Albert Hofmann: Psilocybin, Psilocin and the Morning Glory Seeds

Table of Contents

1. Mushrooms in Mexican Healing Tradition
2. Roger Heim, Gordon Wasson and the Samples Sent to Basel
3. When Animal Tests Failed
4. Isolating Psilocybin (1958)
5. Structure and Synthesis
6. Psilocin and the Serotonin Likeness
7. The 1962 Journey to Huautla
8. Ololiuqui: Ergot Alkaloids in a Flowering Plant
9. The Hidden Fungus: Periglandula
10. What Hofmann’s Natural-Product Method Showed
11. Key Research Papers
12. Connections

1. Mushrooms in Mexican Healing Tradition

Long before any chemist saw them, certain mushrooms held a sacred place in the religious and healing life of the peoples of central and southern Mexico. In Nahuatl, the language of the Aztecs, they were called teonanácatl, which Hofmann, following the ethnomycologists Valentina and R. Gordon Wasson, translated as “sacred mushroom”. The earliest written descriptions come from Spanish chroniclers who arrived soon after the conquest. The Franciscan friar Bernardino de Sahagún described merchants eating mushrooms with honey at a night-time feast and seeing visions of their own futures, and the Dominican friar Diego Durán reported mushrooms eaten at the festivities for the accession of the Aztec ruler Moctezuma II in 1502.

Older evidence may lie in stone. So-called mushroom stones — carved sculptures shaped like a capped mushroom with a face or animal figure on the stem — have been found in El Salvador, Guatemala and the neighbouring highlands of Mexico. Hofmann reported that archaeologists date the oldest to before 500 BC, and that Wasson argued they were linked to the mushroom cult, which would make it more than two thousand years old. Hofmann presented that link as Wasson’s argument, not as settled fact.

Suppressed, then forgotten, then found again

Christian missionaries regarded the visions as the devil’s work and tried to stamp out the practice, but it continued in secret in remote mountain villages. Over the following centuries the chroniclers’ accounts were largely ignored, and in 1915 the American botanist W. E. Safford went so far as to argue that sacred mushrooms had never existed — that the Spanish writers had mistaken dried peyote cactus for mushrooms. The Mexican physician Blas Pablo Reko disputed this, and in the late 1930s the anthropologist Robert J. Weitlaner and the Harvard botanist Richard Evans Schultes collected mushrooms actually used in ceremonies. In 1938 a group of young American anthropologists led by Jean Bassett Johnson became the first outsiders known to attend a night-time mushroom ceremony, in the Mazatec town of Huautla de Jiménez in the state of Oaxaca.

The ceremony as a consultation

From the Wassons’ accounts, Hofmann described the modern Mazatec ceremony as a kind of medical and spiritual consultation. A sick person or their family would come to a curandero or curandera — a healer whose role combined that of physician and priest — who ate the mushrooms at night, in darkness or by candlelight, before an altar bearing Christian images, and answered questions in a chanted, visionary state: whether a sick person would recover, which herbs might help, who had stolen a horse. Old beliefs and Christian ones had merged; the mushrooms were sometimes said to grow only where a drop of Christ’s blood had fallen.

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2. Roger Heim, Gordon Wasson and the Samples Sent to Basel

The modern scientific story begins with the Wassons, a New York banker and his wife, a paediatrician, who had become fascinated by the place of mushrooms in human culture. They began fieldwork in Huautla de Jiménez in 1953. In June 1955, after two years of building trust with Mazatec friends, Gordon Wasson and the photographer Allan Richardson were invited to take part in a night ceremony led by the curandera María Sabina, and became, in Hofmann’s words, “in all likelihood the first outsiders” permitted to eat the sacred mushrooms. The Wassons published their findings in the two-volume Mushrooms, Russia and History (1957).

To bring the mushrooms into the scientific literature, Wasson worked with Roger Heim, director of the Laboratoire de Cryptogamie at the Muséum National d’Histoire Naturelle in Paris. Accompanying the Wassons on later expeditions, Heim identified the sacred mushrooms as gilled fungi of the family Strophariaceae — about a dozen species new to science, most belonging to the genus Psilocybe. He also succeeded in growing several of them in his laboratory, and one species, Psilocybe mexicana, proved especially easy to cultivate.

Why the samples came to Hofmann

Late in 1956 Hofmann read a short newspaper notice about Mexican mushrooms that caused hallucinations, and the subject stayed in his mind. Early in 1957 an inquiry reached his employer’s research management in Basel from Heim himself: would the Basel laboratories take on the chemistry? Earlier attempts in Paris and in two American laboratories had not isolated the active principle, and Heim reasoned that the team that had discovered LSD, whose effects resembled those of the mushrooms, might succeed. “Thus it was LSD that showed teonanácatl the way into our laboratory,” Hofmann later wrote. As head of the natural-products department he had meant to hand the project to a co-worker, but found little enthusiasm for anything connected with LSD, and decided to do the work himself with his long-time laboratory assistant Hans Tscherter.

About 100 grams of dried Psilocybe mexicana, grown by Heim in Paris, were available for the start of the work. Two Basel colleagues, A. Brack and H. Kobel, later improved the laboratory cultivation so that larger quantities of mushroom material could be produced; their cultivation work, with Heim and R. Cailleux, was reported to the French Academy of Sciences in March 1958, together with the demonstration of psilocybin and psilocin in the cultured mushrooms.

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3. When Animal Tests Failed

Isolating an unknown active substance from a plant or fungus usually depends on a bioassay: a test that shows which fractions of an extract still carry the activity, so the chemist knows which to keep and which to discard. Nothing was known about the chemical nature of the mushroom principle, so the activity itself had to be the guide. But when Hofmann and Tscherter tested their various extracts on mice and dogs, none produced a clear effect that pointed to a hallucinogenic substance. It began to look as though the mushrooms grown and dried in Paris might have lost their activity altogether.

The only way to find out, Hofmann concluded, was to test the mushroom material on a human being, and he did so on himself, explaining in his memoir that researchers ought not to ask others to take on a risky self-experiment that their own investigation required. He described a strong effect that began about half an hour later and lasted roughly six hours, in which everything around him seemed to take on Mexican forms and colours; at its height he feared being swept away by the rush of shifting images. He recorded both the visions and his relief at returning to ordinary reality.

A lesson already learned with LSD

The experiment showed, in Hofmann’s words, “once again that human beings react much more sensitively than animals to psychoactive substances.” The extracts had not been inactive; the animals simply did not show this kind of effect in a way the tests could detect. The Chimia obituary of Hofmann (2008) makes the same point about why animal models failed. From then on, with no other test available, the separation was guided by small self-tests of each fraction by Hofmann and colleagues who volunteered, using amounts chosen to give a mild, short-lived but unmistakable effect so that active and inactive fractions could be told apart.

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4. Isolating Psilocybin (1958)

Guided by these human assays, the active principle was concentrated step by step with the newest separation methods of the day and finally obtained in chemically pure form. Two new substances emerged as colourless crystals. Hofmann named them psilocybin and psilocin, after the mushroom genus Psilocybe.

The isolation was published in March 1958 in the Swiss journal Experientia, by Hofmann together with Heim, Brack and Kobel, under the title “Psilocybin, ein psychotroper Wirkstoff aus dem mexikanischen Rauschpilz Psilocybe mexicana Heim” (“Psilocybin, a psychotropic active substance from the Mexican mushroom Psilocybe mexicana Heim”). The parallel note in the Comptes Rendus of the French Academy of Sciences, by Heim, Brack, Kobel, Hofmann and Cailleux, described the conditions under which the cultured fungus formed fruit bodies and sclerotia (hardened resting bodies) and demonstrated psilocybin and psilocin in them.

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5. Structure and Synthesis

Isolating a substance is only the first step; a natural-products chemist then wants to know exactly how its atoms are arranged, and to prove that structure by building the molecule from simple starting materials. Hofmann’s co-workers A. J. Frey, H. Ott, T. Petrzilka and F. Troxler joined him for this stage, and the results — the elucidation of the structure and the synthesis of psilocybin — appeared in the November 1958 issue of Experientia, eight months after the isolation paper. Hofmann and Troxler’s note identifying psilocin followed in 1959.

The structure showed psilocybin to be 4-phosphoryloxy-N,N-dimethyltryptamine — an indole ring like that of the amino acid tryptophan, carrying a short side chain ending in a nitrogen with two methyl groups, and a phosphate group attached at position 4 of the ring. Psilocin is the same molecule without the phosphate: 4-hydroxy-N,N-dimethyltryptamine. Hofmann pointed out that psilocybin, as the phosphoric acid ester of psilocin, was at the time the first and only indole compound containing phosphoric acid that had been found in nature.

From mushroom to flask

Once the structure was known, the total synthesis could be developed into a technical process that did not need the mushroom at all. Hofmann wrote that synthetic production was “more rational and cheaper than extraction from the mushrooms.” He saw a philosophical side to it too: with isolation and synthesis, he wrote, the “demystification of the magic mushrooms was accomplished,” yet the mystery of their effects had only been reduced to the mystery of two crystalline substances, whose action science could describe but not fully explain.

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6. Psilocin and the Serotonin Likeness

The structures revealed a striking family resemblance. Psilocybin and psilocin, like LSD, belong to the indole compounds, a class of substances widespread in plants and animals. More specifically, Hofmann noted, both mushroom compounds have a chemical structure “very similar to the brain factor serotonin” — the messenger molecule (5-hydroxytryptamine) that the body makes from tryptophan and that carries signals between nerve cells. Psilocin differs from serotonin mainly in where its hydroxyl group sits on the indole ring (position 4 rather than 5) and in the two methyl groups on its side-chain nitrogen.

Hofmann also described a practical chemical difference between the two compounds. The phosphate group, he wrote, does not contribute to the activity — psilocin is just as active as psilocybin — but it makes the molecule stable: psilocin is readily decomposed by oxygen in the air, while psilocybin keeps. Comparing them with LSD, he reported that the mushroom compounds were more than a hundred times weaker by weight and that their effects were much shorter, lasting four to six hours against eight to twelve for LSD.

From “serotonin blocker” to receptor science

In the pharmacological experiments of the 1950s, Hofmann wrote, the mushroom compounds, like LSD, blocked the effects of serotonin on various isolated organs. Later research refined this picture considerably. In a 2016 review in Pharmacological Reviews, Nichols summarised the modern view that classic psychedelics act as agonists or partial agonists at the serotonin 5-HT_2A receptor — that is, they activate it rather than simply blocking serotonin — particularly on large pyramidal neurons in layer V of the cerebral cortex. A 2002 review by Passie and colleagues noted how few pharmacological data on psilocybin existed between its 1960s experimental medical use and the turn of the century.

The way serotonin itself works in mood and perception is explained in the site’s serotonin animation; the later clinical research with psilocybin, with its results and limits, is described on the Legacy and Later Research page of this wing.

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7. The 1962 Journey to Huautla

Hofmann and Wasson became friends through the mushroom work, and in the autumn of 1962 Wasson invited Hofmann and his wife Anita to join an expedition to the Mazatec country. Hofmann made the trip privately, as the Chimia obituary notes, not as a project of his employer. They flew to Mexico City on 26 September 1962 and were joined by Irmgard Weitlaner Johnson, widow of Jean Bassett Johnson of the 1938 ceremony.

The leaves of the shepherdess

The purpose of the journey was a third Mazatec sacred plant. Wasson had learned that the pressed juice of leaves called hojas de la Pastora or ska María Pastora — “leaves of Mary the shepherdess” — was used in healing ceremonies much as the mushrooms and the morning-glory seeds were. After some two and a half weeks by mule through the Sierra Mazateca, the party obtained flowering plants and leaves. Along the route Hofmann noticed the blue flowers of the morning glory Ipomoea violacea growing wild — the source of one kind of ololiuhqui seed described below.

The herbarium specimens were identified at Harvard by Carl Epling and Carlos D. Játiva as a previously undescribed species of sage, which they named Salvia divinorum — a relative of the familiar garden and culinary sage. Hofmann’s attempt to identify its active principle in Basel failed: the juice, preserved with alcohol in Mexico, had lost its activity by the time it reached the laboratory, and he concluded the active substance was unstable. (The compound responsible was identified by other researchers decades later.)

María Sabina and the synthetic pills

At Huautla de Jiménez the party visited María Sabina, the curandera in whose home Wasson had attended the 1955 ceremony. Hofmann recorded that her earlier house had been burned, presumably by residents angered that she had shared the secret with outsiders. During a night ceremony she used pills of Hofmann’s synthetic psilocybin in place of mushrooms. At first, by Hofmann’s account, she said the pills lacked the spirit of the mushroom; he and Wasson put this down to slower absorption from a swallowed pill. By dawn she said the pills had the same power as the mushrooms. Hofmann took this as confirmation from “the most competent authority” that the synthetic compound was identical to the natural one.

Hofmann himself was ambivalent about what followed. He credited María Sabina with opening the way to the scientific study of the mushrooms, while recording that some of her own community regarded her openness as a betrayal of a sacred custom, and that the publicity brought a wave of drug-seeking visitors and tourism to Huautla that changed the town.

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8. Ololiuqui: Ergot Alkaloids in a Flowering Plant

With the mushroom problem solved, Hofmann turned to another Mexican sacred drug still chemically unexplained: ololiuhqui (often spelled ololiuqui), the Aztec name for the seeds of certain climbing plants of the morning-glory family (Convolvulaceae). Like peyote and the mushrooms, the seeds were used in pre-Columbian religious ceremonies and healing, and Hofmann noted that Zapotec, Chinantec, Mazatec and Mixtec communities still used them. Sahagún had written of a plant called coatl xoxouhqui (“green snake”) whose seeds “stupefy and deprive one of reason”, and Francisco Hernández, physician to Philip II of Spain, gave the first description and illustration of the plant.

When Hofmann began in 1959, the only chemical study of the seeds, by the Swedish pharmacologist C. G. Santesson in 1937, had not produced a pure active substance, and reports of the seeds’ effects were contradictory. Through Wasson he obtained two samples. The round, light-brown seeds from Huautla proved to be from Rivea corymbosa, now called Turbina corymbosa. The black, angular seeds from the Zapotec town of San Bartolo Yautepec, known locally as badoh negro, were identified as Ipomoea violacea — the same species as the blue morning glory grown as an ornamental in gardens around the world.

A quick test, an astonishing result

Hofmann and Tscherter guessed that the active principles might be indole compounds like LSD, psilocybin and psilocin. That guess could be checked quickly, because indoles give an intense blue colour with a particular reagent, and the seed extracts turned blue. Using that colour test they isolated the indole substances in a short time, and identified them in 1960 as lysergic acid amide (ergine), lysergic acid hydroxyethylamide and closely related alkaloids, along with ergobasine (ergometrine) — the very ergot alkaloid whose synthesis had started Hofmann’s ergot career more than twenty years earlier. Hofmann and A. Cerletti described the findings for physicians in 1961 as the solution of the “ololiuqui puzzle” — the active substances of the third Aztec sacred drug. Hofmann had synthesised lysergic acid amide himself during the work that produced LSD, two decades before finding it in nature.

Doubt from colleagues

When Hofmann presented the results at a natural-products congress in Sydney in the autumn of 1960, he met scepticism. Some suspected the extracts had been contaminated with lysergic acid derivatives from his own laboratory. Others objected on principle: ergot alkaloids were known only from lower fungi such as Claviceps purpurea, the ergot of rye, and finding the same distinctive compounds in a flowering plant from a distant branch of the plant kingdom went against the usual rule that such substances are typical of particular groups. Laboratories in the United States, Germany and the Netherlands later confirmed the findings. Hofmann’s group went on to find ergot alkaloids in seeds of other morning glories, including ergosine, ergosinine and agroclavine from Ipomoea argyrophylla, reported in 1965. Some critics even suggested the seeds might be infected with an alkaloid-making fungus; Hofmann wrote that this had been ruled out experimentally.

Hofmann described the effects of ololiuhqui, as reported at the time, as different from those of LSD — less euphoric and visual, with a feeling of mental emptiness, often anxiety and depression, and marked lassitude — and noted that the seeds were hard on the stomach. The ergot chemistry that underlies all of this is told on the wing’s Ergot and the Discovery of LSD page.

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9. The Hidden Fungus: Periglandula

The puzzle that troubled Hofmann’s critics — how fungal alkaloids came to be in a flowering plant — was finally answered in the twenty-first century, and the answer did involve a fungus, though not the seed contamination the 1960s critics had in mind. Working at the University of Bonn, Leistner, Steiner and colleagues found clavicipitaceous fungi — relatives of the ergot fungus — living on the upper surface of the leaves of Ipomoea asarifolia and Turbina corymbosa, closely associated with tiny secretory glands there.

In a 2008 study in Plant Physiology, Markert and colleagues reported that these fungi are passed on through the seed, and that they carry the gene for the key first step of ergot-alkaloid biosynthesis, dmaW, as part of a cluster of alkaloid genes. Neither the gene nor the ability to make the alkaloids could be detected in the host plants themselves; yet the plants held almost all of the alkaloids, while the fungi held almost none. The authors proposed that a transport system moves the alkaloids from fungus to plant, and that the partnership is a symbiosis in which the alkaloids play an essential role.

A new genus

In 2011, in the journal Mycologia, Steiner and colleagues used DNA sequences to place these fungi in a clade within the Clavicipitaceae and named a new genus, Periglandula — “around the gland” — with two species: Periglandula ipomoeae from Ipomoea asarifolia and Periglandula turbinae from Turbina corymbosa, the original ololiuhqui plant. A 2018 review by Steiner and Leistner in Planta Medica summarised the evidence that the ergot alkaloids of Central American morning glories, including Turbina corymbosa and Ipomoea violacea, come from Periglandula species on the leaf glands, that the alkaloids pass via the glands into the plant, and that both partners benefit.

So the rule Hofmann’s critics invoked held after all — ergot alkaloids are made by fungi — while Hofmann’s chemistry also held: the alkaloids really are in the seeds, placed there by an invisible partner that lives on the leaves and travels with the seed. The story of ergot, which began for Hofmann with a fungus on rye, ended with a fungus on a flowering vine.

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10. What Hofmann’s Natural-Product Method Showed

Hofmann called the sequence of his work a “magic circle”. It began with lysergic acid amides, including the natural ergot alkaloid ergobasine; this led to LSD; LSD’s effects brought the Mexican mushrooms to his laboratory; the mushroom work led to ololiuhqui; and in the seeds he found lysergic acid amides again, ergobasine among them. Each step depended on taking a traditional remedy or sacred plant seriously as a chemical problem.

Several lessons of method stand out in the record:

• Ethnobotany pointed the way. The Mazatec healers, the Spanish chroniclers, and the Wassons’ and Schultes’s fieldwork identified which plants mattered before any chemist touched them.
• Cultivation made chemistry possible. Heim’s laboratory-grown Psilocybe mexicana, improved by Brack and Kobel, gave a reliable supply.
• The assay has to match the effect. Animal tests could not detect the mushroom activity; the work moved forward only with a test that could, and that test carried acknowledged risks.
• A simple chemical hypothesis can be tested fast. The guess that ololiuhqui contained indoles was checked with one colour reaction.
• Surprising results need confirming. The finding of ergot alkaloids in a flowering plant was doubted, confirmed by other laboratories, and only fully explained half a century later by the discovery of Periglandula.

The compounds themselves had very different afterlives. Psilocybin and psilocin passed from 1960s psychiatric research into prohibition and then, in the 2010s, into controlled clinical trials whose results and limits are described on the Legacy and Later Research page. The other mushrooms on this site — culinary and medicinal species such as those in the Mushrooms section — are a separate subject; the site has no page on Psilocybe species. Hofmann’s wider life is told on the Life and Career page.

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Key Research Papers

1. 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
2. Heim R, Brack A, Kobel H, Hofmann A, Cailleux R. [Determinism of carpophore and slerote formation in culture of Psilocybe mexicana Heim, a hallucinogenic agaric of Mexico and demonstration of psilocybine and psicoline]. C R Hebd Seances Acad Sci. 1958;246(9):1346-1351. PubMed PMID: 13537389
3. 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
4. Hofmann A, Troxler F. [Identification of psilocin]. Experientia. 1959;15(3):101-102. PubMed PMID: 13652944
5. 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
6. Hofmann A, Cerletti A. [Active substances of the 3d Aztec magic drug or solution of the "Ololiuqui" puzzle]. Dtsch Med Wochenschr. 1961;86:885-888. PubMed PMID: 13715087
7. Stauffacher D, Tscherter H, Hofmann A. [Isolation of ergosine and ergosinine as well as agroclavine from seeds of Ipomoea argyrophylla Vatke (Convolvulaceae). 64. On ergot alkaloids (1)]. Helv Chim Acta. 1965;48(6):1379-1380. PubMed PMID: 5846759
8. Passie T, Seifert J, Schneider U, Emrich HM. The pharmacology of psilocybin. Addict Biol. 2002;7(4):357-364. PubMed PMID: 14578010
9. Nichols DE. Psychedelics. Pharmacol Rev. 2016;68(2):264-355. PubMed PMID: 26841800
10. Markert A, Steffan N, Ploss K, Hellwig S, Steiner U, Drewke C, Li SM, Boland W, Leistner E. Biosynthesis and accumulation of ergoline alkaloids in a mutualistic association between Ipomoea asarifolia (Convolvulaceae) and a clavicipitalean fungus. Plant Physiol. 2008;147(1):296-305. PubMed PMID: 18344419
11. Steiner U, Leibner S, Schardl CL, Leuchtmann A, Leistner E. Periglandula, a new fungal genus within the Clavicipitaceae and its association with Convolvulaceae. Mycologia. 2011;103(5):1133-1145. PubMed PMID: 21558502
12. Steiner U, Leistner E. Ergot Alkaloids and their Hallucinogenic Potential in Morning Glories. Planta Med. 2018;84(11):751-758. PubMed PMID: 29499587
13. Finney NS, Siegel JS. In Memoriam: Albert Hofmann (1906–2008). Chimia. 2008;62(5):444. DOI: 10.2533/chimia.2008.444

PubMed Topic Searches

1. Psilocybin and Psilocybe: history
2. Hofmann A and psilocybin
3. Ergot alkaloids in the Convolvulaceae
4. Periglandula fungi

Further Reading

• Albert Hofmann. LSD — mein Sorgenkind (1979); English translation by Jonathan Ott, LSD: My Problem Child (1980), chapter 6, “The Mexican Relatives of LSD”. Chapter 6 text
• Valentina Pavlovna Wasson and R. Gordon Wasson. Mushrooms, Russia and History, 2 volumes (1957).
• Richard Evans Schultes. “A Contribution to Our Knowledge of Rivea corymbosa, the Narcotic Ololiuqui of the Aztecs” (Harvard Botanical Museum, 1941).

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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: Legacy and Later Research
• Pharmacology
• Otto Loewi & Henry Dale
• Medicinal Mushrooms
• Brain, Energy and Tonic Mushrooms
• Serotonin, Mood & SSRIs
• Tryptophan
• Sage
• Depression

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