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."