A primer on oral omega-3s and dry eye disease

Despite significant advances in the diagnosis and management of dry eye disease (DED), many patients continue to experience persistent symptoms that resist conventional therapies, such as preservative-free artificial tears, corticosteroids, and topical cyclosporine. This clinical challenge has prompted a renewed interest in nutritional interventions, particularly the use of omega-3 fatty acids. Their biologic relevance to tear film stability and ocular surface homeostasis positions them as an important consideration in contemporary dry eye management. In a 2016 multicenter, prospective, interventional, placebo-controlled, double-masked, institutional review board–approved trial, researchers concluded that the oral consumption of re-esterified omega-3 fatty acids is associated with statistically significant improvement in tear osmolarity, omega-3 index levels, tear breakup time, matrix metalloproteinase-9, and Ocular Surface Disease Index scores.¹ Improvements were observed not only in the clinical signs of DED, but also in the associated patient-reported symptoms. Understanding the mechanisms of action driving omega-3 fatty acids is essential for integrating nutritional strategies into routine optometric care.

What’s happening with omega-3s?

Omega-3 fatty acids serve 3 primary functions.

First, oral supplementation with omega-3 fatty acids alters the fatty-acid profile of meibomian gland secretions, producing a lipid output enriched in unsaturated fatty acids that remain fluid at body temperature. This increased fluidity helps prevent ductal obstruction and meibum stagnation. The resulting improvement in secretion quality decreases tear film evaporation and alleviates DED symptoms.²

When the body lacks an adequate supply of omega-3 fatty acids, it compensates by incorporating omega-6 fatty acids, which results in less fluid or flexible cell membranes and suboptimal cellular activity.³ Omega-6 fatty acids, including γ-linolenic acid (GLA), play important physiologic roles in maintaining cell membrane integrity and supporting normal immune function. Certain omega-6 derivatives can exert anti-inflammatory effects, and formulations containing GLA have demonstrated benefits in some inflammatory conditions, including ocular surface disease.^4-6

Omega-6 fatty acids are found in vegetable oils, nuts, and seeds. They can also be found in poultry, eggs, whole grain bread, and tofu. There are several commercially available supplements for DED that incorporate both omega-6 and omega-3 fatty acids in their formula. Historically, the ideal ratio of omega-6 to omega-3 fatty acids has been between 1:1 and 2:1.⁷ However, Western diets now contain far more omega-6 than omega-3 fatty acids, with ratios ranging from 10:1 to 20:1.^7,8

This imbalance favors the production of proinflammatory mediators and has been implicated in the development and progression of chronic inflammatory conditions, including DED.⁸ Accordingly, clinical emphasis should be placed on restoring an appropriate omega-6 to omega-3 balance, most effectively achieved through targeted omega-3 supplementation rather than routine omega-6 supplementation.

Second, the metabolic processing of omega-3 fatty acids generates anti-inflammatory lipid mediators—including resolvins and protectins—that attenuate inflammatory pathways implicated in meibomian gland dysfunction and ocular surface disease.⁹ Third, omega-3 fatty acids are fundamental structural components of cell membranes, supporting cellular integrity, intercellular communication, and efficient nutrient exchange.⁶

Although mechanistic and clinical data support the role of omega-3 fatty acids in DED, not all findings from clinical trials have demonstrated uniform benefit. The Dry Eye Assessment and Management study, a large, randomized, placebo-controlled trial, did not find a statistically significant difference between omega-3 supplementation and placebo in improving dry eye symptoms over 12 months.¹⁰ However, interpretation of these findings is limited by the use of olive oil as a placebo, which has anti-inflammatory properties; the absence of baseline omega-3 status assessment; and the inclusion of heterogeneous dry eye subtypes without stratification by inflammatory burden or meibomian gland dysfunction.^11-13 These considerations highlight the complexity of DED and underscore the importance of formulation, dosing, and patient selection when evaluating nutritional therapies.

How to prescribe

When prescribing oral omega-3 supplementation, it is important to consider 3 key factors: the ingredients, specific formulation of omega-3, and appropriate dosage required to be effective.

Ingredients

Omega-3 fatty acids are classified as short chain (eg, α-linolenic acid [ALA]) and long chain (eg, eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]).¹⁴ EPA and DHA are derived from fish, shellfish, and algae, and they have more potent immunomodulatory activity than ALA, which is derived from vegetable oils.^15-17 ALA is a metabolic precursor to EPA and DHA, and although it can be converted to EPA and DHA in the body, this conversion is limited, making direct intake of EPA and DHA more effective for achieving therapeutic levels relevant to ocular health, including DED.

Formulations

Most omega-3 fatty acid supplements are formulated in the ethyl ester form, of which only approximately one-third is absorbed systemically. This form is prevalent due to low manufacturing costs.¹⁸ When omega-3 fatty acids are provided in their triglyceride or re-esterified triglyceride forms—the natural form found in fish and seafood—bioavailability increases by approximately 51% compared with ethyl ester formulations.¹⁹ From a clinical perspective, the distinction between ethyl ester and triglyceride formulations primarily relates to the rate of absorption rather than ultimate therapeutic effect. Triglyceride and re-esterified triglyceride forms are incorporated more efficiently and achieve higher plasma levels more rapidly, whereas ethyl ester forms may require a longer duration to reach comparable tissue levels. Given that DED is a chronic condition requiring long-term therapy, these differences may have limited clinical significance over time. However, higher bioavailability formulations may reduce pill burden and improve adherence, offering practical advantages in chronic management. Clinicians can further guide patients by educating them on how to read supplement labels, where omega-3 formulations are typically identified as “ethyl ester,” “EE,” “triglyceride,” or “re-esterified triglyceride.”

Dosage

Many over-the-counter (OTC) forms of fish oil contain less than 400 mg of EPA and DHA per serving. Research shows that achieving therapeutic levels for ocular health typically requires approximately 2000 mg of EPA and DHA in a highly absorbable re-esterified triglyceride form, ideally in a 3:1 ratio of EPA to DHA.¹ Clinicians can counsel patients on increasing omega-3 intake through dietary sources, such as salmon, mackerel, sardines, flaxseeds, chia seeds, and walnuts, or through supplements. Given the significant variability among omega-3 essential fatty acid formulations, careful clinical guidance is necessary to ensure appropriate patient use. Absorption is also influenced by whether the supplement is taken on an empty stomach. To optimize uptake, omega-3 supplements should be taken with a meal.

Think nutrition for dry eye

Despite a robust armamentarium of therapies to help us manage ocular surface disease, many patients continue to seek relief from their symptoms. Sometimes, something as simple as an OTC supplement can make a significant difference. Recommending that patients with DED add omega-3 fatty acids to their diet could provide them with improved tear osmolarity and tear breakup time and fewer DED symptoms,¹ leading to more satisfied patients and a more successful practice.

References

1. Epitropoulos AT, Donnenfeld ED, Shah ZA, et al. Effect of oral re-esterified omega-3 nutritional supplementation on dry eyes. Cornea. 2016;35(9):1185-1191. doi:10.1097/ICO.0000000000000940

2. Macsai MS. The role of omega-3 dietary supplementation in blepharitis and meibomian gland dysfunction (an AOS thesis). Trans Am Ophthalmol Soc. 2008;106:336-356.

3. Capece U, Gugliandolo S, Morciano C, et al. Erythrocyte membrane fluidity and omega-3 fatty acid intake: current outlook and perspectives for a novel, nutritionally modifiable cardiovascular risk factor. Nutrients. 2024;16(24):4318. doi:10.3390/nu16244318

4. Barabino S, Rolando M, Camicione P, et al. Systemic linoleic and gamma-linolenic acid therapy in dry eye syndrome with an inflammatory component. Cornea. 2003;22(2):97-101. doi:10.1097/00003226-200303000-00002

5. Calder PC. Polyunsaturated fatty acids and inflammation. Prostaglandins Leukot Essent Fatty Acids. 2006;75(3):197-202. doi:10.1016/j.plefa.2006.05.012

6. Simopoulos AP. Evolutionary aspects of diet, the omega-6/omega-3 ratio and genetic variation: nutritional implications for chronic diseases. Biomed Pharmacother. 2006;60(9):502-507. doi:10.1016/j.biopha.2006.07.080

7. Simopoulos AP. The omega-6/omega-3 fatty acid ratio: health implications. Oléagineux Corps Gras Lipides. 2010;17(5):267-275. doi:10.1051/ocl.2010.0325

8. Roncone M, Bartlett H, Eperjesi F. Essential fatty acids for dry eye: a review. Cont Lens Anterior Eye. 2010;33(2):49-54. doi:10.1016/j.clae.2009.11.002

9. Djuricic I, Calder PC. Beneficial outcomes of omega-6 and omega-3 polyunsaturated fatty acids on human health: an update for 2021. Nutrients. 2021;13(7):2421. doi:10.3390/nu13072421

10. Asbell PA, Maguire MG, Pistilli M, et al; Dry Eye Assessment and Management Study Research Group. N-3 fatty acid supplementation for the treatment of dry eye disease. N Engl J Med. 2018;378(18):1681-1690. doi:10.1056/NEJMoa1709691

11. Downie LE, Hom MM, Berdy GJ, et al. An artificial tear containing flaxseed oil for treating dry eye disease: A randomized controlled trial. Ocul Surf. 2020;18(1):148-157. doi:10.1016/j.jtos.2019.11.004

12. Jones L, Downie LE, Korb D, et al. TFOS DEWS II management and therapy report. Ocul Surf. 2017;15(3):575-628. doi:10.1016/j.jtos.2017.05.006

13. Yu K, Asbell PA, Shtein RM, Ying GS; Dry Eye Assessment and Management Study Research Group. Dry eye subtypes in the Dry Eye Assessment and Management (DREAM) Study: A latent profile analysis. Transl Vis Sci Technol. 2022;11(11):13. doi:10.1167/tvst.11.11.13

14. Wang WX, Ko ML. Efficacy of omega-3 intake in managing dry eye disease: a systematic review and meta-analysis of randomized controlled trials. J Clin Med. 2023;12(22):7026. doi:10.3390/jcm12227026

15. Surette ME. The science behind dietary omega-3 fatty acids. CMAJ. 2008;178(2):177-180. doi:10.1503/cmaj.071356

16. Baker EJ, Miles EA, Burdge GC, Yaqoob P, Calder PC. Metabolism and functional effects of plant-derived omega-3 fatty acids in humans. Prog Lipid Res. 2016;64:30-56. doi:10.1016/j.plipres.2016.07.002

17. Lane K, Derbyshire E, Li W, Brennan C. Bioavailability and potential uses of vegetarian sources of omega-3 fatty acids: a review of the literature. Crit Rev Food Sci Nutr. 2014;54(5):572-579. doi:10.1080/10408398.2011.596292

18. Gross M, Klein S. Fish oil triglycerides vs ethyl esters. Clinical Applications of Scientific Innovation. April 30, 2014. Accessed January 2, 2026. http://www.casi.org/bid/197170/Fish-Oil-Triglycerides-vs-Ethyl-Esters

19. Lawson LD, Hughes BG. Absorption of eicosapentaenoic acid and docosahexaenoic acid from fish oil triacylglycerols or fish oil ethyl esters co-ingested with a high-fat meal. Biochem Biophys Res Commun. 1988;156(2):960-963. doi:10.1016/s0006-291x(88)80937-9