Ergot and the Pharmacist's Daughter

“Ergot had been trying to get Hofmann's attention for years. It was the fungus that stopped postpartum hemorrhage, caused the Dancing Plague of 1374, and eventually, through his hands, became LSD.”

Albert Hofmann joined the Basel drug company in Basel in 1929 and was assigned to study ergot, the fungus Claviceps purpurea, which grows on rye and other grains and had been known since antiquity for two completely opposite properties.

The first: it caused uterine contractions, making it useful for stopping postpartum hemorrhage. Midwives in medieval Europe had used ergot-contaminated rye for this purpose, passing the knowledge through generations without understanding the mechanism.

The second: it caused what medieval observers called St. Anthony's Fire, a syndrome combining hallucinations, convulsions, burning sensations in the extremities, and sometimes gangrene. The Paris epidemic of 1418 killed fifty thousand people. The Dancing Plague of 1374, in which hundreds of people danced uncontrollably for days, is now attributed to ergot in the grain supply. The Salem witch trials may have been ergot poisoning.

Hofmann's task at the company was to isolate the medically useful alkaloids from ergot and develop pharmaceutical derivatives. He succeeded with ergotamine and ergobasine, both of which became important drugs. In 1938, pursuing the pharmaceutical potential further, he synthesized a derivative of lysergic acid, the backbone structure common to all ergot alkaloids, and called it LSD-25. It was the twenty-fifth compound in the lysergic acid series. The animal tests showed nothing interesting. He filed it and moved on.

Five years later, for reasons he described as a 'peculiar presentiment', he returned to LSD-25. In the final stages of the synthesis, he absorbed a small amount through his skin. The rest is what we know.

What connects ergot's two properties, the obstetrical and the hallucinogenic, is the chemistry of the ergot alkaloids and their action on serotonin receptors. The same receptor family that controls uterine muscle contraction is implicated in the perceptual effects of LSD. Hofmann, working at the boundary between these two pharmacological territories, accidentally synthesized the most potent psychoactive compound known. The fungus had been hiding it in plain sight for millennia.

Sources

• Hofmann, LSD: My Problem Child (1979)
• The Lancet, Albert Hofmann obituary (2008)
• Wacker et al., Cell (2017)