Common Name(s): (3R,3′R, 6′R)beta-epsilon-carotene-3-3′-diol; (CAS registry number 127-40-2), E161b, Lutein, Macular pigment, Xanthophyll
Drug class: Nutraceutical products
Medically reviewed by Drugs.com. Last updated on Nov 22, 2021.
There is a lack of consensus and limited evidence from clinical and epidemiological studies as to whether an association exists between a higher intake of xanthophylls (lutein with or without zeaxanthin) and protection against age-related macular degeneration (AMD) and cataracts. The use of lutein in the management of cardiovascular conditions and cancer has been proposed.
A dose of lutein 5 mg/day is widely used. AMD trials have used lutein 10 to 20 mg/day for 3 to 6 months or longer.
Contraindications have not been identified.
Generally recognized as safe (GRAS) when consumed as food. Lutein and zeaxanthin are found in the milk of lactating women, as well as in the umbilical cord.
None well documented.
No clinically important adverse reactions were reported at doses up to lutein 20 mg/day.
Purified crystalline lutein derived from marigold has US Food and Drug Administration (FDA) GRAS status and can be added to certain foods and beverages. There is strong safety evidence at doses up to 20 mg/day.
Humans (and other primates) are unable to synthesize lutein and must obtain it from dietary vegetable and fruit sources. High amounts of lutein are found in green, leafy vegetables, particularly in spinach and kale. Flowers and the leaves of the nasturtium plant are also rich sources of lutein; carrots and kiwi fruits contain lesser amounts. Wide variation in the lutein content exists in these foods, and processing and storage also influence lutein levels. Animal sources are consequent to animal consumption of vegetable-based lutein and include egg yolks and animal fats. Lutein-fortified milk and eggs are commercially available. Lutein as a commercial food additive is obtained from the petals of the marigold flower (food additive number E161b), and can also be sourced from microalgae.1, 2, 3, 4
Lutein has traditionally been used since the 1950s for the treatment of eye diseases and for its purported protective effect on visual function. In 1996, the incorporation of lutein into dietary substances was accepted (at 6 to 7 mg/day), with marigold-sourced lutein used as a food additive and colorant. Most studies conducted up to the 1990s have investigated the efficacy of total carotenoid content, whereas more recent studies focus specifically on lutein.1, 5, 6
Lutein is a xanthophyll carotenoid, one of about 600 natural carotenoids; however, lutein is not a precursor of vitamin A. It is a red/orange crystalloid substance that is insoluble in water and has a melting point of 190°C (374°F). Lutein is biosynthesized in plants and some microalgae. It is generally accepted that lutein in vegetables exists in the trans form; however cis-lutein has been described. In food substances, lutein may exist in the free or esterified form, or bound to protein. Zeaxanthin is isomeric with lutein. Methods for extraction, identification, and quantification have been described. Crystalline lutein is difficult to handle and is often suspended in corn or safflower oils or in microcapsule form.1, 2, 5, 6, 7
Uses and Pharmacology
In vitro and animal studies show activity of lutein in inhibition of monocyte-mediated inflammatory response, immune enhancement, antioxidant activity, inhibition of peroxidation of membrane lipids, and protection against macular degeneration.5, 8, 9
In vitro studies show antioxidant activity of lutein and suggest macula protection.5 Carotenoid absorption is poor in most animal species, and few relevant animal studies exist. Limited studies in monkeys show diets supplemented with xanthophyll resulted in increased serum lutein concentrations and incorporation into the retina.13 An inverse correlation was demonstrated between orally administered lutein and the incidence of cataracts in mice models of diabetic retinopathy. Clinical trials are lacking for this indication.11
Most,14, 15, 16, 17 but not all,18 studies in healthy populations demonstrated an increase in serum lutein and macular pigment optical density; wide variations in the response of populations have been noted.15 One study in healthy adults failed to demonstrate any difference in distance and near visual acuity, contrast sensitivity, or photo-stress recovery time with supplemental lutein 6 mg/day taken over 18 months.19 However, a 1-year randomized clinical trial conducted in healthy Chinese professional drivers (n = 121) found that supplementation with lutein 20 mg/day significantly improved central macular pigment optical density as well as contrast and glare sensitivity, especially in low light conditions.51
Age-related macular degeneration and cataract
Most clinical studies have shown a correlation between lutein supplementation and increased serum lutein concentrations and macular pigment optical density.12, 20, 21, 22 A relationship between these outcomes and AMD has not been established, however, and the FDA does not recognize them as surrogate end points for the measurement of AMD or age-related cataracts.12, 23 In addition, it has been noted that a poor correlation exists between serum and tissue lutein concentrations and dietary intake.12 In 2004, based on the evidence of 12 interventions and 23 observational studies, the FDA rejected a health claim that supplementation with lutein and zeaxanthin changes the risk of AMD or cataract.23 A meta-analysis of 6 trials (through April 2010) found an overall relative risk of 1.07 (95% confidence interval [CI], 0.8 to 1.45) for the effect of dietary lutein on reducing the risk of early AMD.25 Dietary supplementation with only lutein (10 to 20 mg/day for 4 to 12 months) significantly improved macular pigment optical density, but not visual acuity, in patients with or at risk of AMD according to a 2014 meta-analysis of 5 randomized clinical trials (N = 445 participants).57 Visual performance was found to be improved with lutein and zeaxanthin supplementation in AMD patients according to a meta-analysis of 8 placebo-controlled trials through April 2014.56 Most epidemiological studies support the conclusion that a higher intake of xanthophylls is protective of AMD12, 23; however, an 18-year follow-up in the Nurses’ Health Study did not support a protective role of lutein regarding the risk of early AMD.27
An age-adjusted odds ratio26 of 0.77 (95% CI, 0.62 to 0.96) supported correlation with a lower prevalence of age-related cataracts.7, 27 Other observational studies report equivocal or, at best, modest associations.11, 12, 28, 29 A 2013, multicenter, double-masked, randomized clinical trial evaluated 6,027 study eyes (N = 3,159) for effects of daily lutein 10 mg/zeaxanthin 2mg on subsequent need for cataract surgery in elderly patients at risk of progression to advanced AMD. No difference was found among the treatment groups and placebo in the 5-year probability to progression to cataract surgery. A statistically significant improvement was observed; however, for participants in the lowest quintile of dietary intake of lutein/zeaxanthin.50 Data from a secondary analysis of this multicenter study suggest that supplements with lutein/zeaxanthin may be more beneficial than those with beta-carotene in patients at risk of progressing to late AMD.53 A meta-analysis of 13 observational studies (n =18,999), however, evaluated the association between blood levels of antioxidants and vitamins to the risk of age-related cataract. Based on the results of 6 relevant studies with no substantial heterogeneity, lutein was associated with significantly reduced risk of cataract.52 Another meta-analysis of 8 studies found blood levels of lutein plus zeaxanthin to be associated with a significant reduction in risk of nuclear, but not cortical or subcapsular, cataracts.55 Whereas, dietary intake of lutein/zeaxanthin was not found to be statistically significantly associated with baseline or development of nuclear or cortical lens opacity outcomes in report 37 of the Age-Related Eye Disease Study (N = 3,115).58
Limited clinical studies exist to support a role in therapy. In an efficacy and safety study, an increase in visual field was demonstrated in participants with retinitis pigmentosa,30 while no effect of lutein was found on edema, foveal thickness, or visual acuity. Lutein 10 mg/day was administered for 12 weeks, followed by 12 weeks at 30 mg/day.31 Another study found no difference in the rate of decline of central visual field sensitivity over 4 years with supplemental lutein 12 mg/day. Participants in this study were already taking a vitamin A supplement. Secondary outcome measures were suggestive of improvements.32
Prevention of retinopathy of prematurity
Despite a plausible role for lutein supplementation,33 clinical trials have failed to demonstrate a protective effect of lutein supplementation for any grade of retinopathy of prematurity or other relevant outcome measures. Published data include a multicenter trial of 114 infants up to 32 weeks gestational age evaluating a daily oral dose of lutein 0.14 mg and zeaxanthin 0.006 mg until discharge (mean, 49 days)35 and a similar trial of 63 participants using 0.5 mg/kg/day until discharge (mean, 45 days).36
In vitro and rodent studies have shown inhibition of angiogenesis, modulation of apoptosis and immune function, and the prevention of oxidative damage.7
An epidemiological association has been shown for xanthophylls and cardiovascular health.5, 7 An ancillary Cardiovascular Outcomes Study of the Age-Related Eye Disease Study (AREDS) 2 evaluated the effect of omega-3 fatty acids (DHA 350 mg/day + EPA 650 mg/day) versus macular xanthophylls (lutein 10 mg/day + zeaxanthin 2 mg/day) versus a combination of the 2 versus placebo on cardiovascular outcomes in 4,203 AREDS patients (median age, 74 years) over a median of 4.8 years. Only patients with a negative baseline history for hypertension, cardiovascular disease, or hypercholesterolemia showed significant protective effects from either group of supplements. Serious hyponatremia requiring hospitalization that was considered possibly related to the supplements occurred in one 76-year-old patient who was randomized to the combination supplement group.54
In a subgroup analysis of a study of eye health, some positive effects on verbal fluency (memory test), but not on other memory tests or mental processing tests, were shown with supplemental lutein 12 mg/day in elderly women. An additive effect with docosahexaenoic acid was demonstrated.37
A small clinical study found reduced total hydroperoxides and increased antioxidant potential in healthy neonates at 48 hours who were given lutein 0.28 mg at 12 and 36 hours after birth. Clinical applications have yet to be determined.8 Lutein supplementation in adequately nourished elderly people does not appear to improve markers of oxidative stress.38
Animal studies suggest lutein may be protective against ultraviolet (UV) damage.39 A small clinical trial found improvements in all evaluated skin parameters, including skin lipid content, lipid peroxidation, elasticity, hydration, and protective effects, with oral lutein (10 mg/day) or topical lutein application (100 ppm/day) when skin was exposed to UV light irradiation.39
Data from the United States Department of Agriculture (USDA) suggest the average daily intake of lutein by Americans is 1.7 mg/day, possibly reflecting an inadequate intake of green, leafy vegetables.10 Raw spinach yields approximately 12 mg lutein and zeaxanthin per 100 g, kale contains up to 40 mg lutein per 100 g, and eggs contain approximately 140 mcg lutein per yolk.10, 40, 41
Consumption of or supplementation with lutein 5 mg/day is widely accepted.4
Bioavailability of lutein depends on the source.6 A study comparing free lutein with lutein esters found greater increases in serum lutein with the free form42; another found no difference between free lutein and the supplement lutein diacetate taken over 24 weeks.43
Fat consumption promotes lutein solubility and uptake.7 Body fat may act as a reservoir for carotenoids, including lutein. Weight loss has been associated with a positive and important correlation with increased macular pigment optical density and serum xanthophylls.44 Gains in increased lutein plasma concentrations are mitigated by any increase in body mass index.45
AMD trials have used lutein 10 to 20 mg/day for 3 to 6 months or longer,16, 20, 46, 47, 57 and a linear dose-response (macular pigment optical density) has been described.17 Higher doses and longer durations have been used in limited clinical studies; however, safety at those dosages has not been established.48
Pregnancy / Lactation
GRAS status when consumed as food. Lutein and zeaxanthin are found in the milk of lactating women, as well as in the umbilical cord. The concentration of lutein in breast milk in healthy women has been measured between 3 and 200 mcg/L.6, 8, 49 A randomized clinical study demonstrated that lutein serum concentrations in infants who were fed unfortified milk formula (no added lutein) were approximately one-sixth the amount of those in breast-fed infants.49
Case reports are lacking.
Purified crystalline lutein derived from Tagetes erecta (marigold) has FDA GRAS status and can be added to foods and beverages.6, 7 Animal and in vitro toxicological studies report no terato-, embryo- or genotoxicity or mutagenicity; however, data are limited.6, 48 There is strong evidence of safety at doses up to 20 mg/day. Higher doses (40 mg/day for 9 weeks) have been used in clinical trials; however, methodological issues exist, and safety is not clearly established.48 Serum concentrations of lutein up to 1.05 mcmol/L (less than 600 mcg/L) seem to be safe based on clinical studies and show no evidence of an unacceptable serum lutein profile at this concentration, including an absence of biochemical and hematological changes or carotenodermia.5
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