MARIJUANA AND GLAUCOMA

In this issue of the ARCHIVES, Green[1] elegantly reviews clinical issues
about the potential use of marijuana and cannabinoids in glaucoma therapy.
This editorial deals briefly with the scientific foundation underlying the
marijuana-glaucoma controversy, and like the review, concludes that data,
not demagoguery, should guide our path.

Glaucoma results in the degeneration of retinal ganglion cells and their
optic nerve axons that carry visual impulses from the eye to the brain.
Marijuana and cannabinoids affect the major risk factor for glaucoma,
elevation of intraocular pressure (IOP), which is regulated by the
hydrodynamic systems at the front of the eye.

The ciliary body secretes aqueous humor, which flows into the anterior
chamber, nourishes the lens and the cornea, and leaves the eye via 2
routes. One route is through the trabecular meshwork, a lattice of
connective tissue and endothelial cells embedded in a
glycosaminoglycan-like ground substance, then into the Schlemm canal and
the general venous circulation. A secondary drainage route is between the
bundles of the ciliary muscle. The ciliary muscle controls trabecular
meshwork drainage apparatus by tension on that structure. However, fluid
can also move through the connective tissue-filled spaces within the
ciliary muscle itself, and then through the sclera and out of the eye into
the orbit, a pathway called the uveoscleral outflow route.

The relationship between these various components of aqueous humor
hydrodynamics can be summarized by the Goldmann equation, as follows:

IOPPe+(F-U)/Ctrab

where Pe indicates episcleral venous pressure (the pressure against which
fluid leaving the anterior chamber via the trabecular-canalicular route
must drain); F, aqueous humor flow; U, uveoscleral outflow; and Ctrab,
facility of outflow from the anterior chamber via the trabecular meshwork
and Schlemm canal.

Since the goal in glaucoma therapy is to reduce the IOP, one can use the
equation to see what has to happen. One can either reduce the episcleral
venous pressure, reduce the rate at which fluid is formed by the ciliary
processes, increase fluid drainage via the posterior uveoscleral route, or
increase the hydraulic conductivity of the trabecular meshwork.
Antiglaucoma drugs are currently available for all but the first of these
mechanisms.

There are currently 6 classes of drugs for the medical therapy of glaucoma.
Cholinergic agonists (eg, pilocarpine) contract the ciliary muscle to
deform the trabecular meshwork and make it easier for fluid to pass
through. The 2-adrenergic agonists, such as epinephrine bitartrate or its
prodrug dipivefrin hydrochloride, act directly on the endothelial cells of
the trabecular meshwork via a classical 2-adrenoceptor-mediated mechanism,
perhaps with an ultimate effect on the cytoskeleton that changes the shape
and adhesive properties of these cells and reduces resistance to fluid
flow. The -adrenergic antagonists, such as timolol, interfere with the
ability of the ciliary epithelium to make fluid. The 2-adrenergic agonists,
such as aproclonidine and brimonidine tartrate, and carbonic anhydrase
inhibitors, such as acetazolamide sodium and dorzolamide hydrochloride,
inhibit secretion. Prostaglandin F2 analogs cause the ciliary muscle to
up-regulate the production of matrix metalloproteinases and thereby remodel
the extracellular matrix between the bundles of the muscle, making it
easier for fluid to leave the eye via the uveoscleral route. Other agents
under study act via the cytoskeleton in the trabecular meshwork.

At the time of the initial interest in cannabinoids for IOP reduction, in
the early to mid-1970s, only cholinomimetics, epinephrine, and oral
carbonic anhydrase inhibitors were available; none of these are popular
today because of their side effects. They have been superseded by
- -blockers, 2-adrenergic agonists, prostaglandin F analogs, and topical
carbonic anhydrase inhibitors. The surgical options of laser
trabeculoplasty, trabeculectomy, drainage devices, and cyclodestruction
have also progressed during this time. Thus, the playing field is very
different than it was 20 or 25 years ago.

Where do marijuana and the cannabinoids fit in? Since our present therapy
is directed only at lowering IOP, we must ask whether marijuana lowers the
IOP. The answer in humans is an unequivocal yes. Several good studies show
that smoking a marijuana cigarette reduces the IOP in normal subjects from
approximately 15 to 11 mm Hg, a 24% reduction. The Goldmann equation
indicates that the higher the IOP, the greater the IOP-lowering effect for
a given suppression of fluid formation or enhancement of fluid drainage. In
a group of patients with glaucoma and ocular hypertension, with starting
IOP of approximately 30 mm Hg, smoking a similar marijuana cigarette
decreased IOP to approximately 21 or 22 mm Hg, also a 20% to 25% reduction.
This result is comparable with that of other glaucoma medications,
including the recently approved ones.

However, the duration of action of smoked or ingested marijuana,
delta-9-tetrahydrocannabinol (delta-9-THC), or other cannabinoids is
unacceptably short: about 3.0 to 3.5 hours. To treat glaucoma, IOP must be
controlled around the clock, and thus patient compliance becomes a serious
issue. For marijuana to be a viable therapy, it would have to be smoked
every 3 hours, and getting patients to put drops in their eyes even a few
times a day is very difficult. Instead, the ideal glaucoma drug would
require application at most twice (and preferably once) daily for
compliance purposes. Furthermore, there is the question of whether
cannabinoids can work topically. The supposedly active compound delta-9-THC
does not lower IOP when applied topically.

The mechanism(s) by which delta-9-THC or marijuana lowers IOP is not known.
Mechanistic studies, performed long ago, have not given the answer,
investigator claims to the contrary notwithstanding. We still do not know
whether the action is central or peripheral; whether it is on aqueous
formation or drainage; whether the sympathetic or parasympathetic nervous
system is involved; or whether there is a vascular component.

Rabbit ciliary epithelium exhibits decreased short-circuit current and
secretion; increased hydraulic conductivity, suggesting varying effects on
aqueous production; and increased outflow facility, suggesting an effect on
the trabecular meshwork. No studies have been performed on the ciliary
muscle.

However, there are substantial species differences in responses. For
instance, intravenous delta-9-THC decreases IOP in rabbits but not in
monkeys. The rabbit outflow apparatus anatomically and physiologically
functions quite differently from that of humans and is not an optimal
model. In some monkey species, delta-9-THC given orally decreases IOP, but,
as in humans, topical delta-9-THC has no effect.

Eliminating sympathetic innervation to the eye in rabbits with superior
cervical ganglionectomy or pharmacological ganglionic blockade eliminates
the effect of delta-9-THC, suggesting drug action through the sympathetic
and/or parasympathetic nervous systems. However, in cats neither superior
cervical nor ciliary ganglionectomy has any effect. In rabbits, delta-9-THC
increases outflow facility and decreases aqueous production; in cats,
facility is increased, but production is unchanged.

The story is confusing in part because the techniques used are 20 to 25
years old; the animal models are not necessarily comparable with the
primate; and the compounds are not as specific as those now available.
Measurement techniques have improved since then, and the invasive
techniques for animals are much less traumatic. There are several
noninvasive techniques applicable to animals and humans, and both are much
more precise as to tissue and mechanism affected.

Another problem not recognized as relevant to glaucoma 20 or 25 years ago
is marijuana's ability to reduce blood pressure. Depending on dosage,
frequency, and user experience, the reduction can be rather substantial.
Blood flow to the optic nerve may be important to the nerve's health,
especially in an adverse environment. In an eye with elevated IOP, or an
optic nerve that is not doing well and has unusual susceptibility to
changes in IOP, reduced blood flow may be a very important factor in the
progression of glaucoma.

In summary, decreased blood pressure, decreased optic nerve blood flow, and
short duration of the IOP-lowering effect are significant actual and
potential problems with marijuana, in addition to the psychotropic effects.
Also, because we do not know how the drug works, we do not know how it will
interact with other glaucoma drugs. If the mechanism involves a final
common pathway, cannabinoids may not be additive and might even interfere
with the other compounds. Conversely, some synthetic cannabinoids have
neuroprotective effects in vitro, and thus might possess antiglaucoma
potential independent of IOP.

To rationally determine marijuana's potential place in the antiglaucoma
armamentarium, we should study cannabinoids as we would any other
interesting class of compounds, rather than simply allowing or abandoning
their use at present. We know they lower the IOP substantially, but not
how. Even if unsuitable for therapeutic use themselves, they may provide
mechanistic insights to the development of other drugs. Issues of limited
ocular penetration (because of high lipid and poor water solubility) and
duration of action can be dealt with as with other drugs. We are much
better able to do these things now than when we first attempted it 20 or 25
years ago. In short, science rather than emotion should set the standard.

Paul L. Kaufman, MD Madison, Wis

Reprints: Paul L. Kaufman, MD, Department of Ophthalmology and Visual
Sciences, 600 Highland Ave, Room F4/328 CSC, Madison, WI 53792-3220.

Reference

1. Green K. Marijuana smoking vs cannabinoids for glaucoma therapy. Arch
Ophthalmol. 1998;116:1433-1437.

(Arch Ophthalmol. 1998;116:1512-1513)

Checked-by: Richard Lake