See discussions, stats, and author profiles for this publication at: https://www.researchgate.net/publication/311895248 The arguments for and against cannabinoids application in glaucomatous retinopathy Article in Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie · February 2017 DOI: 10.1016/j.biopha.2016.11.106 CITATIONS 0 READS 86 4 authors: Some of the authors of this publication are also working on these related projects: Clinical trial of some medicinal plants, used in traditional medicine View project Analysis of natural products View project Yunes Panahi Baqiyatallah University of Medical Sciences 191 PUBLICATIONS 1,332 CITATIONS SEE PROFILE Azadeh Manayi Tehran University of Medical Sciences 67 PUBLICATIONS 169 CITATIONS SEE PROFILE Marjan Nikan Tehran University of Medical Sciences 10 PUBLICATIONS 17 CITATIONS SEE PROFILE Mahdi Vazirian Tehran University of Medical Sciences 23 PUBLICATIONS 52 CITATIONS SEE PROFILE All content following this page was uploaded by Mahdi Vazirian on 29 December 2016. The user has requested enhancement of the downloaded file. All in-text references underlined in blue are added to the original document and are linked to publications on ResearchGate, letting you access and read them immediately.
The arguments for and against cannabinoids application inglaucomatous retinopathy
Yunes Panahia, Azadeh Manayib, Marjan Nikanb, Mahdi Vazirianc,*aChemical Injuries Research Center, Baqiyatallah University of Medical Sciences, Tehran, IranbMedicinal Plants Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iranc Pharmacognosy Department, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
A R T I C L E I N F O
Article history:Received 29 October 2016Received in revised form 21 November 2016Accepted 27 November 2016
Glaucoma represents several optic neuropathies leading to irreversible blindness through progressiveretinal ganglion cell (RGC) loss. Reduction of intraocular pressure (IOP) is known as the only modifiablefactor in the treatment of this disorder. Application of exogenous cannabinoids to lower IOP has attractedattention of scientists as potential agents for the treatment of glaucoma. Accordingly, neuroprotectiveeffect of these agents has been recently described through modulation of endocannabinoid system in theeye. In the present work, pertinent information regarding ocular endocannabinoid system, mechanism ofexogenous cannabinoids interaction with the ocular endocannabinoid system to reduce IOP, andneuroprotection property of cannabinoids will be discussed according to current scientific literature. Inaddition to experimental studies, bioavailability of cannabinoids, clinical surveys, and adverse effects ofapplication of cannabinoids in glaucoma will be reviewed.
Glaucoma, a neurodegenerative eye disease, known as a majorfactor for irreversible blindness. It is predicted that more than 80million people by 2020 will be affected by glaucoma leading to atleast 6–8 million bilaterally blind worldwide [1]. Increasedintraocular pressure (IOP) >22 mmHg, due to imbalance of aqueous
humor formation and draining out, is the only known modifiablerisk factor for prevention of glaucoma progress. Although, theelderly are at higher risk for the disease, glaucoma can develop inyoung adults, children, and infants [2,3]. Damage of optic nervemost commonly occurs due to high IOP and progressivedegeneration of retinal ganglion cells (RGCs) leading to irreversiblevision loss [4]. Blood flow alteration as a result of IOP, produceshypoxia and ischemia in the retina and optic nerve [5]. Standardtreatments are restricted to reduction of IOP using medications orsurgery. While, these types of treatments are not effective in somepatients and a subset of glaucoma is not associated with high IOP
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[6]. Protection of retinal ganglion cells from damage and deathdirectly can be considered as a novel approach to combat glaucoma[7].
Resin glands located on secreting trichomes of female-plantflowers of Cannabis sativa (Cannabaceae family) contain consider-able amount of cannabinoids. Smaller quantity of these chemicallyactive compounds was found in the leaves of the cannabis plant(marijuana) [8]. Several cannabinoids have been isolated of theplant, of which D9-tetrahydrocannabinol (D9-THC), cannabichro-mene (CBC), cannabigerol (CBG), cannabinol (CBN) and cannabi-diol (CBD) are the most relevant in the amount of cannabinoids.Synthetic modulators of endogenous cannabinoid system has beenalso investigated for their therapeutic potentials in addition tophytocannabinoids (Fig. 1) [9]. These compounds possess thera-peutic effects on cancer, pain, emesis, inflammation, obesity, andneurodegenerative diseases along with other psychotropic prop-erties [10–13].
The beneficial function of cannabinoids in ocular physiologyand disease dates back to 1971 when it was reported that smokingmarijuana lower the IOP [14]. Role of cannabinoids in retinalcircuitry and vision is supported by the presence of the functionalendocannabinoid system including endogenous cannabinoids,
2-arachidonyl glycerol (2-AG)
OOH
OHO
NH
OHO
anandamide (AEA) N
Endocannabinoids
O
OHH
H
delta9-tetrahydrocannabinol
O
OH
cannabinol
Natural cannabinoids
O
N
N
O
O
WIN55212-2
O
O
H
H
OH
nabilone
Synthetic cannabinoids
Fig. 1. Chemical structures
enzymes of their synthesis and metabolism and cannabinoidreceptors in the retina [15]. The physiological and pharmacologicalactivities of endocannabinoids along with natural and syntheticcannabinoids are mediated mostly by two receptors, cannabinoidreceptor 1 (CB1) and cannabinoid receptor 2 (CB2) [13]. Receptorsof CB1 are predominantly expressed in the central nervous system(CNS), while receptors of CB2 are mainly located in peripheraltissues and immune system and also found in the CNS [16–18].Anandamide (N-arachidonoylethanolamine, AEA) and 2-arachido-noylglycerol (2-AG) (Fig. 1) are the two most studied endogenouscannabinoids. Endocannabinoids also activate other targets,including non-CB1, non-CB2 G-protein-coupled receptors andvarious ion channels [19]. Therapeutic effects of cannabinoids inCNS pathologies like Parkinson’s disease, Alzheimer’s disease,Huntington disease, head trauma, and multiple sclerosis (MS) havebeen reported in the previous studies [20–24]. In this review, theknowledge of therapeutic potential of cannabinoids will beparticularly discussed in glaucoma. Relevant information regard-ing chemistry and bioavailability of cannabinoids, the ocularendocannabinoid system, and ocular hypotensive as well asneuroprotective properties of cannabinoids will be provided inthe treatment of glaucoma.
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2. Natural source of cannabinoids
Cannabis has three specious including C. sativa, Cannabis indica,and Cannabis ruderalis. About 113 cannabinoids with variouseffects were isolated from C. sativa which is an annual herbaceousplant [25]. There are some studies indicate that C. indica containshigher amount of D9-THC than CBD, while C. sativa have moreamount of CBD [26]. Wild specious of cannabis, C. ruderalis, lackmeaningful quantity of psychoactive cannabinoids [27].
3. Biosynthesis of cannabinoids
Cannabinoids are primarily synthesized in glandular trichomesof flowers and, to a lesser extent, leaves of the female plant fromfatty acid and isoprenoid precursors [28]. A type III polyketidesynthase is the first enzyme in the cannabinoid synthesis pathwaywhich catalyzes hexanoyl-CoA condensation with three malonyl-CoA molecules to produce olivetolic acid [28,29]. Olivetolic acid isthen converted by aromatic prenyltransferase to cannabigerolicacid. D9-Tetrahydrocannabinolic acid and cannabidiolic acid, areyielded by the major cannabinoids oxidocyclase enzymes fromcannabigerolic acid. Subsequent non-enzymatic decarboxylationof D9-tetrahydrocannabinolic acid and cannabidiolic acid formsD9-THC and CBD, respectively [30].
4. Chemistry and bioavailability of some natural cannabinoids
D9-Tetrahydrocannabinol (D9-THC) with chemical formula ofC21H30O2, molecular mass 314.469 g/mol [31], is extracted from thebuds, leaves and flowers of C. sativa (Fig. 1). The compound is alsosynthetically available and metabolized to 11-hydroxy D9-THCwhen enters the blood stream, its metabolite absorbs into theadipose tissue and stays for 30 min. Subsequently, it release backinto the blood circulation and entering the brain. The bioavailabil-ity of D9-THC via inhalation ranges between about 10-35% [32–34]and 6-40% when administered in the eye [35]. The maximum peakof D9-THC were evaluated between 94.3-155.1 ng/mL aftersmoking one cigarette containing 1.32- 2.54% D9-THC [36]. Therectal and oral bioavailability of D9-THC were calculated to be13.5% and 5–20%, respectively [37]. The rectal bioavailability of D9-THC is higher since avoid hepatic first pass effect, however, thebioavailability through this route fluctuates with differentformulations [38]. Based on Wall et al. study, participants wereadministered with 15–20 mg of D9-THC dissolved in sesame oil,observed maximum plasma concentrations after 4–6 h [34].Ohlsson et al. reported the oral bioavailability of D9-THC in achocolate cookie was 6 � 3%. Low rates of absorption after oraladministration of D9-THC can occur for many different reasons,including considerable first pass metabolism to active/inactivemetabolites in the liver, degradation of drug in the digestive systemand various absorption [33,39]. Administration of a liposome-entrapped preparation of D9-THC through intratracheal routelowered IOP more efficiently compared to intraperitoneal wayindicating rapid absorption of the drug from alveoli to systemiccirculation. The effect of both intratracheal and intraperitonealroutes remained for 1.5–2 h and its short duration may occurs dueto the large volume of distribution of D9-THC (3.4 L/kg) [40].Optical application of D9-THC to the cornea showed limitedbioavailability with ocular irritation and toxicity [2,41].
Cannabidiol (CBD) with chemical formula of C21H30O2, molec-ular mass 314.46 g/mol [31], soluble in organic solvents butinsoluble in water [42], is found throughout the whole part ofhemp and marijuana, including flowers, stalk and seeds. Previousstudies by Mechoulam et al. [43] and Scuderi et al. showed oralbioavailability of CBD was 13–19% and its inhaled bioavailabilitywas 11–45% (mean 31%) [44]. Cannabinol (CBN) with chemical
formula of C21H26O2, molecular mass 310.4319 g/mol, was isolatedfrom the plant cannabis. Average bioavailability of inhaled CBN is38% (range 8–65%) [9,33,45].
5. Endocannabinoid system in the eye
In addition to the human retina, presence of CB1 and CB2 hasbeen shown in several specious. Generally, CB1 is found in cones,horizontal cells, amacrine, some bipolar cells, RGCs, and ganglioncell axons [13,46–49]. In human, receptors of CB1 are expressed inouter segments of photoreceptor cells, outer plexiform layer, innerplexiform layer, two synaptic layers of the retina, inner nuclearlayer, ganglion cell layer, and retinal pigment epithelium cells. CB2receptors are found in human retinal pigment epithelium cells[47,50,51]. Immunocytochemical methods revealed that transientreceptor potential vanilloid type 1 (TRPV1), a ligand-gated,nonselective cation channel, is widespread in the retina of rabbitand other mammals [52]. Both receptors of cannabinoids, CB1 andCB2, are G-protein-coupled receptors (GPCRs). G-protein-coupledinwardly rectifying potassium channels (GIRKs) is affected byactivation of CB1 receptor, which interacts with several ionchannels including Ca2+ and K+ channels [13]. In addition,cannabinoid receptors regulate signal transduction through cyclicAMP (cAMP) and inhibit inducible nitric oxide synthase (iNOS)production which is a critical contributor of their anti-inflamma-tory and neuroprotective effects [53]. Other cannabinoid relatedreceptors like G-protein-coupled receptor 18 (GPR18) and GPR55are expressed in the retina according to the some experiments[54,55].
The two main endocannabinoid ligands namely AEA and 2-AGare discovered in the retina of human. 2-AG is detected at highlevel, whereas AEA is found at lower level in the human retina[19,56]. Fatty acid amide hydrolase (FAAH), monoacylglycerollipase (MGL), and cyclooxygenase-2 (COX-2) enzymes regulate thecellular level of endogen cannabinoids in the retina [15,50,57,58].The COX-2 enzyme can directly metabolize AEA and 2-AG toprostaglandin ethanolamides (prostamides) and prostaglandinglyceryl esters, respectively [59]. Responsible enzymes for thesynthesis of endocannabinoids, N-acyl phosphatidylethanolaminephospholipase (D-NAPE-PLD) and diacylglycerol lipase (DAGL)have been found in the retina of rodents and other mammals aswell [13].
Activation of CB1 in the retina cause modulation of function ofion channels which may influence retinal circuitry, release ofneurotransmitters, and neuroprotection. Endocannabinoids mayregulate spontaneous transmitter that is important in networkmaintenance in amacrine cells and other inhibitory interneurons[13,60]. Topical administration of synthetic CB1 agonist causes IOPdrop in rabbits, non-human primates, and glaucomatous human[61–63], through decrease of aqueous humor flow and inhibition oftheir inactivation by FAAH or cellular reuptake [64,65].
Cannabinoids modulate release of several neurotransmitters inthe retina such as dopamine, glutamate, gamma aminobutyric acid(GABA), and noradrenaline [66–69]. The cannabinoid system play arole in the phototransduction cascade, the dark and light retinalsensitivity and adaptation and the retinal contrast sensitivity onthe goldfish retina [70,71]. Presence of functional endocannabinoidsystem in the eye and their decrease in certain tissue ofglaucomatous human eye like ciliary body, an important tissuein the regulation of IOP, support their role in the eye physiology andglaucoma pathology [19].
6. Effects of cannabinoids in lowering of IOP
Topical administration of WIN-55-212-2, a synthetic cannabi-noids, which binds both CB1 and CB2 decreased IOP in
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glaucomatous rats without any psychotropic symptoms. Thetherapeutic effect of the compounds remained over the periodof treatment for 4 weeks [72]. This finding is consistent withanother experiment which showed reduction of IOP by adminis-tration of WIN-55-212-2 in patients suffering of glaucoma in a timeand dose dependent manner [62]. Endocannabinoids have beenfound to reduce IOP without any noticeable toxic effects [65,73].Results of clinical experiments regarding administration ofmarijuana or cannabinoids in individuals suffering of glaucomawere summarized in Table 1.
In a nonrandomized study, 9 patients were treated with inhaledmarijuana or D9-THC capsule every 4 h. All of them showedbeneficial effect of treatment on IOP decrease, while seven patientslost beneficial effect of the drug due to treatment tolerance [78].Vasoactivity of abnormal-cannabidiol, a nonpsychoactive atypicalcannabinoid, is predominantly endothelium and vessel tonedependent. Abnormal-cannabidiol is an agonist at the ananda-mide-activated endothelial CBeR receptor but is devoid of activityat the CB1 or CB2. However, antagonist of CB1 block vasoactivity ofabnormal-cannabidiol suggesting that both CB1 and anandamide-activated endothelial CBeR receptor play role in retinal vasoactivityand blood flow [83]. Activation of CB1 in the ciliary blood vesselsmay cause vasodilation and reduce production of aqueous humor[5].
Treatment of non-pigmented epithelium of the ciliary bodywith D9-THC, AEA, and its stable analog methanandamide,enhance expression of COX-2 in the cell culture. As a result, theamount of prostaglandin E2 (PGE2) and metalloproteinases-1, -3,and -9 were increased in the supernatant and matrix of cell culture.These mediators play role in aqueous humor outflow pathways andthus IOP regulation [84]. Therefore, it is suggested that reduction ofIOP by cannabinoids might mediated through CB receptors as wellas cyclooxygenases activation [5]. In animal model of glaucoma,IOP lowering effect of D9-THC attenuated with indomethacin andsteroids that block cyclooxygenases [85].
Activation of CB1 by AEA or CP 55,940, a synthetic cannabinoid,or inhibition of AEA breakdown leads to contraction of ciliarymuscles which is a known phenomenon to promote aqueoushumor outflow [73,86]. Systemic or topical administration ofcannabigerol or D9-THC increase dimension of Schlemm’s canaland make the aqueous humor excretion easier. Activation of kinasemetaloproteinkinase P42/44 using noladin ether (endocannabi-noid agonist) increased sphericity of trabecular mesh cells and
Table 1Studies using cannabinoids in human subjects to lower intraocular pressure (IOP).
Subjects Administration route
15 Male, 18–30 years old smoking marijuana (12 mg D9-TH
10 healthy volunteers, 20–30 years old 0.022 or 0.044 mg/kg of D9-THCintravenously
reduced the production of actin stress fibers and focal adhesion[39]. Nonpsychotropic cannabinoids like HU-211, abnormalcannabidiol (abn-CBD), and cannabigerol-dimethyl heptyl (CBG-DMH) could decrease IOP independent to CB receptors [87]. Thesefindings highlight the potential therapeutic effect of cannabinoidsin the reduction of IOP.
7. Effects of cannabinoids in neuroprotection
Neuroprotective property of cannabinoids has been demon-strated in CNS neurodegenerative diseases with different mecha-nisms. Endocannabinoids exhibit neuroprotection in some modelsof neurodegenerative diseases. Activation of presynaptic CBinhibits glutamate release improving the control of neuronalexcitability and regulating synaptic plasticity [88,89]. Accordingly,CB2 activation modulates inflation of neurons through themicroglya, macrophages and dendritic cells, and increasing theproduction of endocannabinoids [90].
Retinal damage especially in RGCs due to glutamate wasreported in the early studies [91–94]. Antagonists of glutamatereceptors have been conferred neuroprotection in models of RGCsdeath confirmed involvement of excitotoxicity cascade in glauco-ma [95–97]. Activation of glutamate receptors increase intracellu-lar level of calcium which subsequently activate nitric oxidesynthase leading to release of nitrogen radicals and death of RGCs[5]. RGCs death triggered by intravitreal administration of N-methyl-D-aspartate (NMDA), an amino acid mimics glutamateaction, was prevented by systemic administration of D9-THC orCBD with reduction of peroxynitrites in rats. This protective effectwas partially inhibited by a selective CB1 anatgonist, SR141716A[98]. Treatment with D9-THC for 20 weeks decreases IOP andreduces death of RGCs approximately by 75% in the animal modelof glaucoma [12]. Intraretinal level of AEA was reduced in retinalischemia induced by ocular hypertension, which seems happenedas the result of alteration in endocannabinoid metabolism in theretina. Expression and activity of FAAH, the enzyme that hydro-lyzes anandamide, increased after acute hypertonic insult. Acuteincrease of IOP associates with decrease of endocannabinoid tonein the retina [99].
Administration of URB597, a selective FAAH inhibitor, ormethanandamide in retinal ischemia caused by acute ocularhypertension prevents RGCs death in the animal model [100].Activation of CB1 and TRPV1 receptors by WIN 55212-2 and
Observations Ref.
C) significant IOP decrease after 80 min, more frequent users showedlower or no IOP drop
[74]
IOP decrease in 9 patients with low dose and all subjects with highdose
[75]
) or 5– most patients showed IOP reduction, additive effect was seen withconventional glaucoma drugs
[76]
HPPD in patient, no change in the controls [77]
C lower IOP, development of tolerance and significant systemictoxicity that limit the usefulness
[78]
g D9- significant IOP decrease by D9-THC, 40 mg CBD produced atransient IOP increase, no significant side effect
[79]
IOP decreased directly through CB1 [80]
g) IOP decreased by 27.9%, 2–6 h after administration, no visual sideeffect
[81]
4, 8, or BW29Y: ineffective, BWI46Y: IOP drop, lightheaded, dizzy,disorientation, blood pressure drop
Fig. 2. Beneficial effects of cannabinoids in glaucoma. COX-2: cyclooxygenase 2,NO: nitric oxide, TNF: tumor necrosis factor.
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methanandamide seems to exert neuroprotective effect in theretina. This effect abolishes by administration of CB1 and TRPV1antagonists like SR141716A and capsazepine, respectively [5,101].
CB1 activation in CNS inhibits release of excitatory (glutamate)and inhibitory (GABA) neurotransmitters and causes inhibition ofvoltage gated Ca2+ channels and activation of K+ channels.Depolarization of the presynaptic neuron followed by the decreaseof calcium ion influx is associated with reduction in glutamaterelease into the synaptic space [102]. Systemic administration ofMK801, a use-dependent NMDA glutamate receptor antagonist,prevents ganglion-cell death and reduces FAAH activity whichinduced by acute ocular hypertension [97,99]. These findingsprovide supports for correlation of endocannabinoid system withexcitotoxicity and retinal cell death.
Retinal hypoxia due to the reduced retinal blood suppliescontribute to the retinal damage caused by glaucoma. Vasodilationeffect of endogenous cannabinoids is partly through inhibition ofendothelin-1, a potent vasoconstrictor. Metabolism of endothelin-1 is changed and the level of this peptide is higher in the blood ofpatient with low-pressure glaucoma or chronic forms of simpleglaucoma in comparison with healthy control [103,104]. Neuro-protection effect of cannabinoids might be also related to theiranti-inflammatory activity. Release of toxic factors like nitric oxide,glutamate, and tumor necrosis factor (TNF) were reported byactivation of astrocytes, Muller cells, and microglia in theexperimental models of glaucoma [105]. Activation of CB1 andCB2 in the CNS and retina modulates activation and migration ofmicroglia cells and inhibits production of nitric oxide andinflammatory cytokines [106,107]. Neuroprotective of cannabi-noids may not be limited exclusively to the level of CB1 receptors,since application of cannabidiol, a non-psychotropic cannabinoidwith no affinity to CB1, showed neuroprotective effect byprevention of nitrotirosine formation or inhibition of AEAdegradation [98,108]. Some evidences attribute the neuroprotec-tive effect of cannabinoids to their antioxidant activity indepen-dent to CB receptors via blocking reactive oxygen specious (ROS)[109,110].
8. Adverse effects of marijuana
Single-time using of marijuana do not cause addiction, thoughin some cases even occasional or recreational use leading toaddiction or morphological changes in some region of the brainlike nucleus accumbens. Addiction can develop in long time use ofmarijuana even with medical users [4]. The IOP lowering effect ofmarijuana last for 3–4 h, therefore, at least 6–8 times the drug haveto be smoked a day that may lead to the addiction of the patient[111]. In a nonrandomized study, 9 patients were treated withinhaled marijuana or D9-THC capsule every 4 h. All of themshowed beneficial effect of treatment on IOP decrease, while sevenpatients lost beneficial effect of the drug due to treatmenttolerance [78]. Smoking of marijuana containing 12 mg D9-THChave caused IOP reduction, while individuals who used marijuanathe most showed little or no drop in their IOP [74], suggestingtolerance to the IOP lowering effect of marijuana. Down regulationof cannabinoid receptors and desensitization of signal transduc-tion pathway are included as tolerance mechanism after prolongedtreatment using cannabinoids [53].
Inhalation of marijuana in persons with heterologous glaucomacaused hypotensive effects in 60–90 min following by decrease inIOP, which suggest that blood pressure lowering effect ofmarijuana resulted in reduction of IOP [112]. This mechanismmay cause damage due to the poor perfusion of optic nerve [4].However, result of an early research suggested that only high doseof marijuana can change blood pressure [74]. Hallucinogenpersisting perception disorder (HPPD), a temporary recurrence
of disturbances in perception, was reported after chronicconsumption of marijuana in a patient. Cannabinoids effectsdirectly on the retina and retinal pigment epithelium function maycause disturbance in visual function after drug use [77]. Other toxiceffects like dizziness, sleepiness, depression, confusion, distortionof perception, and anxiety were also reported with D9-THCtreatment [78]. Alteration of human vision is correlated with acuteor regular use of cannabis [51]. Though, ocular side effects ofcannabinoids are very few, orthostatic hypotension, tachycardia,euphoria and conjunctival hyperemia are their acute undesirableeffects. Long term adverse effects of them include respiratory,neurological and hormonal untoward effects. Conjunctival hyper-emia, midriasis, chemosis, cases of severe corneal opacificationand neurotoxicity, diplopia, photophobia, nistagmus and blephar-ospasms have also associated with the application of cannabinoids[112].
9. Discussion
The knowledge regarding therapeutic effect of marijuana andits active constituents in glaucoma have not changed from 1970s.The mechanism underlying the beneficial activities of CBs onglaucoma is not completely explained, though numerous experi-mental and clinical studies suggested different pathways such asantioxidation, anti-inflammatory, increase of neural plasticity aswell as synaptic plasticity, IOP reduction and neuroprotection aspossible procedures for beneficial effects of cannabinoids in theeye (Fig. 2). However, there is no data available for drug-drug,drug-vehicle interactions, and the drug safety in pregnancy andlactation [113]. Likewise, drug-disease interactions which areespecially crucial in elderly patients who are more susceptible tothese ineractions because of their chronic diseases and multiplemedication that they take, are not clear about cannabinoids. Theseinformation remains essential in order to use cannabinoids inprevention or treatment of glaucoma that have to be illustrated inthe prospective studies. Administration of marijuana in glaucomais not supported by scientific evidences due to its psychoactive andaddictive side effects, therefore, patients have to be counseledabout its adverse effects by clinicians. Tolerance and short durationof action of CBs on IOP reduction are other obstacles that have to beovercome in application of these compounds for treating glauco-ma. Allosteric modulation and inhibition of endocannabinoidbreakdown [114], topical formulas to avoid systemic side effects ofcannabinoids, synthetic analogues of cannabinoid with morepotency and longer duration of action, sensible utilization of novel
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drug delivery systems namely nanoparticle approaches, andcombination of cannabinoids with other conventional drugs tocontrol glaucoma could be alternative solutions to apply canna-binoids for treating glaucomatous optic neuropathy in upcominginvestigations.
Previous studies in human are not well-controlled trials anddifficult to compare for determination of cannabinoids efficacy inglaucoma, therefore, clinical studies to investigate safety andeffectiveness of the compounds in glaucoma are required in thefuture. Clearly, there is scarce clinical information available aboutrisk-benefit of cannabinoids in glaucomatous patients indicatingthe need for improving our knowledge of these compounds tocontrol or prevent glaucoma.
Conflict of interest
The authors declare that they have no conflict of interest.
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