From Poisoning to Pharmacy: A Tale of Two Ergots

Nov. 2, 2018

Sprinkled throughout medieval European literature are reports of mysterious outbreaks that left thousands of people dead or permanently disabled. Sometimes known as St. Anthony's fire (for the group of monks who attempted to help during one particularly bad outbreak), the illness most frequently surfaced in the summers after cold, wet winters that were followed by long, damp springs. Entire families would find themselves afflicted with either symptoms of burning and eventual gangrene in the hands and feet or with epileptic-like convulsions, headaches and hallucinations.

A 1505 painting of St. Anthony's Fire.
Figure 1. Ergotism, sometimes known as St. Anthony’s fire, is referenced in the central panel of the Triptych of Temptation of St Anthony, a painting by Hieronymus Bosch, c. 1505.

The modern term for this illness is ergotism. The cause of the disease wasn't identified until 1695, in part because of the erratic timing of outbreaks, and because ergotism isn't contagious (between humans, anyway), despite multiple family members often becoming ill at the same time.

Ergotism is a form of poisoning from ingesting grains, typically rye, that have been infected by the ascomycete fungus Claviceps purpurea. The infection replaces individual grains with dark, hard ergots (see image 2A) that get mixed in to the healthy grain during harvest and milling. In the early 1800s, the cause of ergotism finally spread from physicians to the general populace to become common knowledge, prompting several public health and agricultural measures to prevent both crop infection by C. purpurea and ergot contamination of rye harvests. As a result, individual cases are now sporadic and outbreaks since the late 1800s have been rare and localized. But the unusual pharmacologic qualities of C. purpurea ergots that cause ergotism, became harvested themselves, initially by midwives, for centuries of medicinal use.

The (Micro)Biology of Ergot

C. purpurea infects a wide variety of wild (e.g., bluegrass, meadow foxtail, green foxtail and quackgrass) and domesticated (e.g., wheat, barley and oat) grasses. It is most problematic for rye, whose growth cycle often coincides with C. purpurea spread, making it more susceptible to infection. Rye is a robust grain that can withstand colder temperatures and poorer soils better than other grains, so it is frequently planted in the fall to grow slowly over the cold months. Once spring comes, the rye grows quickly, flowers, and ripens in the early fall.

Wild grass bearing a Claviceps purpurea sclerotia; C. purpurea sclerotia (ergot) sprouting mushrooms.
Figure 2. A) Wild grass bearing a Claviceps purpurea sclerotia. B) A C. purpurea sclerotia (ergot) sprouting mushrooms in the spring.

Rye infection begins when airborne C. purpurea spores infect the grain's flowers, producing a sugary, yellow slime that contains additional spores and attracts insects to facilitate transmission of the fungi to other rye flowers. In addition to insects, the wind and rain splash of a damp spring transmit the C. purpurea to uninfected flowers. Instead of turning to grain, the flower is replaced by a hard, dark grey or purple sclerotium. These sclerotium, a.k.a. ergots or spurs, enabled the fungus to spread, either by being accidentally eaten by grazers or by falling to the ground where the sturdy exterior protects the fungus through the winter. In the spring, mushrooms sprout from the ergot and release spores to infect another round of crops (see image 2B).

When ergot-containing rye crops were harvested and prepared for use in the kitchen, the ergots were also. This led to ergotism, ergot poisoning in humans and animals, because in addition to a dormant C. purpurea, the ergot also contains a plethora of poisonous fungal metabolites. These metabolites contain nitrogen atoms, designating them as alkaloids, and are produced from a 14-gene (68.6kb) ergot alkaloid synthesis (EAS) cluster on the C. purpurea genome.  While the ecological role for alkaloid synthesis by C. purpurea isn't clear, researchers have isolated over 40 alkaloids, some studies suggest that the alkaloids deter scavenging of the ergots by insects and are antimicrobials. Alkaloid production is heavily influenced by the soil composition where the rye is planted, leading to complex alkaloid cocktails in each ergot. As a result, the composition and concentration of alkaloids present within a crop of ergots vary both geographically and seasonally, which has implications for ergotism symptoms in humans.

A map showing the Rhine river's location.
Figure 3. Ergotism symptoms varied, according to their location on the east or west side of the Rhine river.

Reports from historical ergotism outbreaks detail symptoms that vary based on the geographic location. For instance, in France and other countries west of the Rhine river, ergotism presented itself as "gangrenous" while outbreaks east of the Rhine (central/eastern Europe and Scandinavia) presented as "convulsive." Outbreaks in Britain and North America primarily resulted in gangrenous ergotism. There are only 6 recorded instances where both types of ergotism occurred in the same outbreak.

The mechanism for ergotism in humans seems to stem from ergot alkaloid activation of a variety of hormone receptors, including those for serotonin, dopamine and epinephrine. This activation primarily results in contraction of the smooth muscles that line internal organs (like the heart and gastrointestinal tract) and arteries, which results in arterial constriction and slows blood flow. Deprived of blood and oxygen, the tissue dies, developing a "dry" gangrene that begins as coldness and tingling in the extremities. Such gangrenous ergotism is usually accompanied by the symptoms you might imagine from a GI tract gone haywire such as vomiting and diarrhea. The second manifestation of ergotism, convulsive ergotism, is dominated by muscular convulsions, double vision, and hallucinations (coincidentally, many ergot alkaloids are chemically similar to LSD).

From Midwifery to Pharmacy

Despite its aggressive and deadly symptoms, midwives began making use of ergot as early as  the 1500s, following a key observation that pregnant sows fed ergots entered premature labor. The earliest recorded use of ergot by midwives to advance a stalled labor was in 1582 and prescribed ingesting 3 intact ergots collected directly from the field. While this contains enough alkaloid to cause ergotism symptoms, the dosage was restricted to a short period of time, until active labor and birth, preventing gangrene. This dose was later shown to contain about 0.5 mg of the utero-active alkaloid ergotmetrine, which is what obstetricians later used in the 1970s.

In the 1750s, ergot was stocked by pharmacies as "pulvis ad partum," or "dust to create," but its use by orthodox medical providers didn't escalate until 1808 when the physician John Stearns wrote a letter to a fellow doctor that became published in the Medical Repository of New York. In his letter, Dr. Stearns described learning of ergot's potential to induce labor from a German immigrant, who noted that "I have seldom found a case that detained me more than three hours," and warning that "you will be surprised with the suddenness of its operation; it is, therefore, necessary to be completely ready before you give the medicine." Unfortunately, while the "New World" medical community adopted pulvis ad partum with enthusiasm, they failed to heed Stearn's warning and as a result of impatience and poor judgment, ergot use was correlated with stillbirths by 1824. Ergot was now "pulvis ad mortem"― the "dust of death."

Ergometrin was purified in 1935, enabling more precise dosage until safer drugs (e.g., oxytocin and methylergotamine) were found for inducing labor. As a potent vasoconstriction agent, though, ergometrine is still considered valuable for preventing postpartum hemorrhage, a major cause of maternal mortality.

In 1868, ergot was adapted to treat another medical condition: migraine headaches. The active ingredient for this treatment, ergotamine, was purified in 1918 and its use in this context remains widespread. In the U.S. and Europe, ergotamine is a drug of choice for patients with infrequent or long-duration headaches and who will comply with the dosing regimen and restrictions. This is particularly important since most reported cases of ergotism are now sporadic and a result of ergot alkaloid treatments. If not properly administered, extended ergot-based therapies can lead to ergot alkaloid accumulation and gangrenous ergotism (purified alkaloids don't cause convulsive ergotism).

The mysterious origins and symptoms of ergot outbreaks make an interesting juxtaposition with the precise use of ergot by midwives for inducing labor and abortion. Ergot's medical legacy has been carried into the present with ergot-based therapies being explored to treat Parkinson's disease and dementia symptoms. Balancing the edge between helpful and harmful, ergot is yet another a classic example of the toxicology adage "sola dosis facit venenum," or "the dose makes the poison."



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Author: Ada Hagan, Ph.D.

Ada Hagan, Ph.D.
Dr. Ada Hagan owns Alliance SciComm & Consulting, "making science accessible."