Teratogenic Effects Of
It has been frequently hypothesized in the past that LSD may be a potential cause of abortions, fetal wastage and congenital malformations. The actual experimental studies of the effect of LSD on embryonic development have been made primarily in rodents. Since free transplacental transfer of LSD has been demonstrated in an autoradiographic study performed by Idanpüün-lieikkilá and Schoolar, (56) it is conceivable that it might influence the developing fetus. In this study, the injected LSD rapidly passed the placental barrier into the fetus; however, according to the authors, the relatively high affinity of LSD for the maternal organs seemed to diminish the amount of the drug available for transfer into the fetus itself.
The experimental data from mice, rats and hamsters have been rather controversial. Auerbach and Hugowski (10) reported a high rate of embryonal malformations in mice following relatively low doses of LSD administered early in pregnancy. In all cases the induced malformations involved characteristic brain defects. Abnormalities of the lower jaw, shifts in the position of the eyes, and modifications of the facial contour were frequently associated with these defects. There was no observable effect on the embryonic development if the LSD exposure occurred later than the seventh day of gestation. These findings were partially supported by Hatiaway (47) who experimented with LSD in mice of a different strain. Using comparable dosages, he described a high incidence of lens abnormalities; however, he was unable to discover any malformation of the central nervous system, even on histological examination. DiPaolo, Givelber and Erwin (27)
administered LSD to pregnant mice and hamsters. The total amount of LSD injected in mice ranged from 0.5 micrograms to 30 micrograms per pregnant animal; Syrian hamsters were injected with a single dose ranging between 10 and 300 micrograms. The authors concluded that their investigation failed to demonstrate that LSD is teratogenic for mice and Syrian hamsters. They interpreted the increased frequency of malformed embryos in some of the experiments as an indication of a potentiating effect of LSD on individual threshold differences. It is necessary to emphasize that the doses used in this study were 25 to 1,000 times the human dosage. Alexander et al. (4) administered 5 micrograms per kg of LSD to pregnant rats. They described a significantly increased frequency of stillbirth and stunting in two of their experiments where LSD was administered early in pregnancy. In the third experiment, where the animals received similar single injections of LSD late in pregnancy, there was no obvious effect on the offspring. Geber (42) reported a study in pregnant hamsters in which he administered LSD, mescaline and a brominated derivative of LSD. He described a markedly increased frequency of runts, dead fetuses and reabsorbed fetuses in the experimental groups. In addition, he observed a variety of malformations of the central nervous system such as exencephaly, spina bifida, interparietal meningocele, omphalocele, hydrocephalus, myelocele and hemorrhages of local brain areas, as well as edema along the spinal axis and in various other body regions. The dosages of LSD used in this experiment ranged between 0.8 micrograms per kg and 240 micrograms per kg. However, there was no correlation between the dose and the percentage of congenital malformation. LSD and mescaline produced similar malformations; mescaline appeared to be a less potent teratogen, as judged by the dose.
There exist a number of studies in which negative results were reported in all the species mentioned. Roux, Duputs and Aubry (88) administered LSD in dosages from 5-500 micrograms per kg per day to mice, rats and hamsters. There was no increase in fetal mortality or decrease in the mean weight of the fetuses for any group of experimental animals. There was no significant increase in the incidence of external malformations, and sections performed in approximately 40 percent of the experimental animals showed no visceral malformations. The authors concluded, on the basis of the results, that in the three species studied, no abortifi-cient, teratogenic or embryonic growth-depressing factors were observed, even after enormous doses.
At least four studies of the teratogenic effect of LSD carried out on rats brought negative results. Warkany and Takacz (113) found no abnormalities in their experimental Wistar rats, despite the fact that they used large doses of LSD (up to eighty times those given by Alexander et al.). (4) The only finding was a reduction in size in one of the young. Nosal (83) administered LSD to pregnant rats in dosages of 5, 25, and 50 micrograms per kg on the fourth and seventh days of gestation. He did not observe any external .malformations of the head, vertebral column and extremities, or macroscopic lesions of the central nervous system and viscera. There were no differences from the controls as to mortality and fetal resorption or reduced number and size of the offspring, even with higher dosages. Negative results were also obtained in two studies performed and published by Uyeno. (109, 110)
Fabro and Sieber (35) studied the effect of LSD and thalidomide on the fetal development of white rabbits. Thalidomide had a marked embryotoxie effect and produced an increased incidence of resorptions, decreased the mean fetal weight, and induced malformations of fetuses. Pregnant rabbits given LSD in a dosage of 20 or 100 micrograms per kg of body weight produced litters which were not significantly different from the controls. Decrease of the mean fetal weight at twenty-eight days was the only effect which could be detected in the litters of does treated with daily doses as high as 100 micrograms per kg.
As emphasized by Dishotsky et al., (28) an overall view of the rodent studies indicates a wide range of individual, strain, and speeics susceptibility to the effects of LSD. The effect, when found, occurs at a highly specific time early in gestation; no effect was reported with exposures occurring late in pregnancy. Extreme caution is required in extrapolating results from the rodent studies to the human situation, since fetal development and growth in these species is markedly different. Rodents lack the chorionic villi in the placenta, so that the fetal blood is separated from the maternal sinuses only by endothelial walls. This makes the rodents much more sensitive than humans to the teratogenic potential of any given substance.
In the only existing experimental study in primates, Kato et al. (66) administered multiple subcutaneous injections of LSD to pregnant Rhesus monkeys. Of four animals treated, one delivered a normal infant, two were stillborn with facial deformities and one died at one month. The two control animals delivered normal offspring. The dosage used in this study was more than 100 times the usual experimental dose for humans. The authors themselves concluded that the small size of their sample made it impossible to draw any definite conclusion.
The information about the influence of LSD on the development of human embryos is scanty and exists only in the form of clinical observations. For obvious reasons, this problem cannot be approached in an experimental manner in humans. There are six reported cases of malformed infants born to women who ingested illicit LSD prior to or during pregnancy. Abbo, Norrls and Zellweger (2) described a child born with a congenital limb anomaly. Both parents of the child had taken alleged LSD of unknown purity and amount from an unidentified source on an indefinite number of occasions. The mother took LSD four times ^ during pregnancy, twice during the first three months, which is the time at which I; the limbs are differentiated. Zellweger, McDonald and Abbo (117) reported the case of a child born with a complex unilateral deformity of the leg. This anomaly, the so-called fibular aplastic syndrome, includes absence of fibula, anterior bowing of the shortened tibia, absence of lateral rays of the foot, shortening of the femur, and dislocation of the hip. The parents of this child took illicit LSD, the mother on the 25th day and three times between the 45th and 98th day after her last menstrual period. The authors emphasized the fact that the seventh week of gestation is the period of most active differentiation of the lower limbs; this was also established for the thalidomide embryopathy. Hecht et al. (49) observed malformation of the arm in the case of a child whose parents had taken LSD and smoked marijuana. The mother took unknown amounts of LSD before and during early pregnancy. The authors concluded that the relation of the deformity to LSD in this case is unclear. Carakushansky, Neu and Gardner (16) reported a similar case. It involved an infant with a terminal transverse deficit of portions of fingers on the left hand and syndactyly of the right hand with shortened fingers. This malformation is characterized by a failure of the fingers to separate and function independently. The mother was believed to have been exposed to LSD and cannabis during pregnancy. Eller and Morion (34) gave a report of a severely deformed baby with an anomaly involving defective development of the thoracic part of the skeleton (spondylothoracic dysplasia). This rare condition had previously been described only in infants of Puerto Rican parents. The mother in this case happened to take LSD once around the time of conception. The authors question the causal relationship between LSD and the deformity. Finally, Hsu, Strauss and Hirschhorn (53) published the report of a female infant born with multiple malformations, to parents who were both LSD users prior to conception. During pregnancy the mother also took marijuana, barbiturates and methedrine. The malformations in this case were associated with chromosomal aberrations indicating the so-called trisomy 13 syndrome.
Berlin and Jacobson (12) studied 127 pregnancies in 112 women where one or both of the parents admitted taking LSD before or after the infant's conception. According to the authors, sixty-two pregnancies resulted in live birth, six of these infants had congenital abnormalities, with one neonatal death. One of the fifty-six normal newborns died from an intrapulmonary hemorrhage. Sixty-five pregnancies were terminated by abortion; seven abortions were spontaneous and four of these fetuses were abnormal. Out of fourteen therapeutic abortions, there were four abnormal fetuses. The rate of defects of the central nervous system was about sixteen times that in the normal population. One of the findings in all the abortion specimens was failure of fusion of the cortex. Three of the six abnormal children born alive had myelomeningocele and hydrocephalus; one had hydrocephalus only. The authors themselves emphasized that the mothers in this study were a very high risk obstetric population for many reasons. In addition to ingestion of alleged LSD, there was multiple drug use (15 percent used narcotics), infectious diseases and malnutrition. Most of the therapeutic abortions were done for psychiatric reasons. Thirty-six percent of the women had undergone extensive radiological investigations for abdominal complaints.
Berlin and Jacobson s study, as well as all the previously mentioned case reports of fetal abnormalities, involve infants born to parents who ingested illicit substances of unknown dosage and origin that were considered to be LSD; to date there is no report of congenital malformations in human offspring exposed to pure LSD. In addition, as Blaine (13) pointed out in his rather bitter and emphatic criticism of the paper by Eller and Morton, (34) there is no scientific evidence in these individual ease histories of a causal relation between the ingestion of illicit substances and the subsequent development of the embryonal malformation. The findings could represent pure coincidences and be related to any number of situations that contribute to congenital abnormalities, such as maternal nutrition, physiological, psychological and pathological states, socio-economic circumstances, or various cultural practices. Differences in type and severity of malformations may be due to genetic factors, both embryonic and parental.
There exists a considerable amount of clinical evidence contradicting or limiting the above findings. Three studies focusing primarily on the frequency of chromosome breaks in children exposed to illicit LSD in utero reported elevated breakage rates of the chromosomes. (27, 33, 54) However, all fourteen infants studied were in good health and had no indications of birth defects. It is interest ing to note in this context that the hypothesis of the possible teratogenic action of LSD was originally derived from observations of increased chromosomal breakage. In the majority of the reported cases of actual congenital malformations attributed to LSD, the chromosomal findings were normal. Conversely, the children exposed to LSD in titero and reported as having chromosome damage did not show any physical abnormalities. Although it is not common, for obvious reasons, to publish case histories with negative results, Sato and Pergamenl (89) presented one in their discussion of the case of Zellweger et al.. (117) They described a newborn whose mother had taken LSD before and during early pregnancy six times. The pregnancy was uneventful, and she gave birth to a full-term, healthy girl. The doses of alleged LSD taken by the mother were sufficient to produce a psychedelic effect. She took LSD during the critical stage for production of limb deformities, as in Zellweger's case, but no fetal deformities developed.
Aase, Laestadius and Smith (1) observed a group of ten pregnant women who were ascertained as having ingested LSD in hallucinatory dosages. These women subsequently delivered ten living and healthy children. There was no evidence of teratogenic effects or chromosomal damage in any of these ten babies considered to have been exposed to LSD in utero. The authors point out a most interesting fact, that all of the delivered children were girls. The low probability of this being a random event suggests that LSD may have an influence on the sex ratio. Healy and Van Houten (48) calculated that the probability of the entire series of ten pregnancies resulting in children of the same sex is 1:1024. They suggested that LSD might enhance the basic immunological incompatibility between male fetuses and their maternal hosts; this results in the detection of the fetal tissue as antigenic. A similar hypothesis was offered in the past as an explanation of the observation that women who became schizophrenic within one month of conception gave birth to female offspring only.
MeGlothlin, Sparkes and Arnold (76) studied 148 human pregnancies following ingestion of LSD; this was part of a larger study of 300 persons randomly drawn from a population of 750 who received LSD orally in either an experimental or psychotherapeutic setting. The number of sessions ranged between one and eighty-five, and the usual dosages were 25-400 micrograms. For twenty-seven pregnancies, there was additional use of LSD under non-medical conditions. In a small percentage marihuana (8 percent) and strong psychedelics such as peyote, mescaline and psilocybin were also used. The authors found no evidence that the use of LSD in reasonable doses by men before intercourse leading to conception, is related to an increase in the rate of abortions, premature births or birth defects. However, they found some evidence that the use of LSD by women prior to conception may increase the incidence of spontaneous abortions; the causal connection between these two events is not clear and requires further research. There was little to suggest that exposure of either parent to LSD prior to conception and in the amounts described in this study increased the risk of having a child with a congenital defect. The only increased risk observed in this study, therefore, was a possible higher incidence of spontaneous abortions among women exposed to LSD. Spontaneous abortions occurred significantly more often when the mother had taken LSD than when the father only had taken it. The authors offered two explanations for this finding: (1) The period required for the maturation process of the ova is very long; it takes several years, as compared to a few weeks for the spermatozoa. (2) In one-half of the cases the mothers were given medical LSD for therapeutic purposes. It is a well-known fact that greater emotional stress in neurotic patients increases the incidence of abortions, and this suggests that the connection found in this survey between LSD and abortion might not be causal at all, but purely coincidental.
Arendsen-Heiti (7) presented at the Congress of the European Medical Association for Psycholytic Therapy at Wurzburg in 1969 data about the offspring of 4,815 former LSD patients from several European countries, including England. Of 170 children born to these patients after they had completed LSD therapy, frequently involving multiple exposures, only two showed congenital anomalies. One child had a dislocation of the left hip joint; another child, born to a couple where the father used LSD, had the little finger and ring finger on one hand grown together (syndactyly). Two women from this sample took LSD within fourteen days after conception (in one case 400 micrograms), and both children were normal. Thus, out of 170 infants, only two showed pathology; the author felt that even in these two cases the anomalies were of a common kind and could not be attributed to LSD for any sound reason.
The experimental and clinical evidence for the teratogenic effects of LSD can be summarized as follows. Increased incidence of congenital malformation has been reported in mice, rats and hamsters; however, there exist a number of papers contradicting these findings. The information from experiments on lower primates, although preliminary, suggests a possible teratogenic effect and deserves further investigation. There exist several case reports of malformed children born to users of illicit LSD, and one study suggesting a high incidence of birth defects and abortions in this group. The causal relation of these malformations to the use of LSD is not established. The unknown chemical composition of the samples of 1 alleged LSD, as well as the existence of many other important variables characterizing the group of "LSD users" (such as infections, malnutrition, multiple drug use, and emotional disorders) leave all the conclusions open to question. There are indications of an increased risk of spontaneous abortions related to the use of LSD. There is no evidence at present that pure LSD causes birth defects or t fetal wastage in humans. However, for practical clinical purposes pregnancy ' should be considered a contraindication for the administration of LSD. This is not something unique and specific to LSD; similar caution is required in regard to many other substances. The balance between the maternal organism and the developing fetus, especially in the first trimester of pregnancy, is very precarious and can be disturbed by a wide variety of external influences.
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