Cinchona and the Plant Alkaloids of Pelletier and Caventou

Table of Contents

1. The Cinchona Trees of the Andes
2. Quechua Knowledge and the Jesuits’ Bark
3. The Countess of Chinchón: A Legend
4. Grey, Yellow and Red Barks
5. Green Leaves: Naming Chlorophyll
6. Ipecacuanha Root and Emetine
7. Strychnos Seeds: Strychnine and Brucine
8. Hellebore, Sabadilla and Autumn Crocus
9. Coffee, a Cousin of Cinchona: Caffeine
10. How Quinine Works, and Cinchonism
11. Key Research Papers
12. Connections
13. Featured Videos

1. The Cinchona Trees of the Andes

Cinchona is a genus of evergreen trees and shrubs native to the forested eastern slopes of the Andes, in the lands that are now Colombia, Ecuador, Peru and Bolivia. The genus belongs to the Rubiaceae, the coffee or madder family, which also holds the coffee plant and the ipecacuanha root that appear later on this page. To Europeans the dried bark of these trees was “Peruvian bark”, “Jesuits’ bark” or simply “the bark”; in French it was quinquina, the word Pelletier and Caventou used in the title of their 1820 memoir, Recherches chimiques sur les quinquinas.

The medicine was in the bark, stripped from the trunk and branches and dried into curled “quills” or flat pieces. For nearly two centuries before 1820 it was sold, powdered and swallowed, steeped in wine or boiled into decoctions, without anyone knowing what in it acted. Barks from different trees, regions and ages varied enormously in strength, and adulteration with the bark of unrelated trees was common. That uncertainty is one reason the isolation of a pure, measurable principle mattered so much: once quinine could be weighed, a dose no longer depended on which shipment of bark a pharmacist happened to hold.

The trees later became objects of imperial competition. The medical historian M. R. Lee describes how the search for the best cinchonas drove exploration, secrecy and power struggles among European states in the nineteenth century, and how a reliable supply of the bark made it possible for Europeans to live and campaign in malarial regions. That later history, including the seeds carried out of Bolivia and the plantations of Java, is told on the Legacy and Later Research page.

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2. Quechua Knowledge and the Jesuits’ Bark

How cinchona first came into European medicine is less certain than the confident textbook versions suggest. A 2023 review of the historical records by Louis Miller and colleagues in the American Journal of Tropical Medicine and Hygiene concludes that the bark’s path out of Peru remains something of a mystery, because the primary Jesuit documents that would settle it are lacking. What the records do support is that Jesuit missionaries learned from the Quechua-speaking people of the Andes that the bark was used against shivering and chills. Whether Andean healers used it specifically for the intermittent fevers of malaria is unknown.

What follows is better documented. A Danish history by Henrik Permin and colleagues dates the first use of the bark for a European with malaria to the 1630s; the Jesuit cardinal Juan de Lugo promoted it in Rome; it was known in England by the 1660s; and physicians including Thomas Sydenham, the English bark-seller Robert Talbor (also spelled Tabor) and the Italian Francesco Torti established its value in intermittent fevers, though arguments about it ran on into the 1730s. Wouter Klein and Toine Pieters, writing in the Journal of the History of Medicine and Allied Sciences, trace how the bark entered the European market around 1640 but took decades to become an accepted medicine, and they single out Paris as the city where medical and public appreciation of it took shape between about 1650 and 1720. It was in that same city, a century later, that Pelletier and Caventou finally took the bark apart chemically.

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3. The Countess of Chinchón: A Legend

The most often repeated origin story is that the wife of a seventeenth-century Spanish viceroy of Peru, the Countess of Chinchón, fell gravely ill with fever in Lima, was cured by the bark, and carried it back to Spain, where it became known as the “countess’s powder”. The genus name Cinchona is usually explained as a misspelled tribute to her title.

Historians treat the cure story as a legend; the work of the medical historian A. W. Haggis, around 1941, is generally credited with showing that the tale does not hold up against the documents. Klein and Pieters note how much of the bark’s early history is wrapped in this kind of legend and obscurity. The story is reported here because it is part of how the tree got its name, not as an account of what happened.

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4. Grey, Yellow and Red Barks

Pharmacists in 1820 sorted cinchona barks by colour, and Pelletier and Caventou’s memoir follows that trade practice. They worked on three kinds, named in their own text with the botanical names then in use:

• Grey cinchona (quinquina gris, which they attributed to Cinchona condaminea). From this bark they obtained the crystallisable alkali that the Lisbon physician Bernardino Antonio Gomes had already noticed and called cinchonin. Out of respect for Gomes they kept his name, adjusted to cinchonine at the request of the Académie des sciences’ examiners Vauquelin, Thénard and Deyeux.
• Yellow cinchona (quinquina jaune, Cinchona cordifolia in their text). This bark gave a different alkali, intensely bitter, which would not crystallise as the free base in their hands. They wrote that they thought it right to name it quinine, to tell it apart from cinchonine by a name that equally indicated its origin.
• Red cinchona (quinquina rouge, Cinchona oblongifolia in their text), which they found to contain both alkalis.

The finding that barks differed in which alkali they carried, and how much, explained much of the old inconsistency of bark medicine. It also gave buyers a chemical test of quality: a bark could now be judged by its quinine content rather than its colour, smell or bitterness. Botanists have since revised the names of many cinchona species, so the 1820 labels do not map neatly onto today’s classification; they are given here as the memoir gives them. How the extraction was done, step by step, is laboratory history and is told on The Discovery of Quinine page.

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5. Green Leaves: Naming Chlorophyll

The first joint project of Pelletier and Caventou was not a medicine at all. In a paper of 1817 and a short note of 1818 they extracted and studied the green pigment of leaves, and gave it the name that has stuck ever since: chlorophylle (spelled chlorophile and chlorophyle in their French), built from the Greek words for “pale green” and “leaf”. A 2024 commentary by Govindjee, Alexandrina Stirbet, Jonathan Lindsey and Hugo Scheer in Photosynthesis Research identifies these two papers as the first use of the word, and publishes English translations of both.

The pigment the two pharmacists isolated was a crude mixture; the chemistry of chlorophyll, its magnesium-centred ring structure and its role in capturing light for photosynthesis were worked out by later generations of chemists. But the episode shows the method that would serve them on cinchona: take a plant material, separate its components by solvents, and give a characteristic, reproducible substance its own name. The site’s Chlorophyll page covers the pigment as it appears in food.

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6. Ipecacuanha Root and Emetine

Ipecacuanha is the dried root of a small tropical American plant now classified as Carapichea ipecacuanha (older name Cephaelis ipecacuanha) — another member of the coffee family. In European medicine it was valued mainly as an emetic, a substance that provokes vomiting, and in smaller amounts as an expectorant and a treatment for dysentery.

In 1817 Pelletier, this time working with the physiologist François Magendie rather than with Caventou, isolated the root’s active principle and named it emetine. Their memoir on emetine and on three kinds of ipecacuanha was presented to the Académie des sciences on 25 February 1817 and also issued in Paris as a book of chemical and physiological research on ipecacuanha. The pairing was typical of the era: a pharmacist-chemist purified the substance, and a physiologist tested its effects on animals. Some modern summaries credit Caventou with emetine; the 1817 records name Pelletier and Magendie.

The bibliographers of the Garrison-Morton medical bibliography note that it was about a century before emetine’s real medical value, against amoebic dysentery caused by the parasite Entamoeba histolytica, was shown. In 1912 the British physician Leonard Rogers reported in the British Medical Journal the rapid cure of amoebic dysentery and amoebic liver abscess by injections of soluble emetine salts, and emetine became the standard treatment for amoebiasis for decades. Emetine blocks protein synthesis in the cells of the parasite, but it is also toxic to human cells, notably heart muscle, which is a large part of why it was later displaced by safer drugs. The disease itself is described on the site’s Amoebic Dysentery and Colitis page.

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7. Strychnos Seeds: Strychnine and Brucine

Saint-Ignatius bean, nux vomica and strychnine (1818)

The genus Strychnos gave the pair their most notorious discovery. In 1818 they isolated a new “vegetable alkali” from the Saint-Ignatius bean (the seed of Strychnos ignatii, a climbing shrub of the Philippines) and from nux vomica (the seed of the South and Southeast Asian tree Strychnos nux-vomica), and named it strychnine; the printed memoir appeared in 1819. Strychnine is intensely bitter and extremely poisonous. In their 1820 cinchona memoir the two men used it as a reference point for how much a single alkali can do, writing that strychnine produces a horrible tetanus.

Science later explained that effect. In 1973 Anne Young and Solomon Snyder at Johns Hopkins showed, in the Proceedings of the National Academy of Sciences, that radioactively labelled strychnine binds selectively to synaptic membranes in the spinal cord at the receptors for glycine, the amino acid the spinal cord uses as its main “brake” signal on motor nerves; binding in each region tracked the amount of glycine there. Strychnine blocks that brake. With inhibition removed, motor nerves fire uncontrollably, producing the violent muscle spasms and convulsions of strychnine poisoning, with death typically from exhaustion and failure of breathing. The glycine receptor is still known in laboratories as the “strychnine-sensitive” glycine receptor. Glycine as a nutrient is covered on the site’s Glycine page.

In nineteenth-century medicine, small amounts of strychnine were nonetheless used as a “tonic” and stimulant, a history surveyed by the medical historian John Haller; it was one of the alkaloids around which Magendie built his Formulaire of new medicines. Today it has no accepted medical use, and its use as a rodent poison has been restricted in many countries.

False angostura bark and brucine (1819)

In 1819 they found a second, related alkali in “false angostura” bark, a bark sold in Europe as a fraudulent or mistaken substitute for the genuine angostura bark used as a bitter tonic. They named it brucine, from the genus Brucea (named after the Scottish explorer James Bruce), the tree the bark was then wrongly believed to come from. The bark was in fact that of Strychnos nux-vomica itself, which explains why its alkali so closely resembled strychnine. A German version of their paper appeared the same year in the Annalen der Physik. Brucine is also poisonous, though less potent than strychnine; its main later use was in chemistry, where it served for separating mirror-image forms of other molecules.

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8. Hellebore, Sabadilla and Autumn Crocus

White hellebore, sabadilla and veratrine

The pair next analysed a group of plants then grouped in the colchicum family: white hellebore (Veratrum album), a tall plant of European mountain meadows, and sabadilla (in French cévadille), the seeds of a Central and South American plant long used as an insecticide and to kill lice. From them, around 1819, they obtained an alkali they called veratrine. In their 1820 cinchona memoir they refer back to “our memoir on the analysis of plants of the colchicum family” and describe veratrine as the principle responsible for the violent sneezing that white hellebore and sabadilla provoke. Veratrine was later shown to be a mixture of several alkaloids. The Veratrum alkaloids are poisonous to the heart and nerves, and accidental poisonings, often from mistaking white hellebore for an edible or medicinal plant, are reported in the medical literature.

Autumn crocus and the colchicum alkaloid

From the corm of the autumn crocus or meadow saffron, Colchicum autumnale (a plant that looks like a crocus but is not related to the saffron crocus), they also drew out a substance around 1819–1820. A 2018 review by Marianna Karamanou and colleagues in Current Pharmaceutical Design dates their isolation of this “peculiar substance” from the roots to 1819. They took it to be veratrine and did not name it colchicine. The German pharmacist Philipp Lorenz Geiger studied it further and gave it the name colchicine in 1833, and it was obtained in crystalline form in 1884.

Colchicum had been used against gout since antiquity, and colchicine remains in medical use: Karamanou and colleagues list gout, familial Mediterranean fever, Behçet’s disease and pericarditis among its modern indications. Colchicine binds to tubulin, the protein from which cells build their internal scaffolding of microtubules, and so interferes with the movement and activity of white blood cells that drive these inflammatory attacks; the same action stops dividing cells in mid-division. It has a narrow margin between effective and toxic amounts, and overdose, including poisoning from mistaking the plant for wild garlic, causes severe gastrointestinal, blood and multi-organ toxicity. The conditions are described on the site’s Familial Mediterranean Fever and Gout pages.

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9. Coffee, a Cousin of Cinchona: Caffeine

Coffee and cinchona belong to the same plant family, and in the early nineteenth century some physicians regarded coffee as a fever remedy. According to Pelletier’s own later dictionary article, as quoted in modern histories of caffeine, that was exactly why he and Caventou went looking in coffee beans: they hoped to find quinine there. They did not. Instead, in 1821, they obtained the bitter stimulant now called caffeine.

They were not the first. The German chemist Friedlieb Ferdinand Runge had isolated the substance in 1819, and in 1821 the French chemist Pierre-Jean Robiquet also obtained it, independently of Pelletier and Caventou. Pelletier’s account says that they left the priority to Robiquet, and his article is reported as the first printed use of the word caféine. So caffeine belongs on the list of their alkaloids only with that context: a parallel, independent isolation in the course of a hunt for quinine, not a first discovery.

The way caffeine acts was understood much later. In the brain it blocks adenosine receptors, the receptors for a messenger that builds up during waking hours and promotes drowsiness; a 1999 review by Bertil Fredholm and colleagues in Pharmacological Reviews describes this blockade as the main basis of caffeine’s effects at the amounts people normally consume. The site’s Coffee page covers the drink itself.

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10. How Quinine Works, and Cinchonism

Action on the malaria parasite

Malaria is caused by Plasmodium parasites, carried by mosquitoes, which multiply inside human red blood cells. Inside the red cell the parasite digests haemoglobin for food. That releases haem, which is toxic to the parasite, so the parasite locks it away in an inert crystalline pigment called haemozoin. Reviews of quinine, including Jane Achan and colleagues’ 2011 review in Malaria Journal, describe its mechanism as not fully understood, with the leading explanation being that quinine interferes with this detoxification step, so that free haem accumulates and poisons the parasite. Quinine acts on the blood stages of the parasite that cause fever, which is why bark and then quinine relieved the periodic fevers of malaria. Achan and colleagues also describe the limits that later made it a second-line drug: poor tolerability and complicated dosing schedules. The disease is covered on the site’s Malaria page.

Cinchonism and the ear

The characteristic side effects of quinine and the other cinchona alkaloids are grouped under the name cinchonism: ringing in the ears (tinnitus), reduced hearing, headache, nausea, dizziness or vertigo and blurred vision. A 2021 review by Maria Guilherme Semedo and colleagues in Otology & Neurotology dates the first report of quinine’s toxicity to the ear to 1824, only four years after Pelletier and Caventou named the compound, and traces how the drug was paradoxically also used in the nineteenth and early twentieth centuries for ear conditions including Ménière’s disease, vertigo and ear pain. Hearing effects usually recede when the drug is stopped, but lasting hearing loss has been reported.

Serious reactions

Beyond cinchonism, quinine can provoke rarer immune-mediated reactions. A 2016 systematic review by Nathan Liles and colleagues in the American Journal of Hematology gathered 142 patients with such reactions, including low platelet counts, kidney injury and the clotting disorder thrombotic microangiopathy; 72% of the reactions followed quinine tablets and 20% followed quinine-containing beverages, 30 patients needed dialysis or other kidney replacement therapy, and 3 died. The authors stressed that severe reactions occurred even with the small amounts in common drinks. Historically, “blackwater fever”, a sudden destruction of red blood cells with dark urine, was linked to quinine use in malaria. What these findings meant for quinine’s later place in medicine, including trials against artesunate and regulators’ actions on its use for leg cramps, is told on the Legacy and Later Research page.

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Key Research Papers

1. Miller LH, Rojas-Jaimes J, Low LM, Corbellini G. What Historical Records Teach Us about the Discovery of Quinine. Am J Trop Med Hyg. 2023;108(1):7-11. PubMed PMID: 36410328
2. Permin H, Norn S, Kruse E, Kruse PR. On the history of Cinchona bark in the treatment of Malaria. Dan Medicinhist Arbog. 2016;44:9-30. PubMed PMID: 29737660
3. Klein W, Pieters T. The Hidden History of a Famous Drug: Tracing the Medical and Public Acculturation of Peruvian Bark in Early Modern Western Europe (c. 1650-1720). J Hist Med Allied Sci. 2016;71(4):400-421. PubMed PMID: 26895817
4. Lee MR. Plants against malaria. Part 1: Cinchona or the Peruvian bark. J R Coll Physicians Edinb. 2002;32(3):189-96. PubMed PMID: 12434796
5. Govindjee G, Stirbet A, Lindsey JS, Scheer H. On the Pelletier and Caventou (1817, 1818) papers on chlorophyll and beyond. Photosynth Res. 2024;160(1):55-60. PubMed PMID: 38488941
6. 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
7. Pelletier, Caventou. Ueber ein neues in der falschen Angustura-Rinde aufgefundenes Pflanzen-Alkali (Brucin). Ann Phys. 1819;63(11):322-338. DOI: 10.1002/andp.18190631107
8. 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
9. 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
10. Karamanou M, Tsoucalas G, Pantos K, Androutsos G. Isolating Colchicine in 19th Century: An Old Drug Revisited. Curr Pharm Des. 2018;24(6):654-658. PubMed PMID: 29336251
11. Fredholm BB, Bättig K, Holmén J, Nehlig A, Zvartau EE. Actions of caffeine in the brain with special reference to factors that contribute to its widespread use. Pharmacol Rev. 1999;51(1):83-133. PubMed PMID: 10049999
12. Achan J, Talisuna AO, Erhart A, Yeka A, Tibenderana JK, Baliraine FN, Rosenthal PJ, D'Alessandro U. Quinine, an old anti-malarial drug in a modern world: role in the treatment of malaria. Malar J. 2011;10:144. PubMed PMID: 21609473
13. Semedo MG, Dias-Silva N, Miguéis J, Pita JR. Quinine in Otology and Neurotology: Ototoxicity and Historic Role in Therapy. Otol Neurotol. 2021;42(1):145-152. PubMed PMID: 33301286
14. Liles NW, Page EE, Liles AL, Vesely SK, Raskob GE, George JN. Diversity and severity of adverse reactions to quinine: A systematic review. Am J Hematol. 2016;91(5):461-6. PubMed PMID: 26822544

PubMed Topic Searches

1. Cinchona bark history
2. Pelletier and Caventou
3. Strychnine and the glycine receptor
4. Colchicine history
5. Cinchonism and quinine ototoxicity

Further Reading

• Pelletier PJ, Caventou JB. “Recherches chimiques sur les quinquinas.” Annales de chimie et de physique 15 (1820). Wellcome Library copy on the Internet Archive: archive.org/details/b30476525
• Magendie F, Pelletier PJ. Recherches chimiques et physiologiques sur l’ipécacuanha. Paris, 1817. Wellcome Collection record: wellcomecollection.org/works/jycuhcmv

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Connections

• Pelletier and Caventou: Quinine from Cinchona Bark
• Pelletier and Caventou: Life and Times
• The Discovery of Quinine (1820)
• Quinine After 1820: Legacy and Later Research
• Pharmacology
• Friedrich Sertürner and Morphine
• Malaria
• Coffee
• Chlorophyll
• Amoebic Dysentery and Colitis
• Glycine
• Familial Mediterranean Fever

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