Role of Endocannabinoids in Glaucoma: A Review

Abstract

Aims: A review of the published literature was done to understand the role of endocannabinoids in glaucoma.

Background: As evidence mounts that intraocular pressure (IOP) is not the only factor in the pathogenesis and progression of glaucoma, a look into other aspects is the need of the hour. From the first instance of a drop in IOP linked to marijuana in the 1970s to the present, research has been ongoing, mostly in animals and in vitro models, with a scarcity of human studies, to delve into the world of the endocannabinoid system (ECS).

Methods: PubMed, ScienceDirect, and Google Scholar were searched for studies relating to endocannabinoids and their role in glaucoma.

Results: The ECS comprises ligands, receptors, and the synthesizing and degrading enzymes and is ubiquitous throughout the human body, including the visual system, from the eye to the occipital lobe. Apart from the IOP-lowering effect of the system, another property being investigated and implicated as an attribute of its receptors is neuroprotection. This neuroprotection seems to be mediated by excitotoxicity reduction and changes in vascular tone by acting on cannabinoid receptors.

Conclusion: The possibilities are indeed immense, and further research into the complex relationship between ECS and glaucoma is imperative to enable us to develop therapies for this otherwise chronic, progressive neuropathy, where the only armament in our hands is early diagnosis and maintenance therapy.

Clinical significance: We still do not have drugs for the prevention of retinal ganglion cell loss and for neuroprotection in glaucoma. Drugs that target cannabinoid receptors can revolutionize glaucoma management owing to their IOP-lowering action and neuroprotective effects. Based on the findings, we argue that further studies on the ECS and its implications in glaucoma are warranted to develop newer, effective, and better-targeted treatment strategies.

How to cite this article: Warjri GB, Gowtham L, Venkatraman V, et al. Role of Endocannabinoids in Glaucoma: A Review. J Curr Glaucoma Pract 2025;19(1):28-37.

Keywords: Cannabinoid enzymes; Cannabinoid ligands; Cannabinoid receptor 1; Cannabinoid receptor 2; Cannabinoid receptors; Endocannabinoid system; Glaucoma; Neuroprotection.

Figs 1A and B:

(A) MAPK signaling pathway; (B) Adenylyl cyclase signaling pathway; AC, adenylyl cyclase; cAMP, cyclic adenosine monophosphate; ERK, extracellular signal regulated kinase; GDP, guanosine diphosphate; Gi/oα are a family of G proteins of the α subunit; αßγ are subunits of G proteins; GPCR, G protein coupled receptor; GTP, guanosine triphosphate; MAPK, mitogen activated protein kinase; MEK, mitogen activated protein kinase; RAF, rapidly accelerated fibrosarcoma; RAS are a group of proteins which are regulators of signal transduction; αßγ are subunits of G proteins

Fig. 2:

Production and metabolism of endocannabinoids. 2-AG, 2-arachidonoylglycerol; ABHD6, α,ß-hydrolase domain-containing 6; AEA, anandamide; CB1, cannabinoid receptor 1; CB2, cannabinoid receptor 2; COX-2, cycloosygenase-2; DAG, diacylglycerol; DGL α/ß, diacylglycerol lipase α/ß; FAAH, fatty acid amide hydrolase; GPR55, G protein-coupled receptor 55; MAGL, monoacylglycerol lipase; NAAA, N-acylethanolamine-hydrolyzing acid amidase; NAPE, N-acyl phosphatidylethanolamine; NAPE-PLD, N-acyl phosphatidylethanolamine-phospholipase D; PLA2, phospholipase A2; PPAR α, peroxisome proliferator-activated receptor alpha; TRPV1, transient receptor potential cation channel subfamily V member 1

Fig. 3:

Production and metabolism of PEA. FAAH, fatty acid amide hydrolase; NAAA, N-acylethanolamine-hydrolyzing acid amidase; NAPE-PLD, N-acyl phosphatidylethanolamine-phospholipase D; NPPE, N-palmitoyl phosphatidylethanolamine PEA, palmitoylethanolamide

Fig. 4:

Allosteric modulator and binding site. CB1, cannabinoid receptor 1; GDP, guanosine diphosphate; GPCR, G protein coupled receptor; GTP, guanosine triphosphate; PAM, positive allosteric modulator; αßγ are subunits of G proteins