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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