A fungus that changed roles over the centuries
Few stories illustrate the idea that poison and medicine are two sides of the same coin as well as the story of ergot. Claviceps purpurea parasitizes rye and other grains, forming those dark, hardened kernels that for centuries went almost unnoticed in the stalks. From that same organism came both the plagues that mutilated and killed entire populations and a modern pharmacopeia—and, ultimately, the most potent entheogen we know.
This final installment of the series dedicated to Hofmann picks up that narrative from the end: how we moved from the anonymous horror of ergotism to the controlled chemical work that closed the circle in the Sandoz laboratories.
Ergotism: The epidemic no one could name
We have already discussed the great waves of ergotism in medieval Europe in previous installments. It is worth placing them in context. After the relative prosperity of the 12th and 13th centuries, the 14th brought the bubonic plague, which wiped out about a third of the European population, with demographic recovery not arriving until the end of the 15th century.
Against this backdrop, some historians—Mary Matossian among them—have suggested that poor harvests and a succession of cold, wet years pushed many people to rely on rye, a cereal more resistant than wheat but also more prone to ergot contamination. The hypothesis holds that the consumption of parasitized bread added a trickle of deaths, infertility, and miscarriages to the plague’s mortality, prolonging the demographic decline beyond what a single infectious disease would explain. It is a suggestive thesis, but it should be taken as a historiographical hypothesis, not a settled fact.
The great obstacle to stopping the malady was that its cause was unknown. The pharmacological scholarship of antiquity had been lost, and it occurred to no one that those black grains harbored a toxic fungus. Contaminated cereal bread, which looked worse, was sold more cheaply; hence, it was the working classes who suffered most.
The Modern Age: The gaze of a keen-eyed physician
Matossian has also linked ergot poisoning to some episodes attributed to witchcraft in the 16th and 17th centuries. It is a broad and debated field, and here it suffices to note it as a hypothesis not all historians share.
More solid, for our purposes, is the figure of Thuillier, a 17th-century French physician who treated ergotism patients. Applying a mindset already close to the physical sciences, he observed that the malady was more prevalent in the countryside than in the city, that it affected the poor more than the rich, and that it was not contagious. The decisive difference was in the diet, specifically rye bread. Upon inspecting the fields, he noticed the dark stalks and confirmed that in colder, wetter years—with more black grains—the epidemics were worse. He also knew that these grains had been used in obstetrics and that, according to Paracelsus’s principle, “dosis sola facit venenum” (the dose makes the poison), a remedy can become a poison through excess. The conclusion was logical. In 1670, he sent his observations to the Academy of Paris, but the peasants still did not believe rye had anything to do with it.
It was not until 1853 that Louis Tulasne experimentally confirmed what had been intuited nearly two centuries earlier: the problem was not the cereal, but the parasitic fungus Claviceps purpurea. Only then did authorities mandate the discarding of contaminated grain. This was joined by better cultivation methods and the spread of the potato—which arrived from the Americas in the 16th century—which eased the dependence on cereals as the sole source of energy. Epidemics became rarer and less severe, though they did not disappear entirely.
The century of alkaloids
The 19th century opened the era of alkaloids: chemistry began extracting active principles from plants to create more potent and measurable pharmaceuticals. Ergot entered this program fully. Its use by midwives to induce labor was ancient—recorded as early as 1582 in the herbal of German physician Adam Lonitzer—and in 1808, American physician John Stearns described it as a uterine contractor.
The key to its action lies in the structural similarity of its alkaloids to serotonin, norepinephrine, and dopamine. This resemblance to neurotransmitters explains why they act on adrenergic, dopaminergic, and serotonergic receptors, hence their range of effects. The chemical history began in 1906, when Barger and Carr isolated ergotoxine, initially thought to be a pure substance and later revealed to be a mixture of four alkaloids. In 1918, Arthur Stoll—in whose team Hofmann would work at Sandoz—isolated ergotamine; in 1935, Dudley and Moir independently obtained ergometrine.
1938: When LSD appeared (and almost no one noticed)
In 1938, Hofmann and Stoll synthesized lysergic acid diethylamide. They found no interesting application for it at the time, and it was archived. Only years later, thanks to Hofmann’s persistence and an accidental poisoning while handling it, was it discovered what he had in his hands. Almost everything has been written about LSD; here it suffices to highlight two features. First, its potency: it acts in the microgram range (one thousand micrograms equals one milligram), a scale that separates it from almost any other psychoactive substance. Second, the expectations Hofmann himself placed in it as a tool for self-knowledge, psychotherapy, and the integration of the individual into nature, and the subsequent disappointment of seeing how the uncontrolled use of the 1960s and the prohibitionist response of governments closed that door for decades.
A less famous but more profitable pharmacopeia
LSD overshadows the rest, but ergot yielded drugs for daily use. Hofmann synthesized dihydroergotamine, used for hypertension and migraines; methylergometrine, a uterine hemostatic; and methysergide, a serotonin antagonist used to prevent migraines. However, the greatest commercial success was dihydroergotoxine—known as Hydergine®—derived from the four alkaloids of ergotoxine. Due to its cerebral vasodilator effects, it became popular as a “smart drug” for age-related cognitive decline, credited with improvements in cerebral oxygenation and intellectual performance. According to Jonathan Ott, for years it was Sandoz’s most profitable product and one of the ten best-selling drugs in the world. It should be noted that many of those indications were formulated with less stringent efficacy criteria than today’s, and several would be viewed with more caution now.
The moral Hofmann liked to draw still stands: poisons are also medicines, and medicines can be poisons; it all depends on knowing how to use them. He summarized it this way: “Ergot has a fascinating history. Over the years, its role and importance have undergone a metamorphosis. What was once a deadly toxin has become a great source of useful drugs.” And, we might add, also of the most famous entheogen of all.
Critical reading and harm reduction
It is best to read this history without idealizing it. Ergotism is not a quaint curiosity: it was a serious poisoning, involving gangrene, convulsions, and death, linked to poverty and ignorance. And ergot alkaloids remain substances with a narrow margin between effect and harm.
Regarding the claims in this narrative, two cautions. Matossian’s thesis linking ergotism to witchcraft or major demographic shifts is attractive but debated among historians, and should not be read as a firm conclusion. And the enthusiasm of the 1960s for Hydergine® as a “cognitive enhancer” reflects the evaluation standards of its time rather than robust evidence.
Regarding LSD and other ergot derivatives: this text is historical education, not a user guide. It does not include—nor should one look for—information on synthesis, procurement, dosage, or consumption. Any substance with activity on serotonin receptors can interact dangerously with other drugs and pre-existing health conditions; the prudent course, in case of any medical doubt, is to consult with healthcare professionals and not rely on anonymous information.
The sources supporting this series are reference works accessible by name: LSD: My Problem Child, by Albert Hofmann himself; Poisons of the Past, by Mary Kilbourne Matossian; and Pharmacotheon, by Jonathan Ott, among the classic historical works on ergot.
