Albert Hofmann: Ergot Medicines and the Discovery of LSD

Table of Contents

1. Ergot: A Fungus on Rye
2. St Anthony’s Fire and the Midwives’ Remedy
3. Untangling Ergot’s Chemistry, 1906–1935
4. Rebuilding Ergometrine from Lysergic Acid
5. Methylergometrine and Bleeding After Childbirth
6. The Hydrogenated Ergot Alkaloids
7. The Twenty-Fifth Lysergic Acid Amide (1938)
8. 16 April 1943: An Accidental Exposure
9. 19 April 1943 in Hofmann’s Own Account
10. How LSD Acts on the Brain
11. Key Research Papers
12. Connections

1. Ergot: A Fungus on Rye

Ergot is not a plant of its own. It is the winter form of a fungus, Claviceps purpurea, that lives as a parasite on rye and, less often, on other cereals and wild grasses. When a rye flower is infected, the fungus takes over the developing kernel. Instead of a grain, a hard, curved peg pushes out of the husk — light brown to violet-black, often longer than the grains around it. Botanists call this resting body a sclerotium. Ergot of rye, known in old pharmacy as Secale cornutum (“horned rye”), is the variety that was used in medicine.

Hofmann described the sclerotium in his memoir LSD: My Problem Child exactly this way, and he stressed the paradox that drew him to it. Ergot is a natural chemical factory: the fungus makes a whole family of ergot alkaloids, nitrogen-containing compounds of great potency that act on blood vessels, the womb and the nervous system. Those same compounds made ergot one of the most feared poisons of the Middle Ages and, at the same time, a medicine for childbirth. In the memoir he wrote that over the centuries ergot’s role and meaning “have been reversed”; in his 1978 survey of the subject he put it this way: “Once a dreaded poison, ergot has changed its role over the centuries to become a rich treasure house of valuable pharmaceuticals.”

The difficulty for medicine was the same as with many plant drugs. The amount of active substance in ergot varies with the strain of fungus, the host grass, the weather, the harvest and the age of the stored material, and the alkaloids themselves are unstable. A dose of powdered ergot could be far too weak or dangerously strong. Arthur Stoll’s research programme at Sandoz, which Hofmann joined in 1929, was built around exactly this problem: isolate the pure active principles of known medicinal plants — foxglove, Mediterranean squill and ergot were his chosen examples — so that a medicine could be measured by weight rather than by guesswork.

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2. St Anthony’s Fire and the Midwives’ Remedy

Ergotism

Ergot first appears in history not as a medicine but as the cause of mass poisonings. When wet seasons favoured the fungus and ergot-laden rye was milled into bread, whole districts fell ill. The disease, ergotism, took two forms. In the gangrenous form the alkaloids clamped down the blood vessels of the limbs; sufferers described burning pain, and fingers, toes, hands and feet could blacken and fall away. In the convulsive form people had fits, spasms and hallucinations. Death was common in both. The medieval names — ignis sacer (“holy fire”), mal des ardents and “St Anthony’s fire” — refer to the burning gangrenous form; the Order of St Anthony ran hospitals that cared for its victims. Van Dongen and de Groot’s 1995 history of the ergot alkaloids describes these epidemics, and the link between spoiled rye and the disease was recognised only in the seventeenth century.

Hofmann recorded in his memoir that the last great epidemic occurred in parts of southern Russia in 1926–27.

From quickening childbirth to stopping bleeding

Alongside the poison ran a folk use. The first written medical mention, which Hofmann cited in both his memoir and his 1978 historical review, is in the herbal of the Frankfurt city physician Adam Lonitzer (Lonicerus) in 1582, who noted that midwives used ergot to hasten labour — the strong contractions it provokes in the womb were the point. Ergot entered university medicine much later, in 1808, through a short report by the American physician John Stearns on what he called a powder for quickening childbirth.

The enthusiasm did not last. Doses were impossible to control, and contractions that were too strong could kill the baby or tear the womb. Van Dongen and de Groot report that the ergot powder sold as pulvis ad partum (“powder for childbirth”) earned the grim nickname pulvis ad mortem (“powder for death”), and that from about 1828 ergot was used mainly to stop bleeding after delivery rather than to speed delivery itself. That shift set the target for the twentieth-century chemists: find the substance in ergot that firmly contracts the womb after birth and squeezes shut its bleeding vessels, and separate it from the substances that cause gangrene. De Costa’s 2002 Lancet history of ergometrine, titled “St Anthony’s fire and living ligatures”, traces this path from St Anthony’s fire to ergometrine.

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3. Untangling Ergot’s Chemistry, 1906–1935

For nearly a century after ergot entered the pharmacopoeias, chemists extracted it without being able to name the substances responsible for its effects. The breakthroughs came in three steps, which Hofmann summarised in his 1978 review and which the physician-historian Michael Lee retells in his three-part history of ergot.

Ergotoxine and Henry Dale (1906)

At the Wellcome laboratories in London, the chemists G. Barger and F. H. Carr obtained an active alkaloid preparation they called ergotoxine — named because it reproduced more of ergot’s toxic effects than its useful ones. (Hofmann’s memoir dates the isolation to 1907; his 1978 review and Lee give 1906.) The young pharmacologist Henry Dale tested it and found something unexpected: besides contracting the womb, ergotoxine blocked some actions of adrenaline on the autonomic nervous system. Dale’s wider work is told on the site’s Otto Loewi and Henry Dale page. Ergotoxine, it later turned out, was not one substance at all.

Ergotamine and Arthur Stoll (1918)

In 1917 Arthur Stoll, newly arrived at Sandoz in Basel, began working on ergot, and in 1918 he isolated ergotamine — the first ergot alkaloid obtained in chemically pure form. It quickly found medical uses, as a remedy against bleeding in obstetrics and, from 1925, in the treatment of migraine attacks, as Tfelt-Hansen and Koehler record in their history of ergotamine in migraine. After that success, Hofmann wrote, chemical research on ergot at Sandoz largely stopped.

Lysergic acid and ergometrine (early 1930s to 1935)

In the early 1930s laboratories in Britain and the United States took up the structure of the ergot alkaloids. At the Rockefeller Institute in New York, W. A. Jacobs and L. C. Craig broke the molecules apart and isolated the core shared by all of them, which they named lysergic acid. Then came the discovery obstetricians had been waiting for: a new, water-soluble alkaloid that was the specific womb-contracting, bleeding-stopping principle of ergot. In Hofmann’s words it was found “simultaneously in four separate laboratories” around 1935, among them H. W. Dudley and J. C. Moir in London, whose note on “the new active principle of ergot” appeared in Science in 1935, and the Sandoz laboratory itself. (Van Dongen and de Groot date Dudley and Moir’s first isolation to 1932.) It received several names — ergometrine in Britain, ergonovine in the United States, ergobasine at Sandoz — for one and the same molecule. Lee describes ergometrine as a life-saving drug in postpartum haemorrhage.

Jacobs and Craig then split ergometrine itself and found that it consisted of just two pieces: lysergic acid joined to a small amino alcohol, propanolamine (2-aminopropanol). That simple structure is what Hofmann seized on.

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4. Rebuilding Ergometrine from Lysergic Acid

Hofmann finished his studies of the cardiac glycosides of Mediterranean squill in 1935 and asked Stoll to let him reopen the ergot work. He argued, by his own account, that Sandoz risked losing its lead in a field the British and American laboratories were now moving fast in. Stoll agreed with a warning, which Hofmann quoted in his memoir: ergot alkaloids were “exceedingly sensitive, easily decomposed substances”, less stable than anything Hofmann had handled so far.

The goal: make a natural alkaloid in the flask

If ergometrine was simply lysergic acid plus propanolamine, then joining those two pieces would rebuild it. Lysergic acid could only be had by breaking down another ergot alkaloid. Hofmann recalled that when he requisitioned half a gram of costly ergotamine for the purpose, Stoll objected to the amount, so he used the cheaper, impure ergotoxine from Portuguese ergot. Lysergic acid proved unstable and hard to couple to other molecules; the method that finally worked was an old route of organic chemistry known as the Curtius synthesis.

Joining lysergic acid to propanolamine gave a compound identical to natural ergobasine — the first artificial production of an ergot alkaloid. Stoll and Hofmann published the result in 1938 in the Zeitschrift für physiologische Chemie, under a title that translates as “Partial synthesis of ergobasine, a natural ergot alkaloid, and of its optical antipode” — the mirror-image form of the molecule, made at the same time.

Why a partial synthesis mattered

Hofmann gave two reasons in his memoir. Scientifically, rebuilding the molecule confirmed its structure, in an era before spectroscopy. Practically, ergometrine — the alkaloid obstetrics most wanted — is present in ergot only in tiny amounts, while other alkaloids are plentiful. With the new method the abundant alkaloids could be split to lysergic acid and turned into ergometrine.

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5. Methylergometrine and Bleeding After Childbirth

Once he could attach lysergic acid to any amino alcohol he liked, Hofmann began changing the small side piece to see whether the drug could be improved. With his colleague J. Peyer he worked out an economical way of making propanolamine and its relatives. Replacing propanolamine with the next amino alcohol in the series, butanolamine (2-aminobutanol), gave a new molecule one carbon atom larger than ergometrine: methylergometrine, known in the United States as methylergonovine.

Hofmann wrote that this “improved ergobasine” surpassed the natural alkaloid in its therapeutic properties, and that it had found worldwide use as a dependable uterotonic and haemostatic remedy — a drug that contracts the womb and stops bleeding — describing it in 1979 as the leading medicine for that purpose in obstetrics.

The medical problem behind the drug is postpartum haemorrhage — heavy bleeding after delivery, usually because the emptied womb fails to contract firmly. Ergometrine and methylergometrine work by making the muscle of the womb contract strongly and steadily, which squeezes the blood vessels at the placental site closed. Later obstetric research reached more mixed conclusions: van Dongen and de Groot reported in 1995 that, because of severe and unpredictable side effects and the drug’s instability, ergometrine was no longer the drug of choice for preventing or treating postpartum haemorrhage. How the ergot medicines fared in later obstetrics is followed on the Legacy and Later Research page.

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6. The Hydrogenated Ergot Alkaloids

Ergotoxine falls apart into three

While purifying ergotoxine as raw material for lysergic acid, Hofmann noticed that it behaved like a mixture rather than a single compound. The decisive clue came from hydrogenation — adding hydrogen atoms across a double bond in the molecule. Pure ergotamine gave one hydrogenated product; ergotoxine gave two distinctly different ones. Patient analysis eventually separated ergotoxine into three alkaloids: ergocristine (which Stoll and E. Burckhardt had just isolated in the production department), and two new ones Hofmann named ergocornine and ergocryptine — from the Greek kryptos, “hidden”, because it had stayed concealed in the mother liquor longest. Ergocryptine was later found in two forms, alpha and beta. By his own reckoning Hofmann proved ergotoxine to be a mixture about thirty-five years after Barger and Carr first described it.

Dihydroergotoxine

Hydrogenating the three alkaloids gave dihydroergocristine, dihydroergocornine and dihydroergocryptine. Ernst Rothlin, head of the Sandoz pharmacology department, tested all three and found medically useful properties. A mixture of the three became dihydroergotoxine, also called co-dergocrine or ergoloid mesylates, which was marketed for circulatory and age-related cerebral complaints. Hofmann wrote in 1979 that it had become the company’s most important pharmaceutical product.

Dihydroergotamine

Hofmann made dihydroergotamine in the same series of experiments. It was introduced in 1943, Tfelt-Hansen and Koehler record, originally as an adrenaline-blocking agent for the circulation and blood pressure; it later became a treatment for migraine attacks, given by injection and later as a nasal spray. Their review also lists the adverse effects documented for the ergot migraine drugs, including medication-overuse headache and ergotism itself — the old disease of the fungus reappearing as a side effect of its medicines. The migraine story continues on the Migraine: History and Discovery page.

Lee’s 2010 history of ergot from 1940 to 1980 opens with the judgement that the period “was dominated by two investigators, Arthur Stoll and Albert Hofmann”.

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7. The Twenty-Fifth Lysergic Acid Amide (1938)

Alongside the work on ergometrine-like drugs, Hofmann used his coupling method to make lysergic acid compounds that were not expected to act on the womb but might, from their structure, show other useful effects. He numbered them in sequence. In 1938 he made the twenty-fifth: lysergic acid diethylamide, abbreviated in the laboratory as LSD-25 from the German Lysergsäure-diäthylamid.

Designed as a breathing and circulation stimulant

The idea, he explained in his memoir, came from a drug already in use: nikethamide (nicotinic acid diethylamide), an analeptic — a stimulant of breathing and circulation. Nikethamide is built from nicotinic acid (the B vitamin niacin) with a diethylamide group attached. Hofmann reasoned that attaching the same diethylamide group to lysergic acid might give a similar stimulant.

Tested and shelved

The Sandoz pharmacology department under Ernst Rothlin tested the new compound in animals. It had a strong effect on the womb — about 70 percent of the activity of ergobasine, by Hofmann’s account — and the report noted in passing that the animals became restless while under anaesthesia. Nothing else stood out. In Hofmann’s words the substance “aroused no special interest” among the company’s pharmacologists and physicians, and testing was stopped. For five years nothing more was heard of LSD-25.

The series of ergobasine-type lysergic acid amides that Hofmann had been building was described by Stoll and Hofmann in a long 1943 paper in Helvetica Chimica Acta, “Partial synthesis of alkaloids of the ergobasine type”, the sixth in their series of communications on ergot alkaloids.

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8. 16 April 1943: An Accidental Exposure

Hofmann insisted in later life that LSD was “discovered by accident” only in part. The compound came out of a planned research programme; the accident was the discovery of its effects, five years later. What brought him back to it was, in his own phrase, “a peculiar presentiment” — a feeling that the shelved substance had properties the first tests had missed. Re-making a compound already dropped from the programme was, he noted, quite unusual. In the spring of 1943 he repeated the synthesis, producing only a few hundredths of a gram, so that the pharmacologists could test it again.

Friday afternoon in the laboratory

On Friday 16 April 1943, during the final step — purifying and crystallising LSD as its tartrate salt — he was overcome by unusual sensations. His memoir reprints the report he wrote to Stoll at the time. He had been forced to stop work in the middle of the afternoon and go home, “being affected by a remarkable restlessness, combined with a slight dizziness”. Lying down at home with his eyes closed (daylight felt unpleasantly glaring), he experienced what he called “an uninterrupted stream of fantastic pictures, extraordinary shapes with intense, kaleidoscopic play of colors”. After about two hours the state faded.

A chemist’s inference

Hofmann suspected the compound he had been handling. Because ergot substances were known to be toxic, he wrote, he kept meticulously clean working habits; his best guess was that a trace of the solution had touched his fingertips during crystallisation and been absorbed through the skin. If so, the substance would have to be extraordinarily potent, since the amount involved could only have been minute. He concluded that the only way to settle the question was a deliberate self-experiment. As he later found with the Mexican mushrooms, self-assay was sometimes the only test available for effects on the mind that animals cannot report.

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9. 19 April 1943 in Hofmann’s Own Account

Everything in this section comes from Hofmann’s own written account — his laboratory journal and report of the time, reprinted in LSD: My Problem Child and in his 1979 article “How LSD originated” — and is told as he told it.

The self-experiment

On Monday 19 April 1943, a little after four in the afternoon, Hofmann took what he believed was the smallest amount likely to produce any effect, judged by the potency of the ergot alkaloids then known: a quarter of a milligram of LSD tartrate, a quarter of one thousandth of a gram. Within about forty minutes his journal records dizziness, anxiety, visual distortions and an urge to laugh. Then the entries break off; he wrote later that he could set down the last words only with great effort. The amount he had judged to be a cautious threshold had proved to be a strong dose.

The bicycle ride

He asked his laboratory assistant to take him home. Cars were restricted in wartime Switzerland, so they went by bicycle. On the way, he wrote, everything in his field of vision wavered and was distorted as if seen in a curved mirror, and he felt he was not moving at all, although his assistant told him afterwards that they had travelled quickly. The ride later gave 19 April its popular name, “Bicycle Day”.

Fear, then recovery

At home the experience turned frightening. Hofmann described furniture taking on grotesque, threatening forms, a neighbour who brought him milk — which he drank as a general antidote to poisoning — appearing to him as a masked witch, and above all a terror of having lost his mind or of dying, leaving his family and his unfinished research behind. When the family doctor arrived, the worst had passed; the doctor found no abnormal signs other than very dilated pupils, with normal pulse, blood pressure and breathing, and prescribed nothing. As the fear ebbed, Hofmann recorded colours and shapes behind his closed eyes, and sounds — a door handle, a passing car — turning into images. He slept, and by his account woke the next morning refreshed, with a clear head, though physically tired.

What he concluded, and Rothlin’s confirmation

Hofmann drew three scientific conclusions in the memoir: no known substance had produced such profound mental effects at such a tiny dose; he remembered the whole experience in detail, so the mind’s recording function had kept working throughout; and he had known all along that he was in an experiment yet could not will the effects away. He reported the experiment to Stoll and to Rothlin. Both, he wrote, telephoned at once to ask whether he had weighed the dose correctly, since nothing until then had shown any mental effect at a fraction of a milligram. Rothlin and two colleagues then repeated the test with one-third of the amount, and found the effects, in Hofmann’s words, “still extremely impressive”. The 1993 Pharmacy in History article “LSD at 50” marked the half-century of this discovery.

Hofmann also wrote that, because his own first experience had shown LSD in its “terrifying, demonic aspect”, he never expected it to become a recreational drug. What happened to LSD in psychiatry and outside it from the 1950s onward, and how Hofmann himself viewed that history, is told on the Legacy and Later Research page.

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10. How LSD Acts on the Brain

A molecule built on the ergot skeleton

LSD is a close chemical relative of the medicines described above. All of them are built on the four-ring ergoline skeleton of lysergic acid, the core the ergot fungus makes. Part of that skeleton is an indole ring — the same ring found in the amino acid tryptophan and in the brain messenger serotonin, which the body makes from tryptophan. This family resemblance is why the ergot alkaloids, the hydrogenated ergot drugs, LSD and the mushroom compound psilocybin all act, in different ways, on receptors for serotonin, dopamine and noradrenaline.

The serotonin 5-HT2A receptor

The pharmacologist David Nichols, in his 2016 review of psychedelic drugs in Pharmacological Reviews, summarises the modern consensus: LSD, psilocybin and related substances act as agonists or partial agonists at the serotonin 5-HT2A receptor, and their characteristic effects come particularly from activating these receptors on large pyramidal neurons in layer V of the cerebral cortex. How serotonin works as a mood messenger is shown in the site’s serotonin and mood animation.

Extraordinary potency

The feature that astonished Stoll and Rothlin in 1943 — activity at a fraction of a milligram — remains LSD’s defining pharmacological trait. Passie and colleagues’ 2008 review of LSD’s pharmacology, drawing on what they estimate as nearly 10,000 scientific papers, dates the synthesis to 1938 and the discovery of its effects to 1943; Hofmann himself wrote that he knew of no other substance with such profound mental effects at such low doses. The same review records how the compound was used in the 1950s and 1960s as an “experimental psychosis” model and in psycholytic and psychedelic therapy, how it became an illegal street drug from the mid-1960s, and the complications documented after uncontrolled use. Those later chapters belong to the Legacy and Later Research page; the chemistry of LSD’s mushroom cousins psilocybin and psilocin is on the Psilocybin and Morning Glory Seeds page.

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Key Research Papers

1. Hofmann A. Historical view on ergot alkaloids. Pharmacology. 1978;16 Suppl 1:1-11. PubMed PMID: 347462
2. Hofmann A. How LSD originated. J Psychedelic Drugs. 1979;11(1-2):53-60. PubMed PMID: 392118
3. Stoll A, Hofmann A. Partialsynthese des Ergobasins, eines natürlichen Mutterkornalkaloids sowie seines optischen Antipoden. Hoppe-Seyler’s Z Physiol Chem. 1938;251(1-6):155-163. DOI: 10.1515/bchm2.1938.251.1-6.155
4. Stoll A, Hofmann A. Partialsynthese von Alkaloiden vom Typus des Ergobasins (6. Mitteilung über Mutterkornalkaloide). Helv Chim Acta. 1943;26(3):944-965. DOI: 10.1002/hlca.19430260326
5. Dudley HW, Moir JC. The new active principle of ergot. Science. 1935;81(2110):559-560. PubMed PMID: 17841110
6. van Dongen PW, de Groot AN. History of ergot alkaloids from ergotism to ergometrine. Eur J Obstet Gynecol Reprod Biol. 1995;60(2):109-116. PubMed PMID: 7641960
7. De Costa C. St Anthony’s fire and living ligatures: a short history of ergometrine. Lancet. 2002;359(9319):1768-1770. PubMed PMID: 12049883
8. Lee MR. The history of ergot of rye (Claviceps purpurea) II: 1900-1940. J R Coll Physicians Edinb. 2009;39(4):365-369. PubMed PMID: 20509463
9. Lee MR. The history of ergot of rye (Claviceps purpurea) III: 1940-80. J R Coll Physicians Edinb. 2010;40(1):77-80. PubMed PMID: 20503690
10. Tfelt-Hansen PC, Koehler PJ. History of the use of ergotamine and dihydroergotamine in migraine from 1906 and onward. Cephalalgia. 2008;28(8):877-886. PubMed PMID: 18460007
11. Montagne M. LSD at 50: Albert Hofmann and his discovery. Pharm Hist. 1993;35(2):70-73. PubMed PMID: 11623342
12. Passie T, Halpern JH, Stichtenoth DO, Emrich HM, Hintzen A. The pharmacology of lysergic acid diethylamide: a review. CNS Neurosci Ther. 2008;14(4):295-314. PubMed PMID: 19040555
13. Nichols DE. Psychedelics. Pharmacol Rev. 2016;68(2):264-355. PubMed PMID: 26841800

PubMed Topic Searches

1. https://pubmed.ncbi.nlm.nih.gov/?term=Hofmann+A%5Bau%5D+AND+ergot
2. https://pubmed.ncbi.nlm.nih.gov/?term=ergometrine+history
3. https://pubmed.ncbi.nlm.nih.gov/?term=ergotism+history
4. https://pubmed.ncbi.nlm.nih.gov/?term=lysergic+acid+diethylamide+history

Further Reading

• Hofmann A. LSD — mein Sorgenkind. Stuttgart; 1979. English translation by Jonathan Ott: LSD: My Problem Child. New York; 1980. Chapter 1, “How LSD Originated”: https://www.psychedelic-library.org/child1.htm
• Hofmann A. Die Mutterkornalkaloide [The ergot alkaloids]. Stuttgart: Enke; 1964.

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Connections

• Albert Hofmann: Ergot Chemist, LSD and the Sacred Mushrooms
• Albert Hofmann: Life and Career
• Albert Hofmann: Psilocybin, Psilocin and the Morning Glory Seeds
• Albert Hofmann: Legacy and Later Research
• Pharmacology
• Otto Loewi & Henry Dale
• Postpartum Hemorrhage
• Migraine
• Migraine: History and Discovery
• Serotonin, Mood & SSRIs
• Tryptophan
• Wheat: History and Origins

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