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Article 11181 (8 more) in alt.drugs:From: an17368@anon.penet.fiSubject: Problem Child: 2. LSD in Animal Experiments and Biological ResearchOrganization: Anonymous contact serviceX-Anonymously-To: alt.drugsDate: Tue, 23 Mar 1993 04:57:36 GMTLines: 2582. LSD in Animal Experiments and Biological ResearchAfter the discovery of its extraordinary psychic effects, the substanceLSD-25, which five years earlier had been excluded from further investigationafter the first trials on animals, was again admitted into the series ofexperimental preparations. Most of the fundamental studies on animals werecarried out by Dr. Aurelio Cerletti in the Sandoz pharmacological department,headed by Professor Rothlin.Before a new active substance can be investigated in systematic clinicaltrials with human subjects, extensive data on its effects and side effectsmust be determined in pharmacological tests on animals. These experiments mustassay the assimilation and elimination of the particular substance inorganisms, and above all its tolerance and relative toxicity. Only the mostimportant reports on animal experiments with LSD, and those intelligible tothe layperson, will be reviewed here. It would greatly exceed the scope ofthis book if I attempted to mention all the results of several hundredpharmacological investigations, which have been conducted all over the worldin connection with the fundamental work on LSD in the Sandoz laboratories.Animal experiments reveal little about the mental alterations caused by LSDbecause psychic effects are scarcely determinable in lower animals, and evenin the more highly developed, they can be established only to a limitedextent. LSD produces its effects above all in the sphere of the higher andhighest psychic and intellectual functions. It is therefore understandablethat speciflc reactions to LSD can be expected only in higher animals. Subtlepsychic changes cannot be established in animals because, even if they shouldbe occurring, the animal could not give them expression. Thus, only relativelyheavy psychic disturbances, expressing themselves in the altered behavior ofresearch animals, become discernible. Quantities that are substantially higherthan the effective dose of LSD in human beings are therefore necessary, evenin higher animals like cats, dogs, and apes.While the mouse under LSD shows only motor disturbances and alterations inlicking behavior, in the cat we see, besides vegetative symptoms likebristling of the hair (piloerection) and salivation, indications that point tothe existence of hallucinations. The animals stare anxiously in the air, andinstead of attacking the mouse, the cat leaves it alone or will even stand infear before the mouse. One could also conclude that the behavior of dogs thatare under the influence of LSD involves hallucinations. A caged community ofchimpanzees 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 anuproar because the LSD chimpanzee no longer observes the laws of its finelycoordinated hierarchic tribal order.Of the remaining animal species on which LSD was tested, only aquarium fishand spiders need be mentioned here. In the fish, unusual swimming postures
 
were observed, and in the spiders, alterations in web building were apparentlyproduced by kSD. At very low optimum doses the webs were even betterproportioned and more exactly built than normally: however, with higher doses,the webs were badly and rudimentarily made.ttHow Toxic Is LSD?HThe toxicity of LSD has been determined in various animal species. A standardfor the toxicity of a substance is the LDso, or the median lethal dose, thatis, the dose with which 50 percent of the treated animals die. In general itfluctuates 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 60thousandths of a gram of LSD per kilogram of animal weight upon injection ofan LSD solution into the veins). In the rat the LDso drops to 16.5 mg/kg, andin rabbits to 0.3 mg/kg. One elephant given 0.297 g of LSD died after a fewiminutes. The weight of this animal was determined to be 5,000 kg, whichcorresponds to a lethal dose of 0.06 mg/kg (0.06 thousandths of a gram perkilogram of body weight). Because this involves only a single case, this valuecannot be generalized, but we can at least deduce from it that the largestland animal reacts proportionally very sensitively to LSD, since the lethaldose in elephants must be some 1,000 times lower than in the mouse. Mostanimals die from a lethal dose of LSD by respiratory arrest.aThe minute doses that cause death in animal experiments may give theimpression that LSD is a very toxic substance. However, if one compares thelethal dose in animals with the effective dose in human beings, which is0.0003-0.001 mg/kg (0.0003 to 0.001 thousandths of a gram per kilogram of bodyweight), this shows an extraordinarily low toxicity for LSD. Only a 300- to600-fold overdose of LSD, compared to the lethal dose in rabbits, or fully a50,000- to 100,000fold overdose, in comparison to the toxicity in the mouse,would have fatal results in human beings. These comparisons of relativetoxicity are, to be sure, only understandable as estimates of orders ofmagnitude, for the determination of the therapeutic index (that is, the ratiobetween the effective and the lethal dose) is only meaningful within a givenspecies. Such a procedure is not possible in this case because the lethal dogeof LSD for humans is not known. To my knowledge, there have not as yetoccurred any casualties that are a direct consequence of LSD poisoning.Numerous episodes of fatal consequences attributed to LSD ingestion haveindeed been recorded, but these were accidents, even suicides, that may beiattributed to the mentally disoriented condition of LSD intoxication. Thedanger of LSD lies not in its toxicity, but rather in the unpredictability ofits psychic effects.iSome years ago reports appeared in the scientific literature and also in thelay press, alleging that damage to chromosomes or the genetic material hadbeen caused by LSD. These effects, however, have been observed in only a fewindividual cases. Subsequent comprehensive investigations of a large,statistically significant number of cases, however, showed that there was noconnection between chromosome anomalies and LSD medication. The same appliesto reports about fetal deformities that had allegedly been produced by LSD. Inanimal experiments, it is indeed possible to induce fetal deformities throughextremely high doses of LSD, which lie well above the doses used in humanbeings. But under these conditions, even harmless substances produce suchdamage. Examination of reported individual cases of human fetal deformitiesreveals, again, no connection between LSD use and such injury. If there had
 
been any such connection, it would long since have attracted attention, forseveral million people by now have taken LSD.ssPharmacological Properties of LSDPLSD is absorbed easily and completely through the gastrointestinal tract. Itis therefore unnecessary to inject LSD, except for special purposes.iExperiments on mice with radioactively labeled LSD have established thatintravenously injected LSD disappeared down to a small vestige, very rapidlyfrom the bloodstream and was distributed throughout the organism.Unexpectedly, the lowest concentration is found in the brain. It isconcentrated here in certain centers of the midbrain that play a role in theregulation of emotion. Such findings give indications as to the localizationof certain psychic functions in the brain.oThe concentration of LSD in the various organs attains maximum values 10 to 15minutes after injection, then falls off again swiftly. The small intestine, inwhich the concentration attains the maximum within two hours, constitutes anexception. The elimination of LSD is conducted for the most part (up to some80 percent) through the intestine via liver and bile. Only 1 to 10 percent ofthe elimination product exists as unaltered LSD; the remainder is made up ofvarious transformation products.vAs the psychic effects of LSD persist even after it can no longer be detectedin the organism, we must assume that LSD is not active as such, but that itrather triggers certain biochemical, neurophysiological, and psychicmechanisms that provoke the inebriated condition and continue in the absenceof the active principle.oLSD stimulates centers of the sympathetic nervous system in the midbrain,which leads to pupillary dilatation, increase in body temperature, and rise inwthe blood-sugar level. The uterine-constricting activity of LSD has alreadybeen mentioned.bAn especially interesting pharmacological property of LSD, discovered by J. H.Gaddum in England, is its serotonin-blocking effect. Serotonin is ahormone-like substance, occurring naturally in various organs of warm-bloodedanimals. Concentrated in the midbrain, it plays an important role in thepropagation of impulses in certain nerves and therefore in the biochemistry ofpsychic functions. The disruption of natural functioning of serotonin by LSDwas 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 thechemical structure of LSD is slightly modified) that exhibit no hallucinogenicproperties, inhibit the effects of serotonin just as strongly, or yet morestrongly, than unaltered LSD. The serotonin-blocking effect of LSD thus doesnot suffice to explain its hallucinogenic properties.nLSD also influences neurophysiological functions that are connected withdopamine, which is, like serotonin, a naturally occurring hormone-likesubstance. Most of the brain centers receptive to dopamine become activated byLSD, while the others are depressed.LAs yet we do not know the biochemical mechanisms through which LSD exerts itspsychic effects. Investigations of the interactions of LSD with brain factorslike serotonin and dopamine, however, are examples of how LSD can serve as a
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