Laboratory studies of the effects of hallucinogenic drugs on chromosomes and developing embryos are reviewed. The author concludes that at present there is no adequate evidence that these drugs cause chromosomal damage in vivo or adversely affect progeny as a result of chromosomal changes. However, these drugs when taken early (but not late) in pregnancy appear to have a teratogenic effect.

MANY CLAIMS, reports, and lurid stories have appeared recently about the dangers of the strong hallucinogenic drugs (LSD, mescaline, psilocybin, peyote, etc.). It has been claimed that these drugs are dangerous because, among other reasons, they cause damage to chromosomes and embryos that may, in either or both cases, lead to "LSD Monsters"(12). This has been likened to the thalidomide tragedy(12) and has caused great concern among physicians, lawmakers, and the general public.

A number of laboratory studies have now been done on the effects of strong hallucinogenic drugs on chromosomes and embryos. This paper will briefly review some of these studies in order to evaluate the adequacy of the claims made about these drugs.

Effects on Chromosomes
The research on the possibility that hallucinogenic drugs cause damage to chromosomes has proceeded along three different avenues, the first of which has been to examine the effect of LSD on the chromosomes of leukocytes cultured in vitro. Cohen, Marinello, and Back(6) conducted such a study in which they compared chromosomes of leukocytes cultured for varying periods of time (four to 48 hours) with varying concentrations of LSD, and chromosomes of cells which had not been cultured with LSD. Their conclusion was that LSD had generally had a damaging effect, but their procedure and subsequent data are misleading.

Cerietti(5) demonstrated that most of an LSD dose is excreted from the body within an hour, yet the minimum time period studied by Cohen and associates was four hours. Also, Loughman, Sargent, and Israelstrom(II) calculated that the maximum effective concentration in the human body after a 100 m g. dose of LSD would be essentially the same concentration as the lowest used by Cohen and associates. For this concentration and an exposure time of four hours, Cohen's data revealed no difference in chromosomal damage between leukocytes cultured in LSD and cells not cultured in LSD.

The second approach to the study of this question has been to examine chromosomes of leukocytes of people who are known to have taken LSD. This research has also yielded somewhat confusing results. Irwin and Egozcue(9) reported an abnormal amount of chromosomal damage in leukocytes of LSD users. However Loughman, Sargent, and Israelstrom(II) failed to find evidence of extraordinary chromosomal damage in eight "hippie" drug users.

Also, Bender and Siva Sankar(3) compared the incidence of chromosomal damage in five psychotic children who had received LSD-25 for psychotherapeutic reasons with five who had not received the LSD. Some of the children had been given LSD each day for as long as two or three years. These investigators found no differences in chromosomal damage between the two groups of children. Sparkes, Melnyk, and Bozzetti(14) compared the frequency of chromosomal aberrations in the lymphocytes of four persons who had received LSD as part of medical treatment and four persons who had taken LSD privately, as well as four control subjects. No significant differences were found between the control group and the two groups of LSD users.

The results of Irwin and Egozcue(9) may have been due to chance; that is, the investigators may just have happened to study people with chromosomal damage who had also taken LSD, or the results may have been due to impurities in the LSD or other drugs their subjects had taken. To this point, Irwin and Egozeue(IO), in replying to Bender and Siva Sankar's(3) report state: ". . . there is no direct evidence to date demonstrating chromosomal damage after pure LSD-25 administration. It might conceivably have been produced by impurities present in the illicit material used" (p. 749).

The implications underlying the possibility that hallucinogenic drugs might cause chromosomal damage are that it would lead to some kind of abnormality in offspring. Up until recently, however, no one has investigated the effect of a hallucinogenic drug on the chromosomes of the germ cells themselves or, more directly, the drug's ultimate effect on offspring.

Skakkebaek, Philip, and Rafaelsen(13) compared germ cell chromosomes of group of male mice who had received an injection of LSD with germ cell chromosomes of a group of mice who had received the drug. There were very small differences between the two groups in the proportions of damaged to undamaged chromosomes. The results were so modest that the investigators refrained from making a statistical test on them.

Recently two studies have been done in which LSD's mutagenic potential has been investigated with Drosophila melanogaster. In one study by Grace, Carlson, and Goodman(8), male drosophila were injected with varying dosages of LSD, and the frequency of mutations in their offspring was compared with that for drosophila injected with a control substance (tartrate solution, 8.7 m g. per ml.). The highest concentration of LSD studied would humans be equivalent to a dose of 500,000m g.! Even at this high a dosage, there was no evidence that LSD led to an unusual frequency of mutations.

Browning(4) studied the effect of bathing the testes of 75 male drosophila with a strong solution of LSD. The results of this study do indicate that LSD in enormous doses and injected in this manner does create an unusual number of mutations. It is important to note, however, that the concentration of LSD Browning studied would be equivalent in humans to a single dose of 256,000,000 m g. of LSD and was so powerful that it killed 80 percent of flies and left a third of the survivors sterile.

In conclusion, there is at present no adequate evidence that hallucinogenic drugs in ordinary doses cause chromosomal damage in the living organism or adversely affect offspring as a result of chromosomal changes.

Effects on Embryos
There have been a number of good recent investigations of the effect of hallucinogenic drugs on developing embryos. Alexander, Miles, Gold, and Alexander(l) compared the effect of LSD injected in rats both early and late in pregnancy with the effect of injecting only saline solution. While they found that there were no apparent effects of LSD on offspring when given late in the mother's pregnancy, there were substantially more stunted and stillborn offspring from the mothers who had received LSD early in pregnancy.

Auerbach and Rugowski(2) performed a similar experiment, this time with mice. Examining the embryos four days after administering a drug to the mothers, they found that there were substantially more embryological abnormalities from the mothers who had been injected with LSD early in pregnancy than in mothers who had been injected during the same period with a control substance or who had not been injected at all. However, there were no gross observable effects when injections were given late in pregnancy.

Geber(7) compared the effects of different dosages of LSD and mescaline on hamster fetuses to the effect of an injection of saline solution. These substances were injected early in hamster pregnancy during a phase that has been demonstrated to be the most effective for evaluating teratogenic compounds. An examination of the fetuses indicated that substantially more had been adversely affected by the hallucinogenic drugs than by the saline solution. While the size of the drug dose was not related to the percentage of congenital abnormalities, it was related to the frequency of resorptions, dead fetuses, and runts.

One of the few dissenting notes in this area comes from a study by Warkany and Takaes(15). They did not find an effect of LSD in either small or large dosages on developing rat fetuses. The authors state that this failure to find an effect may have been due to their studying a different stock of rat than was used by Alexander and associates( 1 ). This introduces the possibility that the effects of these drugs on embryos may not be the same for different species of animals and therefore may not generalize to human fetuses.

Notwithstanding the results of this last study, there is enough evidence that hallucinogenic drugs have adverse effects on developing embryos to cause grave concern. If the period of embryonic development in experimental animals during which these drugs appear to have their most adverse effect is extrapolated to humans, the crucial period for human fetuses is estimated to be between 16 and 22 days of pregnancy(2). This represents a period of few development during which pregnancy is frequently unsuspected; thus it would seem wisest that females who are having sexual intercourse and are not using some kind of contraception should not take hallucinogenic drugs for any reason, medical or private.

Conclusion
After reviewing the laboratory evidence for the effects of hallucinogenic drugs on chromosomes and embryos, it appears that if "LSD monsters" are going to occur, it will be as a result of pregnant women taking one of these drugs at a crucial period in embryonic development, not as a result of mutant chromosomes in the parents.

REFERENCES

1. Alexander, G., Miles, B., Gold, G. M., and Alexander, R. B.: LSD Injection in Early Pregnancy Produces Abnormalities in Offspring in Rats, Science 157:459-460, 1967.
2. Auerbach, R., and Rugowski, J.: LSD, Effect on Embryos, Science 157:1325-1326, 1967.
3. Bender, L., and Siva Sankar, D. V.: Chromosome Damage Not Found in Leukocytes of Children Treated with LSD-25, Science 159:749, 1968.
4. Browning, L. S.: Lysergic Acid Diethylamide: Mutagenic Effects in Drosophila, Science 161:1022-1023, 1968.
5. Cerletti, A.: Neuropharmacology: Transactions of the Second Conference. New York: Josiah Macy, Jr., Foundation, 1956.
6. Cohen, M. M., Marinello, M. J., and Back, N.: Chromosomal Damage in Human Leukocytes Induced by Lysergic Acid Diethylamide, Science 155:1417-1419,1967.
7. Geber, W.: Congenital Malformations Induced by Mescaline, LSD, and Bromolysergic Acid in the Hamster, Science 158:265-266, 1967.
8. Grace, D., Carlson, E. A., and Goodman, P.: Drosophila Melanogaster Treated with LSD: Absence of Mutation and Chromosomal Breakage, Science 161:694-696,1968.
9. Irwin, S., and Egozeue, J.: Chromosomal Abnormalities in Leukocytes. from LSD Users, Science 157:313, 1967.
10. Irwin, S., and Egozcue, J.: reply to Bender, L., and Siva Sankar, D. V.: Chromosome Damage Not Found in Leukocytes of Children Treated with LSD-25, Science 159:749, 1968.
11. Loughman, W. D., Sargent, T. W., and Israelstrom, D. M.: Leukocytes of Humans Exposed to LSD: Lack of Chromosomal Damage, Science 158:508--510,1967.
12. Saxbe, B.: Correspondence: Acid, New Republic 154: May 7, 1966, p. 35.
13. Skakkebaek, N. E., Philip, J., and Rafaelsen O. J.: LSD in Mice: Abnormalities In Meitoic Chromosomes, Science 160:1264-1268, 1968.
14. Sparkes, R. S., Melnyk, J., and Bozzetti, L. P.: Chromosomal Effect In Vivo of Exposure to Lysergic Acid Diethylamide, Science 1343-1344, 1968.
15. Warkany, J., and Takacs, E.: Lysergic Diethylamide (LSD): No Teratogenicity in Rats, Science 159:731-732, 1968.