Lysergic Acid Diethylamide - LSD

Lysergic Acid Diethylamide - LSD

Paul May

School of Chemistry

University of Bristol

December 1998

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LSD is one of the most powerful hallucinogenic drugs known. It was invented in 1938 by the Swiss chemist, Albert Hoffman, who was interested in developing medicines from compounds in ergot, a fungus that attacks rye. Although LSD is purely synthetic, clues to its biological activity can be found by tracing the history of the fungus from which it is derived.

Ergot

Ergot of rye is produced by a lower fungus (Claviceps purpurea) that grows parasitically on rye and, to a lesser extent, on other species of grain and on wild grasses. Kernels infested with this fungus develop into light-brown to violet-brown curved pegs (sclerotia) that push forth from the husk in place of normal grains. Ergot of rye (Secale cornutum) is the variety used medicinally.

Ergot has a fascinating history. Once it was dreaded as a poison, but over the course of time it has become to be regarded as a rich storehouse of valuable medicines. Ergot was first mentioned in the early Middle Ages, as the cause of outbreaks of mass poisonings affecting thousands of persons at a time. The illness appeared in two characteristic forms, one gangrenous (ergotismus gangraenosus) and the other convulsive (ergotismus convulsivus). Popular names for ergotism - such as "mal des ardents", "ignis sacer", "heiliges Feuer" or "St. Anthony's fire" - refer to the gangrenous form of the disease. The patron saint of ergotism victims was St. Anthony, and it was primarily the Order of St. Anthony that treated these patients. Until quite recently, outbreaks of ergot poisoning approaching epidemic proportions were recorded in most European countries including certain areas of Russia. However, in the seventeenth century it was discovered that ergot-containing bread was the cause of the poisonings. This, coupled with progress in agriculture, caused the frequency and extent of ergotism epidemics to diminish considerably. The last great epidemic occurred in certain areas of southern Russia in the years 1926-27.

Ergot as a Medicine

The first mention of a medicinal use of ergot, as a drug to precipitate childbirth, is found in the notes of the Frankfurt city physician Adam Lonitzer in 1582. Although ergot had been used since olden times by midwives, it was not until 1808 that this drug gained entry into academic medicine. The use of ergot for these purposes did not last, however, since the uncertainty of dosage led to uterine spasms and dangers to the child.

The early 1930s brought a new era in ergot research, beginning with the determination of the chemical structure of the main chemically active agents, the ergot alkaloids. Finally, W. A. Jacobs and L.C. Craig of the Rockefeller Institute of New York succeeded in isolating and characterizing the nucleus common to all ergot alkaloids. They named it lysergic acid.

The Discovery of LSD

In the late 1930s, Albert Hoffman was working in the pharmacological department of Sandoz, in Basel, Switzerland. He was studying derivatives of lysergic acid, including systematically reacting the acid group with various reagents, to produce the corresponding amides, anhydrides, esters, etc. One of these derivatives was the diethylamide, made by addition of the -N(C2H5)2 group, and it was named LSD-25. But the new substance didn't appear to have any particularly useful medical properties, although the research report noted, in passing, that "the experimental animals became restless during the narcosis". For the next five years, nothing more was heard of the substance LSD-25.

The structure of lysergic acid diethylamide.

The diethylamide group is shown in red and the indole ring in blue.

But for some reason, Hoffman could not forget the relatively uninteresting LSD-25. In his book he says:

"A peculiar presentiment - the feeling that this substance could possess properties other than those established in the first investigations - induced me, five years after the first synthesis, to produce LSD-25 once again so that a sample could be given to the pharmacological department for further tests."

So, in the spring of 1943, he repeated the synthesis of LSD-25. Quoted below is his entry for this experiment in his laboratory journal of April 19, 1943.

Self-Experiments

17:00: Beginning dizziness, feeling of anxiety, visual distortions, symptoms of paralysis, desire to laugh.

His diary, written later, continues the story:

"Here

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