The Effects of LSD on Chromosomes, Genetic Mutation,
Fetal Development and Malignancy
Stanislav Grof
Appendix II of LSD Psychotherapy, ©1980, 1994 by Stanislav Grof
Hunter House Publishers, Alameda, California.
ISBN 0-89793-158-0 (1994 edition, paperback)
In the last decade, a serious new dimension has been added to
the LSD controversy. A number of scientific papers have been published
indicating that LSD might cause structural changes in the chromosomes,
genetic mutations, disturbances of embryonic development, and
malignant degeneration of cells. However a comparable number of
publications question the accuracy of these allegations. Some
are independent experimental studies which have yielded negative
results, others criticize the original papers for serious conceptual
and methodological inadequacies. Despite all the experimental
work done in this area, and the vast expenditure of time and energy,
the results are ambiguous and contradictory. It seems appropriate
to include in this book a critical review of all the relevant
research because the issue is extraordinarily important to the
future of LSD psychotherapy.
The following discussion is based almost exclusively on careful
study of the existing literature. I have limited firsthand research
experience in this area, and genetics is not my primary field
of interest and expertise. In the LSD study conducted in the Psychiatric
Research Institute in Prague we did not examine the effect of
LSD on the chromosomes or its implications for heredity; there
were at that time no experimental or clinical observations that
would suggest the need for such studies. The first paper that
attracted the attention of scientists to this area did not appear
until the late 1960's. (22)*
After my arrival in the United States, I participated in a major
study concentrating on structural changes of the chromosomes in
the white blood cells following LSD administration. This was one
of the few genetic studies using pure pharmaceutical LSD, a double-blind
approach, and comparison of the samples before and after the administration
of the drug. (106)
The material discussed in this review will be divided into several
thematic groups. The first group includes papers describing structural
changes of the chromosomes produced by LSD in vitro,**
in these experiments various concentrations of LSD are added to
cultures of cells from human, animal, or plant tissues in a test-tube.
The second group involves in vivo studies of LSD; in this
type of research the effect of LSD is studied after the substance
has been ingested by or injected into animals or humans. The papers
in the third group describe the results of experiments studying
the influence of LSD on the genes, and its mutagenic effects.
It includes a small number of papers dealing with the detailed
mechanism of the action of LSD on the deoxyribonucleic acid (DNA),
the most important constituent of the chromosomes. The fourth
group consists of publications describing the consequences of
LSD administration on the growth, development and differentiation
of human and animal embryos. Finally, the fifth group comprises
papers focusing on the possible link between LSD and the development
of malignant changes in cells, especially in the case of leukemia.
In the following sections, the most relevant findings in these
five thematic categories will be briefly reviewed and critically
evaluated.
THE EFFECT OF LSD ON CHROMOSOMAL STRUCTURE
The possibility of inducing structural changes in the chromosomes
by exogenous agents such as radiation, viruses, and a variety
of chemicals, has been a subject of great scientific interest
for a long time. The genetic controversy about LSD started in
1967 when Cohen, Marinello and Back (22) published
a paper suggesting that LSD should be added to the list of substances
capable of causing abnormalities in the chromosomes. Because of
the widespread use of LSD, this information created vivid interest
in scientific circles, and a number of investigators focused their
attention on this area. Two major approaches were used in these
studies; in some the effect of LSD on the chromosomes was studied
in the test tube (in vitro), in others in the living
organism (in vivo). The cells studied were in most
cases human white blood cells (lymphocytes).
In the in vitro studies, the blood samples were drawn from
normal, healthy persons with no history of prior drug injection,
radiation exposure, or recent viral infection. After incubation
at 37° centigrade in appropriate media, colcemide was added
to stop the cell division at the stage of metaphase. The cells
were then harvested, made into specifically stained cytological
preparations and examined with phase contrast microscopy. During
the period of incubation, LSD dissolved in sterile distilled water
was added to the experimental cultures in various concentrations.
In the in vivo studies, the blood samples were drawn from
subjects who had been exposed to either "street acid"
(illicit material allegedly containing LSD) or pharmaceutically
pure LSD. In most of these studies, the chromosomes were examined
after the exposure to LSD (retrospective approach); in a minority
of these studies, the checkups were done both before and after
the administration of the drug (prospective approach). The technical
procedure employed in the in vivo studies did not differ
significantly from that described for the in vitro approach.
A special and rather important subgroup of the in vivo
studies are reports about the influence of LSD on the chromosomes
of the germinal cells (meiotic chromosomes).
IN VITRO STUDIES
Cohen, Marinello and Back (22) added LSD to cultured
human leucocytes obtained from two healthy individuals. They used
five concentrations ranging from 0.001 to 10.0 micrograms of LSD
per cubic centimeter (cc), and the time of exposure was 4, 24,
and 48 hours. The incidence of chromosome breaks for treated cells
was at least twice that of control cells for all treatments, except
at the lowest concentration and time (0.001 micrograms of LSD
per cc for four hours) where no difference existed between treated
and control cells. There was no simple linear relationship between
the frequency of these aberrations and the LSD dosage or duration
of exposure. In a later study, Cohen, Hirschhorn and Frosch
(20) described the results of a larger study in which they used
peripheral leucocyte cultures from six normal, healthy persons;
the concentrations of LSD and the times of exposure were the same
as in the original study. They found a significant inhibition
of cellular division (mitosis) on addition of the drug in any
concentration. The suppression of mitosis was directly proportional
to the duration of exposure. The lowest frequency of chromosomal
breakage among the controls was 3.9 percent of cells; among the
treated cultures, the lowest frequency was almost twice the control
(7.7 percent) and ranged to over four times the control value
(17.5 percent).
In 1968, Jarvik et al. (63) tried to replicate some
of the in vitro experiments of Cohen's group. In addition
to LSD, they used as testing substances ergonovine (a drug commonly
used in obstetric practice), aspirin, and streptonigrine. They
found a higher incidence of chromosome breaks in the LSD samples
(10.2 percent with the range 0.0-15.0) as compared to the control
samples (5.2 percent with the range from 0.0-9.0). They found,
however, approximately the same breakage rate with aspirin (10.0
percent) and ergonovine (9.6 percent). The concentration of LSD
in blood used in this study approximates the level reached one
to four hours after injection of 1,000 micrograms of LSD. On the
other hand, the level of aspirin used was considerably below the
common therapeutic level. Streptonigrine, a substance with a well-known
dramatic effect on the chromosomes, induced chromosome breakage
in 35 percent of the examined cells. It is interesting to note
that two of the eight cases described in this paper did not respond
to LSD with an increase in chromosome breaks.
Corey et al. (24) performed an in vitro study
in ten individuals; 1 microgram per cc of LSD was added to the
culture during the last twenty-four hours of incubation. The authors
found an increase in chromosome breaks in all ten subjects. Although
the in vitro concentration of LSD was much greater than
any known comparable ingested dosage, the mean increase of 4.65
breaks per 100 cells was small compared to the range of frequencies
(0.0-15.2) observed in the untreated cultures.
In this connection it is interesting to mention that Singh,
Kalia and Jain (92) found an increased incidence of
chromosome breakage in the cells of barley root as a result of
exposure to LSD in the concentration 25 micrograms per cc. On
the other hand, MacKenzie and Stone (73) reported
negative results of experiments on lymphocytes, hamster fibroblasts
and on the plant Vicia faba.
The above-mentioned findings of structural changes in chromosomes
following LSD administration became the basis of speculations
concerning the possible influence of this drug on genetic mutations,
fetal development and malignancy. In the atmosphere of national
hysteria then existing, the original report of Cohen, Marinello
and Back (22) was widely publicized by the mass media.
As a result, the significance of their findings was considerably
over-emphasized, and many premature conclusions were drawn for
which there was not sufficient scientific justification.
Several important facts have to be taken into consideration before
we can draw any substantial conclusions from the findings of increased
chromosome breakage associated with LSD in the in vitro
experiments. It must be emphasized that the findings themselves
were not completely consistent. In several studies there were
no indications of increased chromosome breakage following the
exposure to LSD. (27, 73, 105). In addition, the concentrations
of LSD and durations of exposure used in these studies were usually
much greater than those occurring in the human organism after
the ingestion of LSD in the commonly used dosages. Cohen, Marinello
and Back (22) themselves did not find increased breakage
of chromosomes at the lowest concentration and time (0.001 micrograms
of LSD per cc for four hours). Loughman et al. (70)
emphasized that it is precisely the lowest concentration and duration
of exposure used in this study that most closely approximates
the expected concentration in blood, liver and other organs after
a dose of 100 micrograms of LSD ingested by a man weighing 70
kg. If the metabolic degradation of LSD is considered, then the
effective concentration in vivo of unchanged LSD would
be considerably less than this, approximating 0.0001 micrograms
per cc—a concentration used only by Kato and Jarvik,
(65) who found no increase in breakage at this dosage.
In general, special caution is required in extrapolating the in
vitro findings to the situation in the living organism. The
intact human organism differs from isolated cells in the test
tube in its enormous complexity and in its ability to detoxify
and excrete noxious compounds. Substances that are toxic in
vitro do not necessarily have the same effect in vivo.
In addition, some of the techniques used in the in vitro studies
can create an artificial situation and introduce factors that
do not exist in the living organism. This issue has been discussed
in detail in an excellent review on LSD and genetic damage by
Dishotsky et al. (28) These authors point to the fact that
all the studies on cultured lymphocytes have used modifications
of a technique in which the lymphocytes are stimulated by phytohemagglutinin
to enter the reproductive cell cycle. In the normal state in
vivo, small lymphocytes are in a phase of growth which precedes
DNA synthesis; they do not grow, divide or enter the cell cycle.
Thus, in the studies in vitro, lymphocytes are exposed
to chemical agents during developmental stages of the cell cycle,
including the synthesis of DNA, which do not normally occur in
these cells in the body. Damage to a lymphocyte in this phase
generally will not manifest itself as chromatid-type change in
a subsequent division. Most, if not all chromatid-type changes
are initiated by technical procedures, and the great majority
of lesions reported in the in vitro and in vivo
studies were of the chromatid type. The findings of an increased
rate of chromosomal breakage in lymphocytes exposed to LSD in
vitro must therefore be interpreted with great caution.
Many recent studies concerning the structural changes caused in
chromosomes by LSD gave the impression that this effect was something
specific and unique. Most of these reports have silently bypassed
a fact that would have made the issue much less interesting and
sensational. The changes in chromosomal structure described are
not exclusively caused by LSD; they can be induced by a variety
of other conditions and substances. Factors that have been known
to cause chromosomal breakage in vitro include radiation,
changes in temperature, variations in oxygen pressure, impurities
in tap water unless it is distilled twice, and a variety of common
viruses. The long list of chemical substances that increase the
chromosomal breakage rates contains many commonly used drugs,
including aspirin and other salicylates, artificial sweeteners,
the insecticide DDT, morphine, caffeine, theobromine, theophylline,
tranquilizers of the phenothiazine type, some vitamins and hormones,
and many antibiotics such as aureomycin, chloromycetin, terramycin,
streptomycin and penicillin.
In this connection it is interesting to quote Sharma and Sharma,
(91) who have written an extensive summary of the literature on
chemically induced chromosome breaks: "Since the first induction
of chromosomal mutations by chemicals and the demonstration of
definite chromosome breakage by Oehlkers, such a vast multitude
of chemicals have been shown to possess chromosome breaking properties
that the problem has become increasingly complex." Jarvik,
(61) discussing the paper by Judd, Brandkamp and McGlothlin,
(64) was even more explicit: "... and it is likely that
any compound added at the appropriate time, in the appropriate
amount, to the appropriate cell type, will cause chromosome breaks."
IN VIVO STUDIES
Because of the limitations of the in vitro approach, in
vivo studies are preferred for assessing the possible genetic
dangers associated with administration of LSD. Unfortunately,
of the twenty-one reports that have been published by seventeen
laboratories many have serious methodological shortcomings and
are more or less inadequate, while individual reports contradict
each other and their overall results are inconclusive. Two major
approaches have been used in the in vivo studies. In fourteen
of these projects, subjects were exposed to illicit substances
of unknown composition and potency, some of which were alleged
to be LSD. In eleven studies, individuals were exposed to known
quantities of pharmaceutically pure LSD in experimental or therapeutic
settings.
Dishotsky et al. (28) published a review in which
they presented a synopsis of the studies of this kind conducted
prior to 1971. According to this review, of a total of 310 subjects
studied, only 126 were treated with pure LSD; the other 184 subjects
were exposed to illicit or "alleged" LSD. Eighteen of
the 126 subjects (14.29 percent) in the group given pure LSD showed
a higher frequency of chromosome aberration than the controls.
In contrast, 89 of the 184 subjects (48.9 percent) in the group
taking illicit LSD showed an increased incidence of aberrations—more
than three times the frequence reported for subjects given pharmacologically
pure LSD. Only 16.67 percent (18 of 108) of all the subjects reported
to have chromosome damage, were given pure LSD. There is, therefore,
good reason to discuss the two categories of in vivo studies,
those with pure and those with "alleged" LSD, separately.
Illicit LSD and Chromosomal Damage
The initial findings of chromosomal damage in illicit LSD users
were reported by Irwin and Egozcue. (57) They compared
a group of eight illicit LSD users with a group of nine controls.
The users had a mean breakage rate of 23.4 percent, more than
double the 11.0 percent rate in the controls. Only two of the
eight users did not have increased breakage rates. In a later
and more extensive study carried out by Egozcue, Irwin and
Maruffo, (33) the mean breakage rate in forty-six illicit
LSD users was 18.76 percent (with a range between 8 and 45 percent);
this was more than double the rate of 9.03 percent found in control
cells. Only three of the forty-six users did not have a breakage
rate higher than the mean control rate In addition, the authors
studied the chromosomes of four infants exposed to LSD in utero.
All four showed breakage rates above the mean control value. There
was no evidence of disease or physical malformation in any of
these children.
These findings were supported by Cohen, Hirschhorn and
Frosch, (20) who studied eighteen subjects exposed to illicit
LSD. They described an increased chromosomal breakage in this
group (mean 13.2 percent) which was more than triple that of the
control group (3.8 percent). The authors also examined the chromosomes
of four children born to three mothers who took LSD during pregnancy.
The frequency of chromosome breaks was elevated in all four, and
was greater in the two children who were exposed to LSD during
the third and fourth months of pregnancy than in the two infants
exposed to low doses of LSD late in pregnancy.
In a later paper, Cohen et al. (21) reported that
thirteen adults exposed to illicit LSD showed chromosome breakage
rates that were above the control mean. In nine children exposed
to illicit LSD in utero, they found a mean breakage of
9.2 percent, as compared with 4.0 percent in four children whose
mothers had used illicit LSD before but not during pregnancy.
The breakage rate in the control group was 1.0 percent. All but
two children had been exposed to other drugs during pregnancy;
all were in good health and showed no birth defects.
Nielsen, Friedrich and Tsuboi (82) found that their
ten subjects exposed to illicit LSD had a mean breakage rate of
2.5 percent; this was significantly higher than that of the control
group (0.2 percent). However, the allegedly pathological 2.5 percent
rate is lower than that of the controls in other positive studies.
A number of investigators have not been able to demonstrate increased
chromosome breakage in LSD users. The synoptic paper by Dishotsky
et al. (28), quotes nine groups of researchers who
reported negative results of similar studies. At the present time,
therefore, the results of the in vivo studies are considered rather
controversial and at best inconclusive.
Many investigators have attempted to offer explanations for the
existing discrepancies between positive and negative reports.
Some have criticized the breakage rate for controls in the studies
by Cohen et al. (21) (3.8 percent) and Irwin and
Egozcue (57) (11.9 percent and 9.03 percent) as being unusually
high. Others have suggested that the high control values could
have resulted from viral contamination of the cultures, insufficiently
fortified media interfering with chromosome repair, technical
variation in cell culturing, and the approach to chromosome evaluation.
It was also pointed out that in these studies, chromosome-type
and chromatid-type changes were not reported separately but were
combined and then converted to "equivalent numbers of breaks."
Combining the two types of aberrations in a single index obscures
the distinction between real chromosome damage occurring in vivo
and damage arising in the course of cell culture.
However, these factors cannot account for the discrepancies between
the findings of various teams of investigators. If they did, the
aberrations resulting from these effects would be randomly distributed
between groups exposed to illicit LSD and control groups. Since
the distribution is uneven, these factors do not explain the significantly
elevated breakage rates in eighty of the eighty-six subjects exposed
to illicit LSD studied by Cohen et al. and by Irwin and Egozcue.
A much more important clue to the understanding of this controversy
seems to be related to certain characteristics of the group of
the "LSD users." In this type of research, the investigators
depend on the recall and reliability of the subjects in determining
the type of drugs they have used in the past, the number and frequency
of exposures, the alleged dosages, and interval since last exposure.
Even in cases where the reports are accurate, the subjects usually
do not know the content and the quality of the samples they are
using. The content of pure LSD in the illicit LSD samples is almost
always questionable, and various impurities and admixtures rather
frequent. The samples analyzed in the past have been demonstrated
to contain amphetamines, mescaline, DOM (4-methyl-2, 5-dimethoxyamphetamine,
also called STP), phencyclidine (phenylcyclohexylpiperidine, PCP
or "angel dust"), benactyzine and even strychnine. In
addition, all the subjects tested used or abused drugs other than
street LSD. These drugs included, among others, Ritaline, phenothiazines,
alcohol, amphetamines, cocaine, barbiturates, heroin and other
opiates, and various psychedelic substances such as marihuana,
hashish, psilocybin, mescaline, STP, methylenedioxyamphetamine
(MDA), and dimethyltryptamine (DMT). Under the circumstances,
one questions the logic of referring to this group in scientific
papers as "LSD users." Most of these subjects were actually
multiple-drug users or abusers exposed to a variety of chemicals
of unknown composition, quality and potency.
In addition, it has been repeatedly reported that this population
suffered from malnutrition and had very high rates of venereal
disease, hepatitis and various other viral infections. It was
mentioned above that viruses are one of the most common factors
causing chromosomal damage; the possible role of malnutrition
remains to be evaluated. Dishotsky et al. (28) conclude
their review of the in vivo studies involving illicit LSD
by relating the findings of increased chromosome breakage to a
combination of factors such as long-term excessive exposure to
illicit chemical agents, the presence of toxic contaminants, the
intravenous route of administration, and the physical debility
of many drug abusers. According to them, positive results, when
found, are related to the more general effects of drug abuse and
not, as initially reported, specifically to the use of LSD.
Pure LSD and Chromosomal Damage
Chromosomal studies of persons who received pharmaceutically pure
LSD in an experimental or therapeutic framework are much more
relevant and reliable as a source of information than the studies
of illicit drug users. In these studies, there is no uncertainty
concerning purity, dosage, frequency of exposure and the interval
between the latest exposure and blood sampling. Two different
approaches can be distinguished in the chromosome studies using
pure LSD. The studies of the first type are retrospective
and use a "post hoc" design; they examine the chromosomal
changes in subjects who were exposed to pure LSD in the past.
The studies of the second type are prospective; the chromosomal
patterns are examined both before and after the exposure to LSD,
and each subject serves as his own control.
Retrospective Studies of Chromosomal Changes in Pure LSD Users.
A review of the studies in this category reveals that only two
groups of investigators have reported an increased rate of chromosome
breakage in their subjects. Five other teams failed to confirm
these positive findings.
Cohen, Marinello and Back (22) reported in their
initial study that they found chromosomal damage in the white
blood cells of one paranoid schizophrenic patient who had been
treated fifteen times in the past with LSD in dosages between
80 and 200 micrograms. Nielsen, Friedrich and Tsuboi
(80) examined the chromosomes of five persons treated with LSD
and found "no correlation between any specific drug and the
frequency of gaps, breaks, and hyperdiploid cells." The authors
later regrouped their data, forming smaller groups on the basis
of age and sex. (81) After this revision of the original material,
they concluded that LSD induced chromosomal damage. Tjio, Pahnke
and Kurland (106) criticized this study on the basis
of the insufficient number of cells analyzed for a reliable determination
of breakage rates. Three of the five LSD subjects studied had
no chromosomal aberrations, and the two remaining subjects accounted
for all six breaks found. In addition, the 1.7 percent breakage
rate is still within the values reported for the general population.
Another study by Nielsen, Friedrich and Tsuboi (82)
which reported an increased breakage rate of 4.3 percent in a
group of nine former LSD users has been criticized by Dishotsky
et al. (28) on the basis of its unusual approach to data analysis.
Sparkes, Melnyk and Bozzetti (99) did not find an
increase in chromosomal breakage in four patients treated with
LSD in the past for medical reasons Negative results were also
reported by Bender and Siva Sankar, (11) who examined the
chromosomes of seven schizophrenic children who had been treated
in the past by prolonged administration of LSD. These children
received LSD daily in two divided dosages of 100 to 150 micrograms
for a period of weeks or months. The frequency of chromosome breakage
in this group was less than 2 percent and did not differ from
that of the control group.
Siva Sankar, Rozsa and Geisler (93) studied the
chromosome patterns in fifteen children with psychiatric problems
who had been given LSD, UML or a combination of both. LSD was
administered daily; the average dose for the whole group was 142.4
micrograms per day per patient, and the duration of therapy varied
from 2 to 1,366 days. The breakage rate for the group treated
with LSD was 0.8 percent, for the group treated with both LSD
and UML 1.00 percent. This was not significantly higher than the
rate of breakage in the controls. The patients in this study received
LSD two to four years prior to the chromosome studies. The authors
admitted that the effects of LSD on the leucocyte chromosomes
might have been rectified over such a long period of time. In
any case, this would indicate that LSD therapy has no long-lasting
effects on the chromosomes.
Tjio, Pahnke and Kurland (106) published the results
of chromosome analysis of a group of eight "normal"
subjects who had received pure LSD in research experiments one
to twenty-six times, two to fifteen months prior to giving the
blood sample. The mean total chromosomal aberration rate for this
group was 2.8 percent, and the individual rate in none of them
exceeded the pre-LSD mean of 4.3 percent found in the patient
sample.
Corey et al. (24) reported the result of a retrospective
chromosomal study of sixteen patients, five of whom had been treated
with LSD only, five with mescaline only, and six with LSD plus
mescaline. In the eleven individuals who were clinically treated
with LSD dosages ranging from 200 micrograms to 4,350 micrograms,
frequency of chromosome breaks did not differ from that found
in the thirteen controls. The respective frequencies were 7.8
percent for LSD, 5.6 percent for mescaline, 6.4 percent for LSD
plus mescaline, and 7.0 percent for the control group.
In an unpublished study, Dishotsky et al. examined the
chromosomes of five subjects exposed in the past to pure LSD.
The mean breakage rate in this group (0.40 percent) was not significantly
different from that of the eight control persons (0.63 percent).
In their review paper, Dishotsky et al. (28) indicate that
fifty-eight of seventy (82.9 percent) of the subjects studied
after treatment with pure LSD did not have chromosome damage.
Because of incomplete data on nine of the remaining twelve subjects,
they were not able to compute the precise percentage of subjects
with elevated breakage rates. However, they estimated that this
figure would range between 17.1 percent and 4.9 percent. All but
one of the twelve subjects were reported by a single team of investigators.
The authors concluded that in view of the procedures, incomplete
data, questionable re-analysis of the data, and low breakage rates
reported, there is no definite evidence from this type of experiment
that pure LSD causes chromosome damage.
Prospective Studies of Chromosomal Changes in Pure LSD Users.
The studies comparing the chromosomal changes before and after
exposure to pure LSD represent the most adequate scientific approach
to the problem from the methodological point of view, and are
the most reliable source of scientific information. The first
report in this category was published in 1968 by Hungerford
et al. (55) who examined the chromosomes of three psychiatric
patients before and after repeated therapeutic administrations
of LSD. Blood samples were taken from all patients before any
LSD therapy, one hour before and one and fourteen hours after
each dose; follow-up samples were taken at intervals of one to
six months. An increase in chromosome aberrations was observed
after each of three intravenous injections of LSD. The increase
was small in two of the three subjects; however, dicentric and
multiradial figures appeared only after treatment, and acentric
fragments appeared more frequently after treatment. In the follow-up
study, a return to earlier levels was observed in all three patients.
The data from this study indicated that pure LSD may produce transitory
increases of chromosome abnormalities, but that these are no longer
evident one month after administration of the final dose. The
results were slightly complicated by the administration of chlorpromazine
(Thorazine), which in itself can produce chromosomal aberrations.
It is interesting to note that Hungerford's study is the only
one in which LSD was administered intravenously.
Tjio, Pahnke and Kurland (106) reported the results
of a study of thirty-two hospitalized alcoholic or neurotic patients
treated with LSD in the framework of a double-blind controlled
study at the Maryland Psychiatric Research Center. The dosage
of LSD was 50 micrograms in eleven patients and 250-450 micrograms
in twenty-one patients. The number of cells observed in this study
(22,500) was more than twice the total number of cells observed
in all other studies of pure LSD users. The amount of breakage
was not directly proportional to the dosage; actually those in
the low-dose range showed greater increases than those on high
dosage. The authors also examined a group of five persons who
had taken illicit LSD from four to thirty-six times before the
study. In these subjects, blood samples were drawn for seven to
ten consecutive days before, during and after treatment with pure
LSD either two or three times. Statistical analysis revealed no
significant difference in the chromosomal aberration before and
after LSD. In another prospective study, Corey et al. (24)
examined the chromosomes of ten persons before and after the administration
of 200-600 micrograms of pure LSD. The authors found no significant
difference in the rate of chromosome breakage between the pre-
and post-samples and confirmed the negative findings of the previous
study.
It is interesting to mention in this connection two prospective
studies of LSD-related chromosomal damage which were conducted
in Rhesus monkeys (Macaca mulatta); the results
of both studies were rather inconclusive. Egozcue and Irwin
(32) administered high dosages of LSD (40 micrograms per kg.)
four times at ten day intervals. Two of their animals showed increased
chromosomal breaks, whereas the other two stayed within normal
values. Kato et al. (66) described transitory changes in
chromosomes after multiple, subcutaneous injections of LSD in
high doses (125-1000 micrograms per kg. per injection) in Rhesus
monkeys. The authors have not provided a statistical evaluation
of the results; Dishotsky et al., (28) who later analyzed
their data, found them statistically nonsignificant.
Dishotsky et al. (28) also offered a synoptic evaluation
of the prospective LSD studies. According to them, only six of
the fifty-six patients (10.7 percent) studied before and after
treatment with pure LSD had elevated breakage rates; of these,
three received LSD intravenously and one had a viral infection.
Of these six subjects, one individual was not available for follow-up
determinations; in the remaining five, breakage returned to that
observed before treatment. From the total number of subjects studied
before and after treatment, 89.3 percent did not have chromosome
damage. The results of the prospective LSD studies are thus in
agreement with the negative conclusion of five of the seven teams
that studied subjects only after LSD treatment.
Chromosomal Changes in Germinal Cells
In the past, the positive findings of some chromosomal studies
have been used as a basis for far-reaching speculations concerning
the hereditary dangers associated with LSD. Journalists, and also
several scientific workers, described their rather apocalyptic
visions of the offspring of LSD users. Such speculations were
rather premature, and insufficiently substantiated by experimental
data. The reasoning that refers to structural abnormalities of
the chromosomes as "damage" and relates them automatically
to genetic hazards has serious gaps in its logic. In reality,
it is not quite clear whether or not the structural changes in
the chromosomes of the white blood cells have any functional significance,
and whether they are associated with genetic abnormalities. There
exist many chemical substances that cause chromosomal breaks but
have no adverse effects on genetic mutation or fetal development.
The complexity of this problem can be illustrated by the case
of viruses. A variety of virus diseases (such as herpes simplex
and shingles, measles, chicken pox, influenza, yellow fever, and
possibly mumps) induce marked chromosomal damage without causing
fetal malformations. According to Nichols, (79) one of
the exceptions is rubella (German measles), a disease that is
notorious for causing severe fetal malformations when acquired
by the mother in the first trimester of pregnancy.
In addition to the methodological problems involved and the inconsistency
of the findings discussed above, one more important fact has to
be taken into consideration. In all the studies quoted, the effect
of illicit or pure LSD, in vitro or in vivo, was
assessed in the chromosomes of the white blood cells. No direct
conclusions about the hereditary dangers associated with the administration
of LSD can be drawn on the basis of these studies since the lymphocytes
are not involved in the reproductive processes. Speculations about
such dangers could be made only on the basis of chromosomal findings
in germ cells such as the spermatozoids and ova, or their precursor
cells. Unfortunately, the few existing studies of the chromosomes
of germinal cells (the so-called meiotic chromosomes) yielded
as inconclusive results as the studies of the chromosomes of somatic
cells.
Skakkebaek, Phillip and Rafaelsen (95) studied meiotic
chromosomes from six healthy male mice injected with large dosages
of LSD (1,000 micrograms per kg); the number of injections and
intervals between exposures varied. Several chromosomal breaks,
gaps and unidentifiable fragments were found in the treated animals
but, with a few exceptions, not in the control animals. The authors
consider their finding tentative evidence that high doses of LSD
may influence meiotic chromosomes in mice. They admitted that
the number of abnormalities was small and technical errors could
not be excluded, but concluded that the changes found could have
influence on fertility, size of the litter, and the number of
congenital malformations. In a later study, Skakkebaek and
Beatty (94) injected four mice subcutaneously with dosages
of 1,000 micrograms per kg of LSD twice a week for five weeks.
Analysis carried out on a blind basis showed a high frequency
of abnormalities in two of the treated mice. In addition, the
spermatozoa of LSD-treated mice also showed morphological differences,
with a more rounded convex side of the head and broader heads
in general. The practical significance of these findings is considerably
reduced by the fact that the dosages used far exceed anything
used in clinical practice. A comparable dose in humans would come
to 60,000-100,000 micrograms per person, which is 100 to 1,000
times more than the dosages commonly used in experimental and
clinical work with LSD.
Another positive finding of meiotic chromosome damage induced
by LSD was reported by Cohen and Mukherjee. (23) These
authors injected thirteen male mice with a single dose of LSD
at a concentration of 25 micrograms per kg. In this study the
meiotic cells were apparently less vulnerable than somatic cells.
However, there was an obvious tenfold increase in chromosome damage
among the mice treated with LSD. This reached a maximum between
two and seven days after injection, with a subsequent decrease
and return to almost normal levels after three weeks. On the basis
of evidence from clinical human cytogenetic studies, the authors
concluded that chromosome anomalies of this type may lead to reduced
fertility, congenital abnormalities and fetal wastage.
The other existing studies of the effect of LSD on meiotic cells
brought essentially negative results. Egozcue and Irwin
(32) studied the effects of LSD administration in mice and Rhesus
monkeys. The mice in this study received 5 micrograms per kg of
LSD daily in a number of injections increasing from one to ten.
Four adult male Rhesus macaques ingested doses of either 5, 10,
20 or 40 micrograms per kg of LSD. Six months after their single
dose of LSD, three of the monkeys received four doses each, at
ten-day intervals, of 40 micrograms per kg of LSD per dose. The
authors reported essentially negative results in both the mice
and the monkeys. In mice, occasional chromosomal breaks and fragments
were observed in similar proportions in the control and the experimental
groups. In the Rhesus monkeys, no significant differences were
found before or after acute or chronic treatment.
Jagiello and Polani (60) published the results of
a detailed and sophisticated study of the effect of LSD on mouse
germ cells. They performed acute and chronic experiments on both
male and female mice. The dosage of LSD in the chronic experiments
ranged between 0.5-5.0 micrograms; in the acute experiments a
single subcutaneous dose of 1,000 micrograms per kg of LSD was
administered. The results of this study were essentially negative.
The authors attributed the discrepancies with other studies to
mode of administration, dosage and the animal strain involved.
In two of the existing studies, the effects of LSD on the meiotic
chromosomes were tested in the banana fly, Drosophila melanogaster,
an organism that has played an important role in the history of
genetics. In one of these studies, Grace, Carlson and Goodman
(44) injected male flies in concentrations of 1, 100 and 500 micrograms
per cc. The dosage used is equivalent to approximately one liter
of the same solution in humans (1,000, 100,000 and 500,000 micrograms
respectively). No chromosomal breaks were observed in premeiotic,
meiotic or postmeiotic sperm. The authors concluded that LSD is
in a class quite distinct from that of ionizing radiation and
mustard gas. If it is a mutagenic or radiomimetic agent in human
chromosomes, it is not a very powerful one. In another study,
Markowitz, Brosseau and Markowitz (74) fed LSD to
male fruit flies in a 1 percent sucrose solution for twenty-four
hours; the concentrations used were 100, 5,000, and 10,000 micrograms
per cc. In these experiments, LSD had no detectable effect on
chromosome breakage. The authors concluded that LSD is a relatively
ineffective chromosome breaking agent in Drosophila.
Considerable caution is required in extrapolating the data about
the effect of LSD on meiotic chromosomes obtained from animal
experiments to humans, because of rather wide interspecies variability.
The only report about the effect of LSD on human germ cells was
published by Hulten et al. (54) These authors examined
the testicular biopsy in a patient who had used massive doses
of illicit LSD in the past, up to an alleged 1,000 micrograms.
For a period of four weeks he practiced the administration of
these dosages daily. There was no evidence of an increased frequency
of structural chromosome aberrations in the germinal tissue of
the testicles.
Concluding this discussion of the effects of LSD on chromosomal
structure, we can say that the results of the existing studies
are inconclusive despite the fact that the dosages used in many
experiments far exceed the doses used in clinical practice. Whether
LSD causes structural changes in the chromosomes or not remains
an open question. If it does, the circumstances and dosage range
in which these occur have not been established, and the interpretation
of these changes and their functional significance is even more
problematic. This question could not be answered even on the basis
of results of methodologically perfect chromosomal studies. In
future research, much more emphasis should be put on the study
of the effect of LSD on genetic mutation and embryonal development.
MUTAGENIC EFFECTS OF LSD
In the past, the classic experimental animal for the study of
genetic mutations has been the banana fly, Drosophila melanogaster.
Several studies exist in which the effect of LSD on genetic mutation
has been observed in this fly. Grace, Carlson and Goodman
(44) studied the mutagenic effects of intra-abdominal injections
of LSD in concentrations ranging from 1 to 500 micrograms per
cc. They have not found an increase in induced mutations in the
LSD-treated group. On the basis of these negative findings, the
authors consider it improbable that LSD induces mutation in humans.
Markowitz, Brosseau and Markowitz (74) fed LSD to
male flies in concentrations of 100, 5,000 and 10,000 micrograms
per cc. In this experiment, LSD produced a significant increase
in the frequency of sex-linked recessive lethal mutations. The
authors concluded that LSD at high concentrations is a weak mutagen
in Drosophila.
In several studies performed in Drosophila flies, lower concentrations
of LSD had no mutagenic effects, but an increased frequency of
induced mutations was observed after excessive dosages. Vann
(111) reported that dosages of 24,000 micrograms per kg produced
no significant increase in the frequency of recessive lethals,
whereas a dosage of 470,000 micrograms per kg did. Browning
(15) administered intraperitoneal injections of 0.3 microliters
of a solution containing 10,000 micrograms per cc of LSD; this
dosage corresponds to about 4,000,000 micrograms per kg of body
weight. Out of seventy-five flies, only fifteen survived this
procedure, and ten were fertile. Under these circumstances, a
significant increase in recessive lethal mutations in the X-chromosome
of male flies was observed by the author. A 1:1 dilution of the
original solution, when injected into one hundred males, resulted
in thirty-five survivors of which thirty were fertile; the frequency
of mutations markedly dropped. Sram (101) concluded on
the basis of his experiments with LSD in the Drosophila fly that
LSD is a weak mutagen producing gene and chromosome mutations
only when used in very high concentrations; this finding is in
basic agreement with the existing literature on the mutagenic
effects of LSD.
The effects of LSD were also tested on another standard genetic
system, namely the fungus Ophistoma multiannulatum. Zetterberg
(118) exposed the cells of this fungus to 20-50 micrograms per
cc of LSD; he did not find any difference between treated and
control cells. The data on Drosophila flies and fungi suggest
that LSD is a weak mutagenic agent that is effective only in doses
far exceeding those commonly used by human subjects.
There are several interesting studies focusing on the interaction
of LSD with deoxyribonucleic acid (DNA) and ribonucleic acid (RNA);
these studies could contribute to our understanding of the mechanism
of interaction between LSD and the chromosomes or genes. Yielding
and Sterglanz (115), using spectrophotometric methods,
were able to demonstrate binding of LSD, its inactive optical
isomer, and its inactive brominated analogue by helical DNA of
the calf thymus. Binding did not take place with yeast RNA or
nonhelical DNA, suggesting that this binding is specific for helical
DNA.
Wagner (112) concluded on the basis of his experiments
that LSD interacts directly with purified calf thymus DNA, probably
by intercalation, causing conformational changes in the DNA. According
to him, it is unlikely that this could influence the internal
stability of the DNA helix enough to cause chromosomal breakage.
However, it may lead to the dissociation of histones, which could
render DNA susceptible to enzymatic attack. Smythies and Antun
(98) performed similar experiments and arrived at the conclusion
that LSD binds to nucleic acids by intercalation. According to
Dishotsky et al., (28) this evidence of LSD intercalation
into the DNA helix provides a clue to the physical mechanism involved
in the mutagenic effects of high doses of LSD in Drosophila and
the fungus, as reviewed above.
Nosal (83) investigated the effects of LSD on the Purkinje
cells of the cerebellum of growing rats. These studies were specifically
focused on the action of the ribonucleoproteins (RNP) of the differentiating
nucleus-ribosome system. Only large doses of LSD (100-500 micrograms
per kg) seemed to induce changes in the structure and staining
properties of this cellular system.
Obviously, much more research is needed for the final clarification
of the interesting interaction between LSD and various chemical
substances involved in the genetic mechanisms.
TERATOGENIC EFFECTS OF LSD
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 Idanpään-Heikkilä 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 Rugowski (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 Hanaway (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, Dupois 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 abortificient,
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 embryotoxic 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 species 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, Norris 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 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 Morton
(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 case 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 interesting
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 utero 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 Pergament (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.
McClothlin, 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-Hein (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 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 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.
CARCINOGENIC EFFECTS OF LSD
It has repeatedly been mentioned in the literature that LSD might
have carcinogenic potential. This speculation appeared for the
first time in the paper by Cohen, Marinello and Back.
(22) The authors drew this conclusion from their findings of a
markedly increased frequency of chromosomal breakage and a quadriradial
chromosome exchange figure in a patient with paranoid schizophrenia
who had undergone extensive LSD psychotherapy. This is a combination
occurring in three inherited disorders: Bloom's syndrome, Fanconi's
anemia and ataxia teleangiectatica. These disorders are connected
with a high incidence of leukemia and other neoplastic diseases.
The authors also pointed out that cells of neoplastic origin show
a variety of chromosomal aberrations, many of which are not unlike
those they had found in subjects after ingestion of LSD. In addition,
some of the agents known to produce similar-chromosome aberrations,
such as radiation and various viruses, are known carcinogens.
The carcinogenic hypothesis was supported by the finding of Irwin
and Egozcue (57) that nine subjects who had taken illicit
LSD had chromosomal fragments resembling the so-called Philadelphia
(Ph.) chromosome, often associated with chronic granulocytic leukemia.
Grossbard et al. (46) found a Ph1-like chromosome in all
thirty-five peripheral leukocytes from an individual who had used
illicit LSD and other drugs and who later developed acute leukemia.
Several serious objections can be raised against this hypothesis.
First, the evidence that pure LSD causes chromosomal aberrations
is rather problematic and inconclusive. Second, the cause of the
chromosomal lesions in the above mentioned inherited disorders
is not known, nor has it been established whether these lesions
have any relation to subsequent neoplastic developments. There
exist many chromosome breaking agents which are not associated
with leukemia, and quadriradial and other rearrangement figures
have also been found in the white blood cells of normal individuals.
Third, Cohen's comparison of the effects of LSD with those of
radiation does not seem to be well substantiated by experimental
and clinical findings. According to Dishotsky et al., (28)
long-term chromosomal damage following LSD injection has been
reported in three retrospective studies. In two reports of subjects
studied before and after. they took LSD (prospective approach),
the occasional damage that was found was without exception transitory,
suggesting a reversibility of effect unlike that associated with
radiation. Fourth, the Ph1-like chromosome was reported in only
two studies; in both of them it was found in peripheral leucocytes.
In chronic granulocytic leukemia, the Ph1 chromosome is characteristic
only of myeloid and erythroid cells, which normally do not divide
in peripheral blood. Dishotsky et al. (28) quote Nowell
and Hungerford (84) who initially described this lesion:
"A chromosome compatible with the Ph. would have to be observed
in blood cells other than lymphocytes to be relevant to the question
of chronic granulocytic leukemia."
Only two cases of leukemia have been reported in individuals who
were treated in the past with pure LSD. (41, 108) In both of them
it remains to be established whether the association represents
a causal relation or a coincidence. In one of these cases, reported
by Garson and Robson, (41) there was a "remarkable
incidence of childhood malignancies strongly suggestive of a familial
predisposition to malignant disease." At the present time
the carcinogenic hypothesis seems to be rather poorly supported
by experimental and clinical data and remains in the realm of
pure speculation. There appears to be no definite evidence that
LSD is a carcinogenic agent.
SUMMARY AND CONCLUSION
Two-thirds of the existing in vitro studies have reported some
degree of increased chromosomal breakage following exposure to
illicit or pure LSD. With one exception, these changes were observed
with concentrations of LSD and durations of exposure that far
exceeded the dosages commonly used in humans. In none of the studies
was there a clear dosage-response relationship. Since similar
findings have been reported with many commonly used substances,
including artificial sweeteners, aspirin, caffeine, phenothiazine
tranquilizers and antibiotics, there is no reason why LSD should
be singled out and put in a special category. There is no justification
for referring to the structural changes of the chromosomes as
"chromosomal damage"; their functional relevance and
relation to heredity remains to be established. In addition, the
fact that the in vitro experiments bypass the excretory
and detoxifying systems present in the integral organism casts
doubt on the overall relevance of the in vitro results.
In the in vivo chromosomal studies, the majority of positive
findings was reported in persons who had been exposed to illicit,
"alleged" LSD. Dishotsky et al. (28) in their
excellent synoptic review of the chromosomal studies made in the
past, summarized the existing evidence in the in vivo papers
as follows: "In twenty-one in vivo chromosomal studies,
a total of 310 subjects were reported. Of these, 126 were treated
with pure LSD; the other 184 were exposed to illicit, alleged
LSD. Only 18 of 126 (14.3 percent) of the subjects in the pure
LSD group were reported to have chromosomal aberration frequencies
above mean control rates. In contrast, 89 of 184 (48.9 percent)
of the subjects in the illicit LSD group had elevated aberration
frequencies. Of all the subjects reported to have chromosomal
damage, only 18 of 108 (16.7 percent) were exposed to pure LSD.
The frequency of individuals with chromosomal damage reported
among illicit drug users was nearly triple that associated with
the use of pharmacologically pure LSD." These findings indicate
that chromosomal aberrations when found were related to the more
general effects of drug abuse and not to LSD per se; it
is highly improbable that pure LSD ingested in moderate dosages
produces chromosomal aberrations in the white blood cells.
The positive findings in some of the chromosomal studies using
human leucocytes were interpreted as indicating genetic damage
and danger to future generations. To be of direct genetic relevance,
however, the chromosomal damage would have to be demonstrated
in the germinal cells, the sperms and ova, or their precursor
cells. Several existing studies of the effect of LSD on the meiotic
chromosomes have been inconclusive despite the use of excessive
dosages. The mutation studies in Drosophila melanogaster
indicate no mutagenic effect from 0.28 to 500 micrograms of LSD
per cc and a definite mutagenic effect from 2,000-10,000 micrograms
of LSD per cc. The fact that truly astronomic dosages have to
be used to induce mutations in Drosophila shows LSD as a rather
weak mutagen that is unlikely to be mutagenic in any concentration
used by human subjects.
In some of the early studies, LSD was implicated as a potential
cause of congenital malformations, abortions and fetal wastage.
The original reports of teratogenic effects in hamsters, rats
and mice have not been confirmed by later studies. The experiments
in rodents indicated a rather wide range of individual strain
and species susceptibility to the effects of LSD. It is highly
questionable whether and to what extent the results of such investigations
can be extrapolated to the situation in humans. There have been
six individual cases reported of malformed children born to parents
who have used illicit LSD. Only one team of workers reported an
increased frequency of congenital malformations in the offspring
of illicit LSD users. In regard to the high frequency of unexplained
"spontaneous" birth defects and the wide-spread abuse
of LSD, the above observations may be coincidental. The increased
occurrence of malformations in the LSD users reported in one of
the studies may be explained by many other variables characterizing
this group, and there is no logical reason to implicate LSD as
the single or most important factor. At the present time there
is no clear evidence that pure LSD is teratogenic in humans. However,
in view of the high vulnerability of the developing fetus to a
great variety of substances and conditions, the administration
of LSD is contraindicated for the gestation period.
There is no clinical or experimental data demonstrating that LSD
has carcinogenic properties, as suggested by some of the early
studies. No increase in the incidence of tumors among LSD users
has ever been detected. Case reports of leukemia and malignant
tumors in the population of LSD users have been exceedingly rare.
In the three existing case reports of leukemia, there has been
no proof or even indication of a causal relationship, and the
association of leukemia with LSD use may have been merely a coincidence.
As this review shows, no convincing experimental or clinical evidence
exists to prove that the commonly used dosages of pure LSD produce
genetic mutations, congenital malformations or malignant growths.
As far as illicit LSD is concerned, the situation is much more
complex, and the results of the studies of illicit LSD users should
not be considered relevant to the question of the biological dangers
of LSD. Uncertainties about the dosage, and the contamination
of black-market samples of psychedelic drugs by various impurities
and additives contribute a very important dimension to the already
serious psychological hazards associated with unsupervised self-experimentation.
There is absolutely no indication in the research data currently
available that responsible experimental and therapeutic use of
LSD by experienced professionals should be discontinued.
Footnotes
*Numbers apply to references that appear [in
the original publication]. (back)
**In vitro literally means in glass,
and refers to experiments conducted in test-tubes; in vivo
is a medical term for experiments in living organisms. (back)