Translator's Preface

Numerous accounts of the discovery of LSD have been published in English;
none, unfortunately, have been completely accurate. Here, at last, the father
of LSD details the history of his "problem child" and his long and fruitful
career as a research chemist. In a real sense, this book is the inside story
of the birth of the Psychedelic Age, and it cannot be denied that we have here
a highly candid and personal insight into one of the most important scientific
discoveries of our time, the significance of which has yet to dawn on mankind.

Surpassing its historical value is the immense philosophical import of this
work. Never before has a chemist, an expert in the most materialistic of the
sciences, advanced a Weltanschauung of such a mystical and transcendental
nature. LSD, psilocybin, and the other hallucinogens do indeed, as Albert
Hofmann asserts, constitute "cracks" in the edifice of materialistic
rationality, cracks we would do well to explore and perhaps widen.

As a writer, it gives me great satisfaction to know that by this book the
American reader interested in hallucinogens will be introduced to the work of
Rudolf Gelpke, Ernst Junger, and Walter Vogt, writers who are all but unknown
here. With the notable exceptions of Huxley and Wasson, English and American
writers on the hallucinogenic experience have been far less distinguished and
eloquent than they.

This translation has been carefully overseen by Albert Hofmann, which made my
task both simpler and more enjoyable. I am beholden to R. Gordon Wasson for
checking the chapters on LSD's "Mexican relatives" and on "Ska Maria Pastora"
for accuracy and style.

Two chapters of this book - "How LSD Originated" and "LSD Experience and
Reality" - were presented by Albert Hofmann as a paper before the international
conference "Hallucinogens, Shamanism and Modern Life" in San Francisco on the
afternoon of Saturday, September 30, 1978. As a part of the conference
proceedings, the first chapter has been published in the Journal of
Psychedelic Drugs, Vol. 11 (1-2), 1979.

                                                              JONATHAN OTT
                                                 Vashon Island, Washington


FOREWORD

There are experiences that most of us are hesitant to speak about, because
they do not conform to everyday reality and defy rational explanation. These
are not particular external occurrences, but rather events of our inner lives,
which are generally dismissed as figments of the imagination and barred from
our memory. Suddenly, the familiar view of our surroundings is transformed in
a strange, delightful, or alarming way: it appears to us in a new light, takes
on a special meaning. Such an experience can be as light and fleeting as a
breath of air, or it can imprint itself deeply upon our minds.

One enchantment of that kind, which I experienced in childhood, has remained
remarkably vivid in my memory ever since. It happened on a May morning - I
have forgotten the year - but I can still point to the exact spot where it
occurred, on a forest path on Martinsberg above Baden, Switzerland. As I
strolled through the freshly greened woods filled with bird song and lit up by
the morning sun, all at once everything appeared in an uncommonly clear light.
Was this something I had simply failed to notice before? Was I suddenly
discovering the spring forest as it actually looked? It shone with the most
beautiful radiance, speaking to the heart, as though it wanted to encompass me
in its majesty. I was filled with an indescribable sensation of joy, oneness,
and blissful security.

I have no idea how long I stood there spellbound. But I recall the anxious
concern I felt as the radiance slowly dissolved and I hiked on: how could a
vision that was so real and convincing, so directly and deeply felt - how
could it end so soon? And how could I tell anyone about it, as my overflowing
joy compelled me to do, since I knew there were no words to describe what I
had seen? It seemed strange that I, as a child, had seen something so
marvelous, something that adults obviously did not perceive - for I had never
heard them mention it.

While still a child, I experienced several more of these deeply euphoric
moments on my rambles through forest and meadow. It was these experiences that
shaped the main outlines of my world view and convinced me of the existence of
a miraculous, powerful, unfathomable reality that was hidden from everyday
sight.

I was often troubled in those days, wondering if I would ever, as an adult, be
able to communicate these experiences; whether I would have the chance to
depict my visions in poetry or paintings. But knowing that I was not cut out
to be a poet or artist, I assumed I would have to keep these experiences to
myself, important as they were to me.

Unexpectedly - though scarcely by chance - much later, in middle age, a link
was established between my profession and these visionary experiences from
childhood.

Because I wanted to gain insight into the structure and essence of matter, I
became a research chemist. Intrigued by the plant world since early childhood,
I chose to specialize in research on the constituents of medicinal plants. In
the course of this career I was led to the psychoactive, hallucination-causing
substances, which under certain conditions can evoke visionary states similar
to the spontaneous experiences just described. The most important of these
hallucinogenic substances has come to be known as LSD. Hallucinogens, as
active compounds of considerable scientific interest, have gained entry into
medicinal research, biology, and psychiatry, and later -  especially LSD also
obtained wide diffusion in the drug culture.

In studying the literature connected with my work, I became aware of the great
universal significance of visionary experience. It plays a dominant role, not
only in mysticism and the history of religion, but also in the creative
process in art, literature, and science. More recent investigations have shown
that many persons also have visionary experiences in daily life, though most
of us fail to recognize their meaning and value. Mystical experiences, like
those that marked my childhood, are apparently far from rare.

There is today a widespread striving for mystical experience, for visionary
breakthroughs to a deeper, more comprehensive reality than that perceived by
our rational, everyday consciousness. Efforts to transcend our materialistic
world view are being made in various ways, not only by the adherents to
Eastern religious movements, but also by professional psychiatrists, who are
adopting such profound spiritual experiences as a basic therapeutic principle.

I share the belief of many of my contemporaries that the spiritual crisis
pervading all spheres of Western industrial society can be remedied only by a
change in our world view. We shall have to shift from the materialistic,
dualistic belief that people and their environment are separate, toward a new
consciousness of an all-encompassing reality, which embraces the experiencing
ego, a reality in which people feel their oneness with animate nature and all
of creation.

Everything that can contribute to such a fundamental alteration in our
perception of reality must therefore command earnest attention. Foremost among
such approaches are the various methods of meditation, either in a religious
or a secular context, which aim to deepen the consciousness of reality by way
of a total mystical experience. Another important, but still controversial,
path to the same goal is the use of the consciousness-altering properties of
hallucinogenic psychopharmaceuticals. LSD finds such an application in
medicine, by helping patients in psychoanalysis and psychotherapy to perceive
their problems in their true significance.

Deliberate provocation of mystical experience, particularly by LSD and related
hallucinogens, in contrast to spontaneous visionary experiences, entails
dangers that must not be underestimated. Practitioners must take into account
the peculiar effects of these substances, namely their ability to influence
our consciousness, the innermost essence of our being. The history of LSD to
date amply demonstrates the catastrophic consequences that can ensue when its
profound effect is misjudged and the substance is mistaken for a pleasure
drug. Special internal and external advance preparations are required; with
them, an LSD experiment can become a meaningful experience. Wrong and
inappropriate use has caused LSD to become my problem child.

It is my desire in this book to give a comprehensive picture of LSD, its
origin, its effects, and its dangers, in order to guard against increasing
abuse of this extraordinary drug. I hope thereby to emphasize possible uses of
LSD that are compatible with its characteristic action. I believe that if
people would learn to use LSD's vision-inducing capability more wisely, under
suitable conditions, in medical practice and in conjunction with meditation,
then in the future this problem child could become a wonder child.



1. How LSD Originated

    In the realm of scientific observation, luck
    is granted only to those who are prepared.
                                   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 interrelated.

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.


First Chemical Explorations

My doctoral work at Zurich under Professor Paul Karrer had already given me
one chance to pursue my interest 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 distinction."

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

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.

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 haemorrhage (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.


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.

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.


Discovery of the Psyhic Effects of LSD

The solution of the ergotoxine problem had led to fruitful results, described
here only briefly, and had opened up further avenues of research. And yet I
could not forget the relatively uninteresting LSD-25. 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. This was quite unusual;
experimental substances, as a rule, were definitely stricken from the research
program if once found to be lacking in pharmacological interest.

Nevertheless, in the spring of 1943, I repeated the synthesis of LSD-25. As in
the first synthesis, this involved the production of only a few centigrams of
the compound.

In the final step of the synthesis, during the purification and
crystallization of lysergic acid diethylamide in the form of a tartrate
(tartaric acid salt), I was interrupted in my work by unusual sensations. The
following description of this incident comes from the report that I sent at
the time to Professor Stoll:

    Last Friday, April 16,1943, I was forced to interrupt my work in
    the laboratory in the middle of the afternoon and proceed home,
    being affected by a remarkable restlessness, combined with a slight
    dizziness. At home I lay down and sank into a not unpleasant
    intoxicated-like condition, characterized by an extremely stimulated
    imagination. In a dreamlike state, with eyes closed (I found the
    daylight to be unpleasantly glaring), I perceived an uninterrupted
    stream of fantastic pictures, extraordinary shapes with intense,
    kaleidoscopic play of colors. After some two hours this condition
    faded away.

This was, altogether, a remarkable experience -  both in its sudden onset and
its extraordinary course. It seemed to have resulted from some external toxic
influence; I surmised a connection with the substance I had been working with
at the time, lysergic acid diethylamide tartrate. But this led to another
question: how had I managed to absorb this material? Because of the known
toxicity of ergot substances, I always maintained meticulously neat work
habits. Possibly a bit of the LSD solution had contacted my fingertips during
crystallization, and a trace of the substance was absorbed through the skin.
If LSD-25 had indeed been the cause of this bizarre experience, then it must
be a substance of extraordinary potency. There seemed to be only one way of
getting to the bottom of this. I decided on a self-experiment.

Exercising extreme caution, I began the planned series of experiments with the
smallest quantity that could be expected to produce some effect, considering
the activity of the ergot alkaloids known at the time: namely, 0.25 mg (mg =
milligram = one thousandth of a gram) of lysergic acid diethylamide tartrate.
Quoted below is the entry for this experiment in my laboratory journal of
April 19, 1943.


Self-Experiments

    4/19/43 16:20: 0.5 cc of 1/2 promil aqueous solution of diethylamide
    tartrate orally = 0.25 mg tartrate. Taken diluted with about 10 cc
    water. Tasteless.

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

    Supplement of 4/21: Home by bicycle. From 18:00- ca.20:00 most severe
    crisis. (See special report.)

Here the notes in my laboratory journal cease. I was able to write the last
words only with great effort. By now it was already clear to me that LSD had
been the cause of the remarkable experience of the previous Friday, for the
altered perceptions were of the same type as before, only much more intense. I
had to struggle to speak intelligibly. I asked my laboratory assistant, who
was informed of the self-experiment, to escort me home. We went by bicycle, no
automobile being available because of wartime restrictions on their use. On
the way home, my condition began to assume threatening forms. Everything in my
field of vision wavered and was distorted as if seen in a curved mirror. I
also had the sensation of being unable to move from the spot. Nevertheless, my
assistant later told me that we had traveled very rapidly. Finally, we arrived
at home safe and sound, and I was just barely capable of asking my companion
to summon our family doctor and request milk from the neighbors.

In spite of my delirious, bewildered condition, I had brief periods of clear
and effective thinking - and chose milk as a nonspecific antidote for
poisoning.

The dizziness and sensation of fainting became so strong at times that I could
no longer hold myself erect, and had to lie down on a sofa. My surroundings
had now transformed themselves in more terrifying ways. Everything in the room
spun around, and the familiar objects and pieces of furniture assumed
grotesque, threatening forrns. They were in continuous motion, animated, as if
driven by an inner restlessness. The lady next door, whom I scarcely
recognized, brought me milk - in the course of the evening I drank more than
two liters. She was no longer Mrs. R., but rather a malevolent, insidious
witch with a colored mask.

Even worse than these demonic transformations of the outer world, were the
alterations that I perceived in myself, in my inner being. Every exertion of
my will, every attempt to put an end to the disintegration of the outer world
and the dissolution of my ego, seemed to be wasted effort. A demon had invaded
me, had taken possession of my body, mind, and soul. I jumped up and screamed,
trying to free myself from him, but then sank down again and lay helpless on
the sofa. The substance, with which I had wanted to experiment, had vanquished
me. It was the demon that scornfully triumphed over my will. I was seized by
the dreadful fear of going insane. I was taken to another world, another
place, another time. My body seemed to be without sensation, lifeless,
strange. Was I dying? Was this the transition? At times I believed myself to
be outside my body, and then perceived clearly, as an outside observer, the
complete tragedy of my situation. I had not even taken leave of my family (my
wife, with our three children had traveled that day to visit her parents, in
Lucerne). Would they ever understand that I had not experimented
thoughtlessly, irresponsibly, but rather with the utmost caution, an-d that
such a result was in no way foreseeable? My fear and despair intensified, not
only because a young family should lose its father, but also because I dreaded
leaving my chemical research work, which meant so much to me, unfinished in
the midst of fruitful, promising development. Another reflection took shape,
an idea full of bitter irony: if I was now forced to leave this world
prematurely, it was because of this Iysergic acid diethylamide that I myself
had brought forth into the world.

By the time the doctor arrived, the climax of my despondent condition had
already passed. My laboratory assistant informed him about my selfexperiment,
as I myself was not yet able to formulate a coherent sentence. He shook his
head in perplexity, after my attempts to describe the mortal danger that
threatened my body. He could detect no abnormal symptoms other than extremely
dilated pupils. Pulse, blood pressure, breathing were all normal. He saw no
reason to prescribe any medication. Instead he conveyed me to my bed and stood
watch over me. Slowly I came back from a weird, unfamiliar world to reassuring
everyday reality. The horror softened and gave way to a feeling of good
fortune and gratitude, the more normal perceptions and thoughts returned, and
I became more confident that the danger of insanity was conclusively past.

Now, little by little I could begin to enjoy the unprecedented colors and
plays of shapes that persisted behind my closed eyes. Kaleidoscopic, fantastic
images surged in on me, alternating, variegated, opening and then closing
themselves in circles and spirals, exploding in colored fountains, rearranging
and hybridizing themselves in constant flux. It was particularly remarkable
how every acoustic perception, such as the sound of a door handle or a passing
automobile, became transformed into optical perceptions. Every sound generated
a vividly changing image, with its own consistent form and color.

Late in the evening my wife returned from Lucerne. Someone had informed her by
telephone that I was suffering a mysterious breakdown. She had returned home
at once, leaving the children behind with her parents. By now, I had recovered
myself sufficiently to tell her what had happened.

Exhausted, I then slept, to awake next morning refreshed, with a clear head,
though still somewhat tired physically. A sensation of well-being and renewed
life flowed through me. Breakfast tasted delicious and gave me extraordinary
pleasure. When I later walked out into the garden, in which the sun shone now
after a spring rain, everything glistened and sparkled in a fresh light. The
world was as if newly created. All my senses vibrated in a condition of
highest sensitivity, which persisted for the entire day.

This self-experiment showed that LSD-25 behaved as a psychoactive substance
with extraordinary properties and potency. There was to my knowledge no other
known substance that evoked such profound psychic effects in such extremely
low doses, that caused such dramatic changes in human consciousness and our
experience of the inner and outer world.

What seemed even more significant was that I could remember the experience of
LSD inebriation in every detail. This could only mean that the conscious
recording function was not interrupted, even in the climax of the LSD
experience, despite the profound breakdown of the normal world view. For the
entire duration of the experiment, I had even been aware of participating in
an experiment, but despite this recognition of my condition, I could not, with
every exertion of my will, shake off the LSD world. Everything was experienced
as completely real, as alarming reality; alarming, because the picture of the
other, familiar everyday reality was still fully preserved in the memory for
comparison.

Another surprising aspect of LSD was its ability to produce such a
far-reaching, powerful state of inebriation without leaving a hangover. Quite
the contrary, on the day after the LSD experiment I felt myself to be, as
already described, in excellent physical and mental condition.

I was aware that LSD, a new active compound with such properties, would have
to be of use in pharmacology, in neurology, and especially in psychiatry, and
that it would attract the interest of concerned specialists. But at that time
I had no inkling that the new substance would also come to be used beyond
medical science, as an inebriant in the drug scene. Since my self-experiment
had revealed LSD in its terrifying, demonic aspect, the last thing I could
have expected was that this substance could ever find application as anything
approaching a pleasure drug. I failed, moreover, to recognize the meaningful
connection between LSD inebriation and spontaneous visionary experience until
much later, after further experiments, which were carried out with far lower
doses and under different conditions.

The next day I wrote to Professor Stoll the abovementioned report about my
extraordinary experience with LSD-25 and sent a copy to the director of the
pharmacological department, Professor Rothlin.

As expected, the first reaction was incredulous astonishment. Instantly a
telephone call came from the management; Professor Stoll asked: "Are you
certain you made no mistake in the weighing? Is the stated dose really
correct?" Professor Rothlin also called, asking the same question. I was
certain of this point, for I had executed the weighing and dosage with my own
hands. Yet their doubts were justified to some extent, for until then no known
substance had displayed even the slightest psychic effect in
fractionof-a-milligram doses. An active compound of such potency seemed almost
unbelievable.

Professor Rothlin himself and two of his colleagues were the first to repeat
my experiment, with only onethird of the dose I had utilized. But even at that
level, the effects were still extremely impressive, and quite fantastic. All
doubts about the statements in my report were eliminated.



2. LSD in Animal Experiments and Biological Research

After the discovery of its extraordinary psychic effects, the substance
LSD-25, which five years earlier had been excluded from further investigation
after the first trials on animals, was again admitted into the series of
experimental preparations. Most of the fundamental studies on animals were
carried out by Dr. Aurelio Cerletti in the Sandoz pharmacological department,
headed by Professor Rothlin.

Before a new active substance can be investigated in systematic clinical
trials with human subjects, extensive data on its effects and side effects
must be determined in pharmacological tests on animals. These experiments must
assay the assimilation and elimination of the particular substance in
organisms, and above all its tolerance and relative toxicity. Only the most
important reports on animal experiments with LSD, and those intelligible to
the layperson, will be reviewed here. It would greatly exceed the scope of
this book if I attempted to mention all the results of several hundred
pharmacological investigations, which have been conducted all over the world
in connection with the fundamental work on LSD in the Sandoz laboratories.

Animal experiments reveal little about the mental alterations caused by LSD
because psychic effects are scarcely determinable in lower animals, and even
in the more highly developed, they can be established only to a limited
extent. LSD produces its effects above all in the sphere of the higher and
highest psychic and intellectual functions. It is therefore understandable
that speciflc reactions to LSD can be expected only in higher animals. Subtle
psychic changes cannot be established in animals because, even if they should
be occurring, the animal could not give them expression. Thus, only relatively
heavy psychic disturbances, expressing themselves in the altered behavior of
research animals, become discernible. Quantities that are substantially higher
than the effective dose of LSD in human beings are therefore necessary, even
in higher animals like cats, dogs, and apes.

While the mouse under LSD shows only motor disturbances and alterations in
licking behavior, in the cat we see, besides vegetative symptoms like
bristling of the hair (piloerection) and salivation, indications that point to
the existence of hallucinations. The animals stare anxiously in the air, and
instead of attacking the mouse, the cat leaves it alone or will even stand in
fear before the mouse. One could also conclude that the behavior of dogs that
are under the influence of LSD involves hallucinations. A caged community of
chimpanzees reacts very sensitively if a member of the tribe has received LSD.
Even though no changes appear in this single animal, the whole cage gets in an
uproar because the LSD chimpanzee no longer observes the laws of its finely
coordinated hierarchic tribal order.

Of the remaining animal species on which LSD was tested, only aquarium fish
and spiders need be mentioned here. In the fish, unusual swimming postures
were observed, and in the spiders, alterations in web building were apparently
produced by kSD. At very low optimum doses the webs were even better
proportioned and more exactly built than normally: however, with higher doses,
the webs were badly and rudimentarily made.


How Toxic Is LSD?

The toxicity of LSD has been determined in various animal species. A standard
for the toxicity of a substance is the LDso, or the median lethal dose, that
is, the dose with which 50 percent of the treated animals die. In general it
fluctuates broadly, according to the animal species, and so it is with LSD.
The LDso for the mouse amounts to 50-60 mgtkg i.v. (that is, 50 to 60
thousandths of a gram of LSD per kilogram of animal weight upon injection of
an LSD solution into the veins). In the rat the LDso drops to 16.5 mg/kg, and
in rabbits to 0.3 mg/kg. One elephant given 0.297 g of LSD died after a few
minutes. The weight of this animal was determined to be 5,000 kg, which
corresponds to a lethal dose of 0.06 mg/kg (0.06 thousandths of a gram per
kilogram of body weight). Because this involves only a single case, this value
cannot be generalized, but we can at least deduce from it that the largest
land animal reacts proportionally very sensitively to LSD, since the lethal
dose in elephants must be some 1,000 times lower than in the mouse. Most
animals die from a lethal dose of LSD by respiratory arrest.

The minute doses that cause death in animal experiments may give the
impression that LSD is a very toxic substance. However, if one compares the
lethal dose in animals with the effective dose in human beings, which is
0.0003-0.001 mg/kg (0.0003 to 0.001 thousandths of a gram per kilogram of body
weight), this shows an extraordinarily low toxicity for LSD. Only a 300- to
600-fold overdose of LSD, compared to the lethal dose in rabbits, or fully a
50,000- to 100,000fold overdose, in comparison to the toxicity in the mouse,
would have fatal results in human beings. These comparisons of relative
toxicity are, to be sure, only understandable as estimates of orders of
magnitude, for the determination of the therapeutic index (that is, the ratio
between the effective and the lethal dose) is only meaningful within a given
species. Such a procedure is not possible in this case because the lethal doge
of LSD for humans is not known. To my knowledge, there have not as yet
occurred any casualties that are a direct consequence of LSD poisoning.
Numerous episodes of fatal consequences attributed to LSD ingestion have
indeed been recorded, but these were accidents, even suicides, that may be
attributed to the mentally disoriented condition of LSD intoxication. The
danger of LSD lies not in its toxicity, but rather in the unpredictability of
its psychic effects.

Some years ago reports appeared in the scientific literature and also in the
lay press, alleging that damage to chromosomes or the genetic material had
been caused by LSD. These effects, however, have been observed in only a few
individual cases. Subsequent comprehensive investigations of a large,
statistically significant number of cases, however, showed that there was no
connection between chromosome anomalies and LSD medication. The same applies
to reports about fetal deformities that had allegedly been produced by LSD. In
animal experiments, it is indeed possible to induce fetal deformities through
extremely high doses of LSD, which lie well above the doses used in human
beings. But under these conditions, even harmless substances produce such
damage. Examination of reported individual cases of human fetal deformities
reveals, again, no connection between LSD use and such injury. If there had
been any such connection, it would long since have attracted attention, for
several million people by now have taken LSD.


Pharmacological Properties of LSD

LSD is absorbed easily and completely through the gastrointestinal tract. It
is therefore unnecessary to inject LSD, except for special purposes.
Experiments on mice with radioactively labeled LSD have established that
intravenously injected LSD disappeared down to a small vestige, very rapidly
from the bloodstream and was distributed throughout the organism.
Unexpectedly, the lowest concentration is found in the brain. It is
concentrated here in certain centers of the midbrain that play a role in the
regulation of emotion. Such findings give indications as to the localization
of certain psychic functions in the brain.

The concentration of LSD in the various organs attains maximum values 10 to 15
minutes after injection, then falls off again swiftly. The small intestine, in
which the concentration attains the maximum within two hours, constitutes an
exception. The elimination of LSD is conducted for the most part (up to some
80 percent) through the intestine via liver and bile. Only 1 to 10 percent of
the elimination product exists as unaltered LSD; the remainder is made up of
various transformation products.

As the psychic effects of LSD persist even after it can no longer be detected
in the organism, we must assume that LSD is not active as such, but that it
rather triggers certain biochemical, neurophysiological, and psychic
mechanisms that provoke the inebriated condition and continue in the absence
of the active principle.

LSD stimulates centers of the sympathetic nervous system in the midbrain,
which leads to pupillary dilatation, increase in body temperature, and rise in
the blood-sugar level. The uterine-constricting activity of LSD has already
been mentioned.

An especially interesting pharmacological property of LSD, discovered by J. H.
Gaddum in England, is its serotonin-blocking effect. Serotonin is a
hormone-like substance, occurring naturally in various organs of warm-blooded
animals. Concentrated in the midbrain, it plays an important role in the
propagation of impulses in certain nerves and therefore in the biochemistry of
psychic functions. The disruption of natural functioning of serotonin by LSD
was for some time regarded as an explanation of its psychic effects. However,
it was soon shown that even certain derivatives of LSD (compounds in which the
chemical structure of LSD is slightly modified) that exhibit no hallucinogenic
properties, inhibit the effects of serotonin just as strongly, or yet more
strongly, than unaltered LSD. The serotonin-blocking effect of LSD thus does
not suffice to explain its hallucinogenic properties.

LSD also influences neurophysiological functions that are connected with
dopamine, which is, like serotonin, a naturally occurring hormone-like
substance. Most of the brain centers receptive to dopamine become activated by
LSD, while the others are depressed.

As yet we do not know the biochemical mechanisms through which LSD exerts its
psychic effects. Investigations of the interactions of LSD with brain factors
like serotonin and dopamine, however, are examples of how LSD can serve as a
tool in brain research, in the study of the biochemical processes that
underlie the psychic functions.



3. Chemical Modifications of LSD

When a new type of active compound is discovered in pharmaceutical-chemical
research, whether by isolation from a plant drug or from animal organs, or
through synthetic production as in the case of LSD, then the chemist attempts,
through alterations in its molecular structure, to produce new compounds with
similar, perhaps improved activity, or with other valuable active properties.
We call this process achemical modification of this type of active substance.
Of the approximately 20,000 new substances that are produced annually in the
pharmaceutical-chemical research laboratories of the world, the overwhelming
majority are modification products of proportionally few types of active
compounds. The discovery of a really new type of active substance - new with
regard to chemical structure and pharmacological effect - is a rare stroke of
luck.

Soon after the discovery of the psychic effects of LSD, two coworkers were
assigned to join me in carrying out the chemical modification of LSD on a
broader basis and in further investigations in the field of ergot alkaloids.
The work on the chemical structure of ergot alkaloids of the peptide type, to
which ergotamine and the alkaloids of the ergotoxine group belong, continued
with Dr. Theodor Petrzilka. Working with Dr. Franz Troxler, I produced a great
number of chemical modifications of LSD, and we attempted to gain further
insights into the structure of lysergic acid, for which the American
researchers had already proposed a structural formula. In 1949 we succeeded in
correcting this formula and specifying the valid structure of this common
nucleus of all ergot alkaloids, including of course LSD.

The investigations of the peptide alkaloids of ergot led to the complete
structural formulas of these substances, which we published in 1951. Their
correctness was confirmed through the total synthesis of ergotamine, which was
realized ten years later in collaboration with two younger coworkers, Dr.
Albert J. Frey and Dr. Hans Ott. Another coworker, Dr. Paul A. Stadler, was
largely responsible for the development of this synthesis into a process
practicable on an industrial scale. The synthetic production of peptide ergot
alkaloids using lysergic acid obtained from special cultures of the ergot
fungus in tanks has great economic importance. This procedure is used to
produce the starting material for the medicaments Hydergine and Dihydergot.

Now we return to the chemical modifications of LSD. Many LSD derivatives were
produced, since 1945, in collaboration with' Dr. Troxler, but none proved
hallucinogenically more active than LSD. Indeed, the very closest relatives
proved themselves essentially less active in this respect.

There are four different possibilities of spatial arrangement of atoms in the
LSD molecule. They are differentiated in technical language by the prefix
isoand the letters D and L. Besides LSD, which is more precisely designated as
D-lysergic acid diethylamide, I have also produced and likewise tested in
selfexperiments the three other spatially different forms, namely
D-isolysergic acid diethylamide (iso-LSD), L-lysergic acid diethylamide
(L-LSD), and L-isolysergic acid diethylamide (L-iso-LSD). The last three forms
of LSD showed no psychic effects up to a dose of 0.5 mg, which corresponds to
a 20-fold quantity of a still distinctly active LSD dose.

A substance very closely related to LSD, the monoethylamide of lysergic acid
(LAE-23), in which an ethyl group is replaced by a hydrogen atom on the
diethylamide residue of LSD, proved to be some ten times less psychoactive
than LSD. The hallucinogenic effect of this substance is also qualitatively
different: it is characterized by a narcotic component. This narcotic effect
is yet more pronounced in lysergic acid amide (LA-111), in which both ethyl
groups of LSD are displaced by hydrogen atoms. These effects, which I
established in comparative self-experiments with LA-111 and LAE-32, were
corroborated by subsequent clinical investigations.

Fifteen years later we encountered lysergic acid amide, which had been
produced synthetically for these investigations, as a naturally occurring
active principle of the Mexican magic drug olotiuhqui. In a later chapter I
shall deal more fully with this unexpected discovery.

Certain results of the chemical modification of LSD proved valuable to
medicinal research; LSD derivatives were found that were only weakly or not at
all hallucinogenic, but instead exhibited other effects of LSD to an increased
extent. Such an effect of LSD is its blocking effect on the neurotransmitter
serotonin (referred to previously in the discussion of the pharmacological
properties of LSD). As serotonin plays a role in allergic-inflammatory
processes and also in the generation of migraine, a specific
serotonin-blocking substance was of great significance to medicinal research.
We therefore searched systematically for LSD derivatives without
hallucinogenic effects, but with the highest possible activity as serotonin
blockers. The first such active substance was found in bromo-LSD, which has
become known in medicinal-biological research under the designation BOL-148.
In the course of our investigations on serotonin antagonists, Dr. Troxler
produced in the sequel yet stronger and more specifically active compounds.
The most active entered the medicinal market as a medicament for the treatment
of migraine, under the trademark "Deseril" or, in English-speaking countries,
"Sansert."



4. Use of LSD in Psychiatry

Soon after LSD was tried on animals, the first systematic investigation of the
substance was carried out on human beings, at the psychiatric clinic of the
University of Zurich. Werner A. Stoll, M.D. (a son of Professor Arthur Stoll),
who led this research, published his results in 1947 in the Schweizer Archiv
fur Neurologie und Psychiatrie, under the title "Lysergsaure-diathylamid, ein
Phantastikum aus der Mutterkorngruppe" [Lysergic acid diethylamide, a
phantasticum from the ergot group].

The tests involved healthy research subjects as well as schizophrenic
patients. The dosages - substantially lower than in my first self-experiment
with 0.25 mg LSD tartrate - amounted to only 0.02 to 0.13 mg. The emotional
state during the LSD inebriation was here predominantly euphoric, whereas in
my experiment the mood was marked by grave side effects resulting from
overdosage and, of course, fear of the uncertain outcome.

This fundamental publication, which gave a scientific description of all the
basic features of LSD inebriation, classified the new active principle as a
phantas a phantasticum. However, the question of therapeutic application of
LSD remained unanswered. On the other hand, the report emphasized the
extraordinarily high activity of LSD, which corresponds to the activity of
trace substances occurring in the organism that are considered to be
responsible for certain mental disorders. Another subject discussed in this
first publication was the possible application of LSD as a research tool in
psychiatry, which follows from its tremendous psychic activity.


First Self-Experiment by a Psychiatrist

In his paper, W. A. Stoll also gave a detailed description of his own personal
experiment with LSD. Since this was the first self-experiment published by a
psychiatrist, and since it describes many characteristic features of LSD
inebriation, it is interesting to quote extensively from the report. I warmly
thank the author for kind permission to republish this extract.

    At 8 o'clock I took 60 mcg (0.06 milligrams) of LSD. Some 20 minutes
    later, the first symptoms appeared: heaviness in the limbs, slight atactic
    (i.e., confused, uncoordinated) symptoms. A subjectively very unpleasant
    phase of general malaise followed, in parallel with the drop in blood
    pressure registered by the examiners.

    A certain euphoria then set in, though it seemed weaker to me than
    experiences in an earlier experiment. The ataxia increased, and I went
    "sailing" around the room with large strides. I felt somewhat better, but
    was glad to lie down.

    Afterward the room was darkened (dark experiment); there followed an
    unprecedented experience of unimaginable intensity that kept increasing in
    strength. It w as characterized by an unbelievable profusion of optical
    hallucinations that appeared and vanished with great speed, to make way
    for countless new images. I saw a profusion of circles, vortices, sparks,
    showers, crosses, and spirals in constant, racing flux.

    The images appeared to stream in on me predominantly from the center of
    the visual field, or out of the lower left edge. When a picture appeared
    in the middle, the remaining field of vision was simultaneously filled up
    with a vast number of similar visions. All were colored: bright, luminous
    red, yellow, and green predominated.

    I never managed to linger on any picture. When the supervisor of the
    experiment emphasized my great fantasies, the richness of my statements, I
    could only react with a sympathetic smile. I knew, in fact, that I could
    not retain, much less describe, more than a fraction of the pictures. I
    had to force myself to give a description. Terms such as "fireworks" or
    "kaleidoscopic" were poor and inadequate. I felt that I had to immerse
    myself more and more deeply into this strange and fascinating world, in
    order to allow the exuberance, the unimaginable wealth, to work on me.

    At first, the hallucinations were elementary: rays, bundles of rays, rain,
    rings, vortices, loops, sprays, clouds, etc. Then more highly organized
    visions also appeared: arches, rows of arches, a sea of roofs, desert
    landscapes, terraces, flickering fire, starry skies of unbelievable
    splendor. The original, more simple images continued in the midst of these
    more highly organized hallucinations. I remember the following images in
    particular:

    A succession of towering, Gothic vaults, an endless choir, of which I
    could not see the lower portions.

    A landscape of skyscrapers, reminiscent of pictures of the entrance to
    New York harbor: house towers staggered behind and beside one another with
    innumerable rows of windows. Again the foundation was missing.

    A system of masts and ropes, which reminded me of a reproduction of a
    painting seen the previous day (the inside of a circus tent).

    An evening sky of an unimaginable pale blue over the dark roofs of a
    Spanish city. I had a peculiar feeling of anticipation, was full of joy
    and decidedly ready for adventure. All at once the stars flared up,
    amassed, and turned to a dense rain of stars and sparks that streamed
    toward me. City and sky had disappeared.

    I was in a garden, saw brilliant red, yellow, and green lights falling
    through a dark trelliswork, an indescribably joyous experience.

    It was significant that all the images consisted of countless repetitions
    of the same elements: many sparks, many circles, many arches, many
    windows, many fires, etc. I never saw isolated images, but always
    duplications of the same image, endlessly repeated.

    I felt myself one with all romanticists and dreamers, thought of E. T. A.
    Hoffmann, saw the maelstrom of Poe (even though, at the time I had read
    Poe, his description seemed exaggerated). Often I seemed to stand at the
    pinnacle of artistic experience; I luxuriated in the colors of the altar
    of Isenheim, and knew the euphoria and exultation of an artistic vision.
    I must also have spoken again and again of modern art; I thought of
    abstract pictures, which all at once I seemed to understand. Then again,
    there were impressions of an extreme trashiness, both in their shapes and
    their color combinations. The most garish, cheap modern lamp ornaments and
    sofa pillows came into my mind. The train of thought was quickened. But I
    had the feeling the supervisor of the experiment could still keep up with
    me. Of course I knew, intellectually, that I was rushing him. At first I
    had descriptions rapidly at hand. With the increasingly frenzied pace, it
    became impossible to think a thought through to the end. I must have only
    started many sentences.

    When I tried to restrict myself to specific subjects, the experiment
    proved most unsuccessful. My mind would even focus, in a certain sense, on
    contrary images: skyscrapers instead of a church, a broad desert instead
    of a mountain.

    I assumed that I had accurately estimated the elapsed time, but did not
    take the matter very seriously. Such questions did not interest me in the
    slightest.

    My state of mind was consciously euphoric. I enjoyed the condition, was
    serene, and took a most active interest in the experience. From time to
    time I opened my eyes. The weak red light seemed mysterious, much more
    than before. The busily writing research supervisor appeared to me to be
    very far away. Often I had peculiar bodily sensations: I believed my hands
    to be attached to some distant body, but was not certain whether it was my
    own.

    After termination of the first dark experiment, I strolled about in the
    room a bit, was unsure on my legs, and again felt less well. I became cold
    and was thankful that the research supervisor covered me with a blanket. I
    felt unkempt, unshaven, and unwashed. The room seemed strange and broad.
    Later I squatted on a high stool, thinking all the while that I sat there
    like a bird on the roost.

    The supervisor emphasized my own wretched appearance. He seemed remarkably
    graceful. I myself had small, finely formed hands. As I washed them, it
    was happening a long way from me, somewhere down below on the right. It
    was questionable, but utterly unimportant, whether they were my own hands.

    In the landscape outside, well known to me, many things appeared to have
    changed. Besides the hallucinations, I could now see the real as well.
    Later this was no longer possible, although I remained aware that reality
    was otherwise.

    A barracks, and the garage standing before it to the left, suddenly
    changed to a landscape of ruins, shattered to pieces. I saw wall wreckage
    and projecting beams, inspired undoubtedly by the memory of the war events
    in this region.

    In a uniform, extensive field, I kept seeing figures, which I tried to
    draw, but could get no farther than the crudest beginnings. I saw an
    extremely opulent sculptural ornamentation in constant metamorphosis, in
    continuous flux. I was reminded of every possible foreign culture, saw
    Mexican, Indian motifs. Between a grating of small beams and tendrils
    appeared little caricatures, idols, masks, strangely mixed all of a sudden
    with childish drawings of people. The tempo was slackened compared to the
    dark experiment.

    The euphoria had now vanished. I became depressed, especially during the
    second dark experiment, which followed. Whereas during the first dark
    experiment, the hallucinations had alternated with great rapidity in
    bright and luminous colors, now blue, violet, and dark green prevailed.
    The movement of larger images was slower milder, quieter, although even
    these were composed of finely raining "elemental dots," which streamed and
    whirled about quickly. During the first dark experiment, the commotion had
    frequently intruded upon me; now it often led distinctly away from me into
    the center of the picture, where a sucking mouth appeared. I saw grottoes
    with fantastic erosions and stalactites, reminding me of the child's book
    Im Wunderreiche des Bergkonigs [In the wondrous realm of the mountain
    king]. Serene systems of arches rose up. On the right-hand side, a row of
    shed roofs suddenly appeared; I thought of an evening ride homeward during
    military service. Significantly it involved a homeward ride: there was no
    longer anything like departure or love of adventure. I felt protected,
    enveloped by motherliness, was in peace. The hallucinations were no longer
    exciting, but instead mild and attenuated. Somewhat later I had the
    feeling of possessing the same motherly strength. I perceived an
    inclination, a desire to help, and behaved then in an exaggeratedly
    sentimental and trashy manner, where medical ethics are concerned. I
    realized this and was able to stop.

    But the depressed state of mind remained. I tried again and again to see
    bright and joyful images. But to no avail; only dark blue and green
    patterns emerged. I longed to imagine bright fire as in the first dark
    experiment. And I did see fires; however, they were sacrificial fires on
    the gloomy battlement of a citadel on a remote, autumnal heath. Once I
    managed to behold a bright ascending multitude of sparks, but at
    half-altitude it transformed itself into a group of silently moving spots
    from a peacock's tail. During the experiment I was very impressed that my
    state of mind and the type of hallucinations harmonized so consistently
    and uninterruptedly.

    During the second dark experiment I observed that random noises, and also
    noises intentionally produced by the supervisor of the experiment,
    provoked simultaneous changes in the optical impressions (synesthesia). In
    the same manner, pressure on the eyeball produced alterations of visual
    perceptions.

    Toward the end of the second dark experiment, I began to watch for sexual
    fantasies, which were, however, totally absent. In no way could I
    experience sexual desire. I wanted to imagine a picture of a woman; only a
    crude modern-primitive sculpture appeared. It seemed completely unerotic,
    and its forms were immediately replaced by agitated circles and loops.

    After the second dark experiment I felt benumbed and physically unwell. I
    perspired, was exhausted. I was thankful not to have to go to the
    cafeteria for lunch. The laboratory assistant who brought us the food
    appeared to me small and distant, of the same remarkable daintiness as the
    supervisor of the experiment.

    Sometime around 3:00 P.M. I felt better, so that the supervisor could
    pursue his work. With some effort I managed to take notes myself. I sat at
    the table, wanted to read, but could not concentrate. Once I seemed to
    myself like a shape from a surrealistic picture, whose limbs were not
    connected with the body, but were rather painted somewhere close by....

    I was depressed and thought with interest of the possibility of suicide.
    With some terror I apprehended that such thoughts were remarkably familiar
    to me. It seemed singularly self-evident that a depressed person commits
    suicide....

    On the way home and in the evening I was again euphoric, brimming with the
    experiences of the morning. I had experienced unexpected, impressive
    things. It seemed to me that a great epoch of my life had been crowded
    into a few hours. I was tempted to repeat the experiment.

    The next day I was careless in my thinking and conduct, had great trouble
    concentrating, was apathetic. . . . The casual, slightly dream-like
    condition persisted into the afternoon. I had great trouble reporting in
    any organized way on a simple problem. I felt a growing general weariness,
    an increasing awareness that I had now returned to everyday reality.

    The second day after the experiment brought an irresolute state.... Mild,
    but distinct depression was experienced during the following week, a
    feeling which of course could be related only indirectly to LSD.


The Psychic Effects of LSD

The picture of the activity of LSD obtained from these first investigations
was not new to science. It largely matched the commonly held view of
mescaline, an alkaloid that had been investigated as early as the turn of the
century. Mescaline is the psychoactive constituent of a Mexican cactus
Lophophora williamsii (syn. Anhalonium lewinii). This cactus has been eaten by
American Indians ever since pre-Columbian times, and is still used today as a
sacred drug in religious ceremonies. In his monograph Phantastica (Verlag
Georg Stilke, Berlin, 1924), L. Lewin has amply described the history of this
drug, called peyotl by the Aztecs. The alkaloid mescaline was isolated from
the cactus by A. Heffter in 1896, and in 1919 its chemical structure was
elucidated and it was produced synthetically by E. Spath. It was the first
hallucinogen or phantasticum (as this type of active compound was described by
Lewin) to become available as a pure substance, permitting the study of
chemically induced changes of sensory perceptions, mental illusions
(hallucinations), and alterations of consciousness. In the 1920s extended
experiments with mescaline were carried out on animal and human subjects and
described comprehensively by K. Beringer in his book Der Meskalinrausch
(Verlag Julius Springer, Berlin, 1927). Because these investigations failed to
indicate any applications of mescaline in medicine, interest in this active
substance waned.

With the discovery of LSD, hallucinogen research received a new impetus. The
novelty of LSD as opposed to mescaline was its high activity, lying in a
different order of magnitude. The active dose of mescaline, 0.2 to 0.5 g, is
comparable to 0.00002 to 0.0001 g of LSD; in other words, LSD is some 5,000 to
10,000 times more active than mescaline.

LSD's unique position among the psychopharmaceuticals is not only due to its
high activity, in a quantitative sense. The substance also has qualitative
significance: it manifests a high specificity, that is, an activity aimed
specifically at the human psyche. It can be assumed, therefore, that LSD
affects the highest control centers of the psychic and intellectual functions.

The psychic effects of LSD, which are produced by such minimal quantities of
material, are too meaningful and too multiform to be explained by toxic
alterations of brain function. If LSD acted only through a toxic effect on the
brain, then LSD experiences would be entirely psychopathological in meaning,
without any psychological or psychiatric interest. On the contrary, it is
likely that alterations of nerve conductivity and influence on the activity of
nerve connections (synapses), which have been experimentally demonstrated,
play an important role. This could mean that an influence is being exerted on
the extremely complex system of cross-connections and synapses between the
many billions of brain cells, the system on which the higher psychic and
intellectual functions depend. This would be a promising area to explore in
the search for an explanation of LSD's radical efficacy.

The nature of LSD's activity could lead to numerous possibilities of
medicinal-psychiatric uses, as W. A. Stoll's ground-breaking studies had
already shown. Sandoz therefore made the new active substance available to
research institutes and physicians as an experimental drug, giving it the
trade name Delysid (D-Lysergsaure-diathylamid) which I had proposed. The
printed prospectus below describes possible applications of this kind and
voices the necessary precautions.

              Delysid (LSD 25)
      D-lysergic acid diethylamide tartrate


    Sugar-coated tablets containing 0.025 mg. (25 mircog.)
    Ampoules of 1 ml. containing 0.1 mg. (100 microg.) for
    oral administration

    The solution may also be injected s.c. or i.v. The
    effect is identical with that of oral administration
    but sets in more rapidly.


                PROPERTIES

    The administration of very small doses of Delysid
    (1/2-2 microg./kg. body weight) results in transitory
    disturbances of affect, hallucinations, depersonalization,
    reliving of repressed memories, and mild neurovegetative
    symptoms. The effect sets in after 30 to 90 minutes and
    generally lasts 5 to 12 hours. However, intermittent
    disturbances of affect may occasionally persist for several
    days.


           METHOD OF ADMINISTRATION

    For oral administration the contents of 1 ampoule of Delysid
    are diluted with distilled water, a 1% solution of tartaric acid
    or halogen-free tap water.

    The absorption of the solution is somewhat more rapid and more
    constant than that of the tablets.

    Ampoules which have not been opened, which have been protected
    against light and stored in a cool place are stable for an unlimited
    period. Ampoules which have been opened or diluted solutions retain
    their effectiveness for 1 to 2 days, if stored in a refrigerator.


           INDICATIONS AND DOSAGE

    a) Analytical psychotherapy, to elicit release of repressed material
       and provide mental relaxation, particularly in anxiety states and
       obsessional neuroses.

       The initial dose is 25 microg. (1/4 of an ampoule or 1 tablet).
       This dose is increased at each treatment by 25 microg. until the
       optimum dose (usually between 50 and 200 microg.) is found. The
       individual treatments are best given at intervals of one week.

    b) Experimental studies on the nature of psychoses: By taking Delysid
       himself, the psychiatrist is able to gain an insight into the world
       of ideas and sensations of mental patients. Delysid can also be
       used to induce model psychoses of short duration in normal subjects,
       thus facilitating studies on the pathogenesis of mental disease.

       In normal subjects, doses of 25 to 75 microg. are generally
       sufficient to produce a hallucinatory psychosis (on an average
       1 microg./kg. body weight). In certain forms of psychosis and in
       chronic alcoholism, higher doses are necessary (2 to 4 microg./kg.
       body weight).


            PRECAUTIONS

    Pathological mental conditions may be intensified by Delysid. Particular
    caution is necessary in subjects with a suicidal tendency and in those
    cases where a psychotic development appears imminent. The psycho-affective
    liability and the tendency to commit impulsive acts may occasionally last
    for some days.

    Delysid should only be administered under strict medical supervision. The
    supervision should not be discontinued until the effects of the drug have
    completely orn off.


            ANTIDOTE

    The mental effects of Delysid can be rapidly reversed by the i.m.
    administration of 50 mg. chlorpromazine.

           Literature available on request.

           SANDOZ LTD., BASLE, SWITZERLAND


The use of LSD in analytical psychotherapy is based mainly on the following
psychic effects.

In LSD inebriation the accustomed world view undergoes a deep-seated
transformation and disintegration. Connected with this is a loosening or even
suspension of the I-you barrier. Patients who are bogged down in an egocentric
problem cycle can thereby be helped to release themselves from their fixation
and isolation. The result can be an improved rapport with the doctor and a
greater susceptibility to psychotherapeutic influence. The enhanced
suggestibility under the influence of LSD works toward the same goal.

Another significant, psychotherapeutically valuable characteristic of LSD
inebriation is the tendency of long forgotten or suppressed contents of
experience to appear again in consciousness. Traumatic events, which are
sought in psychoanalysis, may then become accessible to psychotherapeutic
treatment. Numerous case histories tell of experiences from even the earliest
childhood that were vividly recalled during psychoanalysis under the influence
of LSD. This does not involve an ordinary recollection, but rather a true
reliving; not a reminiscence, but rather a reviviscence, as the French
psychiatrist Jean Delay has formulated it.

LSD does not act as a true medicament; rather it plays the role of a drug aid
in the context of psychoanalytic and psychotherapeutic treatment and serves to
channel the treatment more effectively and to shorten its duration. It can
fulfill this function in two particular ways.

In one procedure, which was developed in European clinics and given the name
psychotytic therapy, moderately strong doses of LSD are administered in
several successive sessions at regular intervals. Subsequently the LSD
experiences are worked out in group discussions, and in expression therapy by
drawing and painting. The term psycholytic therapy was coined by Ronald A.
Sandison, an English therapist of Jungian orientation and a pioneerof clinical
LSD research. The root -lysis or -lytic signifies the dissolution of tension
or conflicts in the human psyche.

In a second procedure, which is the favored treatment in the United States, a
single, very high LSD dose (0.3 to 0.6 mg) is administered after
correspondingly intensive psychological preparation of the patients. This
method, described as psychedelic therapy, attempts to induce a
mystical-religious experience through the shock effects of LSD. This
experience can then serve as a starting point for a restructuring and curing
of the patient's personality in the accompanying psychotherapeutic treatment.
The term psychedelic, which can be translated as "mind-manifesting" or
"mind-expanding," was introduced by Humphry Osmond, a pioneer of LSD research
in the United States.

LSD's apparent benefits as a drug auxiliary in psychoanalysis and
psychotherapy are derived from properties diametrically opposed to the effects
of tranquilizer-type psychopharmaceuticals. Whereas tranquilizers tend to
cover up the patient's problems and conflicts, reducing their apparent gravity
and importance: LSD, on the contrary, makes them more exposed and more
intensely experienced. This clearer recognition of problems and conflicts
makes them, in turn, more susceptible to psychotherapeutic treatment.

The suitability and success of LSD in psychoanalysis and psychotherapy are
still a subject of controversy in professional circles. The same could be
said, however, of other procedures employed in psychiatry such as
electroshock, insulin therapy, or psychosurgery, procedures that entail,
moreover, a far greater risk than the use of LSD, which under suitable
conditions can be considered practically safe.

Because forgotten or repressed experiences, under the influence of LSD, may
become conscious with considerable speed, the treatment can be correspondingly
shortened. To some psychiatrists, however, this reduction of the therapy's
duration is a disadvantage. They are of the opinion that this precipitation
leaves the patient insufficient time for psychotherapeutic working-through.
The therapeutic effect they believe, persists for a shorter time than when
there is a gradual treatment, including a slow process of becoming conscious
of the traumatic experiences.

Psycholytic and especially psychedelic therapy require thorough preparation of
the patient for the LSD experience, to avoid his or her being frightened by
the unusual and the unfamiliar. Only then is a positive interpretation of the
experience possible. The selection of patients is also important, since not
all types of psychic disturbance respond equally well to these msthods of
treatment. Successful use of LSD-assisted psychoanalysis and psychotherapy
presupposes speclflc knowledge and experience.

In this respect self-examination by psychiatrists, as W. A. Stoll has pointed
out, can be most useful. They provide the doctors with direct insight, based
on firsthand experience into the strange world of LSD inebriation, and make it
possible for them truly to understand these phenomena in their patients, to
interpret them properly, and to take full advantage of them.

The following pioneers in use of LSD as a drug aid in psychoanalysis and
psychotherapy deserve to be named in the front rank: A. K. Busch and W. C.
Johnson, S. Cohen and B. Eisner, H. A. Abramson, H. Osmond, and A. Hoffer in
the United States; R. A. Sandison in England; W. Frederking and H. Leuner in
Germany; and G. Roubicek and S. Grof in Czechoslovakia.

The second indication for LSD cited in the Sandoz prospectus on Delysid
concerns its use in experimental investigations on the nature of psychoses.
This arises from the fact that extraordinary psychic states experimentally
produced by LSD in healthy research subjects are similar to many
manifestations of certain mental disturbances. In the early days of LSD
research, it was often claimed that LSD inebriation has something to do with a
type of "model psychosis." This idea was dismissed, however, because extended
comparative investigations showed that there were essential differences
between the manifestations of psychosis and the LSD experience. With the LSD
model, nevertheless, it is possible to study deviations from the normal
psychic and mental condition, and to observe the biochemical and
electrophysiological alterations associated with them. Perhaps we shall
thereby gain new insights into the nature of psychoses. According to certain
theories, various mental disturbances could be produced by psychotoxic
metabolic products that have the power, even in minimal quantities, to alter
the functions of brain cells. LSD represents a substance that certainly does
not occur in the human organism, but whose existence and activity let it seem
possible that abnormal metabolic products could exist, that even in trace
quantities could produce mental disturbances. As a result, the conception of a
biochemical origin of certain mental disturbances has received broader
support, and research in this direction has been stimulated.

One medicinal use of LSD that touches on fundamental ethical questions is its
administration to the dying. This practice arose from observations in American
clinics that especially severe painful conditions of cancer patients, which no
longer respond to conventional pain-relieving medication, could be alleviated
or completely abolished by LSD. Of course, this does not involve an analgesic
effect in the true sense. The diminution of pain sensitivity may rather occur
because patients under the influence of LSD are psychologically so dissociated
from their bodies that physical pain no longer penetrates their consciousness.
In order for LSD to be effective in such cases, it is especially crucial that
patients be prepared and instructed about the kind of experiences and
transformations that await them. In many cases it has proved beneficial for
either a member of the clergy or a psychotherapist to guide the patient's
thoughts in a religious direction. Numerous case histories tell of patients
who gained meaningful insights about life and death on their deathbeds as,
freed from pain in LSD ecstasy and reconciled to their fate, they faced their
earthly demise fearlessly and in peace.

The hitherto existing knowledge about the administration of LSD to the
terminally ill has been summarized and published by S. Grof and J. Halifax in
their book The Human Encounter with Death (E. P. Dutton, New York, 1977). The
authors, together with E. Kast, S. Cohen, and W. A. Pahnke, are among the
pioneers of this application of LSD.

The most recent comprehensive publication on the use of LSD in psychiatry,
Realms of the Human Unconscious: Observations from LSD Research (The Viking
Press, New York, 1975), likewise comes from S. Grof, the Czech psychiatrist
who has emigrated to the United States. This book offers a critical evaluation
of the LSD experience from the viewpoint of Freud and Jung, as well as of
existential analysis.

Albert Hofmann

LSD - My Problem Child  ©1980 by McGraw-Hill
Published by McGraw-Hill Book Company - ISBN 0-07-029325-2