Supplements and Eye Diseases (Lutein, Zeaxanthin, etc.)

Key Points at a Glance

Key points of this disease

• Large-scale RCTs are investigating the effects of nutrients and supplements such as lutein, zeaxanthin, vitamins C and E, zinc, and omega-3 fatty acids on the prevention and progression suppression of age-related macular degeneration (AMD), cataracts, and dry eye.
• Evidence for suppressing AMD progression has been established in AREDS (3,640 cases)¹⁾, and the AREDS formulation (vitamin C/E, zinc, beta-carotene) reduces the risk of progression of moderate to advanced AMD by approximately 25%¹⁾.
• In AREDS2 (4,203 cases), replacing beta-carotene with lutein 10 mg + zeaxanthin 2 mg/day achieved equivalent progression suppression while avoiding the risk of lung cancer in smokers²⁾.
• The DREAM trial (535 cases) found no significant difference between omega-3 fatty acids and placebo in improving dry eye symptoms⁷⁾.
• Beta-carotene increases the risk of lung cancer in smokers, so AREDS formulations containing beta-carotene are considered contraindicated for smokers ¹³⁾.
• The indication for AREDS2 formulation is moderate to advanced AMD (AREDS categories 3 and 4) in one eye, and its preventive effect in the general population before onset has not been established.
• Supplements are only a supplementary measure, and it is essential to combine them with regular eye examinations.

1. What is the relationship between supplements and eye diseases?

National Eye Institute, National Institutes of Health. Intermediate age-related macular degeneration fundus photograph. Figure 1. Source ID: commons.wikimedia.org/wiki/File:Intermediate_age_related_macular_degeneration.jpg. License: CC BY (Public Domain, U.S. federal government work).

Numerous medium to large drusen (yellow-white deposits) scattered in the macula, showing typical fundus findings of intermediate AMD. This corresponds to the drusen findings of intermediate AMD (AREDS category 3) that were the subject of the AREDS study discussed in the section “1. Relationship between supplements and eye diseases.”

The field examining the scientific evidence of nutrients and supplements for the prevention and progression suppression of eye diseases is attracting attention. In particular, large-scale randomized controlled trials (RCTs) have been conducted for three diseases: age-related macular degeneration (AMD), cataracts, and dry eye.

The largest source of evidence is the Age-Related Eye Disease Study (AREDS) led by the U.S. National Eye Institute (NEI). AREDS, conducted from 1992 to 2001, was a large-scale RCT involving 3,640 participants ¹⁾, evaluating the “AREDS formulation” combining vitamin C 500 mg, vitamin E 400 IU, beta-carotene 15 mg, and zinc oxide 80 mg. It was shown to reduce the risk of AMD progression by approximately 25% in patients with moderate to advanced AMD (AREDS categories 3 and 4) ¹⁾.

In the AREDS2 study (4,203 cases) conducted from 2006 to 2012 ²⁾, the efficacy and safety of a new formulation replacing beta-carotene with 10 mg lutein + 2 mg zeaxanthin per day were verified. The replacement with lutein and zeaxanthin showed an effect equivalent to beta-carotene in suppressing AMD progression ²⁾, while avoiding the increased risk of lung cancer in smokers associated with beta-carotene, making it the current standard formulation.

Importantly, the AREDS/AREDS2 formulation is intended to slow progression in patients with moderate to advanced AMD, and its efficacy in preventing the onset of AMD in the general population without AMD has not been established. Supplements are an adjunct to ophthalmic management, and the foundation is a combination of regular eye examinations for early detection and early treatment.

Q Can supplements prevent age-related macular degeneration?

A

The AREDS formulation has established evidence of reducing the risk of progression of moderate to advanced AMD (AREDS categories 3 and 4) by approximately 25% ¹⁾. However, this is “progression suppression,” and the effect of “preventing onset” in healthy individuals without AMD has not been established at this time. There is no general recommendation for people without AMD risk, and consideration should be given to prescribing the AREDS2 formulation for patients confirmed to have moderate to advanced AMD.

2. Major Supplement Ingredients and Eye Diseases

The main supplement components related to eye diseases are broadly classified into five types.

Lutein and Zeaxanthin

Role: Main component of the pigment in the macula (the most important area at the center of the retina). It functions as a filter that absorbs blue light, scavenges reactive oxygen species (ROS), and protects the retina from photo-oxidative damage³⁾.

AREDS2 prescription dosage: Lutein 10 mg + zeaxanthin 2 mg/day²⁾.

Association with cataracts: Epidemiological studies have shown an inverse relationship between dietary intake of lutein and zeaxanthin and the risk of nuclear cataracts⁵⁾.

Vitamin C and E

Role: Water-soluble (vitamin C) and fat-soluble (vitamin E) antioxidant vitamins. They reduce oxidative stress in the retinal pigment epithelium (RPE).

AREDS formulation dose: Vitamin C 500 mg + Vitamin E 400 IU/day¹⁾.

Cataract prevention: The Cochrane Review (Mathew 2012) concluded that the preventive effect of antioxidant supplements on cataracts is “not confirmed” ⁶⁾. The AREDS study also found no significant preventive effect on cataracts.

Zinc

Role: Supports the metabolism of the retinal pigment epithelium as a cofactor for antioxidant enzymes (e.g., Cu/Zn-SOD, catalase)¹⁾.

AREDS formulation dose: Zinc oxide 80 mg/day (with copper oxide 2 mg/day to prevent copper deficiency anemia) ¹⁾.

Changes in AREDS2: A reduction to 25 mg was considered, but there was no significant difference from the 80 mg group²⁾.

Omega-3 Fatty Acids (EPA/DHA)

AMD: In AREDS2, no additional effect of omega-3 fatty acids (DHA 350 mg + EPA 650 mg/day) on AMD was observed²⁾. Epidemiological studies have reported an association between fish intake and reduced risk of AMD⁸⁾.

Dry eye: In the DREAM study (535 patients, RCT), omega-3 supplements (EPA 2,000 mg + DHA 1,000 mg/day) showed no significant difference from olive oil placebo in improving dry eye symptoms⁷⁾.

Anthocyanins (Bilberry, etc.)

Anthocyanins found in blueberries and bilberries have been reported in basic research to improve dark adaptation and retinal blood flow. However, evidence of efficacy from RCTs is limited⁹⁾, and at present, the evidence is considered insufficient to recommend in clinical practice.

Comparison of AREDS and AREDS2 Formulations

The dosages of each formulation component are shown below.

Component	AREDS formulation	AREDS2 formulation
Vitamin C	500 mg/day	500 mg/day
Vitamin E	400 IU/day	400 IU/day
Beta-carotene	15 mg/day	Excluded (replaced with lutein/zeaxanthin)
Lutein	—	10 mg/day
Zeaxanthin	—	2 mg/day
Zinc oxide	80 mg/day	80 mg/day (25 mg also considered)
Copper oxide	2 mg/day	2 mg/day

Q Should I take lutein supplements?

A

For patients diagnosed with moderate to advanced AMD (AREDS categories 3 and 4), the AREDS2 formulation (containing lutein 10 mg + zeaxanthin 2 mg per day) is recommended ²⁾. On the other hand, there is no general recommendation for healthy individuals without AMD risk; dietary intake from green leafy vegetables such as spinach and kale is fundamental. It is important to make a decision after consulting an ophthalmologist.

3. Details of Evidence

Overview of the AREDS Study

AREDS and AREDS2 are the highest level of evidence sources for ophthalmic supplement research.

AREDS (2001 report)¹⁾:

• Subjects: 3,640 cases of AREDS category 3 (advanced unilateral AMD or numerous medium drusen) and category 4 (advanced bilateral AMD)
• Intervention: vitamin C 500 mg + vitamin E 400 IU + beta-carotene 15 mg + zinc oxide 80 mg/day
• Results: Approximately 25% reduction in risk of AMD progression (RR 0.75). Greatest benefit in the high-risk group.

AREDS2 (reported in 2013)²⁾:

• Subjects: 4,203 cases (AMD patients)
• Major change: replacement of beta-carotene with lutein 10 mg + zeaxanthin 2 mg/day
• Results: Non-inferiority in suppressing AMD progression was demonstrated after substitution. In former smokers, the risk of progression to exudative AMD was further reduced in the lutein/zeaxanthin group.

Long-term follow-up of AREDS2 (2022, 10-year data)¹⁰⁾:

• In the lutein/zeaxanthin group, a further long-term reduction in the risk of progression to exudative AMD was confirmed.
• No long-term safety issues were identified.

Summary of Key Clinical Trials

The characteristics of each trial are shown below.

Trial name	Population	Primary outcome
AREDS (2001)	3,640 AMD patients	AREDS formulation reduced AMD progression risk by approximately 25%1)
AREDS2 (2013)	4,203 AMD patients	Non-inferiority confirmed with lutein/zeaxanthin substitution2)
AREDS2 Long-term (2022)	4,203 AMD patients	10-year follow-up showed sustained benefit of lutein group10)
DREAM (2018)	Dry eye, 535 cases	Omega-3 effect on dry eye: no difference from placebo7)

Association with cataracts

The AREDS formulation was not confirmed to have a preventive effect against cataracts¹⁾. On the other hand, multiple epidemiological studies have shown an inverse association between dietary intake of lutein and zeaxanthin and the risk of nuclear cataracts⁵⁾, suggesting that dietary intake may reduce the risk of cataract development. However, there are still no large-scale RCTs proving the interventional effect of supplements.

A Cochrane review (Mathew 2012, 21 RCTs) concluded that there is no reliable evidence that supplementation with antioxidant vitamins (A, C, E), lutein, and zeaxanthin delays the onset or progression of cataracts⁶⁾.

Association with dry eye

The DREAM trial (2018) was an RCT comparing the efficacy of omega-3 fatty acids (EPA 2,000 mg + DHA 1,000 mg/day for 12 months) with an olive oil placebo in 535 patients with chronic dry eye. There was no significant difference between the two groups in the primary endpoint (OSDI [Ocular Surface Disease Index] score) ⁷⁾, indicating a negative result for the efficacy of omega-3 supplements for dry eye. Although a meta-analysis (Giannaccare 2019) reported some efficacy ¹¹⁾, omega-3 supplements are not included in standard treatment for dry eye due to the high quality of the DREAM trial.

4. Actual Intake

Indications for AREDS2 Formulation

• Indications: Patients diagnosed with moderate to advanced AMD (AREDS categories 3 and 4) in one eye²⁾
• Limited effect on early AMD: AREDS categories 1 and 2 (small drusen) have not shown significant progression suppression. Unnecessary supplement use poses a risk of excessive intake, so caution is needed.
• Confirmation of smoking status: For smokers, choose the AREDS2 formulation without beta-carotene.

Dietary Intake

Nillerdk. Spinach leaves (1 kg, separated from stems). Wikimedia Commons. 2008. Figure 1. Source ID: commons.wikimedia.org/wiki/File:Spinach_leaves.jpg. License: CC BY 3.0.

Spinach leaves, excluding stems, are a representative source of lutein and zeaxanthin, containing about 12 mg/100 g of lutein. This corresponds to dietary intake from green-yellow vegetables (spinach, kale) rich in lutein, as discussed in the section “4. Actual Intake” of the text.

Green and yellow vegetables are excellent sources of lutein and zeaxanthin⁴⁾.

• Spinach: lutein about 12 mg/100 g, zeaxanthin about 1.1 mg/100 g⁴⁾
• Kale: Approximately 22 mg/100 g of lutein (highest level among foods) ⁴⁾
• Broccoli: about 1.4 mg of lutein per 100 g⁴⁾
• Egg yolk: High bioavailability of lutein and zeaxanthin (3–4 times that of vegetables) ⁴⁾

Consuming fish (such as mackerel, Pacific saury, and sardines) at least twice a week is useful as a source of EPA/DHA⁸⁾, and epidemiological studies have reported an association between fish intake and reduced risk of AMD.

Key points for dietary lutein intake

Lutein and zeaxanthin are important nutrients for eye health.

Eat green and yellow vegetables every day: Aim for a daily intake of 6–10 mg of lutein from spinach, kale, broccoli, and the like.

Absorption increases when taken with oil: Since lutein is fat-soluble, stir-frying it with olive oil or eating it with dressing enhances absorption efficiency.

Fish at least twice a week: To supplement EPA/DHA, it is recommended to regularly eat blue-backed fish (such as mackerel and Pacific saury).

Consult an ophthalmologist before taking supplements: Before taking lutein supplements, have your AMD condition checked by an ophthalmologist and discuss whether they are truly necessary.

Foods with Function Claims System

Supplements are classified as food, not medicine. Under the Consumer Affairs Agency’s system for Foods with Function Claims (established in 2015), they are allowed to display functional claims based on certain scientific evidence¹²⁾, but they have not undergone national review for efficacy and safety like pharmaceuticals. When selecting products equivalent to the AREDS2 formulation, check the ingredient content and be careful not to exceed the recommended intake.

Q What foods contain high levels of lutein?

A

Green leafy vegetables such as spinach (about 12 mg/100 g), kale (about 22 mg/100 g), and broccoli are major dietary sources of lutein ⁴⁾. Egg yolks, while not as high in lutein content as vegetables, have high absorption efficiency due to their fat solubility. A daily intake of 6–10 mg of lutein from food is recommended. Actively consuming green leafy vegetables every day is the basis for obtaining lutein from the diet.

5. Precautions and Risk of Overdose

If supplements are not used properly, they can cause side effects and risks. The following points require attention.

Beta-carotene and lung cancer risk in smokers:

• In the ATBC study (1994), beta-carotene supplementation (20 mg/day) in 29,133 male smokers increased lung cancer incidence by 18% ¹³⁾
• In the CARET study, beta-carotene supplementation increased the risk of lung cancer in smokers and asbestos-exposed individuals.
• In AREDS2, based on this finding, beta-carotene was replaced with lutein/zeaxanthin ²⁾
• Do not use AREDS formulations containing beta-carotene in smokers or individuals with a history of smoking, even after quitting.

Excessive zinc intake:

• Copper deficiency anemia has been reported with long-term use of 80 mg/day of zinc oxide in the AREDS formulation¹⁾
• The AREDS formulation contains 2 mg of copper oxide to prevent copper deficiency, but regular blood tests are recommended during long-term use.
• Tolerable upper intake level of zinc for general adults (Japanese Dietary Intake Standards 2020 edition): 45 mg/day for men, 35 mg/day for women

High-dose vitamin E intake:

• Schürk et al. (2010, meta-analysis) suggested an association between high-dose vitamin E intake and increased risk of hemorrhagic stroke¹⁴⁾
• Long-term use of high doses (400 IU/day) requires caution

Drug interactions:

• Vitamin E and omega-3 fatty acids have anticoagulant effects, so caution is needed regarding interactions with anticoagulants such as warfarin.
• Consult your doctor about discontinuing use before surgery.

Risks and Precautions for Overdose

Eye supplements are not necessarily “natural and safe.” Pay attention to the following points.

Smokers should avoid beta-carotene: Beta-carotene increases the risk of lung cancer in smokers. Smokers or those with a history of smoking should always choose the AREDS2 formulation containing lutein/zeaxanthin¹³⁾.

Adhere to the recommended zinc dosage: Long-term use of 80 mg/day of zinc oxide can cause copper deficiency anemia. Ensure that any product equivalent to the AREDS formulation contains 2 mg of copper oxide¹⁾.

Drug interactions: Vitamin E and omega-3 fatty acids have blood-thinning effects. If you are taking warfarin, consult your doctor before taking them.

Limited efficacy for early AMD: In AREDS categories 1 and 2 (only small drusen), no significant progression-inhibiting effect has been confirmed. Unnecessary supplement use poses a risk of excessive intake.

Q Do eye supplements have side effects?

A

Beta-carotene in the AREDS formulation increases the risk of lung cancer in smokers, so it is contraindicated for current or former smokers ¹³⁾. The AREDS2 formulation avoids this risk by replacing beta-carotene with lutein/zeaxanthin. Additionally, long-term use of 80 mg/day zinc oxide can cause copper deficiency anemia, so the formulation always includes 2 mg copper oxide ¹⁾. High-dose long-term vitamin E intake has been associated with an increased risk of hemorrhagic stroke ¹⁴⁾, requiring caution.

6. Pathophysiology and Antioxidant Mechanisms

Oxidative Stress and Eye Diseases

The macula is an area at high risk for light-induced oxidative stress, and ultraviolet and blue light can generate reactive oxygen species (ROS). Oxidative stress is involved in the onset and progression of AMD³⁾.

• ROS production: Photooxidation of lipofuscin (waste product) due to light reactions is the main cause of RPE damage
• Drusen formation: Lipoproteins and complement deposit in the extracellular matrix due to decreased processing capacity of the RPE
• Progression to wet AMD: Oxidative stress and RPE damage induce complement activation and VEGF signaling, leading to neovascularization

Photoprotective effect of macular pigment

Romano MR, Cennamo G, Grassi P, et al. Changes in macular pigment optical density after membrane peeling. PLoS One. 2018;13(5):e0197034. Figure 1. PMID: 29758035; PMCID: PMC5951543; DOI: 10.1371/journal.pone.0197034. License: CC BY 4.0.

A pseudo-color map visualizing macular pigment optical density (MPOD), showing high density (warm colors) of pigment distribution in the fovea. This corresponds to the photoprotective and antioxidant functions of MPOD formed by lutein and zeaxanthin, discussed in Section 6: Pathophysiology and Antioxidant Mechanisms.

Lutein and zeaxanthin selectively accumulate in the macula, forming the macular pigment optical density (MPOD)³⁾.

• Optical filter function: Selectively absorbs blue light (400–500 nm) and reduces its arrival at photoreceptors
• Antioxidant function: Functions as a ROS scavenger that directly eliminates singlet oxygen and peroxy radicals
• Meso-zeaxanthin: The third macular pigment enzymatically converted from lutein within the retina, with the highest concentration in the central macula³⁾

Role of Zinc as a Cofactor for Antioxidant Enzymes

Zinc functions as an essential cofactor in the active site of the antioxidant enzyme Cu/Zn-SOD (copper-zinc superoxide dismutase)¹⁾. SOD converts superoxide anions, a type of ROS, into harmless hydrogen peroxide. It also works together with catalase and glutathione peroxidase to maintain the overall antioxidant defense system. The RPE is a highly metabolic tissue that processes phagosomes shed from photoreceptors, and an adequate supply of zinc is important for maintaining normal function.

Anti-inflammatory effects of omega-3 fatty acids

DHA (docosahexaenoic acid) is an omega-3 long-chain polyunsaturated fatty acid abundantly present in the outer segment membranes of retinal photoreceptors. Along with EPA (eicosapentaenoic acid), it serves as a precursor for the anti-inflammatory lipid mediators resolvins and protectins ⁷⁾. These mediators promote the resolution of inflammation, but clinical effects on dry eye in RCTs are considered insufficient.

7. Latest Research and Future Prospects

Note on Information at the Research Stage

The following content includes topics that are still in the research stage or under consideration. It includes matters that have not yet been established for inclusion in standard treatment, and is not recommended for practice without consulting a physician.

AREDS2 Long-Term Follow-Up Data (2022)

Long-term follow-up data from AREDS2 over 10 years (Report 28: Chew 2022) ¹⁰⁾ confirmed that the lutein/zeaxanthin group further reduced the risk of progression to exudative AMD in the long term. No long-term safety issues were observed, and the benefit of a beta-carotene-free formulation for smokers was reaffirmed.

Utilization of Macular Pigment Optical Density (MPOD) as a Biomarker

MPOD measurement is being studied as an indicator of macular carotenoid levels ³⁾. Evaluation using heterochromatic flicker photometry, resonance Raman spectroscopy, and fundus autofluorescence is being investigated as an objective measure of supplement efficacy.

Personalized nutritional guidance based on genetic polymorphisms

Research suggests that the effectiveness of the AREDS formulation may vary depending on polymorphisms in AMD susceptibility genes (CFH Y402H and ARMS2 A69S)¹⁵⁾. It has been indicated that individuals carrying CFH polymorphisms may have different responses to zinc¹⁵⁾, and in the future, personalized supplement prescriptions based on genetic profiles may become possible.

Gut Microbiota and Carotenoid Absorption

Basic research has accumulated showing that the composition of the gut microbiota affects the absorption efficiency and blood concentration of lutein and zeaxanthin. It is known that even with the same diet and supplement intake, there are large individual differences in blood lutein levels, and strategies to improve absorption efficiency through combination with gut environment improvement (e.g., probiotics) are being explored.

Ongoing Research on Nutritional Interventions for Dry Eye

Although the DREAM study negated the effect of omega-3⁷⁾, research is progressing on the association between overall dietary patterns (such as the Mediterranean diet) and dry eye risk¹¹⁾. The involvement of other nutrients such as polyphenols and vitamin D in dry eye is also being investigated, and new RCTs are being conducted.

8. References

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10. Chew EY, Clemons TE, Agrón E, Domalpally A, Keenan TDL, Vitale S, Weber C, Smith DC, Christen W, AREDS2 Research Group.. Long-term Outcomes of Adding Lutein/Zeaxanthin and ω-3 Fatty Acids to the AREDS Supplements on Age-Related Macular Degeneration Progression: AREDS2 Report 28. JAMA Ophthalmol. 2022;140(7):692-698. doi:10.1001/jamaophthalmol.2022.1640. PMID:35653117; PMCID:PMC9164119.

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