Louis Pasteur
Time and again I hear or read that LSD was discovered by accident. This is only partly true. LSD came into being within a systematic research program, and the "accident" did not occur until much later: when LSD was already five years old, I happened to experience its unforeseeable effects in my own body - or rather, in my own mind.
Looking back over my professional career to trace the influential events and decisions that eventually steered my work toward the synthesis of LSD, I realize that the most decisive step was my choice of employment upon completion of my chemistry studies. If that decision had been different, then this substance, which has become known the world over, might never have been created. In order to tell the story of the origin of LSD, then, I must also touch briefly on my career as a chemist, since the two developments are inextricably interreleted.
In the spring of 1929, on concluding my chemistry studies at the University of Zurich, I joined the Sandoz Company's pharmaceutical-chemical research laboratory in Basel, as a co-worker with Professor Arthur Stoll, founder and director of the pharmaceutical department. I chose this position because it afforded me the opportunity to work on natural products, whereas two other job offers from chemical firms in Basel had involved work in the field of synthetic chemistry.
When I joined the Sandoz firm, the staff of the pharmaceutical-chemical
department was still rather modest in number. Four chemists with doctoral
degrees worked in research, three in production.
In Stoll's laboratory I found employment that completely agreed with me as a
research chemist. The objective that Professor Stoll had set for his
pharmaceutical-chemical research laboratories was to isolate the active
principles (i.e., the effective constituents) of known medicinal plants to
produce pure speciments of these substances. This is particularly important
in the case of medicinal plants whose active principles are unstable, or
whose potency is subject to great variation, which makes an exact dosage
difficult. But if the active principle is available in pure form, it becomes
possible to manufacture a stable pharmaceutical preparation, exactly
quantifiable by weight. With this in mind, Professor Stoll had elected to
study plant substances of recognized value such as the substances from
foxglove (Digitalis), Mediterranean squill (Scilla maritima), and ergot of
rye (Claviceps purpurea or Secale cornutum), which, owning to their
instability and uncertain dosage, nevertheless, had been little used in
medicine.
My first years in the Sandoz laboratories were devoted almost exclusively to
studying the active principles of Mediterranean squill. Dr. Walter Kreis, one
of Professor Stoll's earliest associates, lounched me in this field of
research. The most important constituents of Mediterranean squill already
existed in pure form. Their active agents, as well as those of woolly foxglove
(Digitalis lanata), had been isolated and purified, chiefly by Dr. Kreis, with
extraordinary skill.
The active principles of Mediterranean squill belong to the group of
cardioactive glycosides (glycoside = sugar-containing substance) and serve, as
do those of foxglove, in the treatment of cardiac insufficiency. The cardiac
glycosides are extremely active substances. Because the therapeutic and the
toxic doses differ so little, it becomes especially important here to have an
exact dosage, based on pure compounds.
At the beginning of my investigations, a pharmaceutical preparation with
Scilla glycosides had already been introduced into therapeutics by Sandoz;
however, the chemical structure of these active compounds, with the exception
of the sugar portion, remained largely unknown.
My main contribution to the Scilla research, in which I participated with
enthusiasm, was to elucidate the chemical structure of the common nucleus of
Scilla glycosides, showing on the one hand their differences from the
Digitalis glycosides, and on the other hand their close structural
relationship with the toxic principles isolated from skin glands of toads. In
1935, these studies were temporarily concluded.
Looking for a new field of research, I asked Professor Stoll to let me
continue the investigations on the alkaloids of ergot, which he had begun in
1917 and which had led directly to the isolation of ergotamine in 1918.
Ergotamine, discovered by Stoll, was the first ergot alkaloid obtained in pure
chemical form. Although ergotamine quickly took a significant place in
therapeutics (under the trade name Gynergen) as a hemostatic remedy in
obstetrics and as a medicament in the treatment of migraine, chemical research
on ergot in the Sandoz laboratories was abandoned after the isolation of
ergotamine and the determination of its empirical formula. Meanwhile, at the
beginning of the thirties, English and American laboratories had begun to
determine the chemical structure of ergot alkaloids. They had also discovered
a new, watersoluble ergot alkaloid, which could likewise be isolated from the
mother liquor of ergotamine production. So I thought it was high time that
Sandoz resumed chemical research on ergot alkaloids, unless we wanted to risk
losing our leading role in a field of medicinal research, which was already
becoming so important.
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, 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.
We were very frugal. Individual laboratories were considered a rare
extravagance. During the first six years of my employment with Sandoz, I
shared a laboratory with two colleagues. We three chemists, plus an assistant
each, worked in the same room on three different fields: Dr. Kreiss on cardiac
glycosides; Dr. Wiedemann, who joined Sandoz around the same time as I, on the
leaf pigment chlorophyll; and I ultimately on ergot alkaloids. The laboratory
was equipped with two fume hoods (compartments supplied with outlets),
providing less than effective ventilation by gas flames. When we requested
that these hoods be equipped with ventilators, our chief refused on the gound
that ventilation by gas flame had sufficed in Willstatter's laboratory.
During the last years of World War I, Professor Stoll had been an assistant in
Berlin and Munich to the world-famous chemist and Nobel laureate Professor
Richard Willstatter, and with him had conducted the fundamental investigations
on chlorophyll and the assimilation of carbon dioxide. There was scarcely a
scientific discussion with Professor Stoll in which he did not mention his
revered teacher Professor Willstatter and his work in Willstatter's
laboratory.
The working techniques available to chemists in the field of organic chemistry
at that time (the beginning of the thirties) were essentially the same as
those employed by Justus von Liebig a hundred years earlier. The most
important development achieved since then was the introduction of
microanalysis by B. Pregl, which made it possible to ascertain the elemental
composition of a compound with only a few milligrams of specimen, whereas
earlier a few centigrams were needed. Of the other physical-chemical
techniques at the disposal of the chemist today - techniques which have
changed his way of working, making it faster and more effective, and created
entirely new possibilities, above all for the elucidation of structure - none
yet existed in those days.
For the investigations of Scilla glycosides and the first studies in the ergot
field, I still used the old separation and purification techniques from
Liebig's day: fractional extraction, fractional precipitation, fractional
crystallization, and the like. The introduction of column chromatography, the
first important step in modern laboratory technique, was of great value to me
only in later investigations. For structure determination, which today can be
conducted rapidly and elegantly with the help of spectroscopic methods (UV,
IR, NMR) and X-ray crystallography, we had to rely, in the first fundamental
ergot studies, entirely on the old laborious methods of chemical degradation
and derivatization.
After this first success in the ergot field, my investigations went forward on
two fronts. First, I attempted to improve the pharmacological properties of
ergobasine by variations of its amino alcohol radical. My colleague Dr. J.
Peyer and I developed a process for the economical production of propanolamine
and other amino alcohols. Indeed, by substitution of the propanolamine
contained in ergobasine with the amino alcohol butanolamine, an active
principle was obtained that even surpassed the natural alkaloid in its
therapeutic properties. This improved ergobasine has found worldwide
application as a dependable uterotonic, hemostatic remedy under the trade name
Methergine, and is today the leading medicament for this indication in
obstetrics.
I further employed my synthetic procedure to produce new lysergic acid
compounds for which uterotonic activity was not prominent, but from which, on
the basis of their chemical structure, other types of interesting
pharmacological properties could be expected. In 1938, I produced the
twenty-fifth substance in this series of lysergic acid derivatives: lysergic
acid diethylamide, abbreviated LSD-25 (Lyserg-saure-diathylamid) for
laboratory usage.
I had planned the synthesis of this compound with the intention of obtaining a
circulatory and respiratory stimulant (an analeptic). Such stimulating
properties could be expected for lysergic acid diethylamide, because it shows
similarity in chemical structure to the analeptic already known at that time,
namely nicotinic acid diethylamide (Coramine). During the testing of LSD-25 in
the pharmacological department of Sandoz, whose director at the time was
Professor Ernst Rothlin, a strong effect on the uterus was established. It
amounted to some 70 percent of the activity of ergobasine. The research report
also noted, in passing, that the experimental animals became restless during
the narcosis. The new substance, however, aroused no special interest in our
pharmacologists and physicians; testing was therefore discontinued.
For the next five years, nothing more was heard of the substance LSD-25.
Meanwhile, my work in the ergot field advanced further in other areas. Through
the purification of ergotoxine, the starting material for lysergic acid, I
obtained, as already mentioned, the impression that this alkaloidal
preparation was not homogeneous, but was rather a mixture of different
substances. This doubt as to the homogeneity of ergotoxine was reinforced when
in its hydrogenation two distinctly different hydrogenation products were
obtained, whereas the homogeneous alkaloid ergotamine under the same condition
yielded only a single hydrogenation product (hydrogenation = introduction of
hydrogen). Extended, systematic analytical investigations of the supposed
ergotoxine mixture led ultimately to the separation of this alkaloidal
preparation into three homogeneous components. One of the three chemically
homogeneous ergotoxine alkaloids proved to be identical with an alkaloid
isolated shortly before in the production department, which A. Stoll and E.
Burckhardt had named ergocristine. The other two alkaloids were both new. The
first I named ergocornine; and for the second, the last to be isolated, which
had long remained hidden in the mother liquor, I chose the name ergokryptine
(kryptos = hidden). Later it was found that ergokryptine occurs in two
isomeric forms, which were differentiated as alfa- and beta-ergokryptine.
The solution of the ergotoxine problem was not merely scientifically
interesting, but also had great practical significance. A valuable remedy
arose from it. The three hydrogenated ergotoxine alkaloids that I produced in
the course of these investigations, dihydroergocristine, dihydroergokryptine,
and dihydroergocornine, displayed medicinally useful properties during testing
by Professor Rothlin in the pharmacological department. From these three
substances, the pharmaceutical preparation Hydergine was developed, a
medicament for improvement of peripheral circulation and cerebral function in
the control of geriatric disorders. Hydergine has proven to be an effective
remedy in geriatrics for these indications. Today it is Sandoz's most
important pharmaceutical product.
Dihydroergotamine, which I likewise produced in the course of these
investigations, has also found application in therapeutics as a circulation-
and bloodpressure-stabilizing medicament, under the trade name Dihydergot.
While today research on important projects is almost exclusively carried out
as teamwork, the investigations on ergot alkaloids described above were
conducted by myself alone. Even the further chemical steps in the evolution of
commercial preparations remained in my hands - that is, the preparation of
larger specimens for the clinical trials, and finally the perfection of the
first procedures for mass production of Methergine, Hydergine, and Dihydergot.
This even included the analytical controls for the development of the first
galenical forms of these three preparations: the ampules, liquid solutions,
and tablets. My aides at that time included a laboratory assistant, a
laboratory helper, and later in addition a second laboratory assistant and a
chemical technician. First Chemical Explorations
My doctoral work at Zurich under Professor Paul Karrer had already given me
one chance to pursue my intrest in plant and animal chemistry. Making use of
the gastrointestinal juice of the vineyard snail, I accomplished the enzymatic
degradation of chitin, the structural material of which the shells, wings, and
claws of insects, crustaceans, and other lower animals are composed. I was
able to derive the chemical structure of chitin from the cleavage product, a
nitrogen-containing sugar, obtained by this degradation. Chitin turned out to
be an analogue of cellulose, the structural material of plants. This important
result, obtained after only three months of research, led to a doctoral thesis
rated "with distiction." 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. Barger, 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. Lysergic Acid and Its Derivatives
Lysergic acid proved to be a rather unstable substance, and its rebonding with
basic radicals posed difficulties. In the technique knon as Curtius'
Synthesis, I ultimately found a process that proved useful for combining
lysergic acid with amines. With this method I produced a great number of
lysergic acid compounds. By combining lysergic acid with the amino alcohol
propanolamine, I obtained a compound that was identical to the natural ergot
alkaloid ergobasine. With that, the first synthesis - that is, artificial
production - of an ergot alkaloid was accomplished. This was not only of
scientific interest, as confirmation of the chemical structure of ergobasine,
but also of practical significance, because ergobasine, the specifically
uterotonic, hemostatic principle, is present in ergot only in very trifling
quantities. With this synthesis, the other alkaloids existing abundantly in
ergot could now be converted to ergobasine, which was valuable in obstetrics.