Overview

Glaucoma, a progressive optic neuropathy and the leading cause of irreversible blindness globally. It primarily manifests as increased intraocular pressure (IOP) due to impaired aqueous humour drainage. Although several pharmaceutical options like prostaglandin analogues, beta-blockers, and carbonic anhydrase inhibitors are currently used, cannabinoids have garnered attention for their potential in lowering IOP.

Cannabinoids, particularly Δ-9-THC, CBD, and related compounds, have demonstrated IOP-lowering properties through interactions with cannabinoid receptors CB1 and CB2, present in various ocular tissues. These receptors modulate neurotransmitter release, immune response, and aqueous humour dynamics. Early studies showed that both natural and synthetic THC reduced IOP by up to 30%, supporting its physiological effect on ocular pressure regulation.

Dosage studies have explored multiple forms: oral Palmitoylethanolamide (PEA) tablets, inhaled marijuana cigarettes (18 mg THC), topical applications like Canasol (with limited data), and intravenous THC at 0.044 mg/kg, which showed up to a 37% reduction in IOP.

Despite these promising effects, limitations such as short duration of action, lack of long-term studies, and the potential for abuse have restricted the clinical adoption of cannabinoids for glaucoma management. Furthermore, current cannabinoid formulations lack approval in many regions, such as countries like India. As a result, despite potential neuroprotective and IOP-lowering properties, cannabinoids are yet to be considered reliable first-line or adjunctive therapies for glaucoma.

Introduction

Glaucoma is a diverse collection of disorders caused by the cupping of the optic nerve head and visual field loss. It is the worldwide leading cause of irreversible vision loss because it can be asymptomatic until a relatively late stage, which leads to a delayed diagnosis, and more damage. It is the leading cause of irreversible blindness in the world. The normal intraocular pressure ranges between 10-21 mm of Hg, which is regulated by a balance between the secretions of aqueous humour.¹

There are broadly 2 subtypes of Glaucoma: open-angle glaucoma and angle-closure glaucoma. Among them, open-angle glaucoma is the most prevalent. 

Factors affecting glaucoma:²

•  Age: Ageing, development and childhood all these factors affect the development of glaucoma
• Genetic factors: Family history, genetic predisposition, sex (females are more prevalent) and ethnicity (the Chinese community are more at risk) affect the development
•  Intraocular pressure: Intraocular pressure variation, diurnal variation, seasonal variation, etc
• Ocular characteristics: Cornmeal thickness, reticular thickness of the ganglion cells
• Ocular comorbidities: Myopia, diabetic retinopathy, hyperopia
• Vascular factors: Factors affecting blood flow to the optic nerve and retina, including arteriosclerosis, vasospasm
• Systemic comorbidities: Hypotension, sleep apnea, dementia
• Lifestyle factors: Smoking, diet, supplements, physical activity
• Patient treatment attitude: Treatment adherence, patient understanding, and timely follow-up

Medications

• Prostaglandin analogues: Latanoprost, Travoprost
• β-Adrenergic blockers: Timolol, Carteolo
• α-Adrenergic blockers: Brimonidine
• Carbonic anhydrase inhibitors: Acetazolamide
• Cholinergic agonists: Pilocarpine

Cannabinoids as treatment:^3,4

Cannabinoids have been studied as a potential treatment for glaucoma since the early 1970s. Cannabinoids are a broad class of chemical compounds that are produced artificially by pharmacological synthesis or obtained from the resins of secretory trichomes located on female flowers of Cannabis sativa. The compounds from marijuana most thoroughly studied are Δ-9-tetrahydrocannabinol (Δ-9-THC or better known as THC), cannabidiol (CBD), Δ-8-tetrahydrocannabinol (Δ-8-THC), and cannabinol. Δ-9-THC is the main psychoactive compound in the plant and is primarily, but not solely, responsible for many of the effects sought by recreational users. 

The cannabinoids interact with the receptors in the human body and express themselves. In this way, they can assist in treating glaucoma. There are 2 natural endocannabinoids in the body, i.e. CB1 and CB2. CB1 is present most prominently throughout the central and peripheral nervous systems, where it has been shown to suppress neurotransmitter release at presynaptic neurons. CB2 is found primarily in the immune system and is involved in the modulation of cytokine release. Cannabinoids’ ability to reduce glutamate release and oxidative stress is indeed well documented. Neurodegeneration plays a major role in glaucoma pathogenesis and progression; therefore, cannabinoids may represent a useful tool thanks to their dual therapeutic effect. Research was expanded in 1972 to examine the effects of natural marijuana, synthetic Δ-9-THC spiked plant material, oral THC, and marijuana free of THC on the intraocular pressure of human subjects. The researchers found a pressure reduction of about 30% from both natural marijuana and the Δ-9-THC spiked plant material. This identified Δ-9-THC as one of the active agents in lowering intraocular pressure.

In the human eye, cannabinoid receptors are expressed in the retina, ciliary body, iris, Schlemm’s canal, trabecular meshwork, and retinal pigment epithelium. Cannabinoids help by reducing the generation of aqueous humour and enhancing its outflow. The topical use of a synthetic cannabinoid was used. In their study, 25 μg and 50 μg doses produced a decrease in IOP by 15% and 23% in the first 30 min and by 20% and 31% after 60 min. Although dronabinol and nabilone, synthetic derivatives of THC, have been approved by the US FDA for chemotherapy-induced nausea and vomiting, there are currently no approved medical uses for these in India. Hence, even if any of the cannabis derivatives show a potential advantage over the existing antiglaucoma drugs, the results are likely to receive more scrutiny than any other new drug, given the concerns regarding their misuse and abuse potential.

Dosage potential of cannabinoids:⁵

• Oral Dosage Form: Palmitoylethanolamide (PEA) - 300 mg tablets for 2 months
• Inhaled Dosage Form: 18 mg delta-9-THC (0.9 g marijuana cigarette with 2% delta-9-THC)
• Topical Dosage Form: Marijuana-based eye drops called Canasol have been sold in Jamaica and other Caribbean countries since the early 90s. No scientific evidence and no randomised controlled studies are available. Therefore, its efficacy and safety remain unknown
• Intravenous Dosage Form: A 0.044 mg/Kg dose showed a decrease in 37% of intraocular pressure

Summary

Although special formulations with the potential to improve ocular delivery have been attempted, most of these are in the preclinical phase. Given these issues, the lack of support expressed by various specialist groups a decade ago for the use of any form of cannabinoids in glaucoma, due to lack of efficacy and potential adverse effects, seems to hold strong even today.