MARIJUANA SMOKING VS CANNABINOIDS FOR GLAUCOMA THERAPY (Part 1 of 2)

Objective: To discuss the clinical effects, including toxicological data,
of marijuana and its many constituent compounds on the eye and the
remainder of the body. A perspective is given on the use of marijuana and
the cannabinoids in the treatment of glaucoma.

Results: Although it is undisputed that smoking of marijuana plant material
causes a fall in intraocular pressure (IOP) in 60% to 65% of users,
continued use at a rate needed to control glaucomatous IOP would lead to
substantial systemic toxic effects revealed as pathological changes.

Conclusions: Development of drugs based on the cannabinoid molecule or its
agonists for use as topical or oral antiglaucoma medications seems to be
worthy of further pursuit. Among the latter chemicals, some have no known
adverse psychoactive side effects. Smoking of marijuana plant material for
the reduction of elevated IOP in glaucoma is ill-advised, given its
toxicological profile.

Arch Ophthalmol. 1998;116:1433-1437

Previous reviews of the ocular and toxic effects of marijuana[1-6] have
provided considerable background on general human responses. Use of
marijuana for medicinal purposes decreased markedly in Western
civilizations during the 1930s and 1940s, due to the variable potency of
these herbal preparations and the parallel development of specific
medications that were more potent and targeted toward specific symptoms.
This philosophical alteration in medical therapy reflected changes that
occurred in all branches of medicine.[7] Only in the latter part of this
century has marijuana been used as a pleasure-inducing substance during
liberalization of ethics and social behavior in many cultures.[8-10] After
tobacco, alcohol, and caffeine, it is probably the most widely used drug in
society.

More recently, legislation has been passed by certain states (with
subsequent revocation in 1 state) that has led to a resurgence of interest
in the evaluation of possible medical uses of marijuana. Extensive
evaluations have resulted in 1 report to the director of the National
Institutes of Health,[11] and will result in another from the Institute of
Medicine of the National Academy of Sciences. Furthermore, a meeting on
this topic held in March 1998 at New York University School of Medicine,
New York, will result in publication of a book in the spring of 1999.[12]
In many areas of interest, there is little but anecdotal material on which
to rely, but in the area of glaucoma, there exists a substantial literature.

MEDICAL EFFECTS

A number of health hazards of marijuana have been identified, but some are
difficult to document completely.[9,10,13] Acute effects are increased
pulse rate, orthostatic hypotension, euphoria, and conjunctival
hyperemia.[14,15] Long-term clinical effects in humans include respiratory,
hormonal, and pulmonary toxic effects, although effects on many other organ
systems, including the brain, have been noted.[14,15,16-28] Marijuana
smoking leads to emphysemalike lung changes that are caused by the products
of marijuana burning (ie, cannabinoids) or through the release of tars,
carcinogens, and other volatile materials, as occurs with tobacco
smoke.[16,17] The latter products, however, occur in greater concentration
than in tobacco smoke.[19] The cognitive effects induced by marijuana are
of equal concern; these assume greater relevance with chronic, repetitive
exposure, especially in the age group in which glaucoma is most
prevalent.[18,20-28] These factors must be considered when potential
chronic use of cannabis is considered as a treatment. This is especially
true of glaucoma, where continuous use would be necessary to control this
24-hour-a-day disease, requiring as many as 2920 to 3650 marijuana
cigarettes per year.

The widespread effects of the cannabinoids and marijuana on many biological
systems have been attributed to direct effects on certain biochemical
processes, perturbations in cell membranes, or attachment to 1 of the 2
identified cannabinoid receptors, CB1 and CB2. The CB1 receptor is located
in the central nervous system, whereas CB2 receptors occur in immune system
tissues, such as spleen.[29-33] Through use of cannabinoid agonists such as
WIN5512-2 and methanandamide, identification of cannabinoid receptors, and
evaluation of their role in reflecting the biological activity of the
cannabinoids, a better and more complete picture has arisen of the effects
of these compounds.[29-33,34-38]

OCULAR EFFECTS

Inhalation of marijuana smoke or smoke of cigarettes laced with
delta-9-tetrahydrocannabinol (delta-9-THC), intravenous injection of
cannabinoids, or ingestion of delta-9-THC or marijuana ("brownies") causes
conjunctival hyperemia and decreased lacrimation.[1-4,6,39-41] Ocular side
effects include diplopia, impairment of accommodation, photophobia,
nystagmus, and blepharospasm. The ocular effects of long-term marijuana
inhalation seem to be similar.[42,43] Pupillary effects appear to differ
depending somewhat on the circumstances of marijuana intake.[44,45]

Different cannabinoids reduce intraocular pressure (IOP) in about 60% to
65% of humans, and marijuana and delta-9-THC (inhaled or taken orally) also
decrease IOP in the same percentage of nonglaucomatous
volunteers[4,39,41,42] and of volunteer patients with glaucoma.[4,41,46]
Orthostatic hypotension and 50% decreased lacrimation occur quickly after
inhalation of 2% 9-THC cigarettes,[41] as noted with a synthetic THC
homolog. An apparent dose-response relationship occurred between
cannabinoids or marijuana and IOP when groups were evaluated. Although the
peak fall in IOP was dose related, the time of maximal change was
unchanged. The IOP fell, on average, by about 25% (range, -45% to +5%)
after smoking 2% marijuana through a water-cooled pipe.[39] Duration of the
reduction of IOP is about 3 to 4 hours, by which time the IOP approaches
the presmoking level.[1-4,6,39,41] The major difficulty with marijuana
smoking was to separate the reduction in IOP and the euphoric effect. These
findings confirmed the physiological and pharmacological effects found in
experimental animals after intravenous drug administration.[47-50]

Studies in patients with primary open-angle glaucoma (POAG) indicated a
reduction of IOP in 60% to 65% of the population after marijuana smoking or
delta-9-THC ingestion.[4,39,41,46] Seven of 11 patients in 1 study showed a
reduction in IOP of about 30% after smoking 2% marijuana cigarettes.[46]
More quantities of oral drug or marijuana were needed compared with inhaled
drug, presumably due to the poorer absorption by the former route.

About 300 volunteers (nonglaucomatous subjects or patients with POAG)
overall have participated in studies to examine the acute effects of
marijuana smoking or cannabinoid use (topical, oral, or intravenous). Since
the largest individual group was about 40 persons, this constitutes a large
number of groups and a range of conditions under which marijuana or 1 of
its constituents reduced IOP.

Topical delta-9-THC was examined in rabbits, dogs, and primates for
pharmacological activity[1-6,50,51-55] and toxic effects[56] before being
tested in humans.[57-60] The best vehicle identified for delivery of the
lipophilic agent in the early 1980s[55] has been superseded by vehicles
that permit internalization of lipid-soluble compounds into other materials
that are themselves water soluble. This provides an excellent delivery mode
of a lipophilic drug through the aqueous tear environment to the lipid
corneal epithelium. Other approaches have entailed water-soluble esters of
a maleate salt of a 9-THC-related compound.[5] This prodrug approach offers
a new modality for encouraging greater drug penetration to the site of
action. The development of nonpsychoactive, cannabinoid-related drugs also
has resulted in separation of IOP reduction from euphoric effects, at least
in experimental animal tests,[61] and holds promise for more future
developments. In humans, 9-THC drops were ineffective in reducing IOP in
single-or multiple-drop studies, due to the induction of ocular
irritation.[59,60] This effect was revealed only in humans.

MARIJUANA SMOKING AS TREATMENT FOR GLAUCOMA

Use of marijuana smoking as a treatment for glaucoma is not desirable for
several reasons. Although drug absorption is maximum with smoking, and the
user or patient can titrate the drug to a level of euphoria indicative of a
pharmacological response, this approach is poor. The pathological effects
on the lung already described, exposure to carcinogens, and the other
pulmonary and respiratory changes at the organ and cellular
levels[16,17,19] all make smoking a nonviable mechanism. The systemic toxic
effects that result in pathological changes alone seem sufficient to
discourage smoking marijuana.

Primary open-angle glaucoma is a 365-day-a-year disease, and since the
marijuana-induced fall in IOP lasts only 3 hours, the drug consumption
conceivably needed to reduce and keep IOP at a safe level would be very
high. The IOP is the only readily measurable parameter that one can use as
an index of POAG and is still the major indicator of what is essentially a
neuropathogenic disease.[62] No indication has been obtained or reported
that those highly limited number of persons who consume marijuana
cigarettes as a compassionate investigational new drug have shown any
maintenance of visual function or visual fields or stabilization of optic
disappearance.

Since marijuana reduces IOP for 3 to 4 hours, after which the IOP returns
to baseline, control of IOP at a significantly lowered value, including
maintenance of IOP at a 2-hour minimal low value, requires a marijuana
cigarette to be smoked 8 or l0 times a day (by those persons in whom IOP
actually decreases). This use corresponds to at least 2920 and as many as
3650 marijuana cigarettes consumed per year.[3,6] It is difficult to
imagine anyone consuming that much marijuana and being a productive
individual who is incorporated into society and perhaps operating machinery
or driving on the highways. Similarly, the systemic end-organ effects at
this level of consumption have the potential of being quite high. On the
other hand, the availability of once-or twice-a-day eye drops
(beta-blockers such as timolol maleate, or the prostaglandin agonist
latanoprost) makes IOP control a reality for many patients and provides
round-the-clock IOP reduction.[62]

Glaucoma treatment requires a round-the-clock reduction in IOP, and
treatments are evaluated as successful if this level of activity is
achieved without progression of visual field loss or optic disc changes.
There has been considerable press coverage of the use of marijuana as an
antiemetic[63-66] or as treatment for glaucoma. Dangers arise from 2
considerations of the latter. First, intermittent use would lead to a lack
of IOP reduction on a continued basis, thereby permitting visual function
loss to proceed. Second, full use of enough smoked marijuana leads to the
need, as described above, of an average of at least 3300 cigarettes per
year. Advocates of the latter approach often cite using marijuana for the
relief of symptoms, whereas POAG has no symptoms until too late, when
vision is irreversibly lost.

The advocates of marijuana smoking for glaucoma treatment also must contend
with the lack of standardization of the plant material. The 480 chemicals,
including 66 cannabinoids, in marijuana vary depending on the site and
circumstances of growth and certainly vary in content depending on which
plant part is smoked.[67-69] This variability goes counter to the
requirements of the Food and Drug Administration, Washington, DC,
concerning the chemical identity and performance characteristics of
specific drugs. Indeed, dronabinol (Marinol), an oral form of delta-9-THC,
is approved by the Food and Drug Administration for the treatment of
chemotherapy-induced nausea and acquired immunodeficiency syndrome wasting
syndrome. Further, despite attempts by individual states to change their
laws, marijuana remains a schedule 1 controlled substance, and federal law
prevails.

Lastly, there is an increasing movement at the federal and state levels to
confine tobacco smoking to highly restricted areas to reduce smoking and
the exposure of nonsmokers to second-hand smoke. In the face of this
societal change, it is difficult to advocate increased smoking,
particularly of marijuana, in settings where smoking is normally banned.

CANNABINOIDS FOR GLAUCOMA TREATMENT

Oral or topical cannabinoids show promise for future use in glaucoma
treatment. Newer topical delivery technologies are available for these
lipophilic drugs, including the formation of microemulsions and use of
cyclodextrins to increase the solubility in aqueous-based solutions. This
is a marked improvement over the lipid-based vehicles that were the only
ones available during earlier basic and clinical studies of topical
cannabinoids.[51,56,59,60,70] The development of compounds related to
delta-9-THC, such as HU211 (dexanabinol), that show a complete absence of
euphoric effects while retaining IOP-reducing activity[61] is a major
advance. Increasing knowledge concerning the topical cannabinoid receptors
and ligands that reduce IOP in rabbit or monkey eyes will allow exploration
of different structural analogs that may identify compounds efficacious as
potential glaucoma medications.[70,71-78] Topical administration also has
the advantage of permitting the use of a low mass of drug per delivery
volume. Even at 5% concentration, a 30-uL drop would contain only 1.5 mg.

Oral administration of cannabinoids that lack psychoactive effects but will
reduce IOP could be a significant addition to the ophthalmic armamentarium
against glaucoma. The cannabinoids that exist in the plant material[67-69]
or as metabolites[79,80] do not appear to be viable candidates for oral use
because of the inability to separate their euphoric and IOP-reducing effects.

Because they are readily characterized from a chemical perspective, the
cannabinoids and related substances represent an area of focus for future
studies. Such attention would allow the development of appropriate vehicles
for these chemicals into the predominantly aqueous environment of the
tears. Compounds would be identified that have no euphoric effects or at
least a very high ratio of IOP reduction to euphoric effects. Such
chemicals would eliminate any potential abuse problems while providing
drugs that would reduce IOP by unique interaction with receptors or other
membrane components that could be additive to other currently available
glaucoma medications. In experiments where the action of cannabinoids in
causing an IOP reduction has been sought, evidence points to an influence
on increasing outflow of fluid from the eye as the major component. This is
true for delta-9-THC and HU211, although the binding of each of these
compounds to the cannabinoid receptor differs widely. The rapidity of onset
of the responses strongly suggests that an effect is occurring that can
undergo rapid adjustment rather than be related to slow alterations in
trabecular meshwork glycoproteins.[81]

The perspective presented herein differs in several ways from the
conclusions reached by the National Institutes of Health-assembled panel to
provide a written report on medicinal use of marijuana.[11] The primary
difference is the focus of research efforts, which the panel concluded
should have marijuana smoking as its delivery mode, whereas my review
recommends cannabinoids. The reasons for this divergence of opinion are
given and, I believe, are compelling for glaucoma studies to focus on
individual chemicals rather than a nonstandardized plant material.

The latter has no possibility, due to the inherent variability and the
plant versatility, of reaching the standards required by the Food and Drug
Administration in terms of chemical identity, purity, or characterization.
A contemporary review of medicinal applications that evaluated the effect
of delta-9-THC and marijuana on a broad spectrum of medical problems
indicated that THC may have a role in treating nausea associated with
cancer chemotherapy and in appetite stimulation. Other uses of either
material were not supported.[82]

From the Departments of Ophthalmology, and Physiology and Endocrinology,
Medical College of Georgia, Augusta. The author has no commercial or
proprietary interest in any drug or product mentioned in this article.

Accepted for publication July 21, 1998.

This study was supported in part by an unrestricted departmental award and
a Senior Scientific Investigator award from Research to Prevent Blindness
Inc, New York, NY.

I thank Brenda Sheppard for her valuable secretarial assistance.

Reprints: Keith Green, PhD, DSc, Department of Ophthalmology, Medical
College of Georgia, 112015th St, Augusta, GA 30912-3400 (e-mail:
kgreen@mail.mcg.edu).

[This is Part 1 of 2 - Part 2 contains the references. Due to a technical
problem it was posted first and is at:
http://www.mapinc.org/drugnews/v98.n1057.a09.html ]

Checked-by: Richard Lake