Jacob Bell
New Member
Allan J. Flach, MD
ABSTRACT
Purpose: Evidence exists that the administration of cannabinoid derivatives can lower intraocular pressure. Some
patients with glaucoma believe they are being deprived of a potentially beneficial treatment. Therefore, the Research
Advisory Panel of California instituted the Cannabis Therapeutic Research Program to permit compassionate access to
cannabinoid derivatives. Data about the potential therapeutic usefulness and toxicity of these agents were collected. This
study reviews the results of this program with the specific aim of providing further direction for these investigational
efforts.
Methods: A survey of local ophthalmologists indicated an impressive interest in participating in and contributing patients
with glaucoma unresponsive to treatment to this study. Appropriate patients were treated with either orally administered
delta-9-tetrahydrocannabinol capsules or inhaled marijuana in addition to their existing therapeutic regimen.
Results: Although 20 ophthalmologists were approved as investigators, only nine patients were enrolled in the study. An
initial decrease in intraocular pressure was observed in all patients, and the investigator's therapeutic goal was met in four
of the nine patients. However, the decreases in intraocular pressure were not sustained, and all patients elected to discontinue
treatment within 1 to 9 months for various reasons.
Conclusions: This uncontrolled, unmasked, nonrandomized study does not permit definitive conclusions about the efficacy
or toxicity of cannabinoids in the treatment of glaucoma. There is an impression that this treatment can lower
intraocular pressure, but the development of tolerance and significant systemic toxicity appears to limit the usefulness
of this potential treatment. Both patients and ophthalmologists greatly appreciated the opportunity to participate in this
study.
Trans Am Ophthalmol Soc 2002;100:215-224
INTRODUCTION
The hemp plant, or Cannabis sativa, provides leaves and
flowering parts that, when dried, result in a complex pharmacologic
mixture called marijuana. Hashish is the sticky
resin that is secreted by the plant in hot, dry weather.
These mixtures contain 420 natural products, including 28
natural cannabinoids.1 The cannabinoids share several
pharmacologic actions, including intraocular pressure
(IOP)—lowering effects, central nervous system effects,
and cardiovascular system effects.2-6
The Research Advisory Panel of California was created
in 1969 by the California Legislature to encourage
research into the nature and effects of abused drugs, to
review and approve research involving controlled substances,
and to function as a human subject's protection
committee in research involving controlled substances.
Subsequently, the legislature became concerned that the
status of marijuana as a stringently regulated drug might
be inhibiting research into its possible therapeutic effects.
Therefore, in 1979, the Cannabis Therapeutic Research
Program was established to provide compassionate access
for patients to marijuana or delta-9-tetrahydrocannabinol
(THC) as a potential treatment for nausea and vomiting
associated with cancer chemotherapy.
Evidence exists that the administration of cannabinoid
derivatives can lower IOP in normal and glaucomatous
eyes.2,7 As a consequence, some patients with glaucoma
believe that they are being deprived of a potentially
vision-saving treatment and are using marijuana illegally
and, in many cases, without medical supervision.
Therefore, in 1984, the California legislature, by way of
the Research Advisory Panel and its ongoing Cannabis
Therapeutic Research Program, added to its mandate and
permitted compassionate access for appropriate glaucoma
patients to these cannabinoid derivatives. This study
allowed the collection of preliminary data about the
potential therapeutic usefulness and toxicity of THC and
marijuana in the treatment of end-stage open-angle glaucoma.
This program was effectively ended in October
1986 when THC was marketed as dronabinol (Marinol),
making the availability of free THC unnecessary. This
presentation reviews the data collected during this 2-year
study with the specific aim of providing direction for further
investigational efforts within this area of clinical and
laboratory research.
METHODS
A 1984 survey of ophthalmologists practicing within
California indicated an impressive interest in contributing
patients with glaucoma unresponsive to available treatment
to a study permitting access to cannabinoid derivatives.
Subsequently, a protocol was designed with the goal of permitting
appropriate patients to receive treatment with
either orally administered THC capsules or inhaled marijuana
in addition to their existing therapeutic regimen.8
INVESTIGATORS
California ophthalmologists certified by the American
Board of Ophthalmology could apply to become an investigator.
Following application, the potential investigator
was required to complete a Food and Drug
Administration investigator's form and agree to follow the
Cannabis Protocol for Glaucoma. Participating investigators
were required to assume full responsibility for determining
that their patients conformed to the admission
requirements. Continued participation was conditioned
upon the investigator's complicance with the protocol,
including adequate record keeping on treatment outcome
and timely submission of data forms to the Panel.
EXPERIMENTAL SUBJECTS
A Patient Qualification Review Board appointed by the
Research Advisory Panel reviewed all of the paperwork,
including the patient's medical history and examinations,
and referred the potential subject's material to the author
for possible enrollment. The author approved a patient as
an experimental subject following a lengthy discussion
with the investigator and the patient to determine
whether the patient met the qualifications to enter the
study. Thereafter, the patient was elgible to enroll in the
study and receive THC or marijuana cigarettes from an
approved pharmacy within the area.
DESIGN OF STUDY
This study was designed as an uncontrolled, unmasked,
nonrandomized, prospective evaluation of the effects of
orally administered THC or smoked marijuana on IOP in
subjects with uncontrolled IOP while receiving maximally
tolerated conventional glaucoma treatment. If subjects
began treatment with orally administered THC and the
capsules appeared ineffective, the subject could switch to
marijuana cigarettes. During the study, ancillary glaucoma
medications could not be added or deleted while adjusting
THC or marijuana doses without notifying the investigator.
EXCLUSION CRITERIA
A complete medical history and ocular examination were
submitted for each patient to determine the patient's suitability
for inclusion within this study. Patients were not
accepted as subjects for the study if they met one or more
of the following exclusion criteria: (1) glaucoma other than
primary open-angle glaucoma; (2) occludable angles; (3)
not on maximally tolerated medical therapy, including an
attempt to use the parasympathomimetics, sympathomimetics,
carbonic anhydrase inhibitors, and topically
applied beta blockers; (4) uninformed about the proven
potential therapeutic advantages of conventional glaucoma
surgeries, including laser trabeculoplasty; (5) younger
than 18 years of age; (6) a history of any psychiatric disorder,
unless approved by a psychiatrist; (7) women of childbearing
age unless using a reliable method of birth control;
(8) pregnant or nursing women; (9) significant cardiovascular
problems, including unstable angina pectoris,
cardiac arrhythmias, or hypotensive episodes; (10) a history
of dysphoric reactions to marijuana; (11) suffering from
senility; (12) unwilling to abstain from driving automobiles
or operating machinery; (13) impaired pulmonary or
hepatic function; (14) unwilling or unable to give
informed consent for this study.
BASELINE HISTORY AND EXAMINATION
All subjects provided a baseline history and underwent
examination to identify the presence of exclusion criteria.
This included a history of glaucomatous progression and
treatment, current medical management, a complete ocular
examination, and the investigator's estimation of a maximum
safe IOP level for protection of their optic nerves,
which was then considered the goal of therapy. At the conclusion
of the examination, if the patient was considered
an appropriate subject for the study, the risks, benefits,
and alternatives were explained to the subject, and
informed consent to participate in the study was subsequently
obtained.
INFORMED CONSENT
All subjects read, discussed, and signed the form entitled
Consent to Be a Research Subject in the California
Cannabis Therapeutic Progam. They were informed that
the use of THC or marijuana for the treatment of
glaucoma is experimental and that there is no evidence
showing that this treatment benefits open-angle glaucoma.
Furthermore, they were informed about the potential risks
of taking cannabinoid therapy, including changes in vision,
hearing, mood, and muscle control; wheezing; decreased
blood pressure; feeling faint, intoxicated, confused, nervous,
or scared; and rapid heart beat, red eyes, dry mouth,
daydreams, hallucinations, forgetfulness, decreased energy,
sleepiness, and a distortion of perception. Subjects
were warned that some of the effects may be pleasant or
distressing in an unpredictable fashion and that they may
persist for up to 24 hours. In addition, they were warned
that marijuana cigarettes may be harmful to the lungs and
have the potential to cause lung cancer, which can be
lethal. They were told that they could not operate a car or
any machinery while using these treatments because they
would endanger themselves and others. Finally, alternative
treatments, including different dose forms and higher concentrations
of available medications and conventional surgery,
were reviewed and clearly identified as proven and
efficacious treatments well recognized to benefit glaucoma,
unlike the experimental use of cannabis derivatives. In
addition to signing the consent form, the subjects read and
signed the Experimental Subject's Bill of Rights.
MEASUREMENT OF IOP
The subject's IOP was determined at baseline immediately
prior to the start of cannabis therapy by applanation
tonometry with three consecutive measurements.
Thereafter, the subject's IOP was evaluated weekly, at the
same time of day, until satisfactory control of IOP was
achieved for 2 consecutive weeks. Satisfactory control of
IOP meant a level of IOP that the investigator believed, as
determined from prior experience with the subject, was
safe for the health of the subject's optic nerve. When satisfactory
IOP control was obtained for 2 consecutive
weeks, the frequency of evaluation could be reduced to
once a month. Treatment evaluation forms were returned
to the Panel on a weekly basis and reviewed by the author.
TREATMENT EVALUATIONS
On subsequent visits, complete ocular examinations were
performed with special attention to the subject's IOP and
blood pressure, each measured at the same time of day at
each visit. At the conclusion of the office visit, the investigator
provided a clinical impression of the effectiveness of
treatment since the last evaluation as follows: Improved,
Same, Worsened, Uncertain. Cannabis side effects were
recorded on both a treatment evaluation form by the
investigator and a patient questionnaire by the subject.
PATIENT QUESTIONNAIRE
Subjects were required to complete a side effect and
psychosocial function questionnaire for each week until
their condition stabilized with a given dose of THC or marijuana.
This form was submitted to the Panel and reviewed
monthly along with the investigator's treatment evaluation
form. Additional comments regarding treatment and
coexistent side effects were encouraged from each subject
at each evaluation period in an attempt to monitor side
effects and possible excessive drug accumulation.
TREATMENT MEDICATIONS AND DOSING SCHEDULES
Oral THC and marijuana cigarettes were provided without
charge by the National Cancer Institute and the National
Institute on Drug Abuse and dispensed by approved pharmacies.
The oral THC dosage forms consisted of soft gelatin
capsules containing 2.5 mg or 5 mg of THC dissolved
in sesame oil. Initial dosage for each patient was 2.5 mg or
5 mg given every 4 hours (four times daily) while awake.
The dose was increased or decreased by 2.5-mg increments
as needed to obtain a greater effect or less toxicity,
with a maximum permitted dose of 20 mg four times daily.
Marijuana cigarettes marked in quarters were supplied
and contained 6 mg of THC. Subjects were requested to
inhale one fourth of a cigarette every 3 hours (five times
daily) while awake. They were instructed to inhale deeply,
hold the inhalation for 5 seconds, and then exhale; after 10
seconds the cycle is repeated until the appropriate dose is
smoked in approximately 5 minutes. A flameproof holder
was used to permit delivery of all the cigarette dosage. This
dose was increased or decreased as needed to provide a
greater effect on IOP or less toxicity. Subjects could not
use "street" marijuana during the study.
TERMINATION FROM STUDY
Subjects could withdraw from the study at any time for
any reason. At the time of termination, the reason for discontinuing
treatment (eg, toxic effects, lack of efficacy, too
tedious, geographic change, ocular surgery, other, uncertain)
was noted on the final evaluation form. No subject
was permitted to use these medications for more than 12
months.
RESULTS
During this 2-year period, 20 ophthalmologists were
approved as investigators and nine patients were enrolled
into the study to received oral THC for 1 to 9 months. No
subjects consented to receive smoked marijuana. The
characteristics of these subjects with end-stage openangle
glaucoma are summarized in Table I. At the time of
entry into the study, subjects had uncontrolled IOP
despite using maximally tolerated medical treatment.
Furthermore, the majority of subjects had a history of one
or more glaucoma surgeries.
An initial decrease in IOP was observed in all subjects.
The therapeutic goal of the investigator was
achieved in four of nine subjects, and six of nine were considered
"improved" during at least one visit during their
treatment (Table II). Subject D.F. was improved at every
visit for a 9-month period. Subject C.C. was described as
"improved" during more than 50% of the follow-up visits
during his 5-month treatment. Both of these subjects
were improved at the time of termination from the study,
when each subject underwent cataract surgery. All of the
other subjects appeared to have lost the beneficial effects
of treatment on their IOP at the time of termination.
All subjects experienced toxic effects from oral THC
during their treatment. Intolerable side effects forced
four subjects to be terminated early from the study. These
side effects and the corresponding dose of THC are summarized
in Table III. No subject reported enjoying effects
of THC related to the central nervous system. Subjects
who did not tolerate THC were offered access to
marijuana, but all of them declined
DISCUSSION
The identification of brain, ocular, and peripheral
cannabinoid receptors in several different mammals, the
cloning of cannabinoid receptors, and the discovery of
anandamide, an endogenous cannabimimetic eicosanoid,
has greatly augmented the study of cannabinoid pharmacology
in recent years.9-13 Some of these pharmacologic
investigations have attempted to develop new drugs useful
for the treatment of the glaucomas.14-17 However, thus
far none of these efforts have included the use of cannabinoids
in glaucoma patients with advanced disease.
Therefore, it seemed timely to present this study, which
represents the largest series of end-stage glaucoma
patients treated with a cannabinoid derivative thus far
completed. The data collected during this study are presented
with the aim of providing direction and encouragement
for further investigational efforts within this area
of clinical and laboratory research.
Because this is a small, uncontrolled, unmasked, nonrandomized,
prospective study of short duration, it does
not permit definitive conclusions about the efficacy of
cannabinoids in the treatment of glaucoma. However,
there is an impression from the data collected during this
2-year investigation that treatment with oral THC lowered
IOP in some of this group of end-stage open-angle
glaucoma patients. Following the initiation of THC treatment,
all of the subjects demonstrated at least a transient
improvement in the reduction of IOP (Table II). An
improvement was noted during more than 50% of the
office visits in two of the nine enrolled subjects. In fact,
one of the subjects was considered improved on all of the
follow-up visits over a 36-week treatment period despite
the fact that he never met the goal of treatment which the
investigator considered ideal. The therapeutic goal of the
investigator was achieved in four of nine subjects.
Subjects N.C and C.C. each demonstrated an improved
IOP control while using 5 mg of THC four times daily
despite discontinuing coexistent carbonic anhydrase
inhibitors and parasympathomimetics or sympathomimetics.
Unfortunately, many of the subjects appeared to
develop a tolerance to THC because their IOPs increased
during the latter period of their treatment. Of course, as
with any uncontrolled study, the observed improvements
in IOP control may have been related to enhanced compliance
associated with a subject's participation in the
study or the added attention or encouragement given to
the subject during the treatment period. This appeared to
be the case with at least one subject (R.G.), in the opinion
of the investigator, as indicated in Table II.
All subjects experienced side effects during their
treatment with THC during this study (Table III). The
most commonly described toxic effects were dry mouth,
sleepiness, dizziness, depression, and confusion; these
effects were the same as those reported by other investigators.
18,19 Although many of the side effects were considered
mild and were of little concern to subjects, other
effects were very significant. For example, the reason for
termination from the study for four of the nine subjects
was intolerable side effects, such as distortion of perception,
confusion, anxiety, depression, and severe dizziness.
Changes in blood pressure have been reported with THC
treatment.20,21 Therefore, blood pressures were measured
and the symtoms of systemic hypotension were carefully
searched for at each visit. The dizziness and light-headedness
reported by subjects in this study were never associated
with systemic hypotension.
In most cases, the therapeutic benefit did not outweigh
the toxicity associated with treatment as percieved
by the subject. For example, one subject (N.C.) was
unhappy because he gained weight while enrolled in the
study. It was unclear whether his enhanced appetite was
related to discontinuing acetazolamide or the concurrent
use of THC. In any case, he was upset enough about this
apparent effect that he withdrew from the study despite
an improvement in IOP control and his ophthalmologist's
opinion that he had met the goal of treatment. His termination
from the study was considered to be due to intolerable
side effects of THC.
Although the literature is unclear about the development
of tolerance to the effects of cannabinoid administration,
there was some evidence for tolerance in this
study. There appeared to be a tendency for the beneficial
effects on IOP to outlast the side effects in some patients,
as demonstrated in Table III and as has been previously
reported.22 Unfortunately, there also appeared to be a tendency
for tolerance to the beneficial IOP effects to develop
in most of the subjects, as summarized in Table II.
A major limitation for applying the results of this
study to present-day glaucoma therapy is that this study
was completed in 1986, before many of the glaucoma
medications currently in use were available. More specifically,
prostaglandin derivatives, topically applied carbonic
anhydrase inhibitors, and relatively alpha2-specific
sympathomimetics were not commercially available during
the 1980s. It is possible that if THC were added to the
current therapeutic regimen of maximally tolerated therapy
during the treatment of end-stage glaucoma, it would
provide a less optimistic impression of its therapeutic usefulness.
Throughout the study, there was no observed tendency
for either the physicians or the patients to abuse their
access to cannabinoid derivatives. In fact, none of the subjects
appeared to enjoy the psychotropic effects of THC.
This is consistent with the observation made in previous
studies that the environment, expectations, and reason for
use of individuals during cannabinoid administration
influence the overall personal experience and psychologic
reaction to the effects of the cannabinoids following their
administration.
Finally, it was clear that both the patients and
ophthalmologists greatly appreciated the opportunity to
participate in this study. The program not only provided
patients with legal and compassionate access to cannabinoid
treatment as a last-resort treatment during the the
management of end-stage glaucoma unresponsive to conventional
treatments, but it provided an opportunity for
careful monitoring and extensive education of all of the
patients interested in this potential treatment. Therefore,
this opportunity greatly increased the safety for all of the
patients who participated as subjects and even the
patients who did not qualify for treatment because they
were misinformed about the lack of proven value for the
treatment or were ignorant of the potential dangers of taking
cannabinoids in an attempt to lower IOP.
CONCLUSIONS
This uncontrolled, unmasked, nonrandomized, prospective
study does not permit definitive conclusions about the
efficacy or toxicity of cannabinoids in the treatment of
glaucoma. There is an impression from this study that
treatment with oral THC lowered IOP in this group of
patients with end-stage open-angle glaucoma, but the
development of tolerance and the coexistence of significant
systemic toxicity limited the potential usefulness of
this treatment. It was particularly impressive to the investigators
that throughout the study there was no observed
tendency for either the physicians or the patients to abuse
their access to cannabinoid derivatives. Furthermore, both
the patients and ophthalmologists greatly appreciated the
opportunity to participate in a study that gave them legal
access to cannabinoids as a last-resort treatment for endstage
glaucoma unresponsive to conventional treatments.
REFERENCES
1. Turner CE, Elsohly MA, Boeren EG. Constituents of
Cannabis sativa : a review of the natural constituents. J Nat
Prod 1980;43:169-234.
2. Hepler RS, Frank IM. Marijuana smoking and intraocular
pressure. J Am Med Assoc 1971;217:1392.
3. Hepler RS, Frank IM, Ungerleider JT. Pupillary constriction
after marijuana smoking. Am J Ophthalmol
1972;74:1185-1190.
4. Drew WG, Miller LL. Cannabis: neural mechanisms and
behavior–a theoretical review. Pharmacology 1974;11:12-
32.
5. Benowitz NL, Rosenberg J, Rogers W, et al. Cardiovascular
effects of intravenous delta-9-tetrahydrocannabinol: autonomic
nervous mechanisms. Clin Pharmacol Ther
1979;25:440-446.
6. Hollister LE. Structure-activity relationships in man of
cannabis constituents and homologs and metabolites of
delta-9-tetrahydrocannabinol. Pharmacology 1974;11:3-11.
7. Lockhart AB, West ME, Lowe HIC. The potential use of
Cannabis sativa in ophthalmology. West Indies Med J
1977;26:66-70.
8. Flach AJ, Holsten DW, Icaza L, et al. Cannabis protocol for
glaucoma: oral THC and smoked marijuana for treating
open angle glaucoma patients. For Research Advisory Panel
of California, 1984.
9. Devane WA, Dysarz FA, Johnson MR. Determination and
characterization of a cannabinoid receptor in the rat brain.
Mol Pharmacol 1988;34:605-613.
10. Munro S, Thomas KL, Abu Shaar M. Molecular characterization
of a peripheral receptor for cannabinoids. Nature
1993;365:61-65.
11. Straiker AJ, Maguire G, Mackie K, et al. Localization of
cannabinoid Cb1 receptors in the human anterior eye and
retina. Invest Ophthalmol Vis Sci 1999:40;2442-2448.
12. Matsuda LA, Lolait SJ, Brownstein MJ, et al. Structure of a
cannabinoid receptor and functional expression of the
cloned DNA. Nature 1990;346:561-564.
13. Devane WA, Hanus L, Brever A, et al. Isolation and structure
of a brain constituent that binds to the cannabinoid
receptor. Science 1992;258:1946-1949.
14. Laine K, Jarvinen K, Pate DW, et al. Effect of the enzyme
inhibitor, phenylmethylsulfonyl fluoride, on the IOP profiles
of topical anandamides. Invest Ophthalmol Vis Sci
2002;43:393-397.
15. Buchwald A, Browne CE, Wu WM, et al. Soft cannabinoid
analogues as potential anti-glaucoma agents. Pharmazie
2000;55:196-201.
16. Pate DW, Jarvinen K, Urtti A, et al. Ophthalmic arachidonylethanolamide
decreases intraocular pressure in normotensive
rabbits. Curr Eye Res 1995;14:179-797.
17. Beilin M, Neumann R, Belkin M, et al. Pharmacology of
the intraocular pressure lowering effect of systemic dexanabinol
(HU-211), a non-psychotropic cannabinoid. J Ocular
Pharm Ther 2000;16:217-230.
18. Hollister LE, Gillespie HK. Delta-8- and delta-9-tetrahydrocannabinol.
Clin Pharmacol Ther 1972;14:353-357.
19. Valk LEM. Hemp in connection with ophthalmology.
Ophthalmologica 1973;167:413-421.
20. Merritt JC, Crawkford WJ, Alexander PC, et al. Effect of
marihuana on intraocular and blood pressure in glaucoma.
Ophthalmology 1980;87:222-228.
21. Crawford WJ, Merritt JC. Effect of tetrahydrocannabinol
on arterial and intraocular hypertension. Int J Clin Pharm
Biopharm 1979;17:191-196.
22. Purnell WD, Gregg JM. Delta-9-tetrahydrocannabinol,
euphoria and intraocular pressure in man. Ann Ophthalmol
1975;7:921-922.
DISCUSSION
DR DOUGLAS R. ANDERSON. Thanks to Dr Flach for this
lucid and straightforward report. To summarize the main
conclusions, the author expressed surprise that fewer subjects
enrolled than had been expected, despite wellknown
and continued public interest in use of cannabinoids for medical purposes, including glaucoma.
Perhaps a good part of the public fascination is in possible
use this drug in ordinary cases of glaucoma as an alternative
to already available therapy. The types of cases
recruited for this study were severe cases not adequately
controlled with any other treatment options, and in these
cases THC was inadequately effective or impractical
because of side effects.
It is, however, known that THC will lower the IOP,
and that there are receptors in both the trabecular meshwork
and the ciliary body. A few decades ago, I had a
young patient who knew I could not prescribe marijuana
for him. Having recently opened a business, he had some
projects to get under control before he could proceed
with the surgery I had recommended, and he asked me to
monitor his IOP frequently while waiting. The readings
were variable, and he revealed that on some days, at various
intervals before the measurements, he had smoked
marijuana. He had kept a diary of times and pressures,
and also noted the quality of the particular marijuana he
had smoked on each occasion, judged from the mental
effects he enjoyed. From this he worked out a nice doseresponse
curve and the duration of the effect on IOP. I no
longer remember the details, except that the effect was
not long-lived and did not persist beyond the time he felt
"high." The net result was that he could not focus on his
work and simultaneously keep his IOP at the desired pressure
level. Therefore he did undergo surgery, which
worked well for him for the next several years during
which he remained under my care.
At least for some patients, then, the side effects and
short duration of action may simply outweigh the advantages
compared to standard therapeutic options available.
When patients ask about marijuana, that is exactly how I
explain the situation–that THC may work to lower the
IOP, but perhaps not more effectively than other available
drugs, which have been better tested scientifically, have
longer duration of action, and also have fewer side effects.
Do cannabinoids have a place at all? Dr Paul
Palmberg has one patient under his care with glaucoma
from childhood who has had all known medications, some
not tolerated, and others not fully effective. The patient
has had several operations, the most recent with the complication
of a postoperative suprachoroidal hemorrhage,
so further surgery has been avoided. The IOP can be
brought from 50 mm Hg to 25 mm Hg with either timolol
or marijuana, but in combination to 15 mm Hg. The
patient has used marijuana in this manner for a couple of
decades now. Newer alpha-adrenergic agents and
prostaglandin analogues have not been satisfactory substitutes.
Because of the short duration of action, this treatment
requires 10 NIDA-provided marijuana cigarettes
per day and is thus not so convenient, but for this patient
it is the best alternative.
Based on the experience of this patient and of others
reported to him, Dr Palmberg believes marijuana can be
very effective when the IOP is quite high, but seems minimally
effective in patients with modestly elevated or normal
IOP. He also commented that with continual use, the
lowering of blood pressure and the mental effects disappear,
but the favorable effects on IOP persist, so some of
the problems noted in acute or short-term studies may
have underestimated the potential for this class of drugs.
Dr Palmberg participated in a NIDA-workshop cosponsored
by NIH (Feb 1997) at which various potential
medicinal uses of marijuana were discussed. Dr Paul
Kaufman reviewed the then available studies with respect
to glaucoma for the workshop, and most information dealt
with acute or short-term experiments. The report of this
workshop may provide those interested with a compendium
of background information suggesting a potential not
yet proved or developed.
Presumably, physicians can legally prescribe dronabinol
(Marinol) for glaucoma as an off-label use, although
prior clearance from appropriate authorities might be
wise. Within the past week a well-known entertainer was
arrested at an airport checkpoint for possession of marijuana,
which, it was claimed, was being used to treat glaucoma.
There may thus be some unanalyzed experience
with cannabinoids, although even if collected, scattered
anecdotal information will not substitute for further properly
designed studies of long-term clinical use such as the
one conducted by Dr Flach. Continued interest in the
class of compounds may be warranted if longer-acting
forms can be developed, and if the undesirable effects are
documented to disappear after several days so that
patients can work effectively and drive safely. Of particular
pharmacologic interest is that cannabinoids lower IOP
through mechanisms independent of those of drugs currently
on the market. The implication is that cannabinoids
may work when other classes of drugs don't, and
that it could be additive to other drugs.
DR GEORGE L. SPAETH. I obtained tetrahydrocannabinol
in 1970 and manipulated it into a form that could be used
as eye drops. Masking was attempted, using one eye as
control, but the eyes on the tetrahydrocannabinol turned
beet red. There was no effect on IOP when we compared
the treated and untreated eyes. How does this drug work
to lower pressure? Is it possible to develop some type of
topical product that might limit the problem of the systemic
side effects?
DR LOUIS B.CANTOR. Is there any understanding of the
pharmacology, and do receptors for the cannabinoids
exist? Since this drug appears to lower IOP, do we know
anything about the mechanism? Is the mechanism similar
to that of our other fatty acid lipid compounds that
improve pressure-sensitive or pressure-insensitive outflow
pathways?
DR ALLAN J. FLACH. Dr Anderson mentioned the fascination
that has existed concerning this group of drugs. This
interest has been present for over 3,000 years, as recorded
by one of the first clinical pharmacologists, Emperor
Shen-Nung in 2737 BC. During the late 1800s, the Indian
Hemp Commission Report described cannabis as the
most important drug in the Indian Materia Medica.
During the 20th century, tincture of cannabis was included
in the 1937 United States Pharmacopoeia and, in later
years, in the United States National Formulary. The
preparation was considered useful as an anti-inflammatory
and analgesic agent for the relief of migraine headaches
and prevention of seizures. In addition, it was used to
treat psychiatric illness, including depression.1 In subsequent
years, it was replaced with therapies that were considered
less toxic and more specific in their activity.
As Dr Anderson mentioned, we might have seen
greater effects on IOP following cannabinoid treatment if
we included patients with a condition other than endstage
glaucoma. I believe this is probably true. However,
if one properly informs glaucoma patients about the
proven benefits of conventional glaucoma therapy and
contrasts this with the unproven potential benefits following
marijuana derivatives, one cannot avoid endorsing the
commercial agents much more enthusiastically. This is
particularly true since all of the available cannabinoid
derivatives have significant psychotropic effects. While
these effects follow dose-response relationships that
include drowsiness or feeling comfortably high, which can
progress to depersonalization or even a panic reaction,
external stimuli can abruptly shift the apparent doseresponse
curve so that the patient, while experiencing a
happy high, can rapidly progress into a panic reaction
without additional cannabinoid treatment. This is called
endogenic potentiation.2
I agree with Dr Anderson that there is good evidence
that the cannabinoids are capable of lowering IOP. This
was initially described by Dr Robert Hepler during the
1970s.3 I have included information about US government's
grown marijuana that was available for patients in
this study within the text of this paper. None of the
enrolled subjects wanted to use inhaled marijuana
because they did not like the idea of smoking with the
associated pulmonary irritation and potential risk of lung
cancer.
It is interesting to me that Dr Spaeth observed
excessive toxicity and a lack of therapeutic effect in his
attempts to use a topical form of marijuana in glaucoma
patients. I suspect Dr Spaeth's efforts were based in part
on the initial reports by Dr John Merritt, who described
topically applied marijuana in experimental animals.
However, Dr Merritt was unable to duplicate these potentially
beneficial effects on the IOP of humans.4 Therefore,
Dr Spaeth's observations are not too surprising. For the
past 25 years, I have had the privilege of providing a 4-day
ocular pharmacology and toxicology course at Stanford
University during the summer months as part of a Basic
Science Course for ophthalmologists. Each year, I have
included a section on the cannabinoids and their potential
use within ophthalmology. One of the graduates of this
course who practices in Jamaica sent me a package insert
for a commercially available Cannabis sativa solution
marketed under the name of Canasol. This topically
applied liquid is described as capable of lowering IOP as
effectively as timolol without the side effects. However,
there are no published studies that verify this ability.
I am certain that we are all as interested as Dr Cantor
in the pharmacodynamics of cannabinoids. Dr Keith
Green deserves a lot of credit for the time he has devoted
to this study. His research describes many different
potential mechanisms by which the cannabinoids can
lower IOP.5 However, I think that we need Dr Richard
Brubaker, or someone with his experience studying
human aqueous inflow and outflow, to conscientiously
work out these effects. In conclusion, as I mentioned
within the introduction to this paper, cannabinoid receptors
have been identified within the human eye, but it
remains to be elucidated how these receptors might be
beneficially manipulated by exogenously applied or
endogenously liberated cannabinoids or other lipid compounds
and the mechanism underlying these activities.
1. Pars HG. The other side of marijuana research.
J Anesthesiol 1973;38:519-520.
2. Valk LEM. Hemp in connection with ophthalmology.
Opthalmologica 1973;167:413-421.
3. Hepler RS, Petrus RH. Experiences with administration of
marihuana to glaucoma patients. In Cohen S, Stillman RC,
eds. The Therapeutic Potential of Marihuana, New York:
Plenum 1976:63.
4. Merritt JC, Perry KDD, Russell DN, et al. Topical delta 9-
tetrahydrocannabinol and aqueous dynamics in glaucoma.
J Clin Pharmacol 1981;21:467S-471S.
5. Green K. Marijuana and the eye: a review. J Toxicol. Cutan
Ocul Toxicol 1982;1:3-32.
Source: Delta-9-Tetrahydrocannabinol (THC) In The Treatment Of Endstage Open-Angle Glaucoma
ABSTRACT
Purpose: Evidence exists that the administration of cannabinoid derivatives can lower intraocular pressure. Some
patients with glaucoma believe they are being deprived of a potentially beneficial treatment. Therefore, the Research
Advisory Panel of California instituted the Cannabis Therapeutic Research Program to permit compassionate access to
cannabinoid derivatives. Data about the potential therapeutic usefulness and toxicity of these agents were collected. This
study reviews the results of this program with the specific aim of providing further direction for these investigational
efforts.
Methods: A survey of local ophthalmologists indicated an impressive interest in participating in and contributing patients
with glaucoma unresponsive to treatment to this study. Appropriate patients were treated with either orally administered
delta-9-tetrahydrocannabinol capsules or inhaled marijuana in addition to their existing therapeutic regimen.
Results: Although 20 ophthalmologists were approved as investigators, only nine patients were enrolled in the study. An
initial decrease in intraocular pressure was observed in all patients, and the investigator's therapeutic goal was met in four
of the nine patients. However, the decreases in intraocular pressure were not sustained, and all patients elected to discontinue
treatment within 1 to 9 months for various reasons.
Conclusions: This uncontrolled, unmasked, nonrandomized study does not permit definitive conclusions about the efficacy
or toxicity of cannabinoids in the treatment of glaucoma. There is an impression that this treatment can lower
intraocular pressure, but the development of tolerance and significant systemic toxicity appears to limit the usefulness
of this potential treatment. Both patients and ophthalmologists greatly appreciated the opportunity to participate in this
study.
Trans Am Ophthalmol Soc 2002;100:215-224
INTRODUCTION
The hemp plant, or Cannabis sativa, provides leaves and
flowering parts that, when dried, result in a complex pharmacologic
mixture called marijuana. Hashish is the sticky
resin that is secreted by the plant in hot, dry weather.
These mixtures contain 420 natural products, including 28
natural cannabinoids.1 The cannabinoids share several
pharmacologic actions, including intraocular pressure
(IOP)—lowering effects, central nervous system effects,
and cardiovascular system effects.2-6
The Research Advisory Panel of California was created
in 1969 by the California Legislature to encourage
research into the nature and effects of abused drugs, to
review and approve research involving controlled substances,
and to function as a human subject's protection
committee in research involving controlled substances.
Subsequently, the legislature became concerned that the
status of marijuana as a stringently regulated drug might
be inhibiting research into its possible therapeutic effects.
Therefore, in 1979, the Cannabis Therapeutic Research
Program was established to provide compassionate access
for patients to marijuana or delta-9-tetrahydrocannabinol
(THC) as a potential treatment for nausea and vomiting
associated with cancer chemotherapy.
Evidence exists that the administration of cannabinoid
derivatives can lower IOP in normal and glaucomatous
eyes.2,7 As a consequence, some patients with glaucoma
believe that they are being deprived of a potentially
vision-saving treatment and are using marijuana illegally
and, in many cases, without medical supervision.
Therefore, in 1984, the California legislature, by way of
the Research Advisory Panel and its ongoing Cannabis
Therapeutic Research Program, added to its mandate and
permitted compassionate access for appropriate glaucoma
patients to these cannabinoid derivatives. This study
allowed the collection of preliminary data about the
potential therapeutic usefulness and toxicity of THC and
marijuana in the treatment of end-stage open-angle glaucoma.
This program was effectively ended in October
1986 when THC was marketed as dronabinol (Marinol),
making the availability of free THC unnecessary. This
presentation reviews the data collected during this 2-year
study with the specific aim of providing direction for further
investigational efforts within this area of clinical and
laboratory research.
METHODS
A 1984 survey of ophthalmologists practicing within
California indicated an impressive interest in contributing
patients with glaucoma unresponsive to available treatment
to a study permitting access to cannabinoid derivatives.
Subsequently, a protocol was designed with the goal of permitting
appropriate patients to receive treatment with
either orally administered THC capsules or inhaled marijuana
in addition to their existing therapeutic regimen.8
INVESTIGATORS
California ophthalmologists certified by the American
Board of Ophthalmology could apply to become an investigator.
Following application, the potential investigator
was required to complete a Food and Drug
Administration investigator's form and agree to follow the
Cannabis Protocol for Glaucoma. Participating investigators
were required to assume full responsibility for determining
that their patients conformed to the admission
requirements. Continued participation was conditioned
upon the investigator's complicance with the protocol,
including adequate record keeping on treatment outcome
and timely submission of data forms to the Panel.
EXPERIMENTAL SUBJECTS
A Patient Qualification Review Board appointed by the
Research Advisory Panel reviewed all of the paperwork,
including the patient's medical history and examinations,
and referred the potential subject's material to the author
for possible enrollment. The author approved a patient as
an experimental subject following a lengthy discussion
with the investigator and the patient to determine
whether the patient met the qualifications to enter the
study. Thereafter, the patient was elgible to enroll in the
study and receive THC or marijuana cigarettes from an
approved pharmacy within the area.
DESIGN OF STUDY
This study was designed as an uncontrolled, unmasked,
nonrandomized, prospective evaluation of the effects of
orally administered THC or smoked marijuana on IOP in
subjects with uncontrolled IOP while receiving maximally
tolerated conventional glaucoma treatment. If subjects
began treatment with orally administered THC and the
capsules appeared ineffective, the subject could switch to
marijuana cigarettes. During the study, ancillary glaucoma
medications could not be added or deleted while adjusting
THC or marijuana doses without notifying the investigator.
EXCLUSION CRITERIA
A complete medical history and ocular examination were
submitted for each patient to determine the patient's suitability
for inclusion within this study. Patients were not
accepted as subjects for the study if they met one or more
of the following exclusion criteria: (1) glaucoma other than
primary open-angle glaucoma; (2) occludable angles; (3)
not on maximally tolerated medical therapy, including an
attempt to use the parasympathomimetics, sympathomimetics,
carbonic anhydrase inhibitors, and topically
applied beta blockers; (4) uninformed about the proven
potential therapeutic advantages of conventional glaucoma
surgeries, including laser trabeculoplasty; (5) younger
than 18 years of age; (6) a history of any psychiatric disorder,
unless approved by a psychiatrist; (7) women of childbearing
age unless using a reliable method of birth control;
(8) pregnant or nursing women; (9) significant cardiovascular
problems, including unstable angina pectoris,
cardiac arrhythmias, or hypotensive episodes; (10) a history
of dysphoric reactions to marijuana; (11) suffering from
senility; (12) unwilling to abstain from driving automobiles
or operating machinery; (13) impaired pulmonary or
hepatic function; (14) unwilling or unable to give
informed consent for this study.
BASELINE HISTORY AND EXAMINATION
All subjects provided a baseline history and underwent
examination to identify the presence of exclusion criteria.
This included a history of glaucomatous progression and
treatment, current medical management, a complete ocular
examination, and the investigator's estimation of a maximum
safe IOP level for protection of their optic nerves,
which was then considered the goal of therapy. At the conclusion
of the examination, if the patient was considered
an appropriate subject for the study, the risks, benefits,
and alternatives were explained to the subject, and
informed consent to participate in the study was subsequently
obtained.
INFORMED CONSENT
All subjects read, discussed, and signed the form entitled
Consent to Be a Research Subject in the California
Cannabis Therapeutic Progam. They were informed that
the use of THC or marijuana for the treatment of
glaucoma is experimental and that there is no evidence
showing that this treatment benefits open-angle glaucoma.
Furthermore, they were informed about the potential risks
of taking cannabinoid therapy, including changes in vision,
hearing, mood, and muscle control; wheezing; decreased
blood pressure; feeling faint, intoxicated, confused, nervous,
or scared; and rapid heart beat, red eyes, dry mouth,
daydreams, hallucinations, forgetfulness, decreased energy,
sleepiness, and a distortion of perception. Subjects
were warned that some of the effects may be pleasant or
distressing in an unpredictable fashion and that they may
persist for up to 24 hours. In addition, they were warned
that marijuana cigarettes may be harmful to the lungs and
have the potential to cause lung cancer, which can be
lethal. They were told that they could not operate a car or
any machinery while using these treatments because they
would endanger themselves and others. Finally, alternative
treatments, including different dose forms and higher concentrations
of available medications and conventional surgery,
were reviewed and clearly identified as proven and
efficacious treatments well recognized to benefit glaucoma,
unlike the experimental use of cannabis derivatives. In
addition to signing the consent form, the subjects read and
signed the Experimental Subject's Bill of Rights.
MEASUREMENT OF IOP
The subject's IOP was determined at baseline immediately
prior to the start of cannabis therapy by applanation
tonometry with three consecutive measurements.
Thereafter, the subject's IOP was evaluated weekly, at the
same time of day, until satisfactory control of IOP was
achieved for 2 consecutive weeks. Satisfactory control of
IOP meant a level of IOP that the investigator believed, as
determined from prior experience with the subject, was
safe for the health of the subject's optic nerve. When satisfactory
IOP control was obtained for 2 consecutive
weeks, the frequency of evaluation could be reduced to
once a month. Treatment evaluation forms were returned
to the Panel on a weekly basis and reviewed by the author.
TREATMENT EVALUATIONS
On subsequent visits, complete ocular examinations were
performed with special attention to the subject's IOP and
blood pressure, each measured at the same time of day at
each visit. At the conclusion of the office visit, the investigator
provided a clinical impression of the effectiveness of
treatment since the last evaluation as follows: Improved,
Same, Worsened, Uncertain. Cannabis side effects were
recorded on both a treatment evaluation form by the
investigator and a patient questionnaire by the subject.
PATIENT QUESTIONNAIRE
Subjects were required to complete a side effect and
psychosocial function questionnaire for each week until
their condition stabilized with a given dose of THC or marijuana.
This form was submitted to the Panel and reviewed
monthly along with the investigator's treatment evaluation
form. Additional comments regarding treatment and
coexistent side effects were encouraged from each subject
at each evaluation period in an attempt to monitor side
effects and possible excessive drug accumulation.
TREATMENT MEDICATIONS AND DOSING SCHEDULES
Oral THC and marijuana cigarettes were provided without
charge by the National Cancer Institute and the National
Institute on Drug Abuse and dispensed by approved pharmacies.
The oral THC dosage forms consisted of soft gelatin
capsules containing 2.5 mg or 5 mg of THC dissolved
in sesame oil. Initial dosage for each patient was 2.5 mg or
5 mg given every 4 hours (four times daily) while awake.
The dose was increased or decreased by 2.5-mg increments
as needed to obtain a greater effect or less toxicity,
with a maximum permitted dose of 20 mg four times daily.
Marijuana cigarettes marked in quarters were supplied
and contained 6 mg of THC. Subjects were requested to
inhale one fourth of a cigarette every 3 hours (five times
daily) while awake. They were instructed to inhale deeply,
hold the inhalation for 5 seconds, and then exhale; after 10
seconds the cycle is repeated until the appropriate dose is
smoked in approximately 5 minutes. A flameproof holder
was used to permit delivery of all the cigarette dosage. This
dose was increased or decreased as needed to provide a
greater effect on IOP or less toxicity. Subjects could not
use "street" marijuana during the study.
TERMINATION FROM STUDY
Subjects could withdraw from the study at any time for
any reason. At the time of termination, the reason for discontinuing
treatment (eg, toxic effects, lack of efficacy, too
tedious, geographic change, ocular surgery, other, uncertain)
was noted on the final evaluation form. No subject
was permitted to use these medications for more than 12
months.
RESULTS
During this 2-year period, 20 ophthalmologists were
approved as investigators and nine patients were enrolled
into the study to received oral THC for 1 to 9 months. No
subjects consented to receive smoked marijuana. The
characteristics of these subjects with end-stage openangle
glaucoma are summarized in Table I. At the time of
entry into the study, subjects had uncontrolled IOP
despite using maximally tolerated medical treatment.
Furthermore, the majority of subjects had a history of one
or more glaucoma surgeries.
An initial decrease in IOP was observed in all subjects.
The therapeutic goal of the investigator was
achieved in four of nine subjects, and six of nine were considered
"improved" during at least one visit during their
treatment (Table II). Subject D.F. was improved at every
visit for a 9-month period. Subject C.C. was described as
"improved" during more than 50% of the follow-up visits
during his 5-month treatment. Both of these subjects
were improved at the time of termination from the study,
when each subject underwent cataract surgery. All of the
other subjects appeared to have lost the beneficial effects
of treatment on their IOP at the time of termination.
All subjects experienced toxic effects from oral THC
during their treatment. Intolerable side effects forced
four subjects to be terminated early from the study. These
side effects and the corresponding dose of THC are summarized
in Table III. No subject reported enjoying effects
of THC related to the central nervous system. Subjects
who did not tolerate THC were offered access to
marijuana, but all of them declined
DISCUSSION
The identification of brain, ocular, and peripheral
cannabinoid receptors in several different mammals, the
cloning of cannabinoid receptors, and the discovery of
anandamide, an endogenous cannabimimetic eicosanoid,
has greatly augmented the study of cannabinoid pharmacology
in recent years.9-13 Some of these pharmacologic
investigations have attempted to develop new drugs useful
for the treatment of the glaucomas.14-17 However, thus
far none of these efforts have included the use of cannabinoids
in glaucoma patients with advanced disease.
Therefore, it seemed timely to present this study, which
represents the largest series of end-stage glaucoma
patients treated with a cannabinoid derivative thus far
completed. The data collected during this study are presented
with the aim of providing direction and encouragement
for further investigational efforts within this area
of clinical and laboratory research.
Because this is a small, uncontrolled, unmasked, nonrandomized,
prospective study of short duration, it does
not permit definitive conclusions about the efficacy of
cannabinoids in the treatment of glaucoma. However,
there is an impression from the data collected during this
2-year investigation that treatment with oral THC lowered
IOP in some of this group of end-stage open-angle
glaucoma patients. Following the initiation of THC treatment,
all of the subjects demonstrated at least a transient
improvement in the reduction of IOP (Table II). An
improvement was noted during more than 50% of the
office visits in two of the nine enrolled subjects. In fact,
one of the subjects was considered improved on all of the
follow-up visits over a 36-week treatment period despite
the fact that he never met the goal of treatment which the
investigator considered ideal. The therapeutic goal of the
investigator was achieved in four of nine subjects.
Subjects N.C and C.C. each demonstrated an improved
IOP control while using 5 mg of THC four times daily
despite discontinuing coexistent carbonic anhydrase
inhibitors and parasympathomimetics or sympathomimetics.
Unfortunately, many of the subjects appeared to
develop a tolerance to THC because their IOPs increased
during the latter period of their treatment. Of course, as
with any uncontrolled study, the observed improvements
in IOP control may have been related to enhanced compliance
associated with a subject's participation in the
study or the added attention or encouragement given to
the subject during the treatment period. This appeared to
be the case with at least one subject (R.G.), in the opinion
of the investigator, as indicated in Table II.
All subjects experienced side effects during their
treatment with THC during this study (Table III). The
most commonly described toxic effects were dry mouth,
sleepiness, dizziness, depression, and confusion; these
effects were the same as those reported by other investigators.
18,19 Although many of the side effects were considered
mild and were of little concern to subjects, other
effects were very significant. For example, the reason for
termination from the study for four of the nine subjects
was intolerable side effects, such as distortion of perception,
confusion, anxiety, depression, and severe dizziness.
Changes in blood pressure have been reported with THC
treatment.20,21 Therefore, blood pressures were measured
and the symtoms of systemic hypotension were carefully
searched for at each visit. The dizziness and light-headedness
reported by subjects in this study were never associated
with systemic hypotension.
In most cases, the therapeutic benefit did not outweigh
the toxicity associated with treatment as percieved
by the subject. For example, one subject (N.C.) was
unhappy because he gained weight while enrolled in the
study. It was unclear whether his enhanced appetite was
related to discontinuing acetazolamide or the concurrent
use of THC. In any case, he was upset enough about this
apparent effect that he withdrew from the study despite
an improvement in IOP control and his ophthalmologist's
opinion that he had met the goal of treatment. His termination
from the study was considered to be due to intolerable
side effects of THC.
Although the literature is unclear about the development
of tolerance to the effects of cannabinoid administration,
there was some evidence for tolerance in this
study. There appeared to be a tendency for the beneficial
effects on IOP to outlast the side effects in some patients,
as demonstrated in Table III and as has been previously
reported.22 Unfortunately, there also appeared to be a tendency
for tolerance to the beneficial IOP effects to develop
in most of the subjects, as summarized in Table II.
A major limitation for applying the results of this
study to present-day glaucoma therapy is that this study
was completed in 1986, before many of the glaucoma
medications currently in use were available. More specifically,
prostaglandin derivatives, topically applied carbonic
anhydrase inhibitors, and relatively alpha2-specific
sympathomimetics were not commercially available during
the 1980s. It is possible that if THC were added to the
current therapeutic regimen of maximally tolerated therapy
during the treatment of end-stage glaucoma, it would
provide a less optimistic impression of its therapeutic usefulness.
Throughout the study, there was no observed tendency
for either the physicians or the patients to abuse their
access to cannabinoid derivatives. In fact, none of the subjects
appeared to enjoy the psychotropic effects of THC.
This is consistent with the observation made in previous
studies that the environment, expectations, and reason for
use of individuals during cannabinoid administration
influence the overall personal experience and psychologic
reaction to the effects of the cannabinoids following their
administration.
Finally, it was clear that both the patients and
ophthalmologists greatly appreciated the opportunity to
participate in this study. The program not only provided
patients with legal and compassionate access to cannabinoid
treatment as a last-resort treatment during the the
management of end-stage glaucoma unresponsive to conventional
treatments, but it provided an opportunity for
careful monitoring and extensive education of all of the
patients interested in this potential treatment. Therefore,
this opportunity greatly increased the safety for all of the
patients who participated as subjects and even the
patients who did not qualify for treatment because they
were misinformed about the lack of proven value for the
treatment or were ignorant of the potential dangers of taking
cannabinoids in an attempt to lower IOP.
CONCLUSIONS
This uncontrolled, unmasked, nonrandomized, prospective
study does not permit definitive conclusions about the
efficacy or toxicity of cannabinoids in the treatment of
glaucoma. There is an impression from this study that
treatment with oral THC lowered IOP in this group of
patients with end-stage open-angle glaucoma, but the
development of tolerance and the coexistence of significant
systemic toxicity limited the potential usefulness of
this treatment. It was particularly impressive to the investigators
that throughout the study there was no observed
tendency for either the physicians or the patients to abuse
their access to cannabinoid derivatives. Furthermore, both
the patients and ophthalmologists greatly appreciated the
opportunity to participate in a study that gave them legal
access to cannabinoids as a last-resort treatment for endstage
glaucoma unresponsive to conventional treatments.
REFERENCES
1. Turner CE, Elsohly MA, Boeren EG. Constituents of
Cannabis sativa : a review of the natural constituents. J Nat
Prod 1980;43:169-234.
2. Hepler RS, Frank IM. Marijuana smoking and intraocular
pressure. J Am Med Assoc 1971;217:1392.
3. Hepler RS, Frank IM, Ungerleider JT. Pupillary constriction
after marijuana smoking. Am J Ophthalmol
1972;74:1185-1190.
4. Drew WG, Miller LL. Cannabis: neural mechanisms and
behavior–a theoretical review. Pharmacology 1974;11:12-
32.
5. Benowitz NL, Rosenberg J, Rogers W, et al. Cardiovascular
effects of intravenous delta-9-tetrahydrocannabinol: autonomic
nervous mechanisms. Clin Pharmacol Ther
1979;25:440-446.
6. Hollister LE. Structure-activity relationships in man of
cannabis constituents and homologs and metabolites of
delta-9-tetrahydrocannabinol. Pharmacology 1974;11:3-11.
7. Lockhart AB, West ME, Lowe HIC. The potential use of
Cannabis sativa in ophthalmology. West Indies Med J
1977;26:66-70.
8. Flach AJ, Holsten DW, Icaza L, et al. Cannabis protocol for
glaucoma: oral THC and smoked marijuana for treating
open angle glaucoma patients. For Research Advisory Panel
of California, 1984.
9. Devane WA, Dysarz FA, Johnson MR. Determination and
characterization of a cannabinoid receptor in the rat brain.
Mol Pharmacol 1988;34:605-613.
10. Munro S, Thomas KL, Abu Shaar M. Molecular characterization
of a peripheral receptor for cannabinoids. Nature
1993;365:61-65.
11. Straiker AJ, Maguire G, Mackie K, et al. Localization of
cannabinoid Cb1 receptors in the human anterior eye and
retina. Invest Ophthalmol Vis Sci 1999:40;2442-2448.
12. Matsuda LA, Lolait SJ, Brownstein MJ, et al. Structure of a
cannabinoid receptor and functional expression of the
cloned DNA. Nature 1990;346:561-564.
13. Devane WA, Hanus L, Brever A, et al. Isolation and structure
of a brain constituent that binds to the cannabinoid
receptor. Science 1992;258:1946-1949.
14. Laine K, Jarvinen K, Pate DW, et al. Effect of the enzyme
inhibitor, phenylmethylsulfonyl fluoride, on the IOP profiles
of topical anandamides. Invest Ophthalmol Vis Sci
2002;43:393-397.
15. Buchwald A, Browne CE, Wu WM, et al. Soft cannabinoid
analogues as potential anti-glaucoma agents. Pharmazie
2000;55:196-201.
16. Pate DW, Jarvinen K, Urtti A, et al. Ophthalmic arachidonylethanolamide
decreases intraocular pressure in normotensive
rabbits. Curr Eye Res 1995;14:179-797.
17. Beilin M, Neumann R, Belkin M, et al. Pharmacology of
the intraocular pressure lowering effect of systemic dexanabinol
(HU-211), a non-psychotropic cannabinoid. J Ocular
Pharm Ther 2000;16:217-230.
18. Hollister LE, Gillespie HK. Delta-8- and delta-9-tetrahydrocannabinol.
Clin Pharmacol Ther 1972;14:353-357.
19. Valk LEM. Hemp in connection with ophthalmology.
Ophthalmologica 1973;167:413-421.
20. Merritt JC, Crawkford WJ, Alexander PC, et al. Effect of
marihuana on intraocular and blood pressure in glaucoma.
Ophthalmology 1980;87:222-228.
21. Crawford WJ, Merritt JC. Effect of tetrahydrocannabinol
on arterial and intraocular hypertension. Int J Clin Pharm
Biopharm 1979;17:191-196.
22. Purnell WD, Gregg JM. Delta-9-tetrahydrocannabinol,
euphoria and intraocular pressure in man. Ann Ophthalmol
1975;7:921-922.
DISCUSSION
DR DOUGLAS R. ANDERSON. Thanks to Dr Flach for this
lucid and straightforward report. To summarize the main
conclusions, the author expressed surprise that fewer subjects
enrolled than had been expected, despite wellknown
and continued public interest in use of cannabinoids for medical purposes, including glaucoma.
Perhaps a good part of the public fascination is in possible
use this drug in ordinary cases of glaucoma as an alternative
to already available therapy. The types of cases
recruited for this study were severe cases not adequately
controlled with any other treatment options, and in these
cases THC was inadequately effective or impractical
because of side effects.
It is, however, known that THC will lower the IOP,
and that there are receptors in both the trabecular meshwork
and the ciliary body. A few decades ago, I had a
young patient who knew I could not prescribe marijuana
for him. Having recently opened a business, he had some
projects to get under control before he could proceed
with the surgery I had recommended, and he asked me to
monitor his IOP frequently while waiting. The readings
were variable, and he revealed that on some days, at various
intervals before the measurements, he had smoked
marijuana. He had kept a diary of times and pressures,
and also noted the quality of the particular marijuana he
had smoked on each occasion, judged from the mental
effects he enjoyed. From this he worked out a nice doseresponse
curve and the duration of the effect on IOP. I no
longer remember the details, except that the effect was
not long-lived and did not persist beyond the time he felt
"high." The net result was that he could not focus on his
work and simultaneously keep his IOP at the desired pressure
level. Therefore he did undergo surgery, which
worked well for him for the next several years during
which he remained under my care.
At least for some patients, then, the side effects and
short duration of action may simply outweigh the advantages
compared to standard therapeutic options available.
When patients ask about marijuana, that is exactly how I
explain the situation–that THC may work to lower the
IOP, but perhaps not more effectively than other available
drugs, which have been better tested scientifically, have
longer duration of action, and also have fewer side effects.
Do cannabinoids have a place at all? Dr Paul
Palmberg has one patient under his care with glaucoma
from childhood who has had all known medications, some
not tolerated, and others not fully effective. The patient
has had several operations, the most recent with the complication
of a postoperative suprachoroidal hemorrhage,
so further surgery has been avoided. The IOP can be
brought from 50 mm Hg to 25 mm Hg with either timolol
or marijuana, but in combination to 15 mm Hg. The
patient has used marijuana in this manner for a couple of
decades now. Newer alpha-adrenergic agents and
prostaglandin analogues have not been satisfactory substitutes.
Because of the short duration of action, this treatment
requires 10 NIDA-provided marijuana cigarettes
per day and is thus not so convenient, but for this patient
it is the best alternative.
Based on the experience of this patient and of others
reported to him, Dr Palmberg believes marijuana can be
very effective when the IOP is quite high, but seems minimally
effective in patients with modestly elevated or normal
IOP. He also commented that with continual use, the
lowering of blood pressure and the mental effects disappear,
but the favorable effects on IOP persist, so some of
the problems noted in acute or short-term studies may
have underestimated the potential for this class of drugs.
Dr Palmberg participated in a NIDA-workshop cosponsored
by NIH (Feb 1997) at which various potential
medicinal uses of marijuana were discussed. Dr Paul
Kaufman reviewed the then available studies with respect
to glaucoma for the workshop, and most information dealt
with acute or short-term experiments. The report of this
workshop may provide those interested with a compendium
of background information suggesting a potential not
yet proved or developed.
Presumably, physicians can legally prescribe dronabinol
(Marinol) for glaucoma as an off-label use, although
prior clearance from appropriate authorities might be
wise. Within the past week a well-known entertainer was
arrested at an airport checkpoint for possession of marijuana,
which, it was claimed, was being used to treat glaucoma.
There may thus be some unanalyzed experience
with cannabinoids, although even if collected, scattered
anecdotal information will not substitute for further properly
designed studies of long-term clinical use such as the
one conducted by Dr Flach. Continued interest in the
class of compounds may be warranted if longer-acting
forms can be developed, and if the undesirable effects are
documented to disappear after several days so that
patients can work effectively and drive safely. Of particular
pharmacologic interest is that cannabinoids lower IOP
through mechanisms independent of those of drugs currently
on the market. The implication is that cannabinoids
may work when other classes of drugs don't, and
that it could be additive to other drugs.
DR GEORGE L. SPAETH. I obtained tetrahydrocannabinol
in 1970 and manipulated it into a form that could be used
as eye drops. Masking was attempted, using one eye as
control, but the eyes on the tetrahydrocannabinol turned
beet red. There was no effect on IOP when we compared
the treated and untreated eyes. How does this drug work
to lower pressure? Is it possible to develop some type of
topical product that might limit the problem of the systemic
side effects?
DR LOUIS B.CANTOR. Is there any understanding of the
pharmacology, and do receptors for the cannabinoids
exist? Since this drug appears to lower IOP, do we know
anything about the mechanism? Is the mechanism similar
to that of our other fatty acid lipid compounds that
improve pressure-sensitive or pressure-insensitive outflow
pathways?
DR ALLAN J. FLACH. Dr Anderson mentioned the fascination
that has existed concerning this group of drugs. This
interest has been present for over 3,000 years, as recorded
by one of the first clinical pharmacologists, Emperor
Shen-Nung in 2737 BC. During the late 1800s, the Indian
Hemp Commission Report described cannabis as the
most important drug in the Indian Materia Medica.
During the 20th century, tincture of cannabis was included
in the 1937 United States Pharmacopoeia and, in later
years, in the United States National Formulary. The
preparation was considered useful as an anti-inflammatory
and analgesic agent for the relief of migraine headaches
and prevention of seizures. In addition, it was used to
treat psychiatric illness, including depression.1 In subsequent
years, it was replaced with therapies that were considered
less toxic and more specific in their activity.
As Dr Anderson mentioned, we might have seen
greater effects on IOP following cannabinoid treatment if
we included patients with a condition other than endstage
glaucoma. I believe this is probably true. However,
if one properly informs glaucoma patients about the
proven benefits of conventional glaucoma therapy and
contrasts this with the unproven potential benefits following
marijuana derivatives, one cannot avoid endorsing the
commercial agents much more enthusiastically. This is
particularly true since all of the available cannabinoid
derivatives have significant psychotropic effects. While
these effects follow dose-response relationships that
include drowsiness or feeling comfortably high, which can
progress to depersonalization or even a panic reaction,
external stimuli can abruptly shift the apparent doseresponse
curve so that the patient, while experiencing a
happy high, can rapidly progress into a panic reaction
without additional cannabinoid treatment. This is called
endogenic potentiation.2
I agree with Dr Anderson that there is good evidence
that the cannabinoids are capable of lowering IOP. This
was initially described by Dr Robert Hepler during the
1970s.3 I have included information about US government's
grown marijuana that was available for patients in
this study within the text of this paper. None of the
enrolled subjects wanted to use inhaled marijuana
because they did not like the idea of smoking with the
associated pulmonary irritation and potential risk of lung
cancer.
It is interesting to me that Dr Spaeth observed
excessive toxicity and a lack of therapeutic effect in his
attempts to use a topical form of marijuana in glaucoma
patients. I suspect Dr Spaeth's efforts were based in part
on the initial reports by Dr John Merritt, who described
topically applied marijuana in experimental animals.
However, Dr Merritt was unable to duplicate these potentially
beneficial effects on the IOP of humans.4 Therefore,
Dr Spaeth's observations are not too surprising. For the
past 25 years, I have had the privilege of providing a 4-day
ocular pharmacology and toxicology course at Stanford
University during the summer months as part of a Basic
Science Course for ophthalmologists. Each year, I have
included a section on the cannabinoids and their potential
use within ophthalmology. One of the graduates of this
course who practices in Jamaica sent me a package insert
for a commercially available Cannabis sativa solution
marketed under the name of Canasol. This topically
applied liquid is described as capable of lowering IOP as
effectively as timolol without the side effects. However,
there are no published studies that verify this ability.
I am certain that we are all as interested as Dr Cantor
in the pharmacodynamics of cannabinoids. Dr Keith
Green deserves a lot of credit for the time he has devoted
to this study. His research describes many different
potential mechanisms by which the cannabinoids can
lower IOP.5 However, I think that we need Dr Richard
Brubaker, or someone with his experience studying
human aqueous inflow and outflow, to conscientiously
work out these effects. In conclusion, as I mentioned
within the introduction to this paper, cannabinoid receptors
have been identified within the human eye, but it
remains to be elucidated how these receptors might be
beneficially manipulated by exogenously applied or
endogenously liberated cannabinoids or other lipid compounds
and the mechanism underlying these activities.
1. Pars HG. The other side of marijuana research.
J Anesthesiol 1973;38:519-520.
2. Valk LEM. Hemp in connection with ophthalmology.
Opthalmologica 1973;167:413-421.
3. Hepler RS, Petrus RH. Experiences with administration of
marihuana to glaucoma patients. In Cohen S, Stillman RC,
eds. The Therapeutic Potential of Marihuana, New York:
Plenum 1976:63.
4. Merritt JC, Perry KDD, Russell DN, et al. Topical delta 9-
tetrahydrocannabinol and aqueous dynamics in glaucoma.
J Clin Pharmacol 1981;21:467S-471S.
5. Green K. Marijuana and the eye: a review. J Toxicol. Cutan
Ocul Toxicol 1982;1:3-32.
Source: Delta-9-Tetrahydrocannabinol (THC) In The Treatment Of Endstage Open-Angle Glaucoma
