Carl Koller — Cocaine, the Coca Leaf and the Birth of Local Anesthesia

In the late summer of 1884 a 26-year-old junior doctor at the Vienna eye clinic, Carl Koller (1857–1944), put a few drops of a cocaine solution into the eye of a frog and found that he could touch its cornea without the animal blinking. Within weeks he had shown the same thing in rabbits, dogs, his colleagues and himself, and on 15 September 1884 his short report was read to a meeting of eye surgeons in Heidelberg. Before then, an eye operation meant either general anesthesia, with its vomiting and restlessness, or no anesthesia at all. After it, the surface of the eye could be made numb while the patient stayed awake and still. Historians count it as the beginning of local anesthesia, the family of techniques now used every day in dentistry, eye surgery and the injection of nerves.

The drug itself came from a plant. Cocaine is the main alkaloid of the leaves of Erythroxylum coca, a shrub of the Andes whose leaves people in South America have chewed for thousands of years. This wing tells the story in four deep-dive articles: the man himself, the discovery of 1884, the coca leaf and the chemistry of cocaine, and the safer drugs that followed. The overview below gives the whole story on one page. It is history and pharmacology only; cocaine is a toxic and addictive substance, and nothing here describes its preparation or use.

Table of Contents

  1. Deep-Dive Articles
  2. 1. Who Carl Koller Was
  3. 2. The Discovery on One Page
  4. 3. The Natural Source: The Coca Leaf
  5. 4. From Cocaine to Safer Anesthetics
  6. 5. Timeline at a Glance
  7. 6. Later Significance
  8. Key Research Papers
  9. Connections
  10. Featured Videos

Deep-Dive Articles

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Carl Koller: Life and Career (1857–1944)

A Bohemian merchant’s son who left law for medicine, found fame at 26, lost his Vienna career after an insult and a duel, trained in Utrecht and spent half a century as an eye surgeon in New York.

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The 1884 Discovery: Cocaine and Painless Eye Surgery

Freud’s “Über Coca”, the Vienna self-experiments, the frog, the rabbit and the dog, the Heidelberg reading of 15 September 1884 and the priority question as historians tell it.

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The Coca Leaf: From Andean Chewing to the Cocaine Molecule

Eight thousand years of coca in the Andes, cocaine in ancient mummies, Niemann’s isolation of the alkaloid in 1860 and how the coca plant builds its tropane molecule.

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After Koller: From Cocaine to Procaine, Lidocaine and the Sodium Channel

The first nerve blocks, spinal anesthesia, the toxicity and addiction that drove the search for substitutes, procaine in 1905, lidocaine in the 1940s and how these drugs silence a nerve.

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1. Who Carl Koller Was

Koller was born on 3 December 1857 in Schüttenhofen in Bohemia (today Sušice in the Czech Republic), into a Jewish family; his father, Leopold Koller, was a merchant. The family moved to Vienna in 1862. He began by studying law in 1875–76, then changed to medicine at the University of Vienna, and as a student he did research in embryology in the institute of the experimental pathologist Salomon Stricker. He took his medical degree in 1882 and in 1883 joined the Second University Eye Clinic at the Vienna General Hospital as a junior doctor. The medical historian Howard Markel has described the problem he wanted to solve: eye operations such as cataract surgery under general anesthesia were made difficult by vomiting and movement, and a way to numb the eye alone was badly wanted.

Fame came quickly and so did trouble. In January 1885 a colleague at the hospital insulted him with an antisemitic slur; Koller struck him, and a sabre duel followed in which Koller was unhurt. Duelling was forbidden, and his hopes of an academic post in Vienna ended. Historians read this episode differently: Hruby argued in 1986 that antisemitism was not the principal reason Koller left Vienna, while Amm and Holubar, writing about Koller, Sigmund Lustgarten and Sigmund Freud as a “Vienna Jewish trio”, place it within the antisemitism all three met. From 1885 to 1887 Koller trained in Utrecht with the ophthalmologists Frans Cornelis Donders and Herman Snellen, and in May 1888 he emigrated to New York.

He practised ophthalmology in New York from 1888 until 1942, worked at Mount Sinai Hospital, published on the use of cocaine in eye operations in American journals, and became a United States citizen in 1902. He died in New York in March 1944. His daughter, Hortense Koller Becker, wrote a long memoir of her father and cocaine in 1963 and gave his papers, including his laboratory notes from 1884, to the Library of Congress. The full story is told in Carl Koller: Life and Career.

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2. The Discovery on One Page

The numbing effect of cocaine was not unknown in 1884. Albert Niemann, who isolated and named cocaine in Friedrich Wöhler’s laboratory at Göttingen in 1860, noted that it numbed the tongue; the Peruvian surgeon Moreno y Maíz experimented with it in animals; and in 1880 Basil von Anrep studied cocaine and suggested that it be tested as a local anesthetic. In 1884 Koller’s friend Sigmund Freud published his review “Über Coca”. Freud wrote mainly about cocaine’s general and psychological effects and mentioned its numbing property only in passing, without following it into surgery.

The Vienna group around Freud, Koller and Leopold Königstein tried cocaine on their own mouths and noticed the numbness it left. Koller saw what that could mean for the eye. Working with Joseph Gärtner, an assistant in Stricker’s institute, he dropped a cocaine solution into one eye of a frog: in Gärtner’s later recollection, the frog let its cornea be touched on the treated side while the other eye blinked normally. They repeated the test in rabbits and dogs and then in each other’s eyes and their own. Koller’s notes of these experiments survive in the Library of Congress and were first analysed by the anesthesia historian Goerig in 2015.

Koller could not afford the journey to the Ophthalmological Society’s meeting in Heidelberg, so on 15 September 1884 his preliminary communication was read there for him by the ophthalmologist Josef Brettauer, and a demonstration followed. Koller gave his full report to the Vienna Medical Society on 17 October 1884, and an English version appeared in The Lancet that December. Goerig and colleagues note that the news spread around the world in less than a month; reports from American eye surgeons were already appearing in November 1884.

Who deserves the credit has been argued ever since. Königstein had tested cocaine in eye disease at Freud’s suggestion, and later priority claims were raised for him and for Freud. Wyklicky wrote that Koller conceived the use of cocaine to anesthetise the eye for surgery independently, and dos Reis concluded in 2009 that Freud had no direct part in the discovery of local anesthesia. Markel reports that Freud inscribed an offprint to his friend as “Coca Koller”. The whole story is in The 1884 Discovery.

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3. The Natural Source: The Coca Leaf

Cocaine comes from the leaves of Erythroxylum coca, an Andean shrub of the family Erythroxylaceae. Its use is ancient. On house floors in the Nanchoc Valley of northern Peru, Dillehay and colleagues found coca leaves together with calcite — the lime that chewers add to release the alkaloids — dated to at least 8,000 years ago. Cocaine has been detected in two of eleven mummies of the Alto Ramírez culture of northern Chile, about 3,000 years old, and its breakdown product benzoylecgonine has been found in the hair of pre-Columbian Chilean mummies. Chewers are believed to have noticed long ago that the leaf numbed the mouth.

Grzybowski credits Amerigo Vespucci with the first European description of coca chewing. In 1859 the Italian physician Paolo Mantegazza published an enthusiastic treatise on the leaf, and in the late 1850s an Austrian expedition brought a supply of leaves back to Europe. From those leaves Niemann isolated cocaine in 1860, and Wilhelm Lossen worked out more of its chemistry in 1865. Wahrig has shown that nineteenth-century writers went on treating the leaf as an exotic, many-purpose drug long after the pure alkaloid was known.

Cocaine is a tropane alkaloid, a chemical relative of the atropine and scopolamine made by belladonna and other plants of the nightshade family. A 2012 study by Jirschitzka and colleagues found that the coca plant makes cocaine in its young, expanding leaves using a different family of enzyme from the one the nightshades use, so that plants evolved the ability to make tropane alkaloids more than once. When Penny and colleagues analysed Peruvian coca leaves as a possible food in 2009, they found protein, calcium and iron in the dried leaf but concluded that, at the amounts usually eaten, the leaves offered no real nutritional benefit and that the absorbable cocaine they carry may be harmful. More in The Coca Leaf.

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4. From Cocaine to Safer Anesthetics

Within months, surgeons were using cocaine far beyond the eye. In New York in late 1884 and 1885 William Halsted and Richard Hall injected it near nerves, including the inferior alveolar nerve of the jaw, producing the first nerve blocks and laying the foundation of dental anesthesia; both men became addicted through their self-experiments. Carl Ludwig Schleich introduced infiltration anesthesia with very dilute solutions in 1892, and in 1898 August Bier performed spinal anesthesia with cocaine, testing it on himself and his assistant.

The price soon became clear. Deaths among patients and addiction among doctors drove a search for substitutes. Chemists recognised cocaine as an ester of benzoic acid, and that clue guided the synthesis of new ester anesthetics. Alfred Einhorn’s procaine, an ester of para-aminobenzoic acid (PABA), was introduced in 1905; even so, a committee of the American Medical Association still reported in 1924 that large doses could kill. In Sweden, work that began with Hans von Euler’s study of a compound in barley led through Erdtman’s chemistry to Löfgren and Lundqvist, and Löfgren synthesised lidocaine, the first amide-type local anesthetic, in 1943. Torsten Gordh tested it clinically and reported it in 1949, and it became the standard local anesthetic. Bupivacaine (synthesised in 1957) and ropivacaine (introduced in 1996) followed.

All these drugs act in the same basic way: they block voltage-gated sodium channels in the membranes of nerve cells, so that a pain signal cannot travel along the nerve. Recent structural studies show the drug molecules reaching their binding site through side openings in the channel from the fatty membrane. The full story is in After Koller.

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5. Timeline at a Glance

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6. Later Significance

Koller’s idea outlived the drug that made it possible. Cocaine’s own place in medicine shrank as its toxicity and addictiveness became plain; Altman and colleagues traced its century of use in ophthalmology in 1985, and Grzybowski notes that its anesthetic uses today are strictly limited. What remained was the principle Koller demonstrated — that pain can be blocked at one place in the body while the patient stays awake — and the long line of synthetic drugs, from procaine to lidocaine and beyond, that chemists built by studying cocaine’s structure.

Recognition came late but did come. Hruby records that Koller was honoured by the Vienna Medical Society in 1930 and that he was proposed several times for the Nobel Prize, which was not awarded, by Hruby’s account because the discovery lay too far in the past under the prize’s rules. The European Society of Regional Anaesthesia keeps his name in its Carl Koller lecture and medal. The story also links a plant chewed in the Andes for eight millennia to the numbing injection in a modern dentist’s chair, by way of a frog’s eye in a Vienna laboratory.

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Key Research Papers

  1. Koller C. On the use of cocaine for producing anæsthesia on the eye. The Lancet. 1884;124(3197):990-992. DOI: 10.1016/s0140-6736(02)28859-5
  2. Goerig M, Bacon D, van Zundert A. Carl Koller, cocaine, and local anesthesia: some less known and forgotten facts. Reg Anesth Pain Med. 2012;37(3):318-24. PubMed PMID: 22531385
  3. Goerig M. [From the legacy of Carl Koller. Notations on his experiments with cocaine]. Anaesthesist. 2015;64(6):469-77. PubMed PMID: 26018815
  4. Markel H. Über coca: Sigmund Freud, Carl Koller, and cocaine. JAMA. 2011;305(13):1360-1. PubMed PMID: 21467292
  5. dos Reis A Jr. Sigmund Freud (1856-1939) and Karl Köller (1857-1944) and the discovery of local anesthesia. Rev Bras Anestesiol. 2009;59(2):244-57. PubMed PMID: 19488537
  6. Becker HK. Carl Koller and cocaine. Psychoanal Q. 1963;32:309-73. PubMed PMID: 13970115
  7. Hruby K. [Was Dr. Carl Koller driven from Vienna in 1885?]. Wien Klin Wochenschr. 1986;98(5):155-6. PubMed PMID: 3515769
  8. Wyklicky H. [100 years of local anesthesia]. Wien Klin Wochenschr. 1985;97(10):449-50. PubMed PMID: 3892931
  9. Dillehay TD, Rossen J, Ugent D, Karathanasis A, Vásquez V, Netherly PJ. Early Holocene coca chewing in northern Peru. Antiquity. 2010;84(326):939-953. DOI: 10.1017/s0003598x00067004
  10. Jirschitzka J, Schmidt GW, Reichelt M, Schneider B, Gershenzon J, D’Auria JC. Plant tropane alkaloid biosynthesis evolved independently in the Solanaceae and Erythroxylaceae. Proc Natl Acad Sci U S A. 2012;109(26):10304-9. PubMed PMID: 22665766
  11. Grzybowski A. Cocaine and the eye: a historical overview. Ophthalmologica. 2008;222(5):296-301. PubMed PMID: 18566545
  12. Ruetsch YA, Böni T, Borgeat A. From cocaine to ropivacaine: the history of local anesthetic drugs. Curr Top Med Chem. 2001;1(3):175-82. PubMed PMID: 11895133
  13. Holmdahl MH. Xylocain (lidocaine, lignocaine), its discovery and Gordh’s contribution to its clinical use. Acta Anaesthesiol Scand Suppl. 1998;113:8-12. PubMed PMID: 9932112
  14. Calatayud J, González A. History of the development and evolution of local anesthesia since the coca leaf. Anesthesiology. 2003;98(6):1503-8. PubMed PMID: 12766665

PubMed Topic Searches

  1. PubMed: Carl Koller cocaine
  2. PubMed: history of local anesthesia
  3. PubMed: Erythroxylum coca
  4. PubMed: local anesthetics sodium channel

Further Reading

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Connections

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