Albert Hofmann: Legacy and Later Research

Table of Contents

1. Ergometrine and Methylergometrine in Later Obstetrics
2. Ergot Medicines for Migraine
3. Methysergide and the Serotonin Theory of Migraine
4. Bromocriptine and the Dopamine Receptor
5. LSD in 1950s Psychiatry
6. Prohibition and the End of the First Research Era
7. Hofmann’s Own View of LSD
8. The Psilocybin Trials of the 2010s and 2020s
9. What the Trials Did and Did Not Show
10. Hofmann’s Place in the History of Pharmacology
11. Key Research Papers
12. Connections

1. Ergometrine and Methylergometrine in Later Obstetrics

Ergot had been a childbirth medicine long before Hofmann. Midwives used the dark fungal bodies from rye to speed up labour, and a description of the practice goes back to 1582. The trouble was dosing: the crude powder varied enormously in strength, and the obstetric historians van Dongen and de Groot record that uterine ruptures were so frequent that the preparation’s nickname changed from pulvis ad partum (“powder for childbirth”) to pulvis ad mortem (“powder for death”). After 1828, they write, ergot was no longer given to hasten delivery but only to prevent bleeding after it.

The isolation of ergometrine in the 1930s gave doctors a pure substance with a very specific action on the uterus. The physician-historian Michael Lee describes ergometrine as having proved life-saving in postpartum haemorrhage, the heavy bleeding that can follow birth. Hofmann’s part, told on the ergot and LSD page, was to rebuild ergometrine in the laboratory from lysergic acid in 1938 and then to make a close relative, methylergometrine (also called methylergonovine), which Hofmann himself described as a dependable remedy for bleeding after childbirth used around the world.

The side-effect record

The later record of these drugs is mixed. Ergot alkaloids tighten smooth muscle in blood vessels as well as in the uterus, and the history of the whole family is shadowed by the vessel-narrowing effects that once caused medieval ergotism. In their 1995 review, van Dongen and de Groot concluded that, because of severe and unpredictable side effects and because the drug is chemically unstable, ergometrine is not the drug of choice for either the prevention or the treatment of postpartum haemorrhage. A short history of ergometrine published in The Lancet in 2002, titled “St Anthony’s fire and living ligatures”, traces the same arc from medieval poison to obstetric drug. The site’s postpartum haemorrhage page covers the condition itself.

So the story here is not one of a drug that solved a problem for good. It is one of a natural poison that was tamed into a precise medicine, used widely for most of the twentieth century, and then placed by obstetricians alongside, and often behind, other options as its drawbacks became clear.

Back to Table of Contents

2. Ergot Medicines for Migraine

The second great medical use of ergot was in migraine, and it began before Hofmann joined the field. The Danish and Dutch neurologists Tfelt-Hansen and Koehler trace it back to 1906, when Henry Dale showed that ergot blocks the blood-pressure-raising effect of adrenaline. Arthur Stoll, Hofmann’s chief at Sandoz, isolated ergotamine from ergot in 1918. On the belief that migraine came from overactivity of the sympathetic nervous system, ergotamine was first used to treat migraine attacks by Maier in Switzerland in 1925.

In 1938 Graham and Wolff showed that the throbbing of the temple arteries and the headache fell together after intravenous ergotamine. That observation inspired Harold Wolff’s vascular theory of migraine: an initial narrowing of blood vessels in the brain followed by widening of the vessels outside the skull. For decades this theory shaped how migraine was explained to patients and doctors alike. The site’s migraine history page places it in the longer story of the condition.

Dihydroergotamine

Hofmann’s department produced the hydrogenated ergot alkaloids, in which a chemical double bond in the ergot skeleton is saturated with hydrogen. One of them, dihydroergotamine, was introduced in 1943 as an adrenaline-blocking agent and later became a migraine drug. Tfelt-Hansen and Koehler note that it is still in use, given by injection and as a nasal spray.

The adverse-event record

Before the triptan era, ergotamine and dihydroergotamine were the only specific anti-migraine drugs. From 1950, the same authors write, the world literature on ergotamine was dominated by two adverse events: ergotamine overuse headache, in which frequent use itself drives more headaches, and the relatively rare overt ergotism, the old vessel-narrowing poisoning. Oral ergotamine is very poorly absorbed (less than 1% reaches the bloodstream), and in randomised trials it has done worse than oral triptans. A European consensus in 2000 concluded that ergotamine is not a drug of first choice, while an American review in 2003 suggested it may be considered for selected patients with moderate to severe migraine. The site’s migraine page describes the condition as it is understood today.

Back to Table of Contents

3. Methysergide and the Serotonin Theory of Migraine

Lysergic acid, the chemical core Hofmann used to rebuild ergometrine and to make LSD, became the starting point for yet another migraine drug. The history of it, written by Koehler and Tfelt-Hansen in 2008, begins with Harold Wolff’s search for a substance around the blood vessels that might damage local tissue and make it more sensitive to pain during a migraine attack. Serotonin was among the candidates. It had been isolated in 1948, and because of its actions an anti-serotonin drug was wanted.

Methysergide was made from lysergic acid by adding a methyl group and a butanolamide group. The result was a potent and selective blocker of serotonin (5-HT). Because serotonin was thought to be involved in migraine attacks, the Italian physician Sicuteri introduced methysergide in 1959 as a drug to prevent migraine. Koehler and Tfelt-Hansen describe it as the first effective migraine preventive, and say its clinical effect was often excellent.

Retroperitoneal fibrosis

About five years later, it was found that long-term methysergide could cause retroperitoneal fibrosis, a build-up of scar tissue at the back of the abdomen that can trap the ureters and blood vessels. Its use in migraine declined considerably, and it survived mainly as a third-choice drug and as a serotonin-blocking tool in experiments. Later work by Bredberg and colleagues showed that methysergide is probably a prodrug: the body converts it into methylergometrine, the very childbirth drug Hofmann had made, and the metabolite carries extra dopamine activity that the parent compound lacks. The authors note that how methysergide prevents migraine is still not understood.

The path to the triptans

Methysergide’s most lasting legacy may be indirect. In 1974 the pharmacologist Saxena showed that it narrowed blood vessels selectively in the carotid circulation, and in 1984 he found an unusual serotonin receptor. Koehler and Tfelt-Hansen write that this finding gave an incentive for the development of sumatriptan, the first of the triptan drugs. In that sense a line runs from the ergot fungus on rye, through Hofmann’s lysergic acid chemistry, to the migraine medicines of the 1990s. The site’s serotonin animation shows how this messenger works in the brain, and the cluster headache page covers a related headache disorder.

Back to Table of Contents

4. Bromocriptine and the Dopamine Receptor

The ergot alkaloids turned out to be chemical keys that fit several of the brain’s locks at once: receptors for adrenaline and noradrenaline, for serotonin and for dopamine. That is why one family of molecules could tighten the uterus, narrow blood vessels, alter perception and act on hormones. It is also why the ergot programme Stoll and Hofmann built in Basel kept producing new medicines after the obstetric and migraine drugs.

The most important of these later compounds was bromocriptine, derived from ergocryptine, one of the alkaloids that make up the old “ergotoxine” mixture. In his history of ergot from 1940 to 1980, Lee writes that bromocriptine proved a pivotal substance in the scientific understanding of dopamine receptors in the central nervous system. He lists three widespread uses: suppressing breast-milk production, treating prolactinomas (benign pituitary tumours that make too much of the hormone prolactin), and managing Parkinson’s disease. Lee places bromocriptine in the Stoll–Hofmann era of ergot research as a whole; the sources in this wing do not credit its invention to Hofmann personally.

Each of those uses rests on the same mechanism. Dopamine released from the hypothalamus normally holds back prolactin release from the pituitary, so a drug that mimics dopamine there lowers prolactin; in Parkinson’s disease, the loss of dopamine-making nerve cells can be partly offset by a drug that stimulates dopamine receptors directly. The site’s prolactinoma page and Parkinson’s disease page describe these conditions.

Back to Table of Contents

5. LSD in 1950s Psychiatry

After Hofmann discovered LSD’s effects on the mind in April 1943 (the story is told in his own words on the ergot and LSD page), the substance moved quickly into psychiatric research. Passie and colleagues, in their 2008 review of LSD pharmacology, describe two main uses in the 1950s and 1960s. One was to produce a so-called “experimental psychosis” or “model psychosis” — a temporary, drug-induced state that researchers hoped would reveal the chemistry of mental illness. The other was in psychotherapy, as “psycholytic” therapy (repeated smaller amounts alongside talk therapy) and “psychedelic” therapy (a single large, intense session). The research was enormous: by their count, pharmacological research on LSD produced nearly 10,000 scientific papers.

The hope for schizophrenia

Lee records the excitement when Stoll and Hofmann’s group found such a powerful mind-altering substance: it was thought that LSD would help find the cause of schizophrenia and other psychotic disorders. For that purpose, he writes, it proved a great disappointment. The idea of a chemical cause of mental illness, however, became one of the guiding themes of the new biological psychiatry, and the discovery that LSD is chemically related to serotonin helped push serotonin into the centre of brain research.

The Saskatchewan trials

The historian Erika Dyck has studied some of the most extensive LSD trials anywhere, carried out in the Canadian province of Saskatchewan under the psychiatrists Humphry Osmond, at Weyburn, and Abram Hoffer, at Saskatoon. They were first drawn to LSD because it could produce a model psychosis, and their experiments led them to argue for a biochemical basis of schizophrenia. It was Osmond who coined the word “psychedelic”. Drawing on hospital records, interviews with former research subjects and the two psychiatrists’ private papers, Dyck argues that these trials were not fringe work but a serious branch of psychiatric research, running alongside the trials of the first modern psychiatric drugs such as chlorpromazine and imipramine.

Dyck also notes that, in the popular mind, LSD research has long been linked with the government-funded experiments run by the psychiatrist Ewen Cameron in Montreal. Her paper sets the Saskatchewan work apart from that reputation.

Back to Table of Contents

6. Prohibition and the End of the First Research Era

From the mid-1960s, Passie and colleagues write, LSD became an illegal drug used widely outside medicine. Formal research did not survive the change. Dyck identifies two reasons why the Saskatchewan experiments, and the field with them, failed — one scientific and one cultural.

The scientific reason was that the rules of clinical research changed under the researchers’ feet. In the 1950s and early 1960s, randomised controlled trials became the required standard, and the Saskatchewan studies had not been designed that way. Results from uncontrolled studies, however striking, no longer counted as proof. The cultural reason was that LSD became tied in the public mind to student protests, anti-war demonstrations and the counterculture. Governments stepped in to criminalise the drug, first restricting and then ending formal medical research into its possible therapeutic effects.

Passie’s review adds a pharmacological point to the history. It reports that LSD is physiologically well tolerated and that psychological reactions can be controlled in a medically supervised setting, but that complications may easily result from uncontrolled use by lay people. That contrast between the supervised research setting and uncontrolled use outside it runs through the whole later debate.

Back to Table of Contents

7. Hofmann’s Own View of LSD

Hofmann wrote about his discovery at length. His 1979 book in German was called LSD — mein Sorgenkind, published in English in 1980 as LSD: My Problem Child. A Sorgenkind is a child who causes worry, and the title sums up how he saw the substance: something he had brought into the world, valued, and could not control. In the same year he published a short account of how LSD originated in the Journal of Psychedelic Drugs.

The chemists N. S. Finney and J. S. Siegel, writing his obituary in the Swiss chemistry journal Chimia in 2008, summarise his position. Hofmann stressed LSD’s importance as a tool for understanding the human mind, not as a recreational drug, and he regretted that the cult that grew up around it led to the ban on research. In other words, he objected both to the uncontrolled use and to the end of serious science that followed from it.

Lee adds a more personal note, reported second-hand: Hofmann, he writes, would say later, in private, that he regretted having spent so much time on the compound. The two accounts are not in conflict. Hofmann spent most of his career on medicines for bleeding, circulation and the ageing brain, and on the natural chemistry of mushrooms and seeds; it was LSD, a small part of that work, that made him famous. The centenary symposium held in Basel in January 2006 took its title from the same double nature, calling LSD both a miracle drug and a problem child.

Back to Table of Contents

8. The Psilocybin Trials of the 2010s and 2020s

In the early twenty-first century, with new research methods and closer oversight, scientific interest in these substances resumed. Passie’s 2008 review already noted new interest in LSD as an experimental tool for studying consciousness, and recent work on cluster headache and on people with terminal illness. The pharmacologist David Nichols, in a long 2016 review of psychedelics, summarises the modern consensus on mechanism: these substances act as agonists or partial agonists at the serotonin 5-HT2A receptor, especially on a class of large nerve cells (layer V pyramidal neurons) in the cerebral cortex. Psilocybin, the mushroom compound Hofmann isolated in 1958 (see the mushrooms and morning glory page), became the main subject of the new trials.

LSD for anxiety in serious illness (2014)

A controlled LSD trial published by Gasser and colleagues in Switzerland in 2014 was a double-blind, randomised pilot study of only 12 patients with anxiety linked to life-threatening illness. Two months after treatment, state anxiety was significantly reduced and trait anxiety showed a positive trend; the authors reported no serious treatment-related adverse events, and called for larger controlled studies.

Psilocybin and cancer-related distress (2016)

Griffiths and colleagues at Johns Hopkins studied 51 people with life-threatening cancer and symptoms of depression or anxiety. In a randomised, double-blind crossover design, each participant had one session with a very low, placebo-like amount and one with a high amount, five weeks apart. The high-dose session produced large decreases in clinician-rated and self-rated depressed mood and anxiety, and at six months about 80% of participants still showed clinically significant decreases.

Psilocybin versus escitalopram (2021)

Carhart-Harris and colleagues in London ran a phase 2, double-blind randomised trial in 59 patients with long-standing, moderate-to-severe major depression, comparing psilocybin with the standard antidepressant escitalopram over six weeks; all patients received psychological support. Its results are set out in the next section, because they are often reported more favourably than the paper itself states.

Treatment-resistant depression (2022)

Goodwin and colleagues reported a commercially sponsored phase 2 trial in 233 people with treatment-resistant depression, comparing three single doses of psilocybin, the lowest of which (1 mg) served as the comparison. At three weeks, the highest dose lowered depression scores more than the 1 mg dose (a difference of 6.6 points on the MADRS depression scale), while the middle dose did not differ significantly from it.

Back to Table of Contents

9. What the Trials Did and Did Not Show

Reports of the psychedelic revival in newspapers often run ahead of the evidence. The trials themselves are more cautious, and their limits are part of the record.

The 2021 primary endpoint was not significant

The psilocybin-versus-escitalopram trial named one main (primary) outcome in advance: the change in a self-rated depression score (QIDS-SR-16) at six weeks. Scores fell by an average of 8.0 points with psilocybin and 6.0 with escitalopram, a difference of 2.0 points that was not statistically significant (P = 0.17). The authors’ own conclusion was that the trial did not show a significant difference in antidepressant effect between psilocybin and escitalopram in a selected group of patients. Secondary outcomes generally favoured psilocybin, but, as the authors state, those analyses were not corrected for multiple comparisons, so they cannot be read as proof. Adverse events were similar in the two groups, and the authors called for larger and longer trials.

Adverse events in the 2022 trial

In the 2022 treatment-resistant depression trial, adverse events were reported in 77% of participants, and suicidal ideation, suicidal behaviour or self-injury occurred in every dose group. The trial did not support a sustained response to the highest dose at 12 weeks.

Small samples and difficult blinding

The trials share common limits. Most are small (12, 51 and 59 participants in three of the studies above), short, and run in selected volunteers. Because the mind-altering effects are hard to miss, participants and staff often know who received the active drug, which weakens blinding; the 2016 trial tried to reduce expectancy effects through its instructions to participants and staff. All of them combine the drug with structured psychological support, so the effect of the substance cannot be fully separated from the care around it. Nichols’s review describes the cancer-distress studies and brain-imaging work on the brain’s “default mode network” as active research, not settled findings. Hofmann’s substances are back in the laboratory, but the question of what they can and cannot do in medicine remains open. The site’s depression page covers the condition the largest trials studied.

Back to Table of Contents

10. Hofmann’s Place in the History of Pharmacology

Historians of ergot give Hofmann a central place. Lee writes that the period from 1940 to 1980 in the history of ergot was dominated by two investigators, Arthur Stoll and Albert Hofmann. Hofmann’s own 1978 survey of the field described how ergot was changed from a dreaded poison into a rich treasure house of valuable medicines. That arc — from the fungus that caused St Anthony’s fire to drugs for childbirth bleeding, migraine, circulation and the dopamine system — is the main part of his scientific legacy, and it is a natural-medicine story at heart: every one of those drugs began with a substance made by a living organism.

His second legacy is the method. Hofmann took a crude natural material, found the active compound, worked out its structure, rebuilt it in the laboratory and then varied it to make new medicines. He did this with ergot, with the Mexican mushroom and with morning-glory seeds; his life is told on the life and career page. The same approach links him to the other natural-product pharmacologists in this section, such as Henry Dale, whose 1906 work on ergot opened the field (see Otto Loewi and Henry Dale), and to the later scientists who explained how nerve messengers are released and recycled (see Katz, von Euler and Axelrod).

His third legacy is the one the public knows. Obituaries in 2008, including one in Neuropsychobiology headed “Albert Hofmann, the father of LSD”, led with the 1943 discovery. Historians of pharmacy marked its fiftieth anniversary in 1993 with an essay on “LSD at 50”. His work on LSD and psilocybin opened a line of brain research, closed by law in the 1960s and reopened in his last years, whose medical value is still being tested. He died in 2008 at the age of 102, having seen both the end of the first research era and the beginning of the second.

Back to Table of Contents

Key Research Papers

1. Hofmann A. Historical view on ergot alkaloids. Pharmacology. 1978;16 Suppl 1:1-11. PubMed PMID: 347462
2. 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
3. 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
4. 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
5. De Costa C. St Anthony's fire and living ligatures: a short history of ergometrine. Lancet. 2002;359(9319):1768-1770. PubMed PMID: 12049883
6. 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
7. Koehler PJ, Tfelt-Hansen PC. History of methysergide in migraine. Cephalalgia. 2008;28(11):1126-1135. PubMed PMID: 18644039
8. 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
9. Dyck E. Flashback: psychiatric experimentation with LSD in historical perspective. Can J Psychiatry. 2005;50(7):381-388. PubMed PMID: 16086535
10. Hofmann A. How LSD originated. J Psychedelic Drugs. 1979;11(1-2):53-60. PubMed PMID: 392118
11. Finney NS, Siegel JS. In Memoriam: Albert Hofmann (1906–2008). Chimia. 2008;62(5):444. DOI: 10.2533/chimia.2008.444
12. Nichols DE. Psychedelics. Pharmacol Rev. 2016;68(2):264-355. PubMed PMID: 26841800
13. Gasser P, Holstein D, Michel Y, Doblin R, Yazar-Klosinski B, Passie T, Brenneisen R. Safety and efficacy of lysergic acid diethylamide-assisted psychotherapy for anxiety associated with life-threatening diseases. J Nerv Ment Dis. 2014;202(7):513-520. PubMed PMID: 24594678
14. 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
15. 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
16. Goodwin GM, Aaronson ST, Alvarez O, et al. Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression. N Engl J Med. 2022;387(18):1637-1648. PubMed PMID: 36322843
17. Fusar-Poli P, Borgwardt S. Albert Hofmann, the father of LSD (1906-2008). Neuropsychobiology. 2008;58(1):53-54. PubMed PMID: 18799895
18. Montagne M. LSD at 50: Albert Hofmann and his discovery. Pharm Hist. 1993;35(2):70-73. PubMed PMID: 11623342

PubMed Topic Searches

1. Ergometrine history
2. Methysergide and migraine history
3. Bromocriptine and dopamine receptor history
4. Lysergic acid diethylamide history
5. Psilocybin randomised trials in depression

Further Reading

• Albert Hofmann. LSD — mein Sorgenkind (1979); English translation by Jonathan Ott, LSD: My Problem Child (1980).
• Albert Hofmann. Die Mutterkornalkaloide (1964).

Back to Table of Contents

Connections

• Albert Hofmann: Ergot Chemist, LSD and the Sacred Mushrooms
• Albert Hofmann: Life and Career
• Albert Hofmann: Ergot Medicines and the Discovery of LSD
• Albert Hofmann: Psilocybin, Psilocin and the Morning Glory Seeds
• Pharmacology
• Otto Loewi & Henry Dale
• Katz, von Euler and Axelrod
• Postpartum Hemorrhage
• Migraine
• Migraine: History and Discovery
• Prolactinoma
• Parkinson’s Disease
• Depression
• Serotonin, Mood & SSRIs
• Medicinal Mushrooms