Article 11181 (8 more) in alt.drugs:
From: an17368@anon.penet.fi
Subject: Problem Child: 2. LSD in Animal Experiments and Biological Research
Organization: Anonymous contact service
X-Anonymously-To: alt.drugs
Date: Tue, 23 Mar 1993 04:57:36 GMT
Lines: 258


2. LSD in Animal Experiments and Biological Research

After the discovery of its extraordinary psychic effects, the substance
LSD-25, which five years earlier had been excluded from further investigation
after the first trials on animals, was again admitted into the series of
experimental preparations. Most of the fundamental studies on animals were
carried out by Dr. Aurelio Cerletti in the Sandoz pharmacological department,
headed by Professor Rothlin.

Before a new active substance can be investigated in systematic clinical
trials with human subjects, extensive data on its effects and side effects
must be determined in pharmacological tests on animals. These experiments must
assay the assimilation and elimination of the particular substance in
organisms, and above all its tolerance and relative toxicity. Only the most
important reports on animal experiments with LSD, and those intelligible to

the layperson, will be reviewed here. It would greatly exceed the scope of
this book if I attempted to mention all the results of several hundred
pharmacological investigations, which have been conducted all over the world
in connection with the fundamental work on LSD in the Sandoz laboratories.

Animal experiments reveal little about the mental alterations caused by LSD
because psychic effects are scarcely determinable in lower animals, and even
in the more highly developed, they can be established only to a limited
extent. LSD produces its effects above all in the sphere of the higher and
highest psychic and intellectual functions. It is therefore understandable
that speciflc reactions to LSD can be expected only in higher animals. Subtle
psychic changes cannot be established in animals because, even if they should
be occurring, the animal could not give them expression. Thus, only relatively
heavy psychic disturbances, expressing themselves in the altered behavior of
research animals, become discernible. Quantities that are substantially higher
than the effective dose of LSD in human beings are therefore necessary, even
in higher animals like cats, dogs, and apes.

While the mouse under LSD shows only motor disturbances and alterations in
licking behavior, in the cat we see, besides vegetative symptoms like
bristling of the hair (piloerection) and salivation, indications that point to
the existence of hallucinations. The animals stare anxiously in the air, and
instead of attacking the mouse, the cat leaves it alone or will even stand in
fear before the mouse. One could also conclude that the behavior of dogs that

are under the influence of LSD involves hallucinations. A caged community of
chimpanzees reacts very sensitively if a member of the tribe has received LSD.
Even though no changes appear in this single animal, the whole cage gets in an
uproar because the LSD chimpanzee no longer observes the laws of its finely
coordinated hierarchic tribal order.

Of the remaining animal species on which LSD was tested, only aquarium fish
and spiders need be mentioned here. In the fish, unusual swimming postures
were observed, and in the spiders, alterations in web building were apparently
produced by kSD. At very low optimum doses the webs were even better
proportioned and more exactly built than normally: however, with higher doses,
the webs were badly and rudimentarily made.


How Toxic Is LSD?

The toxicity of LSD has been determined in various animal species. A standard
for the toxicity of a substance is the LDso, or the median lethal dose, that
is, the dose with which 50 percent of the treated animals die. In general it
fluctuates broadly, according to the animal species, and so it is with LSD.
The LDso for the mouse amounts to 50-60 mgtkg i.v. (that is, 50 to 60
thousandths of a gram of LSD per kilogram of animal weight upon injection of
an LSD solution into the veins). In the rat the LDso drops to 16.5 mg/kg, and
in rabbits to 0.3 mg/kg. One elephant given 0.297 g of LSD died after a few

minutes. The weight of this animal was determined to be 5,000 kg, which
corresponds to a lethal dose of 0.06 mg/kg (0.06 thousandths of a gram per
kilogram of body weight). Because this involves only a single case, this value
cannot be generalized, but we can at least deduce from it that the largest
land animal reacts proportionally very sensitively to LSD, since the lethal
dose in elephants must be some 1,000 times lower than in the mouse. Most
animals die from a lethal dose of LSD by respiratory arrest.

The minute doses that cause death in animal experiments may give the
impression that LSD is a very toxic substance. However, if one compares the
lethal dose in animals with the effective dose in human beings, which is
0.0003-0.001 mg/kg (0.0003 to 0.001 thousandths of a gram per kilogram of body
weight), this shows an extraordinarily low toxicity for LSD. Only a 300- to
600-fold overdose of LSD, compared to the lethal dose in rabbits, or fully a
50,000- to 100,000fold overdose, in comparison to the toxicity in the mouse,
would have fatal results in human beings. These comparisons of relative
toxicity are, to be sure, only understandable as estimates of orders of
magnitude, for the determination of the therapeutic index (that is, the ratio
between the effective and the lethal dose) is only meaningful within a given
species. Such a procedure is not possible in this case because the lethal doge
of LSD for humans is not known. To my knowledge, there have not as yet
occurred any casualties that are a direct consequence of LSD poisoning.
Numerous episodes of fatal consequences attributed to LSD ingestion have
indeed been recorded, but these were accidents, even suicides, that may be

attributed to the mentally disoriented condition of LSD intoxication. The
danger of LSD lies not in its toxicity, but rather in the unpredictability of
its psychic effects.

Some years ago reports appeared in the scientific literature and also in the
lay press, alleging that damage to chromosomes or the genetic material had
been caused by LSD. These effects, however, have been observed in only a few
individual cases. Subsequent comprehensive investigations of a large,
statistically significant number of cases, however, showed that there was no
connection between chromosome anomalies and LSD medication. The same applies
to reports about fetal deformities that had allegedly been produced by LSD. In
animal experiments, it is indeed possible to induce fetal deformities through
extremely high doses of LSD, which lie well above the doses used in human
beings. But under these conditions, even harmless substances produce such
damage. Examination of reported individual cases of human fetal deformities
reveals, again, no connection between LSD use and such injury. If there had
been any such connection, it would long since have attracted attention, for
several million people by now have taken LSD.


Pharmacological Properties of LSD

LSD is absorbed easily and completely through the gastrointestinal tract. It
is therefore unnecessary to inject LSD, except for special purposes.

Experiments on mice with radioactively labeled LSD have established that
intravenously injected LSD disappeared down to a small vestige, very rapidly
from the bloodstream and was distributed throughout the organism.
Unexpectedly, the lowest concentration is found in the brain. It is
concentrated here in certain centers of the midbrain that play a role in the
regulation of emotion. Such findings give indications as to the localization
of certain psychic functions in the brain.

The concentration of LSD in the various organs attains maximum values 10 to 15
minutes after injection, then falls off again swiftly. The small intestine, in
which the concentration attains the maximum within two hours, constitutes an
exception. The elimination of LSD is conducted for the most part (up to some
80 percent) through the intestine via liver and bile. Only 1 to 10 percent of
the elimination product exists as unaltered LSD; the remainder is made up of
various transformation products.

As the psychic effects of LSD persist even after it can no longer be detected
in the organism, we must assume that LSD is not active as such, but that it
rather triggers certain biochemical, neurophysiological, and psychic
mechanisms that provoke the inebriated condition and continue in the absence
of the active principle.

LSD stimulates centers of the sympathetic nervous system in the midbrain,
which leads to pupillary dilatation, increase in body temperature, and rise in

the blood-sugar level. The uterine-constricting activity of LSD has already
been mentioned.

An especially interesting pharmacological property of LSD, discovered by J. H.
Gaddum in England, is its serotonin-blocking effect. Serotonin is a
hormone-like substance, occurring naturally in various organs of warm-blooded
animals. Concentrated in the midbrain, it plays an important role in the
propagation of impulses in certain nerves and therefore in the biochemistry of
psychic functions. The disruption of natural functioning of serotonin by LSD
was for some time regarded as an explanation of its psychic effects. However,
it was soon shown that even certain derivatives of LSD (compounds in which the
chemical structure of LSD is slightly modified) that exhibit no hallucinogenic
properties, inhibit the effects of serotonin just as strongly, or yet more
strongly, than unaltered LSD. The serotonin-blocking effect of LSD thus does
not suffice to explain its hallucinogenic properties.

LSD also influences neurophysiological functions that are connected with
dopamine, which is, like serotonin, a naturally occurring hormone-like
substance. Most of the brain centers receptive to dopamine become activated by
LSD, while the others are depressed.

As yet we do not know the biochemical mechanisms through which LSD exerts its
psychic effects. Investigations of the interactions of LSD with brain factors
like serotonin and dopamine, however, are examples of how LSD can serve as a

tool in brain research, in the study of the biochemical processes that
underlie the psychic functions.



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."


-------------------------------------------------------------------------
To find out more about the anon service, send mail to help@anon.penet.fi.
Due to the double-blind, any mail replies to this message will be anonymized,
and an anonymous id will be allocated automatically. You have been warned.

Please report any problems, inappropriate use etc. to admin@anon.penet.fi.
*IMPORTANT server security update*, mail to update@anon.penet.fi for details.
End of article 11181 (of 11189)--what next? [npq]