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(IOP) in 60% to 65% of users, continued use at a rate needed

to control glaucomatous

Cannabinoids

Marijuana Smoking vsfor Glaucoma TherapyKeith Green,

Objective: To discuss the clinical effects, including toxi-

cological data, of marijuana and its many constituent com-

pounds

would lead to substantial sys-

temic toxic effects revealed as pathological changes.

is

the

in

and the remainder of the body.

the

of marijuana and the

have provided con-

siderable background on

general human

responses.

Use

of marijuana-for medicinal p&poses de-

creased markedly in Western civilizations

during the 1930s and

able

of these herbal preparations

and the parallel development of specificmedications that were more potent and tar-

geted toward specific symptoms. This philo-

sophical alteration in medical therapy re-

flected changes that occurred in all branches

of medicine. Only in the latter part of this

century has marijuana been used as a plea-

sure-inducing substance during liberaliza-

tion of ethics and social behavior in many


4/35

cultures.- After tobacco, alcohol. and caf-

feine, it is probably the most widely used

drug in society.

See

More recently, legislation has beenpassed by certain states (with subsequent

revocation in 1 state) that has led to a re-

surgence of interest in the evaluation of

possible medical uses of marijuana. Ex-

tensive evaluations have resulted in 1 re-

port to the director of the National Insti-

tutes of Health, and will result in another

from the Institute of Medicine of the Na-

tional

of Sciences. Further-

more. a meeting on rhis topic held

i n

P

1998 at New

of the ocu-

lar and toxic effects of mari-

juana

REVIEWS

due to the

Conclusions: Development of drugs based on the

nabinoid molecule or its agonists for use as topical or


5/35

oral antiglaucoma medications seems to he

side no

effects. Smoking of

marijuana

IOP in glaucoma is ill-advised. given its toxicological

profile.

of

further pursuit. Among

School

adverse

toxic effects. although effects on

many other organ systems. including the

brain, have been

Marijuana smok-

ing leads to emphysemalike lung changes

that are caused by the products of mari-

juana burning

cannabinoids) or through

the release of tars, carcinogens. and other

volatile materials, as occurs

oc-

cur in greater concentration than

in to-bacco

is little but

anecdotal material on which to rely, but

in the area of glaucoma, there exists a sub-

stantial literature.

MEDICAL EFFECTS

A number of health hazards of marijuana

have been identified, but some are diffi-

cult to document

tobaccosmoke.- The latter products.

The cognitive effects

induced by marijuana are of equal

these assume greater relevance with

chronic, repetitive exposure, especially in


6/35

of Medicine, New York. will result in pub-

lication of a book in the spring of

In many areas of

Acute

effects are increased pulse rate, orthostatic

hypotension. euphoria. and conjunctival

Long-rerm peremia.

clinical effects in hu-

mans include respirator), hormonal, and

material for

chemicals. some

reduction of


7/35

Seven of 11 patients in 1 study showed a

reduction in IOP of abour 30% after smoking 2% mari-


8/35

juana cigarettes.

More quantities of oral drug or mari-

juana were needed compared with inhaled drug, pre-

sumably due to the poorer absorption by the former route.

hour-a-day disease, requiring as many as 2920 to 3650

marijuana cigarettes per year.The widespread effects of the cannabinoids and mari-

juana on many biological systems have been attributed

to direct effects on certain biochemical processes, per-

turbations in cell membranes, or attachment to 1 of the

2 identified cannabinoid receptors,

or mari-

juana (brownies) causes conjunctival

Different cannabinoids reduce intraocular pres-

sure (IOP) in about 60% to 65% of humans, and mari-

juana and

intravenous in-

jection of cannabinoids, or ingestion of

log. An apparent dose-response relationship occurred be-

tween 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.

after

ing level,

The major difficulty with marijuana smok-

ing was to separate the reduction in IOP and the eu-

phoric effect. These findings confirmed the physiological

and pharmacological effects found in experimental ani-

mals after intravenous drug

Studies in patients with primary open-angle glau-

coma (POAG) indicated a reduction of

of the population after marijuana smoking or

true of glaucoma, where

continuous use would be necessary to control this

receptor is located in the central nervous system,

whereas

receptors occur in immune system tissues,


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such as

a better and more complete picture has arisen of

the effects of these compounds.-

OCULAR EFFECTS

Inhalation of marijuana smoke or smoke of cigarettes laced

with A-tetrahydrocannabinol

lary effects appear to differ depending somewhat on the

circumstances of marijuana

(inhaled or taken orally) also de-

crease IOP in the same percentage of nonglaucomatous

volunteers

and of volunteer patients with glau-

coma.+,

THC cigarettes. as noted with a synthetic THC

2% marijuana through a water-cooled

pipe. Duration of the reduction of IOP is about 3 to =t

hours,

Through use of cannabinoid ago-

nists such as

and de-

creased lacrimation.

tagmus. and blepharospasm. The ocular effects of

term marijuana inhalation seem to be

and methanandamide, identi-

fication of cannabinoid receptors, and evaluation of their

role in reflecting the biological activity of the

Orthostatic hvpotension and 50% decreased

lacrimation occur

This is

chronic

impairment of accommodation, photophobia,

which time the IOP approaches the


10/35

of

about

after inhalation of 2%

Ocular side effects include

(range,

in 60% to

and

ARCH OPHTHALMOWOL 116, NOV 1998

1434

w h e n

to

The

disease. No in-

dication has been obtained or reported that those highly

limited number of persons who consume marijuana ciga-

rettes as a compassionate investigational new drug have

shown any maintenance of visual function or visual fieldsor 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

minimal low value, requires a marijuana ciga-

rette to be smoked 8 or

a day (by those persons

in whom

cannabinoid use (topical, oral, or intravenous). Since the

largest individual group was about 40 persons, this con-

stitutes a large number of groups and a range of condi-

tions under which marijuana or 1 of its constituents

reduced IOP.

Topical

ies to

This effect was re-


11/35

vealed 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 ab-

sorption is maximum with smoking, and the user or

patient can titrate the drug to a level of euphoria indica-tive 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

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

was examined in rabbits. dogs, and

primates for pharmacological

The best ve-

hicle identified for delivery of the lipophilic agent in the

early

has been superseded by vehicles that per-

mit internalization of lipid-soluble compounds into other

materials that are themselves water soluble. This pro-

vides an excellent delivery mode of a lipophilic drug

through the aqueous tear environment to the lipid

approach offers a new modality for

encouraging greater drug penetration to the site of ac-tion. The development of nonpsychoactive, cannabinoid-

related drugs also has resulted in separation of IOP re-

duction from euphoric effects, at least in experimental

animal tests, and holds promise for more future devel-

opments. In humans,

drops were ineffective in

reducing IOP in single= or multiple-drop studies, due to

the induction of ocular

all make smoking a nonviable mechanism. The sys-

temic toxic effects that result in pathological changes alone

seem sufficient to discourage smoking marijuana.

Primary open-angle glaucoma is a

dis-

ease, and since the marijuana-induced fall in IOP lasts

soluble esters of a

3 hours, the drug consumption


12/35

com-

pound. This

and keep

epithelium. Other approaches have entailed

before being tested in

actually

the acute effects of marijuana smoking

at a safe level would be

j

salt of a

This use corresponds

needed to

and toxic

in


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to at least 2920 and

many as 3650 marijuana ciga-


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rettes consumed per year.

It is difficult to imagine any-

one consuming that much

individual who is incorporated into society and

perhaps operating machinery or driving on the high-

ways. Similarly, the systemic end-organ effects at this levelof consumption have the potential of being quite high.

On the other hand, the availability of once- or

field loss or optic disc changes. There has

been considerable press coverage of the use of mari-

juana as an

or day eye drops (P-blockers such as timolol

the

prostaglandin agonist latanoprost) makes IOP control a

reality for many patients and provides round-the-clock

reduction.@

Glaucoma treatment requires a round-the-clock re-

duction in IOP, and treatments are evaluated as success-

ful if this level of activity is achieved without progres-

sion of

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 func-

tion loss to proceed. Second, full use of enough smoked

marijuana leads to the need, as described above, of anaverage of at least 3300 cigarettes per year. Advocates of

the latter approach often cite using marijuana for the re-

lief of symptoms, whereas POAG has no symptoms un-

til too late, when vision is irreversibly lost.

The advocates of marijuana smoking for glaucoma

treatment also must contend with the lack of standardiza-

tion 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 de-

pending on which plant part is

This variabil-

ity goes counter to the requirements of the Food and Drug

Administration. Washington, DC. concerning the chemi-

cal

and performance characteristics of specific drugs.

Indeed, dronabinol

is

approved by the Food and Drug Administration for the treat-

ment of chemotherapy-induced nausea and acquired


15/35

munodeficiency syndrome wasting syndrome. Further, de-

spite attempts by individual states to change their laws,

marijuana remains a schedule

controlled substance, and

federal law prevails.

Lastly, there is an increasing movement at the fed-

eral and state levels to confine tobacco smoking to highlyrestricted areas to reduce smoking and the exposure of

nonsmokers to second-hand smoke.

the face of this

societal change, it is difficult to advocate increased smok-

ing particularly of marijuana, in settings where smok-

ing is normally banned.

CANNABINOIDS

FOR GLAUCOMA TREATMENT

Oral or topical cannabinoids show promise for future use

in glaucoma treatment. Newer topical delivery technolo-

gies are available for these lipophilic drugs. including the

formation of microemulsions and use of cyclodextrins to

increase thein aqueous-based solutions. This is

a marked improvement over the lipid-based vehicles that

were the

ones available during earlier basic and clini-

cal studies of topical

an oral form of

and being a

The

ment of compounds related to

(dexanabinol), that show a complete absence of euphoric

effects while retaining IOP-reducing

is a major

advance. Increasing knowledge concerning the topical

that nabinoid receptors and

reduce IOP in rabbit

or monkey eyes will allow exploration of different struc-

tural analogs that may identify compounds efficacious aspotential glaucoma medications.+ Topical administra-

tion also has the advantage of permitting the use of a low

mass of drug per delivery volume. Even at 5% concentra-

tion, a

drop would contain only 1.5 mg.

Oral administration of cannabinoids that lack psy-

choactive effects but will reduce IOP could be a signifi-

cant addition to the ophthalmic armamentarium against


16/35

glaucoma. The cannabinoids that exist in the plant ma-

terial- or as

do not appear to be viable

candidates for oral use because of the inability to

rate their euphoric and

cal perspective, the cannabinoids and related sub-

stances represent an area of focus for future studies. Such

attention would allow the development of appropriate

vehicles for these chemicals into the predominantly aque-

ous environment of the tears. Compounds would be iden-

tified that have no euphoric effects or at least a

binoids in causing an

high

ratio of IOP reduction to euphoric effects. Such chemi-

cals would eliminate any potential abuse problems while

providing drugs that would reduce IOP

unique inter-

action with receptors or other membrane components that

could be additive to other currently available glaucoma

medications.

reduction has been sought, evi-

dence points to an influence on increasing outflow of fluid

from the eye as the major component. This is true for

receptor- differs widely.

The rapidity of onset of the responses strongly suggests

that an effect is occurring that can undergo rapid adjust-

ment rather than be related to slow alterations in

ular meshwork

in several

ways from the conclusions reached

believe, are compelling for glaucoma studies to fo-

cus on individual chemicals rather than a nonstandard-

ized 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 Administra-

tion in terms of chemical identity,

although the binding of each of these

compounds to the


17/35

the National In-

stitutes of Health-assembled panel to provide a written

report on medicinal use of marijuana. The primary dif-

ference is the focus of research efforts, which the panel

concluded should have marijuana smoking as its deliv-

ery mode, whereas my review recommends

The reasons for this divergence of opinion are given

and,

review ization. A

of medicinal appli-

cations that evaluated the effect of

and

marijuana on a broad spectrum of medical problems

indicated that THC may have a role in treating nausea

associated

and in appetite

stimulation. Other uses of either materialnot

supported.

effects.

Because they are readily characterized from a

The perspective presented herein

and

experiments where the action of

cancer

such as

or


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21.

22.


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23.

24.

25.

26

11.

12.13.

14.

15.

16.

17.

18.

19.

3

4

5

67

8

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