Professor Stoll granted my request, with some misgivings: "I must warn you of the difficulties you face in working with ergot alkaloids. These are-exceedingly sensitive, easily decomposed substances, less stable than any of the compounds you have investigated in the cardiac glycoside field. But you are welcome to try."

And so the switches were thrown, and I found myself engaged in a field of study that would become the main theme of my professional career. I have never forgotten the creative joy, the eager anticipation I felt in embarking on the study of ergot alkaloids, at that time a relatively uncharted field of research.

Ergot

It may be helpful here to give some background information about ergot itself.[For further information on ergot, readers should refer to the monographs of G. Berger, Ergot and Ergotism (Gurney and Jackson, London, 1931 ) and A. Hofmann, Die Mutterkornalkaloide (F. Enke Verlag, Stuttgart, 1964). The former is a classical presentation of the history of the drug, while the latter emphasizes the chemical aspects.]

It 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 is described botanically as a sclerotium, the form that the ergot fungus takes in winter. Ergot of rye ( Secale cornutum) is the variety used medicinally.

Ergot, more than any other drug, has a fascinating history, in the course of which its role and meaning have been reversed: once dreaded as a poison, in the course of time it has changed to a rich storehouse of valuable remedies. Ergot first appeared on the stage of history in the early Middle Ages, as the cause of outbreaks of mass poisonings affecting thousands of persons at a time. The illness, whose connection with ergot was for a long time obscure, 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 recent times, epidemic-like outbreaks of ergot poisoning have been recorded in most European countries including certain areas of Russia. With progress in agriculture, and since the realization, in the seventeenth century, that ergot-containing bread was the cause, the frequency and extent of ergotism epidemics diminished considerably. The last great epidemic occurred in certain areas of southern Russia in the years 1926-27. [The mass poisoning in the southern French city of Pont-St. Esprit in the year 1951, which many writers have attributed to ergot-containing bread, actually had nothing to do with ergotism. It rather involved poisoning by an organic mercury compound that was utilized for disinfecting seed.]

The first mention of a medicinal use of ergot, namely as an ecbolic (a medicament to precipitate childbirth), is found in the herbal of the Frankfurt city physician Adam Lonitzer (Lonicerus) in the year 1582. Although ergot, as Lonitzer stated, had been used since olden times by midwives, it was not until 1808 that this drug gained entry into academic medicine, on the strength of a work by the American physician John Stearns entitled Account of the Putvis Parturiens, a Remedy for Quickening Childbirth. The use of ergot as an ecbolic did not, however, endure. Practitioners became aware quite early of the great danger to the child, owing primarily to the uncertainty of dosage, which when too high led to uterine spasms. From then on, the use of ergot in obstetrics was confined to stopping postpartum hemorrhage (bleeding after childbirth).

It was not until ergot's recognition in various pharmacopoeias during the first half of the nineteenth century that the first steps were taken toward isolating the active principles of the drug. However, of all the researchers who assayed this problem during the first hundred years, not one succeeded in identifying the actual substances responsible for the therapeutic activity. In 1907, the Englishmen G. Barger and F. H. Carr were the first to isolate an active alkaloidal preparation, which they named ergotoxine because it produced more of the toxic than therapeutic properties of ergot. (This preparation was not homogeneous, but rather a mixture of several alkaloids, as I was able to show thirty-five years later.) Nevertheless, the pharmacologist H. H. Dale discovered that ergotoxine, besides the uterotonic effect, also had an antagonistic activity on adrenaline in the autonomic nervous system that could lead to the therapeutic use of ergot alkaloids. Only with the isolation of ergotamine by A. Stoll (as mentioned previously) did an ergot alkaloid find entry and widespread use in therapeutics.

The early 1930s brought a new era in ergot research, beginning with the determination of the chemical structure of ergot alkaloids, as mentioned, in English and American laboratories. By chemical cleavage, 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. Then came a major development, both for chemistry and for medicine: the isolation of the specifically uterotonic, hemostatic principle of ergot, which was published simultaneously and quite independently by four institutions, including the Sandoz laboratories. The substance, an alkaloid of comparatively simple structure, was named ergobasine (syn. ergometrine, ergonovine) by A. Stoll and E. Burckhardt. By the chemical degradation of ergobasine, W. A. Jacobs and L. C. Craig obtained lysergic acid and the amino alcohol propanolamine as cleavage products.

I set as my first goal the problem of preparing this alkaloid synthetically, through chemical linking of the two components of ergobasine, lysergic acid and propanolamine (see structural formulas in the appendix).

The lysergic acid necessary for these studies had to be obtained by chemical cleavage of some other ergot alkaloid. Since only ergotamine was available as a pure alkaloid, and was already being produced in kilogram quantities in the pharmaceutical production department, I chose this alkaloid as the starting material for my work. I set about obtaining 0.5 gm of ergotamine from the ergot production people. When I sent the internal requisition form to Professor Stoll for his countersignature, he appeared in my laboratory and reproved me: "If you want to work with ergot alkaloids, you will have to familiarize yourself with the techniques of microchemistry. I can't have you consuming such a large amount of my expensive ergotamine for your experiments."

The ergot production department, besides using ergot of Swiss origin to obtain ergotamine, also dealt with Portuguese ergot, which yielded an amorphous alkaloidal preparation that corresponded to the aforementioned ergotoxine first produced by Barger and Carr. I decided to use this less expensive material for the preparation of lysergic acid.

The alkaloid obtained from the production department had to be purified further, before it would be suitable for cleavage to lysergic acid. Observations made during the purification process led me to think that ergotoxine could be a mixture of several alkaloids, rather than one homogeneous alkaloid. I will speak later of the far-reaching sequelae of these observations.

Here I must digress briefly to describe the working conditions and techniques that prevailed in those days. These remarks may be of interest to the present generation of research chemists in industry, who are accustomed to far better conditions.