pierre-Joseph Pelletier published a memoir on emetine and on three kinds of ipecacuanha, announcing emetine, the active principle of the root. It was one of the first alkaloids isolated after morphine, and one of the clearest successes of Magendie’s programme: the strength of a famous root traced to one substance that could be weighed and tested in animals.

Emetine and its close relative cephaeline cause vomiting in two ways. They irritate the lining of the stomach, and they act on the brainstem area that controls the vomiting reflex. The body’s side of this reflex — the sensors, the brainstem control centre and the sequence of muscle movements — is shown in the site’s animation of the nausea and vomiting reflex.

For much of the twentieth century a syrup made from ipecacuanha was kept in households as a first-aid emetic after poisoning. Later research found that inducing vomiting did not improve the outcome of poisoning, and in 2003 the American Academy of Pediatrics issued a policy statement against the routine home use of syrup of ipecac. That policy is reported here as the Academy’s statement. The repeated misuse of ipecac in eating disorders has also been documented as a cause of emetine damage to the heart and muscles.

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7. Emetine and Amoebic Dysentery

The old use of ipecacuanha root for dysentery turned out to contain a real pharmacological finding, although it took nearly a century after Magendie to see it clearly. Amoebic dysentery is caused by the single-celled parasite Entamoeba histolytica, which invades the lining of the large bowel and can spread to the liver to form abscesses. The disease and its symptoms are described on the site’s page on amoebic dysentery and colitis.

In 1912 Leonard Rogers, working in Calcutta, reported in the British Medical Journal what he called the rapid cure of amoebic dysentery and hepatitis by hypodermic injections of soluble salts of emetine. Purified emetine, given by injection rather than swallowed as the nauseating root, could reach the amoebae in the bowel wall and liver in amounts the crude drug never allowed. Rogers’ report made emetine the standard treatment for amoebic disease for several decades. Later laboratory work showed that emetine blocks protein-making in the cells of the parasite, which explains how it kills the amoeba.

The same action makes emetine a poison to human cells. Physicians of the emetine era recorded its toxicity in detail: damage to heart muscle with changes in heart rhythm, muscle weakness and pain, and digestive upset, accumulating with repeated courses. A chemically modified form, dehydroemetine, was developed in the hope of a safer drug. From the 1960s the synthetic drug metronidazole took over most of emetine’s role, and emetine passed into the history books.

Emetine’s career mirrors the whole Formulaire story. A root valued in folk medicine yielded a pure principle; the pure principle could be dosed by weight and studied; and that precision revealed both a genuine effect against a disease and a toxicity that limited its use.

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8. Opium, Cinchona and Hellebore in the Formulaire

The 1822 second edition of the Formulaire announced its contents on the title page: “la noix vomique, la morphine, l’acide prussique, la strychnine, la vératrine, les alcalis des quinquinas, l’émétine, l’iode”. Behind most of these names stands a plant with a long history in folk and learned medicine.

The opium poppy

The dried latex of the unripe seed head of the opium poppy, Papaver somniferum, had been used against pain and for sleep since antiquity. In the early nineteenth century chemists broke it into separate substances. The French pharmacist Charles Derosne described a crystalline material from opium in 1803, later called narcotine (today noscapine), and the Formulaire has a chapter on this “matière de Derosnes”. The German apothecary Friedrich Sertürner isolated morphine, the main pain-relieving principle. The plant and its chemistry are explained on the Sertürner opium poppy page. Morphine and its relatives are addictive and can stop breathing; they appear here only as history.

Cinchona bark

The bark of South American Cinchona trees, the “Jesuits’ bark”, had been used against intermittent fevers since the seventeenth century. In 1820 Pelletier and Caventou isolated quinine and cinchonine from it. Magendie gathered them in the Formulaire as “les alcalis des quinquinas”, the alkalis of the cinchonas. Pure quinine soon became the standard treatment for malaria, a story told in the site’s history of malaria.

White hellebore and sabadilla

Veratrine came from two plants of the lily order: the seeds of sabadilla (Schoenocaulon officinale), a Mexican and Central American plant, and the root of white hellebore (Veratrum album), a European mountain plant. Both had old reputations as violent purges and as poisons for lice and other vermin. Chemists at the end of the 1810s, among them Pelletier and Caventou, extracted the alkaloid mixture called veratrine. Later research showed that the veratrum alkaloids hold open the sodium channels of nerve and muscle cells, causing repetitive firing — which fits the tingling, slowing of the heart and collapse recorded in veratrum poisoning. White hellebore is still mistaken for yellow gentian in the mountains, with serious results, as described on the site’s page on veratrum mix-ups and poisoning.

Gentian, nightshade and stavesacre

The 1822 edition also has short chapters on gentianin, a bitter principle the chemists of the day extracted from gentian root, the classic European bitter; on solanine, the alkaloid of potato shoots and the nightshade family; and on delphine, an alkaloid from the seeds of stavesacre, a larkspur once used against lice. Together they show how widely the Paris chemists searched for new pure principles in the plants already known to medicine.

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9. Iodine, Bromine and Prussic Acid

Not every new medicine in the Formulaire came from a flowering plant. Three of the most important came from the sea and from chemistry.

Iodine from seaweed

In 1811 the French saltpetre maker Bernard Courtois noticed violet vapours rising from the ash of seaweed treated with acid. The new element was named iodine, from the Greek word for violet. Physicians soon connected it with the old practice of treating goitre, the swelling of the thyroid gland, with burnt sponge and seaweed ash: the active ingredient in those folk remedies was iodine. Magendie’s 1822 Formulaire ends with a chapter on iodine, and historians of the work credit it with spreading the medical use of iodine and its salts. Iodine’s role as an essential nutrient for the thyroid is covered on the site’s iodine page.

Bromine from salt water

In 1826 the young Montpellier chemist Antoine-Jérôme Balard discovered bromine in the brine of salt marshes. The title of the 1829 edition of the Formulaire adds bromine to the list of new medicines, and bromide salts went on to become the first widely used sedatives and anti-seizure drugs of the nineteenth century, before chronic bromide poisoning (“bromism”) and better drugs ended that era.

Prussic acid

Prussic acid is hydrogen cyanide dissolved in water. The Swedish chemist Carl Wilhelm Scheele prepared it in 1782 from the pigment Prussian blue, which gave it its name. In nature it is released from substances in the kernels of bitter almonds, the leaves of cherry laurel and the seeds of related fruits. Physicians of Magendie’s time used very dilute preparations as a sedative for coughs and nervous complaints, and the Formulaire has a chapter on it. Its toxicity is extreme: cyanide stops cells from using oxygen by blocking the final enzyme of the respiratory chain, cytochrome c oxidase. Its later history in medicine is mainly that of a poison.

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10. Why a Pure Alkaloid Is Predictable

Why did Magendie think pure substances were better than the plants they came from? His answer, in the preface to the 1822 Formulaire, was consistency. The new substances act in small amounts, they are mixed with nothing that masks their action, and because their chemical nature and their preparation are fixed, “on n’a point à craindre de variation dans leur force” — there is no need to fear variation in their strength. He added that time alone would show their advantages and drawbacks.

The problem he was answering was real. A crude plant drug varies from batch to batch. The amount of alkaloid in a bark, seed or root changes with the species and variety, the soil and climate, the season of harvest, the part of the plant, and the way it was dried and stored. Bark sold as cinchona might come from a rich species or a poor one; ipecacuanha might be mixed with other roots. Magendie’s memoir with Pelletier on “three kinds of ipecacuanha” addressed exactly this kind of confusion. With a crude drug, the same weight could carry very different amounts of active substance.

A pure alkaloid removes that uncertainty. A weighed amount of strychnine or quinine is the same today as it was last year, in Paris or in Calcutta. That made three new things possible. Effects could be compared between animals and people, which Magendie believed act the same way: his preface states “que la manière d’agir des médicamens et des poisons est la même sur l’homme et sur les animaux”. Results could be repeated by other physicians. And the action could be traced to a definite site in the body — for strychnine, the spinal cord. Historians Alain Ségal and François Trépardoux note that Magendie standardised animal tests of activity and safety for these substances, anticipating the evaluation of drugs for registration in the twentieth century.

Purity had a price, which the history on this page records. Concentrated into a few grains of powder, the strychnos poison, emetine, morphine and cyanide became far easier to overdose than the bulky plant materials. Historians of early drug-action theories, such as M. P. Earles, and of poison research, such as José Ramón Bertomeu-Sánchez on Magendie and Mateu Orfila, show how closely the new pharmacology and the new science of toxicology grew up together. The same precision that let Magendie predict a drug’s action also made its dangers measurable — the double edge that runs through pharmacology to this day. The wider story of what Magendie built on these foundations is told on the legacy page.

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Key Research Papers

1. Young AB, Snyder SH. Strychnine binding associated with glycine receptors of the central nervous system. Proc Natl Acad Sci U S A. 1973;70(10):2832-6. PubMed PMID: 4200724
2. Haller JS Jr. The history of strychnine in the nineteenth-century materia medica. Trans Stud Coll Physicians Phila. 1973;40(4):226-38. PubMed PMID: 4574625
3. Rogers L. The rapid cure of amoebic dysentery and hepatitis by hypodermic injections of soluble salts of emetine. Br Med J. 1912;1(2686):1424-5. PubMed PMID: 20766221
4. Ségal A, Trépardoux F. [The Formulaires of Magendie (1821-1840) of the chemical pharmacy to pharmacology]. Hist Sci Med. 2015;49(2):141-56. PubMed PMID: 26492670
5. Bertomeu-Sánchez JR. Animal experiments, vital forces and courtrooms: Mateu Orfila, François Magendie and the study of poisons in nineteenth-century France. Ann Sci. 2012;69(1):1-26. PubMed PMID: 22530381
6. Earles MP. Early theories of the mode of action of drugs and poisons. Annals of Science. 1961;17(2):97-110. DOI: 10.1080/00033796100202571
7. Grmek MD. [Unpublished notes of Claude Bernard on the physiologic properties of arrow poisons (curare, upas, strychnine and others)]. Biol Med (Paris). 1966;55:Suppl:i-clix. PubMed PMID: 4222865
8. Mazliak P. [Medical recollections. François Magendie, creator of the pharmacology, inspirer of Claude Bernard’s researches]. Rev Prat. 2013;63(7):1030-3. PubMed PMID: 24167908
9. Tubbs RS, Loukas M, Shoja MM, Shokouhi G, Oakes WJ. François Magendie (1783-1855) and his contributions to the foundations of neuroscience and neurosurgery. J Neurosurg. 2008;108(5):1038-42. PubMed PMID: 18447728
10. Stahnisch FW. François Magendie (1783-1855). J Neurol. 2009;256(11):1950-2. PubMed PMID: 19693629

PubMed Topic Searches

1. Strychnine history
2. Strychnine and the glycine receptor
3. Emetine and ipecacuanha
4. Emetine in amoebiasis
5. Magendie Formulaire

Further Reading

• Magendie F. Formulaire pour la préparation et l’emploi de plusieurs nouveaux médicamens. 2nd ed. Paris: Méquignon-Marvis; 1822. Internet Archive
• Grmek MD. “Magendie, François.” Complete Dictionary of Scientific Biography. Encyclopedia.com

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Connections

• François Magendie — Nux Vomica, Pure Alkaloids and the Birth of Experimental Pharmacology
• François Magendie: Life and Career (1783–1855)
• The Formulaire of 1821: Magendie and the First Pure Medicines
• Magendie’s Legacy: Claude Bernard, the Bell–Magendie Law and Experimental Medicine
• Pharmacology
• Claude Bernard
• Claude Bernard: Curare, the Plant and the Science
• Cinchona and the Plant Alkaloids of Pelletier and Caventou
• The Opium Poppy and the Chemistry of Morphine
• Glycine
• Entamoeba histolytica — The Cause of Amebiasis
• Gentian (Gentiana lutea)

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