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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