LSD — My Problem Child
Albert Hofmann
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 specific 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 LSD. 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
LD50, 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 LD50 for the mouse
amounts to 50-60 mg/kg. 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 LD50 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 dose 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.
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