Ergot

• 1. Introduction

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  Around 600 BC, an Assyrian tablet recorded a warning about a 'noxious pustule in the ear of grain.' The pustule belongs to ergot, a group of fungi in the genus Claviceps. Its best-known member, Claviceps purpurea, is called the rye ergot fungus. Over the centuries ergot appears in the record as a crop parasite, a poison, a medicine and a suspect in several historical puzzles. How does a fungus manage to pass itself off as part of a grain crop? Why did a medieval order of monks build hospitals for its victims? And how did one organism end up behind both a dreaded disease and a family of modern drugs?

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• 2. A Seed Impostor

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  Rye, known to botanists as Secale cereale, is the host most often chosen by Claviceps purpurea, and the reason lies in its flowers. The fungal spore must reach the stigma, so the fungus mostly infects open-flowered, outcrossing grasses such as rye and the ryegrasses of the genus Lolium. Triticale, wheat and barley can also be infected, while oats are only rarely hit.

  Once on the stigma, the spore imitates a pollen grain growing down into an ovary during fertilization. The fungal threads, called mycelium, then destroy the ovary and tap into the vascular bundle that was meant to feed a seed. The first visible stage is a soft white tissue called sphacelia, which oozes a sugary honeydew. That honeydew drips from the florets and holds millions of asexual spores called conidia, which insects carry to other florets. Later the sphacelia harden into a dry sclerotium inside the husk, and alkaloids and lipids build up within it.

  About 50 species of Claviceps are known, mostly in the tropics. C. fusiformis grows on pearl millet and buffel grass, C. paspali on dallis grass, C. africana on sorghum and C. lutea on paspalum. Even C. purpurea has at least three races. G1 lives on grasses of open meadows and fields, and G2 on grasses of moist forest and mountain habitats. G3, named var. spartinae, lives on salt marsh grasses such as Spartina and Distichlis.

  The black, protruding sclerotium of C. purpurea is the famous face of the disease. Many tropical ergots instead form brown or greyish sclerotia shaped like the host's own seed, so the infection is often overlooked. Tropical and subtropical species also make a second kind of spore in their honeydew, which forms a white, frost-like surface and spreads on the wind. Four northern temperate species skip this step: C. purpurea, C. grohii, C. nigricans and C. zizaniae.

  When a mature sclerotium falls to the ground, it waits for the onset of spring or a spell of rain. It then sprouts one or several fruiting bodies with heads and stalks, resembling tiny mushrooms. Threadlike sexual spores in the heads are shot out together just as suitable grasses come into flower. Flies and moths also carry conidia, though nobody knows whether they spread the fungus from sick plants to healthy ones.

  An amber fossil discovered in 2020 holds a grass spikelet together with an ergot-like parasitic fungus. It suggests that the earliest hosts of the family Clavicipitaceae could have been grasses, and it sets a minimum age for psychotropic compounds in fungi. Over time, evolution diversified the alkaloids these fungi make, and an enzyme nicknamed the old yellow enzyme, EasA, shows how. Its variants differ in whether they reoxidize a particular chemical bond after rotation. That difference separates most Clavicipitaceae from the family Trichocomaceae. It also divides the classical ergot alkaloids from the dihydroergot alkaloids, which drug makers often prefer because they have relatively few side effects.

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• 3. Two Kinds of Poison

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  Up to 2 percent of an ergot sclerotium's dry mass can be ergotamine, an alkaloid built around a lysergic acid unit. Alongside it sit other ergoline alkaloids that the fungus makes itself. Together they act on both circulation and neurotransmission, and that double reach shows up in the two forms of the illness they cause.

  Ergotism comes in two forms, and the first is convulsive. Victims suffer muscle spasms, fever and hallucinations. They may seem dazed, lose the ability to speak, turn manic or develop tremors and paralysis. Certain alkaloids overstimulate serotonin signaling in the central nervous system, and that is the cause.

  In the second form, fingers and toes burn violently, their pulses vanish and shooting pain follows. The alkaloids are narrowing the blood vessels. Severely restricted circulation can lead to gangrene and the loss of limbs.

  Among the other effects are strong uterine contractions, nausea, seizures, high fever, vomiting, loss of muscle strength, unconsciousness and sometimes death. In naturally occurring ergotism from infected rye, both gangrenous and convulsive symptoms appear. Only the gangrenous kind has been reported after excessive ergotamine tartrate. Today, clinical ergotism comes almost entirely from too much ergotamine tartrate taken for migraine.

  Animals suffer too. A livestock overview by Klotz ties the toxicity to ergot alkaloids blocking or mimicking dopamine, serotonin and norepinephrine. Potent, long-lasting vasoconstriction can bring intense burning pain, swelling, bluish skin, dry gangrene and even the loss of hooves in cattle. Dopamine receptors in the pituitary also respond, lowering the hormone prolactin. Low prolactin is tied to reproductive trouble in cattle and especially in horses. Mares can fail to produce milk or conceive, lose foals late in pregnancy, and sometimes die from difficult births with thickened placentas.

  Claviceps paspali adds its own toxins, called tremorgens, which cause 'paspalum staggers' in cattle. Fungi of the genera Penicillium and Aspergillus also make ergot alkaloids, including some isolates of the human pathogen Aspergillus fumigatus. Such fungi have been isolated from plants in the family Convolvulaceae, of which morning glory is the best known.

  Ergot does not contain LSD. It holds lysergic acid and ergotamine, and lysergic acid is a precursor for synthesizing LSD. Hopes of medical use drove intensive research from the 1950s onward. That work produced legal drugs such as bromocriptine and illegal ones such as LSD, along with deep knowledge of the enzymes and genes behind ergot alkaloid production.

  On the 4th of January 2007, the New England Journal of Medicine published a British study of more than 11,000 Parkinson's disease patients. It found that two ergot-derived drugs, pergolide and cabergoline, may raise the risk of leaky heart valves by up to 700 percent.

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• 4. Saint Anthony's Fire

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  The Hospital Brothers of St. Anthony, an order of monks established in 1095, made a specialty of treating ergotism victims. Their name gave the disease its common label, St. Anthony's fire, which also points to the severe burning in the limbs. Anthony himself was a 3rd century Egyptian ascetic who lived by the Red Sea. He was known for long fasts during which he faced terrible visions and temptations sent by the Devil. Two noblemen credited him with helping them recover from the disease, and they founded the order in his honor.

  A large blue T sewn on the monks' shoulders marked the order. It stood for the crutch used by the ill and injured, and it was Anthony's symbol. The Antonites grew quickly, and their hospitals spread through France, Germany and Scandinavia. Grateful patrons gave money and goods, and the hospitals gained wealth and power. By the end of the Middle Ages the order owned 396 settlements and 372 hospitals. Pilgrims traveled to them, and people donated limbs lost to ergotism, which were displayed near shrines to the saint.

  Food was the heart of the cure. Patients were served ergot-free meals, and keeping rye bread and other ergot-containing food away from them stopped the disease from advancing. They also received wines with vasodilating and pain-relieving herbs, and the monks applied Antonites-balsam, described as the first transdermal therapeutic system in medical history. There was no known cure for ergotism itself, only treatment of symptoms. These centers are described as the first specialized medical welfare systems in Europe.

  After 1130, monks were no longer permitted to perform operations, so barber surgeons were hired to remove gangrenous limbs and treat open sores. In 1214, three barbers founded a hospital in Memmingen for the gangrenous form. Patients were fed and housed, and the stronger ones worked as orderlies and assistants. Those with convulsive ergotism, ergotismus convulsivus, were welcomed for only nine days before being asked to leave, since their condition was seen as less damaging. Despite irreversible effects, most returned to their families and livelihoods.

  The Antonites declined once physicians discovered where ergotism came from and advised removing the sclerotia from rye crops. In 1776, their cloisters were absorbed into the Maltese Knights Hospitaller. Much of their medical history was lost in the process, and the cures and recipes faded from lack of use and preservation.

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• 5. Bread and Plague

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  Ergotism is the earliest recorded example of mycotoxicosis, poisoning caused by toxic molds. Germany in 857 supplies the first mention of a plague of gangrenous ergotism in Europe. France and Scandinavia later suffered similar outbreaks. England stands out as absent, because its main food was wheat, which resists ergot. In 994, a massive outbreak possibly caused by ergotism killed 40,000 people across Aquitaine, Limousin, Périgord and Angoumois in France.

  Radulf Glaber wrote of 'hidden fire,' ignus ocultus, in which burning in a limb is followed by its separation from the body, often consuming the victim in one night. Ancient Syria called ergot the 'Daughter of Blood.' In 350 BC, the Parsees blamed noxious grasses for pregnant women dying in childbed.

  Bread was the delivery system. Ergot withstands heat and water, so it was baked straight into loaves made from rye flour. Medieval Europeans rarely ate other grasses. Victims did not know the cause and kept eating tainted food for weeks, while the trunk of the body stayed largely untouched until the final stages. Peasants and children were thought to suffer most, though the wealthy were struck as well. Sometimes entire villages depended on tainted crops, and in famine ergotism reached every house. The effects varied with the dose and mix of ergot compounds and with a person's age and nutrition.

  In Hesse in 1596, Wendelin Thelius became one of the first to blame the grain. In 1778, S. Tessier watched a huge epidemic in Sologne, France, that killed more than 8,000 people. He recommended draining fields, compulsory cleaning of grain, and substituting potatoes for the affected grain.

  In 1722, Tsar Peter the Great's campaign against the Ottoman Empire stalled when his army, marching down the Terek steppe, was struck by ergotism. The troops had to retreat to find edible grain. A diary entry of the time says that soon after eating the poisoned bread, people grew dizzy with such strong nerve contractions that survivors of the first day found their hands and feet falling off, like frostbite. That outbreak went by the Latin name ignis sacer.

  Some historical events, such as the Great Fear in France at the start of the French Revolution, have been linked to ergot poisoning. In 1588, Johannes Thallius recorded ergot's German name, rockenmutter, or 'Mother of Rye,' and noted that it was used to halt bleeding.

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• 6. Midwives and Medicine

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  A Nuremberg manuscript of 1474 prescribed powdered ergot, mixed with laurel fruits and the rhizomes of Solomon's seal, for pain in the lower abdomen blamed on an 'uprising of the womb.' Midwives and a few doctors across Europe used ergot extracts for centuries. In a printed book of 1582, the German physician Adam Lonicer wrote that midwives gave three sclerotia several times a day for womb pain. Joachim Camerarius the Younger wrote in 1586 that a sclerotium held under the tongue would stop bleeding.

  In 1774, the French pharmacist Antoine-Augustin Parmentier edited a letter from Madame Dupile, a midwife of Chaumont-en-Vexin, to show that ergot was harmless. She wrote that when contractions were too weak during the expulsion stage, she and her mother gave a thimbleful of peeled ergot dispersed in water, wine or broth. A mild birth followed within 15 minutes. The French physician Jean-Baptiste Desgranges met midwives in Lyon in 1777 who treated weak contractions with ergot powder. From 1777 to 1804 he used it to ease childbirth for more than twenty women and never saw a side effect.

  In 1807, Dr. John Stearns of Saratoga County, New York, wrote to a friend that he had used a powder he called pulvis parturiens for several years with complete success in cases of 'lingering parturitation.' It was ergot, which he called a 'spurious groth of rye.' He boiled half a drachm, about 2 grams, in half a pint of water and gave a third every twenty minutes. In 1813, Dr. Oliver Prescott of Newburyport, Massachusetts, published a dissertation drawn from five years of using ergot when the second stage of labor stalled. The 1836 Dispensatory of the United States advised fifteen or twenty grains of powder every twenty minutes. In 1837, the French Codex required every pharmacy to keep ergot in stock.

  The danger was that, until anesthesia became available, nothing could reverse ergot's effects. If the fetus did not move as expected, the uterus could mold itself around the child and rupture, killing the child. David Hosack, an American physician, noted the many stillbirths and said the powder should be called pulvis ad mortem, a name that points to death, instead of pulvis ad partum. He began to advocate its use for stopping bleeding after birth. Doctors eventually restricted ergot to expelling the placenta or stopping hemorrhage.

  In 1926, the Swiss psychiatrist Hans Maier suggested ergotamine for migraine-type vascular headaches. Pharmaceutical products followed. Cafergot combines caffeine with ergotamine or ergoline to treat migraine, and ergometrine induces uterine contractions and controls bleeding after childbirth. A 2018 Cochrane Systematic Review concluded that oxytocin, syntometrine and prostaglandins may be preferred over ergot alkaloids. Evidence for injected ergot alkaloids is low, and oral forms are not well studied.

  In the 1930s, companies marketed pills such as Molex and Cote to women who were 'delayed,' since selling abortifacients was illegal. The recommended dose was seven grains of ergotin a day. The United States Federal Trade Commission found they contained ergotin, aloes, Black Hellebore and other substances, deemed them unsafe and ineffective, and demanded the sales stop. More than a thousand compounds have since been derived from ergot ingredients.

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• 7. Speculative Suspects

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  The Eleusinian Mysteries of ancient Greece centered on a beverage called Kykeon. It has been posited that Kykeon drew on hallucinogens from ergotamine, a relative of LSD's precursors, and ergonovine.

  The 23rd of July 1881 edition of Scientific American ran an article titled 'A New Exhilarating Substance.' It described cases of euphoria after people took tincture of ergot of rye, especially when mixed with phosphate of soda and sweetened water. In rainy years, rye bread was thought to contain more than 5 percent ergot.

  The British author John Grigsby contends that ergot in the stomachs of some bog bodies, Iron Age remains from the peat bogs of northeast Europe such as the Tollund Man, points to ritual drinks in a prehistoric fertility cult. He compares it to the Greek Eleusinian Mysteries. In his 2005 book Beowulf and Grendel, he argues that the Anglo-Saxon poem Beowulf remembers followers of Odin quelling this cult. He reads the hero's name as 'barley-wolf' and notes that ergot was known in German as the 'tooth of the wolf.'

  In 1976, Linnda R. Caporael posited that the hysterical symptoms of the young women behind the Salem witch trials came from eating ergot-tainted rye. Nicholas P. Spanos and Jack Gottlieb reviewed the historical and medical evidence and later disputed her conclusions. Other authors have also cast doubt on ergotism as the cause.

  The theory has reached television. In the Bones episode 'The Witch in the Wardrobe,' Season 5, Episode 20, ergot is blamed for the death of a witch named Zephrya. The coven's ritual rye flour was infected, and the hallucinations it caused made them fear her, leading to her murder.

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• 8. Modern Fields

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  In 1998, Germany lost almost its entire rye crop to ergot, and in 2005 ergot turned up widely in barley across the US Midwest. Contamination is expensive even in ordinary years. Average contamination in Germany from 1995 to 2004 stayed fairly steady at 0.11 percent by weight. Cleaning contaminated grain is estimated to cost 2 euros per decitonne. The European Union allows no more than 0.05 percent ergot in grain for human consumption, and selling grain above that brings fines and fees. The United States and Canada hold similar standards. Farmers reduce the risk by changing crop rotations and ploughing more deeply.

  C. purpurea has long been linked to extremely cold winters followed by rainy summers. Livestock face the problem on pasture and in feed grain. Cows, sheep and horses are the main victims. In the United States, cow losses from tall fescue toxicosis were first seen in the 1930s, and in 1990 the economic loss was estimated at more than $600 million. Affected animals gain less weight, lose fat tissue, give less milk and breed less well. A condition called fescue foot, mostly seen in winter, brings dry gangrene.

  A famine from 1903 to 1906 in northern Cameroon is blamed on Claviceps africana, the sorghum ergot. It also occurs in eastern and southern Africa, especially Zimbabwe and South Africa. The disease became a problem in sorghum and pearl millet when growers adopted hybrid technology, which made the crops more susceptible. The fungus only infects unfertilized ovaries, so self-pollination and fertilization reduce it. Male-sterile lines, called A-lines, are extremely vulnerable, as first recognized in the 1960s, and seed yield losses have been massive. Infection is associated with night temperatures below 12 degrees Celsius two to three weeks before flowering. Its honeydew attracts flies, beetles and wasps, which help carry the fungus to healthy plants.

  Once restricted to Africa and Asia, where it was first recorded more than 90 years earlier, C. africana spread rapidly. By the mid-1990s it had reached Brazil, South Africa and Australia. By 1997 it had reached most South American countries and the Caribbean, including Mexico, and had arrived in Texas.

  Partners in the CABI-led programme Plantwise, including Zambia's Ministry of Agriculture and Livestock, recommend planting tolerant varieties. They also advise disking fields after harvest to stop sorghum ratoon and volunteer plants from growing, removing infected plants, and rotating with legumes over three years.

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