May 2004
I Tomida, R G Pertwee, and A Azuara-Blanco
Abstract
Glaucoma is one of the leading causes of blindness in the world. In spite of the diverse therapeutic possibilities, new and better treatments for glaucoma are highly desirable. Cannabinoids effectively lower the intraocular pressure (IOP) and have neuroprotective actions. Thus, they could potentially be useful in the treatment of glaucoma. The purpose of this article is to provide the reader with an overview of the latest achievements in research into the potential use of cannabinoids for glaucoma.
Cannabinoids and Glaucoma
In 1971, Hepler and Frank reported a 25–30% IOP lowering effect of smoking marijuana in a small number of subjects.28 The duration of action of marijuana after smoking was relatively short, about 3–4 hours, and there seemed to be a dose-response relation.28,29 Other ocular effects were observed such as conjunctival hyperaemia, reduced tear production, and change in pupil size.29 Acute systemic side effects induced by marijuana smoking included reduction of systemic blood pressure and tachycardia.4 Psychotropic effects were very variable and included euphoria or dysphoria, disruption of short term memory, cognitive impairments, sense of time distortion, reduced coordination, and sleepiness.4
An earlier report on the effect of smoked marijuana indicated the possibility of tolerance. Thus, the IOP reduction appeared to be inversely related to the duration of marijuana use.30 In contrast, Dawson et al31 reported on their ophthalmological findings comparing non-users with long term users of marijuana (10 years or more). After applying the water loading test to both groups, the reduction of IOP associated with marijuana treatment was similar between users and non-users.
Since these early observations numerous studies have been conducted confirming that different cannabinoids, including cannabidiol, cannabigerol, endogenous cannabinoids, and some synthetic cannabinoids, can reduce the IOP when administered systemically and topically (see below). Obviously, smoking of marijuana is not advisable as a long term treatment. In addition to the acute side effects, long term marijuana smoking is associated with emphysema-like lung changes, and possible increase in the frequency of lung cancer.32 Oral administration has been evaluated. However, there is a poor and variable absorption with this route,33 at least for the cannabinoid formulations that have been investigated so far.
Mechanism of IOP reduction
The mechanism of action of cannabinoids in the human eye is not fully understood. Until recently, the effect of cannabinoids on IOP was assumed to be mediated through the CNS. Studies involving unilateral topical application of cannabinoids34,35 showed a large difference between the treated and untreated eye, suggesting a localised action. The experiments of Liu et al36 revealed evidence pointing in the same direction: bolus administration of Δ9-THC into the cerebral ventricles, as well as ventriculocisternal perfusion with Δ9-THC in rabbits, in contrast with intravenous administration, did not change the IOP. Thus, the main site of action of cannabinoids on IOP is not in the central nervous system.
Pharmacological and histological studies support the direct role of ocular CB1 receptors in the IOP reduction induced by cannabinoids. Straiker et al11 detected CB1 receptors in ocular tissues of the human eye, including the ciliary epithelium, the trabecular meshwork, Schlemm’s canal, ciliary muscle, ciliary body vessels, and retina. Porcella et al10 found high levels of CB1 mRNA in the ciliary body. The anatomical distribution of cannabinoid receptors suggests a possible influence of endogenous cannabinoids on trabecular and uveoscleral aqueous humour outflow and on aqueous humour production. In addition to the proved IOP lowering effect of CB1 receptor agonists, Pate et al37 could antagonise the IOP lowering effect of CP-55,940 (a synthetic CB1 agonist) by pretreating the animals with SR 141716A (a CB1 receptor antagonist). Similarly, Song et al38 found that the IOP lowering effect of topical WIN-55,212-2 was significantly reduced by topically administered SR141716A.
Using the synthetic cannabinoid WIN-55,212-2, Chien et al39 could demonstrate an 18% reduction in the aqueous humour production in monkeys but without significant change in the trabecular outflow facility. As this percentage appeared not sufficient to account for the total IOP lowering effect, other additional mechanisms were thought to be involved.
The IOP reducing effect does not seem to be related to a systemic reduction of arterial blood pressure.40 However, a direct effect on the ciliary processes, and specifically a reduction in capillary pressure, leading to changes in aqueous humour dynamics, has been proposed.41 Green et al42 showed that Δ9-THC decreased the secretion of ciliary processes and led to a dilatation of the ocular blood vessels through a possible β adrenergic action. In addition, Sugrue43 indicated that cannabinoids may inhibit calcium influx through presynaptic channels and in this way reduce the noradrenaline release in the ciliary body, leading to a decrease in the production of aqueous humour. Porcella et al10 proposed that cannabinoids might be acting as vasodilators on blood vessels of the anterior uvea, thus improving the aqueous humour uveoscleral outflow.
Green et al44,45 postulated that some cannabinoids may influence the IOP through a prostaglandin mediated mechanism. For example, topically applied AEA is hydrolysed to arachidonic acid, which is a COX pathway precursor of prostaglandins.46,47
The topical application of the CB2 receptor agonist JWH-133 used in in vivo experiments by Laine et al48 did not have any effect on IOP compared to vehicle treatments, indicating that CB2 receptor agonists may not be involved in the regulation of IOP.
Topical application of cannabinoids
To minimise possible systemic adverse side effects and maximise the dose at the site of action, topical application would be the ideal form of administration. However, natural cannabinoid extracts as well as synthetic forms are highly lipophilic and have low aqueous solubility, creating practical difficulties for this mode of administration.
After instillation of an eye drop of any medication, loss of the instilled solution via the lacrimal drainage system and poor drug penetration results in only <5% of an applied dose reaching the intraocular tissues. The cornea is usually the major pathway for intraocular penetration of topical medications. The corneal epithelium is highly lipophilic and its penetration is a rate limiting step for lipophilic drugs. Aqueous solubility is another drug property important for efficacy of delivery, as the surface of the eye is constantly moistened by tear fluid. Additional factors affecting corneal absorption include the molecular size, charge, and degree of ionisation.49
Previous experiments with topical cannabinoid solutions involved the use of light mineral oil as a vehicle, but proved to be irritant to the human eye.50,51 Recently, different microemulsions and cyclodextrins (macrocyclic oligosaccharides) have been shown to improve the corneal penetration of cannabinoids. These formulations successfully induced an unilateral IOP lowering effect.52–58 Cyclodextrins have already been used efficiently by Porcella et al56 to administer the synthetic cannabinoid WIN-55,212-2 topically to glaucoma patients.
Neuroprotective and vascular actions of cannabinoids
In glaucoma, the final pathway leading to visual loss is the selective death of retinal ganglion cells through apoptosis. Apoptosis is initiated by axonal injury at the optic disc, either by compression and/or by ischaemia. In ischaemia, glutamate is released and activates NMDA receptors. NMDA receptor activation appears to be one of several pathways that result in apoptotic cell death. After activation of NMDA receptors there is an influx of calcium into the cells and free radicals are generated. Substances that prevent this cascade of events and inhibit the retinal ganglion cell death are currently under investigation.59
Recent studies have documented the neuroprotective properties of cannabinoids. There is evidence that Δ9-THC can inhibit glutamic acid release by increasing K+ and decreasing Ca2+ permeability and that the synthetic cannabinoid HU-211 can block glutamate (NMDA) receptors.8,9,18,59–62 These actions are mediated by presynaptic CB1 receptors. Yoles et al, using a calibrated crush injury to adult rat optic nerve (optic nerve axotomy), showed a beneficial effect of HU-211 on injury induced metabolic and electrophysiological deficits.63 However, the optic nerve crush model may not resemble the mechanisms responsible for glaucomatous nerve damage.
Classic cannabinoids such as Δ9-THC, HU-211, and CBD have antioxidant properties that are not mediated by the CB1 receptor. As a result, they can prevent neuronal death by scavenging toxic reactive oxygen species produced by overstimulation of receptors for the excitatory neurotransmitter, glutamic acid.7,16–18,64
Cannabinoids have vasorelaxant properties and so might be able to increase the ocular blood flow. The mediator endothelin-1, produced by vascular endothelial cells, has a significant role in the regulation of local circulation, producing vasoconstriction and being involved in the pathophysiological processes of ischaemic and haemorrhagic stroke, Raynaud’s phenomenon, ischaemic heart disease and pulmonary arterial hypertension, among others.65 The possible role of endothelin-1 in the pathogenesis of glaucoma has been suggested.
For example, patients with open angle glaucoma may have an abnormal increase in plasma endothelin-1 in response to vasospastic stimuli.66,67 Mechoulam et al61 could demonstrate that 2-arachidonoylglycerol, an endogenous cannabinoid, was able to reduce endothelin induced Ca2+ mobilisation, inhibiting vasoconstriction. Thus, cannabinoids may have beneficial properties in ischaemia induced optic nerve damage.
Future directions
Cannabinoids have the potential of becoming a useful treatment for glaucoma, as they seem to have neuroprotective properties and effectively reduce intraocular pressure. However, several challenges need to be overcome, including the problems associated with unwanted systemic side effects (psychotropic, reduction in systemic blood pressure), possible tolerance, and the difficulty in formulating a stable and effective topical preparation. Some cannabinoids such as HU-211 and cannabidiol do not have psycotropic effects, while maintaining their IOP lowering action, so that further research on these compounds would be desirable. Tolerance may develop after repeated use of cannabinoids.30 However, tolerance might be beneficial if it develops only or preferentially to unwanted side effects. There has been recent progress in the use of microemulsions and cyclodextrins to overcome the barriers in ocular penetration of topically applied cannabinoids.
Other possible applications of cannabinoids in ophthalmology could be explored. Age related macular degeneration (AMD) is the leading cause of blindness in the United Kingdom. Perhaps the potent antioxidant properties of the cannabinoids may be beneficial in AMD, offering a possible alternative to established antioxidant supplements.68 Cannabinoids have been shown to inhibit angiogenesis, leading to a decrease in the expression of proangiogenic factors such as VEGF.69 Evidence suggests that VEGF plays a major part in the development of choroidal neovascularisation in AMD, and clinical trials using anti-VEGF therapies are being conducted.70 The CB2 receptors are also under intense investigation for their possible immunomodulatory effects.71 The anti-inflammatory properties of CB2 receptor agonists might also prove to be of therapeutic relevance in different forms of inflammatory eye disease.
