Physiol Biochem 2021;55(S5):1-14
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Review

Cannabidiol Signaling in the Eye and Its
Potential as an Ocular Therapeutic Agent
Alyssa Aebersold

Max Duff

Lucy Sloan

Zhao-Hui SongDepartment of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville,
Kentucky, USA

Key Words
Cannabidiol • Molecular target • Mechanism of action • Therapeutic potential • Ocularpharmacology
Abstract
Cannabidiol (CBD), the major non-intoxicating constituent of Cannabis sativa, has gained
recent attention due to its putative therapeutic uses for a wide variety of diseases. CBD
was discovered in the 1940s and its structure fully characterized in the 1960s. However, formany years most research efforts related to cannabis derived chemicals have focused on
D9-tetrahydrocannabinol (THC). In contrast to THC, the lack of intoxicating psychoactivity
associated with CBD highlights the potential of this cannabinoid for clinical drug development.
This review details in vitro and in vivo studies of CBD related to the eye, the therapeuticpotential of cannabidiol for various ocular conditions, and molecular targets and mechanisms
for CBD-induced ocular effects. In addition, challenges of CBD applications for clinical oculartherapeutics and future directions are discussed.
© 2021 The Author(s). Published by
Cell Physiol Biochem Press GmbH&Co. KG

Introduction

A brief history of cannabis
Cannabis sativa is a plant species that includes both cannabis and hemp. It first
appeared in Chinese medical texts around 2000 years ago [1]. Records from Britain indicatethat cannabis was brought from Egypt by Napoleon’s troops in the early 1800s [2]. Shortly
thereafter, hemp was introduced to Western medicine when in 1840, a hemp tincture fromground plant matter was reported to be an effective treatment for convulsive disorders andtetanus [3]. By 1851, a cannabis extract was included in the 3rd edition of the Unites States
Pharmacopoeia and readily available in American pharmacies [4, 5].
In 1913, however, cannabis was made illegal in California due to a wide-spread antinarcotics campaign [5]. Cannabis became federally illegal when Harry Anslinger from
California introduced the Marijuana Tax Act of 1937 banning the sale and use of cannabis
A. Aebersold and M. Duff contributed equally to this work.

Zhao-Hui SongDepartment of Pharmacology and Toxicology, University of Louisville School of Medicine,Louisville, Kentucky, 40292 (USA)
Tel. +1-502-852-5160, Fax +1-502-852-7868, E-Mail zhsong@louisville.edu

1Physiol Biochem 2021;55(S5):1-14
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Aebersold et al.: Cannabidiol Signaling and Therapeutic Potential for the Eyenationally [5, 6]. A negative stigma continued to develop in the US around cannabis, thenassociated with narcotics, that culminated with the Controlled Substances Act (CSA) of 1970,
which classified cannabis and cannabinoids as Schedule I with no recognized medical use [7].
Recently, America is witnessing a revival in the popularity of cannabis, both medically andrecreationally. In 1996, California was the first state to legalize cannabis for medical use andmore states have followed California in recent years [8]. To date, 16 states and Washington
D.C. have legalized both medical and recreational cannabis with an additional 26 states
legalizing medical cannabis at varying degrees. Moreover, the Agricultural Acts of 2014 and2018 removed hemp from the list of controlled substances and redefined industrial hemp as
cannabis containing less than 0.3% THC [9, 10]. As a result of the recent wave of recreationaland medical cannabis legalization, in conjunction with the end to the prohibition of hemp,
cannabis research is quickly expanding.

Cannabidiol
Cannabidiol (CBD) is one of over 120 chemicals produced by the Cannabis sativa planttermed phytocannabinoids [11, 12]. There are potentially more, as 21 previously unknown
cannabinoids were recently identified [13]. The two most abundant phytocannabinoids
in cannabis are psychoactive and intoxicating D9-tetrahydrocannabinol (THC) and nonintoxicating CBD.
CBD was first isolated in the 1940 and its structure and stereochemistry fully determinedin 1963 [14, 15]. CBD and THC are both derived from cannabigerolic acid [16]. Although
the structure of CBD was discovered before THC [15, 17], THC had been the major focus ofresearch related to cannabis and cannabinoids. This focus is driven, in part, by the activity of
THC at the canonical cannabinoid receptors, CB1 and CB2. However, there are many targets
for cannabinoids other than CB1 and CB2. For example, CBD has upwards of 65 known
targets consisting of receptors, enzymes, ion channels and transient receptor potential(TRP) channels [18].
Cannabinoids in pharmaceuticals
Cannabinoid containing drugs are approved for medical use in the USA and othercountries. The drugs differ in their formulation and indicated uses. Dronabinol (Marinol)
was the first cannabinoid-containing medicine approved by the FDA in 1985. It is a softgel capsule containing synthetic THC [19]. Syndros is an oral solution of dronabinol [20].
Cesamet (nabilone) is the third synthetic cannabinoid drug approved by the FDA in May of2006 [21]. All three are prescribed for anorexia associated with weight loss in AIDS patientsand nausea/vomiting in cancer patients [19-22]. While plant-derived THC is a Schedule
I substance, Marinol is listed under Schedule III and Cesamet and Syndros are controlled
under Schedule II [19-21].
Epidiolex is an oil formulation of CBD approved by the FDA in June of 2018 for treatmentof Lennox-Gastaut syndrome and Dravet syndrome, two rare and severe forms of pediatricepilepsy [23]. In July of 2020, it was approved for treating seizures in a rare genetic disease,tuberous sclerosis complex (TSC) [24]. Epidiolex is the only FDA approved drug containing
a compound directly derived from cannabis. It was originally classified as schedule V, but
is no longer a controlled substance as the FDA deemed it safe and effective for treatmentof the aforementioned conditions [25]. Sativex is a 1:1 alcohol solution of THC and CBDadministered as an oromucosal spray that is approved in 25 countries for the treatment ofpain and spasticity in multiple sclerosis patients [26]. Despite its approval in other countries,
Sativex is not yet approved by the FDA in the US.
Research on cannabidiol
CBD, through a variety of mechanisms and targets, has numerous potential therapeutic
uses for a plethora of conditions. The assertion of potential therapeutic actions of CBD
is based on pre-clinical data, limited clinical data and ongoing human clinical trials. Preclinical studies show that CBD has antioxidant [27, 28] anti-inflammatory [27], anti-

2Physiol Biochem 2021;55(S5):1-14
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Aebersold et al.: Cannabidiol Signaling and Therapeutic Potential for the Eye

convulsant [29, 30], neuroprotective [31], and anti-cancer properties [32]. CBD also shows
potential as a therapeutic agent in cardiovascular [33], neurological, and neuropsychiatricdisorders [26]. The completed clinical trials involve CBD use in epilepsy and seizures
disorders (21 trials), general pain and pain associated disorders (19 trials), drug abuse anduse disorders (14 trials), other neurologic conditions (4 trials) and psychiatric conditions (11trials). In addition, there are currently 85 active clinical trials in the United States containing
CBD (including Epidiolex and Sativex) on clinicaltrials.gov.
Over the past two decades, multiple studies have investigated the therapeutic potentials
of CBD in the eye. There are several published reviews of cannabinoids for treatmentof glaucoma [34, 35], and retinal disorders [36, 37]. Nevertheless, there are currently noreviews that focus solely on CBD for ocular conditions. In this review, we aim to fill the gap inliterature with a focus on CBD ocular pharmacology. We will discuss therapeutic potentials
of CBD for ocular conditions, ocular molecular targets for CBD, and mechanisms of actionsof CBD in the eye.
Results

Therapeutic potentials of cannabidiol for ocular conditions
CBD is recognized for its antioxidant, anti-inflammatory and neuroprotective properties.
In this section, we discuss the observed effects of CBD in ocular tissues and its indication forocular disorders. Specifically, we will discuss studies of CBD in corneal inflammation andpain, endotoxin-induced inflammation, excitotoxicity, diabetic retinopathy, and intraocularpressure (Table 1 and Table 2).

Corneal Inflammation and pain
The cornea is a thin and avascular tissue that is innervated by sensory nerves. Whencorneal damage occurs due to infection, surgery, or trauma, it can develop into corneal
neuropathic pain characterized by hyperalgesia, chronic and debilitating pain, andinflammation [38, 39]. The inflammatory response to corneal damage leads to the productionof proinflammatory cytokines, recruitment of leukocytes, release of pain-producing
neuropeptides, and neovascularization (NV) in the cornea [38, 39].
In a recent study, CBD was found to be anti-nociceptive and anti-inflammatory in amouse model of corneal hyperalgesia [39] (Table 1). Mice with silver nitrate cauterized
corneas that treated with CBD showed lower pain scores in capsaicin pain challenges,
indicating an antinociceptive effect of CBD. Moreover, CBD treated corneas showed lesscorneal neutrophil infiltration which is indicative of a CBD-induced anti-inflammatory
effect. Lastly, WAY100635, a 5HT1A antagonist, blocked the effects of CBD, suggesting thatthe anti-inflammatory and anti-nociceptive effects are likely mediated through activation of
the serotonin 5HT1A receptor [39]. This study highlights CBD as a potential therapeutic forcorneal pain and inflammation.
Table 1. Therapeutic potentials of CBD for ocular conditionsǤ

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Physiol Biochem 2021;55(S5):1-14
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Aebersold et al.: Cannabidiol Signaling and Therapeutic Potential for the Eye

Table 2. The effects of CBD on intraocular pressure 

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The mammalian retina contains three distinct glia cells types: Müller cells, astrocytes,
and microglia. Microglial cells are the residentmacrophages of the retina and play importantroles in retinal homeostasis [40]. Activation of microglial cells induces the release of proinflammatory cytokines, such as IL-1b and TNFα,
instigating an inflammatory response.
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Prolonged microglial activation and chronic inflammation contribute to disease pathology
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The degree of microglial activation may relate
to the severity of injury. In vitro and invivo treatment with lipopolysaccharide (LPS), an endotoxin from bacteria, is used to study
inflammation through activated microglia [41]. Extracellular adenosine can function as anendogenous anti-inflammatory agent suppressing
immune cell responses. For example,
adenosine inhibits pro-inflammatory cytokine
expression such as TNFα [42]. However,
the anti-inflammatory effects of adenosine areshort, as it is rapidly taken up by adjacentcells. Inhibitors of adenosine uptake may enhance the adenosine signaling and endogenous
activity [43]. CBD has been shown to decrease
TNFα expression and inhibit equilibrative
nucleoside transporter 1 (ENT1) reuptake of adenosine in LPS treated primary microglia
cells and retinas from LPS treated rats [44] (Table1). The effect of CBD is primarily mediated
through the activation of the A2A receptor, the most abundant adenosine receptor in the ratretina, as a result of CBD-induced inhibition of adenosine
reuptake [44]. These results suggestthat CBD may be a good anti-inflammatory agent
for endotoxin-induced retinal damage.


Excitotoxicity
Excitotoxicity is implicated in glaucoma as a result of elevated levels of the excitatoryneurotransmitter glutamate in the retina [45, 46]. Over-stimulation of a glutamate receptor,
such as the N-methyl-D-aspartate (NMDA) receptor, a sodium and calcium permeablechannel, results in excess intracellular calcium. Increased intracellular calcium is cytotoxic,
as well as induces release of more glutamate, cellular swelling, and eventually cell death [47,48]. The process of excitotoxicity also involves the activation of nitric oxide (NO) synthase
and accumulation of NO and superoxide. Overproduction of these oxygen species produces
oxidative stress leading to lipid peroxidation, mitochondrial dysfunction, DNA damage andeventually, cell death [46, 49].
One method to measure oxidative stress is through peroxynitrite/nitrotyrosine
formation and lipid peroxidation [50]. Peroxynitrite is a product of a superoxide reaction
primarily responsible for oxide- and superoxide-dependent cytotoxicity. It is highly unstable,highly reactive and difficult to measure, therefore the presence of peroxynitrite is measured
by levels of nitrotyrosine which is formed by nitration of protein-bound tyrosine [50].

4Physiol Biochem 2021;55(S5):1-14
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Aebersold et al.: Cannabidiol Signaling and Therapeutic Potential for the Eye

In a rat model of neurotoxicity, intravitreal injection of NMDA induces nitrite/
nitrate accumulation, lipid peroxidation, nitrotyrosine production, apoptosis, and innerretinal neuronal loss [51]. CBD treatment decreased levels of peroxynitrite/nitrotyrosine
production, prevented neurotoxicity, and lowered the amount of apoptosis (Table 1). The
neuroprotective effect of CBD was dependent upon blockage of nitrotyrosine formation[51]. The retinal antioxidant and neuroprotective effects of CBD in the rat model of retinal
excitotoxicity suggest that it may be beneficial as a neuroprotectant for the treatment ofocular conditions such as glaucoma.

Diabetic retinopathy
Globally, diabetic retinopathy is a major cause of vision loss. Oxidative stress, caused byreactive oxygen species, is one of the main factors in diabetic retinopathy progression [52].
The retina is particularly sensitive to reactive oxygen species because it is the mostmetabolically active tissue in the body and therefore easily affected by diabetes [52]. Diabetic
retinopathy is characterized by retinal hypoxia, increased retinal vascular permeability, andretinal angiogenesis [52, 53]. These processes cause the death of inner retinal and ganglion
cells and ultimately, vision loss.
Inflammation is another important component in diabetic retinopathy. Hyperglycemia
triggers the release of proinflammatory cytokines such as vascular endothelial growth factor(VEGF), Intercellular adhesion molecule-1 (ICAM-1), and Tumor necrosis factor α (TNFα)[54, 55]. The elevation of these proinflammatory cytokines further facilitates pathologicchanges in diabetic retinopathy as a result of neovascularization by VEGF, leukocyte
adhesion and transmigration by ICAM-1 and further release of cytokines by TNFα [53-55].
Research shows that VEGF, ICAM-1, and TNFα are upstream regulators of proinflammatory
and oxidative stress pathways which activate p38 MAP kinase [55]. Activation of p38 MAP
kinase has been reported in diabetic retinas in high glucose conditions and is implicated inretinal ganglion cell apoptotic death [56-58]. In addition, p38 MAP kinase activity is linked
to vascular hyperpermeability in diabetic retinas [55].
One report assessed the therapeutic potential of CBD in a streptozotocin-induced diabetic
rat model through measurement of oxidative stress and proinflammatory cytokines [58](Table 1). The antibiotic streptozotocin (produced by Streptomyces achromogens) induces
type 1 diabetes through partial destruction of the pancreatic β cells after a single injection.
In the streptozotocin-induced diabetic rat model there were increases in oxidative stress,
retinal neuronal cell death, and vascular hyperpermeability associated with increased levelsof VEGF, ICAM-1, TNFα, and activation of p38 MAP kinase [58]. Importantly, CBD decreased
reactive oxygen species (ROS) formation, suppressed VEGF, ICAM-1, and TNF-a expression,and prevented activation of p38 MAP kinase [58]. Taken together, these findings suggest that
CBD is a potential therapeutic agent for diabetic retinopathy capable of protecting against
inflammation, retinal neuronal cell death, and preservation of the blood-retinal barrier.
Intraocular pressure
An estimated 3 million Americans have glaucoma, a major cause of irreversible blindness
with no cure [59, 60]. Even with therapeutic intervention, approximately 10% of thosediagnosed still experience vision loss [59, 60]. Although not always elevated, intraocularpressure (IOP) is currently the only treatable factor of the disease. Drug therapies suchas prostaglandin analogs, b-adrenergic antagonists, cholinergic agonists, a2-adrenergic
agonists, and carbonic anhydrase inhibitors are used either independently or in combination,
to reduce ocular pressure [61, 62]. In 2018, the FDA approved Rhopressa, a Rho kinase
inhibitor, as a novel IOP-lowering drug [61, 62]. These IOP-lowering drugs work to decrease
aqueous humor production in the ciliary body and/or increase aqueous humor drainage
through the trabecular meshwork or the uveoscleral pathway [61, 62]. For patients that do
not respond to the above drugs or drug combinations, or patients developed tolerance toexisting drugs, novel medications are needed to lower IOP and to prevent future optic nerve
damage and vision loss associated with glaucoma.

5

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THC is well documented and is consistently shown to decrease IOP [63-69]. However,
the effect of CBD on IOP is much more controversial (Table 2). So far, nine independent
reports have published regarding the effects of CBD on IOP: Four reports indicate that CBD
has no effect on IOP [70-73], three reports demonstrate that CBD decreases IOP [74-76], andtwo reports show an CBD-induced increase in IOP [63, 64].
A recently published study in mice showed an increase in IOP at 1 and 4 hours post
topical application of CBD at a 5 mM dose [63]. Interestingly, CBD significantly decreased IOP
1 hour post treatment in CB1 knockout mice and the effect is attributed to GPR18 activation[63]. This article was cited by the American academy of ophthalmology with the headline“CBD oil may worsen glaucoma” [77]. Altogether, the literature does not conclusively showwhether CBD increases, decreases, or causes no change to IOP.

Molecular targets and mechanisms for CBD-induced ocular effects
CBD has numerous targets in different categories such as G protein-coupled receptors,
enzymes, nuclear receptors, ligand-gated ion channels, transient receptor potential (TRP)
channels, and potentially others [18]. Many of these CBD targets are expressed in the eye.
This section of the review focuses on the effects of CBD on these molecular targets in the eye(Table 3). It is important to point out that systemic CBD administration may result in CBD
metabolites that act through molecular mechanisms different from those of CBD itself.

Serotonin receptor
Thapa et al. showed that CBD can reduce the pain score and neutrophil infiltration inmice after corneal cauterization and capsaicin challenge and this effect is mediated, in part,by 5-HT1A agonism [39] (Table 3). The hypoalgesic and anti-inflammatory effects of CBDseen in wild-type mice were still present in CB2 knockout mice, as well as CB2 knockout
mice pretreated with AM251, a CB1 selective antagonist. These results suggest that the
hypoalgesic and anti-inflammatory effects of CBD are not mediated by CB1 or CB2 receptors.
Moreover, the effects of CBD were blocked in wild-type mice treated with WAY100635, a
5-HT1A receptor antagonist. These data demonstrate that the effect of CBD on corneal
hyperalgesia inflammation is mediated by 5-HT1A agonism [39]. In support of the findingsof Thapa et al. in the eye [39], CBD has been shown to be a 5-HT1A agonist in other tissues aswell [78, 79].

Equilibrative nucleoside transporter 1 and A2A adenosine receptor
CBD has been shown to inhibit TNF-α response to LPS stimulation by inhibiting
adenosine reuptake in retinal microglia via adenosine equilibrative nucleoside transporter 1(ENT1) [44] (Table 3). Cells that were pre-treated with CBD showed inhibition of LPS-induced
release of TNF-α. The inhibition of TNF-α release was not further enhanced nor inhibited by
pretreatment of NBMPR, an ENT1 selective inhibitor [44]. These results suggest that CBD
Table 3. Molecular targets and mechanisms for CBD-induced ocular effects

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↓ pain score↓neutrophil infiltration

↑IOP in wildǦ ↓IOP in CB1 knockout mice↓ growth cone size↓filopodia number
↑chemorepulsion↑ intracellular CaʹΪ↑ current density ↑ membrane conductance ͷǦ ͳǡ  ͷǦ ͳͳͲͲ͸͵ͷͳǡ ͳ ʹ ǡ  ʹʹͶͳ͵ͺͷͳ ͳͺǡ   ͳͺͳͻͳͺͷͷǡ  ͷͷ  ʹǡ  ʹ  Ǧͻ͸͵͸ͷʹǡ  ʹ  Ǧͻ͸͵͸ͷ

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Physiol Biochem 2021;55(S5):1-14
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and Biochemistry Published online: 14 May 2021 Cell Physiol Biochem Press GmbH&Co. KG

Aebersold et al.: Cannabidiol Signaling and Therapeutic Potential for the Eyecompetes with NBMPR for ENT1. Furthermore, CBD inhibited TNF-α in the presence of A1A
adenosine antagonist CPX, whereas the effect of CBD was blocked by pre-treatment with A2A
adenosine receptor antagonist ZM241385. When CBD and adenosine were co-administered,
TNF-α release was greatly reduced showing a synergistic effect that is greater than wheneither compound was administered alone [44]. In sum, Liou et al. showed that CBD inhibits
adenosine reuptake through ENT1, which indirectly causes the enhanced activation of A2A
adenosine receptor and reduction of TNF-α release [44]. The effects of CBD on ENT1 andadenosine receptors are corroborated by reports in rat and mouse striatal terminals [80]and in EOC-20 murine microglial cells [81].

CB1 and GPR18
CB1 is a well-established cannabinoid receptor and CBD has been shown to be anegative allosteric modulator of CB1 [82]. CB1 is expressed in the anterior of the eye inthe ciliary and corneal epithelium and trabecular meshwork, as well as the posterior of theeye in the retina [83, 84]. GPR18 is a recently identified putative cannabinoid receptor andresearchers have shown that GPR18 is activated by N-arachidonoyl glycine, a carboxylic
metabolite of the endocannabinoid anandamide [85]. GPR18 was further characterized in2012 when anandamide and THC, in addition to N-arachidonoyl glycine, were shown tostimulate GPR18-mediated ERK1/2 phosphorylation [86]. Furthermore, CBD was shown to
be a biased agonist for GPR18 in 2014 [87]. GPR18 is widely expressed in the ocular tissues,
specifically in the ciliary and corneal epithelium, trabecular meshwork, and retina [88, 89].
To date a single paper has reported on the effect of CBD at both CB1 and GPR18
receptors in the eye (Table 3). Miller et al. showed that CBD increases IOP in wild-typemice but decreases IOP in CB1 knockout mice [63]. No CBD effect on IOP was seen in CB1
knockout mice pretreated with O-1918, a GPR18 antagonist. This report highlights that CBD
has independent actions both on CB1 as a negative allosteric modulator to raise IOP and on
GPR18 as an agonist to lower IOP [63].

GPR55
GPR55 is an orphan receptor activated by lysophosphatidylinositol (LPI) [90]. GPR55
is frequently referred to as a putative cannabinoid receptor because it is activated byphytocannabinoids, endocannabinoids, and synthetic cannabinoids [91]. CBD has beenshown to be a GPR55 antagonist [91].
One group studied the involvement of GPR55 in the retina during development [92].
Growth cones are regions of developing neurites which facilitate axon growth by extending
actin filaments into filopodia. Filopodia guide the growth cone in response to chemical
or electrical stimulus. Cherif et al. found that GPR55 is expressed in growth cones during
development, and its activity regulates morphology and growth [92]. Mouse embryonicneurons from GPR55 knockout mice showed smaller growth cones, fewer filopodia, anddecreased outgrowth compared to neurons from wild type mice. Furthermore, retinal
ganglion cells from wild type mice treated with GPR55 agonists LPI and O-1602 showed
increased growth cone size and filopodia number and demonstrated chemoattraction. In
contrast, CBD, a GPR55 antagonist, decreased growth cone size and filopodia number, andinduced chemorepulsion (Table 3). GPR55 ligands had no effects in embryonic neurons fromGPR55 knockout mice [92]. These data suggest that CBD inhibits growth cone activity andaxonal growth in the retinain this experimental model.
TRPV Channels
Transient receptor potential (TRP) ion channels are trans-membrane proteins involvedin a wide range of chemical and physical sensations including smell, taste, vision, temperature,and pressure [93]. CBD has been shown to be an agonist of TRPV 1, 2, 3, 4 and TRPA1 [94,95]. TRPV channels are implicated in the activation and desensitization of inflammatory
processes and chronic pain [96, 97]. Therefore, CBD may be a desirable therapeutic forchronic pain because it can activate and desensitize the TRPV channels [94, 95].

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Aebersold et al.: Cannabidiol Signaling and Therapeutic Potential for the Eye

One group investigated the calcium influx activity of TRPV2 channel activity in
porcine retinal pigment epithelial (RPE) cells [98]. They found that CBD strongly increased
intracellular Ca2+ levels (Table 3). In the presence of TRPV2 channel inhibitor SKF96365,
CBD-mediated Ca2+ intracellular increase was partially blocked [98]. These data suggest that
CBD modulation of Ca2+ involves TRPV2, as well as other TRPV channels that are not blocked
by SKF96365.
Another study looked at TRPV2 channel regulation in ARPE-19, a human RPE cellline [99]. ARPE-19 cells preincubated with CBD demonstrated a 3-fold increase in current
density, an effect that was blocked by SKF96365 (Table 3). CBD also increased membrane
conductance and TRPV2 surface expression. TRPV2 are heat sensitive ion channels and heatfurther increased the CBD mediated increase in membrane conductance. Furthermore, thePI3 kinase inhibitor LY294002 abolished the effect of CBD on membrane conductance andsurface expression. These data led to the conclusion that CBD acts through activation of
TRPV2 and a PI3 kinase dependent pathway to increase cell surface expression of TRPV2channels [99].
Discussion

Challenges of using CBD as an ocular therapeutic agent
There are several challenges for practical applications of CBD as an ocular therapeutic
agent. Some of these challenges include poor bioavailability, difficulty in topical delivery, andshort duration of action.

Bioavailability
An FDA approved drug containing CBD is administered orally [23]. However, oral
administration is inefficient due to poor bioavailability of CBD. Low bioavailability of CBD
requires that it to be administered at high doses to achieve therapeutic effects. However, aconsequence of high dosing is an increase in adverse side effects [100, 101]. The potential
adverse effects of CBD include drowsiness, dry mouth, reduced appetite, nausea, andgastrointestinal issues. The most notable serious adverse side effects of CBD are abnormalliver function tests (elevated liver enzymes) [102].
One major factor contributing to the poor bioavailability of CBD is its extensive first passmetabolism [100, 101]. Another factor limiting CBD bioavailability is its hydrophobicity. The
chemical structure of CBD contains aromatic rings and an aliphatic side chain, which make ita highly hydrophobic molecule. The hydrophobicity of CBD limits its solubility in water andmakes diffusion across aqueous barriers a rate limiting step for diffusion and absorption[100, 101].

Topical delivery
Therapeutic treatments for ocular conditions are frequently administered orally or
topically to the eye. Extensive first pass metabolism of CBD prevents a significant amount ofdrug reaching the eye from oral administration. Therefore, topical administration of CBD isdesired.
Developing an ocular topical delivery system is a difficult task. The eye contains
sophisticated protective mechanisms and physical barriers to prevent foreign material fromentering, which includes the multi-layered cornea and pre-corneal tear film. The alternating
lipophilic and hydrophilic nature of the cornea makes ocular drug delivery exceptionallydifficult. As a result, less than 5% of drugs applied topically enter the eye [103-105].
CBD is highly hydrophobic and insoluble in water. Studies applying CBD topically usednon-aqueous vehicles for delivery [39, 63, 75]. Previously, CBD was topically delivered tothe eye in mineral oil, sesame oil, soybean oil, and a soya oil/water emulsion, Tocrisolve[39, 63, 75]. In one report, CBD delivered in mineral oil produced an IOP-lowering effectwhilst the effect is absent in sesame oil [75]. With Tocrisolve as a vehicle, Miller et al. [63]8Physiol Biochem 2021;55(S5):1-14
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and Biochemistry Published online: 14 May 2021 Cell Physiol Biochem Press GmbH&Co. KG

Aebersold et al.: Cannabidiol Signaling and Therapeutic Potential for the Eyedemonstrated that a high dose of CBD increases IOP in wildtype mice, but decreases IOP
in CB1 knockout mice. This indicates that at large doses CBD produces off-target effects
which are detrimental. Since CBD has at least 65 targets [18], off-target effects of CBD athigh doses are very likely. These results highlight a critical need for a vehicle with high ocularpermeation to administer CBD in a therapeutically relevant dose.

Duration of action
Another difficulty associated with CBD as an ocular therapeutic is its short durationof action, e.g., in lowering IOP. One report indicated CBD decreased IOP 1-2 hours after
topical application to rabbit eyes, and IOP-lowering effects of CBD lasted for up to 5 hours
after intravenous administration [75]. In another study, CBD required constant infusion via
minipump to induce a decrease in IOP [76]. A short duration of action implies that CBD needs
to be applied multiple times throughout the day to maintain therapeutic effects. However,patient compliance will be worsened with frequent dosing. In contrast, greater patientcompliance is observed in prescribed medications with once daily dosing [106].
Future directions
So far, CBD has been studied preclinically for its therapeutic potentials in glaucoma,
diabetic retinopathy, and corneal injury. Considering its anti-inflammatory, antioxidant, andneuroprotective properties, in the future it would be worthwhile to explore the potential of
CBD in treating other ocular conditions, such as uveitis and age-related macular degeneration.
It is important to elucidate the mechanisms of action of CBD in the eye. As highlighted
in this review, there are multiple molecular targets of CBD in the eye. Understanding whichtargets are responsible for the therapeutic and adverse effects of CBD is critical for its
effective and safe use as an ocular therapeutic agent.
Finally, in the future, solving the puzzles of dosing and proper formulation for efficient,prolonged topical delivery will usher CBD forth for numerous potential ocular therapeutic
indications.
Acknowledgements

The authors acknowledge the support of Department of Pharmacology and Toxicology,
University of Louisville School of Medicine.
Author Contributions
AA and MD wrote the initial versions of the review. LS and ZHS edited and finalized themanuscript.

Funding Sources
While writing this manuscript, AA is supported in part by NIH grant T32 ES011564;
MD is supported in part by NIH grant R25 CA134283; LS is supported in part by Universityof Louisville Integrated Programs in Biomedical Sciences (IPIBS) Fellowship; and ZHS is
supported in part by NIH grant EY030186.
Statement of Ethics
The authors have no ethical conflicts to disclose.
Disclosure Statement

The authors have no conflicts of interest to declare.

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