Glaucoma is a disease characterized by degeneration of retinal ganglion cells and is the most common cause of irreversible blindness worldwide. Elevated intraocular pressure is a major risk factor, but multiple factors such as impaired blood supply to the optic nerve, oxidative stress, inflammation, and excitotoxicity are involved in the onset and progression.
Interest in complementary and alternative medicine (CAM) has been increasing year by year. A 2012 survey found that about 11% of glaucoma patients used some form of CAM. The most common form was the use of herbal medicines, followed by dietary changes and vitamin/mineral supplements.
However, for many complementary therapies, evidence demonstrating definitive efficacy on glaucoma outcomes is lacking or inconclusive 1).
QCan glaucoma be treated with complementary therapies alone?
A
No, there is currently no evidence that complementary therapies alone can adequately manage glaucoma. Lowering intraocular pressure with eye drops, laser treatment, and surgery is the only established treatment. Complementary therapies are only adjunctive, and it is important to use them in combination with standard treatment after consulting your doctor.
5. Types of Complementary Therapies and Current Evaluation
Marijuana (cannabis) has been shown to lower intraocular pressure by up to 30% in the short term. The effect lasts 3 to 4 hours, and sustained cannabinoid levels are needed to maintain benefit. The main active ingredients are THC (tetrahydrocannabinol) and CBD (cannabidiol).
Effective routes of administration are only sublingual and intravenous. THC eye drops are not effective due to poor penetration, but a synthetic topical cannabinoid (WIN55212-2) has been reported to lower intraocular pressure by 20–30%. However, the effect is short-lived, lasting about 1 hour. Strains with a high CBD-to-THC ratio have been reported to actually increase intraocular pressure.
The 5th edition of the EGS also mentions the role of cannabinoids in glaucoma management, but currently the evidence is considered insufficient 1). The American Glaucoma Society states that “marijuana can lower intraocular pressure, but due to side effects, short duration of action, and lack of evidence that it alters the course of glaucoma, it cannot be recommended as a treatment.”
Ginkgo biloba is a natural compound widely used as an alternative therapy for glaucoma. The following actions have been proposed.
Antioxidant effect: Rather than simply neutralizing free radicals, it acts at the mitochondrial level to stabilize and protect mitochondrial membranes.
Vasodilatory and anti-inflammatory effects: Animal studies have shown increased retinal and choroidal circulation, but this has not been sufficiently verified in humans.
Several randomized controlled trials evaluating the effects on intraocular pressure and visual field have been conducted, but some studies show improvement and others do not, so no conclusion has been reached. For normal-tension glaucoma (NTG), two studies were performed: one showed visual field improvement that was not maintained after a washout period, and the other could not replicate the results. Hemorrhagic side effects due to the antithrombotic properties of ginkgo biloba have been reported, but some studies consider the risk negligible.
Consumption of dark green leafy vegetables is associated with a reduced risk of developing glaucoma. Green leafy vegetables contain vitamins A, C, K, and nitrates, which are involved in the nitric oxide (NO) pathway.
NO is produced in the anterior and posterior chambers of the eye. Through the NO-GC-1 pathway, it relaxes the trabecular meshwork and increases the permeability of Schlemm’s canal cells, thereby promoting aqueous humor outflow and lowering intraocular pressure. NO receptor-deficient mice have been shown to develop optic neuropathy and elevated intraocular pressure.
A new drug that utilizes this pathway is latanoprostene bunod, an NO-donating prostaglandin F2α analog that lowers intraocular pressure.
Omega-3 fatty acids exert antioxidant and anti-inflammatory effects in the retina and are also involved in rhodopsin regeneration. Dietary omega-3 DHA (docosahexaenoic acid) is a component of photoreceptor membranes and also helps prevent vascular endothelial dysfunction.
A diet high in omega-3 relative to omega-6 may reduce the risk of inflammatory diseases. However, evidence for a direct therapeutic effect on glaucoma is conflicting and insufficient to recommend as a substitute for standard treatment.
The GRAS (generally recognized as safe) intake is 3 g/day; exceeding this may increase bleeding risk due to antithrombotic and antihemostatic effects.
Vitamins
Vitamin A: Has antioxidant properties and is important for retinal and rhodopsin function. Protective effects have been suggested, but intake exceeding 3,000 μg carries risks of night blindness and increased intracranial pressure.
B vitamins: Low levels of B9 and B12 may contribute to retinal ganglion cell damage via elevated homocysteine. Patients with primary open-angle glaucoma (POAG) have elevated homocysteine in aqueous humor and plasma. Nicotinamide (a form of B3) at 3 g/day has been reported to cause severe drug-induced liver injury.
Vitamin C: Present in aqueous and vitreous humor at 20–70 times plasma concentration, involved in protection against free radicals. High-dose intravenous administration has been reported to lower intraocular pressure osmotically, but is not clinically practical. Doses above 2,000 mg/day carry a risk of gastrointestinal symptoms.
Vitamin E: Known for its role as an antioxidant, but a direct link with primary open-angle glaucoma has not been established. The recommended intake is 15 mg/day; doses above 1,000 mg increase bleeding risk.
Other Natural Compounds
Bilberry: May reduce retinal ganglion cell death after injury and increase expression of chaperone molecules, providing neuroprotective effects. Reliable information on upper intake limits and toxicity has not been established.
Melatonin: Suggested to have antioxidant and neuroprotective effects in ocular tissues. It may also be involved in the diurnal variation of intraocular pressure, and nighttime use could be beneficial for elderly glaucoma patients with circadian rhythm disorders.
Bioflavonoids: Baicalein, baicalin, and wogonin have antioxidant, anti-inflammatory, and anti-apoptotic properties. Animal studies have shown ischemic protection of retinal ganglion cells.
Curcumin (turmeric): Has anti-inflammatory and antioxidant effects via NF-κB inhibition. Animal models have shown reduced markers of mitochondrial damage. Low solubility and oral bioavailability are challenges, and high concentrations may cause liver toxicity.
Green tea has antioxidant properties and low risk when consumed as part of the diet. Very high doses (above 33 mg of catechins and epigallocatechin gallate) may cause liver toxicity, but this is not reached with typical tea beverages.
The relationship between caffeine intake and glaucoma is also discussed in the EGS 5th edition as a lifestyle factor 1). A 2021 study showed that continuous caffeine intake was weakly associated with lower intraocular pressure, but the overall association with glaucoma was inconclusive. However, in individuals with a strong genetic predisposition to elevated intraocular pressure, high caffeine intake was associated with higher intraocular pressure and glaucoma risk.
Intraocular pressure (IOP) has diurnal variation, and many patients experience IOP peaks at night. This effect is due to increased episcleral venous pressure and choroidal congestion associated with postural changes. Even if daytime IOP is well controlled, high nighttime peak pressure may lead to glaucoma progression. Nocturnal IOP elevation is a particularly important factor in patients already at high risk for glaucoma.
QDoes marijuana work for glaucoma?
A
Marijuana (cannabinoids) has been shown to lower IOP by up to 30% in the short term, but the effect lasts only 3–4 hours. Side effects include psychoactive effects, hypotension, and tachycardia, and the American Glaucoma Society does not recommend it as a treatment. It is not suitable for long-term management of glaucoma, so please continue standard treatment after consulting your doctor.
QShould glaucoma patients avoid caffeine?
A
In general, there is no strong association between caffeine intake and increased glaucoma risk. However, in individuals with a strong genetic predisposition to IOP elevation, high caffeine intake has been reported to be associated with higher IOP. Those at high risk for glaucoma may consider limiting excessive caffeine intake.
6. Main Mechanisms of Action of Alternative Therapies
Oxidative stress is involved in retinal ganglion cell damage in glaucoma. Many natural compounds such as vitamins A, C, E, ginkgo biloba, bilberry, bioflavonoids, and curcumin may exert antioxidant effects through neutralization of free radicals and mitochondrial protection.
NO relaxes the trabecular meshwork via the NO-GC-1 pathway and increases the permeability of Schlemm’s canal cells. Impairment of this pathway leads to reduced aqueous humor outflow and elevated intraocular pressure. Nitrates found in green leafy vegetables serve as substrates for the NO pathway, and latanoprost bunod is clinically used as an NO-donating prostaglandin.
Curcumin suppresses inflammation-related pathways such as NF-κB, COX-2, and TNF-α. Bioflavonoids show protection of ganglion cells from retinal ischemia and suppression of MMP-9 and VEGF production. Omega-3 fatty acids exert anti-inflammatory effects at the cellular level.
Low levels of vitamin B9 (folate) and B12 can lead to elevated homocysteine, which may promote oxidative stress and apoptosis in retinal ganglion cells. Elevated homocysteine in aqueous humor and plasma has been reported in patients with primary open-angle glaucoma.
Currently, the following research is ongoing in the field of alternative therapies for glaucoma.
Development of synthetic cannabinoids: Research on synthetic cannabinoids such as WIN55212-2 and BW146Y is underway, but due to side effects, they have not yet reached clinical application. Improving the THC/CBD ratio and topical formulations remains a challenge.
Clinical application of NO-donating drugs: Latanoprost bunod is the first eye drop to utilize the NO pathway for glaucoma treatment, and the development of new drugs targeting this pathway is expected.
Improving the bioavailability of curcumin: Low solubility and oral bioavailability are barriers to the clinical application of curcumin. Research is underway to improve bioavailability through new formulation technologies.
Neuroprotection of nicotinamide (vitamin B3): Nicotinamide is being investigated in clinical trials for neuroprotection in glaucoma, but severe drug-induced liver injury has been reported at high doses of 3 g/day, and establishing safety remains a challenge.
The EGS 5th edition notes that lifestyle factors such as smoking, caffeine intake, alcohol consumption, nutrition, exercise, and meditation may be associated with glaucoma through both intraocular pressure-dependent and independent mechanisms, but states that there are many conflicting data.
Overall, many alternative therapies have shown promising results in animal experiments and small-scale studies, but there is a lack of verification of efficacy through large-scale clinical trials. Currently, no alternative therapy has reached a level of evidence that can be recommended as a substitute for standard glaucoma treatment.
