The Coca Leaf: From Andean Chewing to the Cocaine Molecule

When Carl Koller dropped a cocaine solution onto the eye of a frog in Vienna in 1884, the substance in his bottle was barely a quarter of a century old as a pure chemical. The plant it came from was another matter. People in the Andes of South America had been chewing the leaves of the coca shrub for thousands of years before any European saw them, and archaeologists have now traced that habit back at least eight millennia. Long before chemists had a name for cocaine, Andean chewers knew one of its effects at first hand: the leaf left the mouth and tongue numb.

This page follows the natural source of Koller’s discovery. It begins with the shrub itself and the archaeological record of coca in Peru and Chile, then turns to the first European descriptions, the isolation of cocaine in a German laboratory in 1860, and the chemistry that followed. It closes with what modern plant science has learned about how the leaf makes cocaine, what a nutritional analysis of the leaf found, and why nineteenth-century doctors treated the leaf and the pure alkaloid as two different things. It is history and science only; it contains no information on preparing or using coca or cocaine. Koller’s own experiments are told on a separate page.

Table of Contents

  1. Erythroxylum coca, a Shrub of the Andes
  2. Eight Thousand Years of Coca at Nanchoc
  3. Cocaine in Ancient Mummies
  4. Lime, Leaves and a Numb Mouth
  5. Coca in European Eyes: Vespucci to Mantegazza
  6. Niemann Isolates Cocaine, 1860
  7. Lossen and the Chemistry of Cocaine
  8. How the Coca Plant Makes Cocaine
  9. The Coca Leaf Analysed as Food
  10. Leaf Versus Alkaloid in Nineteenth-Century Medicine
  11. Key Research Papers
  12. Connections
  13. Featured Videos

1. Erythroxylum coca, a Shrub of the Andes

Coca is the leaf of Erythroxylum coca, a shrub of the family Erythroxylaceae that grows on the eastern slopes and valleys of the Andes. The plant is not related to the cacao tree that gives chocolate, despite the similar-sounding names, nor to the kola nut. Its small, oval, bright-green leaves are the part that people have harvested, dried and carried for millennia, and they are the part of the plant that holds the alkaloids. Nutrition researchers who analysed the leaf in 2009 described it simply as the leaves of Erythroxylum coca, the plant at the centre of a long Andean tradition of chewing.

Botanists place coca in a different family from the plants that are more famous in Europe for their alkaloids. The deadly nightshade (belladonna), henbane and the thorn apple belong to the Solanaceae, the potato and tomato family; their leaves and roots make atropine and scopolamine. Those compounds and cocaine share a common chemical skeleton, the tropane ring, which is why chemists group them together as tropane alkaloids. For a long time it seemed natural to assume that the two families had inherited one shared recipe for making them. As section 8 explains, laboratory work published in 2012 showed that this assumption was wrong.

Where the alkaloid sits

Cocaine is concentrated in the leaves rather than the stems or roots, and the laboratory studies of the plant’s chemistry found that the young, expanding leaves are where it is actively made. That detail matters for the history: what travelled across the Atlantic in the nineteenth century was dried leaf, and the amount of active alkaloid in a bale of leaves depended on how they had been grown, dried and stored. The variability of the leaf would become one of the reasons chemists were so keen to isolate the pure substance.

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2. Eight Thousand Years of Coca at Nanchoc

The oldest firm evidence of people using coca comes from the Nanchoc Valley, on the lower western slopes of the Andes in northern Peru. In 2010 the archaeologist Tom Dillehay and his colleagues reported on excavations of early village sites there. On the floors of small houses they found preserved coca leaves together with pieces of calcite — a form of calcium carbonate, the mineral that lime is made from. Chewers in the Andes have long added a pinch of lime or plant ash to the leaf, and the authors read the leaf-and-calcite pairing as the earliest physical trace of that practice.

Radiocarbon dating placed the finds at least 8,000 calibrated years before the present, in the early Holocene, the period after the last Ice Age. That makes coca chewing one of the oldest known uses of a plant stimulant anywhere in the world, thousands of years older than the first Andean cities. The team titled their paper “Early Holocene coca chewing in northern Peru.”

What the finds tell us

The Nanchoc evidence suggests that coca was not a casual wild snack. The leaves were brought into houses, stored, and processed with a mineral that had to be gathered or prepared on purpose. In other words, by the time the first farming villages were taking shape in the region, coca already had a settled place in daily life — and its users had already learned that lime changed the experience of chewing it.

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3. Cocaine in Ancient Mummies

Leaves and lime on a house floor show that coca was handled. The bodies of the dead can show that it was actually consumed, because cocaine and its breakdown products leave chemical traces in the body. The dry coastal deserts of northern Chile and southern Peru are among the best places on earth for natural mummification, and researchers have used those mummies to test for cocaine directly.

The Alto Ramírez mummies

In 2005 Mario Rivera, Arthur Aufderheide and colleagues reported tests on mummies of the Alto Ramírez culture of northern Chile, dated to about 3,000 years before the present. Cocaine was detected in two of the eleven bodies examined. The authors presented this as a 3,000-year archaeological record of coca-leaf chewing in the south-central Andes.

Clues in mummy hair

Hair is a useful record because substances in the blood are laid down in the growing hair shaft and stay there. An earlier study by Larry Cartmell and colleagues, published in 1991, looked at scalp hair from eight Chilean mummies spanning roughly 2000 BC to AD 1500. They tested for benzoylecgonine, the main compound the human body makes when it breaks cocaine down, and reported that this metabolite is stable in ancient hair — which is what makes such long-range detection possible. The same chemistry is used in modern forensic testing of hair; in the mummies it turned an ancient habit into a measurable trace.

Taken together, the Nanchoc house floors, the Alto Ramírez bodies and the mummy-hair tests describe a continuous Andean relationship with the leaf stretching from the early Holocene to the arrival of Europeans. A 1985 review of cocaine in eye medicine by Altman, Albert and Fournier opened its account with this ancient use before turning to Koller.

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4. Lime, Leaves and a Numb Mouth

Why would early chewers add a mineral to a leaf? The chemistry of alkaloids gives a likely answer. Alkaloids such as cocaine are bases: in the plant they are largely held as salts, bound up with plant acids. An alkaline substance such as lime or plant ash shifts that balance and frees the alkaloid in its uncombined form, which passes more easily through the lining of the mouth. The evidence from Nanchoc — leaves and calcite found side by side — is why archaeologists describe lime as the companion that released the leaf’s alkaloids for its users.

The first observation of local numbness

The other effect that chewers met at once was numbness. Cocaine blocks the signals of the nerves it touches, so a leaf held in the cheek leaves the lips, tongue and inner cheek feeling dulled. Historians of anaesthesia, such as Biscoping and Bachmann-Mennenga in their review of local anaesthetics from esters to modern isomers, note that this numbing of the mouth was believed to have been noticed by Andean chewers long before anyone in Europe described it. In a sense, the property that made Koller famous had been experienced in the Andes for thousands of years; what was missing was the pure substance and the idea of putting that numbness to work in surgery.

The gap between experience and application is a recurring theme in the history of plant medicines. Willow bark was used for pain before aspirin, and the opium poppy for pain and sleep before morphine. In each case, a chemist first had to pull a single active compound out of the plant before doctors could study it precisely — and in each case the pure compound turned out to be stronger and more dangerous than the plant it came from.

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5. Coca in European Eyes: Vespucci to Mantegazza

Europeans met coca within a few years of their first voyages to South America. The Polish ophthalmologist and historian Andrzej Grzybowski, in his 2007 history of cocaine in medicine, attributes the first European description of coca chewing to the Florentine navigator Amerigo Vespucci. Under Spanish rule coca became an object of trade and taxation in the Andes, and accounts of the leaf filtered back to Europe through travellers and chroniclers for the next three centuries.

Why the leaf stayed exotic

For most of that time coca remained a curiosity in Europe rather than a medicine. Dried leaves are generally said to have travelled poorly, losing much of their strength on the long sea voyage. The leaf was known mainly through travellers’ descriptions of Andean porters and labourers who chewed it to work and walk long distances with little food.

Mantegazza’s treatise of 1859

That began to change in the mid-nineteenth century. The Italian physician and anthropologist Paolo Mantegazza published a long treatise in 1859 praising coca and describing its effects in glowing terms. The historian of science Bettina Wahrig, who studied nineteenth-century writing about coca and cocaine, discusses Mantegazza’s treatise among the nineteenth-century drug narratives — her title borrows the phrase “fabulous things” — enthusiastic accounts that presented the leaf as a remarkable, many-purpose remedy. These narratives helped to build European interest at exactly the moment when chemists were able to investigate the leaf in the laboratory.

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6. Niemann Isolates Cocaine, 1860

By 1860 chemists had already pulled several famous alkaloids out of plants. Friedrich Sertürner had isolated morphine from opium early in the century, and Pierre-Joseph Pelletier and Joseph-Bienaimé Caventou had isolated quinine from cinchona bark in 1820. Coca was an obvious next target, but chemists who tried it were hampered by the poor quality of the leaves that reached Europe.

Leaves from an Austrian expedition

A good supply finally arrived through an Austrian scientific voyage. The frigate Novara sailed around the world between 1857 and 1859, and one of its members, Karl von Scherzer, brought a quantity of coca leaves back to Europe. (A 2001 history of local anaesthetics by Ruetsch, Böni and Borgeat gives the date as 1850; since the voyage itself took place in the late 1850s, that year appears to be a slip.) Part of the supply went to the University of Göttingen, to the laboratory of the chemist Friedrich Wöhler, already famous for making urea in the laboratory in 1828.

A new organic base

Wöhler passed the leaves to a young chemist in his laboratory, Albert Niemann. Niemann extracted the leaves and obtained a crystalline alkaloid, which he named cocaine. He published his results in 1860 in the Archiv der Pharmazie under the title “Ueber eine neue organische Base in den Cocablättern” — “On a new organic base in coca leaves” — a paper that ran across two issues of the journal. The site’s sources agree on Niemann, Wöhler’s laboratory, Göttingen and 1860 as the essentials of the discovery.

Niemann and Wöhler noticed the property that would matter so much later. As the Heritage Centre of the Association of Anaesthetists recounts, Wöhler recorded that the new compound tasted bitter and produced a peculiar effect on the nerves of the tongue, leaving it temporarily numb. The observation was made, written down, and then left aside: neither chemist was a surgeon, and the idea of a numbing drug for operations was not yet on anyone’s mind. Niemann himself died young, in 1861, and never saw what his alkaloid would become.

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7. Lossen and the Chemistry of Cocaine

Isolating a crystal is only the first step; chemists then need to know what it is made of. That work was taken up by the chemist Wilhelm Lossen, who published “Ueber das Cocaïn” (“On cocaine”) in the Annalen der Chemie in 1865. Lossen refined Niemann’s work and established the composition of the molecule, the formula still given for cocaine today (C17H21NO4).

An ester with three parts

The chemistry that emerged from this period showed that cocaine is an ester — a compound formed when an acid is joined to an alcohol. When cocaine is broken apart with water, it falls into three pieces: a tropane alkaloid core called ecgonine, benzoic acid, and methanol. The body performs a version of the same split, which is why benzoylecgonine (ecgonine still carrying its benzoic acid) turns up in hair and urine after cocaine use, and why it could be measured in the Chilean mummies.

The fact that cocaine is a benzoic-acid ester turned out to be important far beyond the laboratory. Biscoping and Bachmann-Mennenga, in their review of local anaesthetics, explain that recognising cocaine as an ester of benzoic acid guided chemists in the decades after Koller as they set out to make safer substitutes. Procaine, introduced in 1905, was built on the same ester plan, with a different acid — para-aminobenzoic acid. That story belongs to the page on local anaesthesia after Koller.

Twenty years of waiting

Between Lossen’s paper and Koller’s experiment lay nearly twenty years in which cocaine was available, described and even known to numb the tongue, but not used in surgery. Grzybowski’s history notes that several investigators remarked on the numbing effect in that interval — among them the Peruvian surgeon Moreno y Maíz, who experimented on animals, and Basil von Anrep, who in 1880 studied cocaine’s actions and suggested that it might be tried as a local anaesthetic. None of them took the step into the operating room. How Koller did is told on the page about the 1884 discovery.

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8. How the Coca Plant Makes Cocaine

For more than a century after Niemann, the question of how the coca shrub actually builds cocaine was only partly answered. The general outline was clear from studies of the nightshade family: tropane alkaloids begin with simple nitrogen-containing building blocks from the plant’s amino-acid metabolism, which are joined and folded into the two-ring tropane skeleton. But the enzymes in coca itself had not been identified.

The first step

A research group at the Max Planck Institute for Chemical Ecology in Jena took up the problem. In a 2012 paper in Plant Molecular Biology, Tiziana Docimo, John D’Auria and colleagues characterised the enzymes that carry out the first step of the pathway in Erythroxylum coca — arginine and ornithine decarboxylases, which turn amino acids into the small amines from which the tropane ring is eventually built.

A different enzyme for the same job

The more surprising finding came in a paper published the same year in the Proceedings of the National Academy of Sciences by Jan Jirschitzka, John D’Auria and colleagues. They identified the enzyme that carries out a key reduction step in the cocaine pathway, which they called methylecgonone reductase. It is most active in the young, expanding leaves of the coca plant, where cocaine is made.

In the nightshade family, the matching step on the way to atropine and scopolamine is carried out by an enzyme from a family known as short-chain dehydrogenases/reductases. The coca enzyme belongs to an entirely different family, the aldo-keto reductases. Two unrelated enzymes had been recruited to do the same chemical job. The authors concluded that tropane alkaloid production arose independently in the Erythroxylaceae and the Solanaceae: coca and belladonna arrived at related molecules by separate evolutionary routes, an example of what biologists call convergent evolution.

Why a plant makes cocaine

Plants make alkaloids for their own purposes, not for ours. Many tropane alkaloids act on the nervous systems of insects and grazing animals, and the concentration of cocaine in young leaves, the tissue most valuable to the plant and most attractive to leaf-eaters, fits the general idea that such compounds serve as chemical defences. The fact that evolution invented the tropane skeleton more than once suggests how useful it has been to plants in very different lineages.

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9. The Coca Leaf Analysed as Food

Because the leaf has been part of Andean life for so long, a recurring question in Peru and Bolivia has been whether coca leaves, for example ground into flour, could help improve nutrition. A team led by the nutrition researcher Mary Penny set out to measure what the leaf actually contains and published their findings in the Food and Nutrition Bulletin in 2009.

What the analysis found

The researchers analysed eight samples of coca leaves from Peru. Per 100 grams of dried leaf, they reported about:

On paper, those mineral figures look high. But the team also considered the amounts people would realistically eat. They calculated that two spoonfuls of coca-leaf flour would supply less than 10% of daily needs for the critical nutrients they examined; they also noted that the leaf carries cocaine and other alkaloids that the body can absorb.

The authors’ conclusion

Penny and colleagues concluded that coca leaves do not provide a nutritional benefit at the amounts usually consumed, and that the cocaine the body can absorb from the leaf may be harmful. Their study is a useful reminder that a plant’s nutrient table and its effect on the body are different questions: the leaf that ancient chewers valued, and that Koller’s cocaine came from, was prized for its alkaloid, not as a food.

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10. Leaf Versus Alkaloid in Nineteenth-Century Medicine

One might expect that once cocaine had been isolated, European medicine would simply have switched from the leaf to the pure compound. The historical record is messier. Wahrig’s study of nineteenth-century coca narratives shows that, for decades after Niemann and Lossen, writers continued to treat coca as an exotic, many-purpose drug whose powers were somehow greater than the sum of its chemistry. The leaf carried the romance of the Andes, of tireless porters and of Mantegazza’s enthusiastic prose; the white crystal was, at first, simply a laboratory product.

Two different things

Doctors of the period were in fact dealing with two different materials. A leaf delivered a small and variable amount of alkaloid, released slowly and mixed with many other plant substances. The pure alkaloid delivered a precise, concentrated dose of one compound. That precision was what made Koller’s experiment possible: a measured solution of a known substance could be dropped onto an eye, tested on animals, and its effect reproduced by others within weeks. It was also what made the drug far more dangerous than the leaf. The toxicity and addiction that followed the spread of pure cocaine in the late 1880s are described on the page about local anaesthesia after Koller.

From the Andes to Vienna

Wahrig traces how these narratives ran on into the 1880s, the decade in which Koller’s discovery brought the pure substance to the centre of European medicine. By then the line from the Andean shrub to the Viennese eye clinic was complete: an ancient habit noticed by Vespucci, praised by Mantegazza, chemically isolated by Niemann, analysed by Lossen, and finally applied as a local anaesthetic by Koller. Grzybowski’s 2007 history notes that the pure alkaloid’s anaesthetic uses were later strictly limited because of its harms and the risk of addiction. The coca leaf, meanwhile, remains what it was at Nanchoc eight thousand years ago — a plant whose chemistry humans discovered by experience long before they understood it.

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Key Research Papers

  1. 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
  2. Rivera MA, Aufderheide AC, Cartmell LW, Torres CM, Langsjoen O. Antiquity of coca-leaf chewing in the south central Andes: a 3,000 year archaeological record of coca-leaf chewing from northern Chile. J Psychoactive Drugs. 2005;37(4):455-8. PubMed PMID: 16480174
  3. Cartmell LW, Aufderhide A, Weems C. Cocaine metabolites in pre-Columbian mummy hair. J Okla State Med Assoc. 1991;84(1):11-2. PubMed PMID: 2002413
  4. Grzybowski A. [The history of cocaine in medicine and its importance to the discovery of the different forms of anaesthesia]. Klin Oczna. 2007;109(1-3):101-5. PubMed PMID: 17687926
  5. Wahrig B. ["Fabulous things". Drug narratives about coca and cocaine in the 19th century]. Ber Wiss. 2009;32(4):345-64. PubMed PMID: 20481059
  6. Niemann A. Ueber eine neue organische Base in den Cocablättern. Archiv der Pharmazie. 1860;153(2):129-155. DOI: 10.1002/ardp.18601530202
  7. Lossen W. Ueber das Cocaïn. Justus Liebigs Annalen der Chemie. 1865;133(3):351-371. DOI: 10.1002/jlac.18651330312
  8. Biscoping J, Bachmann-Mennenga MB. [Local anesthetics from ester to isomer]. Anasthesiol Intensivmed Notfallmed Schmerzther. 2000;35(5):285-92. PubMed PMID: 10858837
  9. Docimo T, Reichelt M, Schneider B, Kai M, Kunert G, Gershenzon J, D’Auria JC. The first step in the biosynthesis of cocaine in Erythroxylum coca: the characterization of arginine and ornithine decarboxylases. Plant Mol Biol. 2012;78(6):599-615. PubMed PMID: 22311164
  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. Penny ME, Zavaleta A, Lemay M, Liria MR, Huaylinas ML, Alminger M, McChesney J, Alcaraz F, Reddy MB. Can coca leaves contribute to improving the nutritional status of the Andean population? Food Nutr Bull. 2009;30(3):205-16. PubMed PMID: 19927600
  12. Altman AJ, Albert DM, Fournier GA. Cocaine’s use in ophthalmology: our 100-year heritage. Surv Ophthalmol. 1985;29(4):300-6. PubMed PMID: 3885453
  13. 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
  14. Grzybowski A. Cocaine and the eye: a historical overview. Ophthalmologica. 2008;222(5):296-301. PubMed PMID: 18566545

PubMed Topic Searches

  1. https://pubmed.ncbi.nlm.nih.gov/?term=Erythroxylum+coca
  2. https://pubmed.ncbi.nlm.nih.gov/?term=coca+leaf+chewing+archaeology
  3. https://pubmed.ncbi.nlm.nih.gov/?term=cocaine+biosynthesis+Erythroxylum
  4. https://pubmed.ncbi.nlm.nih.gov/?term=tropane+alkaloid+evolution
  5. https://pubmed.ncbi.nlm.nih.gov/?term=history+of+cocaine+medicine

Further Reading

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