Controls at Sandoz became ever more stringent. Arthur Stoll watched to see that raw materials were treated sparingly and criticized Hofmann for his allegedly wasteful methods. Hofmann recalls: “Once, when I requisitioned 0.5 grams of ergotamine from the ergot plant which produced it in batches of several kilograms, Professor Stoll personally came to my lab and reproached me for using so much. I needed to adopt microchemical procedures if I was to work with his costly substances.”7 Hofmann found a way out thereafter by working with the less expensive ergotoxine.
In 1934, American scientists W.A. Jacobs and L.C. Craig succeeded in determining the chemical structure of lysergic acid, the basic component of many ergot alkaloids. Lysergic acid proved to be a substance that easily decomposed. It was 1938 before Hofmann applied the Curtius Synthesis, a method which enabled him to combine and stabilize lysergic acid with basic groups for further ergot research. From lysergic acid he began synthesizing the indole derivative ergobasine. This gave him a more rational method of producing a substance that is present only in extremely small quantities in ergotamine. Moreover, the synthesis led to the eagerly sought clarification of its structure, which had previously remained unresolved.
Hofmann achieved the first synthesis of a natural ergot alkaloid by combining lysergic acid with propanolamine. After Stoll’s isolation of ergotamine, this was a further step in ergot research and proved to be of practical as well as scientific importance. This partial synthesis made it possible to convert the other alkaloids in ergot into ergobasine, which was valuable in obstetrics. Hofmann’s method of synthesis became the generally recognized basis for producing a number of related structures from the original ergot alkaloid.
Hofmann subsequently produced many more lysergic acid derivatives, among them the twenty-fifth on November 16, 1938, which was lysergic acid diethylamide; hence the designation LSD-25. He was planning to synthesize an analog to the cardiovascular agent Coramine which was produced by Ciba, a competing pharmaceutical firm on the opposite bank of the Rhine. He recalled that: “I ate lunch that day in the lab rather than the cafeteria and fed myself a slice of bread with honey and butter, and a glass of the milk which was delivered every morning from the Sandoz experimental farm. It was delicious. I had just finished and had begun to pace back and forth and think about my work. Suddenly, I thought of the circulatory stimulant, Coramine, and had the idea of producing an analog compound based on lysergic acid, the building block of ergot alkaloids. Chemically, Coramine is nicotinic acid diethylamide so I decided to produce lysergic acid diethylamide. The chemical and structural relationship of these two compounds led me to suspect they might have similar pharmacological properties. I hoped that lysergic acid diethylamide would be a new and improved cardiovascular stimulant.”8 The experiments carried out by the pharmacological department at Sandoz with LSD-25 found it had approximately seventy percent of the effect of ergobasine. The trial audit mentioned slight restlessness in lab animals. Because the effects observed were less than expected, the physicians and pharmacologists at Sandoz quickly lost interest in the new substance. For the next five years, nothing more was done with LSD-25.
However, LSD-25 didn’t pass into oblivion; Albert Hofmann could not stop thinking about the substance. “I had a strange premonition that this drug might have additional effects to those exhibited during the first trial. This led me to produce LSD-25 again five years after the first synthesis and pass it on to the pharmacological department for further trials. This was unusual, because test compounds were normally struck from the research program once declared to be of no pharmacological interest.” Later, Hofmann could neither find a rational explanation for his hunch nor for the rest of his life reconstruct why it was that he chose to resurrect that particular compound out of the many he had created. “It was more a feeling—the chemical structure appealed to me—that prompted me to take that extraordinary step.” (Bröckers, Liggenstorfer 2006) Most chemists would have rejected such a diffuse feeling as irrational fantasy and forgotten the matter, but Hofmann trusted and followed his intuition.