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Glaucoma
1. What research has been done and what is known about the possible
medical uses of
marijuana?
Marijuana is not generally accepted as a safe and effective treatment for
glaucoma. The
American Academy of Ophthalmology (1992) stated: "There is evidence that
marijuana (or its
components), taken orally or by inhalation can lower intraocular pressure.
However, there are no
conclusive studies to date to indicate that marijuana (or its components) can
safely and
effectively lower intraocular pressure enough to prevent optic nerve damage. . .
. The dose of
marijuana necessary to produce a clinically relevant effect in the short term
appears to produce
an unacceptable level of undesirable side effects such as euphoria, systemic
hypotension, and/or
dry eye and conjunctival hyperemia in the majority of glaucoma patients in whom
the drug has
been carefully studied. No data have been published on studies of long-term
ocular and systemic
effects of the use of marijuana by glaucoma patients.
". . . Because the possibility exists that marijuana (or its components) may
be useful in treating
glaucoma, the American Academy on Ophthalmology Committee on Drugs believes that
a long
term clinical study, designed to test the safety and efficacy of marijuana in the
prevention of
progressive optic nerve damage and consequent visual field loss, appears
appropriate."
The National Eye Institute (1997) has recently stated much the same thing.
"Studies in the early
1970s showed that marijuana, when smoked, lowers intraocular pressure in people
with normal
pressure and those with glaucoma. . . . However, none of those studies
demonstrated that
marijuana--or any of its components--could safely and effectively lower
intraocular pressure
any more than a variety of drugs then on the market. . . . [and] some potentially
serious side
effects were noted. . . . Research to date has not investigated whether
marijuana use offers any
advantages over currently available glaucoma treatments or if it is useful when
used in
combination with standard therapies. . . . [t]he National Eye Institute stands
ready to evaluate any
well-designed studies for treatment of eye diseases, including those involving
marijuana for
treatment of glaucoma."
The initial observation that smoked marijuana lowered intraocular pressure
(IOP) in humans in
acute experiments was made by Hepler and Frank in 1971. Hepler and Petrus (1976)
later
reported in greater detail that 4 percent (tetrahydrocannabinol (THC)) marijuana
cigarettes
lowered the IOP about 27 percent more than did a placebo at 30 minutes in normal
volunteers, and
that 20 mg of oral THC lowered the IOP about 17 percent more than placebo at 30
minutes. They
also reported that smoked marijuana lowered IOP much more dramatically in
patients with poorly
controlled glaucoma, with 10 of 12 responding, and presented graphs showing the
timecourse.
One patient demonstrated a reduction from 40 mm Hg to 10 mm Hg in one eye and
from 35 mm
Hg to 15 mm Hg in the other. Since patients with severe glaucoma did not
discontinue their
current therapy (pilocarpine - 4 percent, epinephrine - 2 percent, or oral
acetazolamide) Hepler
and Petrus concluded that smoked marijuana or oral THC were additive to the
then-known
classes of therapeutic agents, and presumably worked by an independent mechanism
(Hepler and
Petrus 1976). In these short-term studies, lasting up to 4 hours, 2 cigarettes
were as effective as
20 cigarettes, and intoxication occurred. Others confirmed that the marijuana
could have a
significant adjunctive effect in glaucoma patients, with Cuendet and colleagues
reporting that
12/16 eyes of 10 patients had a reduction of 15 percent or more (Cuendet et al.
1976).
Flom and colleagues (1975) concluded that in normal volunteers in acute
studies the lowering of
IOP was proportional to the "high," and that experienced users who did not
experience a "high"
did not have a lowering of IOP. Merritt and colleagues (1980) studied the blood
pressure (BP)
and IOP of 18 glaucoma patients in short-term studies, which compared smoking a
single
2 percent THC cigarette versus a placebo cigarette of the same smell and taste
and concluded that
the IOP was reduced by 4 mm Hg at 30 minutes and by 6 mm Hg at 90 minutes (in
patients with
either open-angle or synechial angle-closure glaucoma), returning to baseline by
4 hours with
THC, while there was no change with the placebo, but that the pulse rose from 82
beats per
minute (bpm) to 123 bpm at 15 minutes, and the systolic BP fell 11 mm Hg and
diastolic BP fell
5 mm Hg, suggesting that reduced perfusion of the ciliary body accounted for the
reduction in
IOP and that the adverse systemic effects, including postural hypotension, would
limit the
potential usefulness of marijuana. Indeed, Merritt concluded in an editorial in
the Journal of the
National Medical Association (1982) that "Systemic delta-9 THC therapies
invariably produce a
decreased perfusion pressure to the eye. This decreased perfusion to an already
damaged optic
nerve may not be of long-term benefit to glaucoma victims." However, there are
several anecdotal
reports that, on continued use, tolerance develops to the undesirable
cardiovascular and mood
effects of marijuana, while tolerance does not develop to the beneficial effects
on IOP in patients
with glaucoma (Palmberg 1997).
Efforts to avoid systemic effects of THC in glaucoma treatment led to studies
of topical preparations,
such as 1 percent THC in peanut oil. However, no effect of the preparation on
IOP was found by
Jay and Green (1983).
Animal studies have yielded conflicting results about the mechanism of action
of THC on the
IOP. The studies by Green in rabbits suggested central effects mediated through
the adrenergic
nervous system (Green 1979), but the studies of Colasanti (1990) in cats
indicated no effect of
either sympathetic or parasympathetic denervation on the action of THC. She also
found that
THC has no effect on aqueous production in anesthetized cats, but rather
increased aqueous
outflow facility threefold.
The mechanism in humans has never been investigated by modern means, including
fluorophotometry,
coupled with the older method of tonography, which could yield clear information
about the
mechanism of action, whether on inflow, conventional outflow, or uveo-scleral
outflow. In
addition, it would now be possible to test the additivity of marijuana to a wide
variety of agents
now available, including beta-1 and beta-2 agonists and antagonists, alpha-2
agonists, dorzolamide,
and latanoprost, to see whether or not THC works by a separate mechanism.
2. What are the major unanswered scientific questions?
Researchers do not know the mechanism of action of cannabis on IOP, given
either as smoked
marijuana or as oral THC.
Additional studies of long-term marijuana use are needed to determine if there
are or are not
important adverse pulmonary, central nervous system (CNS), or immune system
problems.
It needs to be determined if smoked or eaten marijuana is more effective in
lowering IOP on a
chronic basis than THC alone, as marijuana advocates maintain on the basis of
anecdotal
experience, or if pure THC, without the particulates and carcinogens of marijuana
smoke, could
be inhaled by means other than smoking, or taken orally, with equal long-term
effect on IOP.
Researchers do not know if marijuana would be additive to the new, very potent
types of eyedrops
now available to treat glaucoma, including alpha-2 agonists, dorzolamide and
latanoprost (a
prostaglandin that increases uveoscleral outflow and, like THC, causes
conjunctival hyperemia).
If marijuana were not to be additive to one of these agents, marijuana would be
obsolete, since
these agents have no systemic side effects (other than slightly dry mouth in some
patients with
apraclonidine and bromonidine), and they have a duration of action of 12 to 24
hours.
What are the diseases or conditions for which marijuana might have
potential as a treatment
and which merit further study?
Further studies to define the mechanism of action and to determine the
efficacy of delta-9-tetrahydrocannabinol and marijuana in the treatment of
glaucoma are justified.
In glaucoma, there does not appear to be any obvious reason to use smoked
marijuana as a
primary " stand alone" investigational therapy, as there are many available
agents for treatment,
and these topical preparations seem to be potentially ideal. An approach that
may be useful is to
study smoked marijuana in incomplete responders to standard therapies. The
suggested design
for clinical studies is to add marijuana, oral THC, or placebo to standard
therapy under double-blind conditions. Studies proposed should consider the
following measures:
References
American Academy of Ophthalmology. "The Use of Marijuana in the Treatment of Glaucoma." Statement by the Board of Directors of the American Academy of Ophthalmology, PO Box 7424, San Francisco, CA, June 1992.
Colasanti, B.K. Review: Ocular hypotensive effect of marijuana cannabinoids: Correlate of central action or separate phenomenon? J Ocular Pharmacol 6(4):259-269, 1990.
Cuendet, J.F.; Saprio, D.; Calanca, A.; Faggioni, R.; and Ducrey, N. Action of delta-9-tetrahydrocannabinol on ophthalmotonus. Opthalmologica 172:122-127, 1976.
Flom, M.C.; Adams, A.J.; and Jones, R.T. Marijuana smoking and reduced pressure in human eyes: Drug action or epiphenomenon? Invest Ophthalmol 14(1):52-55, 1975.
Green, K. Marihuana in ophthalmology--past, present and future. (Editorial). Ann Ophthalmol 11(2):203-205, 1979.
Hepler, R.S., and Frank, I.R. Marijuana smoking and intraocular pressure. (Letter). JAMA 217:1392, 1971.
Hepler, R.S., and Petrus, R.J. Experiences with administration of marihuana to glaucoma patients. In: Cohen, S., and Stillman, R.C., eds. The Therapeutic Potential of Marihuana. New York: Plenum Medical Books, 1976. pp. 63-75.
Jay, W.M., and Green, K. Multiple-drop study of topically applied 1% delta 9-tetrahydrocannabinol in human eyes. Arch Ophthalmol 101(4):591-593, 1983.
Merritt, J.C. Glaucoma, hypertension, and marijuana. (Editorial). J Natl Med Assn
74(8):715-716, 1982.
Merritt, J.C.; Crawford, W.J.; Alexander, P.C.; Anduze, A.L.; and Gelbart, S.S. Effect of marihuana on intraocular and blood pressure in glaucoma. Ophthalmology 87(3):222-228, 1980.
National Eye Institute. "The Use of Marijuana for Glaucoma." Statement of the National Eye Institute of the National Institutes of Health, February 18, 1997.
Palmberg, P. Unpublished observations presented at the Workshop on the Medical Utility of Marijuana, National Institutes of Health, Bethesda, MD, February 20, 1997.
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