LSD — My Problem Child
Albert Hofmann
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 a chemical 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 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."
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