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Lysergamides LSD chromosome damage myth

red22

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Nov 23, 2009
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1,216
This is a collection of things I've gathered related to this myth, including archive footage of concerned researchers talking about it.

The Mindbenders: Scary Drug Education Films from the 60's, volumes 1 and 2

https://www.imdb.com/title/tt0230530/
https://www.imdb.com/title/tt0299036/

Downloads: https://drive.google.com/drive/folders/1OSwyAgN0cy1JSMFD8itZ51CjcFQPgIEB?usp=drive_link (Downloaded from Something Weird Video)


Quotes from researchers:

Research concluding that LSD produced chromosome damage and birth defects appeared in prominent scientific and medical journals and was repeated often in the popular press. While these findings were soon discredited, the additional negative contribution to LSD’s reputation had been accomplished and there was no going back (Dishotsky, Loughman, Mogar, & Lipscomb, 1971; Presti & Beck, 2001).

Dishotsky, N. I., Loughman, W. D., Mogar, R. E., & Lipscomb, W. R. (1971). LSD and genetic damage. Science, 172, 431–440.

Presti, D. E., & Beck, J. E. (2001). Strychnine and other enduring myths: Expert and user folklore surrounding LSD. In T. B. Roberts (Ed.), Psychoactive sacramentals: Essays on entheogens and religion (pp. 125–137). San Francisco: Council on Spiritual Practices

Handbook of Medical Hallucinogens (Grob & Grigsby, 2021). New York, NY: Guilford Press. ISBN 9781462551897. Chapter 8: LSD (Kristine Panik & David E. Presti), p. 169, first column
Code:
https://mcb.berkeley.edu/labs2/presti/sites/mcb.berkeley.edu.labs2.presti/files/u3/2021%20LSD%20Chapter%20Panik%20Presti.pdf


When in 1967 a scientifically-flimsy report alleged that ʟsᴅ caused chromosome damage in human lymphocytes or white blood cells (Cohen et al. 1967), the National Institutes of Health seized the opportunity to mount a vigorous propaganda campaign, as outlined in the first chapter (Weil 1972). Significantly, this federally-endowed research organization ordered no tests to verify the preliminary report, which was taken at face value since it was welcome news to the government. The then-docile information media fell hook, line and sinker for the great chromosome-damage scare, and ʟsᴅ became the new scapegoat (Braden 1970). The media and the government played on fears generated in the public mind by the Thalidomide tragedy of the late fifties and early sixties, still a vivid and gruesome memory to ʟsᴅ users and non-users alike (see Chapter 1).

No scientific report, however, had ever demonstrated that ʟsᴅ was, like Thalidomide, a teratogen (a substance causing birth defects). When controlled studies were conducted with ʟsᴅ and chromosomes, and when long-time ʟsᴅ users were examined, it was found that there was no significant link between ʟsᴅ use and chromosome damage (Bender & Sankar 1968; Dishotsky et al. 1971; Tjio et al. 1969). It was also found that viral infections as well as many drugs, including caffeine and aspirin, could cause chromosome breaks in lymphocytes in vitro. Although ʟsᴅ use declined initially in the face of the big scare, the end result was the irreparable loss of the United States government's credibility vis á vis drugs (Weil 1972). The government attempted to foist a few other spurious scares on the public: the “flashback” scare, the ʟsᴅ-produces-psychosis scare, ad nauseam. Given the U.S. government’s lack of credibility on drug-related issues, it is not surprising that these scare tactics had only minimal, if any, efficacy at deterring the extra-medical use of ʟsᴅ.

Pharmacotheon: Entheogenic Drugs, Their Plant Sources and History. Jonathan Ott, 1993, 1996

Chapter II: ʟsᴅ, Ololiuhqui, Kykeon: The Ergoline Complex

Section: LSD AND MORNING GLORY SEEDS AS LUDIBLE DRUGS (pages 136-137)

Because of my interest in natural ergolines, I recently uploaded this entire chapter: https://files.catbox.moe/58pcay.pdf And the full book is on the Internet Archive, but it's not directly downloadable, but one can manipulate the Sources feature in Chrome's Developer Tools (i.e. the pages pop up as one flips pages under ia804609.us.archive.org).


In the late fifties, a new tranquilizer known as Thalidomide was admitted for medical use in Germany and other countries. It becamse apparent that the drug was strongly teratogenic, that is, that it produced grave birth defects if taken at the wrong time by pregnant women. The tragic result was a generation of “Thalidomide babies” with hideous and crippling deformities. The drug was immediately taken off the market, and regulations concerning the introduction of new drugs were tightened considerably in many countries.

At this time, under the trade name Delysid, ʟsᴅ-25 was being distributed as an experimental drug by Sandoz ʟᴛᴅ. of Switzerland (see Chapter 2). Since the drug was thought to produce a “model psychosis,” Sandoz felt it might ultimately be an effective psychotherapeutic agent, and indeed it showed considerable promise in early trials. When in 1967 a report in the New England Journal of Medicine alleged that ʟsᴅ caused chromosome damage (Cohen et al. 1967), the scare was on. No matter that the report did not support this allegation, which in later controlled experiments proved to be false (Dishotsky et al. 1971; Tjio et al. 1969), nor show that ʟsᴅ is teratogenic (it is not). The media and governments seized this allegation as a means of attacking ʟsᴅ use, which was spreading rapidly. The media mounted a vigorous scare campaign against ʟsᴅ, which continues to this day.

ʟsᴅ users in the sixties were principally in their late teens or early twenties, and many had vivid memories of the well-publicized Thalidomide tragedy, which had been graphically and luridly chronicled by the press. Many people came to fear ʟsᴅ as a result of the scare campaign. Popular interest in ʟsᴅ had stimulated interest in other entheogenic drugs. One result was the reprinting of Huxley’s and Klüver’s hitherto obscure books on mescaline, and an increasing awareness that ʟsᴅ was not the only entheogenic drug.

Pharmacotheon: Entheogenic Drugs, Their Plant Sources and History. Jonathan Ott, 1993, 1996

Chapter 1: Mescaline, Péyotl, San Pedro, Phenethylamines

Section: NON-INDIAN USE OF PÉYOTL AND MESCALINE (p. 97)

References:

Cohen, M.M. et al. 1967. “In vivo and in vitro chromosomal damage induced by LSD-25” New England Journal of Medicine 227: 1043.

Weil, A.T. 1972. The Natural Mind—A New Way of Looking at Drugs and the Higher Consciousness. Houghton-Mifflin, Boston, ᴍᴀ. Revised edition in 1986. The Natural Mind—An Investigation of Drugs and the Higher Consciousness. Houghton-Mifflin, Boston, ᴍᴀ. German translation, 1974. Das Erweiterte Bewußtsein. Svattgart, Germany. Translated into Portuguese, 1975. Drogas e Estados Superiores da Consciência. Ground, São Paulo, Brasil.

Braden, W. 1970. “LSD and the press” In: Aaronson, B. and H. Osmond (Eds.) Psychedelics: The Uses and Implications of Hallucinogenic Drugs. Doubleday/Anchor, Garden City, ɴᴊ. pp. 400-418.

Bender, L. and DVS. Sankar 1968. “Chromosome damage not found in leukocytes of children treated with ʟsᴅ-25” Science 159. Letter to the editor, 10 January issue.

Dishotsky, N.I. et al. 1971. “ʟsᴅ and genetic damage” Science 172: 431.

Tjio, J.H. et al. 1969. “ʟsᴅ and chromosomes: A controlled experiment” Journal of the American Medical Association 210: 849.
 
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Yeah, I remember those scare tactics back in the day. 👍

But then they also claimed that cannabis would cause insanity, so many people didn't trust the drug propaganda. As a side note, my kids turned out fine.
"One puff and they're lost forever!!!!" was on one of the reefer madness ads iirc,

Oh, and my kids are fine too, oddly enough. All much better at the game of life than I am tbh (One of them was actually conceived on the tail end of a heroic mushroom dose too :cool:).
 
“Based on extensive human experience, it is generally acknowledged that psychedelics do not elicit addiction or compulsive use and that there is little evidence for an association between psychedelic use and birth defects, chromosome damage, lasting mental illness, or toxic effects to the brain or other body organs,” (Teri Krebs quoted in Rothkopf 2015)

EmmaSofia and the case for psychedelic legalization. Joanna Rothkopf, 4/3/15, salon


“The classical serotonergic psychedelics LSD, psilocybin, mescaline are not known to cause brain damage and are regarded as non-addictive.”

Psychedelics and Mental Health: A Population Study. Teri S. Krebs, Pål-Ørjan Johansen. PLoS ONE 8(8): e63972. Aug 19, 2013. DOI: 10.1371/journal.pone.0063972 (Abstract)


“There is no evidence that LSD causes permanent brain damage — and quite a lot of evidence that it doesn't.”

“We are lucky that we have over 1,000 papers written in the '50s and '60s when LSD was given to thousands and thousands of research subjects so we have a pretty good idea at this point what it does and does not do.” - Dr. Andrew Sewell

LSD: The Geek's Wonder Drug? Jan 16, 2006. Wired


“Illegal status means that standard human safety studies can’t be done,” [David] Nutt says. “But we have lots of real world data (like millions of users) with no long term harms apparent.” Albert Hofman, the Swiss scientist who first synthesized LSD in 1938, used the drug regularly, Nutt notes. “Hofman lived till over 100 years as did other pioneers. What more would they like as proof?”

LSD’s Health Benefits Convince Norway to Relax Punishment For Possession. Zachary Siegel, 10/10/17, Vice


“LSD and related substances are not drugs in the usual sense, but are part of the sacred substances, which have been used for thousands of years in ritual settings. The classic psychedelics like LSD, psilocybin and mescaline are characterized by the fact that they are neither toxic nor addictive. It is my great concern to separate psychedelics from the ongoing debates about drugs, and to highlight the tremendous potential inherent to these substances for self-awareness, as an adjunct in therapy, and for fundamental research into the human mind.” (Albert Hofmann)

From a speech given on Hofmann's 100th or 102nd birthday, included in the fourth edition of Stanislav Grof's LSD Psychotherapy.


Added the info in this post in Wikipedia's LSD Talk page: https://en.wikipedia.org/wiki/Talk:LSD#Chromosome_damage_myth

 
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This is probably the most in-depth thing ever written on the subject. Sorry about the OCR typos.

LSD: A Total Study. D.V. Siva Sankar. 1975. PJD Publications Ltd.: Westbury, NY. GENETIC ASPECTS, pages 470–499

TABLE OF CONTENTS

Effects of LSD on Chromosomes and
Genetic Reproduction
Human Studies Studies on Animals
Effects of Other Drugs
Effects of LSD on Plants etc.
Interactions of LSD with Macromolecules
Comparative Studies on Other Drugs
References


Effects on Pregnancy, Chromosomes, Offspring

The studies on LSD in the area of genetics have been clouded with emotion: fair, accurate and inaccurate inferences from several types of studies, reaction to inferences by communication media and popular public information, etc. Further, many of the street drugs have been shown (40, 139, 140) to contain adulterants including more active and more dangerous drugs and combination of drugs all the way to urinary and other excretory material.

The most important work pointing out chromosomal danger in human leucocytes induced by LSD was carried out by Cohen and his coworkers including Back and Hirschhom (1, 2, 3).They reported in Science in 1967 that LSD added to cultured human leucocytes from two healthy individuals caused a marked increase of chromosomal abnormalities. Distinction should be made from the very beginning between the in oitro addition of drugs to a growing tissue cultured in the laboratory and the effects of administration in vivo to a living subject or animal. Any kind of substance in the in vitro technique would cause aberrations in the tissue. As such, experiments conducted in this manner on the effects of drugs to tissue cultures should be taken under criticism. Cohen, et al. extended their work to human beings who have been taking LSD. They did find abnormalities in these humans also. Further, they reported that children exposed to LSD in utero manifested increased chromosomal breakages if the mother had ingested 300 micrograms or more of 'LSD. Chlorpromazine administration also produced breaks which disappeared when the drug was withdrawn.

Experiments with humans who have taken LSD must include an investigaion of their chromosomes before and after the usage of drugs to be a background parameter. Further, the subject should be placed on carefully controlled dosage of the pure drug given under experimental conditions. Without these qualifications, the earlier work of Cohen, et al. began to hit the public in several reports both in professional and popular media. For example, the Medical World News (4) reported almost immediately that researchers have demonstrated that small doses of LSD will similarly damage human chromosomes in vitro and larger doses will produce more widespread damage. To state that these results are preliminary, is comparable to evidence produced in a court to the jury, but struck off the records. It is not this author’s opinion that LSD has no chromosomal effects or effects on pregnancy. We are not aware of these effects in a very rigorous manner and nobody has any real business taking LSD for any non-medical reason till now. LSD has great promises in terms of organic chemical synthesis of analogs which may have particular potent action. D-LSD-25 is an extremely potent hallucinogenic drug. The ergot alkaloids have potent action on the uterus and metabolism of biogenic amines as we have seen in the earlier chapters. As such, their administration will naturally lead to grave problems. Abuse of such drugs should be stopped in the name of research devoted to the production of analogs of therapeutic value.

Nielsen, et al. (5) studied five patients who have been treated for 3 to 39 months with larger doses of LSD. Compared to 40 controls, more chromatid and isochromatid gaps and hyperdiploid cells were seen in the LSD users. Geiger, et al. (6) found that LSD slowed down pulling movements of the neuronal perikarya in cultures from mature brain, but not in neonatal brains. LSD also slowed down axoplasmic flow and movements of boutons at the axosomatic synapsis only in the mature neurons. However, the astrocytes and oligodendroglia remain in a relaxed state upon the addition of LSD. Quimi (7) found that LSD caused numerous chromosomal breaks in Antheraea eucalypti tissue cells cultured in vitro. Gayer and Pribys (8) also reported that the exposure of Hela cells to LSD in vitro caused changes in the sizes and shapes of the nucleoli, and in the rate of their disappearance. On the other hand, Kato and J arvik (9) found that cells from two out of eight subjects did not respond to the in vitro additon of LSD with an increase in chromosomal aberrations. There were, however, varying effects in the other subjects.

Zellweger et al. (10) reported in 1967 that a girl with a malformed right leg was born to a 19-year old woman who had taken LSD on the 25th day after her last menstrual period and three times between the 45th and 98th days. Chromatid breaks were found B1 the child, mother and father (who had also taken the drug). It was suggested that the second dose, taken at a critical period for the production of extremities, may justify the suspicion of a causal relationship. Cohen, et al. (11) reported a larger number of studies on nine children exposed to LSD in utero and four children of LSD users not exposed to LSD in utero. They found significantly elevated frequencies of chromosomal damage in the in utero cases as compared to the matched controls. Besides chromosomal aberrations, the subjects in this study proved to be apparently healthy and showed no obvious birth defects. Abbo et al. (12) in an extension of their previous work found that the incidence of chromosomal drugs in nine psychiatric patients treated with LSD and a young married couple (who have taken LSD) and their child had a higher incidence of chromosomal breaks than 32 normal controls without a history of drug use. Garson and Robson (13) reported a second case of acute leukemia developing after the administration of LSD. They found an unusual pattern of bone marrow chromosomes. The presence of polynucleolar cells may suggest a causal relationship. It may be pointed out that in most of these studies, it was not the same person who was a control for the use of LSD. It was two different sets of human beings; one a non-drug using population, and the other, a drug-using group. However, the results of these studies are formidable enough to suggest that LSD is a potent, but yet dangerous drug.

There are several reports of the effects of LSD in uncontrolled human populations. Hirschhorn and Cohen (14) have done the lead work in this area. They pointed out that the total damage caused to the human population by LSD, both genetically and psychologically, may not be ascertainable for some time to come. This statement is equally valid if the word “LSD” is replaced by “phenothiazines” or “automobiles”. Irwin and Egozcue (15) also found significantly higher chromosomal abnormalities in six out of eight LSD users as compared to non-users. The subjects whose cells showed damage were tested between one day and six months after the last dose of LSD. It may be pointed out that LSD, as a sympathomimetic compound may produce an increased metabolic rate accompanied with hyperthermia, and as such, may affect the rate of regeneration of several regenerating cellular elements. This faster regeneration, obviously, may involve less accurate regeneration.

The radio-mimetic properties of LSD (16) were also highlighted. Radiation is knovsm to produce chromosomal and genetic abnormalities because of the direct hits scored by radiant energy on the gene. This write-up (16) in the New England Journal of Medicine pointed out that the average LSD user may experience somatic mutations and cell depletion at rates equivalent to a dose of 25-50 Roentgens per day of chronic whole body gamma radiation. It further suggested the possibility that the chromosome breaks may be augmented synergistically without other drugs ingested. Cohen has written several papers (17). He concluded that LSD leads to a definite break in the leucocytes, crossed the placental barrier into the fetus, etc. Eighty percent of the humans using LSD may be affected and may contract Bloom's syndrome, Fanconi’s anemia, and ataxia telangiectasia,and possibly leukemia,other cancers,psycl1iatric distasia, etc. Grossbard, et al. (18) also reported the occurrence of acute leukemia in a user of several hallucinogenic drugs. A Philadelphia-like chromosome was also found. Egozcue (19) studied the effects of LSD in 50 LSD users-four of whom had been exposed to the drug in utero. They found that the mean percentage of drugs in user population was almost twice that of the non-user group. The infants exposed to LSD in utero, however, had a chromosomal breakage rate comparable to the mean control'(non-LSD user) value. No correlation was found between the breakage rate, the number of doses and the amount per dose, total dosage or the time interval between the last dose and experimentation. Similarly, there was no correlation between the breakage rate and the number and nature of drugs used. The most common kind of abnormalities were the chromatid and the isochromatid breakages. Cecil J acobson’s work was reported by the New York Times (20) along with that of Hirschhom, Frosch and others on the relation between the use of LSD and genetic abnormalities. The paper concluded that Dr. Jacobson ‘hopes to compile about 20 case histories for presentation to the American Medical Association” four months later. The Joumal of the American Medical Association, in the same year, (21) reported that LSD can produce alterations in human chromosomes. These abnormalities could include fetal loss, congenital malformations, mental retardation, and possibly neoplasia. Jacobson’s work (22) has pointed out chromosomal breakage in more than 50 LSD users in the Washington, D.C. area. Two cases of LSD embryopathy were also pointed out. Eller and Morton (23) reported the birth of an extremely deformed child to a nineteen-year-old woman who had taken LSD once at approximately the time of conception. These deformities included a short neck, a smaller left hemithorax, a protruberant abdomen, clubfoot, etc. X-rays showed multiple hemivertebrae, neural arch defects, etc. The female neonate died at age 40 days. Post-mortem examinations revealed a horseshoe kidney, single midline adrenal gland, etc. Chromosome studies, however, showed normal results.

Hsu, Strauss and Hirschhom (24) reported the congenital abnormalities compatible with D trisomy in a 22year-old female who had taken three doses of LSD nine months prior to conception and one dose three years earlier. They pointed out that LSD might have damaged the germ cells (as the father was also using drugs) prior to fertilization. Intrauterine amputations, amniotic-band syndrome and other teratogenic effects, or a pre-disposition to early rupture, or separation of amniotic membranes may be produced by LSD (25). Amarose and Schuster (26) concluded that although the chromosome breakage between former illicit drug users and controls is statistically different, there is no proof of drug causality between drug abuse and chromosomal damage. It is realized also by the present author that human experimentation in this area is neither freely advisable nor easily possible.

The experiments in controlled setting show less frightening effects of LSD and quite often no statistically valid effects at all. Loughman, Sargent and Israelstam (27) reported in 1967 that the leucocytes from eight human subjects who recently used large doses of LSD showed no significantly higher abnormalities. Sparkes, et al. (28) also found a similar lack of significant differences. However, the statistical treatment of Sparkes’ results (28) were questioned by Kruskal and Haberman (29). Hungerford and his associates (30) studied the effect of LSD-25 treatment in four patients. They found a transitory increase in chromosomal abnormalities after injection of pharmacologically pure LSD. However, these increases were not apparent two to six months later. They concluded that continued use of LSD-25 in a therapeutic settilhg implied no greater risk than other diagnostic and therapeutic procedures. Similar statistically indifferent results were also reported by Lucas and Lehrnbecher (31). Sankar, Rozsa and Geisler (32) studied the chromosomes of 57 child psyciatric patients and 8 non-hospitalized non-drug treated volunteer controls. The patients received either LSD-25 or UML or both. After two years or longer since the time of administration of pure LSD in a therapeutic environment, they reported a much smaller percentage of chromosomal breakage than other workers and found no significant statistical differences between the drug-treated and Similar results in controlled the control populations. Tjio and coworkers (33, 34). by reported were experiments and after the administrabefore chromosomes They studied The pre and post LSD populations. same tion of LSD to the breaks were of the same order. They chromosome aberration suggested that the LSD aberrations found by other workers may be due to impurities or adulterations in the LSD employed, or due to other drugs or upper respiratory infections and hepatitis among such drug-abusing populations; Virus infections are known to be accompanied by chromosomal abnormalities. The statistical analysis of the results of Tjio et al. (34) was questioned by Markowitz and Klotz (35).

Lucas and Lehmbecher (36) used radioautographic studies and found that LSD did not produce a change of a normal labeling pattern of replication of the chromosomes. Corey et al (37) also used a well-designed study. They found no relation between the rate of chromosome breakage, chromosomal aberrations, and LSD dosage or time elapsed between treatment and experimentation. They concluded there was no cytogenetic evidence that LSD produced chromosomal damage in a therapeutic setup (38). Fernandez et al. (39) more recently, also could not detect any increased chromosomal breakage in psychiatric patients administered LSD in therapeutic doses. The purity of the LSD and the use of LSD alone, as opposed to a combination of several abused drugs,becomes important in the studies. Schnoll and Vogel (40) reported that the street samples of drugs collected in Philadelphia and in rock festivals contained mescaline, scopolamine, stryclmine, tetrahydrocannabinol etc.

Hulten, et al. (41) studied the mitotic and meiotic chromosomes in subjects exposed to LSD. A normally formed female baby was born to parents who used LSD before and during the pregnancy. This baby had an increased frequency of chromosome breakage including an interchanged figure at five weeks, but not at eight months of age. There was no evidence of increased frequency of breakage of structural chromosomes in two physically healthy men of whom one had consumed large amounts of LSD six months earlier. Judd, Brandkamp and McGloth]in (42) could not find significant differences in chromosome breakage rates among heavy users of LSD who discontinued the drug, heavy users of LSD who have continued to use it, and drugfree controlled subjects. Stenchever and Jarvis (43) could not find significant breakage in chromosomes from twelve users of LSD, one infant born to an LSD user, and eight controls.

Dorrance, J aniger and Teplitz (44) investigated lymphocyte chomomosomes in 14 subjects exposed to illicit LSD, nine exposed to marijuana, and age-matched controls. They could find no damaged lymphocyte chromosomes. They concluded that the damaged chromosomes might have gone undetected because of selective elimination of cln'omosome damaged cells, or the chromosomes might have been repaired before analysis. Warren, et al. (45) studied LSD exposure in utero . A clinically nonnal child was born with a normal karyotype in spite of repeated exposure to LSD during the first four months of fetal life.

McGlothlin, Sparkes and Arnold (46) reported that the frequencies of spontaneous abortions, premature births and birth defects in 121 human pregnancies, following relatively infrequent low doses of medically administered LSD, were within the normal ranges.

The effect of LSD on the gender of the progeny has attracted some attention (43). Aase, et al. (47) could find evidence of neither teratogenic effect nor chromosomal damage in the offspring of mothers known to have taken LSD during pregnancy. The most unusual feature of their findings was that all the 10 children born to the 10 women using LSD, were females. However, this observation may still be due to fortuitous coincidence and requires further confirmation.

Many studies have been carried out on the effect of . LSD on animals. These studies have the advantage of 1.controlling the subject population, 2.use of animals not previously exposed to any drugs at all, 3.use of pure LSD, etc. The majority of these investigations do not seem to emphasize the genetic effects of LSD that are so often reported in drug abusing humans. DiPaolo, et al. (Q48 and 49) reported no significant differences between control groups and experimental animals in an evaluation of the teratogenicity. J agiello and Polani (50) investigated the effects of LSD-25 on mouse germ cells. They administered LSD for a total duration of 31 days, sacrificing different animals of different experimental groups at different intervals. Over the range of doses reported to be effective in terabogenesis and in chromosome damage in leukocyte cultures of human blood, no convincing effect was found on the chromosomes of first or second meiotic divisions, nor in the bone marrow of the spermatogonial metaphases. They concluded that LSD does not produce favorable chromosomal abnormalities in the germ cells of mice. Nosal (51) treated rats with LSD for the first eight days after birth. No microscopic detectable modifications in the nucleoribosomal system of the Purkinje cells in the cerebellar cortex could be found. When pregnant rats were administered LSD on the 4th, 7th, -or 8th days of gestation, there were no teratogenic or toxic effects of the fetuses examined on the 19th day of gestation. The usual gestation period in the rat is approximately 21 days. Uyeno (52) found that no differences in behavioral tests on locomotive and learning abilities were produced by LSD in the offspring of female rats given LSD. He also could not find any significant differences either in the reproduction success or in the occurrence of teratogenic effects between the control and LSD-treated groups. Similar lack of teratogenic action of LSD in rats, mice and hamsters were reported by Roux, et al. (53). This group studied 98 pregnant rats, 67 mice and 22 hamsters, and a total of 1,003 rat fetuses, 521 mouse fetuses and 189 hamster fetuses. They could not find any growth depressing, abortifacient or teratogenic activity on the part of LSD. Sato, et al. (54) also reported that exposure of pregnant rats to LSD during implantation or during the period of differentiation did not result in any chromosome damage in the mother, in the embryos, or adult offspring.

LSD is not unique in being involved in genetically damaging effects. Treatment of pregnant rats with chlorpromazine was shown to result in more resorptions of fetuses than in controls by Beall (55). On the other hand, Emerit, Roux and Feingold (56) found that the administration of LSD from the 4th to the 13th days of pregnancy to pregnant rats did not produce any in vivo chromosome damage either in the embryos or in matemal bone marrow. Gayer (57) also could not find any effects of LSD on the average number of chromosomes in diploid somatic cells in the bone marrow of mice. These results do point out rather strongly that LSD may not have any significant effects on the genetic system. Howevér, the effects involved on the smooth muscular system and on the related effects on blood and circulation, blood pressure, vasoconstriction, metabolic rate, etc. could induce adequate damage to rule out LSD as an innocuous compound.

Obstetric complications and abortion may result from these effects of LSD in a manner unrelated to the genetic reproduction. Sommer and Buchanan (58) found that ergotoxine or ergotamine injected into rats during the second half of gestation affected lactation adversely. The total milk yield diminished with the fat content of the milk. Astrom and Samelius (59) investigated the action of serotonin and LSD on the umbilical veins of the human placenta. They found that serotoniniwas ten times more potent phrine in this vasoconstrictor action on placenta. This action of serotonin was antagonized by anti-epinephrine compounds like phentolamine or chlorpromazine. LSD and tryptamine exerted specific and strong anti-serotonin activity. Gant and Dyer (60) found that both LSD and serotonin contracted isolated human umbilical veins. LSD may cross the placental barrier, cause constriction of umbilical blood vessels, and result in fetal hypoxia, death and/or expulsion. Thalidomide produced teratogenic effects on rabbit fetuses while LSD did not (61).

Ingestion of LSD by a pregnant mother who produced a deformed child was reported (62). The distal phalanges of the third finger of the infant’s right hand were absent, and there was a freely movable stump. However, karyotypes of both mother and child were normal and there was no sign of chromosomal damage. These authors pointed out that in many cases reported the LSD lesions may have been more severe on the right side. McGlothlin, et al. (46) reported on the possible untoward effects of LSD on human pregnancy. The undesirable effects seem to be more frequent when the mother received LSD as opposed to the father only. However, examination of 121 pregnancies involving the use of LSD did not permit establishment of a clear causal relationship. Stone, et al. (63) found a higher incidence of maternal complications in LSD users than in the general population. The possible teratogenic effects of LSD consisting of amniotic band syndrome, etc. have been mentioned earlier (Blanc et al. 25).

Darrieulat and Parant (64) found that UML counteracted the abortive effect of the Salmonella endotoxin in mice. Sankar and Geisler reported that chlorpromazine increased chromosomal breakage in mouse leucocytes cultured in vitro while aspirin had no effect (65).

Jacobson and Berlin (66), as was promptly reported by the press (68), studied 140 women who have used LSD prior to or during pregnancy through 148 pregnancies. About half of the pregnant women took 2 to 20 doses of LSD both before and during pregnancy. One hundred percent of the cases ingested marijuana, and a significant proportion ingested several other drugs as well. The other possible mutagens, besides the psychotropic drugs included coffee or tea, cyclamates, tobacco and X-rays. Of the 148 pregnancies, only 85 ended with live infants. Seventy five of these infants were normal -the other three neonates had major congenital anomalies. Jacobson concluded that there cannot be a definitive correlation of increased genetic damage with LSD ingested in this population. The subjects seem to have used so many drugs that one does wonder whether they were normal at all to begin with under any circumstances.

Messier (67) found that the in vitro addition of LSD to the culture medium of chick embryos retarded the segmentation of mesoderm and somites and caused a collapse of the roof of the neural tube. However, the effects on the infants were not uinque to LSD only. Studies (69) on the use of marijuana and heroin have shown that the consumption of heroin by the mother led to a low birth weight of the neonate, who may have later problems arising from low birth weight.

Only results subsequent to the administration of LSD to animals have also been reported. Cohen and Mukherjee (70) reported that there was an approximately three-fold increase in the number of chromosomal breaks in the femoral bone marrow, spermatogonal and meiotic cells from male mice injected with a single dose of LSD. The meiotic cell chromosomal aberrations reached a maximum between two to seven days and retumed to control levels in three weeks. Skakkebaek, et al. (71) injected healthy male mice with ‘LSD from one to eight times for a period of up to three days. They found several changes, aberrations, and breaks, while the location of most changes on a chromosome could not be explained. They concluded that if the chromosomal abnormalities are due to LSD, use of this drug may have serious effects on the litter size and number of congenital malformations in mice, Stasik and Kidwell (72) found that LSD had a greater adverse effect on inbred mice than on cross-breeds in T-maze learning. In the baboon [Papio papio] (73,74) LSD caused an increase in the leucocyte alkaline phosphatase activity along with the appearance of morphologically abnormal blast cells, both of which disappeared in eight weeks. Bick (75) exposed the kangaroo rat leucocytes to LSD or heliotrine or radiation. He found that a signicant proportion of the damaging effects produced by LSD occurred in the heterochromatin. LSD initially inhibited mitosis, but later stimulated cell division. He also found that the chromosome damage was linearly related to the concentration of LSD. One hundred R of X-rays were equivalent in their effects on chromosome damage to approximately 4.2 micrograms of LSD per milliliter.

Treatment of Xenopus laevis embryos (76) with‘LSD at various stages of development resulted in long-lasting changes. The whole embryo and the brain differed in terms of their periods of maximum sensitivity to LSD. Administration of LSD (77) on the eighth day of pregnancy to mice produced fetal absorption in 7.6 percent of the mice and teratogenicity in % of the offspring, as examined ve days after LSD. Most of the damaged fetuses displayed circulatory disorders and deformation of the third primitive cerebral vesicle. On the other hand, Scheuer (78) reported that LSD was embryo toxic, but not teratogenic in mice at a dose of ten micrograms per day orally on days one to twelve of pregnancy. Mutagenic damage effects of LSD were found in the Drosophila (79). One-fifth of 75 males injected intraperitoneally with massive doses of LSD survived and ten were mated. Recessive lethals were found among the progeny of six of the ten treated males. On the other hand, Kastratsis (80) reported that there were no significant differences between the LSD and untreated control groups either in the egg-to-adult viability or egg-laying capacity in Drosophila. These results were contradicted in further work by Vann (81) who found that LSD-25 increased lethal mutations in Drosophila; the increase becoming statistically significant only at a higher dose level (2 milligrams per He found that injection of LSD was more milliliter). effective than its oral ingestion. LSD apparently acts primarily on the mature post meiotic sperm of Drosophila.

Administration of LSD to male mice twice weekly for five weeks caused (82) the production of deformed spermatozoa. The changes in the diakinesis/metaphase I were located on the X chromosome. Work by Markowitz, et al. (83) also showed that feeding high concentrations of LSD to Drosophila males produced a significant increase in the frequency of sex-linked recessive lethal mutations, but no detectable increase in chromosomal rearrangements. There is probably a threshold dose of LSD in Drosophila for producing the mutagenic effect. A similar increase of the frequency of sex-linked recessive lethal mutates in the more mature sperm cells of Drosophila subsequent to the injection of LSD was also reported by Mazar, et al. (84).

Auerbach and Rugowski (85) administered LSD to mice on the seventh day of pregnancy. Four days later, examination of the embryos revealed that 57 percent of the experimental embryos were deformed as compared to ten percent of the control embryos (still a high percent of deformed in control animals). The malformations involved brain defects, abnonnalities of the lower jaw, eye position, etc. Medical Newsweek (86) reported that the Neurotoxicology Research Unit of the New York Stte Psychiatric Institute (87) found birth defects induced in rats by minute doses of LSD. These defects included stunted offspring, resorption of the fetus, delivery of still bom and abnormally small litter size. Alexander, et al. (88) further demonstrated the inheritance of abnormalities in three generations of offspring of LSD-treated rats. They found that the mating of 43 second-generation treated rats resulted in 29 pregnancies, 13 of them abnormal. When both parents were offspring of treated females, 70 percent of the pregnancies were abnormal while 32 percent abnormalities were found in pregnancies resulting from one treated parent.

Geber (89) also found several congenital malformations in hamsters treated with doses of mescaline, LSD or BOL on the eighth day of pregnancy. No correlation could be established between dose and percentage of congenital malformations. LSD can easily penetrate into the young hamster’s fetus (90), but the placenta appeared to decrease the transfer during the last week of pregnancy. High doses of LSD administered to mice on the sixth,seventh,eighth,or ninth day of pregnancy resulted in a high incidence of abnormalities of the lens of the eye (91).

In the Rhesus monkey (92), administration of LSD was associated with a transient increase in chromosome breaks. LSD was given to hundreds of pregnant rats by Alexander, et al. (93). Incidence of intrauterine fetal deaths, abortions, resorptions, runting, still born, etc. was increased, while teratogenicity during any particular period could not be demonstrated. Treatment during the first seven days (one-third of the gestational period in the rat) was hannful. Later treatment was ineffective. Several congenital deformities were noted by Eller and Morton (94) in an infant whose mother used LSD only at approximately the time of conception. LSD was also shown to possess teratogenic activity in chick blastoderms (95) while no increase in mortality or growth depression could be found. Nineteeen percent of 1,015 embryos resulting from 96 LSD-treated mice were deformed, while 14 percent were absorbed (96). In control mice 15 percent of the embryos were deformed and 9 percent were absorbed. Similarly, the egg-laying capacity of Drosophila and the egg-adult viability were also adversely affected by LSD (97).

The transplacental penetration of LSD was studied (98) in the mice using radio-actively labeled LSD. As was reported earlier (see chapter on metabolism of LSD), the LSD passed in a few minutes from the blood into the tissues, the higher uptake being found in the brain, adrenals, hypothesis, kidneys, liver and lungs. Excretion into the bile also started immediately. The biliary secretion of LSD is comparable to that of drugs like Warfarin. In the early stages of pregnancy, appoximately 2.5 percent and in the later stages 0.5 percent of the radio-activity passed the placental barrier in five minutes into the fetus. Over 70 percent of the radio-activity in the fetus was due to unchanged LSD (98, 99).

The effects of LSD in the plant kingdom have also attracted some attention. Germinated seeds of barley were treated with LSD and squashed root tubes studied for chromosomal aberrations (100). Extensive chromosomal aberrations were found, most being chromosome breaks and only half of them occurring in the region ‘of the primary constriction. Other reports could not find any adverse effects of LSD on the plants. For example, Zetterberg (101) found that LSD was not toxic, did not affect the growth rate of ascomycete Ophiostoma multiannulatum. LSD was not effective in inducing forward mutations and had no significant inuence on biogenic mutations. Riley and Neuroth (102) could not find any effects of LSD on the chromosomes of the broad bean (Vicia faba) or the onion (Allium sepa). Similarly, LSD had no effect on the chromosomes of the meristematic root cells of Alium sativum (103 ). The question of permeability of LSD into the plant tissues in order to exert the effect was also raised.

In Escherichia coli (104) LSD produced a significant number of auxotrophic mutations; the response being linearly related to dose. The mutation rate increased by 0.0001 percent over the spontaneous level, with a possible threshold dose of 0.1 miligram per milliliter. Interesting studies have been made (105) on the effects of LSD on the photodynamic inactivation to repair deficient E. coli and bacteriophage. LSD, if present during the exposure of the microorganism to This a dose of irradiation, markedly decreased survival. survival of the coliphage, preirradiated and sensitized with LSD, was higher when the exposed phages were plated on The relatively high hosts capable of repairing DNA. amounts of LSD used did not produce detectable DNA damage in the absence of radiation.


INTERACTIONS OF LSD WITH MACROMOLECULES

One of the earlier works on the binding of LSD by a macromolecule was done by Fisher (10_6), who found a reverse correlation between the affinity to wool (binding), and the doses of mescaline, methadone and LSD required to cause psychotomimetic reactions in humans. Wagner (107) found that LSD markedly changed the ultra-violet circular dichroic spectrum of calf thymus DNA. He suggested that LSD may intercalate within the DNA helix or disassociate the histones from chromosomal _DNA by neutralizing the phosphate anions. Yielding and Sterglanz, (108) reported changes in the absorption spectrum of LSD on addition of DNA with an equimolecular binding ratio. Binding was abolished on heating the DNA to 100° and cooling suddenly. Magnesium chloride or loss of helical structures at acid pH reduced the binding. The effect was more specific to DNA than to RNA. BOL also showed similar binding properties (109). Smythies suggested that the serotonin receptor site (109). Smythies (110 - see also chapter by Bradley and Smythies in this book) suggested that the serotonin receptor site in the brain may be a segment of helical RNA. In the planarians, treatment with LSD increased the amount of RNA in cephalic pieces containing the cerebral plexus of “brain” very rich in nerve cells (111). Inasmuch as BOL also reacted (109) with the DNA the question of the specificity of the effects of LSD remains unanswered.

Further studies (112) raised significant doubts as to the validity of the binding of LSD to DNA. There were no changes in the circular dichroic spectra of DNA in the presence of LSD (113). This was true even when the DNA was heated in the presence of LSD. Equilibrium dialysis and circular dichroism studies also could not indicate any binding between the DNA and D-or L-LSD. These studies, unfortunately, do not support the much fancied specific interaction of LSD to DNA (114).

LSD was shown to be antigenic with its use as a hapten on an antigenic macromolecule (115). This property has been used by several workers to develop an analytical radioimmune assay technique for the determination of LSD.

SOME STUDIES ON THE EFFECTS OF OTHER DRUGS

Dihydroergotamine failed to block (116) the actions of adrenaline and noradrenaline in pregnancy and labor. The effects of several drugs on the behavior of adult mammalian brain cells in culture was studied by Geiger (117). LSD in extremely small doses had a visible effect on the number of structural units of the living neurons. Acetyl choline had similar effects, while serotonin, epinephrine, norepinephrine, and pentylenetetrazole often produced chromatolysis in neurons. J arvik (118) found that other agents like aspirin and streptonigrin produced chromosome breaks as effectively as LSD did. He listed the factors which could inuence the final frequency of chromosome breakage to be: radiation, viral infections, chemical and biological agents, differences in media, stains, use of antibiotics and the methods of distilling water, etc. Streptonigrin administered from the fifth day to the 17th day of pregnancy produced malformations (119) including cleft palate, exencephaly, etc. Streptomycin also produced (120) chromatic lesions while chromatid and isochromatid breaks were not induced. Tetrahydrocannabinols added to human leucocyte cultures induced (121) a decrease in the mitotic index without increasing the number of chromosome breaks and/or gaps. Diazepam (122) did not manifest any damaging effects on human lymphoblast chromosomes. Indospicine (123) administered to pregnant rats on the 13th day of gestation produced cleft palate in 81 percent of the viable fetuses. Chlorpromazine administered to mice (124) was shown to induce increased chromosomal breakage over control untreated mice. In summary, several drugs have effects which range from producing breaks in chromosomes to teratogenic,mutagenic and carcinogenic activities. LSD, however, is strongly implied in such processes. Especially in the absence of any therapeutic prescription, LSD should be avoided.

There have been several review-type articles linking LSD to adverse genetic efects. The Journal of the American Medical Association warned the public of such possibilities (125). The British Medical Journal (126) also warned of such powerful cytogenic effects. Similar reviews were published by other media also (127, 128, 129). Di Paolo and Alexander pointed out (130) that a better planned experimentation of administering LSD at different times of pregnancy besides preimplantation and several routes of administration should be investigated. Prince (131) pointed out the possible abuse in Cohen’s work and the possibility of technical errors creeping into the work. He also questioned the relation between chromosomal breakage and possible developmental anomalies. Fitzgerald and Dobson (132) questioned the condemnation of LSD as a radiomimetic compound with genetic hazards. Similar challenge against the inculpation of LSD was made by Blaine( 133).Houston( 134) concluded that there is no adequate evidence that LSD could cause chromosomal damage or adversely affect pregnancy. However, he warned against taking LSD early in pregnancy. Fort (135) also pointed out the increased hazard of LSD administration early in pregnancy. Fort (135) also came to the conclusion that the question of the genetic effects of 'LSD is still scientifically undecided. He also pointed out the increased hazard of LSD administration early in pregnancy and also the hazards related to direct physiological effects of the drug. Friedel (136) reported the effects of LSD on chromosomes and came to comparable conclusions. Long (137) reviewed the effects of LSD including the reports of limb defects in five children out of 161 children of parents who took LSD. Long concluded that LSD cannot be given a clean bill of health and in therapeutic use should be weighed against possible risks.

The most extensive review on the genetic damage of LSD was carried out by Dishotsky and his associates (138). They summarized literature available till the end of 1970 in a masterful manner. They pointed out that of nine in vitro subjects, six reported some degree of induced chromosome breakage after exposure to LSD while the three could not confirm these results. They concluded the validity of these in vitro results correctly. As pointed out in this chapter, most chemicals would have effects on tissue cultures of leucocytes. This problem is further magnified due to the absence of the excretory and detoxifying systems in an in vitro culture. Of the 21 in vivo chromosomal studies comprising a population of 310 subjects, 126 were treated with pure LSD and the rest were exposed to illicit LSD. It was pointed earlier (40) that the street LSD is by no means at all pure. Of all the illicit drugs, methamphetamine has been reported to be most contaminated (139, 140). In one study (139) samples of street methamphetamine have been found to contain solvent residues, mercury, methylamine, etc., whereas in another sample of methamphetamine human urine and a toxic oor cleaner (140) were detected. In subjects using pure LSD, 14.29 percent were reported to have higher than normal frequency of chromosomal aberrations whereas 48.9 percent of the illicit LSD users had higher frequencies of chromosomal aberrations. Of the 108 subjects with chromosomal damage, only 18 were exposed to pure LSD. Dishotsky, et al. (138) pointed out that the mutagenic effect of LSD was noticeable at concentrations of two to ten milligrams LSD per milliliter. This is comparbale, assuming six liters of blood in an average person, to a total body dose of 12 to 60 grams of LSD per human subject. The average hallucinogenic dose of LSD in humans is 1/10 of a milligram 0r1 / 10,000 of a gram. In view of this, the mutagenic effects of LSD are by no means unique or specific to LSD only.


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138. Dishotsky,N.I., Loughman,W.D., Mogar,R.E., and Lipscomb,W.R. Science 172, 431 (1971).

139. Sager,R.K. Fed. Bur. Narc. Dangerous Drugs. San Francisco. Personal communication to Dr. Dishotsky, et al. cf. 138.

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The irony is that thalidomide doesn’t cause chromosomal damage either.

It acts as an adaptor for the cell’s protein degradation machinery (in addition to being a barbiturate-like sedative).

Cells tag proteins for degradation by attaching chains of a small protein called ubiquitin to them. Ubiquitinated proteins then get shredded back to their amino acids.

Thalidomide binds to a protein called an E3 ligase (cereblon in particular, which I am only mentioning because it is a sick name), which attaches ubiquitin to soon to be degraded proteins, and alters the clients to that ligase.

This means you have proteins that escape degradation when they normally would be degraded, and proteins which would normally be stable being degraded. This is particularly important in development, when the synthesis and degradation of proteins called transcription factors, which begin a gene’s journey through mRNA to protein, as there is a tightly coordinated ballet of transcription factor activation and silencing in development.

Thalidomide gums this up, causing massive birth defects. Even worse it was indicated as a morning sickness remedy. These days the E3 ligase effects are used in the treatment of some cancers, and it has inspired the class of drugs known as protacs, or targeted protein degraders.

Protacs are basically any drug which binds a protein linked to the pharmacophore of thalidomide by some kind of chain (often poly ethylene glycol or polyethylamine linkages). These bring the target of the first drug (often kinase inhibitors) in proximity to E3 ligases, causing them to get degraded. As the drug doesn’t get degraded these compounds have very potent pharmacokinetics.
 
the pharmaceutical industry is full of bunko meds, and a few good ones
meantime LSD is amazingly nontoxic while powerfully psychedelic.
 
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