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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