Glaucoma is one of the leading causes of blindness worldwide. Elevated intraocular pressure (IOP) is the primary risk factor for optic nerve damage in glaucoma. Many studies conducted on human subjects and animal models have shown that marijuana and its active components, cannabinoids, lower IOP. The presence of CB1/CB2 cannabinoid receptors, their endogenous ligands, and endocannabinoid metabolic enzyme activity in the eye provides the context for a mechanism independent of current medications used in lowering IOP. The main goal of this study was to investigate and understand the mechanisms by which cannabinoids, potential therapeutic agents for glaucoma, lower intraocular pressure (IOP).

A perfused anterior segment organ culture model and an uveoscleral perfusion model were used to study the mechanism of the IOP-lowering effects of cannabinoids, and to investigate the potential roles that cannabinoids and their receptors play in the modulation of aqueous humor outflow. These models are able to preserve the architecture of the outflow pathways and mimic what happens in vivo. The findings from this study showed that administration of the endogenous cannabinoid ligands Noladin ether, Anandamide (AEA) and 2-arachidonoylglycerol (2-AG) on pert used anterior segments increased aqueous humor outflow facility. These outflow-enhancing effects were regulated by CB1 and CB2 cannabinoid receptors. In addition, the outflow enhancing effects of AEA and 2-AG, the least stable endocannabinoids, were prolonged upon inhibition of their metabolizing enzymes. The administration of noladin ether, a CB1-selective cannabinoid agonist and JWH015, a CB2-selective cannabinoid agonist on porcine enucleated eyes induced an increase in outflow facility through the uveoscleral route. This outflow-enhancing effect was partially dependent and partly independent of cannabinoid receptors. In addition, the mechanism of noladin ether- and JWH015-induced increase in uveoscleral outflow is independent of an effect on matrix metalloproteinases, and may be due to relaxation of the ciliary muscle.

The results from this study indicated that an increased aqueous humor outflow facility is among the most important mechanism for cannabinoids to lower IOP, and that the endogenous cannabinoid system might be involved in maintaining aqueous humor outflow. I therefore postulate that synthetic and endogenous cannabinoid compounds targeted at cannabinoid receptors may be useful additions to the therapeutic regiments for glaucoma treatment.