Alternative Treatments for Glaucoma
Introduction: Glaucoma is the most common cause of irreversible blindness worldwide characterized by degeneration of retinal ganglion cells(1). While increased intraocular pressure (IOP) can cause axonal damage and disruption of axonal transport of the optic nerve, there are also other factors at play including disruptions in blood supply to the optic nerve, oxidative stress, inflammation and excitotoxicity(2). Further understanding of all of these factors that play a role in glaucoma development or progression open the door to understanding a multifactorial approach to treatment. Interest in and use of alternative treatments for all health issues, including glaucoma, has increased in US adults over time(3). A 2012 study showed that nearly 1 in 9 glaucoma patients have used some form of alternative treatments. The most common form of alternative treatment is use of herbal medications followed by dietary modifications and vitamin/mineral supplements(4). While there are many alternative treatments that have been proposed, the research on most forms of alternative treatment is either lacking or inconclusive to prove a definitive effect on Glaucoma outcomes. We hope this review will shed light on this topic and assist clinicians in addressing patient inquiry and concerns.
Review of alternative treatments:
Marijuana: Marijuana/cannabis has been shown to produce a short-term decrease in IOP of up to 30%. Effects typically last 3-4 hours and receiving benefit would require maintaining consistent levels of cannabinoids. The two compounds that exert physiologic effects are THC and CBD(5). For an in-depth analysis of the mechanisms of THC and CBD’s effects on the eye please refer to EyeWiki’s article on “”Cannabinoids for Glaucoma”(6). Currently, there are multiple routes for administering THC which include inhalation, oral, sublingual, intravenous. Sublingual and intravenous administration are the only effective routes of using cannabis compounds to lower IOP(6). Topical administration of THC has not been found to be effective in ocular treatment as it has poor penetration, though newer treatments with a synthetic topical cannabinoid (WIN55212-2) have been shown to decrease IOP by 20-30% though effects only last approximately 1 hour and further research is needed to address clinical viability(5,7). Additionally, more research is needed to address specific formulations for clinical use, as strains with a higher CBD:THC ratio have been shown to actually increase IOP(6). There is ongoing research regarding synthetic cannabinoids and one compound, BW146Y, was found to lower IOP though patients still had some side effects, so ongoing research is needed to address viability for treatment(7). While administration of cannabinoids can provide short term IOP benefits, there are many adverse effects associated with marijuana and cannabinoid derivatives including psychotropic effects, tachycardia, hypotension, dry eyes, impaired short-term memory, reduced coordination and dizziness(5). Thus, treatment is not currently clinically viable as the other side effects of marijuana use outweigh the short-term benefits on IOP. The current position statement from the American glaucoma Society Reads “Although marijuana can lower the intraocular pressure (IOP), its side effects and short duration of action, coupled with a lack of evidence that its use alters the course of glaucoma, preclude recommending this drug in any form for the treatment of glaucoma at the present time”(9).This is an area with much ongoing research and will likely continue to develop in the near future.(5,6)
Ginkgo Biloba: Ginkgo Biloba is a popular alternative treatment for glaucoma. It’s proposed mechanism of protection in glaucoma is related to antioxidant properties. It is slightly different than other antioxidants though, as it is proposed to work at the level of the mitochondria to stabilize and protect the mitochondrial membrane from damage as opposed to just neutralizing free radicals(5). Additionally, it has been shown to have vasodilatory properties and anti-inflammatory properties. These properties have been proposed to provide a neuroprotective effect in the treatment of glaucoma. While animal studies have shown increased retinal and choroidal circulation which could provide benefits to the retina, this effect is not fully studied in humans(10). There have been multiple randomized control trials conducted evaluating the effects of ginkgo biloba on IOP and visual fields which were ultimately inconclusive given that some studies found improvement after administration of ginkgo biloba and some did not. Specifically, there was some consideration of gingko biloba as a treatment for normal tension glaucoma and two studies were done on this. One of which showed improvement in visual fields, which was not maintained after washout, with no significant change in IOP. A second study was done with ginkgo and NGT and the results of the first were not replicated, with no significant changes in visual biloba fields or IOP. Ultimately, there is some evidence that ginkgo biloba can provide antioxidant, circulatory and neuroprotective benefits in the eye and it is generally a low-risk option, though further study is needed(5). There are some case reports indicating adverse effects of ginkgo biloba given it’s antithrombotic properties which include intracranial bleeding and retinal hemorrhage, though there are also trials indicating risk of bleeding is insignificant, so this is also inconclusive.(10,11)
Nitric Oxide/Consumption of Dark, Leafy Greens: Consumption of dark, leafy greens has been associated with decreased likelihood of developing glaucoma. Because most dark, leafy greens contain Vitamin A, C, K and nitrate it is unclear what the exact source of the benefit is(12). Nitrate plays a role in the nitric oxide pathway which may be associated with glaucoma, while Vitamin A, C and K may also provide benefit(13). There is evidence that nitric oxide plays a role in the regulation of IOP and issues with this pathway may play a role in glaucoma incidence and progression. Nitric Oxide is produced in both the anterior and posterior chambers of the eye and through the NO-GC-1 pathway it allows relaxation of the trabecular meshwork, permeability of cells in Schlemm’s canal and thus increased outflow of aqueous humor and lower IOP. Disruption of this pathway is hypothesized to lead to decreased outflow and increased IOP(14).Additionally, studies on mice that are deficient in a receptor for nitric oxide had optic neuropathy and elevated IOP(15). A new drug, latanoprostene bunod, a NO-donating prostaglandin F2A analog works through this pathway to lower IOP in the treatment of glaucoma(14). While the link between leafy green consumption and glaucoma may be attributable to multiple components or vitamins in leafy greens, it’s intake can be encouraged in moderation as part of a healthy diet in patients given its nutrient rich makeup and potential for glaucoma benefit.
Omega3s: Consumption of essential fatty acids, including Omega3 and Omega 6 have been shown to play a role in many diseases. Whether these essential fatty acids promote or prevent diseases is dependent on ratios of intake. In many western diets there is a very high ratio of consumption of omega-6 polyunsaturated fatty acids as compared to omega-3 essential fatty acids. This imbalance can contribute to the progression of many pathologies including inflammatory and autoimmune processes, cancer and cardiovascular disease. Whereas a diet that is higher in levels of omega-3 fatty acids as compared to omega-6 can result in decreased mortality(16). Specifically in regards to glaucoma, Omega-3 fatty acids act on a cellular level within the retina through complex mechanisms to exert anti-oxidant and anti-inflammatory effects as well as play a role in rhodopsin regeneration. Additionally, Docosahexaenoic Acid (DHA), a dietary omega-3 fatty acid, is a component of photoreceptor membranes and acts in a pathway that prevents endothelial cell dysfunction and vascular remodeling(17). Through these protective mechanisms, Omega-3 specifically provides some protective effects from oxidative stress in glaucoma. While there is evidence regarding Omega-3:Omega-6 ratio and the effects of this, there is conflicting evidence about whether there is a direct link between dietary Omega3 or Omega6 intake and glaucoma that is sufficient enough to recommend it as a treatment compared to current standard of care (18,19). As with many supplements, there are risks associated with large intake. Essential fatty acids have anti-thrombotic and anti-hemostatic effects and intake above 3g/d, which is the GRAS (generally regarded as safe) dietary intake level, there is some risk of hemorrhage(17).
Vitamin A: Vitamin A is an important compound for normal functioning of the retina and rhodopsin and acts as an antioxidant. Studies have some variability but show that Vitamin A may have a protective effect in the disease course of Glaucoma. The exact nature of this association is unclear and may potentially be related to their role as antioxidants(13). Use of vitamin A is not without risk though and consumption in excess of 3,000mcg can result in night blindness and intracranial hypertension(20) .
B Vitamins: A review of studies on B complex vitamins included 19 studies of the association between various B complex vitamins and glaucoma. There were no studies performed on vitamin B2 or B3, one study on vitamin B1, and multiple on B6, B9 and B12. Some studies focused on the association between low serum levels of vitamin B9 and B12 and higher homocysteine levels which can cause oxidative stress and apoptosis in retinal ganglion cells. These showed that increased levels of homocysteine in aqueous humor and plasma were found in patients with POAG(13). Serum levels of B1 complex were inconclusive with one study indicating an association between dietary intake levels of B1 having a protective effect and one finding no association. For vitamin B12, a link was not found with dietary intake and POAG, though there is one study that used OCT to compare retinal nerve fiber layer thickness in patients with vitamin B12 deficiency against healthy controls. This study found that on average patients with vitamin B12 deficiency had thinner retinal nerve fiber layers and thus vitamin B12 may have a neuroprotective effect on the retina(21). Many of the B vitamins do not have listed upper limits as excess is not stored in the body, exceptions to this are Vitamin B3 with an upper limit of 35mg and Vitamin B6 with an upper limit of 100mg(20).
Vitamin C: The role of Vitamin C in glaucoma is unclear. There are high levels of Vitamin C in the aqueous and vitreous humor, up to as much as 20-70x the level found in plasma. This is hypothesized to act as a protective mechanism against free radicals from sunlight and oxidative damage(22). While antioxidant effects have a protective mechanism on the retina, which may provide protection against retinal damage in glaucoma, there was also one study done that showed that high dietary intake of Vitamin C can effectively reduce IOP via an osmotic effect. Though it must be used in very high doses given intravenously and this is not clinically practical(23,5). Additionally, when given at such high levels (above 2,000mg/day) there may be other symptoms that limit treatment including diarrhea and dehydration(13,20) .
Vitamin E: There is some question as to whether Vitamin E has a protective effect as an antioxidant, though again the data is conflicting and inconclusive(13). While Vitamin E is known to play a role as an antioxidant, multiple studies have provided inconclusive links between plasma levels of Vitamin E, dietary intake of Vitamin E and a direct association with POAG. The recommended daily intake of Vitamin E for adults is 15mg/day, at these levels vitamin E can play a role in the oxidation of LDLs and reducing free-radicals. Deficiency of Vitamin E can result in peripheral neuropathy and retinopathy. Excessive intake of vitamin E, typically above 1000mg oral intake, can result in a Vitamin K deficiency resulting in bleeding, as well as muscle weakness, fatigue, nausea and diarrhea(13,20).
Bilberry: There is some evidence to suggest that Bilberry extract may decrease retinal ganglion cell death after injury, such as is the case in glaucoma, and provide a neuroprotective effect. This effect is mediated specifically by increasing levels of chaperone molecules that suppress apoptosis after bilberry extract administration. Though this link has not yet been proven to alter the course of glaucoma in patients, it suggests that administration of bilberry may play a role in mitigating damage to the retina and optic nerve(5,24). Reliable information on bilberry intake levels and toxicity was not found at this time, which may also be a reason to be cautious in recommending bilberry as a treatment for patients.
Melatonin: Glaucoma may frequently be associated with sleep disorders or psychological disorders such as depression and anxiety(25). This association is partially related to the direct disturbance of sleep and the circadian rhythm after retinal damage in glaucoma, which is a cycle where melatonin plays a central role. In addition to its effect on the circadian rhythm and potential role in comorbidities associated with glaucoma, melatonin may play a role as an antioxidant in ocular tissue and thus have neuroprotective effects. There is also data showing significantly decreased levels of melatonin in rats with high IOP, indicating it may have a role in regulating IOP and be related to regular daily, cyclic shifts in IOP. Melatonin requires further study to determine if it can play a therapeutic role and may be clinically limited, especially for use during the day, due to other effects including sleepiness(26). Though given the prevalence of both sleep and circadian disturbances and glaucoma in the elderly population, this may be a beneficial treatment at night in this population. Additionally, melatonin may be beneficial in patients with significant vision loss from glaucoma to address both circadian disturbances and glaucoma. Given the strong link between depression, anxiety and sleep disturbances in patients with glaucoma, melatonin may sit at a crossroads of addressing both glaucoma and comorbid conditions(26). Melatonin also appears to be a very supplement, with some clinical reports of side effects including headache and gastrointestinal upset at “large doses” though an official upper limit of intake and study of toxicity has not been determined(27).
Bioflavonoids: Bioflavonoids are found in many fruits and vegetables and contribute to their pigmentation. Many have been studied and have shown potential as having natural antioxidant, anti-inflammatory, anti-apoptotic anti-excitotoxic properties. Three flavonoids with this potential include baicalein, baicalin and wogonin which are all extracted from the root of S. Baicalensis, an herbal medicine. Currently, S. Baicalensis is a commonly used herbal medicine in many Asian countries. Specifically in regards to glaucoma, there have been in vivo studies in rats showing that bioflavonoids had the ability to protect retinal ganglion cells from retinal ischemic and apoptosis. Additionally, a study in humans showed protection of retinal pigment epithelium cells by suppressing production of matrix metallo-proteinase-9 and VEGF(28). Given this, it demonstrates potential as a neuroprotective treatment and further studies in humans to determine clinical viability, pharmacodynamic and pharmacokinetic properties are needed.
Curcumin/Turmeric: Turmeric is a popular Indian spice and one of the main components of turmeric is curcumin. Studies have shown that turmeric has anti-inflammatory, antioxidant and antitumor properties. In regards to it’s role in inflammation and cancer, studies have shown that curcumin is able to inhibit the activation of NF-kB, which in turn is able to downregulate apoptosis, proliferation and transformation of cells. Additionally, it can downregulate many pathways involved in inflammation including COX-2, PGE-2, Interleukins 1, 6 and 8, TNF-alpha and expression of the IkBa gene. Specifically, in regard to glaucoma, animal models have shown that pre-treatment with curcumin decreased levels mitochondrial injury markers in glaucoma and elevated levels of protective markers after retinal ischemia induced by high IOP. There are currently limitations to the use of curcumin because it has a low solubility and oral bioavailability. There is work being done to enhance bioavailability and evaluate better methods of administering curcumin to enhance therapeutic results. Overall, curcumin is very safe, partially attributable to its low bioavailability (29). When given in high concentrated doses though, curcumin can be hepatotoxic, though the recommended dose varies widely given the different preparations (100-1,000 mg daily) and thus more information on this toxicity would be needed prior to patient recommendation(30).
Green Tea/Caffeine Consumption: Evidence is inconclusive on the role of green tea in macular degeneration and glaucoma. Antioxidants may be useful in treatment of macular degeneration and glaucoma and given the antioxidant properties of green tea and low overall risk of green tea intake as part of the diet, this may confer some benefit. At very high doses, some green tea components (greater than 33mg of catechin and epigallocatechingallate) may cause hepatotoxicity, but this level generally is not reached through consumptions in tea preparations(31). Green tea also contains caffeine and caffeine consumption has been explored as a potential risk for glaucoma given concerns regarding its effect on IOP. A 2021 study showed that consistent caffeine consumption had a weak association with lower IOP but the overall association between caffeine consumption and glaucoma was inconclusive. Although, in individuals with a strong genetic predisposition to elevated IOP there was an association between higher caffeine consumption and higher IOP and glaucoma risk. Thus, in the general population caffeine consumption does not have a strong association with increased glaucoma risk, though in those patients already at high risk of glaucoma, limiting caffeine consumption may be beneficial(32).
Sleeping Position: Managing IOP is an important factor in control of glaucoma progression(33). There are daily fluctuations in IOP, with many patients showing a peak elevated IOP at night. This effect seems to be mainly due to elevated episcleral venous pressure (EVP) and choroidal congestion due to gravity-dependent positional fluid shifts(34). These changes in IOP at night are important because patients with higher peak nighttime pressures can have progression of glaucoma, despite adequate daytime IOP control(35). Elevated nighttime pressures do not seem to be an issue for patients with low risk for glaucoma, but are a significant factor in those patients who are already higher risk for glaucoma development or progression(33). Additionally, preferentially sleeping on one side has been shown to be correlated with worsened IOP and outcomes on the dependent side and asymmetric glaucoma progression. Therefore, nighttime IOP increases are an important factor in controlling progression of glaucoma. Sleeping with the head inclined at 20 degrees may decrease IOP overnight when individuals are in the supine position and advising patients to avoid sleeping on one side consistently may help avoid progression in the dependent eye. Discussing sleep habits with glaucoma patients could help improve fluctuations in IOP overnight(36,37). Additionally, trabeculectomy decreases position-dependent IOP fluctuations overnight more effectively than IOP-lowering medications and may be an option for treatment in high-risk patients(34).
BMI/Weight: Studies have shown links between both low BMI (<18.5) and high BMI (>30) and POAG. A cross-sectional study in Korea in 2020 focused on BMI and glaucoma found that specifically women with low BMI had higher rates of glaucoma. This was hypothesized to be due to lower intake of all nutrients, but especially low protein and thiamine intake, and females were more affected than males(38). A prospective cohort study in Korea in 2020 found that individuals with a BMI greater than 30 were more likely to develop POAG(39). This study also found an association between high fasting glucose, blood pressure and cholesterol and POAG so the association with glaucoma and BMI could be multifactorial and related to metabolic syndrome(39). Given our knowledge that glaucoma is a multifactorial disease that is related to inflammatory processes, encouraging patients to maintain their overall health and encouraging a healthy weight and nutritional status should be standard of care for glaucoma treatment.
Exercise: Moderate exercise can result in lowering of IOP. This effect can last several months. It also has many other health benefits, including lowered blood pressure which may also have a positive effect on IOP. Thus, given the known health benefits of exercise, this can be suggested to patients as a general recommendation for overall and eye health(3).
Smoking Cessation: There is mixed evidence on a link between smoking and direct risk of developing glaucoma. More recent studies have shown there may be a risk between heavy smoking and glaucoma as well as IOP fluctuations and smoking. While the evidence of direct causation of glaucoma is still under investigation, the risks of smoking are known. Free radical formation from smoking is damaging to ocular tissues and increases inflammation in the body. Thus, smoking cessation can still be promoted as a protective mechanism in all patients for overall and eye health(40).
Meditation/Yoga: Glaucoma is frequently comorbid with anxiety and depression due to the stress of having a chronic blinding illness. Anxiety and depression in turn can lead to an increase in cortisol and IOP(41). Long term practice of meditation may help reduce IOP and stress biomarkers, especially in those with acute angle closure glaucoma that may be associated with stress(41,42). While it’s definitive effect on glaucoma outcomes is still unknown, given the low risk of its use along with other proven health benefits in management of chronic illness including cardiovascular disease, diabetes and major depression, it could be safely recommended for patients to add to their lifestyle(3,41). Yoga is another form of therapy that has been shown to improve health-related quality of life in many patients and has been shown to improve both physical and mental health(43). In patients with glaucoma specifically though, clinicians should discuss avoidance of yoga positions that place the practitioner in the head down position, including inversions. These positions have been shown to raise IOP between 6-11 mmHg in both healthy individuals and those with glaucoma within one minute of assuming the pose. While the IOP returns to baseline shortly after returning to a normal position, this elevation in IOP may be detrimental, especially to those with a high risk of glaucoma. The direct effect of these transient elevations in IOP due to yoga on glaucoma has not been definitively proven, though the risk of elevations in IOP on glaucoma progression is known and thus avoidance of these behaviors in those at high risk of glaucoma is recommended(44).
Acupuncture: Acupuncture has been proposed as an alternative treatment for glaucoma and some animal studies have shown acupuncture had a protective effect on the retina through elevating expression of bcl-xl and BDNF proteins(45). Though a recent systemic review of completed and ongoing clinical trials in humans for acupuncture as a treatment for glaucoma found that there is insufficient data to support acupuncture as a current treatment modality for glaucoma compared to the current standard of care. This systematic review showed that data from the clinical trials in humans was incomplete, biased or contradictory(45). Therefore, acupuncture warrants further study before being proposed as a treatment for glaucoma.
Conclusion: While there is a wide interest in the use of alternative treatments for glaucoma, there is still much research to be done about the effectiveness of alternative treatments and clinical feasibility. General lifestyle improvements including smoking cessation, exercise, meditation and a balanced diet that includes leafy greens may have a very modest effect on risk of development glaucoma(3,12,40).Though given the low risk nature of these interventions and proven overall health benefits, they are still feasible as suggestions to improve overall and eye health. Additional low risk benefits include sleeping on the back with head inclined to 20 degrees to limit nighttime increase in IOP due to positional changes(36,37). While there is much ongoing research into vitamins and their role in glaucoma, the research is too inconclusive at this point to be able to offer natural supplements as an alternative to the current standard of care.
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