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The arguments for and against application in glaucomatous retinopathy

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Biomedicine & Pharmacotherapy 86 (2017) 620–627

Available online at ScienceDirect www.sciencedirect.com

Review

The arguments for and against cannabinoids application in

glaucomatous retinopathy

a b b c,

Yunes Panahi , Azadeh Manayi , Marjan Nikan , Mahdi Vazirian *

a

Chemical Injuries Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran

b

Medicinal Plants Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran

c

Pharmacognosy Department, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran

A R T I C L E I N F O A B S T R A C T

Article history:

Received 29 October 2016 Glaucoma represents several optic neuropathies leading to irreversible blindness through progressive

Received in revised form 21 November 2016 retinal ganglion cell (RGC) loss. Reduction of intraocular pressure (IOP) is known as the only modifiable

Accepted 27 November 2016 factor in the treatment of this disorder. Application of exogenous cannabinoids to lower IOP has attracted

attention of scientists as potential agents for the treatment of glaucoma. Accordingly, neuroprotective

Keywords: effect of these agents has been recently described through modulation of in the

Cannabis sativa

eye. In the present work, pertinent information regarding ocular endocannabinoid system, mechanism of

Endocannabinoid system

exogenous cannabinoids interaction with the ocular endocannabinoid system to reduce IOP, and

Glaucoma

neuroprotection property of cannabinoids will be discussed according to current scientific literature. In

Intraocular pressure

addition to experimental studies, bioavailability of cannabinoids, clinical surveys, and adverse effects of

Marijuana

Neuroprotection application of cannabinoids in glaucoma will be reviewed.

© 2016 Elsevier Masson SAS. All rights reserved.

Contents

1. Introduction ...... 1

2. Natural source of cannabinoids ...... 3

3. Biosynthesis of cannabinoids ...... 3

4. Chemistry and bioavailability of some natural cannabinoids ...... 3

5. Endocannabinoid system in the eye ...... 3

6. Effects of cannabinoids in lowering of IOP ...... 3

7. Effects of cannabinoids in neuroprotection ...... 4

8. Adverse effects of marijuana ...... 5

9. Discussion ...... 5

Conflict of interest ...... 6

References ...... 6

1. Introduction humor formation and draining out, is the only known modifiable

risk factor for prevention of glaucoma progress. Although, the

Glaucoma, a neurodegenerative eye disease, known as a major elderly are at higher risk for the disease, glaucoma can develop in

factor for irreversible blindness. It is predicted that more than 80 young adults, children, and infants [2,3]. Damage of optic nerve

million people by 2020 will be affected by glaucoma leading to at most commonly occurs due to high IOP and progressive

least 6–8 million bilaterally blind worldwide [1]. Increased degeneration of retinal ganglion cells (RGCs) leading to irreversible

intraocular pressure (IOP) >22 mmHg, due to imbalance of aqueous vision loss [4]. Blood flow alteration as a result of IOP, produces

hypoxia and ischemia in the retina and optic nerve [5]. Standard

treatments are restricted to reduction of IOP using medications or

surgery. While, these types of treatments are not effective in some

* Corresponding author.

patients and a subset of glaucoma is not associated with high IOP

E-mail address: [email protected] (M. Vazirian).

http://dx.doi.org/10.1016/j.biopha.2016.11.106

0753-3322/© 2016 Elsevier Masson SAS. All rights reserved.

Y. Panahi et al. / Biomedicine & Pharmacotherapy 86 (2017) 620–627 621

[6]. Protection of retinal ganglion cells from damage and death enzymes of their synthesis and metabolism and

directly can be considered as a novel approach to combat glaucoma receptors in the retina [15]. The physiological and pharmacological

[7]. activities of endocannabinoids along with natural and synthetic

Resin glands located on secreting trichomes of female-plant cannabinoids are mediated mostly by two receptors, cannabinoid

flowers of sativa (Cannabaceae family) contain consider- receptor 1 (CB1) and 2 (CB2) [13]. Receptors

able amount of cannabinoids. Smaller quantity of these chemically of CB1 are predominantly expressed in the central nervous system

active compounds was found in the leaves of the cannabis plant (CNS), while receptors of CB2 are mainly located in peripheral

(marijuana) [8]. Several cannabinoids have been isolated of the tissues and immune system and also found in the CNS [16–18].

plant, of which D9- (D9-THC), cannabichro- (N-arachidonoylethanolamine, AEA) and 2-arachido-

mene (CBC), (CBG), (CBN) and cannabi- noylglycerol (2-AG) (Fig. 1) are the two most studied endogenous

diol (CBD) are the most relevant in the amount of cannabinoids. cannabinoids. Endocannabinoids also activate other targets,

Synthetic modulators of endogenous cannabinoid system has been including non-CB1, non-CB2 G-protein-coupled receptors and

also investigated for their therapeutic potentials in addition to various ion channels [19]. Therapeutic effects of cannabinoids in

phytocannabinoids (Fig. 1) [9]. These compounds possess thera- CNS pathologies like Parkinson’s disease, Alzheimer’s disease,

peutic effects on cancer, pain, emesis, inflammation, obesity, and Huntington disease, head trauma, and multiple sclerosis (MS) have

neurodegenerative diseases along with other psychotropic prop- been reported in the previous studies [20–24]. In this review, the

erties [10–13]. knowledge of therapeutic potential of cannabinoids will be

The beneficial function of cannabinoids in ocular physiology particularly discussed in glaucoma. Relevant information regard-

and disease dates back to 1971 when it was reported that smoking ing chemistry and bioavailability of cannabinoids, the ocular

marijuana lower the IOP [14]. Role of cannabinoids in retinal endocannabinoid system, and ocular hypotensive as well as

circuitry and vision is supported by the presence of the functional neuroprotective properties of cannabinoids will be provided in

endocannabinoid system including endogenous cannabinoids, the treatment of glaucoma.

OH OH O

OH OH

O O

2-arachidonyl glycerol (2-AG) 2-arachidonyl glyceryl ether

OH

H O OH N OH N O H

anandamide (AEA) N-arachidonyl dopamine (NADA)

Endocannabinoids

OH H OH OH H H H

O O HO

delta9-tetrahydrocannabinol cannabinol

Natural cannabinoids

O HO O OH H H O H N O O H

N O WIN55212-2

Synthetic cannabinoids

Fig. 1. Chemical structures of some cannabinoids.

622 Y. Panahi et al. / Biomedicine & Pharmacotherapy 86 (2017) 620–627

2. Natural source of cannabinoids formula of C21H26O2, molecular mass 310.4319 g/mol, was isolated

from the plant cannabis. Average bioavailability of inhaled CBN is

Cannabis has three specious including C. sativa, , 38% (range 8–65%) [9,33,45].

and . About 113 cannabinoids with various

effects were isolated from C. sativa which is an annual herbaceous 5. Endocannabinoid system in the eye

plant [25]. There are some studies indicate that C. indica contains

higher amount of D9-THC than CBD, while C. sativa have more In addition to the human retina, presence of CB1 and CB2 has

amount of CBD [26]. Wild specious of cannabis, C. ruderalis, lack been shown in several specious. Generally, CB1 is found in cones,

meaningful quantity of psychoactive cannabinoids [27]. horizontal cells, amacrine, some bipolar cells, RGCs, and ganglion

cell axons [13,46–49]. In human, receptors of CB1 are expressed in

3. Biosynthesis of cannabinoids outer segments of photoreceptor cells, outer plexiform layer, inner

plexiform layer, two synaptic layers of the retina, inner nuclear

Cannabinoids are primarily synthesized in glandular trichomes layer, ganglion cell layer, and retinal pigment epithelium cells. CB2

of flowers and, to a lesser extent, leaves of the female plant from receptors are found in human retinal pigment epithelium cells

fatty acid and isoprenoid precursors [28]. A type III polyketide [47,50,51]. Immunocytochemical methods revealed that transient

synthase is the first enzyme in the cannabinoid synthesis pathway receptor potential vanilloid type 1 (TRPV1), a ligand-gated,

which catalyzes hexanoyl-CoA condensation with three malonyl- nonselective cation channel, is widespread in the retina of rabbit

CoA molecules to produce olivetolic acid [28,29]. Olivetolic acid is and other mammals [52]. Both receptors of cannabinoids, CB1 and

then converted by aromatic prenyltransferase to cannabigerolic CB2, are G-protein-coupled receptors (GPCRs). G-protein-coupled

acid. D9-Tetrahydrocannabinolic acid and cannabidiolic acid, are inwardly rectifying potassium channels (GIRKs) is affected by

yielded by the major cannabinoids oxidocyclase enzymes from activation of CB1 receptor, which interacts with several ion

2+ +

. Subsequent non-enzymatic decarboxylation channels including Ca and K channels [13]. In addition,

of D9-tetrahydrocannabinolic acid and cannabidiolic acid forms cannabinoid receptors regulate signal transduction through cyclic

D9-THC and CBD, respectively [30]. AMP (cAMP) and inhibit inducible nitric oxide synthase (iNOS)

production which is a critical contributor of their anti-inflamma-

4. Chemistry and bioavailability of some natural cannabinoids tory and neuroprotective effects [53]. Other cannabinoid related

receptors like G-protein-coupled receptor 18 (GPR18) and GPR55

D9-Tetrahydrocannabinol (D9-THC) with chemical formula of are expressed in the retina according to the some experiments

C21H30O2, molecular mass 314.469 g/mol [31], is extracted from the [54,55].

buds, leaves and flowers of C. sativa (Fig. 1). The compound is also The two main endocannabinoid ligands namely AEA and 2-AG

synthetically available and metabolized to 11-hydroxy D9-THC are discovered in the retina of human. 2-AG is detected at high

when enters the blood stream, its metabolite absorbs into the level, whereas AEA is found at lower level in the human retina

adipose tissue and stays for 30 min. Subsequently, it release back [19,56]. Fatty acid amide hydrolase (FAAH), monoacylglycerol

into the blood circulation and entering the brain. The bioavailabil- lipase (MGL), and cyclooxygenase-2 (COX-2) enzymes regulate the

ity of D9-THC via inhalation ranges between about 10-35% [32–34] cellular level of endogen cannabinoids in the retina [15,50,57,58].

and 6-40% when administered in the eye [35]. The maximum peak The COX-2 enzyme can directly metabolize AEA and 2-AG to

of D9-THC were evaluated between 94.3-155.1 ng/mL after prostaglandin ethanolamides (prostamides) and prostaglandin

smoking one cigarette containing 1.32- 2.54% D9-THC [36]. The glyceryl esters, respectively [59]. Responsible enzymes for the

rectal and oral bioavailability of D9-THC were calculated to be synthesis of endocannabinoids, N-acyl phosphatidylethanolamine

13.5% and 5–20%, respectively [37]. The rectal bioavailability of D9- phospholipase (D-NAPE-PLD) and diacylglycerol lipase (DAGL)

THC is higher since avoid hepatic first pass effect, however, the have been found in the retina of rodents and other mammals as

bioavailability through this route fluctuates with different well [13].

formulations [38]. Based on Wall et al. study, participants were Activation of CB1 in the retina cause modulation of function of

administered with 15–20 mg of D9-THC dissolved in sesame oil, ion channels which may influence retinal circuitry, release of

observed maximum plasma concentrations after 4–6 h [34]. neurotransmitters, and neuroprotection. Endocannabinoids may

Ohlsson et al. reported the oral bioavailability of D9-THC in a regulate spontaneous transmitter that is important in network

chocolate cookie was 6 Æ 3%. Low rates of absorption after oral maintenance in amacrine cells and other inhibitory interneurons

administration of D9-THC can occur for many different reasons, [13,60]. Topical administration of synthetic CB1 agonist causes IOP

including considerable first pass metabolism to active/inactive drop in rabbits, non-human primates, and glaucomatous human

metabolites in the liver, degradation of drug in the digestive system [61–63], through decrease of aqueous humor flow and inhibition of

and various absorption [33,39]. Administration of a liposome- their inactivation by FAAH or cellular reuptake [64,65].

entrapped preparation of D9-THC through intratracheal route Cannabinoids modulate release of several neurotransmitters in

lowered IOP more efficiently compared to intraperitoneal way the retina such as dopamine, glutamate, gamma aminobutyric acid

indicating rapid absorption of the drug from alveoli to systemic (GABA), and noradrenaline [66–69]. The cannabinoid system play a

circulation. The effect of both intratracheal and intraperitoneal role in the phototransduction cascade, the dark and light retinal

routes remained for 1.5–2 h and its short duration may occurs due sensitivity and adaptation and the retinal contrast sensitivity on

to the large volume of distribution of D9-THC (3.4 L/kg) [40]. the goldfish retina [70,71]. Presence of functional endocannabinoid

Optical application of D9-THC to the cornea showed limited system in the eye and their decrease in certain tissue of

bioavailability with ocular irritation and toxicity [2,41]. glaucomatous human eye like ciliary body, an important tissue

Cannabidiol (CBD) with chemical formula of C21H30O2, molec- in the regulation of IOP, support their role in the eye physiology and

ular mass 314.46 g/mol [31], soluble in organic solvents but glaucoma pathology [19].

insoluble in water [42], is found throughout the whole part of

hemp and marijuana, including flowers, stalk and seeds. Previous 6. Effects of cannabinoids in lowering of IOP

studies by Mechoulam et al. [43] and Scuderi et al. showed oral

bioavailability of CBD was 13–19% and its inhaled bioavailability Topical administration of WIN-55-212-2, a synthetic cannabi-

was 11–45% (mean 31%) [44]. Cannabinol (CBN) with chemical noids, which binds both CB1 and CB2 decreased IOP in

Y. Panahi et al. / Biomedicine & Pharmacotherapy 86 (2017) 620–627 623

glaucomatous rats without any psychotropic symptoms. The reduced the production of actin stress fibers and focal adhesion

therapeutic effect of the compounds remained over the period [39]. Nonpsychotropic cannabinoids like HU-211, abnormal

of treatment for 4 weeks [72]. This finding is consistent with cannabidiol (abn-CBD), and cannabigerol-dimethyl heptyl (CBG-

another experiment which showed reduction of IOP by adminis- DMH) could decrease IOP independent to CB receptors [87]. These

tration of WIN-55-212-2 in patients suffering of glaucoma in a time findings highlight the potential therapeutic effect of cannabinoids

and dose dependent manner [62]. Endocannabinoids have been in the reduction of IOP.

found to reduce IOP without any noticeable toxic effects [65,73].

Results of clinical experiments regarding administration of 7. Effects of cannabinoids in neuroprotection

marijuana or cannabinoids in individuals suffering of glaucoma

were summarized in Table 1. Neuroprotective property of cannabinoids has been demon-

In a nonrandomized study, 9 patients were treated with inhaled strated in CNS neurodegenerative diseases with different mecha-

marijuana or D9-THC capsule every 4 h. All of them showed nisms. Endocannabinoids exhibit neuroprotection in some models

beneficial effect of treatment on IOP decrease, while seven patients of neurodegenerative diseases. Activation of presynaptic CB

lost beneficial effect of the drug due to treatment tolerance [78]. inhibits glutamate release improving the control of neuronal

Vasoactivity of abnormal-cannabidiol, a nonpsychoactive atypical excitability and regulating synaptic plasticity [88,89]. Accordingly,

cannabinoid, is predominantly endothelium and vessel tone CB2 activation modulates inflation of neurons through the

dependent. Abnormal-cannabidiol is an agonist at the ananda- microglya, macrophages and dendritic cells, and increasing the

mide-activated endothelial CBeR receptor but is devoid of activity production of endocannabinoids [90].

at the CB1 or CB2. However, antagonist of CB1 block vasoactivity of Retinal damage especially in RGCs due to glutamate was

abnormal-cannabidiol suggesting that both CB1 and anandamide- reported in the early studies [91–94]. Antagonists of glutamate

activated endothelial CBeR receptor play role in retinal vasoactivity receptors have been conferred neuroprotection in models of RGCs

and blood flow [83]. Activation of CB1 in the ciliary blood vessels death confirmed involvement of excitotoxicity cascade in glauco-

may cause and reduce production of aqueous humor ma [95–97]. Activation of glutamate receptors increase intracellu-

[5]. lar level of calcium which subsequently activate nitric oxide

Treatment of non-pigmented epithelium of the ciliary body synthase leading to release of nitrogen radicals and death of RGCs

with D9-THC, AEA, and its stable analog , [5]. RGCs death triggered by intravitreal administration of N-

enhance expression of COX-2 in the cell culture. As a result, the methyl-D-aspartate (NMDA), an amino acid mimics glutamate

amount of prostaglandin E2 (PGE2) and metalloproteinases-1, -3, action, was prevented by systemic administration of D9-THC or

and -9 were increased in the supernatant and matrix of cell culture. CBD with reduction of peroxynitrites in rats. This protective effect

These mediators play role in aqueous humor outflow pathways and was partially inhibited by a selective CB1 anatgonist, SR141716A

thus IOP regulation [84]. Therefore, it is suggested that reduction of [98]. Treatment with D9-THC for 20 weeks decreases IOP and

IOP by cannabinoids might mediated through CB receptors as well reduces death of RGCs approximately by 75% in the animal model

as cyclooxygenases activation [5]. In animal model of glaucoma, of glaucoma [12]. Intraretinal level of AEA was reduced in retinal

IOP lowering effect of D9-THC attenuated with indomethacin and ischemia induced by ocular hypertension, which seems happened

steroids that block cyclooxygenases [85]. as the result of alteration in endocannabinoid metabolism in the

Activation of CB1 by AEA or CP 55,940, a synthetic cannabinoid, retina. Expression and activity of FAAH, the enzyme that hydro-

or inhibition of AEA breakdown leads to contraction of ciliary lyzes anandamide, increased after acute hypertonic insult. Acute

muscles which is a known phenomenon to promote aqueous increase of IOP associates with decrease of endocannabinoid tone

humor outflow [73,86]. Systemic or topical administration of in the retina [99].

cannabigerol or D9-THC increase dimension of Schlemm’s canal Administration of URB597, a selective FAAH inhibitor, or

and make the aqueous humor excretion easier. Activation of kinase methanandamide in retinal ischemia caused by acute ocular

metaloproteinkinase P42/44 using noladin ether (endocannabi- hypertension prevents RGCs death in the animal model [100].

noid agonist) increased sphericity of trabecular mesh cells and Activation of CB1 and TRPV1 receptors by WIN 55212-2 and

Table 1

Studies using cannabinoids in human subjects to lower intraocular pressure (IOP).

Subjects Administration route Observations Ref.

9

15 Male, 18–30 years old smoking marijuana (12 mg D -THC) significant IOP decrease after 80 min, more frequent users showed [74]

lower or no IOP drop

9

10 healthy volunteers, 20–30 years old 0.022 or 0.044 mg/kg of D -THC IOP decrease in 9 patients with low dose and all subjects with high [75] intravenously dose

9

256 glaucomatous patients smoking marijuana (1–4% D -THC) or 5– most patients showed IOP reduction, additive effect was seen with [76]

9

20 mg oral D -THC conventional glaucoma drugs

A 23-year-old male (suffers of HPPD), 4 young smoking marijuana HPPD in patient, no change in the controls [77]

subjects (control), 23–28 years old

9

9 patients with end-stage open angle glaucoma, smoking marijuana or oral D -THC lower IOP, development of tolerance and significant systemic [78]

38–77 years old capsules toxicity that limit the usefulness

9 9

6 patients with ocular hypertension or early single sublingual preparation (5 mg D - significant IOP decrease by D -THC, 40 mg CBD produced a [79]

primary open angle glaucoma THC or 20 and 40 mg CBD) transient IOP increase, no significant side effect

8 patients with glaucoma resistant to conventional topical application of IOP decreased directly through CB1 [80]

treatments, 53–72 years old WIN55212-2

18 patients suffers of glaucoma single oral dose of nabilone (0.5 mg) IOP decreased by 27.9%, 2–6 h after administration, no visual side [81]

effect

32 patients suffers of glaucoma BW29Y (5 or 10 mg) or BWI46Y (4, 8, or BW29Y: ineffective, BWI46Y: IOP drop, lightheaded, dizzy, [82]

12 mg) disorientation, blood pressure drop

9 9

HPPD: persisting perception disorder; IOP: intraocular pressure; D -THC: D -tetrahydrocannabinol; CBD: cannabidiol; WIN55212-2, Nabilone, BW29Y,

BWI46Y: .

624 Y. Panahi et al. / Biomedicine & Pharmacotherapy 86 (2017) 620–627

methanandamide seems to exert neuroprotective effect in the of disturbances in perception, was reported after chronic

retina. This effect abolishes by administration of CB1 and TRPV1 consumption of marijuana in a patient. Cannabinoids effects

antagonists like SR141716A and capsazepine, respectively [5,101]. directly on the retina and retinal pigment epithelium function may

CB1 activation in CNS inhibits release of excitatory (glutamate) cause disturbance in visual function after drug use [77]. Other toxic

and inhibitory (GABA) neurotransmitters and causes inhibition of effects like dizziness, sleepiness, depression, confusion, distortion

2+ +

voltage gated Ca channels and activation of K channels. of perception, and anxiety were also reported with D9-THC

Depolarization of the presynaptic neuron followed by the decrease treatment [78]. Alteration of human vision is correlated with acute

of calcium ion influx is associated with reduction in glutamate or regular use of cannabis [51]. Though, ocular side effects of

release into the synaptic space [102]. Systemic administration of cannabinoids are very few, orthostatic hypotension, tachycardia,

MK801, a use-dependent NMDA glutamate receptor antagonist, euphoria and conjunctival hyperemia are their acute undesirable

prevents ganglion-cell death and reduces FAAH activity which effects. Long term adverse effects of them include respiratory,

induced by acute ocular hypertension [97,99]. These findings neurological and hormonal untoward effects. Conjunctival hyper-

provide supports for correlation of endocannabinoid system with emia, midriasis, chemosis, cases of severe corneal opacification

excitotoxicity and retinal cell death. and neurotoxicity, diplopia, photophobia, nistagmus and blephar-

Retinal hypoxia due to the reduced retinal blood supplies ospasms have also associated with the application of cannabinoids

contribute to the retinal damage caused by glaucoma. Vasodilation [112].

effect of endogenous cannabinoids is partly through inhibition of

endothelin-1, a potent vasoconstrictor. Metabolism of endothelin- 9. Discussion

1 is changed and the level of this peptide is higher in the blood of

patient with low-pressure glaucoma or chronic forms of simple The knowledge regarding therapeutic effect of marijuana and

glaucoma in comparison with healthy control [103,104]. Neuro- its active constituents in glaucoma have not changed from 1970s.

protection effect of cannabinoids might be also related to their The mechanism underlying the beneficial activities of CBs on

anti-inflammatory activity. Release of toxic factors like nitric oxide, glaucoma is not completely explained, though numerous experi-

glutamate, and tumor necrosis factor (TNF) were reported by mental and clinical studies suggested different pathways such as

activation of astrocytes, Muller cells, and microglia in the antioxidation, anti-inflammatory, increase of neural plasticity as

experimental models of glaucoma [105]. Activation of CB1 and well as synaptic plasticity, IOP reduction and neuroprotection as

CB2 in the CNS and retina modulates activation and migration of possible procedures for beneficial effects of cannabinoids in the

microglia cells and inhibits production of nitric oxide and eye (Fig. 2). However, there is no data available for drug-drug,

inflammatory cytokines [106,107]. Neuroprotective of cannabi- drug-vehicle interactions, and the drug safety in pregnancy and

noids may not be limited exclusively to the level of CB1 receptors, lactation [113]. Likewise, drug-disease interactions which are

since application of cannabidiol, a non-psychotropic cannabinoid especially crucial in elderly patients who are more susceptible to

with no affinity to CB1, showed neuroprotective effect by these ineractions because of their chronic diseases and multiple

prevention of nitrotirosine formation or inhibition of AEA medication that they take, are not clear about cannabinoids. These

degradation [98,108]. Some evidences attribute the neuroprotec- information remains essential in order to use cannabinoids in

tive effect of cannabinoids to their antioxidant activity indepen- prevention or treatment of glaucoma that have to be illustrated in

dent to CB receptors via blocking reactive oxygen specious (ROS) the prospective studies. Administration of marijuana in glaucoma

[109,110]. is not supported by scientific evidences due to its psychoactive and

addictive side effects, therefore, patients have to be counseled

8. Adverse effects of marijuana about its adverse effects by clinicians. Tolerance and short duration

of action of CBs on IOP reduction are other obstacles that have to be

Single-time using of marijuana do not cause addiction, though overcome in application of these compounds for treating glauco-

in some cases even occasional or recreational use leading to ma. Allosteric modulation and inhibition of endocannabinoid

addiction or morphological changes in some region of the brain breakdown [114], topical formulas to avoid systemic side effects of

like nucleus accumbens. Addiction can develop in long time use of cannabinoids, synthetic analogues of cannabinoid with more

marijuana even with medical users [4]. The IOP lowering effect of potency and longer duration of action, sensible utilization of novel

marijuana last for 3–4 h, therefore, at least 6–8 times the drug have

to be smoked a day that may lead to the addiction of the patient

[111]. In a nonrandomized study, 9 patients were treated with

inhaled marijuana or D9-THC capsule every 4 h. All of them

showed beneficial effect of treatment on IOP decrease, while seven

patients lost beneficial effect of the drug due to treatment

tolerance [78]. Smoking of marijuana containing 12 mg D9-THC

have caused IOP reduction, while individuals who used marijuana

the most showed little or no drop in their IOP [74], suggesting

tolerance to the IOP lowering effect of marijuana. Down regulation

of cannabinoid receptors and desensitization of signal transduc-

tion pathway are included as tolerance mechanism after prolonged

treatment using cannabinoids [53].

Inhalation of marijuana in persons with heterologous glaucoma

caused hypotensive effects in 60–90 min following by decrease in

IOP, which suggest that blood pressure lowering effect of

marijuana resulted in reduction of IOP [112]. This mechanism

may cause damage due to the poor perfusion of optic nerve [4].

However, result of an early research suggested that only high dose

of marijuana can change blood pressure [74]. Hallucinogen

Fig. 2. Beneficial effects of cannabinoids in glaucoma. COX-2: cyclooxygenase 2,

persisting perception disorder (HPPD), a temporary recurrence NO: nitric oxide, TNF: tumor necrosis factor.

Y. Panahi et al. / Biomedicine & Pharmacotherapy 86 (2017) 620–627 625

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