Jacob Bell
New Member
APRIL 1975 Vol. 14/4
The first report of a decrease in intraocular
pressure following smoking of marihuana1
was received with a fair amount
of skepticism, mirth, and bad publicity in
the press, such as articles informing the
public of a new "cure" for glaucoma. Now
that the smoke has cleared, it is time to
evaluate the effects of marihuana on the
eye and make an objective assessment of
the potential therapeutic value of this drug
(rather, a group of drugs) in ophthalmology,
while putting aside the moral and
ethical discussion of the use of marihuana
in society as a drug of abuse.
Many questions are immediately forthcoming.
Does the drug really act to consistently
reduce intraocular pressure? If so,
how does it work? What are the side effects?
Can one use a topical drop? Is there
a compound which is active as regards
intraocular pressure without producing
undesired systemic and central effects?
Some of these questions can be answered
at this time while others await more
detailed examination.
It is now well documented that marihuana,
or its primary active ingredient
delta-9-tetrahydrocannabinol (A;' THC),
when given to rabbit or man by several
routes, reduces intraocular pressure. The
group at UCLA, continuing their initial
efforts, find that chronic smoking of marihuana
by inpatients (average of 15 "joints"
per day for 94 clays) always causes an
intraocular pressure fall which lasts for
four to five hours even after one "joint."-
The intraocular pressure decrease appears
to be unrelated to the total number of cigarettes
smoked, suggesting that the plasma
dose of THC reached after one cigarette is
sufficient to evoke the maximal response.
No immediate or cumulative effects were
observed on any measure of ocular status,
including visual fields, visual acuity, tonography,
slit lamp biomicroscopy, electroretinogram
(ERG), and the appearance of
the lundus. Only ocular pulse pressure and
tear secretion decreased after THC, both
by statistically significant amounts, together
with a slight pupillary constriction.
In patients with ocular hypertension or
glaucoma, seven of 11 patients showed an
intraocular pressure fall of 30 per cent.
Another study, however, also utilizing
confined patients,'1 revealed that a tolerance
developed to the oral administration of
A!I-THC; the dose level, however, was
much higher than that used in the study
where the marihuana was smoked. The
intraocular pressure showed an initial fall
after oral use and returned to baseline as
tolerance developed. Further smoking of
marihuana in this patient group failed to
cause a fall in intraocular pressure. Prob-
lems arise in the interpretation of this data,
however, since oral administration causes
both longer lasting and higher plasma
levels of THC than after smoking, thus
the findings may vary with sustained high
or low plasma concentrations. One study
on long-term (one year) marihuana
smokers in Costa Rica has shown that there
are no discernible effects on intraocular
pressure or color vision, compared to a
control group of non-users. A more detailed
study, examining many more ocular parameters
is currently in progress. One-time
examination of marihuana users in Europe1
revealed changes in visual acuity, marked
blepharospasm, and a degree of photophobia
associated with long-term use, as
well as a prolonged fall in intraocular
pressure as long as three weeks after the
last admitted use of the drug. This latter
study suffers from the problem that the patients
may have been multiple drug users
and, since they were not inpatients, also
faulty reporting on the part of the users
who often exaggerate the time since last
drug use. The use of a nonpsychotropic
dose in open-angle glaucoma is being investigated
currently. Single intravenous
infusions of A"-THC and several
derivatives by several investigators also
reveal substantial intraocular pressure
falls.
The reduction in ocular pressure pulse
seen in man, together with studies in rabbit
which show an increased blood-aqueous
barrier permeability (measured directly in
vitro and by increased aqueous protein in
vivo) concurrent with the intraocular pressure
fall, suggest that the action of the
cannabinoids is a vasoconstriction of the
afferent vessels of the ciliary body causing
a pressure fall in the capillaries. This effect
occurs concurrently and paradoxically
with an engorgement of conjunctival vessels
by a mechanism which is not yet understood.
Whether the inhibition of prostaglandin
synthesis by A°-THC is of importance
in the nonstimulated eye remains to
be determined; certainly THC inhibits the
formation of prostaglandin from arachidonic
acid when the latter is given in large
quantities to the eye.
Obviously, smoking and intravenous infusion
are neither feasible nor desirable as
a means of treatment for the reduction of
intraocular pressure in man. The most advantageous
route is topical administration
but, thus far, tests have only been made
in the rabbit using An-THC and several
derivatives. The UCLA group using A!)-
THC in normal eyes and Mechoulam and
Dikstein in Jerusalem using cannabinol
acetate in buphthalmic eyes, find a substantial
reduction in intraocular pressure
after use. Work at the Medical College of
Georgia, using A!)-THC and many derivatives
applied to the eye in sesame oil, has
demonstrated the relative potency of these
compounds"' and, currently, dose-response
curves for the active drugs are being established.
Some compounds which reduce intraocular
pressure when applied topically to
the rabbit eye, such as cannabinol, 8a- and
S/Ml-diOH-A9-THC and Ar"-THC are
known to have little or no central effects
and, as such, are high in priority for study,
since if there is systemic absorption (as
occurs in the rabbit at the presently used
dose levels, and occurs in man with other
drugs) fewer side effects are desirable and
necessary. The vehicle of choice for the
drug as a topical agent is of great importance
since it must satisfy the requirements
of THC solubility, shelf stability, and
release of the drug into the eye. An intensive
investigation using a multidisciplinary
approach would answer many unresolved
questions concerning the potential use of
these agents in ophthalmology. It is immediately
obvious that there is a great
need for further study of these compounds,
and the ophthalmologist in clinical
practice and research should not only be
aware of the clinical effects of these drugs
in man but also of their potential therapeutic
use.
Preclinical and clinical studies indicate,
thus far, that the intraocular pressure fall
is as good as or better than most agents
currently available. The decrease in intraocular
pressure probably represents one
of the most potentially valuable therapeutic
uses of these compounds. If clinical trials
indicate no long-term effects, either local
or systemic, following the use of a topically
applied cannabinoid it is most likely that
such an agent will be made available for
clinical use for the ophthalmologist. It
would be unfortunate if the possible importance
of these chemically unique drugs
in ophthalmology were to be clouded by
the notoriety which the drug has achieved
in society.
Keith Green
Department of Ophthalmology
Medical College of Georgia
Augusta, Ga.
REFERENCES
1. Hepler, R. S., and Frank, I. M.: Marihuana
smoking and intraocular pressure, ]. A. M. A.
217: 1392, 1971.
2. Hepler, R. S., Frank, I. M., and Petrus, R.:
Ocular effects of marihuana, in: Pharmacology
of Cannabis, S/ara, S., and Braude, M. C, editors.
New York, 1975, Raven Press. In
press.
3. Jones, R. T.: The 30-day trip–clinical studies
of cannabis tolerance and dependence, in:
Pharmacology of Cannabis, Szara, S., and
Braude, M. C, editors. New York, 1975,
Raven Press. In press.
4. Shapiro, D.: The ocular manifestations of
the cannabinols, Ophthalmologica Ifi8: 366,
1974.
5. Creen, K., and Bowman, K.: Effect of marihuana
derivatives on intraocular pressure in
rabbit, in: Pharmacology of Cannabis, Szara,
S., and Braude, M. C., editors. New York,
1975, Raven Press. In press.
Source: Marihuana and the eye.
The first report of a decrease in intraocular
pressure following smoking of marihuana1
was received with a fair amount
of skepticism, mirth, and bad publicity in
the press, such as articles informing the
public of a new "cure" for glaucoma. Now
that the smoke has cleared, it is time to
evaluate the effects of marihuana on the
eye and make an objective assessment of
the potential therapeutic value of this drug
(rather, a group of drugs) in ophthalmology,
while putting aside the moral and
ethical discussion of the use of marihuana
in society as a drug of abuse.
Many questions are immediately forthcoming.
Does the drug really act to consistently
reduce intraocular pressure? If so,
how does it work? What are the side effects?
Can one use a topical drop? Is there
a compound which is active as regards
intraocular pressure without producing
undesired systemic and central effects?
Some of these questions can be answered
at this time while others await more
detailed examination.
It is now well documented that marihuana,
or its primary active ingredient
delta-9-tetrahydrocannabinol (A;' THC),
when given to rabbit or man by several
routes, reduces intraocular pressure. The
group at UCLA, continuing their initial
efforts, find that chronic smoking of marihuana
by inpatients (average of 15 "joints"
per day for 94 clays) always causes an
intraocular pressure fall which lasts for
four to five hours even after one "joint."-
The intraocular pressure decrease appears
to be unrelated to the total number of cigarettes
smoked, suggesting that the plasma
dose of THC reached after one cigarette is
sufficient to evoke the maximal response.
No immediate or cumulative effects were
observed on any measure of ocular status,
including visual fields, visual acuity, tonography,
slit lamp biomicroscopy, electroretinogram
(ERG), and the appearance of
the lundus. Only ocular pulse pressure and
tear secretion decreased after THC, both
by statistically significant amounts, together
with a slight pupillary constriction.
In patients with ocular hypertension or
glaucoma, seven of 11 patients showed an
intraocular pressure fall of 30 per cent.
Another study, however, also utilizing
confined patients,'1 revealed that a tolerance
developed to the oral administration of
A!I-THC; the dose level, however, was
much higher than that used in the study
where the marihuana was smoked. The
intraocular pressure showed an initial fall
after oral use and returned to baseline as
tolerance developed. Further smoking of
marihuana in this patient group failed to
cause a fall in intraocular pressure. Prob-
lems arise in the interpretation of this data,
however, since oral administration causes
both longer lasting and higher plasma
levels of THC than after smoking, thus
the findings may vary with sustained high
or low plasma concentrations. One study
on long-term (one year) marihuana
smokers in Costa Rica has shown that there
are no discernible effects on intraocular
pressure or color vision, compared to a
control group of non-users. A more detailed
study, examining many more ocular parameters
is currently in progress. One-time
examination of marihuana users in Europe1
revealed changes in visual acuity, marked
blepharospasm, and a degree of photophobia
associated with long-term use, as
well as a prolonged fall in intraocular
pressure as long as three weeks after the
last admitted use of the drug. This latter
study suffers from the problem that the patients
may have been multiple drug users
and, since they were not inpatients, also
faulty reporting on the part of the users
who often exaggerate the time since last
drug use. The use of a nonpsychotropic
dose in open-angle glaucoma is being investigated
currently. Single intravenous
infusions of A"-THC and several
derivatives by several investigators also
reveal substantial intraocular pressure
falls.
The reduction in ocular pressure pulse
seen in man, together with studies in rabbit
which show an increased blood-aqueous
barrier permeability (measured directly in
vitro and by increased aqueous protein in
vivo) concurrent with the intraocular pressure
fall, suggest that the action of the
cannabinoids is a vasoconstriction of the
afferent vessels of the ciliary body causing
a pressure fall in the capillaries. This effect
occurs concurrently and paradoxically
with an engorgement of conjunctival vessels
by a mechanism which is not yet understood.
Whether the inhibition of prostaglandin
synthesis by A°-THC is of importance
in the nonstimulated eye remains to
be determined; certainly THC inhibits the
formation of prostaglandin from arachidonic
acid when the latter is given in large
quantities to the eye.
Obviously, smoking and intravenous infusion
are neither feasible nor desirable as
a means of treatment for the reduction of
intraocular pressure in man. The most advantageous
route is topical administration
but, thus far, tests have only been made
in the rabbit using An-THC and several
derivatives. The UCLA group using A!)-
THC in normal eyes and Mechoulam and
Dikstein in Jerusalem using cannabinol
acetate in buphthalmic eyes, find a substantial
reduction in intraocular pressure
after use. Work at the Medical College of
Georgia, using A!)-THC and many derivatives
applied to the eye in sesame oil, has
demonstrated the relative potency of these
compounds"' and, currently, dose-response
curves for the active drugs are being established.
Some compounds which reduce intraocular
pressure when applied topically to
the rabbit eye, such as cannabinol, 8a- and
S/Ml-diOH-A9-THC and Ar"-THC are
known to have little or no central effects
and, as such, are high in priority for study,
since if there is systemic absorption (as
occurs in the rabbit at the presently used
dose levels, and occurs in man with other
drugs) fewer side effects are desirable and
necessary. The vehicle of choice for the
drug as a topical agent is of great importance
since it must satisfy the requirements
of THC solubility, shelf stability, and
release of the drug into the eye. An intensive
investigation using a multidisciplinary
approach would answer many unresolved
questions concerning the potential use of
these agents in ophthalmology. It is immediately
obvious that there is a great
need for further study of these compounds,
and the ophthalmologist in clinical
practice and research should not only be
aware of the clinical effects of these drugs
in man but also of their potential therapeutic
use.
Preclinical and clinical studies indicate,
thus far, that the intraocular pressure fall
is as good as or better than most agents
currently available. The decrease in intraocular
pressure probably represents one
of the most potentially valuable therapeutic
uses of these compounds. If clinical trials
indicate no long-term effects, either local
or systemic, following the use of a topically
applied cannabinoid it is most likely that
such an agent will be made available for
clinical use for the ophthalmologist. It
would be unfortunate if the possible importance
of these chemically unique drugs
in ophthalmology were to be clouded by
the notoriety which the drug has achieved
in society.
Keith Green
Department of Ophthalmology
Medical College of Georgia
Augusta, Ga.
REFERENCES
1. Hepler, R. S., and Frank, I. M.: Marihuana
smoking and intraocular pressure, ]. A. M. A.
217: 1392, 1971.
2. Hepler, R. S., Frank, I. M., and Petrus, R.:
Ocular effects of marihuana, in: Pharmacology
of Cannabis, S/ara, S., and Braude, M. C, editors.
New York, 1975, Raven Press. In
press.
3. Jones, R. T.: The 30-day trip–clinical studies
of cannabis tolerance and dependence, in:
Pharmacology of Cannabis, Szara, S., and
Braude, M. C, editors. New York, 1975,
Raven Press. In press.
4. Shapiro, D.: The ocular manifestations of
the cannabinols, Ophthalmologica Ifi8: 366,
1974.
5. Creen, K., and Bowman, K.: Effect of marihuana
derivatives on intraocular pressure in
rabbit, in: Pharmacology of Cannabis, Szara,
S., and Braude, M. C., editors. New York,
1975, Raven Press. In press.
Source: Marihuana and the eye.
