Jacob Bell
New Member
William W. Dawson, Carlos F. Jimenez-Antillon, Jose M. Perez, and
Jeffrey A. Zeskind
Several tests of visual function were applied to an abstaining user (10 years or more) group
and a nonuser group carefully preselected to be free of clinical signs of eye disease. The
groups were matched on several criteria. The results show that all findings from both groups
are within established limits of normalcy. Small differences and trends were found between
the groups. These would have been undetected without large samples. Relative to the nonuser
group, tests showed these user trends: increased basal lacrimation, increased intraocular
pressure, increased photosensitivity, decreased dark adaptation, decreased color-match limits,
and decreased Snellen acuity. These differences were associated with statistical probabilities,
p = 0.07 to p = 0.001. There were no significant differences or clear trends between the
user and nonuser groups in incidence of pathological fundus signs, conjunctioal hyperemia,
pterygia, or color-match midpoints.
Key words: marijuana, vision, acuity, intraocular pressure, pupil, hyperemia, dark adaptation.
-Lhere have been a number of excellent
reports describing the visual and ophthalmic
consequences of acute marijuana use.
Alteration of color discrimination has been
detected.13 Changes in resting pupillarydiameters
(PD) have been reported.4
Aqueous humor dynamics have been studied
intensively and reductions of intraocular
pressure (IOP) have been reported
by several authors.5"8 Both vernier2 and
Snellen acuity9 decrease following marijuana
consumption. Thomas and Chester11
and Valk10 also described reductions in the
total range of accommodation to between
2.50 and 5.00 diopters in a group of marijuana
users. General changes have been reported
in the conjunctival sac and the uveal
tract with vascular symptoms similar to
those found in iritis.9"11
The majority of the studies which implicate
eye function have considered the
results of measurements made during or
immediately following marijuana consumption.
However, when chronic effects have
been discussed in the literature they have
usually been limited to days or weeks,
whereas the "experienced" user has been
accepted with levels of use as low as one
marijuana cigarette a week.12 Consequently,
true long-term use, in the order of years
and involving numerous cigarettes per day,
is a virtually untouched area in the literature
dealing with eye toxicity and function.
The visual experiments reported here
were part of a broad group of socioanthropological
and medical studies. The general
design required that the measures should
test a variety of eye functions as a means
for generating or excluding future, more
specific research into the consequences of
long-term use. Test devices were limited
to those that are well known in the ophthalmic
community and whose results
could be readily interpreted.
Methods
Costa Rica was chosen as the study site because
of governmental cooperation, high literacy
rate (90 percent), and high-quality medical personnel
and facilities. Subjects were identified
only after 2 years of interrelationship development
and screening by teams of anthropologists
and sociologists. The teams took up residence
in and became part of the urban neighborhoods
of San Jose. Data given by subjects were crossvalidated
with relatives and neighbors by the
resident-team members. Life and nutritional histories
were developed. After the research began,
subjects and records were identified only
by number. Personnel administering and scoring
tests used these numbers and were not aware
of user or nonuser group assignments.
Over-all subject selection assumed that the
tests should be made to determine the limits
of normal function in persons with 10 or more
years' experience with marijuana consumption.
The inclusion of random (or nonrandom) eye
disease could tend to increase further the variance
of the results, which is always high for inexperienced
subjects. Consequently, the general
medical screening and ophthalmic examinations
at the Hospital Mexico identified for exclusion
some of the preliminary sample (N=240) who
had visual defects which limited correctable acuity
to less than 20/40, IOP (by applanation) in
excess of 20 mm. Hg, or defective color vision
as measured by the Ishihara plates. Subjects with
positive serological tests for syphilis were also
excluded as potential retinitis cases. With exclusion
for other medical causes and attrition from
the requirements of the matching procedures,
39 pairs of users and nonusers became available.
User-nonuser (matched pair) samples were
established with a mean age of 29 years (range
19 to 50), with each pair matched to -4 years.
Pairs were matched also for marital status and
for education, which was divided into five levels
(from none through completed secondary). Occupation
was matched by general category, i.e.,
artisan or white-collar worker. Subjects were also
matched (within four points) for alcohol consumption
on a standardized scale of 0 to 17 and
tobacco cumulative use was matched (-2 years)
based on pack-years.
The nonusers had never had a verified experience
with marijuana, whereas the users had consumed
the drug for 10 or more years. At the
time of the study the average user consumed
nine marijuana cigarettes0 a day (range 1 to
40), had smoked 15.7 pack-years of tobacco
cigarettes, had an incomplete primary school
education, was a skilled worker, was a "moderate"
alcohol user, was free of any disease which
seemed remotely relevant to the project, was
29 years of age, and was a married man. Anthropologically
the sample of matched pairs and the
Costa Rican population, in general, are considered
to be remarkably uniform by North
American standards. Except where noted, results
are given on the 39 matched pairs sample.
During testing corrective spectacles were worn.
Subjects had agreed not to consume marijuana
for a period of at least 3 hr. before going to the
hospital for testing. Since they were taken by
taxi to the hospital between 7:00 and 9:00 A.M.,
and usually waited 1 to 3 hr. at the hospital,
it is likely that little or no smoking occurred
in the user group for at least 10 hr. before
testing. Marijuana is not consumed publicly in
Costa Rica, where it is illegal and enforcement
is vigorous.
Pupil measures. Pupil diameters of the right
eye were measured in a Goldmann-Weekers dark
adaptation apparatus at the end of a period of
30 minutes of total dark adaptation with fixation
on a small red lamp in the adapting sphere.
Pupil diameters were filmed immediately after
the onset of the adapting lights (2.7 log footlamberts).
A 20 sec. record of pupillary diameters
was generated by measuring single motion picture
frames (18 FPS) to the nearest 0.02 mm. across
the largest diameter.
Intraocular pressure–water loading test. The
subjects were seated in a quiet room late in the
morning. After ingestion of 1 L. of water in
about 3 min., IOP was immediately measured
in each eye by applanation and measured again
at 20, 40, and 60 min. The utility of this pro-
cedure in examining marginal changes in aqueous
humor dynamics was described recently by
Kronfeld.13
Dark-adaptation threshold. Thresholds were
measured during dark adaptation of the right
eye of each subject. The subject was seated in
front of a Goldmann-Weekers adaptometer.14 The
left eye was patched. Fixation lights were arranged
with a chin support so that a 12° area
was tested 14° temporal to the fovea of the
right eye. Before dark adaptation there was
adaptation to 2.7 log foot-lamberts for 4 min.
Group data were scored for threshold and time
at the inflection (alpha point) which signifies the
end of the cone adaptation period and for threshold
at 30 min.
Decimal acuity with varied luminance.15 A
standard Bausch and Lomb Orthorater with Snellen
acuity transparency was used in this test.
The Orthorater was modified so that neutral tint
filters could be placed in the viewing pathway.
Seven rows of different Snellen letters could be
seen by either the left or right eye. These letter
lines ranged in size at threshold from 20/20 to
20/200. Each eye was tested separately. Then
each eye was occluded in turn, and the appropriate
column was read again as illumination was increased
in log unit steps. The subject read the
smallest visible line and if he made more than
one error, read the next larger line. Final
scores were converted to decimal acuity for each
eye.
Color matching–anomaloscope. The Hecht/
Schlaer anomaloscope uses a bipartite field. The
left half field was a standard yellow. The right
half field may be adjusted to match the color
and brightness of the left field. Both eyes were
measured. The subject was allowed to choose
which eye was to be used first. The other eye
was occluded. Initially, the right field was set
so that it contained excess red or green. After
the brightness had been adjusted to a match the
subject indicated whether the field was too green
or too red. Beginning with excess green, the
adjustment was continued in steps with the variable
mixture moving from the "too green" side
until the subject reported that the two fields
appeared equal in color. At that point the mixture
was changed so that it was too red and the
procedure was repeated. In this way the acceptable
limits of the color match were defined. The
technician also recorded the brightness settings
as a means for identifying the brightness match.
The sequence was repeated on the opposite eye.
These color results were converted to the comparative
units1'1 and contrasted with match midpoint
data and match limit ranges previously found
in the literature.
The Schirmer test for lacrimal fluid secretion
The test and its physiological basis have been
described by Jones.17 In order to test the basic
secretory system and exclude the reflex system,
one drop of 0.5 percent proparacaine HC1 was
placed into each eye and this procedure was repeated
after 5 min. Measurements were made
for 5 min. on both eyes of each subject. Fluid
migration was measured in millimeters. This
procedure is occasionally rejected for use in clinics
because of its lack of standardization18 and more
objective, quantitative methods have been generated.
The latter tests use fluorophotometric methods19
not available in Costa Rica.
Fundus evaluation. Color photographs of each
fundus were taken. Photographs were made of
each of the four quadrants of the fundus, with
a fifth centered upon the optic disc. All exposed
films were returned to the United States for commercial
processing. This resulted in some losses,
necessitating elimination of a "pair." Evaluations
were made by a practiced staff member and
were divided into categories: vessels, retina, disc,
and macula. Regions were evaluated as "normal"
or "abnormal," with comments on the extent of
the apparent abnormality when present.
Results
Pupil response. Records of pupil size of
the right eye were divided into 250 msec,
periods. The first readable frame in each
period for the first 11 periods was taken
for measurement. From dark adaptation,
pupil size was sampled at regular intervals
during the first 2.75 sec. after the onset of
the adapting light. Fig. 1 shows that the
pupillary construction became asymptotic
at about 2.2 sec. Mean pupil diameters are
very similar for both user and nonuser
groups; however, the user group means are
uniformly smaller. Variability, as indicated
by the standard deviation, was about twice
as large for the user group early in constriction.
After most active constriction was
complete the variability of the two groups
was about the same. Analysis of variance
(ANOVA) disclosed no significant differences
between the over-all group means.
We found that the number of individuals
giving usable pupil data decreased
rapidly after the onset of the light adaptation
because many subjects had a strong
tendency toward reflex withdrawal (blepharospasm
or rolling the eyes upward)
shortly after the onset of light adaptation.
At the beginning (during response latency)
and end of pupil measurements both user
and nonuser groups contributed approximately the same number of measurements.
However, during the period of greatest
pupil activity reflex withdrawal from the
illumination appeared more frequently in
the user group (Fig. 2). Results were
statistically significant (p < 0.05) if the
analysis was confined to the period of active
constriction.
Intraocular pressure with water load.
IOP was measured by applanation immediately
after and at 20 min. intervals
following the ingestion of 1 L. of water.
The resulting IOP means for 78 eyes in
both groups are shown in Fig. 3. The limit
marks shown above mean values are ± 1
S.E. ANOVA showed that there were no
statistically valid differences between individual
pairs of measurements, such as
between users and nonusers, at any particular
point on the time axis. Nor was
there a difference between any two adjacent
time periods. However, when taken
as a whole, the analyses show that there
was a difference (p = 0.06) where IOP
was higher for the users. Fig. 3 suggests
that this is a basal pressure difference and
is not related to the way in which the water
load was handled.
Dark adaptation. Visual thresholds at
times after the onset of dark adaptation
are presented in Fig. 4. The smooth-drawn
portion of the functions approximate the
"average" subject whose final cone limb
threshold and final threshold corresponded
to the respective group means. The time
between 0 and 4 min. was the light
adaptation period. Statistical analyses were
done at the "alpha" (A) point of inflection
between cone- and rod-dominated
portions of the function. The A point appeared
at approximately 6 min. after the
beginning of dark adaptation. Other mean
points were generated at the asymptote
for dark adaptation, which occurred at
about 30 min. Limit marks are +(U, users),
-(NU, nonusers) 1 S.E. By ANOVA the
times to the A point were not statistically
different for the user and nonuser groups.
Thresholds taken separately for the cone
and rod limbs were not different for the
groups. However, the over-all ANOVA for
both sets of thresholds indicated a marginal
difference (p = 0.07). The users
showed less complete adaptation than the
nonusers.
Acuity at different luminances. Ability
to read "Snellen" letters at different luminance
levels was measured and the Snellen
notation values were converted to decimal
acuities (Fig. 5). Except at about -0.7
millilamberts, the nonusers mean monocular
acuity was superior to that of the
user group. ANOVA showed large, highly
significant differences for acuity between
light levels for both groups. Differences
for left or right eyes taken separately or
differences between groups at any par
ticular luminance level did not approach
significance. However, ANOVA for overall
differences between groups across all
luminance levels was associated with a
p = 0.07.
Color match–anomaloscope test. The
widths of the brightness and color-match
limits were measured by the Hecht/Schlaer
anomaloscope. The upper portion of Fig.
6 shows the range of normative match
midpoints produced by 49 observers studied
by Willis and Famsworth as described
by Jameson and Hurvich.10 The midpoint
lies in the center of the range of acceptable
matches. The limits of the acceptable
matches plus the midpoints for the normative
group ("match limit range") of 49
are displayed just below. Midpoints for the
user and nonuser groups are filled circles.
The related match limits are also shown
to the left and right of each midpoint.
ANOVA showed a statistical difference of
p = 0.01 for the direction (green or red)
from which the match was initiated. This
result is expected. The analysis showed no
difference between groups for the match
midpoint. However, there was a statistically
significant difference (p = 0.01)
between the user and nonuser groups for
the breadth of the match limits for color
and for brightness. Brightness data are not
pictured in Fig. 6. The widths of the match
limits for color were 1.63 for the users
and 3.42 for the nonusers. Limits for
brightness of the users were 3.61 and those
of nonusers were 5.21. For the color match,
these values and the means have been converted
to "comparative units" in Fig. 6 so
that they may be compared with the normative
data. The comparative unit scale
was described by Jameson and Hurvich.16
All data presented in Fig. 6 are within the
limits of normalcy. The primary difference
between groups in this study is the extent
of the match ranges which were judged acceptable.
The smokers were less tolerant
of deviations from the "midpoint."
Although the preliminary screening with
the Ishihara color plates was designed to
eliminate persons with eye defects, the
Farnsworth Dichotomous Test, Panel D-15,
20 was administered later. None of the
subjects who had previously passed the
Ishihara test failed to pass the Farnsworth
test.
Lacrimal fluid production. Basal (in distinction
to reflex) lacrimal fluid production
was measured by the Schirmer test.
Results of tests performed on both eyes
simultaneously indicate that the mean distance
of fluid migration for the users' eyes
was 2.8 mm. and for the nonusers" eyes,
2.6 mm. ANOVA for differences between
groups indicate that the u group showed
more fluid migration (p = 0.001).
Other observations. Results of the evaluation
of the fundus photographs are presented
in Table I. Photographs of five
fundus regions of eyes in each group were
examined. Areas judged abnormal are
listed. Nine users had at least one fundus
area judged abnormal and seven nonusers
showed at least one abnormal fundus area.
Although these are probably high for a
randomly drawn sample, there is no basis
for assuming a difference in incidence of
abnormality between the two groups.
The data from the dynamic acuity test
have not been presented. These results
showed evidence of such great variability
that no conclusion can be justified. An
analysis of clinical examination data showed
the presence of conjunctival hyperemia in
16 of the user group and 13 of the nonuser
group. Similarly, two users were found
to have pterygia whereas none of the controls
had them. Numbers such as these are
difficult to submit to statistical analysis.
However, there may be a trend in the user
group toward signs of more frequent irritation
of the conjunctiva. Results are summarized
in Table II.
Discussion
It is important to consider carefully the
finally matched subject samples, the methodology,
and the philosophy which produced
them. Before development of the
matched groups, an extensive clinical evaluation
had been done to select out of the
basic samples (N = 240) all "abnormal"
subjects. Four users and four nonusers
were excluded because of uncorrectable
visual acuity; 3 users and 13 nonusers for
color vision defect; 20 users and 17 nonusers
for postive serological test for syphilis;
eight users and 17 nonusers for pulmonary
lesions; and three users and nine
nonusers for other serious diseases. Then
the user and nonuser groups were carefully
matched on an array of medical, educational,
social, and anthropological criteria.
If a bias was instituted by these
procedures, it would serve to reduce differences
between the user and nonuser groups.
The participants in each sample were
unfamiliar with the types of judgments
which were required from them in the
various eye tests. Consequently, the variability
associated with the results from
these extensive samples would be expected
to be greater than that found in intensive
testing on a few highly practiced subjects.
It may be argued that one should accept
as real only those group results where
differences are associated with probability
coefficients of 0.05 or less. This traditional
but arbitrary cutoff level could be dangerous
if applied without attention to sampling
techniques. For these reasons, we
have elected to consider values of p =
0.07 or less as indicative of real trends.
An elaborate discussion of the results of
this project can yield little more than is
presented in Table II. There is little experimental
literature on chronic use to provide
a background for discussion. With
this caution, it is emphasized that the following
discussion is an integration with
the literature on acute marijuana use and
with classical and recent concepts in ophthalmology
of both statistically significant
findings and trends from our experiments.
The relevant clinical signs are presented
as "typical" but will vary widely between
individual cases.21
Anterior segment irritability. There are
threads common to the majority of the
findings of differences between the user
and nonuser groups and these relate also
to the acute-use literature. Among these
are symptoms which are typical of many
irritative states of the anterior segment of
the eye.22' " Excellent general descriptions
of the symptoms have been presented by
Duke-Elder21 and by Duke-Elder and Perkins.
24 Table III compares these common
symptoms of eye disease with findings associated
with the user group of this project
and with reports from the literature on
acute use.
Conjunctival hyperemia is typical of
many irritative states and also has been
documented repeatedly as a result of acute
marijuana use.4'10-X1 In this study the user
group had abstained from marijuana consumption
for at least 4 and more likely 10
to 12 hr. prior to testing. Clinically determined
conjunctival hyperemia was only
slightly more frequent in the users than in
their matched counterparts. This may be
because of an adaptation to chronic use,
dissipation of the condition, or masking of
the effect by the high incidence of hyperemia
in the nonusers.
Light sensitivity or "photophobia" is
common21 in irritations of the anterior segment
due to disease but its pathophysiology
is poorly understood.25 There was no quantitative
measure of "light sensitivity" in
our tests but the high frequency of reflex
withdrawal of user eyes from the light
which was used to excite pupillary constriction
tends to suggest heightened sensitivity
of the user group. In addition, there
was a statistically significant difference in
brightness limits and color-match limits for
the anomaloscope tests. If subjective brightness
sensitivity is increased in the user
group, it is possible that this accounts for
their unusual performance on the anomaloscope-
based color measures.
Acuity is often decreased in anterior segment
disease. This may be due to many
causes, not the least of which are slight
changes in the refraction or transmission
characteristics of the various optical layers
of the anterior segment, usually caused
by edema. This type of acuity loss would
be uncorrectable by optical methods. An
apparently optically uncorrectable acuity
deficit was found in the chronic users, although
subjects were carefully refracted
and corrective lenses provided. In acute
users reduced Snellen and vernier acuity
has been reported,2'9> 10 but Hepler et al.4
found no change.
Intraocular pressure elevation and elevation
of protein content of the aqueous
humor is also a corollary of diseases of
the anterior segment of the eye.22-23; 2<1> 27
Green and Pederson5 have shown that protein
elevation in the anterior chamber is
seen in the rabbit anterior segment which
was treated with A^THC. The findings we
have presented on chronic user IOP conflict
with several reports of decreased intraocular
pressure in nonchronic users.4'7> 9
There are great differences in the established
degrees of "experience" of the subjects.
Flom et al.8 replicated previous findings
of reduced IOP in acute smokers with
little use-experience but found little or no
IOP change in subjects with extensive use
history. This important findings emphasizes
the experience variable, which has been
considered rarely in prior publications.
Mean pupil diameter was slightly but
very consistently decreased during the
acute phase of constriction in our users.
The characteristics of the pupillary active
light response in conditions of anterior segment
irritation are not known, but the
affected resting pupil is often smaller than
normal in clinical cases of eye irritation.23
Duke-Elder accounted for this as a mechanical
effect of iris vascular engorgement
due to irritation.21 Bhattarchjee23 considered
the constricted pupil a typical component
of the syndrome of eye irritation
which he associated with the liberation of
prostaglandins from eye tissues. Hepler et
al.4 reported mild pupillary constriction
during marijuana smoking.
Prostaglandins have been associated recently
with the entire syndrome of anterior
segment irritation. This literature has
been reviewed by Eakins et al.22 and more
recently Neufeld and Sears.28 Prostaglandin
production in the eye appears to be closely
connected with the consequences of disease
or trauma of the anterior segment. If prostaglandins
and their release are specifically
inhibited, the irritative response of the
eye (as seen in Table III) does not occur.
28' 29 Green and Bowman0 reported
that A9-THC (tetrahydrocannabinol) inhibits
the formation of prostaglandins. If
this is correct in the eye, for all products
of THC, it is unlikely that prostaglandin
production can be directly responsible for
the signs of irritation which may be seen
in the acute phase of marijuana consumption.
However, in the absence of other information,
it is possible that in the longterm
chronic user there is a prostaglandin
rebound or hyperproduction during periods
of abstention. The moderations of prostaglandin
effects or physiology which could
occur during adaptation to 10 years of use
are difficult to guess. As in cigarette smoking,
a more important question is, "What
trends are set whose results are felt clearly
in 15 to 20 years?"
The visual and ocular signs that have
been described in chronic users but not
found in our results may also originate
directly or indirectly from neurophysiological
effects. There are no direct data on
chronic THC-neural interaction in the eye;
however, changes in pupil dimensions, vasomotor
activity, accommodation, and lacrimation
are discussed classically in association
with the balance between sympathetic and
parasympathetic divisions of the autonomic
nervous system. These were reviewed by
Walsh and Hoyt.25 More recent findings
have also implicated neural control of intraocular
pressure.30-31 Even the indications
of heightened brightness sensitivity
may have specific neural origins. Bieger
and Hockman32 have recorded large changes
in lateral geniculate nucleus function in
the presence of circulating A1-THC. Also
the modulation of visual function in both
retina and optic nerve has a well-estab
lished link to the sympathetic nervous system.'
13' '" Ng et al.35 seem to have presented
a clear case for modulation of general peripheral
sympathetic activity by A9-THC.
Recently a direct link has been established
by Green and Kim for the control of several
IOP factors by sympathomimetic actions
of THC in rabbits. There is no reason
to assume independence between the
conjunctival or uveal irritative signs and
the neural implications of chronic use as
indicated by brightness sensitivity or "photophobia."
This link has been established
for some time as the "trigeminal syndrome,"
1'5 a common clinical entity. The
primary factors in this hypothetical link
are yet to be identified.
The results presented here are available because
of the extensive cooperation given by the parent
project and its professional staff in the United
States of America and Costa Rica. Of particular
value were efforts by Drs. William Carter, Wilmer
Coggins, and Paul Doughty from the University
of Florida and Dr. Frederico Faerron from the
Social Security System, Republic of Costa Rica.
The Vision Committee, NAS-NRC working group
36, assisted in experimental design.
REFERENCES
1. Kiplinger, G. F., Manno, J. E., Rodda, B. E.,
and Forney, R. B.: Dose response analysis
of the effects of tetrahydrocannabinol in
man, Clin. Pharmacol. Ther. 12:650, 1971.
2. Agurell, S., et al.: Pharmacokinetics of As.
THC in man after smoking: Relations to
physiological and psychological effects. In
Braude, M. C, and Szara, S., editors: The
Pharmacology of Marihuana, New York, 1976,
Raven Press, vol. 1, pp. 49-61.
3. Domino, E., Rennick, P., and Pearl, J. H.:
Short-term neuropsychopharmacological effects
of marihuana smoking in experienced
male users, In Braude, M. C., and Szara, S.,
editors: The Pharmacology of Marihuana,
New York, 1976, Raven Press, vol. 1, pp.
393-412.
4. Hepler, R. S., Frank, I. M., and Ungerleider,
J. T.: Pupillary constriction after marijuana
smoking, Am. J. Ophthalmol. 74:1185, 1972.
5. Green, K., and Pederson, J. E.: Effect of
A1-tetrahydrocannabinol on aqueous dynamics
and ciliary body permeability in the rabbit,
Exp. Eye Res. 15:499, 1973.
6. Green, K., and Bowman, K.: Effect of marihuana
and derivatives on aqueous humor
dynamics in the rabbit. In Braude, M. C,
and Szara, S., editors: The Pharmacology of
Marihuana, New York, 1976, Raven Press,
vol. 2, pp. 803-813.
7. Hepler, R. S., Frank, I. M., and Petrus, R.:
Ocular effects of marihuana smoking. In
Braude, M. C, and Szara, S., editors: The
Pharmacology of Marihuana, New York, 1976,
Raven Press, vol. 2, pp. 815-824.
8. Flom, M. C, Adams, A. J., and Jones, R. T.:
Marijuana smoking and reduced pressure in
human eyes: drug actions or epiphenomena?
INVEST. OPHTHALMOL. 14:52, 1975.
9. Shapiro, D.: The ocular manifestations of
cannabinols, Ophthalmologia 168:366, 1974.
10. Valk, L.: Hemp in connection with ophthalmology,
Neth. Ophthalmol. Soc. 167:413,
1973.
11. Thomas, R., and Chester, G.: The pharmacology
of marihuana, Med. J. Aust. 2:229,
1973.
12. Marihuana and Health. Second Annual Report
by Secretary HEW to Congress, Washington,
D. C, 1972, U. S. Govt. Printing Office, p.
137.
13. Kronfeld, P. C : Water drinking and outflow
facility, INVEST. OPHTHALMOL. 14:49, 1975.
14. Frankhauser, F., and Schmidt, T.: Studies
on the functions of the dark-adapted eye
with the Goldmann-Weekers adaptometer,
Ophthalmologica 133:264, 1957.
15. Hecht, S.: A quantitative basis for the relation
between visual acuity and illumination,
Proc. Natl. Acad. Sci. 13:569, 1927.
16. Jameson, D., and Hurvich, L.: Theoretical
analysis of anomalous trichromatic color vision,
J. Optical Soc. Am. 46:1075, 1956.
17. Jones, L. T.: The lacrimal secretory system
and its treatment, Am. J. Ophthalmol. 62:47,
1966.
18. Doughman, D.: Clinical tests. In Holly, F. J.,
and Lemp, M., editors: The Preocular Tear
Film and Dry Eye Syndromes, Int. Ophthalmol.
Clin. 13:199, 1973.
19. Mishima, S., Gassett, A., Klyce, S. D., and
Baum, J. L.: Determination of tear volume
and tear flow, INVEST. OPHTHALMOL. 5:264,
1966.
20. Farnsworth, D.: The Farnsworth Dichotomous
Test for Color Blindness–Panel D-15,
New York, 1947, Psychological Corp.
21. Duke-Elder, W. S.: Parsons' Diseases of the
Eye, Boston, 1964, Little Brown & Company,
pp. 230-233.
22. Eakins, K. E., Whitelocke, R. A., Bennett, A.,
and Martenet, A. C: Prostaglandin like activity
in ocular inflammation, Br. Med. J. 3:
452, 1972.
23. Bhattarchjee, P., and Eakins, K. E.: Inhibi
tion of the ocular effects of sodium archidonate
by anti-inflammatory compounds,
Prostaglandins 9:175, 1975.
24. Duke-Elder, W. S., and Perkins, E. S.: System
of Ophthalmology, St. Louis, 1966, The
C. V. Mosby Co., Vol. 19, pp. 133-166.
25. Walsh, F., and Hoyt, W.: Clinical neuroophthalmology,
Baltimore, 1969, The Williams
& Wilkins Company, pp. 414-465.
26. Eakins, K. E.: Increased intraocular pressure
produced by prostaglandins Ei and Eu in the
cat eye, Exp. Eye Res. 10:87, 1970.
27. Vegge, T., Neufeld, A. H., and Sears, M. L.:
Morphology of the breakdown of bloodaqueous
barrier of ciliary processes of the
rabbit eye after prostaglandin E2, INVEST.
OPHTHALMOL. 14:33, 1975.
28. Neufeld, A. H., and Sears, M. L.: Prostaglandin
and eye, Prostaglandins 4:157, 1973.
29. Neufeld, A., Jampol, L., and Sears, M. L.:
Aspirin prevents the disruption of the blood
aqueous barrier in the rabbit eye, Nature
238:158, 1972.
30. Cox, C. E., Fitzgerald, C. R., and King, R.
L.: A preliminary report on the supraoptic
nucleus and control of intraocular pressure,
INVEST. OPHTHALMOL. 14:26, 1975.
31. Macri, F. J., and Cevarino, S. J.: Ciliary
ganglion stimulation. I. Effects on aqueous
humor inflow and outflow, INVEST. OPHTHALMOL.
14:28, 1975.
32. Bieger, D., and Hockman, C. H.: Differential
effects produced by Ai -tetrahydrocannabinol
on lateral geniculate neurons, Neuropharmacology
12:269, 1973.
33. Mascetti, G. C, Marzi, C. A., and Berlucchi,
G.: Sympathetic influences on the dark- discharge
of the retina in the freely moving cat,
Arch. Ital. Biol. 107:158, 1969.
34. Marini, R., and Pettrossi, V. E.: Electroretinogram
and the superior cervical ganglion,
Arch. Ital. Biol. 112:337, 1974.
35. Ng, L., Lamprecht, F., Williams, R. B., and
Kopin, I. J.: A^-Tetrahydrocannabinol and
ethanol: differential effects on sympathetic
activity in differing environmental setting,
Science 180:1368, 1973.
36. Green, K., and Kim, K.: Mediation of ocular
and tetrahydrocannabinol effects by adrenergic
nervous system, Exp. Eye Res. 23:443,
1976.
Source: Marijuana and vision--after ten years' use in Costa Rica.
Jeffrey A. Zeskind
Several tests of visual function were applied to an abstaining user (10 years or more) group
and a nonuser group carefully preselected to be free of clinical signs of eye disease. The
groups were matched on several criteria. The results show that all findings from both groups
are within established limits of normalcy. Small differences and trends were found between
the groups. These would have been undetected without large samples. Relative to the nonuser
group, tests showed these user trends: increased basal lacrimation, increased intraocular
pressure, increased photosensitivity, decreased dark adaptation, decreased color-match limits,
and decreased Snellen acuity. These differences were associated with statistical probabilities,
p = 0.07 to p = 0.001. There were no significant differences or clear trends between the
user and nonuser groups in incidence of pathological fundus signs, conjunctioal hyperemia,
pterygia, or color-match midpoints.
Key words: marijuana, vision, acuity, intraocular pressure, pupil, hyperemia, dark adaptation.
-Lhere have been a number of excellent
reports describing the visual and ophthalmic
consequences of acute marijuana use.
Alteration of color discrimination has been
detected.13 Changes in resting pupillarydiameters
(PD) have been reported.4
Aqueous humor dynamics have been studied
intensively and reductions of intraocular
pressure (IOP) have been reported
by several authors.5"8 Both vernier2 and
Snellen acuity9 decrease following marijuana
consumption. Thomas and Chester11
and Valk10 also described reductions in the
total range of accommodation to between
2.50 and 5.00 diopters in a group of marijuana
users. General changes have been reported
in the conjunctival sac and the uveal
tract with vascular symptoms similar to
those found in iritis.9"11
The majority of the studies which implicate
eye function have considered the
results of measurements made during or
immediately following marijuana consumption.
However, when chronic effects have
been discussed in the literature they have
usually been limited to days or weeks,
whereas the "experienced" user has been
accepted with levels of use as low as one
marijuana cigarette a week.12 Consequently,
true long-term use, in the order of years
and involving numerous cigarettes per day,
is a virtually untouched area in the literature
dealing with eye toxicity and function.
The visual experiments reported here
were part of a broad group of socioanthropological
and medical studies. The general
design required that the measures should
test a variety of eye functions as a means
for generating or excluding future, more
specific research into the consequences of
long-term use. Test devices were limited
to those that are well known in the ophthalmic
community and whose results
could be readily interpreted.
Methods
Costa Rica was chosen as the study site because
of governmental cooperation, high literacy
rate (90 percent), and high-quality medical personnel
and facilities. Subjects were identified
only after 2 years of interrelationship development
and screening by teams of anthropologists
and sociologists. The teams took up residence
in and became part of the urban neighborhoods
of San Jose. Data given by subjects were crossvalidated
with relatives and neighbors by the
resident-team members. Life and nutritional histories
were developed. After the research began,
subjects and records were identified only
by number. Personnel administering and scoring
tests used these numbers and were not aware
of user or nonuser group assignments.
Over-all subject selection assumed that the
tests should be made to determine the limits
of normal function in persons with 10 or more
years' experience with marijuana consumption.
The inclusion of random (or nonrandom) eye
disease could tend to increase further the variance
of the results, which is always high for inexperienced
subjects. Consequently, the general
medical screening and ophthalmic examinations
at the Hospital Mexico identified for exclusion
some of the preliminary sample (N=240) who
had visual defects which limited correctable acuity
to less than 20/40, IOP (by applanation) in
excess of 20 mm. Hg, or defective color vision
as measured by the Ishihara plates. Subjects with
positive serological tests for syphilis were also
excluded as potential retinitis cases. With exclusion
for other medical causes and attrition from
the requirements of the matching procedures,
39 pairs of users and nonusers became available.
User-nonuser (matched pair) samples were
established with a mean age of 29 years (range
19 to 50), with each pair matched to -4 years.
Pairs were matched also for marital status and
for education, which was divided into five levels
(from none through completed secondary). Occupation
was matched by general category, i.e.,
artisan or white-collar worker. Subjects were also
matched (within four points) for alcohol consumption
on a standardized scale of 0 to 17 and
tobacco cumulative use was matched (-2 years)
based on pack-years.
The nonusers had never had a verified experience
with marijuana, whereas the users had consumed
the drug for 10 or more years. At the
time of the study the average user consumed
nine marijuana cigarettes0 a day (range 1 to
40), had smoked 15.7 pack-years of tobacco
cigarettes, had an incomplete primary school
education, was a skilled worker, was a "moderate"
alcohol user, was free of any disease which
seemed remotely relevant to the project, was
29 years of age, and was a married man. Anthropologically
the sample of matched pairs and the
Costa Rican population, in general, are considered
to be remarkably uniform by North
American standards. Except where noted, results
are given on the 39 matched pairs sample.
During testing corrective spectacles were worn.
Subjects had agreed not to consume marijuana
for a period of at least 3 hr. before going to the
hospital for testing. Since they were taken by
taxi to the hospital between 7:00 and 9:00 A.M.,
and usually waited 1 to 3 hr. at the hospital,
it is likely that little or no smoking occurred
in the user group for at least 10 hr. before
testing. Marijuana is not consumed publicly in
Costa Rica, where it is illegal and enforcement
is vigorous.
Pupil measures. Pupil diameters of the right
eye were measured in a Goldmann-Weekers dark
adaptation apparatus at the end of a period of
30 minutes of total dark adaptation with fixation
on a small red lamp in the adapting sphere.
Pupil diameters were filmed immediately after
the onset of the adapting lights (2.7 log footlamberts).
A 20 sec. record of pupillary diameters
was generated by measuring single motion picture
frames (18 FPS) to the nearest 0.02 mm. across
the largest diameter.
Intraocular pressure–water loading test. The
subjects were seated in a quiet room late in the
morning. After ingestion of 1 L. of water in
about 3 min., IOP was immediately measured
in each eye by applanation and measured again
at 20, 40, and 60 min. The utility of this pro-
cedure in examining marginal changes in aqueous
humor dynamics was described recently by
Kronfeld.13
Dark-adaptation threshold. Thresholds were
measured during dark adaptation of the right
eye of each subject. The subject was seated in
front of a Goldmann-Weekers adaptometer.14 The
left eye was patched. Fixation lights were arranged
with a chin support so that a 12° area
was tested 14° temporal to the fovea of the
right eye. Before dark adaptation there was
adaptation to 2.7 log foot-lamberts for 4 min.
Group data were scored for threshold and time
at the inflection (alpha point) which signifies the
end of the cone adaptation period and for threshold
at 30 min.
Decimal acuity with varied luminance.15 A
standard Bausch and Lomb Orthorater with Snellen
acuity transparency was used in this test.
The Orthorater was modified so that neutral tint
filters could be placed in the viewing pathway.
Seven rows of different Snellen letters could be
seen by either the left or right eye. These letter
lines ranged in size at threshold from 20/20 to
20/200. Each eye was tested separately. Then
each eye was occluded in turn, and the appropriate
column was read again as illumination was increased
in log unit steps. The subject read the
smallest visible line and if he made more than
one error, read the next larger line. Final
scores were converted to decimal acuity for each
eye.
Color matching–anomaloscope. The Hecht/
Schlaer anomaloscope uses a bipartite field. The
left half field was a standard yellow. The right
half field may be adjusted to match the color
and brightness of the left field. Both eyes were
measured. The subject was allowed to choose
which eye was to be used first. The other eye
was occluded. Initially, the right field was set
so that it contained excess red or green. After
the brightness had been adjusted to a match the
subject indicated whether the field was too green
or too red. Beginning with excess green, the
adjustment was continued in steps with the variable
mixture moving from the "too green" side
until the subject reported that the two fields
appeared equal in color. At that point the mixture
was changed so that it was too red and the
procedure was repeated. In this way the acceptable
limits of the color match were defined. The
technician also recorded the brightness settings
as a means for identifying the brightness match.
The sequence was repeated on the opposite eye.
These color results were converted to the comparative
units1'1 and contrasted with match midpoint
data and match limit ranges previously found
in the literature.
The Schirmer test for lacrimal fluid secretion
The test and its physiological basis have been
described by Jones.17 In order to test the basic
secretory system and exclude the reflex system,
one drop of 0.5 percent proparacaine HC1 was
placed into each eye and this procedure was repeated
after 5 min. Measurements were made
for 5 min. on both eyes of each subject. Fluid
migration was measured in millimeters. This
procedure is occasionally rejected for use in clinics
because of its lack of standardization18 and more
objective, quantitative methods have been generated.
The latter tests use fluorophotometric methods19
not available in Costa Rica.
Fundus evaluation. Color photographs of each
fundus were taken. Photographs were made of
each of the four quadrants of the fundus, with
a fifth centered upon the optic disc. All exposed
films were returned to the United States for commercial
processing. This resulted in some losses,
necessitating elimination of a "pair." Evaluations
were made by a practiced staff member and
were divided into categories: vessels, retina, disc,
and macula. Regions were evaluated as "normal"
or "abnormal," with comments on the extent of
the apparent abnormality when present.
Results
Pupil response. Records of pupil size of
the right eye were divided into 250 msec,
periods. The first readable frame in each
period for the first 11 periods was taken
for measurement. From dark adaptation,
pupil size was sampled at regular intervals
during the first 2.75 sec. after the onset of
the adapting light. Fig. 1 shows that the
pupillary construction became asymptotic
at about 2.2 sec. Mean pupil diameters are
very similar for both user and nonuser
groups; however, the user group means are
uniformly smaller. Variability, as indicated
by the standard deviation, was about twice
as large for the user group early in constriction.
After most active constriction was
complete the variability of the two groups
was about the same. Analysis of variance
(ANOVA) disclosed no significant differences
between the over-all group means.
We found that the number of individuals
giving usable pupil data decreased
rapidly after the onset of the light adaptation
because many subjects had a strong
tendency toward reflex withdrawal (blepharospasm
or rolling the eyes upward)
shortly after the onset of light adaptation.
At the beginning (during response latency)
and end of pupil measurements both user
and nonuser groups contributed approximately the same number of measurements.
However, during the period of greatest
pupil activity reflex withdrawal from the
illumination appeared more frequently in
the user group (Fig. 2). Results were
statistically significant (p < 0.05) if the
analysis was confined to the period of active
constriction.
Intraocular pressure with water load.
IOP was measured by applanation immediately
after and at 20 min. intervals
following the ingestion of 1 L. of water.
The resulting IOP means for 78 eyes in
both groups are shown in Fig. 3. The limit
marks shown above mean values are ± 1
S.E. ANOVA showed that there were no
statistically valid differences between individual
pairs of measurements, such as
between users and nonusers, at any particular
point on the time axis. Nor was
there a difference between any two adjacent
time periods. However, when taken
as a whole, the analyses show that there
was a difference (p = 0.06) where IOP
was higher for the users. Fig. 3 suggests
that this is a basal pressure difference and
is not related to the way in which the water
load was handled.
Dark adaptation. Visual thresholds at
times after the onset of dark adaptation
are presented in Fig. 4. The smooth-drawn
portion of the functions approximate the
"average" subject whose final cone limb
threshold and final threshold corresponded
to the respective group means. The time
between 0 and 4 min. was the light
adaptation period. Statistical analyses were
done at the "alpha" (A) point of inflection
between cone- and rod-dominated
portions of the function. The A point appeared
at approximately 6 min. after the
beginning of dark adaptation. Other mean
points were generated at the asymptote
for dark adaptation, which occurred at
about 30 min. Limit marks are +(U, users),
-(NU, nonusers) 1 S.E. By ANOVA the
times to the A point were not statistically
different for the user and nonuser groups.
Thresholds taken separately for the cone
and rod limbs were not different for the
groups. However, the over-all ANOVA for
both sets of thresholds indicated a marginal
difference (p = 0.07). The users
showed less complete adaptation than the
nonusers.
Acuity at different luminances. Ability
to read "Snellen" letters at different luminance
levels was measured and the Snellen
notation values were converted to decimal
acuities (Fig. 5). Except at about -0.7
millilamberts, the nonusers mean monocular
acuity was superior to that of the
user group. ANOVA showed large, highly
significant differences for acuity between
light levels for both groups. Differences
for left or right eyes taken separately or
differences between groups at any par
ticular luminance level did not approach
significance. However, ANOVA for overall
differences between groups across all
luminance levels was associated with a
p = 0.07.
Color match–anomaloscope test. The
widths of the brightness and color-match
limits were measured by the Hecht/Schlaer
anomaloscope. The upper portion of Fig.
6 shows the range of normative match
midpoints produced by 49 observers studied
by Willis and Famsworth as described
by Jameson and Hurvich.10 The midpoint
lies in the center of the range of acceptable
matches. The limits of the acceptable
matches plus the midpoints for the normative
group ("match limit range") of 49
are displayed just below. Midpoints for the
user and nonuser groups are filled circles.
The related match limits are also shown
to the left and right of each midpoint.
ANOVA showed a statistical difference of
p = 0.01 for the direction (green or red)
from which the match was initiated. This
result is expected. The analysis showed no
difference between groups for the match
midpoint. However, there was a statistically
significant difference (p = 0.01)
between the user and nonuser groups for
the breadth of the match limits for color
and for brightness. Brightness data are not
pictured in Fig. 6. The widths of the match
limits for color were 1.63 for the users
and 3.42 for the nonusers. Limits for
brightness of the users were 3.61 and those
of nonusers were 5.21. For the color match,
these values and the means have been converted
to "comparative units" in Fig. 6 so
that they may be compared with the normative
data. The comparative unit scale
was described by Jameson and Hurvich.16
All data presented in Fig. 6 are within the
limits of normalcy. The primary difference
between groups in this study is the extent
of the match ranges which were judged acceptable.
The smokers were less tolerant
of deviations from the "midpoint."
Although the preliminary screening with
the Ishihara color plates was designed to
eliminate persons with eye defects, the
Farnsworth Dichotomous Test, Panel D-15,
20 was administered later. None of the
subjects who had previously passed the
Ishihara test failed to pass the Farnsworth
test.
Lacrimal fluid production. Basal (in distinction
to reflex) lacrimal fluid production
was measured by the Schirmer test.
Results of tests performed on both eyes
simultaneously indicate that the mean distance
of fluid migration for the users' eyes
was 2.8 mm. and for the nonusers" eyes,
2.6 mm. ANOVA for differences between
groups indicate that the u group showed
more fluid migration (p = 0.001).
Other observations. Results of the evaluation
of the fundus photographs are presented
in Table I. Photographs of five
fundus regions of eyes in each group were
examined. Areas judged abnormal are
listed. Nine users had at least one fundus
area judged abnormal and seven nonusers
showed at least one abnormal fundus area.
Although these are probably high for a
randomly drawn sample, there is no basis
for assuming a difference in incidence of
abnormality between the two groups.
The data from the dynamic acuity test
have not been presented. These results
showed evidence of such great variability
that no conclusion can be justified. An
analysis of clinical examination data showed
the presence of conjunctival hyperemia in
16 of the user group and 13 of the nonuser
group. Similarly, two users were found
to have pterygia whereas none of the controls
had them. Numbers such as these are
difficult to submit to statistical analysis.
However, there may be a trend in the user
group toward signs of more frequent irritation
of the conjunctiva. Results are summarized
in Table II.
Discussion
It is important to consider carefully the
finally matched subject samples, the methodology,
and the philosophy which produced
them. Before development of the
matched groups, an extensive clinical evaluation
had been done to select out of the
basic samples (N = 240) all "abnormal"
subjects. Four users and four nonusers
were excluded because of uncorrectable
visual acuity; 3 users and 13 nonusers for
color vision defect; 20 users and 17 nonusers
for postive serological test for syphilis;
eight users and 17 nonusers for pulmonary
lesions; and three users and nine
nonusers for other serious diseases. Then
the user and nonuser groups were carefully
matched on an array of medical, educational,
social, and anthropological criteria.
If a bias was instituted by these
procedures, it would serve to reduce differences
between the user and nonuser groups.
The participants in each sample were
unfamiliar with the types of judgments
which were required from them in the
various eye tests. Consequently, the variability
associated with the results from
these extensive samples would be expected
to be greater than that found in intensive
testing on a few highly practiced subjects.
It may be argued that one should accept
as real only those group results where
differences are associated with probability
coefficients of 0.05 or less. This traditional
but arbitrary cutoff level could be dangerous
if applied without attention to sampling
techniques. For these reasons, we
have elected to consider values of p =
0.07 or less as indicative of real trends.
An elaborate discussion of the results of
this project can yield little more than is
presented in Table II. There is little experimental
literature on chronic use to provide
a background for discussion. With
this caution, it is emphasized that the following
discussion is an integration with
the literature on acute marijuana use and
with classical and recent concepts in ophthalmology
of both statistically significant
findings and trends from our experiments.
The relevant clinical signs are presented
as "typical" but will vary widely between
individual cases.21
Anterior segment irritability. There are
threads common to the majority of the
findings of differences between the user
and nonuser groups and these relate also
to the acute-use literature. Among these
are symptoms which are typical of many
irritative states of the anterior segment of
the eye.22' " Excellent general descriptions
of the symptoms have been presented by
Duke-Elder21 and by Duke-Elder and Perkins.
24 Table III compares these common
symptoms of eye disease with findings associated
with the user group of this project
and with reports from the literature on
acute use.
Conjunctival hyperemia is typical of
many irritative states and also has been
documented repeatedly as a result of acute
marijuana use.4'10-X1 In this study the user
group had abstained from marijuana consumption
for at least 4 and more likely 10
to 12 hr. prior to testing. Clinically determined
conjunctival hyperemia was only
slightly more frequent in the users than in
their matched counterparts. This may be
because of an adaptation to chronic use,
dissipation of the condition, or masking of
the effect by the high incidence of hyperemia
in the nonusers.
Light sensitivity or "photophobia" is
common21 in irritations of the anterior segment
due to disease but its pathophysiology
is poorly understood.25 There was no quantitative
measure of "light sensitivity" in
our tests but the high frequency of reflex
withdrawal of user eyes from the light
which was used to excite pupillary constriction
tends to suggest heightened sensitivity
of the user group. In addition, there
was a statistically significant difference in
brightness limits and color-match limits for
the anomaloscope tests. If subjective brightness
sensitivity is increased in the user
group, it is possible that this accounts for
their unusual performance on the anomaloscope-
based color measures.
Acuity is often decreased in anterior segment
disease. This may be due to many
causes, not the least of which are slight
changes in the refraction or transmission
characteristics of the various optical layers
of the anterior segment, usually caused
by edema. This type of acuity loss would
be uncorrectable by optical methods. An
apparently optically uncorrectable acuity
deficit was found in the chronic users, although
subjects were carefully refracted
and corrective lenses provided. In acute
users reduced Snellen and vernier acuity
has been reported,2'9> 10 but Hepler et al.4
found no change.
Intraocular pressure elevation and elevation
of protein content of the aqueous
humor is also a corollary of diseases of
the anterior segment of the eye.22-23; 2<1> 27
Green and Pederson5 have shown that protein
elevation in the anterior chamber is
seen in the rabbit anterior segment which
was treated with A^THC. The findings we
have presented on chronic user IOP conflict
with several reports of decreased intraocular
pressure in nonchronic users.4'7> 9
There are great differences in the established
degrees of "experience" of the subjects.
Flom et al.8 replicated previous findings
of reduced IOP in acute smokers with
little use-experience but found little or no
IOP change in subjects with extensive use
history. This important findings emphasizes
the experience variable, which has been
considered rarely in prior publications.
Mean pupil diameter was slightly but
very consistently decreased during the
acute phase of constriction in our users.
The characteristics of the pupillary active
light response in conditions of anterior segment
irritation are not known, but the
affected resting pupil is often smaller than
normal in clinical cases of eye irritation.23
Duke-Elder accounted for this as a mechanical
effect of iris vascular engorgement
due to irritation.21 Bhattarchjee23 considered
the constricted pupil a typical component
of the syndrome of eye irritation
which he associated with the liberation of
prostaglandins from eye tissues. Hepler et
al.4 reported mild pupillary constriction
during marijuana smoking.
Prostaglandins have been associated recently
with the entire syndrome of anterior
segment irritation. This literature has
been reviewed by Eakins et al.22 and more
recently Neufeld and Sears.28 Prostaglandin
production in the eye appears to be closely
connected with the consequences of disease
or trauma of the anterior segment. If prostaglandins
and their release are specifically
inhibited, the irritative response of the
eye (as seen in Table III) does not occur.
28' 29 Green and Bowman0 reported
that A9-THC (tetrahydrocannabinol) inhibits
the formation of prostaglandins. If
this is correct in the eye, for all products
of THC, it is unlikely that prostaglandin
production can be directly responsible for
the signs of irritation which may be seen
in the acute phase of marijuana consumption.
However, in the absence of other information,
it is possible that in the longterm
chronic user there is a prostaglandin
rebound or hyperproduction during periods
of abstention. The moderations of prostaglandin
effects or physiology which could
occur during adaptation to 10 years of use
are difficult to guess. As in cigarette smoking,
a more important question is, "What
trends are set whose results are felt clearly
in 15 to 20 years?"
The visual and ocular signs that have
been described in chronic users but not
found in our results may also originate
directly or indirectly from neurophysiological
effects. There are no direct data on
chronic THC-neural interaction in the eye;
however, changes in pupil dimensions, vasomotor
activity, accommodation, and lacrimation
are discussed classically in association
with the balance between sympathetic and
parasympathetic divisions of the autonomic
nervous system. These were reviewed by
Walsh and Hoyt.25 More recent findings
have also implicated neural control of intraocular
pressure.30-31 Even the indications
of heightened brightness sensitivity
may have specific neural origins. Bieger
and Hockman32 have recorded large changes
in lateral geniculate nucleus function in
the presence of circulating A1-THC. Also
the modulation of visual function in both
retina and optic nerve has a well-estab
lished link to the sympathetic nervous system.'
13' '" Ng et al.35 seem to have presented
a clear case for modulation of general peripheral
sympathetic activity by A9-THC.
Recently a direct link has been established
by Green and Kim for the control of several
IOP factors by sympathomimetic actions
of THC in rabbits. There is no reason
to assume independence between the
conjunctival or uveal irritative signs and
the neural implications of chronic use as
indicated by brightness sensitivity or "photophobia."
This link has been established
for some time as the "trigeminal syndrome,"
1'5 a common clinical entity. The
primary factors in this hypothetical link
are yet to be identified.
The results presented here are available because
of the extensive cooperation given by the parent
project and its professional staff in the United
States of America and Costa Rica. Of particular
value were efforts by Drs. William Carter, Wilmer
Coggins, and Paul Doughty from the University
of Florida and Dr. Frederico Faerron from the
Social Security System, Republic of Costa Rica.
The Vision Committee, NAS-NRC working group
36, assisted in experimental design.
REFERENCES
1. Kiplinger, G. F., Manno, J. E., Rodda, B. E.,
and Forney, R. B.: Dose response analysis
of the effects of tetrahydrocannabinol in
man, Clin. Pharmacol. Ther. 12:650, 1971.
2. Agurell, S., et al.: Pharmacokinetics of As.
THC in man after smoking: Relations to
physiological and psychological effects. In
Braude, M. C, and Szara, S., editors: The
Pharmacology of Marihuana, New York, 1976,
Raven Press, vol. 1, pp. 49-61.
3. Domino, E., Rennick, P., and Pearl, J. H.:
Short-term neuropsychopharmacological effects
of marihuana smoking in experienced
male users, In Braude, M. C., and Szara, S.,
editors: The Pharmacology of Marihuana,
New York, 1976, Raven Press, vol. 1, pp.
393-412.
4. Hepler, R. S., Frank, I. M., and Ungerleider,
J. T.: Pupillary constriction after marijuana
smoking, Am. J. Ophthalmol. 74:1185, 1972.
5. Green, K., and Pederson, J. E.: Effect of
A1-tetrahydrocannabinol on aqueous dynamics
and ciliary body permeability in the rabbit,
Exp. Eye Res. 15:499, 1973.
6. Green, K., and Bowman, K.: Effect of marihuana
and derivatives on aqueous humor
dynamics in the rabbit. In Braude, M. C,
and Szara, S., editors: The Pharmacology of
Marihuana, New York, 1976, Raven Press,
vol. 2, pp. 803-813.
7. Hepler, R. S., Frank, I. M., and Petrus, R.:
Ocular effects of marihuana smoking. In
Braude, M. C, and Szara, S., editors: The
Pharmacology of Marihuana, New York, 1976,
Raven Press, vol. 2, pp. 815-824.
8. Flom, M. C, Adams, A. J., and Jones, R. T.:
Marijuana smoking and reduced pressure in
human eyes: drug actions or epiphenomena?
INVEST. OPHTHALMOL. 14:52, 1975.
9. Shapiro, D.: The ocular manifestations of
cannabinols, Ophthalmologia 168:366, 1974.
10. Valk, L.: Hemp in connection with ophthalmology,
Neth. Ophthalmol. Soc. 167:413,
1973.
11. Thomas, R., and Chester, G.: The pharmacology
of marihuana, Med. J. Aust. 2:229,
1973.
12. Marihuana and Health. Second Annual Report
by Secretary HEW to Congress, Washington,
D. C, 1972, U. S. Govt. Printing Office, p.
137.
13. Kronfeld, P. C : Water drinking and outflow
facility, INVEST. OPHTHALMOL. 14:49, 1975.
14. Frankhauser, F., and Schmidt, T.: Studies
on the functions of the dark-adapted eye
with the Goldmann-Weekers adaptometer,
Ophthalmologica 133:264, 1957.
15. Hecht, S.: A quantitative basis for the relation
between visual acuity and illumination,
Proc. Natl. Acad. Sci. 13:569, 1927.
16. Jameson, D., and Hurvich, L.: Theoretical
analysis of anomalous trichromatic color vision,
J. Optical Soc. Am. 46:1075, 1956.
17. Jones, L. T.: The lacrimal secretory system
and its treatment, Am. J. Ophthalmol. 62:47,
1966.
18. Doughman, D.: Clinical tests. In Holly, F. J.,
and Lemp, M., editors: The Preocular Tear
Film and Dry Eye Syndromes, Int. Ophthalmol.
Clin. 13:199, 1973.
19. Mishima, S., Gassett, A., Klyce, S. D., and
Baum, J. L.: Determination of tear volume
and tear flow, INVEST. OPHTHALMOL. 5:264,
1966.
20. Farnsworth, D.: The Farnsworth Dichotomous
Test for Color Blindness–Panel D-15,
New York, 1947, Psychological Corp.
21. Duke-Elder, W. S.: Parsons' Diseases of the
Eye, Boston, 1964, Little Brown & Company,
pp. 230-233.
22. Eakins, K. E., Whitelocke, R. A., Bennett, A.,
and Martenet, A. C: Prostaglandin like activity
in ocular inflammation, Br. Med. J. 3:
452, 1972.
23. Bhattarchjee, P., and Eakins, K. E.: Inhibi
tion of the ocular effects of sodium archidonate
by anti-inflammatory compounds,
Prostaglandins 9:175, 1975.
24. Duke-Elder, W. S., and Perkins, E. S.: System
of Ophthalmology, St. Louis, 1966, The
C. V. Mosby Co., Vol. 19, pp. 133-166.
25. Walsh, F., and Hoyt, W.: Clinical neuroophthalmology,
Baltimore, 1969, The Williams
& Wilkins Company, pp. 414-465.
26. Eakins, K. E.: Increased intraocular pressure
produced by prostaglandins Ei and Eu in the
cat eye, Exp. Eye Res. 10:87, 1970.
27. Vegge, T., Neufeld, A. H., and Sears, M. L.:
Morphology of the breakdown of bloodaqueous
barrier of ciliary processes of the
rabbit eye after prostaglandin E2, INVEST.
OPHTHALMOL. 14:33, 1975.
28. Neufeld, A. H., and Sears, M. L.: Prostaglandin
and eye, Prostaglandins 4:157, 1973.
29. Neufeld, A., Jampol, L., and Sears, M. L.:
Aspirin prevents the disruption of the blood
aqueous barrier in the rabbit eye, Nature
238:158, 1972.
30. Cox, C. E., Fitzgerald, C. R., and King, R.
L.: A preliminary report on the supraoptic
nucleus and control of intraocular pressure,
INVEST. OPHTHALMOL. 14:26, 1975.
31. Macri, F. J., and Cevarino, S. J.: Ciliary
ganglion stimulation. I. Effects on aqueous
humor inflow and outflow, INVEST. OPHTHALMOL.
14:28, 1975.
32. Bieger, D., and Hockman, C. H.: Differential
effects produced by Ai -tetrahydrocannabinol
on lateral geniculate neurons, Neuropharmacology
12:269, 1973.
33. Mascetti, G. C, Marzi, C. A., and Berlucchi,
G.: Sympathetic influences on the dark- discharge
of the retina in the freely moving cat,
Arch. Ital. Biol. 107:158, 1969.
34. Marini, R., and Pettrossi, V. E.: Electroretinogram
and the superior cervical ganglion,
Arch. Ital. Biol. 112:337, 1974.
35. Ng, L., Lamprecht, F., Williams, R. B., and
Kopin, I. J.: A^-Tetrahydrocannabinol and
ethanol: differential effects on sympathetic
activity in differing environmental setting,
Science 180:1368, 1973.
36. Green, K., and Kim, K.: Mediation of ocular
and tetrahydrocannabinol effects by adrenergic
nervous system, Exp. Eye Res. 23:443,
1976.
Source: Marijuana and vision--after ten years' use in Costa Rica.
