Glaucoma is a disease characterized by characteristic changes in the optic nerve and visual field, in which lowering intraocular pressure is expected to improve or suppress optic nerve damage 2). Intraocular pressure is the factor most strongly associated with the onset and progression of glaucoma and is the only modifiable risk factor 1)2).
Cannabinoids are a group of compounds derived from the cannabis plant (Cannabis sativa). Since Hepler and Frank reported in 1971 that cannabis smoking reduced intraocular pressure by about 25% in healthy individuals, the potential for glaucoma treatment has been investigated 1).
There are three types of cannabinoids: phytocannabinoids (Δ9-THC, CBD, etc.), synthetic cannabinoids (WIN55212-2, nabilone, etc.), and endogenous cannabinoids (endocannabinoids) 1). They act on receptors of the endocannabinoid system (ECS), which is widely distributed in the eye, affecting aqueous humor dynamics and retinal ganglion cell survival 1).
However, due to the short duration of action, systemic side effects, limitations in administration routes, and lack of clinical evidence, cannabinoids are not currently positioned as standard treatment in glaucoma management 1)3)4).
Δ9-THC, the main component of cannabis, temporarily lowers intraocular pressure, but the effect lasts only 3–4 hours, requiring 6–8 doses per day for 24-hour pressure control 1). Due to systemic side effects (tachycardia, hypotension, psychoactive effects) and tolerance issues, the American Glaucoma Society, Canadian Ophthalmological Society, and American Academy of Ophthalmology do not recommend cannabis for glaucoma treatment. Existing eye drops and laser therapy are more effective and safer.
The ECS is distributed throughout ocular tissues, including the cornea, conjunctiva, ciliary body, trabecular meshwork, Schlemm’s canal, and retina 1). The main endocannabinoids are arachidonoyl ethanolamide (anandamide; AEA) and 2-arachidonoylglycerol (2-AG) 1).
In glaucomatous eyes, the concentrations of 2-AG and palmitoylethanolamide (PEA) in the ciliary body are reduced, suggesting that the ECS is involved in intraocular pressure regulation 1).
| Receptor | Ocular Distribution | Main Function |
|---|---|---|
| CB1 | Ciliary body, trabecular meshwork, retina | Intraocular pressure reduction, neuroprotection |
| CB2 | Cornea, trabecular meshwork, retina | Anti-inflammatory, neuroprotection |
| GPR18/55 | Trabecular meshwork, ciliary body, retina | Intraocular pressure regulation |
Cannabinoids lower intraocular pressure through the following pathways1).
CBD acts as a negative allosteric modulator of the CB1 receptor, reducing the potency and efficacy of Δ9-THC 1). Therefore, cannabis strains with a high CBD:THC ratio may paradoxically increase intraocular pressure.
| Route of Administration | IOP Reduction Rate | Peak | Duration |
|---|---|---|---|
| Inhalation | 13–34% | Approximately 90 minutes | 3–4 hours |
| Oral | 10–30% | 2–4 hours | 3–4 hours |
| Intravenous | 29–62% | 30–90 minutes | Short duration |
Lindner et al. (2023) comprehensively reviewed clinical studies on the intraocular pressure (IOP)-lowering effect of cannabinoids, noting that systemic administration of Δ9-THC transiently reduces IOP, but based on a therapeutic effect of 3–4 hours, administration 6–8 times daily is required, exposing patients to the risk of substance dependence 1).
Theoretical advantages
IOP-lowering effect: Systemic administration of Δ9-THC reliably reduces IOP 1).
Potential neuroprotection: CB1/CB2 receptor-mediated retinal ganglion cell protective effects have been shown in animal models 1).
Potential blood flow improvement: Vasodilation may improve optic nerve head blood flow 1).
Combined action: In addition to lowering intraocular pressure, it also has anti-inflammatory, antioxidant, and anti-apoptotic effects1).
Clinical Limitations
Short duration of action: With effects lasting only 3–4 hours, 24-hour intraocular pressure management is difficult1).
Systemic side effects: Tachycardia, hypotension, euphoria, dizziness, and psychiatric symptoms have been reported1).
Development of tolerance: The intraocular pressure-lowering effect diminishes with repeated use (tachyphylaxis)1).
Difficulty of topical administration: Due to high lipophilicity, effective eye drop formulations have not been developed1).
The side effects of cannabinoids affect multiple organ systems1).
CBD does not lower intraocular pressure1). In a study by Tomida et al., sublingual administration of 20 mg CBD showed no change in intraocular pressure, while 40 mg CBD paradoxically caused a transient increase in intraocular pressure1). CBD acts as a negative allosteric modulator of the CB1 receptor and may inhibit the intraocular pressure-lowering effect of Δ9-THC1). Cannabis products with a high CBD:THC ratio may be harmful for glaucoma, so caution is needed.
Components of the ECS have been identified in the retina and trabecular meshwork, and they possess the ability to regulate intraocular pressure and provide neuroprotection through the activity of metabolic enzymes (COX-2, FAAH, MAGL)1).
The targets of phytocannabinoids and endocannabinoids partially overlap1). Δ9-THC is a partial agonist of CB1/CB2 receptors and also acts as an agonist of TRPV2-4 channels1). CBD functions as an inverse agonist or negative allosteric modulator of CB1/CB2 receptors1).
In open-angle glaucoma, a specific loss of COX-2 in the non-pigmented ciliary epithelium has been reported1). Cannabinoids stimulate the expression of COX-2 and matrix metalloproteinases, improving aqueous humor outflow through dilation of Schlemm’s canal and remodeling of the extracellular matrix1).
Through the COX pathway, hydrolysis of endocannabinoids produces arachidonic acid, which serves as a precursor for prostanoid synthesis1). COX-2 oxidizes AEA and 2-AG into a series of prostaglandin ethanolamides (prostamides) and prostaglandin glyceryl esters1). Prostamides act via the uveoscleral outflow pathway, and bimatoprost corresponds to this prostamide analog1).
TRPV4 is expressed in the trabecular meshwork and plays an important role in intraocular pressure regulation1). Impairment of TRPV4-mediated eNOS signaling has been reported to be involved in intraocular pressure elevation in the trabecular meshwork1).
TRPV1 is expressed in retinal ganglion cells, and its expression increases under high intraocular pressure1). Activation of TRPV1 causes extracellular calcium influx, which net hyperpolarizes the firing rate of ganglion cells, functioning as a compensatory mechanism to protect RGCs1). Weitlauf et al. showed that RGCs of TRPV1 knockout mice do not exhibit a compensatory increase in firing rate in response to elevated intraocular pressure, supporting this hypothesis1).
Although clinical evidence is limited, preclinical studies have shown neuroprotective effects of cannabinoids 1).
Crandall et al. (2007) reported that intraperitoneal administration of Δ9-THC 5 mg/kg in a rat model of unilateral glaucoma induced by episcleral vein cauterization, observed for 20 weeks, resulted in RGC loss suppressed to 10–20% (compared to 40–50% loss in the control group) 1).
The synthetic non-psychoactive cannabinoid HU-211 promoted regenerative growth and axonal sprouting after optic nerve transection at 30 days 1).
Reported neuroprotective mechanisms via CB2 receptors include suppression of microglial activation, reduction of ROS/RNS production, inhibition of leukocyte migration, and attenuation of vascular inflammation 1). Since CB2 receptor agonists lack psychoactive effects, they are considered promising therapeutic targets 1).
The vasodilatory effects of cannabinoids may improve optic nerve head blood flow 1). In glaucomatous eyes, capillary loss at the optic nerve head and peripapillary capillary dropout are observed, and impaired blood flow is thought to contribute to the pathology.
Hommer et al. (2020) conducted a randomized clinical trial in healthy subjects to examine the effect of oral administration of synthetic THC (dronabinol) on optic nerve head blood flow 1).
To overcome the limitations of topical administration, the following drug delivery technologies are being studied 1).
PEA is a homolog of anandamide, and its intraocular pressure-lowering effect has been reported in patients with ocular hypertension, glaucoma, and after prophylactic iridotomy 1).
Rossi et al. (2020) conducted a randomized single-blind crossover trial in glaucoma patients to evaluate the effect of PEA on inner retinal function using pattern electroretinography 1).
Currently, new drug delivery technologies such as cyclodextrin formulations, prodrugs, and nanoparticles are under research to overcome the high lipophilicity of cannabinoids 1). In particular, a cyclodextrin formulation of WIN55212-2 has shown efficacy in a small number of glaucoma patients 1). However, many hurdles remain for practical use, including establishing efficacy and safety through large-scale clinical trials and regulatory challenges.
