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  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.

Chapter 3

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