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."