s u r v e y o f o p h t h a l m o l o g y 6 6 ( 2 0 2 1 ) 3 2 7 e3 4 5

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Review

Cannabinoids and the eye

Michael T.M. Wang, MBChB,

Helen V. Danesh-Meyer, MBChB, MD, PhD, FRANZCO*
Department of Ophthalmology, New Zealand National Eye Centre, University of Auckland, Auckland, New
Zealand

article info abstract

Article history: Cannabis ranks among the most commonly used psychotropic drugs worldwide. In the
Received 18 February 2020 context of the global movement toward more widespread legalisation, there is a
Received in revised form 23 July 2020 growing need toward developing a better understanding of the physiological and
Available online 4 August 2020 pathological effects. We provide an overview of the current evidence on the effects of
cannabinoids on the eye. Of the identified cannabinoids, D9-tetrahydrocannabinol is
Keywords: recognized to be the primary psychotropic compound, and cannabidiol is the
cannabis predominant nonpsychoactive ingredient. Despite demonstrating ocular hypotensive
cornea and neuroprotective activity, the use of cannabinoids as a treatment for glaucoma is
eyelid limited by a large number of potential systemic and ophthalmic side effects. Anterior
glaucoma segment effects of cannabinoids are complex, with preliminary evidence showing
intraocular pressure decreased corneal endothelial density in chronic cannabinoid users. Experiments in
marijuana rodents, however, have shown potential promise for the treatment of ocular surface
optic nerve injury via antinociceptive and antiinflammatory effects. Electroretinography studies
retina demonstrating adverse effects on photoreceptor, bipolar, and ganglion cell function
suggest links between cannabis and neuroretinal dysfunction. Neuro-ophthalmic
associations include ocular motility deficits and decrements in smooth pursuit and
saccadic eye movements, although potential therapeutic effects for congenital and
acquired nystagmus have been observed.
ª 2020 Elsevier Inc. All rights reserved.

1. Introduction In addition to recreational use, cannabis is also one of the

Cannabis or marijuana is consumed by more than 180 million
people worldwide and ranks among the most commonly used
psychotropic drugs.38 In recent years, there has been a sub-
stantial increase in the global consumption of cannabis,
driven in part by decriminalization and legalization in a
number of jurisdictions.8,34,38,148
oldest drugs used for medical and therapeutic purposes.6,8,43
The medical use of cannabis has spanned over the past five
millennia in ancient civilisations throughout China, India,
Greece, Assyria, Egypt, and the Roman Empire.8,43 The
introduction of cannabis and its derivatives to Western
medicine occurred during the 19th century on account of its
analgesic, antiemetic, anti-inflammatory, and anticonvulsant

* Corresponding author: Professor Helen V. Danesh-Meyer, MBChB, MD, PhD, FRANZCO, Department of Ophthalmology, New Zealand
National Eye Centre, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
E-mail address: helendm@gmail.com (H.V. Danesh-Meyer).
0039-6257/$ e see front matter ª 2020 Elsevier Inc. All rights reserved.
https://doi.org/10.1016/j.survophthal.2020.07.002
328 s u r v e y o f o p h t h a l m o l o g y 6 6 ( 2 0 2 1 ) 3 2 7 e3 4 5
properties6,8,43; however, concerns surrounding its significant
psychotropic effects led to the widespread prohibition of
cannabis use in the 1920s and 1930s.6,8 Nevertheless, in the
past two decades, there has been a resurgence in interest in
the potential therapeutic efficacy of cannabis for a wide range
of medical conditions, including chronic pain, Crohn disease,
posttraumatic stress disorder, Parkinson disease, multiple
sclerosis, and spinal cord injuries.6,8,34,148
There has been a growing body of literature
investigating the ophthalmic impacts of cannabinoids
since potential intraocular pressure lowering effects were
first reported in the 1970s.53,68,91,103,144 In addition, several
studies have also explored the effects of cannabis on the
retina, cornea, and ocular motility.64,107,110,112,127 In the
context of the global movement toward more widespread
legalization of cannabis for medical or recreational
purposes,8,34,38,145,148 there is a growing need to develop a
better understanding of its ophthalmic impacts. We
therefore provide an overview of the current evidence on
the effects of cannabis on the structures and disorders of
the eye.
2. Pharmacology of cannabinoids
The Cannabis sativa plant contains around 540 natural
compounds, of which more than 100 are classified as
cannabinoids on account of shared chemical structure.8,145
Cannabinoids consist of a lipid backbone with the
incorporation of alkylresorcinol and monoterpene groups.55
Despite the large number of cannabinoids that have been
identified, D9-tetrahydrocannabinol (D9-THC) and
cannabidiol (CBD) have been the most extensively studied
ones,8,145 and their chemical structures are illustrated in
Fig. 1. D9-THC is recognized to be the primary psychotropic
compound of cannabis, while CBD is the predominant
nonpsychoactive ingredient.8,145
D9-THC is thought to exert the majority of its effects
through partial agonist activity at the cannabinoid receptors,
including CB1, CB2, and GPR18.8,69,145 CB1 receptors are pri-
marily located in the central nervous system and are partic-
ularly abundant in the substantia nigra, globus pallidus,
hippocampus, cerebral cortex, putamen, caudate, cerebellum,
and amygdala.8,14,61,82 In addition, CB1 receptors are also
distributed in a number of peripheral tissues, including the
lungs, heart, and urogenital and gastrointestinal
tracts.8,61,82,145 In contrast, CB2 receptors are predominantly
expressed in the peripheral nervous system and tissues of the
immune system, including the tonsils and spleen.8,61,82,145
Fig. 1 e Chemical structures of (A) D9-tetrahydrocannabinol
and (B) cannabidiol.
GPR18 receptors have been reported to be present in the hy-
pothalamus, brainstem, cerebellum, and striatum of the
brain, as well as the lungs, thyroid, thymus, spleen, testes,
ovary, and peripheral blood leukocytes.44,69 In the eye, CB1
receptors have been identified in the corneal epithelium and
endothelium, iris, ciliary body, trabecular meshwork,
Schlemm canal, choroid, as well as the ganglion cell layer,
inner plexiform layer, inner nuclear layer, outer plexiform
layer, and outer segments of photoreceptor cells of the
retina26,79,113,114,133; CB2 receptors are expressed in the corneal
and retinal pigment epithelium.99,147 Murine models have
shown that GPR18 receptors are present in the corneal and
ciliary epithelium and the trabecular meshwork.20 CB1 re-
ceptors modulate the release of neurotransmitters, while CB2
receptors are involved in regulating cytokine signaling.8,145
Both CB1 and CB2 receptors are coupled via Gi/o proteins and
are negatively linked to adenylate cyclase and positively
linked to mitogen-activated protein kinase.8,67 On the other
hand, CBD demonstrates poor binding affinity for CB1 and CB2
receptors, although it is capable of acting as an antagonist to
both cannabinoid receptors in the presence of D9-THC.77,140
CBD has also been reported to exert antagonistic action to
GPR55 receptors, which is thought to be one of the
mechanisms underlying its anticonvulsant properties.96 In
addition, CBD has been shown to be an agonist of the
serotonin 1A (5-HT1A) receptor, an allosteric modulator of the
m- and d-opioid receptors, and may also activate the
adenosine A1A receptor, gamma-aminobutyric acid type A
receptor, and nuclear peroxisome proliferator-activated
receptor g.95,140,145
Cannabinoids exert a diverse range of systemic effects on a
number of organ systems in the human body, although the
acute physiological effects generally subside within 2 to
6 hours after consumption.51,106 The psychotropic effects of
cannabinoids are variable and can alternate between
euphoria, sedation, anxiety, and dysphoria and result in
increased sensory perception, creativity, hallucinations,
alteration of time perception, and aggravation of psychotic
states.51,76,82 Acute cannabis intoxication can adversely
impact psychomotor and cognitive performance and cause
fragmented thinking, unsteady gait, ataxia, dysarthria,
weakness, and impaired motor co-ordination.51,76 A number
of physiological effects are mediated by the central nervous
system, including analgesia, muscle relaxation, appetite
enhancement, and antiemetic action, as well as reduction of
core body temperature.8,34,51,76,145,148 Cardiorespiratory effects
of cannabinoid consumption include bronchodilation, tachy-
cardia, vasodilation, and orthostatic hypotension.12,51,59,76,82
Other physiological effects associated with long-term
cannabis use include impaired cell-mediated and humoral
immunity, inhibition of platelet aggregation, altered pituitary
hormone secretion, reduced sperm count, and disturbances of
the menstrual cycle.16,51,62,76 Fetal exposure to cannabinoids
may result in malformations and growth retardation, as well
as impairment in cerebral development and cognitive
function.47,51
The pharmacokinetic profile of cannabinoids differs with
the route of administration, as summarized in Table 1.65,104
The bioavailability of cannabinoids can also vary with indi-
vidual factors, including weight, age, gender, health, and
 s u r v e y o f o p h t h a l m o l o g y 6 6 ( 2 0 2 1 ) 3 2 7 e3 4 5
Table 1 e Summary of pharmacokinetic profile of different routes of cannabinoid administration5,104
Route Peak concentration
Intravenous 0 minutes
Inhalation Within 20 minutes
Oral 60 to 120 minutes
Sublingual 30 minutes
Rectal 15 minutes
Transdermal 120 minutes
Eye drops No clinical data available; peak intraocular pressure
lowering effect at 30 minutes in rabbit models
physiological background.7,8,65,145 Inhaled cannabinoids are
absorbed rapidly into the bloodstream within 20 minutes and
exhibit similar pharmacokinetic properties to intravenous
administration.7,65 In contrast, orally administered cannabi-
noids undergo first-pass metabolism in the liver before
reaching the systemic circulation, and peak blood concen-
trations are delayed by 1e2 hours and occur at lower levels
than by inhalation.7,8,65,145 Transdermal and topical
ophthalmic administration has been studied to a lesser
extent, although permeability across the skin and cornea is
thought to be limited by the hydrophobic nature of
cannabinoids.8,49,72,82,143,145
The highly lipophilic properties of cannabinoids result in a
change in distribution pattern over time from the bloodstream
to adipose tissues.51,76 Cannabinoids are rapidly distributed
into well-vascularized organs, including the heart, lungs,
liver, spleen, small intestines, mammary gland, placenta,
adrenal cortex, thyroid, and pituitary glands within minutes
of reaching the peak plasma concentration.8,19,89 Cannabi-
noids readily cross the blood-brain barrier, and peak brain D9-
THC concentration occurs within 15 minutes after inhalation
or intravenous administration, which coincides with the
onset of maximal physiological and psychological effects that
plateau for 2 to 4 hours, before declining to low levels after
6 hours.51,60,76 Cannabinoids can also pass into breast milk
and rapidly cross the placenta, with fetal concentrations being
reported to be a third of maternal plasma concentrations after
inhalation and intravenous administration.2,51,76,88 Accumu-
lation of cannabinoids in adipose tissues occurs more gradu-
ally, with pseudoequilibrium occurring approximately 6 hours
after intravenous administration.25,51 There is a slow rediffu-
sion of cannabinoids between adipose tissues and the blood-
stream, with the consequent sequestration resulting in a
prolonged elimination half-life of more than 20 hours, and it
can take several days to weeks for cannabinoids to fully clear
from adipose tissues.8,51,65,66,100,106
The excretion of cannabinoids, in the form of metabolites,
occurs over the course of days to weeks after initial con-
sumption.51,76 D9-THC is metabolized by the cytochrome P450
complex in the liver and converted into a number of metab-
olites, including the psychoactive 11-OH-THC and the non-
psychoactive 11-COOH-THC.8,65 Most D9-THC are excreted via
the gastrointestinal tract as 11-OH-THC, although
329
Bioavailability Compounding factors
100% Nil.
2 to 56% Depth of inhalation, frequency of puffs,
breath hold.
10 to 20% Gastric degradation, high hepatic first-pass
metabolism.
10 to 20% High hepatic first-pass metabolism.
20 to 40% Low hepatic first-pass metabolism.
10% Delayed transcutaneous transport due to
lipophilic nature of cannabinoids.
No clinical data Low corneal permeability of nonmodified
available lipophilic cannabinoids.
approximately 20% is excreted in urine as 11-COOH-THC.130
CBD is also hepatically metabolized by the cytochrome P450
complex, with the primary metabolite being 7-OH-CBD, which
is predominantly excreted via the gastrointestinal tract.45,82
In recent decades, there has been a growing emergence of
synthetic cannabinoids, the majority of which are analogues
of D9-THC that demonstrates greater potency and binding
affinity to CB1 and CB2 receptors.21,136,137 A number of studies
have suggested that recreational synthetic cannabinoid use is
associated with significantly greater toxicity than natural
cannabis consumption.1,136,137 Although the acute and long-
term effects of synthetic cannabinoid consumption remain
poorly understood, relatively high incidences of adverse
effectsdincluding acute psychosis, agitation, anxiety, confu-
sion, drowsiness, convulsions, respiratory depression, acid-
aemia, nausea, vomiting, tachycardia, dizziness, and chest
paindhave been reported with their use.37,42,116,123,136 There
are now more than 180 analytically confirmed synthetic
cannabinoid receptor agonists.116 Synthetic cannabinoids
have complex molecular structures that offer multiple op-
portunities for chemical modification, although the WIN-, HU-
, CP-, JWH-, UR-, PB-, and AM-series of compounds that were
initially developed for pharmaceutical purposes remain the
most widely known.116,136
3. Cannabinoids and glaucoma
Glaucoma, a leading cause of irreversible blindness world-
wide, is characterized by progressive degeneration of the optic
nerve with loss of retinal ganglion cells.73,86 Intraocular pres-
sure control is recognized to be the most significant modifi-
able risk factor.73,86
Studies investigating the antiglaucoma effects of canna-
binoids are summarized in Table 2. The potential therapeutic
efficacy of cannabinoids in the treatment of glaucoma has
been investigated both in terms of their intraocular pressure
lowering effects as well as their potential role as neuro-
protective agents. The first study that reported the ocular
hypotensive effects of cannabinoids was in 1971 by Hepler and
Frank.53 This observational study included 11 healthy subjects
and detected a 25% decrease in intraocular pressure one hour
330 s u r v e y o f o p h t h a l m o l o g y 6 6 ( 2 0 2 1 ) 3 2 7 e3 4 5

Table 2 e Summary of key studies investigating the ophthalmic impacts of cannabinoids

Study Design Population Exposures and interventions Outcomes

Cannabinoids and intraocular pressure

Adelli et al., Experimental Animal: 12 rabbits with a- Single administration of topical D9- Topical D9-THC-Val-HS in
20175 prospective chymotrypsin induced glaucoma THC 0.5% or 0.8%, D9-THC-Val-HS Tocrisolve application resulted in a
vehicle- 0.6%, or Tocrisolve vehicle. peak reduction of intraocular
controlled pressure of more than 47%, with
observational ocular hypotensive effects lasting
study for 4 hours. Topical D9-THC 0.5%
and 0.8% in Tocrisolve application
resulted in peak reductions of
intraocular pressure of 34% and
36%, respectively, with ocular
hypotensive effects for 2 hours.
Cohen, Clinical Human: 11 patients with glaucoma Single inhalation of D9-THC 20 mg. 30% decrease in intraocular
197627 prospective (not otherwise specified) pressure in 7 of 11 patients with
single-group glaucoma after single inhalation of
observational D9-THC 20 mg, with ocular
study hypotensive effects subsiding
within 4 to 5 hours.
Cooler and Clinical Human: 10 healthy subjects Single administration of 37% decrease in intraocular
Gregg, prospective intravenous D9-THC 0.044 mg/kg, pressure one hour after single
197728 placebo- D9-THC 0.022 mg/kg, diazepam administration of intravenous D9-
controlled 0.157 mg/kg, and placebo serum THC 0.044 mg/kg, and 29% decrease
crossover albumin solution. in intraocular pressure one hour
observational after single administration of
study intravenous D9-THC 0.044 mg/kg,
with ocular hypotensive effects
lasting longer than 90 minutes.
There were no analgesic effects.
Adverse effects reported included
increased heart rate and anxiety.
Green and Clinical Human: 35 healthy subjects Single administration of topical D9- No significant in intraocular
Roth, prospective THC or mineral oil vehicle only. pressure after single administration
198250 vehicle- Concentration not specified. of topical D9-THC during the 7-hour
controlled follow-up period.
observational
study
Hepler and Clinical Human: 11 healthy subjects Single inhalation of D9-THC 18 mg. 25% decrease in intraocular
Frank, prospective pressure one hour after single
197153 single group inhalation of D9-THC 18 mg.
observational
study
Jay and Clinical Human: 28 healthy subjects One-week treatment with topical No significant change in intraocular
Green, prospective D9-THC 1% or mineral oil vehicle pressure after one week of
198372 vehicle- only four times daily. treatment with topical D9-THC 1%
controlled four times daily.
observational
study
Merritt Clinical Human: 18 patients with Single inhalation of D9-THC 18 mg or Peak reduction of intraocular
et al., prospective heterogenous glaucoma (not placebo marijuana cigarette with pressure from 28 to 22 mmHg after
198091 placebo- otherwise specified) alcohol extractable cannabinoids single inhalation of 18 mg of D9-
controlled removed. THC, with ocular hypotensive
crossover effects subsiding within 4 hours.
observational Adverse effects reported included
study postural hypotension, tachycardia,
palpitations, and alterations of
mental status.
(continued on next page)
 s u r v e y o f o p h t h a l m o l o g y 6 6 ( 2 0 2 1 ) 3 2 7 e3 4 5 331

Table 2 e (continued )
Study Design Population Exposures and interventions Outcomes

Miller et al., Experimental Animal: 85 mice Single administration of topical D9- Single administration of topical D9-
201893 prospective THC and/or CBD dissolved in THC dissolved in Tocrisolve lowered
comparative Tocrisolve vehicle. Concentration intraocular pressure by 28% in male
observational not specified. mice, with ocular hypotensive
study effects lasting for 8 hours. In female
mice, the effects of D9-THC were
more modest and lasted for only
4 hours. Coadministration of CBD
prevented the ocular hypotensive
effects of D9-THC.
Newell Clinical Human: 18 patients, including 14 Single administration of oral Peak reduction of intraocular
et al., prospective patients with open angle glaucoma, nabilone 0.5 mg to 2 mg. pressure by 28% between 2 to
1979101 single-group 2 patients with ocular hypertension, 6 hours after single administration
observational 1 patient with secondary glaucoma of oral nabilone 0.5 mg to 2 mg.
study due to intraocular foreign body, and
1 patient without glaucoma.
Porcella Clinical Human: 8 patients with bilateral Single administration of topical Peak reduction of intraocular
et al., prospective glaucoma (not otherwise specified) cyclodextrin-complexed WIN55212- pressure by 20% and 31%,
2001115 comparative 2 25 mg or 50 mg. respectively, within 1 hour after
observational single administration of topical
study cyclodextrin-complexed WIN55212-
2 25 mg or 50 mg, with ocular
hypotensive effects subsiding
within 2 hours.
Tiedeman Clinical Human: 44 patients with ocular Single administration of oral Peak reduction of intraocular
et al., randomized hypertension. BW146Y 5 mg or 10 mg, oral BW29Y pressure by 14% with single
1981142 controlled trial 4 mg, 8 mg, or 12 mg or placebo administration of oral BW146Y
lactose capsules. 10 mg, and peak reduction of
intraocular pressure by 9% with
single administration of oral
BW146Y 5 mg, with ocular
hypotensive effects subsiding
within 8 hours. Oral BW29Y 4 mg,
8 mg, and 12 mg demonstrated no
significant intraocular pressure
elowering effects.
Tomida Clinical Human: 6 patients with ocular Single administration of sublingual Reduction of intraocular pressure
et al., randomized hypertension or early primary D9-THC 5 mg, CBD 20 mg or 40 mg, or from 27.3 mmHg to 23.5 mmHg
2006143 crossover trial open-angle glaucoma placebo. 2 hours after single administration
of sublingual D9-THC 5 mg, with
ocular hypotensive effects
subsiding within 4 hours. No
significant change in intraocular
pressure after single administration
of sublingual CBD 20 mg. Transient
elevation in intraocular pressure
from 23.2 mmHg to 25.9 mm Hg
detected 4 hours after single
administration of sublingual CBD
40 mg.
Cannabinoids and optic nerve neuroprotection
Crandall Experimental Animal: 14 rats with unilateral Twenty-week treatment with In vehicle-treated eyes with
et al., randomized episcleral vessel cauterization intraperitoneal D9-THC 5 mg/kg or episceral vessel cauterization, there
200731 vehicle- induced glaucoma ethanol solution vehicle once was 50% and 40% loss of retinal
controlled study weekly. ganglion cells in the peripheral and
central retina, respectively. In
operated eyes of rats undergoing 20-
week treatment of intraperitoneal
D9-THC 5 mg/kg once weekly,
retinal ganglion cell loss was
reduced to 10% to 20%.
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Table 2 e (continued )
Study Design Population Exposures and interventions Outcomes

Liu et al., Experimental Animal: 18 rats with episcleral Four-week treatment with Retinal ganglion cell density was
201481 randomized vessel cauterization induced intravitreal HU-211 1 mg or saline
significantly greater in the group
saline-controlled glaucoma every other day. receiving 4-week treatment with
study intravitreal HU-211 1 mg every other
day than the saline group (47.1

1.4 cells/field versus 15.1
2.1 cells/
field).
Pinar- Experimental Animal: 27 rats with saline infusion Two-day treatment with topical Retinal ganglion cell loss was
Sueiro randomized induced acute intraocular pressure WIN55212-2 1%, WIN55212-2 1% 12.33% in vehicle-treated eyes.
et al., vehicle- elevation and AM251 1%, or Tocrisolve vehicle Topical WIN55212-2 1% treatment
2013109 controlled study once daily. resulted in a reduction of retinal
ganglion cell loss to 2.45%, although
these effects were reversed with
coadministration of AM251 1%.
Yoles et al., Experimental Animal: rats with graded optic Single administration of Intraperitoneal administration of
1996149 prospective nerve crush injury, sample size not intraperitoneal HU-211 3 mg/kg, HU-211 reduce injury-induced
vehicle- specified 7 mg/kg, 20 mg/kg, or vehicle. metabolic and electrophysiological
controlled deficits, with optimal effects being
observational observed at a dose of 7 mg/kg, and
study the treatment was most effective
when administered at the time of
injury.
Zalish and Experimental Animal: 18 rats with optic nerve Single administration of Transmission electron microscopic
Lavie, prospective crush injury intraperitoneal HU-211 7 mg/kg, or analysis performed 30 days after
2003151 vehicle- vehicle. treatment administration
controlled demonstrated that the site of injury
observational was traversed by unmyelinated in
study HU-211 treated rats, and no growth
was detected in vehicle treated rats.
Viable axons were found 0.5 mm
distal to the site of injury in 6 of 8
HU-211 treated rats, but in only 1 of
10 vehicle treated rats.
Cannabinoids and the retina
Araújo Experimental Animals: chicks with oxygen and Retinal pieces were exposed to A combination of WIN 55212-2 and
et al., prospective glucose deprivation induced retinal mediums containing a combination AM251/O-2050 or AM630 decreased
20179 comparative ischemia, sample size not specified. of WIN55212-2 (1 or 10 mM), AM251/ the release of lactate
observational O-2050 (1 or 10 mM), and/or AM630 (1 dehydrogenase, although each drug
study. and 10 mM). alone exhibited no effect.
Bouskila Experimental Animal: 13 vervet monkeys Single administration of Scotopic b-wave amplitudes
et al., prospective intravitreal, increased after intravitreal injection
201614 vehicle- lysophosphatidylglucoside, of lysophosphatidylglucoside and
controlled CID16020046, or dimethyl sulfoxide decreased after intravitreal
observational vehicle, concentration not specified injection of CID16020046. No
study changes in a-wave amplitude, a-
wave, and b-wave latencies of
scotopic electroretinogram were
detected, and no changes in
photopic electroretinogram
waveforms were observed.
Cécyre Experimental Animal: 58 mice (wild type, CB1 CB1 receptor-knockout and CB2 In CB2 receptor-knockout mice,
et al., cross-sectional receptor-knockout, and CB2 receptor-knockout mice. there were increased a-wave
201323 study receptor-knockout) amplitudes under scotopic
conditions and greater time
required for b-wave amplitudes to
reach stable values in photopic
conditions. No changes were
observed in CB1 receptor-knockout
mice.
(continued on next page)
 s u r v e y o f o p h t h a l m o l o g y 6 6 ( 2 0 2 1 ) 3 2 7 e3 4 5 333

Table 2 e (continued )
Study Design Population Exposures and interventions Outcomes

Chen et al., Experimental Animal: 40 mice with N-methyl-N- Single administration of SR141716A treatment recovered
201824 prospective nitrosourea induced retinitis intraperitoneal SR141716A 1 mg/kg, photoreceptor loss, reduce glial
saline-controlled pigmentosa SR144528 1 mg/kg, WIN55212-2 reactivity, and decrease abnormal
observational 1 mg/kg, or saline. vascular complexes.
study
Corvi et al., Clinical case Human: 1 cannabis user reporting Acute inhalation of a single joint of Central retinal vein occlusion with
201529 report occasionally smoking part of joint cannabis symptom onset occurring
for 8 months, but daily 15 minutes after smoking a joint of
consumption of 1 joint in the past cannabis.
2 weeks
El-Remessy Experimental Animal: 21 rats with NMDA-induced Single administration of Both D9-THC and CBD
et al., prospective retinal excitotoxicity intravenous intravenous injection administration resulted in
200336 comparative of D9-THC 0.4 mg/kg or 2 mg/kg, decreased retinal apoptosis,
observational SR141716A 1 mg/kg or 2 mg/kg, or through inhibiting peroxynitrite
study CBD 2 mg/kg formation. The neuroprotective
activity of THC was also partially
mediated by the CB1 receptor.
El-Remessy Experimental Animal: 127 rats with Four-week treatment with CBD treatment decreased oxidative
et al., prospective streptozotocin-induced diabetic intraperitoneal CBD 10 mg/kg or stress; reduced tumor necrosis
200635 vehicle- retinopathy vehicle every other day. factor-alpha, vascular endothelial
controlled growth factor, and intercellular
observational adhesion molecule-1 levels
study decreased retinal cell death,
prevented vascular
hyperpermeability, and inhibited
p38 MAP kinase in the diabetic
retina model.
Faure et al., Clinical case Human: 1 chronic hashish user Chronic hashish consumption (5 Multiple subretinal fluid blebs on
201640 report joints per day for 9 years). optical coherence tomography,
which resolved 6 months after the
termination of cannabis use.
Lax et al., Experimental Animal: 11 transgenic P23H rats Intraperitoneal administration of Electroretinogram recordings
201478 prospective with retinitis pigmentosa HU210 100 mg/kg or saline three demonstrated amelioration of
saline-controlled times a week from P24 to P90. vision loss in HU210 treated
observational animals, with greater scotopic a-
study wave amplitudes at P60 and P90,
higher scotopic b-wave amplitudes
at P30, P60, and P90. HU210-treated
animals also exhibited 40% more
photoreceptors, delayed
photoreceptor degeneration,
preservation of retinal
cytoarchitecture, and preservation
of synaptic contacts between
photoreceptors and bipolar or
horizontal cells.
Lucas et al., Clinical case Human: 45 regular cannabis users Cannabis consumption of at least 7 Flash electroretinography
201983 control study and 26 healthy controls cannabis joints per week and demonstrated increased magnitude
presence of tetrahydrocannabinol of retinal background noise, which
metabolites in urine in the exposure might reflect the neurotoxicity of
group. cannabis consumption.
Maccarone Experimental Animal: 90 rats Single administration of intravitreal Intravitreal injection of selective
et al., prospective of SR141716A or SR144528 (0.1 mM in CB1 and CB2 receptor antagonists,
201684 saline-controlled 2 ml 0.9% saline), or 2 ml 0.9% saline SR141716A and SR144528, reduced
observational only. photoreceptor death and outer
study nuclear layer damage, and
preserved retinal morphology after
bright continuous light exposure,
although the neuroprotective
effects conferred by the CB2
receptor antagonist was more
pronounced.
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334 s u r v e y o f o p h t h a l m o l o g y 6 6 ( 2 0 2 1 ) 3 2 7 e3 4 5

Table 2 e (continued )
Study Design Population Exposures and interventions Outcomes

MacIntyre Experimental Animal: 72 rats Abnormal cannabidiol applied to Abnormal cannabidiol exerts
et al., prospective retinal arterioles precontracted vasorelaxant effects with 10 to 20%
201485 comparative with endothelin-1 increases in the vessel diameter of
observational retinal arterioles precontracted
study with endothelin-1.
Onur et al., Clinical case Human: 60 synthetic cannabinoid Synthetic cannabinoid No differences in optical coherence
2016107 control study users and 30 healthy controls consumption not specified in the tomography retinal parameters
exposure group. were detected between synthetic
cannabinoid users and healthy
controls, although choroidal
thinning was limited to current
synthetic cannabinoid users.
Plange Clinical Human: 8 healthy subjects Single administration of oral D9- Two hours after administration of
et al., prospective THC 7.5 mg oral D9-THC 7.5 mg, average retinal
2007110 single group arteriovenous passage time
observational decreased from 1.77 to 1.57 seconds.
study
Russo Clinical Human: 4 healthy subjects Single administration of oral D9- Improvements in dark adaptation
et al., prospective case THC 2.5 mg to 20 mg, or single and scotopic sensitivity testing after
2004122 series inhalation of cannabis (dose not single administration of oral D9-
specified) THC or cannabis inhalation.
Schwitzer Clinical case Human: 1 heavy cannabis user (20 Single inhalation of 1 joint of After acute inhalation of a single
et al., report joints per month for 33 year) cannabis. joint of cannabis, a 48% reduction in
2016126 a-wave amplitude was detected on
full-field electroretinogram.
Schwitzer Clinical case Human: 28 regular cannabis users Cannabis consumption of at least 7 Delayed transmission of action
et al., control study and 24 healthy controls cannabis joints per week and potentials by retinal ganglion cells
2017127 presence of tetrahydrocannabinol with increased N95 implicit time on
metabolites in urine in the exposure pattern electroretinography in
group. regular cannabis users.
Schwitzer Clinical case Human: 53 regular cannabis users Cannabis consumption of at least 7 Delayed ganglion and bipolar cell
et al., control study and 29 healthy controls cannabis joints per week and responses with significantly
2018129 presence of tetrahydrocannabinol increased N95 and light-adapted
metabolites in urine in the exposure 3.0 b-wave peak times on pattern
group. and flash electroretinography,
respectively, in regular cannabis
users.
Schwitzer Clinical case Human: 49 regular cannabis users Cannabis consumption of at least 7 Delayed transmission of visual
et al., control study and 21 healthy controls cannabis joints per week and information from the central retina
2020125 presence of tetrahydrocannabinol to the near periphery in regular
metabolites in urine in the exposure cannabis users, with an increased
group. N2 implicit time and decreased N1
amplitude in the <2 region, an
increased in N2 and P1 implicit
times in the 2 to 5 region,
increased P1 and N1 implicit times
in the 5 to 10 region, and increased
P1 implicit time in the 10 to 15
region.
Struik Experimental Animal: 17 goldfish retinas Bath application of WIN55212-2 Application of WIN55212-2
et al., prospective 10 mM solution to goldfish retinas. accelerated the cone response to
2006134 single group light offset and enhanced the
observational depolarizing overshoot, with the
study time contrast of the offset response
reduced from 292
28 ms to 180

11 ms. No effect on the absolute
sensitivity of cone receptors, or the
kinetics of the onset response were
observed.
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 s u r v e y o f o p h t h a l m o l o g y 6 6 ( 2 0 2 1 ) 3 2 7 e3 4 5 335

Table 2 e (continued )
Study Design Population Exposures and interventions Outcomes

Su et al., Experimental Animal: 1 pig Abnormal cannabidiol applied to Abnormal cannabidiol exerts
2015135 observational retinal arterioles with and without vasorelaxant effects with 10 to 20%
study precontraction using endothelin-1 increases in the vessel diameter of
retinal arterioles precontracted
with endothelin-1.
Zhang Experimental Animal: 20 mice Two-month treatment with Two-month treatment with
et al., prospective intraperitoneal D9-THC 1 mg/kg or intraperitoneal D9-THC resulted in
2020152 vehicle- 2 mg/kg, or vehicle daily. functional loss on
controlled electroretinography and increased
observational apoptosis of photoreceptor cells,
study heightened inflammatory
responses and oxidative stress.
Zobor et al., Clinical cross- Human: 1 patient with cannabis- Diagnosis of cannabis-induced Higher Arden ratios and reduced
2015153 sectional study induced hallucinogen persisting hallucinogen persisting perception electrically evoked phosphine
perception disorder and 4 heavy disorder, or heavy cannabis thresholds were observed in a
cannabis smokers with no visual consumption (not specified) with no patient with cannabis-induced
disturbances visual disturbances. hallucinogen persisting perception
disorder compared to 4 heavy
cannabis smokers with no visual
disturbances.
Cannabinoids and the cornea
Polat et al., Clinical case Human: 28 patients diagnosed with Cannabinoid use more than three Corneal endothelial cell density was
2018112 control study cannabinoid use disorder and 32 age days per week over the past year in significantly lower in patients with
and sex-matched healthy controls the exposure group. long-term cannabis use than in
healthy controls (2900
211 cells/
mm2 versus 3097
214 cells/mm2)
Thapa Experimental Animal: 124 mice (wild type, and Administration of topical D8-THC Topical treatment with D8THC, CBD,
et al., prospective CB2 receptor-knockout) with (0.2%, 0.4%, 0.5%, or 1%), CBD (3% or and HU-308 reduced pain score and
2018138 vehicle- chemical cauterization induced 5%), HU-308 (1% or 1.5%), or vehicle, neutrophil infiltration in wildtype
controlled corneal hyperalgesia 30, 60, and 120 minutes after mice, although the antinociceptive
observational cauterization. and antiinflammatory actions of
study D8THC were blocked with
coadministration of AM251.
Antinociceptive and
antiinflammatory activity of D8THC
and CBD were observed in CB2
knockout mice, but not HU-308.
Thapa Experimental Animal: 124 mice (wild-type and CB2 Administration of topical D8-THC Topical treatment with GAT228
et al., prospective knockout) with chemical (0.2% or 0.4%), GAT211 (0.5%, 1%, or reduced pain scores, but not GA 229
2020139 vehicle- cauterization induced corneal 2%), GAT229 (0.5%, 1%, or 2%), or GAT211. Combination treatments
controlled hyperalgesia GAT228 (0.5%, 1%, or 2%), D8-THC of GAT229 0.5% and D8-THC 0.4% or
observational 0.4% and GAT 211 1%, D8-THC 0.2% GAT211 1% and D8-THC 0.4% also
study and GAT 229 0.5%, D8-THC 0.4% and reduced pain scores. The
GAT 229 0.5%, or vehicle, dosing antinociceptive effects of both
schedule not specified. GAT229 and GAT228 were blocked
with coadministration of AM251.
GAT228 2% or D8-THC 0.2% and GAT
229 0.5% reduced corneal
inflammation.
Cannabinoids and ocular motility
Adams Clinical Human: 10 healthy subjects Single inhalation of D9-THC 8 mg or Decrements in dynamic visual
et al., prospective 15 mg, or placebo. acuity for moving targets that
19754 placebo- require coordinated eye movements
controlled for resolution were observed up to
crossover 4 hours after single inhalation of D9-
observational THC 8 mg or 15 mg. No changes in
study static visual acuity were detected.
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336 s u r v e y o f o p h t h a l m o l o g y 6 6 ( 2 0 2 1 ) 3 2 7 e3 4 5

Table 2 e (continued )
Study Design Population Exposures and interventions Outcomes

Baloh et al., Clinical Human: 24 healthy subjects Single inhalation of D9-THC 100 mg/ Single inhalation of D9-THC 100 mg/
197911 prospective kg or placebo at three different kg at the three serum ethanol
placebo- serum ethanol concentrations (0%, concentrations, did not result in
controlled 0.05%, or 0.1%). significantly greater impairment of
crossover saccade maximum velocity and
observational reaction time, smooth pursuit
study velocity, and optokinetic slow-
component velocity than placebo
inhalation.
Fant et al., Clinical Human: 10 healthy subjects Single inhalation of D9-THC 1.8% or Decrements in smooth pursuit eye
199839 prospective 3.6%, or placebo. tracking were detected in the first 2
placebo- to 4 hours after single inhalation of
controlled a D9-THC 1.8% or 3.6% cigarette.
crossover
observational
study
Flom et al., Clinical Human: 10 subjects consuming Single inhalation of D9-THC 8 mg or No significant changes in smooth
197641 prospective alcohol at least once a week, and 15 mg, or placebo. and saccadic tracking eye
placebo- smoking 2 to 5 cannabis cigarettes movement recordings were
controlled each week detected after single inhalation of
crossover D9-THC 8 mg or 15 mg.
observational
study
Huestegge Clinical case Human: 20 long-term cannabis Long-term cannabis use, with age of Long-term cannabis users exhibited
et al., control study users and 20 healthy controls onset less than 17 years in the increased latency in prosaccade and
200964 exposure group. antisaccade tasks, prolonged
saccade amplitudes in antisaccade
memory-guided tasks, compared to
healthy controls
Huestegge Clinical case Human: 20 long-term cannabis Long-term cannabis use, with age of Long-term cannabis users
et al., control study users and 20 healthy controls onset less than 17 years in the demonstrated greater fixation
201063 exposure group. durations, increased revisiting of
text previously inspected, and
elevated word viewing times,
especially for longer or less
commonly used words.
Mohan and Clinical case Human: 1 patient after acute Acute intoxication with food Conjugate deviation of the eyes
Sood, report intoxication with Cannabis indica containing Cannabis indica. after acute intoxication with food
196494 containing Cannabis indica,
persisting for 6 weeks before
resolving
Moskowitz Clinical Human: 12 healthy subjects Single inhalation of D9-THC 50 mg/ Progressive impairment in the
et al., prospective kg, 100 mg/kg or 200 mg/kg, or ability to detect peripheral light
197297 placebo- placebo. stimuli were observed 30 minutes
controlled after single inhalation of increasing
crossover doses of D9-THC from 50 mg/kg to
observational 200 mg/kg.
study
Moskowitz Clinical Human: 10 social cannabis users Single inhalation of D9-THC 200 mg/ Single inhalation of D9-THC 200 mg/
et al., prospective kg or placebo. kg demonstrated no effect on visual
197698 placebo- scanning patterns in a simulated
controlled driving situation.
crossover
observational
study
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 s u r v e y o f o p h t h a l m o l o g y 6 6 ( 2 0 2 1 ) 3 2 7 e3 4 5 337

Table 2 e (continued )
Study Design Population Exposures and interventions Outcomes

Ploner Clinical Human: 12 healthy subjects Single administration of oral D9- Two hours after single
et al., prospective THC 10 mg. administration of oral D9-THC
2002111 single-group 10 mg, there were increased
observational latencies of reflexive visually guided
study saccades, although there was no
change in accuracy. Latencies of
memory guided saccades were
unaffected, although average gain
and gain variability increased. The
frequency of anticipated memory-
guided saccades and antisaccade
errors increased, while the saccade
amplitude to peak velocity
relationships were unaffected.
Pradeep Clinical case Human: 1 patient with congenital Single inhalation of cannabis 10 mg Reduction of intensity of nystagmus
et al., report nystagmus by 10 to 40% and improvement of
2008117 visual acuity by 2 to 3 logMAR lines,
30 minutes after single inhalation of
cannabis 10 mg.
Schon Clinical case Human: 1 patient with multiple Single inhalation of two cannabis- Suppression of acquired pendular
et al., report sclerosis and acquired pendular containing cigarettes (serum D9- nystagmus for four hours after
1999124 nystagmus THC exceeding 80 mg/L) single inhalation of two cannabis-
containing cigarettes, with serum
D9-THC exceeding 80 mg/L. Oral
nabilone up to 6 mg daily and
cannabis oil capsules up to 40 mg of
D9-THC daily, of unspecified
treatment duration, demonstrated
no therapeutic benefits.
Yoon et al., Clinical case Human: 42 patients with cannabis Diagnosis of cannabis use disorder Patients with cannabis use disorder
2019150 control study use disorder, and 11 healthy in the exposure group. had a higher frequency of
controls. antisaccade errors than healthy
controls. Antisaccade errors were
correlated with the Perceived Stress
Scale.
Zuurman Clinical Human: 12 healthy subjects Single administration of vaporized No changes in saccadic eye
et al., randomized D9-THC (2 mg, 4 mg, 6 mg, or 8 mg) movements, smooth pursuit or
2008154 placebo- or vehicle. adaptive tracking performance
controlled cross- were observed after administration
over study of vaporized D9-THC.

D9-THC, D9-tetrahydrocannabinol; CBD, cannabidiol; NMDA, N-methyl-D-aspartate; MAP, mitogen activated protein.

after smoking 18 mg of D9-THC. A further observational study
corroborated these findings and demonstrated a 30% reduc-
tion in intraocular pressure in 7 of 11 patients with glaucoma
after smoking 20 mg of D9-THC, although the transient ocular
hypotensive effects subsided within 4 to 5 hours.27 The first
placebo-controlled study was carried out in 1980 and involved
18 patients with glaucoma. The study demonstrated a peak
reduction of mean intraocular pressure from 28 to 22 mmHg
after smoking 18 mg of D9-THC but also found that the ocular
hypotensive effects lasted for less than 4 hours.91 Subsequent
clinical studies investigating the effects of oral D9-THC,
BW146Y, and nabilone (synthetic cannabinoids) and intrave-
nous administration of D9-THC, D8-THC, and 11-OH-THC have
demonstrated similar transient ocular hypotensive effects
lasting only 3 to 4 hours, while oral CBD and 8-b-OH-THC and
intravenous BW29Y have failed to demonstrate efficacy in
lowering intraocular pressure.28,74,101,108,142 More recently, a
double-masked randomized crossover trial of 6 patients with
ocular hypertension or early primary open-angle glaucoma
demonstrated that 5 mg of sublingual D9-THC exerted a
maximum reduction of intraocular pressure from 27.3 to
23.5 mmHg at 2 hours, although the therapeutic effects sub-
sided by 4 hours.143 No ocular hypotensive effects were
observed with 20 mg of CBD, and a transient elevation of
intraocular pressure from 23.2 to 25.9 mmHg at 4 hours was
observed with 40 mg of CBD.143
The mechanisms by which cannabinoids might result in
intraocular pressure reduction remain poorly
understood.26,48,68,74,103,113,133,143 It has been suggested that
the temporary reduction of intraocular pressure might be
partially associated with the concurrent decrease in systemic
blood pressure91; however, the presence of CB1 and GPR18
receptors in the ciliary body, trabecular meshwork, and
Schlemm canal would suggest that modulatory effects on
aqueous humor production and trabecular outflow might also
be implicated.20,26,113,133 The potential vasodilatory effects of
cannabinoids on the blood vessels of the anterior uvea have
also been hypothesized to promote uveoscleral outflow.113 A
338 s u r v e y o f o p h t h a l m o l o g y 6 6 ( 2 0 2 1 ) 3 2 7 e3 4 5
recent murine study showed that the ocular hypotensive ef-
fects of D9-THC were mediated by the combined activation of
CB1 and GPR18 receptors, while CBD had an opposing effect
and resulted in an elevation of intraocular pressure.93
Although the magnitude of intraocular pressure reduction
appears to be dose-dependent, no relationship was observed
between the duration of effect and dosing.48 In addition, it
remains unclear whether repeated dosing might result in
physiological tolerance and subsequently diminished ocular
hypotensive efficacy.74
Nevertheless, an extensive range of systemic adverse ef-
fects have also been reported with inhaled and systemic
administration of cannabinoids in studies of their efficacy in
lowering intraocular pressures, including postural hypoten-
sion, tachycardia, palpitations, and variable mental status
alterations.28,32,68,90,91,103,142 Such side effects would generally
preclude repeated dosing of cannabinoids for the purposes of
maintaining sustained intraocular pressure control, especially
among elderly patients with comorbid cardiovascular or ce-
rebrovascular disease.68 A placebo-controlled study reported
substantial decreases in systolic blood pressure, ranging be-
tween 12 and 52 mmHg in 16 glaucoma patients within
30 minutes of smoking 18 mg of D9-THC, although blood
pressure measurements subsequently normalized over a
course of 4 hours.32 A further case series found 3 patients
experienced orthostatic hypotension within 10 minutes of
smoking 18 mg of D9-THC, with systolic blood pressure drops
in the order of 40 to 60 mmHg.90 There have been concerns
that the reduction in blood pressure that can be associated
with systemic cannabinoid administration may also
compromise blood flow to the optic nerve, which might
represent further insult to an already vulnerable optic nerve
and contribute to further disease progression.68,146
Topical application of cannabinoids as eye drops has
received some interest on account of the potential for mini-
mizing systemic adverse effects, while maximizing the dose
delivered to the site of action.50,72 Early clinical studies, how-
ever, using mineral oil as a vehicle for D9-THC did not
demonstrate ocular hypotensive efficacy but produced sig-
nificant ocular surface irritation and eyelid swelling.50,72 The
lack of therapeutic efficacy was thought to be attributed to the
limited corneal permeability and low levels of intraocular
penetration secondary to the highly lipophilic nature and
limited aqueous solubility of cannabinoids.50,72 More recent
preclinical studies involving microemulsions of D9-THC and
D8-THC with cyclodextrins show promise for enhanced
corneal permeability, higher aqueous solubility, increased
stability, and improved intraocular bioavailability.49,58,71,75
Stable formulations of aqueous soluble prodrugs that are
converted intraocularly into D9-THC have been developed,141
and animal studies have shown that prodrug emulsions
demonstrated significantly improved transcorneal penetra-
tion to the anterior chamber and enhanced ocular hypoten-
sive efficacy in rabbit glaucoma models.5,56,57 In addition,
another rabbit study also reported that topical solid lipid
nanoparticle and fast gelling film formulations were both
capable of successfully delivering D8-THC to therapeutically
meaningful concentrations in all ocular tissues except the
vitreous, although the solid lipid nanoparticle formulation
demonstrated greater tissue penetration.119 Transient ocular
hypotensive effects of a cyclodextrin-complexed WIN55212-2
eye drop solution were observed in a preliminary human
study of 8 glaucoma patients.115 The cyclodextrin-complexed
WIN55212-2 solution applied topically at doses of 25 and 50 mg
demonstrated peak intraocular pressure reductions of 20 and
31%, respectively, although these ocular hypotensive effects
lasted less than 2 hours.115
In addition to intraocular pressure-lowering effects, early
evidence from animal studies has also raised the possibility of
a neuroprotective action of cannabinoids on the optic
nerve.31,81,109,149 A few animal studies have demonstrated that
cannabinoid administration can reduce the loss of retinal
ganglion cell density in experimental rat models of glaucoma
and elevated intraocular pressure.31,81,109 Administration of
the synthetic nonpsychotropic cannabinoid HU-211 was also
shown to reduce injury-induced metabolic and electrophysi-
ological deficits during the course of 6 hours after optic nerve
axotomy in an experimental rat model.149 Moreover, a single
administration of HU-211 in a rat optic nerve crush model was
associated with regenerative growth and axonal sprouting
30 days after the initial injury, which was absent in control
animals.151 These trends are in agreement with the previously
reported neuroprotective properties of cannabinoids in the
central nervous system, as well as the limitation of glutamate-
mediated excitotoxicity.87,118,120,121 D9-THC has been shown to
inhibit glutamate release by increasing Kþ and decreasing
Ca2þ permeability via the activation of presynaptic CB1 re-
ceptors, while HU-211 acts as a noncompetitive antagonist to
the N-methyl-D-aspartate glutamate receptor.87,118,120,121,144
Moreover, D9-THC, CBD, and HU-211 have also exhibited
antioxidant properties, independent of the activation of
cannabinoid receptors, and might promote neuronal survival
by scavenging toxic reactive oxygen species that are produced
by glutamate-mediated excitotoxicity.87,118,121,144
In summary, although cannabinoids demonstrate ocular
hypotensive and neuroprotective properties, their use is
limited by a significant number of potential side effects. On
account of the current evidence, the most recent position
statement released by the American Glaucoma Society rec-
ommends against the use of cannabinoids for the treatment of
glaucoma.70
4. Cannabinoids and the retina
Cannabinoid receptors have been identified in the human
retina, although the distribution differs between CB1 and CB2
receptors.128 CB1 receptors have been detected in the ganglion
cell layer, inner plexiform layer, inner nuclear layer, outer
plexiform layer, and outer segments of photoreceptor cells in
postmortem human eyes.133 Expression of both CB1 and CB2
receptors have also been demonstrated in human retinal
pigment epithelium cells;147 however, a recent study showed
that immunohistochemistry staining for a number of
commonly used CB2 receptor antibodies lacked specificity
when tested on the retinal tissues of CB2-knockout mice and
would suggest that caution is warranted when interpreting
earlier studies using CB2 receptor antibodies.22
 s u r v e y o f o p h t h a l m o l o g y 6 6 ( 2 0 2 1 ) 3 2 7 e3 4 5
Studies investigating the effects of cannabinoids on the
retina are summarized in Table 2. The potential association
between cannabis and neuroretinal dysfunction has been
assessed in a number of preclinical and clinical
studies.40,46,107,125-127,129,134,152,153 An animal study showed
that intraperitoneal administration of D9-THC resulted in
retinal toxicity in mice, with functional loss on electroreti-
nography and increased apoptosis of photoreceptor cells, as
well as heightened inflammatory responses and oxidative
stress.152 On the contrary, synthetic WIN 55,212-2 was
demonstrated to accelerate the cone response to light offset in
the goldfish retina, which may indicate enhanced contrast
sensitivity.134 A study comparing electroretinographic re-
sponses from CB2 receptor-knockout mice demonstrated
increased a-wave amplitudes under scotopic conditions and
greater time required for b-wave amplitudes to reach stable
values in photopic conditions, although no changes were
observed in CB1 receptor-knockout mice.23 The potential role
of GPR55 receptors in mediating scotopic vision was high-
lighted by another animal study in monkeys which showed
that b-wave amplitudes were elevated and reduced, respec-
tively, after the intravitreal injection of a GPR55 agonist
(lysophosphatidylglucoside) and antagonist (CID16020046).14
A case report demonstrated transient changes in photore-
ceptor function 30 minutes after acute inhalation of a single
joint of cannabis in a heavy smoker, with 48% reduction in a-
wave amplitude being detected on full-field electroretino-
gram.126 Another case report described the presence of mul-
tiple subretinal fluid blebs on optical coherence tomography
in a chronic hashish smoker, which resolved 6 months after
the termination of cannabis use.40 Interestingly, a case series
of four subjects reported short-term improvements in dark
adaptation and scotopic sensitivity testing after synthetic D9-
THC or cannabis consumption.122 A small comparative study
reported higher Arden ratios and reduced electrically evoked
phosphine thresholds in a patient with cannabis-induced
hallucinogen persisting perception disorder compared with
four heavy cannabis smokers with no visual disturbances.153
A case control study comparing 28 regular cannabis users
and 24 healthy controls demonstrated delayed transmission
of action potentials by retinal ganglion cells with increased
N95 implicit time on pattern electroretinography.127 These
findings were corroborated by another study comparing 53
regular cannabis users and 29 healthy controls, which showed
delayed ganglion and bipolar cell responses with significantly
increased N95 and light-adapted b-wave peak times on
pattern and flash electroretinography, respectively.129 More-
over, a case control study comparing multifocal electroreti-
nogram responses of 49 regular cannabis users and 21 healthy
controls also demonstrated delayed transmission of visual
information from the central retina to the near periphery.125 A
flash electroretinogram study comparing 45 regular cannabis
users and 26 healthy controls demonstrated increased
magnitude of retinal background noise, which was thought to
represent reflect the neurotoxicity of cannabis.83 In contrast, a
case control study of 60 synthetic cannabinoid users and 30
healthy controls demonstrated no differences in optical
coherence tomography retinal parameters, although
choroidal thinning was limited to current synthetic cannabi-
noid users.107 Nevertheless, it is acknowledged that the
339
findings of these clinical studies are limited by modest sample
sizes, and the potential for self-reporting bias of cannabinoid
exposure cannot be excluded.
A few studies have also suggested that cannabinoids might
alter vasoactivity and blood flow in the retinal arterioles.110
Two animal studies conducted on rats and pigs have
showed that CBD exerts vasorelaxant effects with 10 to 20%
increases in the vessel diameter of retinal arterioles precon-
tracted with endothelin-1.85,135 In addition, a small observa-
tional study demonstrated increased retinal blood flow on
angiofluoresceinography in eight healthy human subjects
2 hours after oral administration of 7.5 mg of D9-THC, with the
average retinal arteriovenous passage time decreasing from
1.77 to 1.57 seconds.110 These findings are consistent with the
vascular effects of cannabinoids reported in other parts of the
body, including vasodilation of the mesenteric and pulmonary
vasculatures that are thought to be mediated by the activation
of CB1 receptors10,13; however, a case report has also described
central retinal vein occlusion with symptom onset occurring
15 minutes after smoking a joint of cannabis,29 although the
presence of a causal relationship is difficult to establish.
The potential neuroprotective effects of cannabinoids on
the retina is an area of significant interest. D9-THC and CBD
have been reported to reduce retinal neuron apoptosis in an
N-methyl-D-aspartateeinduced retinal excitotoxicity rat
model, with the neuroprotective effects being mediated by
inhibiting peroxynitrite formation.36 CBD has also been
demonstrated to reduce neurotoxicity, oxidative stress, in-
flammatory marker expression, retinal cell death, and blood-
retinal barrier breakdown in a streptozotocin-induced dia-
betic retinopathy rat model, which is thought to be mediated
by the inhibition of p38 MAP kinase.35 A combination of syn-
thetic WIN 55,212-2 and cannabinoid receptor antagonists,
AM251/O-2050 or AM630, was reported to decrease the release
of lactate dehydrogenase induced by retinal ischemia in an
oxygen and glucose deprivation chick retina model.9 Admin-
istration of the CB1 receptor antagonist SR141716A has been
shown to recover photoreceptor loss, decrease glial reactivity,
and reduce abnormal vascular complexes in an N-methyl-N-
nitrosoureaeinduced retinitis pigmentosa mouse model.24
Synthetic HU-210 administration in a transgenic P23H rat
model of retinitis pigmentosa has also been reported to
attenuate photoreceptor degeneration measured on electro-
retinography, which correlated with preservation of retinal
cytoarchitecture on immunohistochemistry analysis.78 An
experimental study showed that the intravitreal injection of
selective CB1 and CB2 receptor antagonists SR141716A and
SR144528 reduced photoreceptor death and outer nuclear
layer damage and preserved retinal morphology after bright
continuous light exposure in the albino rat retina, although
the neuroprotective effects conferred by the CB2 receptor
antagonist were more pronounced than the CB1 receptor
antagonist.84
5. Cannabinoids and the cornea
The presence of cannabinoid receptors in the cornea has been
reported in a few studies, with CB1 receptors being detected in
the corneal epithelium and endothelium,133 while CB2
340 s u r v e y o f o p h t h a l m o l o g y 6 6 ( 2 0 2 1 ) 3 2 7 e3 4 5
receptors can be upregulated in corneal epithelial cells after a
corneal injury.99
There have been a limited number of studies that have
explored the effects of cannabinoids on the cornea, as sum-
marized in Table 2.112,138,139 An animal study investigated the
antinociceptive and antiinflammatory effects of cannabinoids
using an experimental mice model of corneal hyperalgesia
generated by chemical cauterisation.138 This study showed
that topical application of D9-THC, CBD, and HU-308 resulted
in a reduction in pain scores and corneal neutrophil infiltra-
tion. Interestingly, although the analgesic and antiin-
flammatory action of D9-THC were mediated via CB1
receptors, the effects of CBD and HU-308 involved activation
of CB2 and serotonin 5-HT1A receptors. Another animal study
reported that allosteric CB1 receptor ligands, including GAT-
228 or a combination of GAT-229 with GAT-211, demon-
strated antinociceptive effects in an experimental mice
model, while GAT-228 or a combination of D8-THC with GAT-
229 reduced corneal neutrophil infiltration.139 Nevertheless,
the potential therapeutic utility of cannabinoids in the treat-
ment of corneal pain and inflammation resulting from ocular
surface injury requires further investigation.
A case-control study used spectral microscopy to compare
corneal endothelial cell density in 28 patients diagnosed with
cannabinoid use disorder and 32 years of age and sex-
matched healthy controls.112 Participants in the cannabinoid
group were selected from patients who had been using the
substance more than three days per week over the past year,
with no consumption of other illicit drugs. The findings
demonstrated that corneal endothelial cell density was
significantly lower in patients with long-term cannabis use. It
was hypothesized that these changes might reflect the toxic
effects of cannabinoids on the corneal endothelium, although
the exact mechanisms remain unclear.
6. Cannabinoids and ocular motility
The association between cannabis and oculomotor deficits
has been investigated in a number of studies, although mixed
findings have been reported, as summarized in
Table 2.4,11,17,39,41,63,64,94,97,98,111,131,150,154 A case report
described conjugate deviation of the eyes after acute intoxi-
cation with food containing Cannabis indica that persisted for
6 weeks before resolving.94 A study of 10 healthy subjects
demonstrated a decrease in dynamic visual acuity for moving
targets that require coordinated eye movements for resolu-
tion up to 4 hours after smoking 15 mg of D9-THC, although no
changes in static visual acuity were observed during the same
time period.4,17 Decrements in smooth pursuit eye tracking
were observed in a cross-over study of 10 healthy volunteers
in the first 2 to 4 hours after smoking one cannabis cigarette of
1.8 or 3.6% D9-THC.39 Another crossover study reported dose-
related reductions in the ability to detect peripheral light
stimuli 30 minutes after smoking 50 to 200 mg/kg body weight
of D9-THC in 12 participants, although it was unclear whether
these findings were secondary to changes in visual acuity,
ocular motility, or attention.97 A study that conducted oculo-
motor testing 2 hours after oral administration of 10 mg of D9-
THC in 12 healthy participants demonstrated increased
latencies of reflexive visually guided saccades and higher
frequencies of antisaccade errors.111 Similar trends were re-
ported in a case control study which also demonstrated a
higher frequency of antisaccade errors among 42 individuals
with cannabis use disorders than the 11 healthy controls.150
Another case control study compared 20 long-term cannabis
users with 20 healthy controls and showed increased latency
in prosaccade and antisaccade tasks, as well as prolonged
saccade amplitudes in antisaccade and memory-guided
tasks.64 Moreover, when eye movement control during
reading was assessed, long-term cannabis users demon-
strated increased fixation durations, more revisiting of previ-
ously inspected text, and a substantial prolongation of word
viewing times.63 A number of studies, however, found no ef-
fect on smooth pursuit and saccadic movements, visual
search, or gaze, positional, and optokinetic nystagmus with
smoked cannabis up to 22 mg of D9-THC, doses that generally
exceed those used recreationally.11,41,98,154
The potential therapeutic benefits of cannabis for the
treatment of congenital and acquired nystagmus have been
analyzed by two case reports.117,124 The first case report
documented the suppression of acquired pendular nystagmus
in a patient with multiple sclerosis 90 minutes after smoking
two cannabis-containing cigarettes, with serum D9-THC
exceeding 80 mg/L and therapeutic effects lasting up to four
hours.124 Interestingly, oral nabilone up to 6 mg daily and
cannabis oil capsules up to 40 mg of D9-THC daily demon-
strated no therapeutic benefits.124 Similar trends were
observed in the second case report, which described a 10 to
40% reduction in the intensity of congenital nystagmus
30 minutes after smoking 10 mg of cannabis, which was
accompanied by improvement of 2 to 3 logMAR lines in visual
acuity.117
7. Other ophthalmic effects of cannabinoids
Other ocular effects that have been commonly reported with
cannabis consumption include conjunctival hyperemia and
changes in pupillary diameter and
reaction.3,15,18,27,30,33,39,50,54,60,80,92,102,105,106,132 Conjunctival
hyperemia is thought to be mediated by the vasodilatory
properties of cannabinoids,15,60,110 which have been previ-
ously discussed. Pharmacological studies have reported that
conjunctival hyperemia occurs within 10 minutes of inhala-
tion or intravenous administration of 10 mg and 5 mg of D9-
THC, respectively, although these effects subside within
3 hours.60,105,106 In contrast, conjunctival hyperemia did not
occur until 30 to 60 minutes after oral administration of 20 mg
of D9-THC, although the effects were more prolonged,
declining gradually over a course of 6 hours.105 Although most
studies report slower pupillary reaction to light within 4 to
6 hours of cannabis consumption,3,15,39 considerable contro-
versy remains regarding the effects on pupillary size, with a
number of studies reporting mydriasis,3,15,52,80,92,102,132 while
others have noted miosis or no significant changes in pupil-
lary diameter.18,27,30,33,39,54 A cross-sectional study of 589
drivers testing positive for D9-THC reported that mydriasis
and conjunctival injection were more common among sub-
jects with a serum D9-THC concentration of greater 2.9 mg/L,
 s u r v e y o f o p h t h a l m o l o g y 6 6 ( 2 0 2 1 ) 3 2 7 e3 4 5
while there was no association between blood D9-THC levels
and miosis.15
8. Conclusions
In conclusion, there is a public health need for developing a
greater understanding of the physiological and pathological
effects of cannabis because of the growing movement toward
its decriminalization worldwide. Although there is some evi-
dence that points toward the ocular hypotensive and neuro-
protective effects of cannabinoids, their use as a treatment for
glaucoma is limited by a large number of potential systemic
and ophthalmic side effects. Preliminary evidence from case
reports and animal studies has suggested that cannabinoids
might demonstrate some promise for the treatment of ocular
surface injury and congenital and acquired nystagmus,
although further research is required to substantiate these
early observations. Finally, a number of clinical studies have
suggested that cannabis use might be associated with neu-
roretinal dysfunction, corneal endothelial toxicity, and ocu-
lomotor deficits. These potential adverse ocular effects
warrant further investigation.
9. Method of literature search
The literature search was conducted in January 2020 using
four electronic databases, including MEDLINE, EMBASE,
PubMed, and the Cochrane Database of Systematic Reviews.
Appropriate keywords, subject headings, free text, and
thesaurus search terms were used in order to maximize
sensitivity for the search strategy and included the following
terms used in various combinations: “cannabis, cannabinoids,
marijuana, eye, pharmacology, pharmacokinetics, pharma-
codynamics, intraocular pressure, glaucoma, optic nerve,
retina, cornea, eyelid, blepharospasm, eye movement, ocular
motility, extraocular movement, idiopathic intracranial hy-
pertension, pseudotumor cerebri, benign intracranial hyper-
tension, intracranial pressure”. No time range limits were set
for the literature search. Published English abstracts for arti-
cles written in other languages were reviewed where avail-
able. The reference lists of retrieved articles were also
reviewed for further identification of potentially relevant
studies.
10. Disclosures
The authors report no conflicts of interest.
Sources of support: This research did not receive any spe-
cific grants from funding agencies in the public, commercial,
or not-for-profit sectors.
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