Quinine After 1820: Legacy and Later Research

When Pierre-Joseph Pelletier and Joseph Bienaimé Caventou read their memoir on the cinchona barks to the Académie des sciences in September 1820, they ended it with a hope rather than a claim: that some careful physician would test the new alkalis and give their chemistry a medical use. Within fifteen years quinine sulfate was a standard medicine in French hospitals and armies. Within a century the bark that supplied it had reshaped colonial agriculture, and within two centuries quinine had become the subject of some of the largest drug trials ever run in malaria.

This page follows that long afterlife. It covers how quinine sulfate became an ordinary medicine, how the pair’s alkaloids became the model for the idea of a drug’s “active principle”, the empire built on cinchona plantations, the shock of 1942 and the synthetic antimalarials that followed, William Perkin’s accidental dye, the long argument over who first made quinine in a flask, the trials that moved artesunate ahead of quinine for severe malaria, the research on quinine for muscle cramps and its adverse reactions, and what later became of emetine, strychnine and colchicine. The story of the discovery itself is told on The Discovery of Quinine (1820); the plants are described on Cinchona and the Plant Alkaloids.

Table of Contents

  1. Quinine Sulfate Becomes a Standard Medicine
  2. A Model for Active Principles
  3. Cinchona and Empire
  4. Ledger’s Seeds and the Java Plantations
  5. 1942 and the Rise of Synthetic Antimalarials
  6. Perkin’s Mauve and the Quest to Make Quinine
  7. The Synthesis Controversy
  8. Artesunate Versus Quinine: SEAQUAMAT and AQUAMAT
  9. Quinine for Cramps, the FDA and Adverse Reactions
  10. Emetine, Strychnine and Colchicine Later On
  11. Key Research Papers
  12. Connections
  13. Featured Videos

1. Quinine Sulfate Becomes a Standard Medicine

The free quinine base that Pelletier and Caventou obtained from yellow cinchona bark would not crystallise in their hands, and it was intensely bitter. What reached patients was a salt: quinine combined with sulfuric acid to make quinine sulfate, a white crystalline powder that could be weighed accurately, stored, shipped and given in a small dose. That was the practical promise of the 1820 memoir. The authors had written that there would be circumstances in which a physician would be glad to give the principle pure, since some patients could not swallow an ounce of bark powder or a glass of bitter decoction.

The clinical record of the following years, as summarised in the French historical literature, moved quickly. The Paris physician François-Joseph Double reported early trials in fever patients in 1820. The English physician John Elliotson reviewed the European results by 1823. By the 1829 edition of his Formulaire, the physiologist François Magendie described quinine as the specific remedy for intermittent fevers, the old name for the recurring fevers of malaria.

Military medicine supplied the largest test. French army physicians reported quinine’s effect on intermittent fevers during the Spanish campaign of 1823 and the Morea expedition in Greece in 1828. In Algeria the army physician François Clément Maillot treated soldiers with large doses and reported his results to the Académie de médecine on 30 May 1835; the historian of pharmacy Guy Devaux credits him with establishing the large-dose use of quinine sulfate in Algeria.

Manufacture spread beyond France from the mid-1820s, with works in the German states and in Philadelphia taking up the method. Because the two pharmacists had published their procedure rather than patenting it, no licence was needed to copy it. They also manufactured quinine sulfate themselves, a fact reported alongside the no-patent decision on The Discovery of Quinine. In 1827 the Académie des sciences awarded them a Montyon prize of 10,000 francs for the discovery.

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2. A Model for Active Principles

Before 1800, medicines from plants were whole materials: a bark, a root, a leaf, a resin, or an extract made from them. Their strength varied with the harvest, the species, the age of the material and the skill of the apothecary. The alkaloid chemists changed the question. If a plant’s action came from one definite substance, that substance could be isolated, weighed and given in a known amount.

Pelletier and Caventou made this argument openly in 1820. Morphine, they wrote, represented the calming action of opium; strychnine produced a terrible tetanus; it would be strange, they argued, to find a vegetable alkali in cinchona and refuse it without examination a special action of its own. At the same time they stopped short of saying the whole bark was finished. They wrote that they were far from holding that cinchona in its natural form had no further place in medicine.

The French historian of pharmacy J. Fournier places the pair at the close of what the chemist Michel-Eugène Chevreul called the first era of alkaloid history. That era ran from Charles Derosne’s work on opium in 1803, through Armand Séguin and Friedrich Sertürner’s morphine, to Pelletier and Caventou, Pierre Robiquet and Bernardino Gomes of Lisbon around 1820. Fournier describes the later era as shaped by Louis Pasteur’s stereochemistry and Claude Bernard’s experimental physiology, both of which built on the existence of pure, well-defined plant compounds.

The link from chemistry to prescribing ran through Magendie. Alain Ségal and François Trépardoux have described his Formulaire, issued nine times between 1821 and 1836, as a book built around the new pure alkaloids, above all strychnine, quinine and morphine, drawing on the work of Pelletier, Caventou and others. Magendie tested the activity and safety of these substances on animals before describing them for use in people. Ségal and Trépardoux note that this approach anticipated, in outline, the requirements later written into drug-registration rules.

The same pattern repeated through the century: morphine from the opium poppy, quinine from cinchona, atropine from belladonna, cocaine from coca, and in the twentieth century digoxin from foxglove and artemisinin from sweet wormwood. The site’s pages on Friedrich Sertürner, William Withering and Tu Youyou follow three of those threads.

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3. Cinchona and Empire

The bark itself had a long European history before 1820. Henrik Permin and colleagues, in their review of cinchona in the treatment of malaria, describe its first reported use for a European in the 1630s, its promotion in Rome by Cardinal Juan de Lugo, and its arrival in England by the 1660s, where Thomas Sydenham, Robert Talbor (also spelled Tabor) and later the Italian physician Francesco Torti helped to establish its value. Wouter Klein and Toine Pieters trace how slowly it was accepted: the bark entered the European market around 1640, but it took decades and much argument before physicians and the public trusted it, with Paris playing a central part between about 1650 and 1720.

Isolating quinine changed the economics of that trade. Once the active substance could be measured, bark could be graded by its quinine content, and the richest barks became valuable commodities. All of it, for most of the nineteenth century, came from wild trees in the Andean forests of what are now Peru, Bolivia, Ecuador and Colombia, where the governments of the new republics sought to control its export.

The physician and pharmacologist M. R. Lee, in his history of cinchona as a plant against malaria, describes the nineteenth-century story as one of exploration, exploitation and secrecy. European powers competed to obtain seeds and seedlings and to grow the trees in their own colonies, because a reliable quinine supply allowed soldiers, officials and settlers to survive in malarial regions. Lee and other historians link cinchona directly to the exploration of tropical Africa and the expansion of European empires there.

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4. Ledger’s Seeds and the Java Plantations

Charles Ledger was an English trader living in South America. The malaria historian Gramiccia, in a 1987 paper subtitled “a composite of field experience, chance, and intuition”, describes how Ledger and his Bolivian servant Manuel, whose name is usually given as Manuel Incra Mamani, located stands of exceptionally productive cinchona trees and collected their seeds. Manuel’s knowledge of the forests was central to the find.

According to Gramiccia, the British authorities failed to recognise the importance of the seeds. Part of the consignment was bought by the Dutch colonial government and planted in Java. The trees grown from them, later classified under the name Cinchona ledgeriana, turned out to have far higher quinine content than most of the cinchonas then in cultivation. Through selection and grafting, the Dutch plantations built on that stock and came to hold what Gramiccia calls a practical monopoly of the world’s quinine.

By the 1930s the Java plantations are reported to have supplied about 97 per cent of the world’s quinine. A medicine first isolated by two Paris pharmacists from South American bark was by then made almost entirely from trees grown on one island in Southeast Asia, and the price and supply were controlled by a small group of producers there. That concentration made the next event a crisis.

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5. 1942 and the Rise of Synthetic Antimalarials

In 1942 Japanese forces occupied the Dutch East Indies, including Java. Permin and colleagues describe how this cut off the Allied powers from almost all of the world’s quinine at the moment when their armies were fighting in the malarial regions of the Pacific, Southeast Asia and North Africa. Existing stocks were rationed, cinchona collecting was restarted in South America, and governments put large resources into synthetic alternatives.

The search for synthetic antimalarials was not new — chemists had been trying to imitate or improve on quinine since the late nineteenth century, and Paul Ehrlich had shown in 1891 that the dye methylene blue had some effect against malaria. But the wartime shortage turned that search into a large organised effort. Its most important product was chloroquine, a synthetic compound whose ring system resembles part of the quinine molecule. After the war chloroquine became the mainstay of malaria treatment and of the global malaria eradication campaign.

The same review traces what came next. The malaria parasite Plasmodium falciparum developed resistance to chloroquine, which spread across Asia, South America and Africa in the second half of the twentieth century. Quinine, to which resistance developed more slowly, came back into use for severe and resistant malaria. The next major advance came from another plant: artemisinin, isolated in China from sweet wormwood (Artemisia annua) by Tu Youyou’s team in the 1970s. The site describes that work on Tu Youyou and on Artemisinin and Malaria.

Since 2006 the World Health Organization has not listed quinine as a first-line treatment for uncomplicated malaria, where artemisinin-based combination therapies took its place. The modern range of antimalarial drugs is described on Antimalarial Drugs and Artemisinin Combination Therapy.

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6. Perkin’s Mauve and the Quest to Make Quinine

Quinine’s value made it an early target for chemists who wanted to make natural products in the laboratory. In 1856 an eighteen-year-old student in London, William Henry Perkin, tried to make quinine from chemicals derived from coal tar. The chemistry of the time knew roughly how many carbon, hydrogen, nitrogen and oxygen atoms quinine contained, but not how they were arranged, and the attempt could not succeed. Instead Perkin obtained a purple substance, mauveine, which became the first synthetic dye.

Mauveine started the synthetic dye industry. That industry, in turn, trained the chemists and built the laboratories that later produced synthetic drugs, including Ehrlich’s arsenical salvarsan and the sulfonamides. In that roundabout sense, an unsuccessful attempt to make Pelletier and Caventou’s alkaloid helped to found modern pharmaceutical chemistry. The connection is traced on the site’s Paul Ehrlich wing.

Working out the structure of quinine took most of the following century. Teodoro Kaufman and Edmundo Rúveda, in their review “The quest for quinine: those who won the battles and those who won the war”, survey that history: the experiments that led to quinine’s isolation and its structure, the partial syntheses, and the full syntheses of the twentieth and early twenty-first centuries. The molecule contains a quinoline ring joined to a bicyclic quinuclidine system, with several stereocentres — points where the atoms can be arranged in mirror-image ways — which made a controlled synthesis very difficult.

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7. The Synthesis Controversy

The best-known episode in that history concerns who first made quinine. In 1918 the German chemists Paul Rabe and Karl Kindler reported converting a compound called d-quinotoxine (quinotoxine, an isomer of quinine obtained from it) back into quinine. In 1944, in the middle of the wartime quinine shortage, Robert Burns Woodward and William von Eggers Doering at Harvard announced that they had made d-quinotoxine from simple starting materials. Because Rabe and Kindler had already shown how to turn quinotoxine into quinine, Woodward and Doering described their work, in a short 1944 communication, as “the total synthesis of quinine”. It was widely reported in the press at the time.

The claim rested on Rabe and Kindler’s step, which Woodward and Doering did not repeat. Jeffrey Seeman’s 2007 review, “setting the record straight”, documents what followed. Rabe and Kindler had never published full experimental details of their conversion. Gilbert Stork, whose group published the first stereoselective total synthesis of quinine in 2001, questioned whether the 1918 conversion could have worked as reported and called the Woodward–Doering total synthesis a “myth”. Seeman reviewed the record in detail and set out the arguments on both sides.

The dispute was settled experimentally. In 2008 Aaron Smith and Robert Williams repeated the Rabe–Kindler conversion of d-quinotoxine into quinine, following the old procedure as closely as the record allowed, and confirmed that it works. Their paper, titled “Rabe rest in peace”, described the result as an experimental affirmation of the Woodward–Doering formal total synthesis. A “formal” synthesis, in chemists’ language, is one that makes a compound already known to have been converted into the target.

Stork’s 2001 synthesis remains a landmark for another reason. It controlled the three-dimensional arrangement of the molecule at each stage, producing the natural form of quinine selectively rather than as a mixture. Kaufman and Rúveda describe further syntheses published in 2004. None of these routes has replaced the cinchona tree: quinine is still extracted from cultivated bark, because the plant makes it more cheaply than any laboratory route.

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8. Artesunate Versus Quinine: SEAQUAMAT and AQUAMAT

For much of the twentieth century, intravenous quinine was the main treatment for severe falciparum malaria, the form that can cause coma, kidney failure and death. When artemisinin derivatives became available, two large randomised trials compared intravenous artesunate, a water-soluble artemisinin derivative, directly with quinine. The clinical picture of severe malaria is described on Severe and Cerebral Malaria.

SEAQUAMAT (2005)

The South East Asian Quinine Artesunate Malaria Trial enrolled 1,461 adults and children with severe malaria in Bangladesh, India, Indonesia and Myanmar. Arjen Dondorp and colleagues reported in The Lancet that mortality was 15 per cent (107 of 730 patients) in the artesunate group and 22 per cent (164 of 731) in the quinine group. Quinine treatment was also associated with hypoglycaemia (low blood sugar), with a relative risk of 3.2 compared with artesunate. Quinine stimulates insulin release, which is one known reason for this effect.

AQUAMAT (2010)

Most deaths from severe malaria occur in African children, so a second trial was run in that population. AQUAMAT enrolled 5,425 children at 11 centres in nine African countries. The investigators reported that 8.5 per cent of children treated with artesunate died, compared with 10.9 per cent of those treated with quinine (odds ratio 0.75, 95% confidence interval 0.63–0.90). Coma, convulsions and hypoglycaemia developing after admission were less frequent with artesunate. The authors concluded that parenteral artesunate was the better treatment and called for it to replace quinine for severe falciparum malaria.

Quinine’s remaining roles

Jane Achan and colleagues, reviewing quinine’s place in 2011, described it as still important “almost 400 years after its effectiveness was first documented”. They noted its limitations — poor tolerability, and treatment regimens that are long and complex — and its continuing roles: intravenous artesunate had become first-line treatment for severe malaria, with quinine as the alternative where artesunate is not available, and quinine remained important in the treatment of malaria in the first trimester of pregnancy. The review also noted quinine’s wide availability and low cost in many malaria-endemic countries.

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9. Quinine for Cramps, the FDA and Adverse Reactions

Muscle cramps

Outside malaria, quinine was used for decades for night-time leg cramps. The Cochrane review by Sherif El-Tawil and colleagues, updated in 2015, pooled 23 trials with 1,586 participants. Compared with placebo, quinine reduced the number of cramps by about 28 per cent, cramp intensity by about 10 per cent and the number of days with cramps by about 20 per cent; the reviewers rated the quality of this evidence as low to moderate. Minor adverse events were more common with quinine than with placebo. Serious adverse events were rare, but the reviewers noted that they can be fatal, and that for this reason prescription of quinine for cramps is restricted in some countries. Cramps as a symptom are described on Muscle Cramps.

The US FDA

The US Food and Drug Administration stopped the over-the-counter marketing of quinine for leg cramps in 1994. On 8 July 2010 it announced a risk-management programme and a warning against the off-label use of prescription quinine sulfate for night-time leg cramps. The agency’s review described 38 serious adverse events in the United States associated with that use, 24 of them haematologic — including severe drops in platelet count (thrombocytopenia) and haemolytic uraemic syndrome or thrombotic thrombocytopenic purpura — and two deaths. Quinine sulfate remains approved in the United States for the treatment of uncomplicated malaria.

Adverse reactions, including from drinks

Quinine’s familiar side effects are grouped under the name cinchonism: headache, nausea, ringing in the ears (tinnitus), hearing impairment, dizziness and blurred vision. Its effect on the ear has a long record. Maria Guilherme Semedo and colleagues, reviewing quinine in otology, date the first report of quinine ototoxicity to 1824, only four years after its isolation.

A rarer group of reactions is immune-mediated. Nathan Liles and colleagues, in a 2016 systematic review, gathered reports of 142 patients with such reactions. Seventy-two per cent were attributed to quinine tablets and 20 per cent to quinine-containing beverages such as tonic water. The reactions ranged from blood disorders to acute kidney injury; among patients with reactions other than skin reactions, 91 per cent were admitted to hospital, 30 needed renal replacement therapy (dialysis) and three died. The authors noted that severe reactions occurred “even with only minute exposure from common beverages”. Tonic water in the United States is limited to 83 milligrams of quinine per litre, and in the European Union to 100 milligrams per litre.

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10. Emetine, Strychnine and Colchicine Later On

Quinine was the pair’s most famous alkaloid, but not their only one with a long afterlife. The plant sources are described on Cinchona and the Plant Alkaloids; here the later history is summarised.

Emetine

Emetine, isolated from ipecacuanha root by Pelletier with Magendie in 1817, had to wait almost a century for its main medical use. In 1912 the British physician Leonard Rogers reported in the British Medical Journal the rapid cure of amoebic dysentery and amoebic liver infection by injections of soluble emetine salts. Emetine became the standard treatment for amoebiasis for decades, until less toxic drugs replaced it; its toxicity to heart muscle was a major limitation. The disease is described on Amoebic Dysentery and Colitis.

Strychnine

Strychnine, found by the pair in 1818, was used in nineteenth-century medicine in small amounts as a “tonic” and stimulant, a history surveyed by the medical historian John Haller in 1973. Its real importance came in neuroscience. In 1973 Anne Young and Solomon Snyder showed that radiolabelled strychnine binds selectively to synaptic membranes in the spinal cord and brainstem at the receptors for glycine, an inhibitory nerve transmitter, and that its binding pattern follows the distribution of glycine in the nervous system. By blocking glycine’s braking signal, strychnine lets motor nerves fire uncontrolled, which explains the convulsions the pair described in 1820. Strychnine became a standard tool for studying glycine receptors, and has no accepted medical use today. Glycine itself is described on Glycine.

Colchicine

Around 1819–1820 the pair isolated a substance from the roots of autumn crocus (Colchicum autumnale), which they took for veratrine. Marianna Karamanou and colleagues describe how the German pharmacist Philipp Lorenz Geiger analysed it further and named it colchicine in 1833, and how the French pharmacist Alfred Houdé obtained it in crystalline form in 1884. Colchicine is still in use. Karamanou and colleagues list familial Mediterranean fever, Behçet’s disease and pericarditis among its modern indications, alongside its old use in gout. See Familial Mediterranean Fever and Gout.

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Key Research Papers

  1. Fournier J. [Alcaloids discovery, markers for the history of organic chemistry]. Rev Hist Pharm (Paris). 2001;49(331):315-32. PubMed PMID: 11776272
  2. 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
  3. 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
  4. 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
  5. 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
  6. Gramiccia G. Ledger’s cinchona seeds: a composite of field experience, chance, and intuition. Parassitologia. 1987;29(2-3):207-20. PubMed PMID: 3334083
  7. 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
  8. Woodward RB, Doering WE. The total synthesis of quinine. J Am Chem Soc. 1944;66(5):849. DOI: 10.1021/ja01233a516
  9. Stork G, Niu D, Fujimoto RA, Koft ER, Balkovec JM, Tata JR, Dake GR. The first stereoselective total synthesis of quinine. J Am Chem Soc. 2001;123(14):3239-42. PubMed PMID: 11457058
  10. Seeman JI. The Woodward-Doering/Rabe-Kindler total synthesis of quinine: setting the record straight. Angew Chem Int Ed Engl. 2007;46(9):1378-413. PubMed PMID: 17294412
  11. Smith AC, Williams RM. Rabe rest in peace: confirmation of the rabe-kindler conversion of D-quinotoxine into quinine: experimental affirmation of the Woodward-Doering formal total synthesis of quinine. Angew Chem Int Ed Engl. 2008;47(9):1736-40. PubMed PMID: 18236503
  12. Dondorp A, Nosten F, Stepniewska K, Day N, White N; South East Asian Quinine Artesunate Malaria Trial (SEAQUAMAT) group. Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial. Lancet. 2005;366(9487):717-25. PubMed PMID: 16125588
  13. Dondorp AM, Fanello CI, Hendriksen IC, Gomes E, Seni A, Chhaganlal KD, Bojang K, Olaosebikan R, Anunobi N, Maitland K, et al.; AQUAMAT group. Artesunate versus quinine in the treatment of severe falciparum malaria in African children (AQUAMAT): an open-label, randomised trial. Lancet. 2010;376(9753):1647-57. PubMed PMID: 21062666
  14. 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
  15. El-Tawil S, Al Musa T, Valli H, Lunn MP, Brassington R, El-Tawil T, Weber M. Quinine for muscle cramps. Cochrane Database Syst Rev. 2015;2015(4):CD005044. PubMed PMID: 25842375
  16. 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
  17. 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
  18. 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
  19. 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
  20. 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
  21. 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

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