Muscarine, the Fly Agaric and the Plant Drugs of Buchheim and Schmiedeberg

The first experimental pharmacologists did not work with drugs invented in a laboratory. They worked with what the apothecary’s shelf already held: mushrooms, seeds, leaves, roots, fungi and oils, most of them taken from plants and used for centuries. Rudolf Buchheim (1820–1879) and his pupil Oswald Schmiedeberg (1838–1921) set out to find which substance inside each of these natural materials actually did the work, and what that substance did to a living body. Their most famous result came from the red-and-white fly agaric mushroom: in 1869 Schmiedeberg and his Dorpat colleague Koppe published a book on muscarine, the poison they drew from it, and showed that it slowed and stopped the frog heart in the same way as the vagus nerve, an effect that atropine reversed.

This page follows that natural thread. It tells the story of muscarine from the mushroom to the 1876 synthesis attempt, to Henry Dale and Otto Loewi’s discovery of acetylcholine and the “muscarinic” receptor that still carries the mushroom’s name, and to the 1950s work that finally settled muscarine’s chemical structure. It explains why later chemists found that the fly agaric’s own effects come mostly from two other compounds, while the mushrooms that carry large amounts of muscarine are quite different ones. It then turns to Schmiedeberg’s study of foxglove, Buchheim’s papers on ergot, pepper, croton oil, the atropine group, kousso and cod liver oil, and Schmiedeberg’s later paper on solanine in potatoes, ending with pilocarpine from the jaborandi plant. The men’s lives, the Dorpat laboratory and the Strasbourg school each have their own pages, linked under Connections.

Table of Contents

  1. The Fly Agaric
  2. Schmiedeberg and Koppe, 1869
  3. The Frog Heart, the Vagus Nerve and Atropine
  4. Making Muscarine in the Laboratory, 1876
  5. From Muscarine to Acetylcholine: Dale and Loewi
  6. Muscarinic Receptors and the 1957 Structure
  7. Ibotenic Acid, Muscimol and the Mushrooms That Carry Real Muscarine
  8. Foxglove: Schmiedeberg’s Digitoxin
  9. Ergot, Pepper, Croton Oil and Kousso
  10. Solanine in Potatoes and Pilocarpine from Jaborandi
  11. Key Research Papers
  12. Connections

1. The Fly Agaric

The fly agaric, Amanita muscaria, is the mushroom of fairy-tale pictures: a bright red cap scattered with white flecks, standing on a white stem in birch and pine woods across the northern hemisphere. Its scientific name and its common name in several European languages both point to flies. The Latin musca means fly, and in their 2018 history of the mushroom Lee, Dukan and Milne note that the name “fly agaric” suggests it was once used to kill flies.

The mushroom also had a much older reputation. Lee and colleagues describe its use by Siberian shamans as an inebriant, and the mushroom has drawn the attention of ethnographers and historians for that reason ever since European travellers first wrote about it. Michelot and Melendez-Howell’s 2003 review gathers its chemistry, biology, toxicology and ethnomycology (the study of how people have used fungi) in one place. This page treats that history only as history; nothing here is guidance on any use of any mushroom.

For nineteenth-century pharmacologists the fly agaric posed a clear question. It was well known to be poisonous, and its effects on people and animals had been described many times, but nobody knew which substance inside it caused them. Answering that kind of question, with chemistry to separate the substance and animal experiments to test it, was exactly the method that Buchheim had built at Dorpat (see the Dorpat page under Connections). The fly agaric became one of the first great tests of that method.

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2. Schmiedeberg and Koppe, 1869

In 1869 Oswald Schmiedeberg, then a young lecturer at the Dorpat pharmacological institute, published with his colleague Koppe a book titled Das Muscarin, das giftige Alkaloid des Fliegenpilzes — “Muscarine, the poisonous alkaloid of the fly agaric” (Leipzig, 1869). The title itself announced the result: a single active substance, muscarine (named after the mushroom’s Latin name), had been drawn out of the fly agaric and could be studied on its own.

Philippu and Seifert’s 2023 genealogy of the Tartu (Dorpat) department lists the muscarine findings of Schmiedeberg and Koppe among Schmiedeberg’s first experimental publications, alongside studies of the effects of drugs on the frog heart and of the nerve supply of the dog heart. Helmut Greim’s 2024 biography of Schmiedeberg counts the muscarine work as one of his major achievements. (Greim dates it 1871–1872; the book itself and the other sources give 1869, which this page follows.)

Calling muscarine an “alkaloid” reflected the chemistry of the day: alkaloids were the nitrogen-containing plant bases, such as morphine, quinine and atropine, that had been isolated one after another since the early 1800s. Muscarine later proved to be a quaternary ammonium compound rather than a classic alkaloid, but the 1869 title kept the older word. The book is not indexed in PubMed and has no DOI, so it is listed under Further Reading below.

The muscarine study came at an important moment in Schmiedeberg’s career. Buchheim had trained him, supervised his 1866 doctoral thesis and, after leaving for Giessen in 1867, left him in charge of the Dorpat institute. The muscarine book showed that the pupil could carry the teacher’s method from simple chemical questions into the study of how a poison acts on the nerves and the heart.

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3. The Frog Heart, the Vagus Nerve and Atropine

The experiment at the centre of the muscarine book used the frog heart, one of the classic preparations of nineteenth-century physiology. A frog’s heart keeps beating for a long time after it is exposed, so its rate and force can be watched directly and recorded. Schmiedeberg had learned such recording methods, including the kymograph (a rotating drum that traces movement onto paper) and the isolated frog heart, on a visit to Carl Ludwig’s physiological institute in Leipzig, as Greim describes.

When muscarine was applied, the frog heart slowed, and at higher concentrations it stopped beating altogether. This was strikingly like what happens when the vagus nerve, the long nerve that runs from the brain to the heart and gut, is stimulated electrically: the heart slows and can pause. Muscarine, in other words, seemed to imitate the vagus nerve.

Atropine as the antagonist

The second half of the finding was just as important. Atropine, the alkaloid of deadly nightshade (Atropa belladonna), was already known to block the vagus nerve’s slowing of the heart. Schmiedeberg and Koppe found that atropine also blocked the action of muscarine on the heart. Greim sums up the achievement as “the identification of muscarine as the stimulant of the nervus vagus and its antidote atropine.”

Here, decades before anyone knew how nerves pass their signals on, two plant and fungal substances had been shown to act in opposite directions on the same nerve-controlled process. One copied the vagus nerve; the other blocked both the nerve and the poison. That pairing, an agonist and its antagonist, became one of the basic ideas of pharmacology, and the muscarine–atropine pair remained a standard teaching example for generations. Schmiedeberg returned to the subject in a short 1881 paper of remarks on the action of muscarine.

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4. Making Muscarine in the Laboratory, 1876

Once a natural substance had been isolated and its action described, the next ambition of nineteenth-century chemistry was to make it from simpler starting materials. In 1876, now at Strasbourg, Schmiedeberg published with his pupil Erich Harnack a paper titled “Ueber die Synthese des Muscarins und über muscarinartig wirkende Ammoniumbasen” — “On the synthesis of muscarine and on ammonium bases that act like muscarine.” It appeared in the Archiv für experimentelle Pathologie und Pharmakologie, the journal Schmiedeberg had co-founded in 1873.

The title shows what the two men were after. They attempted to build muscarine in the laboratory, and they studied a family of related ammonium compounds whose actions resembled muscarine’s. This was an early example of a question that runs through all later drug chemistry: which part of a molecule produces its effect, and can other molecules that share that part do the same thing?

The text of the 1876 paper was not read for this page, so its detailed results are not given here. What is clear is that muscarine’s exact chemical structure was still unknown at the time, and it would remain unsettled for about eighty more years (see section 6). Harnack, who went on to his own chair of pharmacology, is better known today for early studies of apomorphine made in Dorpat, described by Taba, Lees and Stern as part of the “pharmacological dynasty” of Buchheim and Schmiedeberg (see the Strasbourg page).

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5. From Muscarine to Acetylcholine: Dale and Loewi

Muscarine’s greatest importance turned out to lie far beyond the mushroom. If a substance from a fungus could imitate the vagus nerve so exactly, perhaps the nerve itself worked by releasing a chemical. That idea took decades to prove, and muscarine was part of the path.

In 1914 the English physiologist Henry Dale published a long study titled “The action of certain esters and ethers of choline, and their relation to muscarine.” Choline esters are small molecules built on choline, acetylcholine among them, and the paper’s title shows that Dale was measuring their actions against those of muscarine. Lee and colleagues write that Dale suggested muscarine, or a related substance, might be the transmitter of the parasympathetic nerves, the branch of the nervous system to which the vagus belongs.

In 1921 the Austrian-German pharmacologist Otto Loewi, himself a scientific grandson of Schmiedeberg through his long years with Hans Horst Meyer, published his short paper on the humoral (chemical) transmission of the heart nerves’ action. Using frog hearts, the same preparation Schmiedeberg and Koppe had used half a century earlier, Loewi showed that the vagus nerve acts on the heart by releasing a chemical substance. That substance proved to be acetylcholine. Dale and Loewi shared the 1936 Nobel Prize in Physiology or Medicine for this work, which is told in full on the Loewi and Dale wing linked below. (Loewi’s own later account of how the experiment came to him in a dream is a famous story that rests on his recollection.)

So the chain runs from a forest mushroom, to Schmiedeberg’s frog heart in 1869, to Dale’s comparison of choline esters with muscarine, to Loewi’s proof of chemical transmission. Lee and colleagues trace exactly this route in the title of their review: from a shamanistic hallucinogen to the search for acetylcholine.

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6. Muscarinic Receptors and the 1957 Structure

Acetylcholine acts on two great families of receptors, the molecular “locks” on cells that its “key” fits. One family responds to nicotine, the alkaloid of the tobacco plant, and is called nicotinic. The other responds to muscarine and is called muscarinic, as Lee and colleagues note. The muscarinic receptors are the ones the vagus nerve uses to slow the heart, and the ones that control many glands and smooth muscles of the gut, bladder, airways and eye. Every time a pharmacology textbook speaks of a muscarinic receptor, it is quietly naming the fly agaric and the Dorpat experiments.

The International Union of Pharmacology (IUPHAR) published its formal classification of the muscarinic acetylcholine receptors in 1998, in a review by Caulfield and Birdsall in Pharmacological Reviews. Drugs that block these receptors are called antimuscarinics or anticholinergics; atropine, the very antagonist Schmiedeberg and Koppe used, is the classic example. Lee and colleagues name pilocarpine, which stimulates the receptors, and ipratropium, which blocks them, as later drugs that grew out of this knowledge, used in glaucoma and in lung disease respectively (see section 10).

The structure, at last

For all its fame, muscarine kept one secret for almost ninety years: its exact chemical structure. The work that settled it was done in the 1950s. In 1957 Fritz Kögl, H. C. Cox and C. A. Salemink published a short paper titled “Über Muscarin” (On muscarine) in Experientia, part of the work of that decade that established the molecule’s shape. Muscarine turned out to be a small ring-shaped molecule carrying a positively charged nitrogen, the kind of structure that also lets it fit the acetylcholine receptor.

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7. Ibotenic Acid, Muscimol and the Mushrooms That Carry Real Muscarine

One of the surprises of twentieth-century mushroom chemistry was that muscarine, although first found in the fly agaric, is not what gives the fly agaric most of its effects. Lee and colleagues list four compounds isolated from the mushroom: muscarine, muscimol, muscazone and ibotenic acid. The fly agaric contains only traces of muscarine. Michelot and Melendez-Howell describe ibotenic acid and muscimol as the active components behind the poisoning syndrome caused by the fly agaric and its relative the panther cap (Amanita pantherina), known in the medical literature as the “pantherina” syndrome. Those two compounds act mainly on the brain, on systems quite different from the muscarinic receptors.

Where muscarine is plentiful

Muscarine itself is found in much larger amounts in some small, dull-coloured mushrooms of quite different groups: the fibre-caps (Inocybe and the related genus Pseudosperma) and certain funnel-caps (Clitocybe). In a 2024 study, Dörner and colleagues describe muscarine-producing mushrooms such as Clitocybe rivulosa and Inocybe and Pseudosperma species as a severe threat, reporting that eating them can cause circulatory collapse or death.

The same study added a new piece of chemistry. Dörner and colleagues identified 4′-phosphomuscarine, a harmless phosphorylated precursor in these mushrooms that releases muscarine when the mushroom’s cells are injured, as their paper’s title states. They tested the compounds on the M3 subtype of the muscarinic receptor. Here, 155 years after Schmiedeberg’s book, the same receptor family named after the fly agaric was being used to measure the poison of entirely different mushrooms.

The effects of muscarine poisoning follow directly from the Dorpat experiments: muscarine over-stimulates the receptors the vagus and related nerves use, so the clinical picture described in the literature includes slowed heart rate, sweating, salivation and tears. Atropine, the antagonist Schmiedeberg and Koppe showed in 1869, is the classic antidote described for this type of poisoning. Mushroom identification and any question of eating wild mushrooms are outside the scope of this history page; poisonings are matters for poison centres and emergency medicine.

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8. Foxglove: Schmiedeberg’s Digitoxin

Foxglove (Digitalis purpurea) had entered medicine in 1785 through William Withering’s account of its use in dropsy, the swelling now understood mostly as a sign of heart failure (see the Withering wing). By the 1870s apothecaries sold several preparations called “digitalin”, but they differed from one maker and country to another, and no one knew exactly which substances in the leaf acted on the heart.

Schmiedeberg took up that question in a long paper, “Untersuchungen über die pharmakologisch wirksamen Bestandtheile der Digitalis purpurea L.” (Investigations on the pharmacologically active constituents of Digitalis purpurea), published in volume 3 of the Archiv in 1874–75. Directly before it in the same issue stood Buchheim’s paper on ergot, so teacher and pupil opened the volume side by side with two plant drugs.

The 1898 King’s American Dispensatory, a standard reference of the period, summed up the result: “To Schmiedeberg (1874) we are indebted for a critical study of the more important digitalins of commerce.” According to the Dispensatory, Schmiedeberg concluded that these preparations consisted mainly of four substances, which he named digitonin, digitoxin, digitalin and digitalein, and that digitonin was medicinally inert. Histories of medicine credit him with the isolation of digitoxin from foxglove in 1875. Digitoxin is one of the cardiac glycosides, the class to which the foxglove heart medicines belong; the related digoxin, from the woolly foxglove, came later.

Schmiedeberg kept returning to foxglove. He published further papers on the digitalin group in 1882 and, in 1910, on the testing of dried digitalis leaves, and Greim lists the effects of digitalis on heart muscle among his main research areas. The story of digitalis in heart-failure medicine is told on the site’s Heart Failure History page. Cardiac glycosides have a narrow margin between effective and toxic doses, a hazard recorded throughout the foxglove literature from Withering onward.

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9. Ergot, Pepper, Croton Oil and Kousso

Buchheim’s own research ranged across the plant and animal remedies of the materia medica. He grouped drugs with many common features into “pharmacological groups”, each named after its best-known member, as Reznikov describes, and his paper titles show that system at work. The texts of these papers were not read for this page, so what follows names what he studied, not what he concluded.

Taken together, the list reads like a tour of the remedies a nineteenth-century doctor actually prescribed: a purgative seed oil, a fish-liver oil, a cereal fungus, a kitchen spice, a nightshade alkaloid and a worm-flower from Ethiopia. Buchheim’s aim, as historians of his work describe it, was to replace traditional claims about such remedies with knowledge gained from chemistry and animal experiment. Buchheim’s method and his groups are covered in more detail on the Dorpat page.

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10. Solanine in Potatoes and Pilocarpine from Jaborandi

Solanine in potatoes, 1895

Schmiedeberg’s interest in natural poisons reached the dinner table. In 1895 he published “Ueber die toxikologische Bedeutung des Solaningehaltes der Kartoffeln” (On the toxicological significance of the solanine content of potatoes). Solanine is a glycoalkaloid made by the potato plant and other members of the nightshade family; it is concentrated in green and sprouting parts of the tuber. The paper’s text was not read for this page, so its conclusions are not reported here; the title shows that the question of how much solanine potatoes contain, and what that means for people who eat them, was already a pharmacologist’s question in the 1890s. The site’s Nightshades page describes the glycoalkaloids of the nightshade family.

Pilocarpine from jaborandi

The muscarine story has a botanical partner. Jaborandi is the name for the leaves of Pilocarpus shrubs from Brazil, used in South American folk medicine to bring on sweating and salivation. Holmstedt, Wassén and Schultes, in their 1979 interdisciplinary appraisal of jaborandi, trace how the plant reached European medicine in the 1870s and how its alkaloid, pilocarpine, was isolated in 1875 — just six years after the muscarine book.

Pilocarpine turned out to act on the same receptors as muscarine: it stimulates the muscarinic receptors and produces the sweating, salivation and slowed heart that the Dorpat experiments had described, effects that atropine again blocks. Lee and colleagues name pilocarpine as one of the drugs that grew out of this line of knowledge, and it entered eye medicine for glaucoma. A plant from the Brazilian forest and a mushroom from the northern woods thus came to illustrate the same receptor, discovered through the experimental method that Buchheim founded and Schmiedeberg carried to Strasbourg.

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Key Research Papers

  1. Lee MR, Dukan E, Milne I. Amanita muscaria (fly agaric): from a shamanistic hallucinogen to the search for acetylcholine. J R Coll Physicians Edinb. 2018;48(1):85-91. PubMed PMID: 29741535
  2. Michelot D, Melendez-Howell LM. Amanita muscaria: chemistry, biology, toxicology, and ethnomycology. Mycol Res. 2003;107(Pt 2):131-46. PubMed PMID: 12747324
  3. Dörner S, Trottmann F, Jordan PM, Rogge K, Bartels B, Werz O, Hertweck C, Hoffmeister D. The Fatal Mushroom Neurotoxin Muscarine is Released from a Harmless Phosphorylated Precursor upon Cellular Injury. Angew Chem Int Ed Engl. 2024;63(52):e202417220. PubMed PMID: 39432715
  4. Greim H. Oswald Schmiedeberg (1838-1921) : Ninth Pharmacologic‑Historical Forum, 2024, Munich, Germany. Naunyn Schmiedebergs Arch Pharmacol. 2024;397(12):9591-9596. PubMed PMID: 39042158
  5. Philippu A, Seifert R. History of pharmacology: 1-the Department of Pharmacology of the University of Tartu (Dorpat): genealogy and biographies. Naunyn Schmiedebergs Arch Pharmacol. 2023;396(1):5-17. PubMed PMID: 36413339
  6. Caulfield MP, Birdsall NJ. International Union of Pharmacology. XVII. Classification of muscarinic acetylcholine receptors. Pharmacol Rev. 1998;50(2):279-90. PubMed PMID: 9647869
  7. Holmstedt B, Wassén SH, Schultes RE. Jaborandi: an interdisciplinary appraisal. J Ethnopharmacol. 1979;1(1):3-21. PubMed PMID: 397371
  8. Taba P, Lees A, Stern G. Erich Harnack (1852-1915) and a short history of apomorphine. Eur Neurol. 2013;69(6):321-4. PubMed PMID: 23549143
  9. Schmiedeberg O, Harnack E. Ueber die Synthese des Muscarins und über muscarinartig wirkende Ammoniumbasen. Archiv für Experimentelle Pathologie und Pharmakologie. 1876;6(1-2):101-112. DOI: 10.1007/bf01830800
  10. Schmiedeberg O. Bemerkungen über die Muscarinwirkung. Archiv für Experimentelle Pathologie und Pharmakologie. 1881;14(4-5):376-378. DOI: 10.1007/bf01831055
  11. Dale HH. The action of certain esters and ethers of choline, and their relation to muscarine. The Journal of Pharmacology and Experimental Therapeutics. 1914;6(2):147-190. DOI: 10.1016/s0022-3565(25)08268-0
  12. Loewi O. Über humorale Übertragbarkeit der Herznervenwirkung. Pflügers Archiv für die Gesamte Physiologie des Menschen und der Tiere. 1921;189:239-242. DOI: 10.1007/bf01738910
  13. Kögl F, Cox HC, Salemink CA. Über Muscarin. Experientia. 1957;13(4):137-138. DOI: 10.1007/bf02158130
  14. Schmiedeberg O. Untersuchungen über die pharmakologisch wirksamen Bestandtheile der Digitalis purpurea L. Archiv für Experimentelle Pathologie und Pharmakologie. 1874;3(1):16-43. DOI: 10.1007/bf01958772
  15. Buchheim R. Ueber den wirksamen Bestandtheil des Mutterkorns. Archiv für Experimentelle Pathologie und Pharmakologie. 1874;3(1):1-15. DOI: 10.1007/bf01958771
  16. Buchheim R. Ueber die pharmakologische Gruppe des Crotonöls. Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin. 1857;12(1):1-26. DOI: 10.1007/bf01938745
  17. Buchheim R. Ueber die pharmakologische Gruppe des Piperins. Archiv für Experimentelle Pathologie und Pharmakologie. 1876;5(6):455-462. DOI: 10.1007/bf01976906
  18. Buchheim R. Ueber die pharmakologische Gruppe des Atropins. Archiv für Experimentelle Pathologie und Pharmakologie. 1876;5(6):463-472. DOI: 10.1007/bf01976907
  19. Buchheim R. Ueber die Wirkung des Leberthrans. Archiv für Experimentelle Pathologie und Pharmakologie. 1874;3(2):118-124. DOI: 10.1007/bf01915981
  20. Buchheim. Ueber das Kosin. Archiv der Pharmazie. 1876;208(5):414-417. DOI: 10.1002/ardp.18762080504
  21. Schmiedeberg O. Ueber die toxikologische Bedeutung des Solaningehaltes der Kartoffeln. Archiv für Experimentelle Pathologie und Pharmakologie. 1895;36(5-6):373-384. DOI: 10.1007/bf01824321

PubMed Topic Searches

  1. PubMed: Amanita muscaria muscarine
  2. PubMed: muscarinic acetylcholine receptor history
  3. PubMed: Inocybe muscarine poisoning
  4. PubMed: Oswald Schmiedeberg
  5. PubMed: jaborandi pilocarpine history

Further Reading

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Connections