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 iso- and 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 self-experiments 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 ololiuqui. 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

"Lysergsäure-diathylämid, 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 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.