Albert Hofmann: Ergot Chemist, LSD and the Sacred Mushrooms

Table of Contents

1. Deep-Dive Articles
2. 1. Who Albert Hofmann Was
3. 2. Ergot Medicines and LSD on One Page
4. 3. The Sacred Mushroom and the Morning-Glory Seeds
5. 4. The Natural Sources: Ergot, Mushroom and Morning Glory
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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1. Who Albert Hofmann Was

Hofmann was born on 11 January 1906 in Baden, in the Swiss canton of Aargau, the eldest of the four children of a toolmaker. When his father fell ill he left formal schooling for a commercial apprenticeship to help support the family, kept up Latin and languages on the side, and at about twenty completed the Matura (the Swiss university-entrance examination) at a private school in Zurich with help from an anonymous benefactor. He then studied chemistry with Paul Karrer at the University of Zurich. His doctoral thesis was on the enzymatic breakdown of chitin, the material of insect and crab shells: using extracts of the edible snail Helix pomatia, he made one of the first preparations of the enzyme chitinase and showed that chitin is a chain of N-acetylglucosamine units.

In the spring of 1929 he joined the pharmaceutical-chemical research laboratory of Sandoz in Basel under Arthur Stoll, choosing it, by his own account, because it offered work on natural products. His first project was the heart-active glycosides of the Mediterranean squill, or sea onion. He rose from Stoll’s co-worker to group leader and finally head of the natural-products department, and retired in 1971 after more than a hundred scientific papers. In retirement he wrote books, among them LSD — mein Sorgenkind (1979; in English LSD: My Problem Child, 1980). He died at his home in Burg im Leimental on 29 April 2008, aged 102. The full story is told in Albert Hofmann: Life and Career.

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2. Ergot Medicines and LSD on One Page

Rebuilding an ergot medicine

By the mid-1930s chemists in several countries had separated ergot’s active substances. In 1918 Stoll had isolated ergotamine, the first chemically pure ergot alkaloid, and in 1935 the substance responsible for ergot’s action on the womb, ergometrine (also called ergonovine or ergobasine), was found, in Hofmann’s words, simultaneously in four separate laboratories. Hofmann’s first great achievement, published with Stoll in 1938, was to build ergometrine in the laboratory from lysergic acid, the core shared by all these alkaloids, and an amino-alcohol called propanolamine. Swapping in a slightly larger amino-alcohol, butanolamine, gave methylergometrine (methylergonovine), which he described as a dependable remedy against bleeding after childbirth. Adding hydrogen to other ergot alkaloids gave dihydroergotoxine and dihydroergotamine, the second of which later became a migraine medicine.

LSD-25

Using the same method he made a series of new lysergic acid amides. The twenty-fifth, lysergic acid diethylamide, was made in 1938 in the hope of a circulatory and breathing stimulant, by analogy with the drug nikethamide (nicotinic acid diethylamide). Sandoz pharmacologists found a strong effect on the womb but, Hofmann wrote, it aroused no special interest. In the spring of 1943 he made it again. By his own account, on 16 April 1943 he felt a remarkable restlessness and dizziness during the final purification and went home, where he experienced vivid imagery; on 19 April he took a deliberate small amount to test whether LSD was the cause, and the strong effects that followed during his bicycle ride home later gave that date the name “Bicycle Day”. The Sandoz pharmacologist Ernst Rothlin and colleagues repeated the test with a third of the amount and found the effects still extremely impressive. The detail is in Ergot Medicines and the Discovery of LSD.

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3. The Sacred Mushroom and the Morning-Glory Seeds

In 1957 the French mycologist Roger Heim, who had identified the Mexican sacred mushrooms with the American ethnographer R. Gordon Wasson, sent Sandoz dried Psilocybe mexicana grown in Paris. Animal tests gave no clear signal, so Hofmann used self-assay to follow the active fractions. In March 1958 he reported the isolation of psilocybin; by November 1958 his group had worked out its structure and made it synthetically, and in 1959 he identified the closely related psilocin. Both are indole compounds structurally very close to the brain messenger serotonin. In 1960, with Hans Tscherter, he found that ololiuqui, the seeds of the morning glory Rivea corymbosa (now Turbina corymbosa), contained lysergic acid alkaloids, chiefly lysergic acid amide — the first time ergot-type alkaloids had been found in a flowering plant. The detail is in Psilocybin, Psilocin and the Morning Glory Seeds.

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4. The Natural Sources: Ergot, Mushroom and Morning Glory

Ergot is the hard, dark resting body (sclerotium) of the fungus Claviceps purpurea, which replaces the grain on an ear of rye. Bread made from contaminated rye caused the medieval epidemics of ergotism known as St Anthony’s fire, with gangrene of the limbs, convulsions and death. The same fungus had a medical history too: the Frankfurt physician Adam Lonitzer recorded in 1582 that midwives used it to quicken childbirth. Because its strength in crude form was unpredictable, it caused ruptures of the womb, and the historians van Dongen and de Groot report that after 1828 it was used mainly to prevent bleeding after delivery rather than to hasten it. Hofmann later summed up the change in his 1978 historical survey: ergot had turned from a dreaded poison into a rich treasure house of valuable pharmaceuticals.

The mushroom came from the mountains of southern Mexico, where Mazatec healers used Psilocybe mushrooms in healing ceremonies. In 1962 Hofmann, his wife Anita, Wasson and the ethnographer Irmgard Weitlaner Johnson travelled to Huautla de Jiménez, where the Mazatec healer María Sabina held a ceremony with synthetic psilocybin pills; from that trip came the plant the botanists Epling and Játiva described as a new species of sage, Salvia divinorum. The morning-glory puzzle — how a flowering plant could make alkaloids otherwise known from a fungus — was answered only in the twenty-first century: Steiner and Leistner review the evidence that the alkaloids in Turbina corymbosa, Ipomoea violacea and related morning glories are made by seed-transmitted fungi of the genus Periglandula living on the leaves and moved into the plant. The site has no psilocybin page; its Medicinal Mushrooms section covers the edible and medicinal fungi.

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5. Timeline at a Glance

• 1906 — Born 11 January in Baden, Aargau, Switzerland.
• 1918 — Arthur Stoll at Sandoz isolates ergotamine, the first pure ergot alkaloid.
• 1926 — Begins chemistry studies with Paul Karrer at the University of Zurich; doctorate on snail chitinase and chitin.
• 1929 — Joins Stoll’s natural-products laboratory at Sandoz in Basel; first project on squill glycosides.
• 1935 — Ergometrine, the womb-acting ergot alkaloid, is found in four laboratories.
• 1938 — With Stoll, publishes the partial synthesis of ergometrine; makes LSD-25 in the lysergic acid amide series.
• 1943 — Re-synthesises LSD; 16 April accidental exposure; 19 April deliberate self-test; dihydroergotamine introduced.
• 1958 — Isolation (March) and structure and synthesis (November) of psilocybin.
• 1959 — Identification of psilocin.
• 1960 — With Tscherter, isolates lysergic acid alkaloids from ololiuqui morning-glory seeds.
• 1962 — Private field trip to Huautla de Jiménez, Mexico, with Wasson.
• 1971 — Retires as head of the natural-products department.
• 1979 — Publishes LSD — mein Sorgenkind (English edition 1980).
• 2006 — Centenary symposium in Basel.
• 2008 — Dies 29 April at Burg im Leimental, aged 102.

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6. Later Significance

The medical historian M. R. Lee writes that the 1940–80 history of ergot was dominated by two investigators, Arthur Stoll and Albert Hofmann. The ergot programme they led left lasting medicines and lasting knowledge. Ergometrine and methylergometrine entered obstetrics as medicines against bleeding after childbirth, though van Dongen and de Groot report that its severe and unpredictable side effects and its instability mean it is no longer the drug of choice for that purpose. Dihydroergotamine, introduced in 1943, is still used for migraine, according to Tfelt-Hansen and Koehler; methysergide, made from lysergic acid, was introduced for migraine prevention in 1959 and later found to cause retroperitoneal fibrosis. Lee describes bromocriptine, a later ergot derivative, as pivotal to the understanding of dopamine receptors.

LSD had a stormier history. Passie and colleagues describe its use in 1950s and 1960s psychiatric research as a “model psychosis” and in psycholytic and psychedelic therapy, its spread as an illegal street drug from the mid-1960s, and a literature of nearly 10,000 papers on its pharmacology. Dyck traces the end of the Saskatchewan LSD trials to their lack of the newly required randomised design and to criminalisation. Lee reports that the hope that LSD would explain schizophrenia proved a great disappointment. The chemists who wrote his obituary in Chimia recall that Hofmann saw LSD as a tool for understanding the mind and regretted that the cult around it led to the ban on research. In the twenty-first century trials of psilocybin resumed: a 2016 randomised trial in people with life-threatening cancer reported large and sustained decreases in depressed mood and anxiety, while a 2021 trial comparing psilocybin with the antidepressant escitalopram found no significant difference on its primary measure. Nichols’ 2016 review describes how these compounds act on serotonin 5-HT2A receptors. The detail, including the trials’ limits, is in Albert Hofmann: Legacy and Later Research.

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Key Research Papers

1. Hofmann A. How LSD originated. J Psychedelic Drugs. 1979;11(1-2):53-60. PubMed PMID: 392118
2. Hofmann A. Historical view on ergot alkaloids. Pharmacology. 1978;16 Suppl 1:1-11. PubMed PMID: 347462
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. Hofmann A, Heim R, Brack A, Kobel H. [Psilocybin, a psychotropic substance from the Mexican mushroom Psilicybe mexicana Heim]. Experientia. 1958;14(3):107-109. PubMed PMID: 13537892
5. Hofmann A, Frey A, Ott H, Petrzilka T, Troxler F. [Elucidation of the structure and the synthesis of psilocybin]. Experientia. 1958;14(11):397-399. PubMed PMID: 13609599
6. Hofmann A, Tscherter H. [Isolation of lysergic acid alkaloids from the Mexican drug ololiuqui (Rivea corymbosa (L.) Hall.f.)]. Experientia. 1960;16(9):414. PubMed PMID: 13715089
7. Finney NS, Siegel JS. In Memoriam: Albert Hofmann (1906–2008). Chimia. 2008;62(5):444. DOI: 10.2533/chimia.2008.444
8. Sticher O, Hamburger M. Albert Hofmann (1906 - 2008) - an obituary. Planta Med. 2008;74(8):791-793. PubMed PMID: 18600602
9. 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
10. 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
11. 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
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. Dyck E. Flashback: psychiatric experimentation with LSD in historical perspective. Can J Psychiatry. 2005;50(7):381-388. PubMed PMID: 16086535
14. Steiner U, Leistner E. Ergot Alkaloids and their Hallucinogenic Potential in Morning Glories. Planta Med. 2018;84(11):751-758. PubMed PMID: 29499587
15. Nichols DE. Psychedelics. Pharmacol Rev. 2016;68(2):264-355. PubMed PMID: 26841800
16. Griffiths RR, Johnson MW, Carducci MA, Umbricht A, Richards WA, Richards BD, Cosimano MP, Klinedinst MA. Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial. J Psychopharmacol. 2016;30(12):1181-1197. PubMed PMID: 27909165
17. Carhart-Harris R, Giribaldi B, Watts R, Baker-Jones M, Murphy-Beiner A, Murphy R, Martell J, Blemings A, Erritzoe D, Nutt DJ. Trial of Psilocybin versus Escitalopram for Depression. N Engl J Med. 2021;384(15):1402-1411. PubMed PMID: 33852780

PubMed Topic Searches

1. Hofmann A and ergot alkaloids
2. History of ergometrine
3. Psilocybin and Psilocybe: history
4. Ergot alkaloids in morning glories (Convolvulaceae)
5. History of lysergic acid diethylamide

Further Reading

• Hofmann A. LSD — mein Sorgenkind. 1979. English edition: LSD: My Problem Child, translated by Jonathan Ott, 1980.
• Hofmann A. Die Mutterkornalkaloide. 1964.

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Connections

• Pharmacology
• Albert Hofmann: Life and Career
• Albert Hofmann: Ergot Medicines and the Discovery of LSD
• Albert Hofmann: Psilocybin, Psilocin and the Morning Glory Seeds
• Albert Hofmann: Legacy and Later Research
• Otto Loewi & Henry Dale: Acetylcholine and the Chemistry of Nerve Signals
• Katz, von Euler and Axelrod: How Nerves Talk, and How Antidepressants Work
• Medicinal Mushrooms
• Postpartum Hemorrhage
• Migraine: History and Discovery
• Serotonin, Mood & SSRIs
• Wheat: History and Origins

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