Ergot, LSD, and the Accidental Discovery That Changed Everything

The rye fields of medieval Europe were beautiful in autumn. Golden stalks heavy with grain, bending in the wind off the rivers, promising bread for the winter. But some years, if you looked closely, you would have noticed something wrong. Dark, purplish-black growths — hard, curved, like tiny horns — protruding from the grain heads where healthy kernels should have been.

The peasants had a word for them. The French called them ergots — “spurs” — because they looked like the spurs on a rooster’s foot. What they didn’t know, what nobody would understand for centuries, was that those dark protrusions were the fruiting bodies of Claviceps purpurea, a parasitic fungus that had quietly hijacked the rye plant’s reproductive system. And inside those dark horns was a chemistry set that would, over the next thousand years, drive tens of thousands of people insane, kill entire villages, possibly fuel the Salem witch trials, and — in one Swiss chemist’s laboratory on an ordinary afternoon in 1943 — accidentally produce the most potent psychoactive substance ever discovered.

This is the story of ergot. It is not a small story.

The Fungus That Ate History

Claviceps purpurea is, by any reasonable measure, one of the most consequential organisms in human history. A parasitic ascomycete fungus that infects cereal grains — particularly rye, but also wheat, barley, and oats — it replaces developing seeds with hard, dark structures called sclerotia. Each sclerotium is a pharmaceutical factory of staggering complexity.

Inside a single ergot body, you will find dozens of alkaloid compounds. Ergotamine, a vasoconstrictor so powerful it is still used today to treat migraines. Ergocristine, another vasoactive alkaloid. Ergonovine, used in modern obstetrics to control postpartum hemorrhage. And — most significantly for our story — lysergic acid amide (LSA), a psychoactive tryptamine and natural precursor to lysergic acid diethylamide.

You know it as LSD.

But we are getting ahead of ourselves by about nine hundred years.

St. Anthony’s Fire

The earliest clear references to mass ergot poisoning — what medieval Europeans called ignis sacer, “holy fire,” or later, St. Anthony’s Fire — appear in the annals of the Frankish kingdoms in the ninth and tenth centuries. The disease came in two forms, and both were horrifying.

The convulsive form produced violent seizures, muscle spasms that could break bones, crawling sensations on the skin (formication — the feeling of insects beneath the flesh), and vivid, terrifying hallucinations. Victims screamed that they were being eaten alive by invisible fire. They saw demons. They twisted and contorted in ways that, to medieval observers with no concept of alkaloid poisoning, looked exactly like demonic possession.

The gangrenous form was, if anything, worse. Ergotamine and its related compounds are potent vasoconstrictors. Chronic exposure, through eating contaminated bread over weeks or months, gradually cut off blood flow to the extremities. Fingers turned black. Toes fell off. Limbs withered and dropped away. The “fire” in St. Anthony’s Fire referred to the burning pain that preceded the necrosis — a sensation so agonizing that victims described it as being consumed by flames from the inside out.

The epidemic of 944 CE in the Aquitaine region of France remains the most catastrophic recorded outbreak. Contemporary chronicles, notably those associated with the monastery at Limoges, describe a wave of illness that killed an estimated 40,000 people across the region. The dead were not soldiers. They were not plague victims. They were ordinary people who had eaten their bread.

The connection between ergot and the disease was not understood for centuries. The Order of St. Anthony, founded in 1095, devoted itself to treating victims of the “holy fire” — hence the name. Their hospitals, scattered across Europe, became the primary treatment centers. One detail the monks noticed, though they could not explain it: patients who came to the monasteries and ate the monks' bread instead of their own often improved. The monks, of course, attributed this to divine intervention. The actual explanation was simpler and more bitter. The monasteries, wealthier than the surrounding peasantry, could afford wheat flour. Wheat is less susceptible to ergot than rye. The cure was not prayer. It was better bread.

Major outbreaks continued for centuries. France, 1039. Germany, 1089. Spain, 1581. Russia, 1722. As late as 1951, the town of Pont-Saint-Esprit in southern France experienced a mass poisoning that left hundreds ill and several dead — ergot contamination of the local bread supply remains the most widely accepted explanation.

Ergot did not just kill. It shaped institutions, influenced art — Hieronymus Bosch’s hallucinatory hellscapes may owe something to a culture steeped in ergotism’s visions — and changed agriculture, driving the gradual shift from rye to wheat. And it may have shaped something even larger.

The Salem Question

In 1976, a graduate student named Linnda Caporael published a paper in Science that detonated a quiet explosion across two academic fields at once. The paper, “Ergotism: The Satan Loosed in Salem?”, proposed that the bizarre symptoms exhibited by the “afflicted” girls in Salem, Massachusetts, in 1692 — the convulsions, the hallucinations, the sensation of being pinched and bitten by invisible agents, the screaming fits — were consistent with convulsive ergotism caused by ergot-contaminated rye.

The argument was not wild. It was methodical. Caporael noted that the initial accusers lived in the western portion of Salem Village, near the Wooleston River and its swampy, low-lying farmland — precisely the damp, warm conditions in which Claviceps purpurea thrives. Rye was a staple crop in the region. The “bewitchments” began in late winter 1691-1692, consistent with the consumption of grain harvested the previous autumn. The symptoms — convulsions, prickling and pinching sensations, visual and auditory hallucinations, temporary paralysis — mapped closely onto known presentations of convulsive ergotism. And when the accusations and fits eventually subsided, the timing coincided with a notably dry growing season that would have suppressed ergot development in the subsequent harvest.

The theory attracted immediate and fierce pushback. Historian Nicholas Spanos and psychologist Jack Gottlieb published a rebuttal in Science the same year, arguing that ergotism produces symptoms bilaterally (both sides of the body simultaneously), while the Salem afflictions were described as localized. They noted that ergotism typically affects entire households that share the same grain supply, but not all members of the accusers' households were afflicted. They also pointed out that gastrointestinal symptoms — vomiting, diarrhea — are prominent in ergot poisoning but largely absent from the Salem records.

Caporael countered some of these objections. The debate continued in academic journals for years and has never been fully resolved. The consensus today is that ergot contamination may have been a contributing factor — one variable among many in a situation that also involved social tensions, land disputes, adolescent psychology, Puritan theology, and the dynamics of mass hysteria. The ergot hypothesis does not explain everything about Salem. But it explains some things that nothing else does.

What is not in dispute is this: a parasitic fungus that grows on rye produces alkaloids capable of inducing hallucinations, convulsions, and altered states of consciousness. Whether those alkaloids were present in Salem in 1692 is debatable. That they were present in the grain supply of medieval Europe for centuries, affecting millions, is not.

The Kykeon and the Eleusinian Mysteries

There is one more chapter to write about ergot before we reach a laboratory in Basel.

For nearly two thousand years — from approximately 1500 BCE to 392 CE — the most prestigious religious ceremony in the ancient Greek world took place annually at Eleusis, a town thirteen miles northwest of Athens. The Eleusinian Mysteries were open to all Greek-speaking people who had not committed murder. Initiates — who included Plato, Aristotle, Sophocles, Cicero, Marcus Aurelius, and virtually every significant figure in the ancient world — underwent a multi-day ritual that climaxed with the drinking of a sacramental beverage called the kykeon.

What happened next was, by universal agreement, transformative. Cicero wrote that the Mysteries gave initiates “a reason not only to live with joy but also to die with better hope.” Plato’s philosophy — the allegory of the cave, the world of ideal forms, the journey from darkness into blinding light — bears structural similarities to the Eleusinian experience that scholars have noted for centuries. But nobody wrote down what was in the kykeon, because the penalty for revealing the secrets of the Mysteries was death.

In 1978, three scholars — R. Gordon Wasson (the ethnomycologist who had introduced psilocybin mushrooms to the Western world), Albert Hofmann (the chemist who had synthesized LSD), and Carl Ruck (a classicist at Boston University) — published The Road to Eleusis: Unveiling the Secret of the Mysteries. Their central argument: the kykeon contained ergot. Specifically, they proposed that the ancient Greeks had discovered a method of extracting the water-soluble psychoactive alkaloids from Claviceps purpurea growing on barley, while leaving behind the toxic vasoconstrictive compounds.

The theory remains debated. But the basic chemistry is sound. Ergot alkaloids vary in water solubility — the psychoactive compounds (lysergic acid amide and its relatives) dissolve more readily than the vasoconstrictors (ergotamine, ergocristine). A simple aqueous extraction could, in principle, produce a psychoactive beverage without the gangrenous horrors of ergotism. Whether the Eleusinian priests knew this is unknown. That the chemistry permits it is established.

If Wasson, Hofmann, and Ruck were right, then ergot did not merely cause suffering and madness. It also fueled the visionary experiences that shaped Western philosophy, the concept of the afterlife, and the very structure of Greek — and therefore Western — thought.

For the full story of the Eleusinian Mysteries, see our deep dive: The Eleusinian Mysteries: The Trip That Built Western Civilization.

Albert Hofmann’s Laboratory

Basel, Switzerland. 1938.

Albert Hofmann was thirty-two years old and working in the pharmaceutical research division of Sandoz Laboratories. His focus was natural product chemistry — specifically, the alkaloids of medicinal plants. He had been assigned to work with ergot, which Sandoz had been investigating since the 1910s for its pharmaceutical potential. Ergot alkaloids, properly isolated, had genuine medical applications: they could induce uterine contractions (useful in obstetrics), constrict blood vessels (useful for migraines), and stimulate circulation.

Hofmann was systematic. He was synthesizing derivatives of lysergic acid, the core molecular structure shared by all ergot alkaloids, looking for a compound that might serve as a circulatory and respiratory stimulant. He worked through the derivatives methodically. LSD-1. LSD-2. LSD-3. Twenty-four compounds, tested and set aside. Useful data, unremarkable results.

On November 16, 1938, Hofmann synthesized the twenty-fifth compound in the series: lysergic acid diethylamide, designated LSD-25. It was tested on animals at Sandoz. The pharmacologists noted some restlessness in the test subjects and a modest uterotonic effect, but nothing that justified further investigation. LSD-25 went into the files. Five years passed.

This is where the story becomes one of those moments that makes you wonder whether there is, somewhere in the machinery of things, a sense of dramatic timing.

On April 16, 1943, Hofmann returned to LSD-25. He would later describe a “peculiar presentiment — the feeling that this substance could possess properties other than those established in the first investigations.” It was an intuition. Nothing more. No new data prompted the decision. He simply felt, after five years, that the compound deserved a second look.

While re-synthesizing the substance that afternoon, Hofmann began to feel strange. Dizzy. Restless. Slightly intoxicated. He went home early and lay down. With his eyes closed, he experienced what he described as “an uninterrupted stream of fantastic pictures, extraordinary shapes with intense, kaleidoscopic play of colors.” The experience lasted about two hours.

He had absorbed a minute quantity of LSD-25 through his fingertips.

This was the first LSD experience in human history. It was an accident. And Hofmann, being a meticulous Swiss chemist, immediately recognized that the dose must have been extraordinarily small — the compound had passed through his skin in trace amounts. No known psychoactive substance was active in such tiny quantities. He needed to test this deliberately.

Bicycle Day

Three days later, on April 19, 1943, Hofmann made the first intentional ingestion of LSD in human history. He measured out what he considered a conservative dose: 250 micrograms — a quarter of a milligram, a barely visible speck of white crystalline powder dissolved in water.

We now know that 250 micrograms is a strong dose. A typical psychedelic dose ranges from 75 to 150 micrograms. Hofmann had given himself roughly two to three times what most people would take today. He did not know this. Nobody did.

At 4:20 PM, he noted in his laboratory journal: “Beginning dizziness, feeling of anxiety, visual distortions, symptoms of paralysis, desire to laugh.”

At 5:00 PM, the effects had intensified to the point where Hofmann could no longer continue working. He asked his laboratory assistant, Susi Ramstein, to escort him home. Wartime restrictions meant no automobile was available. They rode bicycles.

That bicycle ride — April 19, 1943, through the streets of Basel — has become one of the most celebrated moments in the history of psychopharmacology, commemorated annually as Bicycle Day. The ride was not pleasant. Hofmann’s account in his book LSD: My Problem Child describes a journey through increasingly alien territory:

“Everything in my field of vision wavered and was distorted as if seen in a curved mirror. I also had the sensation of being unable to move from the spot. Nevertheless, my assistant later told me that we had traveled very rapidly.”

At home, the experience deepened into genuine terror. His neighbor, a woman he knew well, brought him a glass of milk. She appeared to Hofmann as “a malevolent, insidious witch with a colored mask.” The room around him seemed to dissolve and re-form. His body felt possessed by a demon. He was convinced he was dying, or going permanently insane.

He asked his assistant to call a doctor. The doctor arrived, examined Hofmann, and found nothing physically wrong — pulse slightly elevated, pupils dilated, but vital signs stable. There was nothing to treat. Hofmann was left to ride it out.

And then, gradually, the terror began to lift. The threatening shapes softened. The kaleidoscopic colors, which had been sinister, became beautiful.

“Kaleidoscopic, fantastic images surged in on me, alternating, variegated, opening and then closing themselves in circles and spirals, exploding in colored fountains, rearranging and hybridizing themselves in constant flux.”

By the next morning, Hofmann felt not only recovered but renewed. The world seemed freshly made. Colors were more vivid. The garden was breathtaking. He had been to the far end of consciousness and come back with a molecule that would reshape the twentieth century.

He spent the next several decades reckoning with what he had found. He called LSD his “problem child” — a discovery of immense promise that the world proved unable to handle responsibly. It was a phrase freighted with a parent’s love and a parent’s grief.

The Golden Age

What followed Hofmann’s discovery was, for approximately two decades, the most productive period of psychedelic research in history.

Sandoz Laboratories began distributing LSD to researchers and clinicians worldwide under the brand name Delysid, accompanied by a remarkable product insert that recommended the drug for two uses: as an aid to psychotherapy (allowing patients to access repressed memories and emotions) and as a tool for psychiatrists to experience altered states firsthand, in order to better understand their patients.

Between the late 1940s and the mid-1960s, researchers published over 1,000 peer-reviewed papers on LSD. More than 40,000 patients received the drug in clinical settings. It was studied as a treatment for alcoholism, depression, anxiety in terminal cancer patients, cluster headaches, and various neuroses. Some of this research produced results that, even by modern standards, were remarkable.

Cary Grant, one of the biggest movie stars in the world, underwent more than 100 LSD-assisted therapy sessions in the late 1950s and early 1960s under the supervision of psychiatrists Mortimer Hartman and Arthur Chandler at the Psychiatric Institute of Beverly Hills. Grant spoke about it openly, telling Good Housekeeping magazine in 1959: “I have been born again. I have been through a psychiatric experience which has completely changed me.” He credited LSD therapy with resolving childhood trauma, saving his third marriage, and giving him an emotional depth he had never previously accessed. The reserved, guarded persona that defined his screen presence was, he claimed, the person LSD helped him stop being.

Bill Wilson, co-founder of Alcoholics Anonymous, experimented with LSD in the late 1950s under the supervision of psychiatrist Sidney Cohen and with the encouragement of Aldous Huxley. Wilson believed that LSD could induce the “spiritual awakening” that AA’s Twelve Steps aimed to produce — the transformative moment of ego surrender that Wilson considered essential to recovery. He reported that his own LSD experience was one of the most significant spiritual experiences of his life, second only to the spontaneous vision that had led him to sobriety in 1934. Wilson advocated for LSD’s inclusion in the treatment of alcoholism. The AA board, understandably concerned about public perception, asked him to stop. He did, reluctantly.

But there was a darker chapter, and it must be told.

MKUltra: The Betrayal

Beginning in 1953 and continuing for at least a decade, the Central Intelligence Agency ran a covert program designated MKUltra — a series of experiments designed to investigate whether LSD and other substances could be used for mind control, interrogation, and psychological warfare. Under the direction of chemist Sidney Gottlieb, the program administered LSD to subjects who had not consented and, in many cases, did not know what was happening to them.

Military personnel were dosed at secret facilities. Psychiatric patients at hospitals were given LSD without their knowledge. The CIA funded research at universities and hospitals through front organizations. In at least one documented case — that of Frank Olson, a biological warfare researcher — the administration of LSD to an unwitting subject may have contributed to his death.

MKUltra was the precise opposite of therapeutic psychedelic use. It weaponized the vulnerability of the psychedelic state. It violated every principle of set, setting, and consent that researchers like Hofmann and therapists like Stanislav Grof were establishing as essential to safe and productive use. When the program was partially revealed in 1975 during the Church Committee hearings, and more fully exposed in 1977, it confirmed the worst fears of those who had argued that psychedelics were too dangerous to be allowed.

The irony was savage. The CIA’s abuse of LSD became one of the primary justifications for banning the very substance they had abused. The victims of MKUltra were used, retroactively, as evidence that victims of LSD were inevitable.

Turn On, Tune In, Drop Out

By the early 1960s, LSD had escaped the laboratory.

Timothy Leary was a respected clinical psychologist at Harvard when he first encountered psilocybin mushrooms in Cuernavaca, Mexico, in 1960. He returned transformed and, with colleague Richard Alpert (later Ram Dass), launched the Harvard Psilocybin Project. The experiments were genuinely interesting: the Concord Prison Experiment (1961-1963) tested psilocybin-assisted therapy for reducing recidivism. The Good Friday Experiment (1962), conducted by Walter Pahnke under Leary’s supervision, gave psilocybin to divinity students in a chapel to test whether the substance could occasion genuine mystical experience. Nearly all of the psilocybin group reported that it did — a finding confirmed in Rick Doblin’s 25-year follow-up study in 1991.

But the experiments were not the problem. The problem was that Leary became a prophet.

He began giving LSD to students, artists, and anyone who was interested. The protocols dissolved. The science gave way to evangelism. In 1963, Harvard fired Leary and Alpert. Leary, unshackled from institutional constraints, doubled down. He became the public face of LSD, coining the phrase that would haunt psychedelic research for half a century: “Turn on, tune in, drop out.”

The phrase was a disaster. Whatever Leary meant by it — and his explanations varied over the years — what the public heard was: take LSD and abandon society. The counterculture embraced it. Conservative America recoiled. LSD became inseparable from anti-war protests, the Summer of Love, campus radicalism, long hair, and everything that Richard Nixon’s “silent majority” feared and despised.

Nixon, who understood the politics of cultural warfare better than almost anyone, called Leary “the most dangerous man in America.” The characterization was absurd in one sense — Leary was a showman, not a revolutionary — and devastatingly effective in another. It tied LSD to everything the establishment wanted to destroy.

The legislative response was swift and comprehensive. The Controlled Substances Act of 1970 placed LSD in Schedule I — the most restrictive category, reserved for substances deemed to have “no currently accepted medical use” and “a high potential for abuse.” This classification was not based on a review of the existing clinical literature. If it had been, the over 1,000 published papers and 40,000 treated patients would have complicated the narrative considerably.

Psilocybin was placed in Schedule I alongside LSD. So was mescaline. So was DMT. The scheduling was not pharmacological triage. It was a political act, sweeping an entire class of compounds into a regulatory category that made further research virtually impossible.

The vault door slammed shut. It would stay closed for decades.

The Fifty-Year Blackout

What followed was not an absence of interest. It was an absence of permission.

Between approximately 1970 and the late 1990s, virtually no clinical research on psychedelic substances was conducted in the United States. The few researchers who maintained interest — people like Alexander Shulgin, who synthesized and tested hundreds of psychedelic compounds, documenting his work in the legendary books PiHKAL and TiHKAL — operated at the margins, tolerated but unfunded.

The human cost of this blackout is difficult to calculate. For fifty years, a class of compounds that had shown genuine promise for treating alcoholism, depression, end-of-life anxiety, PTSD, and cluster headaches was locked away. The research that had been conducted in the 1950s and 1960s — much of it methodologically primitive by modern standards but clearly pointing somewhere important — was not refined, replicated, or extended. It was abandoned.

The compounds did not disappear, of course. LSD and psilocybin remained widely available on the black market. People continued to use them — some carelessly, some carefully. Nobody was collecting data either way.

Suppressing research does not make molecules go away. It just means we learn slower.

The Renaissance

The thaw began quietly.

In 1986, Rick Doblin — then a twenty-three-year-old who had decided to pursue a PhD at Harvard’s Kennedy School specifically to learn how to navigate the regulatory system — founded the Multidisciplinary Association for Psychedelic Studies (MAPS). The organization’s mission was straightforward: develop psychedelic substances into FDA-approved medicines by following the same rigorous clinical trial process as any pharmaceutical company. No counterculture. No evangelism. Just data.

In 2000, Roland Griffiths at Johns Hopkins University received approval to conduct the first rigorously controlled study of psilocybin in healthy volunteers in over three decades. The results, published in Psychopharmacology in 2006, were remarkable: 67% of participants rated their psilocybin experience among the five most meaningful events of their entire lives. Thirty percent called it the single most meaningful experience. These numbers held at 14-month follow-up. The study didn’t prove psilocybin was medicine, but it proved that the experiences it produced were real, measurable, and enduring.

At Imperial College London, neuroscientist Robin Carhart-Harris began using fMRI brain imaging to study what psilocybin actually does to the brain. His research introduced the concept of the default mode network — the brain’s autopilot system, responsible for self-referential thinking, rumination, and the persistent narrative of “I” — and showed that psilocybin temporarily disrupts it. This disruption, Carhart-Harris argued, is not a breakdown. It is a reset. The rigid patterns of thought that characterize depression, addiction, and PTSD are loosened. New connections form. The brain, briefly freed from its own habits, has a chance to reorganize.

The dam broke. NYU published data on psilocybin for end-of-life anxiety. MAPS advanced MDMA-assisted therapy for PTSD through Phase 3 clinical trials. The FDA granted “breakthrough therapy” designation to psilocybin for treatment-resistant depression — a designation reserved for therapies that show substantial improvement over existing treatments. Australia became the first country to officially approve psilocybin and MDMA as medicines in 2023.

We are living in the second wave. We are trying, with better tools and harder-won humility, to recover what the first wave lost.

The Thread

Stand back far enough and a single thread runs through this entire story.

A fungus grows on grain. Its alkaloids — lysergic acid and its derivatives — are among the most pharmacologically active compounds in nature. For centuries, those alkaloids manifested as plague: burning flesh, gangrenous limbs, convulsions, madness. Tens of thousands died. Nobody understood why.

In ancient Greece, someone may have figured out how to separate the poison from the vision. For two thousand years at Eleusis, initiates drank the kykeon and returned forever changed. Plato went. Aristotle went. The experience shaped Western philosophy at its foundations.

In 1938, a Swiss chemist synthesized one particular arrangement of that lysergic acid molecule. In 1943, he touched it. In the decades that followed, the compound was studied, celebrated, weaponized, evangelized, demonized, and prohibited. The research stopped. The questions didn’t.

And now, in the opening decades of the twenty-first century, we are picking up the thread again. Different compounds — psilocybin more than LSD, this time around — but the same fundamental questions. Can these molecules heal? Can they transform? What happens when we stop being afraid of what consciousness is capable of becoming?

The fungus has been waiting. It has always been waiting. It grew on the grain before we invented agriculture. It will grow on the grain long after we are gone.

What we do with its gifts, and how wisely we handle its dangers, is entirely up to us.

For the deep history of the ceremony that may have used ergot’s alkaloids for two thousand years, see The Eleusinian Mysteries: The Trip That Built Western Civilization. For the science of psilocybin — ergot’s tryptamine cousin — see our Complete Guide to Psilocybin.