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Editorial

Treating Glaucoma with Medical Marijuana: Peering through the Smoke

Rathin Pujari, BA (Cantab) - Cambridge, United Kingdom
Henry D. Jampel, MD, MHS - Baltimore, Maryland

For several decades, we have known that marijuana con- SR141716, which is a CB1 antagonist.10 Therefore, when
sumption lowers intraocular pressure (IOP) in humans.1,2 In one is discussing the use of marijuana for the treatment of
2010, the American Glaucoma Society published its posi- glaucoma, one must consider the differences between the
tion paper on marijuana,3 followed by a similar position plant and any of its purified components.
paper from the Canadian Glaucoma Society.4 At that time,
we stated that a lack of evidence precluded the use of The Potency of Marijuana Derivatives Has
marijuana for the treatment of glaucoma. Recent Greatly Increased Since the Time of the
legalization of marijuana for medical use in 30 states and Often-Referenced Studies
the District of Columbia has fuelled a surge of interest in
its use for many medical conditions, including Crohn’s As noted by Lieberman6 and Novack,7 the concentration of
disease, cancer, epilepsy, depression, and multiple tetrahydrocannabinol used in published clinical studies was
sclerosis,5 as well as glaucoma. Furthermore, the much lower than the concentration available in marijuana
availability of recreational marijuana in several states and products sold at today’s dispensaries. For instance,
throughout Canada provides an additional option for the participants in the study by Hepler and Frank1
patients to augment or replace their current treatment with inhaled marijuana with a concentration of 0.9%
marijuana. Herein, we provide an update on what has tetrahydrocannabinol, and Merritt et al reported a
happened in the world of medicinal marijuana over the past concentration of 2.0%.2 In contrast, at our local dispensary
decade. The interested reader will surely want to digest the in Baltimore, a marijuana cigarette with a concentration of
informative and amusing tetrahydrocannabinol as high as
editorial entitled “‘Recredicinal’ The adoption of laws permitting 33% can be purchased. Clearly,
Marijuana” by Lieberman6 and medicinal and recreational use of the effect of this higher
the scholarly review of concentration on IOP and blood
cannabinoids for the treatment of marijuana does not alter the fact that pressure (and who knows what
glaucoma by Novack.7 rigorous evidence supporting its use in else) could be greatly different
medicine in general is limited and for the than the lower concentrations
Recognition of the previously evaluated.
treatment of glaucoma is nonexistent.
Differences between
Cannabidiol and Tetrahydrocannabinol General Medical Use
Although there are hundreds of components in smoked The most widespread use of medicinal marijuana has been
marijuana, the 2 major active components are cannabidiol for chronic pain, which includes both neuropathic pain and
and tetrahydrocannabinol. Tetrahydrocannabinol is the pain resulting from cancer.5 One meta-analysis of 28 studies
psychoactive component of cannabis. It produces a euphoric for treatment of chronic pain using marijuana suggested
high that has the potential to lead to addiction. Although improvements in pain measures.5 However, the meta-
cannabidiol does not have the same psychoactive qualities analysis noted that statistical significance was not reached
of tetrahydrocannabinol, it is still pharmacologically active in all of these studies and that most studies were prone to
in the brain as it is used in inherited epilepsy syndromes and bias. However, a more recent meta-analysis of cannabis-
can modulate tetrahydrocannabinol effects. However, with based medicines for chronic neuropathic pain likewise
regard to glaucoma treatment, cannabidiol, unlike tetrahy- showed only small beneficial effects.11 When a 30%
drocannabinol, shows no demonstrable IOP-lowering ef- reduction in pain was taken as the end point in that meta-
fects. In fact, one older study using sublingual analysis, 39% of patients treated with cannabis versus
administration in humans8 and a recent study in mice9 30% in the control arm reached the measured end point (risk
suggest that cannabidiol can raise IOP. This latter study difference, 0.09; 95% confidence interval, 0.03e0.15);
showed that cannabidiol may act as an antagonist at the number needed to treat for additional beneficial outcome
CB1 receptor, thereby increasing IOP.9 When was 11 (95% confidence interval, 7e33). Even the author of
coadministered alongside tetrahydrocannabinol, it may the meta-analysis concluded that the potential benefits may
negate the IOP-lowering effects of tetrahydrocannabinol, be outweighed by potential harms. One difficulty in
which also acts at the CB1 receptor. This effect has been assessing the effect of marijuana is that the formulation
noted when the IOP-lowering effects of the synthetic CB1 (herbal vs. synthetic), method of delivery (e.g., inhalation
agonist WIN55212-2 are attenuated by the addition of vs. oral), and concentration varied from study to study.

Ó 2019 by the American Academy of Ophthalmology https://doi.org/10.1016/j.ogla.2019.02.007 201

Published by Elsevier Inc. ISSN 2589-4196/19
 Ophthalmology Glaucoma Volume 2, Number 4, July/August 2019
Marijuana also has been used to treat spasticity resulting
from multiple sclerosis; this was the first approved use
of cannabinoids in the United Kingdom in 2011. A
meta-analysis of 11 studies concluded that there was mod-
erate evidence to support the use of cannabinoids for this
indication.5
Specific childhood epilepsy syndromes such as Lennox-
Gastaut syndrome and Dravet syndrome have been identi-
fied as diseases for which cannabidiol can be useful.
Double-masked trials in both syndromes have shown a
significant decrease in the median frequency of seizures per
month.12,13 In June 2018, the Food and Drug Administration
granted its first approval of a marijuana-derived drug,
Epidiolex (cannabidiol; GW Pharmaceuticals, Cambridge,
UK) for the treatment of these 2 rare forms of epilepsy.
Ophthalmic Use
Glaucoma. There have not been any new clinical discov-
eries regarding the use of cannabis in glaucoma since the
position statement of 2010. Novack7 searched the literature
in April 2015 for the terms marijuana or cannabinoids and
glaucoma or IOP and found no clinical articles since 2006.
We found nothing since then, either.
Other Ocular Disease
There have been no cannabinoids approved for treatment of
any ocular disease. However, recent research into effects of
cannabinoids in the eye has revealed neuroprotective and
anti-inflammatory properties that may lead to the use of
cannabinoids. Cannabinoids have established neuro-
protective effects on neurons and studies have shown that
this benefit extends to retinal ganglion cells.14 The most
commonly proposed neuroprotective mechanism is that
cannabinoids block the glutamate-mediated excitotoxicity
of neurons via CB1 receptors.15,16 Other studies have shown
that cannabinoids have protective effects on ganglion cells
exposed to elevated IOP.17e19 Topical administration of
WIN55212-2 (a synthetic analog of tetrahydrocannabinol)
was neuroprotective in a model of high IOP-induced
ischemia reperfusion injury.17 Similarly, P23H rats (a
model for retinitis pigmentosa) were used to test the effect
of the synthetic cannabinoid HU210. Results showed that
the P23H rats administered HU210 showed better
preservation of retinal structure and function compared
with the control group.20 These results indicate that long-
term use of cannabinoids in the eye may have beneficial
effects on the retina and optic nerve that could be used for
treatment.
The Promise of Cannabinoids for the Treatment
of Glaucoma
The use of tetrahydrocannabinol so far has been hampered
by its short half-life, psychoactive properties, and tolerance
to its effects.7 However, in both cannabidiol and
tetrahydrocannabinol we have potentially important drugs
for the treatment of glaucoma because of their
neuroprotective effects, which may negate the selective
apoptosis of retinal ganglion cells in glaucoma.21 The
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neuroprotective effects seen on tetrahydrocannabinol
administration are shown to be mediated primarily by the
activation of CB1 receptors, which results in the
reduction of glutamate-mediated excitotoxicity.15,16,22
Similar neuroprotective effects are seen against ischemia
caused by high IOP.18,19 Despite the relative paucity of
high-level evidence, cannabidiol without any psychotropic
effects may help prevent degeneration of the optic nerve
not related to IOP when used in conjunction with IOP-
lowering therapies. In contrast, tetrahydrocannabinol de-
rivatives, despite their psychoactive component, could be
used as a double attack on glaucoma by both reducing IOP
and exerting a neuroprotective effect on retinal ganglion
cells. However, much research into the mechanism of ac-
tion of these agents and confirmation of their usefulness
through clinical trials remains to be conducted before we
can consider them for use alongside present conventional
therapies.
In conclusion, the adoption of laws permitting medicinal
and recreational use of marijuana does not alter the fact that
rigorous evidence supporting its use in medicine in general
is limited and for the treatment of glaucoma is nonexistent.
A beautiful graphic depicting the amount of interest in
marijuana for treating medical conditions along with the
strength of the evidence is available at https://informatio-
nisbeautiful.net/visualizations/snake-oil-cannabis-the-scien-
tific-evidence-for-medical-marijuana/. In its current forms,
its short duration of action and side effects make it a poor
candidate for glaucoma therapy. A topical formulation
would be desirable that could overcome the lipophilicity of
its components without irritating the ocular surface.
Although cannabidiol generally is considered the safe
component of marijuana, such that products containing it are
available in food stores, studies in mice suggest that it in fact
may raise IOP, and therefore be unsafe for glaucoma pa-
tients. Although many authors of scientific articles close
with the trite observation that “further research is needed,”
that statement is particularly true for marijuana and
glaucoma.
References
1. Hepler RS, Frank IR. Marihuana smoking and intraocular
pressure. JAMA. 1971;217(10):1392.
2. Merritt JC, Crawford WJ, Alexander PC, et al. Effect of
marihuana on intraocular and blood pressure in glaucoma.
Ophthalmology. 1980;87:222e228.
3. Jampel H. American Glaucoma Society Position Statement:
marijuana and the treatment of glaucoma. J Glaucoma.
2010;19(2):75e76.
4. Buys YM, Rafuse PE. Canadian Ophthalmological Society
policy statement on the medical use of marijuana for glau-
coma. Can J Ophthalmol. 2010;45(4):324e326.
5. Whiting PF, Wolff RF, Deshpande S, et al. Cannabinoids for
medical use. JAMA. 2015;313(24):2456.
6. Lieberman MF. “Recredicinal” marijuana. Am J Ophthalmol.
2017;177:xvexviii.
7. Novack GD. Cannabinoids for treatment of glaucoma. Curr
Opin Ophthalmol. 2016;27(2):146e150.
8. Tomida I, Azuara-Blanco A, House H, et al. Effect of sub-
lingual application of cannabinoids on intraocular pressure: a
pilot study. J Glaucoma. 2006;15(5):349e353.
 Editorial
9. Miller S, Daily L, Leishman E, et al. D9-Tetrahydrocannabinol
and cannabidiol differentially regulate intraocular pressure.
Invest Ophthalmol Vis Sci. 2018;59(15):5904e5911.
10. Oltmanns MH, Samudre SS, Castillo IG, et al. Topical
WIN55212-2 alleviates intraocular hypertension in rats
through a CB1 receptor mediated mechanism of action. J Ocul
Pharmacol Ther. 2008;24(1):104e115.
11. Mücke M, Phillips T, Radbruch L, et al. Cannabis-based
medicines for chronic neuropathic pain in adults. Cochrane
Database Syst Rev. 2018;3:1465e1858.
12. Devinsky O, Cross JH, Laux L, et al. Trial of cannabidiol for
drug-resistant seizures in the Dravet syndrome. N Engl J Med.
2017;376(21):2011e2020.
13. Devinsky O, Patel AD, Cross JH, et al. Effect of cannabidiol
on drop seizures in the LennoxeGastaut syndrome. N Engl J
Med. 2018;378(20):1888e1897.
14. Yazulla S. Endocannabinoids in the retina: from marijuana to
neuroprotection. Prog Retin Eye Res. 2008;27(5):501e526.
15. Opere CA, Zheng WD, Zhao M, et al. Inhibition of potassium-
and ischemia-evoked [3H] D-aspartate release from isolated
bovine retina by cannabinoids. Curr Eye Res. 2006;31(7e8):
645e653.
16. El-Remessy AB, Khalil IE, Matragoon S, et al. Neuroprotective
effect of (-)Delta9-tetrahydrocannabinol and cannabidiol in
Footnotes and Financial Disclosures
Financial Disclosure(s): The author(s) have no proprietary or commercial
interest in any materials discussed in this article.
N-methyl-D-aspartate-induced retinal neurotoxicity: involve-
ment of peroxynitrite. Am J Pathol. 2003;163(5):1997e2008.
17. Pinar-Sueiro S, Zorrilla Hurtado JÁ, Veiga-Crespo P, et al.
Neuroprotective effects of topical CB1 agonist WIN 55212-
2 on retinal ganglion cells after acute rise in intraocular
pressure induced ischemia in rat. Exp Eye Res. 2013;110:
55e58.
18. Nucci C, Gasperi V, Tartaglione R, et al. Involvement of the
endocannabinoid system in retinal damage after high intraoc-
ular pressureeinduced ischemia in rats. Invest Ophthalmol Vis
Sci. 2007;48(7):2997.
19. Crandall J, Matragoon S, Khalifa YM, et al. Neuroprotective
and intraocular pressure-lowering effects of (-)Delta9-tetrahy-
drocannabinol in a rat model of glaucoma. Ophthalmic Res.
2007;39(2):69e75.
20. Lax P, Esquiva G, Altavilla C, Cuenca N. Neuroprotective
effects of the cannabinoid agonist HU210 on retinal degener-
ation. Exp Eye Res. 2014;120:175e185.
21. Quigley HA. Neuronal death in glaucoma. Prog Retin Eye Res.
1999;18:39e57.
22. Hampson AJ, Grimaldi M, Axelrod J, Wink D. Cannabidiol
and (-)Delta9-tetrahydrocannabinol are neuroprotective
antioxidants. Proc Natl Acad Sci U S A. 1998;95(14):
8268e8273.
Correspondence:
Henry Jampel, MD, MHS, Johns Hopkins Woods 155B, 1800 Orleans
Street, Baltimore, MD 21287-9205. E-mail: hjampel@jhmi.edu.
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