The Discovery of Quinine (1820)

For almost two hundred years before 1820, European physicians had treated intermittent fevers — the shaking chills and fevers that came back every second or third day, most of them malaria — with the powdered bark of an Andean tree, cinchona. They knew the bark worked. They did not know why, the dose was uncertain, the bark was bulky and bitter, and not every bark sold under the name worked equally well. On 11 September 1820 two Paris pharmacists, Pierre-Joseph Pelletier and Joseph Bienaimé Caventou, read a memoir to the Académie des sciences that changed this. They had pulled two pure substances out of cinchona bark, shown that both were plant “alkalis”, and given the one from yellow bark a new name: quinine.

This page tells that story as far as possible in their own words, from the memoir Recherches chimiques sur les quinquinas (“Chemical research on the cinchona barks”) printed in the Annales de chimie et de physique later that year. Quotations are given in the original French with a plain English rendering. The laboratory steps appear only as history. The trees and the other plants the pair worked on are covered on a companion page about cinchona and the plant alkaloids. What happened to quinine after the 1830s is covered on Quinine After 1820.

Table of Contents

  1. A Bark Everyone Used and No One Understood
  2. Gomes of Lisbon and the Cinchonin Clue
  3. Vegetable Alkalis After Morphine
  4. Grey Bark and Cinchonine
  5. Yellow Bark and a New Alkali
  6. Naming Quinine
  7. The Memoir of 11 September 1820
  8. From Laboratory to Bedside: Double and Magendie
  9. Publishing Instead of Patenting
  10. Confirmation in the Field: Spain, the Morea and Algeria
  11. Key Research Papers
  12. Connections
  13. Featured Videos

1. A Bark Everyone Used and No One Understood

Cinchona bark (“Peruvian bark” or “Jesuit’s bark”) reached European medicine in the seventeenth century. According to a 2016 history by Permin and colleagues, it was first given to a European for malaria in the 1630s, was known in England by the 1660s, and had its value established by physicians such as Thomas Sydenham and Francesco Torti, with arguments over it running into the 1730s. Klein and Pieters, in a study of its early modern reception, trace how it entered the European market around 1640 but took decades to be accepted, with Paris one of the places where medical and public opinion of it took shape between about 1650 and 1720.

By 1800 the bark was a standard remedy, and it had become a favourite subject for chemists. Pelletier and Caventou opened their memoir by saying so: cinchona barks, they wrote, were “at the head” of the substances that chemists returned to again and again, and it would be hard even to list all the work done on them, from those of Bucquet to the recent analyses of a chemist named Lauber.

They singled out two French predecessors by name:

Vauquelin’s practical test mattered later in the story. He had noticed that the barks generally recognised as fever-curing gave a precipitate with an infusion of oak galls, and the weak ones did not. Something in the good barks reacted; no one yet knew what it was. Chemists had proposed one “febrifuge principle” after another — a “cinchonic bitter”, a bitter yellow matter, a supposed pure resin — without settling the question.

Back to Table of Contents

2. Gomes of Lisbon and the Cinchonin Clue

The clue that Pelletier and Caventou followed came from Portugal. The Lisbon physician Bernardino Antonio Gomes had obtained a crystallisable substance from grey cinchona bark and named it cinchonin. They did not hide their debt. In the first paragraph of the memoir they wrote that a paper by Reuss of Moscow would deserve mention “if the work of M. Gomes, of Lisbon, did not claim all our attention”:

“c’est à ce dernier chimiste qu’on doit la découverte d’un principe particulier dans le quinquina, principe que nous avons reconnu être une base salifiable organique dont l’étude fera un des objets principaux de notre Mémoire.”

In English: it is to this chemist that we owe the discovery of a particular principle in cinchona, a principle that we have recognised to be an organic salt-forming base, and whose study will be one of the main subjects of our memoir.

That last phrase carried the whole new idea. Gomes had stated that his cinchonin was neither acid nor alkaline. Pelletier and Caventou explain that this was exactly what made them suspicious. Plant alkalis had just been discovered in other drugs, and they were “so constantly the active matter of the plants that contain them” that it was natural to look for one in cinchona. If Gomes’s cinchonin really was the substance through which the bark acted on the body, as Gomes believed, then it was necessary, they wrote, to check whether he had made an error in the last stage of his preparation.

They also wrote that, out of respect for Gomes’s rights, they kept his name cinchonin when they read the memoir aloud. The change to the French form cinchonine, ending like the other plant bases, was made afterwards at the wish of the Académie’s reviewing commissioners. Near the end of the memoir they returned to him once more, calling Gomes the man “qui, le premier, a obtenu la cinchonine” — who first obtained cinchonine — even though he had not recognised its alkaline nature.

Back to Table of Contents

3. Vegetable Alkalis After Morphine

To chemists of 1800, alkalis — substances such as potash, soda, lime and ammonia that neutralise acids and form salts with them — belonged to the mineral world. Plants were thought to yield acids, gums, resins and oils, not bases. That changed with opium. The German pharmacist Friedrich Sertürner reported an alkaline substance from opium in 1805, and in 1817 published his paper on Morphium as “a new salt-forming base”; a French translation arranged by Joseph Louis Gay-Lussac the same year brought it to Paris (the story is told in the isolation of morphine page of the Sertürner wing).

Paris chemists, Pelletier and Caventou above all, followed up at once. The French historian of pharmacy J. Fournier, in a 2001 study of alkaloid discovery, describes the first era of alkaloid chemistry as running from Derosne’s work on opium in 1803, through Seguin and Sertürner, and closing around 1820 with Pelletier and Caventou, Robiquet and Gomes of Lisbon. In the three years before the cinchona memoir, the pair (and Pelletier with the physiologist François Magendie) had already worked on ipecacuanha root, on the green pigment of leaves, which they named chlorophyll, on the Saint-Ignatius bean and nux vomica, from which they obtained strychnine in 1818, on false angostura bark, which gave brucine, and on white hellebore and sabadilla, which gave the substance they called veratrine. Those plants and alkaloids are described on the plant alkaloids page.

By 1820 they had a working method and a working idea. The idea is stated in their second paragraph: “La découverte des alcalis végétaux fait époque dans la science” — the discovery of the vegetable alkalis marks an epoch in science. It explained, they wrote, a run of puzzles in plant analysis. Cinchona was the obvious next target.

Back to Table of Contents

4. Grey Bark and Cinchonine

They began with grey cinchona (quinquina gris, which they identified as Cinchona condaminea, the “loxa” bark), “generally regarded as the type” of the cinchona barks. Their first aim, they wrote, was to examine the crystallisable matter Gomes had described. They followed his procedure as it had been passed to Lauber through Vauquelin and printed in Thénard’s chemistry textbook, quoting it word for word in the memoir.

In outline, and as history rather than as a method, the work went like this. They soaked the crushed bark repeatedly in hot strong alcohol and distilled the alcohol off. The resin-like residue was washed with water made slightly alkaline with potash until the washings ran clear. What remained was, they wrote, “le cinchonin du docteur Gomès” — Dr Gomes’s cinchonin. But it was not pure. When they dissolved it in very dilute acid it gave up a large amount of a green fatty matter, the same that Lauber had found. They then took the acid solution and added pure magnesia. Magnesia is itself a mild base and took the acid away from the dissolved substance, which settled out with the magnesia. Treated again with alcohol, this deposit gave white, shining needle-shaped crystals: “Ces cristaux sont de la cinchonine très-pure” — these crystals are very pure cinchonine.

The point that overturned Gomes’s description was its chemistry. The purified cinchonine dissolved in acids and formed true salts with them, as ammonia or potash would. It was a base. Gomes’s preparation had left it bound to fat and colouring matter, which hid its alkaline nature.

They also asked what the base was combined with inside the living bark. The magnesia had captured an acid that formed a soluble salt with it. Because it behaved like the acid Vauquelin had found in cinchona combined with lime, they suspected it was the same, and isolating it “confirmed our suspicion”. In the bark, then, cinchonine sits as a salt of quinic acid.

Back to Table of Contents

5. Yellow Bark and a New Alkali

Next came yellow cinchona (quinquina jaune, which they called Cinchona cordifolia). Following Vauquelin’s example of treating all the barks the same way, they expected to find cinchonine again. They prepared the same extracts, separated the fat, dissolved the bitter substance in dilute hydrochloric acid, and precipitated it with magnesia. Then, they wrote, they waited for a fine crop of cinchonine crystals:

“quelle a été notre surprise de n’obtenir qu’une substance jaunâtre transparente et nullement cristalline !”

“What was our surprise to obtain only a transparent, yellowish substance, not crystalline at all!”

Their first assumption was that this was cinchonine spoiled by some impurity peculiar to yellow bark, and they spent a long time trying to remove it. They tried fresh acid, a lead salt to strip out any yellow colouring matter, and ether. The ether test was telling: cinchonine dissolves in ether only to a limited extent, but the new substance dissolved in it “entirely, with the greatest ease”, and still would not crystallise. With ammonium oxalate it gave a brilliant white precipitate that looked like calcium oxalate but dissolved in alcohol. Yet it dissolved in every acid and formed very white salts that crystallised more readily than the salts of cinchonine and looked different from them.

“By the force of things”, as they put it, they were led to treat the bitter matter of yellow bark as a separate salt-forming base. They stressed that they decided this only “after mature reflection”, many trials and the preparation of a great number of salts. The deciding argument, they wrote, was that the two substances occur together in some barks and can be separated from each other. If the yellow-bark substance were merely impure cinchonine, it would make no sense to separate pure cinchonine from impure cinchonine in the same mixture.

The third bark they examined, red cinchona (quinquina rouge, which they called Cinchona oblongifolia), settled the matter in practice. It held both bases. In their figures, a kilogram of grey bark gave them 2 grams of cinchonine and a kilogram of yellow bark 9 grams of the new base. A kilogram of red bark (the rolled variety) gave 8 grams of cinchonine and 17 grams of the new base. They added in a footnote that they had probably not extracted all the alkali from any of the barks. From these differences they drew a cautious inference. If the active principle of cinchona lay in its bases, that would explain why physicians found grey and yellow bark alike but not identical in their effects, and why red bark, containing both in large amounts, might be “le quinquina par excellence”.

Back to Table of Contents

6. Naming Quinine

A new substance needed a name. Their reasoning is set down in one sentence:

“comme, d’ailleurs, cette substance, bien caractérisée, mérite aussi-bien un nom particulier que sa congénère dans le quinquina gris, nous avons cru devoir la nommer quinine, pour la distinguer de la cinchonine par un nom qui indique également son origine.”

In English: since this well-defined substance deserves its own name as much as its relative in grey bark, we thought it right to call it quinine, to distinguish it from cinchonine by a name that also shows where it comes from. Both names point to the same source. Cinchonine comes from the botanical genus Cinchona. Quinine comes from quinquina, the French name for the bark, the word used in the title of their memoir.

The memoir describes the new base closely. In their hands quinine as a free base “ne cristallise jamais” (“never crystallises”). Dried, it formed a porous, off-white mass. It was barely soluble in water and yet “très-amère”, very bitter. Its salts were another matter. Sulphuric acid, they reported, formed with it a neutral salt that crystallised very easily. They described it as narrow, pearly, slightly flexible needles “resembling asbestos” that grouped into star-shaped tufts. It was less soluble in cold water and more soluble when hot, it melted to something like wax, and it dissolved freely in alcohol. That salt, quinine sulphate, is the form in which quinine went into medicine (section 8).

The 2021 review of quinine in ear medicine by Semedo and colleagues dates the isolation and naming of quinine by Pelletier and Caventou to 1820.

Back to Table of Contents

7. The Memoir of 11 September 1820

The printed memoir carries the line “Lues à l’Académie des Sciences le 11 septembre 1820” — read to the Académie des sciences on 11 September 1820. It fills two instalments of volume 15 of the Annales de chimie et de physique, and a separate edition appeared in Paris the same year. The Académie referred it to three commissioners, the chemists Vauquelin, Louis Jacques Thénard and Nicolas Deyeux, the same men whose wish led to the spelling cinchonine.

The argument that the alkali is the active principle

Toward the end, Pelletier and Caventou turned from chemistry to medicine, and the memoir builds its case step by step:

Then came the argument by analogy, the sentence most often quoted from the memoir:

“La morphine représente l’action calmante de l’opium ; la strychnine produit un horrible tétanos ; la picrotoxine agit sur le cerveau ; la vératrine est, dans l’hellébore blanc et dans la cévadille, le principe sternutatoire : il existe dans le quinquina un alcali végétal, et on lui refuserait sans examen une action spéciale !”

In English: morphine represents the calming action of opium; strychnine produces a horrible tetanus; picrotoxin acts on the brain; veratrine is the sneezing principle in white hellebore and sabadilla. There is a vegetable alkali in cinchona, and one would deny it a special action without examining it!

Not a case against the whole bark

The memoir did not argue that the natural bark had become useless. “Nous sommes loin, cependant, de soutenir qu’il ne faut plus employer le quinquina en nature”, they wrote: “We are far, however, from maintaining that cinchona in its natural form is no longer to be used.” Even if their view rested on many confirmed medical observations, they added, they would not say that. The other substances in the bark might modify the alkali’s action in useful ways that physiology did not yet understand. Such modifications, they argued, still presuppose that the property being modified exists. They then answered the objection that the bark’s virtue lay only in the intimate union of all its parts. On that view, they wrote, one would have to say that nux vomica does not act through its strychnine. One would have to “prendre les médicamens tels que la nature nous les offre, et bannir les sciences chimiques du sanctuaire de la Médecine”: take medicines just as nature offers them, and banish chemistry from the sanctuary of medicine.

They gave practical reasons for wanting the pure principle. There would be circumstances, they wrote, in which it would be fortunate to give it pure, at full strength. “Il est des cas où un malade ne peut prendre une once de poudre ou un verre de liquide”: there are cases where a patient cannot take an ounce of powder or a glass of liquid. Knowing the active principle would also show which pharmacy formulas were reasoned and which were “empirical, absurd and often dangerous”.

The closing hope

They were pharmacists and chemists, not physicians, and they closed the memoir by leaving the medical test to others:

“Du reste, espérons que quelque praticien habile, joignant la prudence à la sagacité, fera des recherches thérapeutiques sur les alcalis du quinquina, et donnera ainsi à notre travail une utilité médicale.”

“For the rest, let us hope that some skilled practitioner, joining prudence to sagacity, will carry out therapeutic research on the alkalis of cinchona, and so give our work a medical usefulness.”

Back to Table of Contents

8. From Laboratory to Bedside: Double and Magendie

The physicians did not keep them waiting long. According to the Encyclopædia Universalis account of Caventou’s work, the Paris physician François-Joseph Double tried the new alkaloids in fever patients and reported results in 1820. By 1823 the London physician John Elliotson was reviewing results gathered in Europe. In the 1829 edition of his Formulaire, François Magendie called quinine the specific remedy for intermittent fevers.

Magendie’s Formulaire matters because it turned laboratory chemistry into everyday prescribing. Ségal and Trépardoux, in a 2015 history, describe how its successive issues from 1821 were devoted to the new pure plant principles — strychnine, quinine and morphine among them — and drew on the work of Pelletier, Caventou and other pharmacists. Magendie tested their activity and safety in animals, a practice the authors see as anticipating later rules for registering medicines. A physician could now write a prescription for a measured weight of a pure, crystalline salt rather than an uncertain quantity of bark.

The salt that physicians used was quinine sulphate, the easily crystallised form described in the memoir (section 6). A small weighed amount of a pure salt could take the place of a large dose of bark. This was the advantage the memoir had predicted for the patient who “cannot take an ounce of powder”. The story of the isolation is retold in a short history note by Pai-Dhungat and in Kaufman and Rúveda’s longer chemical history, The quest for quinine.

Quinine’s drawbacks were noticed early too. Semedo and colleagues date the first report of its harmful effect on hearing to 1824, four years after its isolation. The group of side effects later called cinchonism, which includes ringing in the ears, is covered on the plant alkaloids page.

Back to Table of Contents

9. Publishing Instead of Patenting

Pelletier and Caventou published their full method in a widely read journal, and they did not patent it. The memoir sets out their procedures step by step. The English-language Wikipedia biography of Caventou states that neither partner chose to patent the discovery. A French popular-science account says they did not wish to patent it so that everyone could have access to the treatment. The 1911 Catholic Encyclopedia says Pelletier published his results to the world without any thought of the money that keeping the discovery secret might have brought. The detailed modern studies of the discovery, such as François Chast’s 2020 paper and Marcel Delépine’s 1951 biographical article, are listed below for readers who wish to follow the question further.

The other half of the story is that publishing did not mean staying out of the business. The pair went on to make quinine sulphate commercially themselves, and the French Wikipédia biography of Caventou says they created their own factory. Because the method was public, other makers could use it as well. According to the French medical newspaper Le Quotidien du Médecin, manufacture had spread to Germany and to Philadelphia by 1826. Production figures for these years differ widely between sources, and none are given here.

The Académie des sciences gave its judgement in 1827, when it awarded Pelletier and Caventou a shared Montyon prize of 10,000 francs for the discovery of quinine. Their careers, honours and the later monument to them in Paris are told on the Life and Times page.

Back to Table of Contents

10. Confirmation in the Field: Spain, the Morea and Algeria

Paris hospital trials showed that quinine worked. Military medicine showed it at scale. French army physicians, according to the historian of pharmacy Guy Devaux, confirmed quinine’s effect against intermittent fevers during the French campaign in Spain in 1823 and again during the Morea expedition of 1828 in southern Greece.

The most important field work came in French North Africa. The army physician François Clément Maillot established the use of quinine sulphate in large doses among French troops with fever in Algeria. He reported his results to the Académie de médecine on 30 May 1835. Devaux’s 2005 paper on the monument later raised to Pelletier and Caventou in Paris records these confirmations, ending with Maillot’s report of 1835. The doses Maillot used are history and are not given here.

Within fifteen years of the memoir, the “skilled practitioner” that Pelletier and Caventou had hoped for had come forward many times over. The alkali they had extracted, named and described, and whose action they had predicted only by analogy, had been confirmed in hospital and army practice. Permin and colleagues’ history follows what came next: the Dutch cinchona plantations, the 1942 supply crisis and the synthetic antimalarials. That later history is told on Quinine After 1820. The disease is described on the site’s malaria page.

Back to Table of Contents

Key Research Papers

  1. Pai-Dhungat JV. Caventou, Pelletier &--History Of Quinine. J Assoc Physicians India. 2015;63(3):58. PubMed PMID: 26540843
  2. Fournier J. [Alcaloids discovery, markers for the history of organic chemistry]. Rev Hist Pharm (Paris). 2001;49(331):315-32. PubMed PMID: 11776272
  3. 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
  4. Kaufman TS, Rúveda EA. The quest for quinine: those who won the battles and those who won the war. Angew Chem Int Ed Engl. 2005;44(6):854-85. PubMed PMID: 15669029
  5. 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
  6. 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
  7. 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
  8. Chast F. La découverte de la quinine par Joseph Pelletier et Joseph B. Caventou (1820). Revue de biologie médicale. 2020;(356):51-66. DOI: 10.3917/rbm.356.0051
  9. Delepine M. Joseph Pelletier and Joseph Caventou. J Chem Educ. 1951;28(9):454. DOI: 10.1021/ed028p454
  10. Devaux G. Le monument à Pelletier et Caventou : ses souscripteurs girondins. Rev Hist Pharm. 2005;93(345):136-142. DOI: 10.3406/pharm.2005.5787

PubMed Topic Searches

  1. Pelletier and Caventou, quinine
  2. History of quinine and cinchona
  3. History of alkaloid chemistry in the nineteenth century
  4. Magendie’s Formulaire

Further Reading

Back to Table of Contents

Connections

Back to Table of Contents