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Effect of lutein and antioxidant dietary supplementation on contrast sensitivity in age-related macular disease: a randomized controlled trial



The aim of the study is to determine the effect of lutein combined with vitamin and mineral supplementation on contrast sensitivity in people with age-related macular disease (ARMD).


A prospective, 9-month, double-masked randomized controlled trial.


Aston University, Birmingham, UK and a UK optometric clinical practice.


Age-related maculopathy (ARM) and atrophic age-related macular degeneration (AMD) participants were randomized (using a random number generator) to either placebo (n=10) or active (n=15) groups. Three of the placebo group and two of the active group dropped out.


The active group supplemented daily with 6 mg lutein combined with vitamins and minerals. The outcome measure was contrast sensitivity (CS) measured using the Pelli–Robson chart, for which the study had 80% power at the 5% significance level to detect a change of 0.3 log units.


The CS score increased by 0.07±0.07 and decreased by 0.02±0.18 log units for the placebo and active groups, respectively. The difference between these values is not statistically significant (z=−0.903, P=0.376).


The results suggest that 6 mg of lutein supplementation in combination with other antioxidants is not beneficial for this group. Further work is required to establish optimum dosage levels.


There is interest in the use of nutrition as a prevention and treatment strategy for age-related macular disease (ARMD) as it is the leading cause of visual disability in the developed World (Klein et al., 1997), and because treatment options are currently lacking (Zarbin, 2004). According to an international classification and grading system (Bird et al., 1995), this condition can be divided into early (age-related maculopathy, (ARM)) and late (age-related macular degeneration, (AMD)) stages.

Interest has been raised into the protective role of the oxygenated xanthophylls group of carotenoids in the eye, particularly the retina. Lutein, zeaxanthin and its isomer meso-zeaxanthin are the only carotenoids present in the lens (Yeum et al., 1995) and retina (Landrum and Bone, 1995) and are also known as macular pigment (MP). It has been suggested that they play a similar role in humans as in plants, as antioxidants and screeners of high-energy blue light (Krinsky, 2002).

The absorbance spectrum of MP peaks at 460 nm and it is purported to act as a broadband filter, reducing the sensitivity of the macular region to short wavelength light, which is most damaging in the 440–460 nm range (Reading and Weale, 1974; Pease et al., 1987). Zeaxanthin is reported to be a superior photoprotector during prolonged light exposure; the shorter time-scale of protective efficacy of lutein has been attributed to oxidative damage of the carotenoid itself (Sujak et al., 1999).

The MP also acts as a scavenger of reactive oxygen species (ROS). The relatively high concentration of MP in the inner retinal layers (Snodderly et al., 1984) is very likely to indicate a photoprotective role, whereas the presence of MP in the rod outer segments (Sommerburg et al., 1999), is suggestive of a ROS-quenching function. Lutein and zeaxanthin have been found in higher concentration in the rod outer segments of the perifoveal retina than the peripheral retina, again lending support to their proposed protective role in ARM and AMD (Rapp et al., 2000).

This randomized control trial (RCT) was designed to investigate the effect of 6 mg lutein combined with 750 μg retinol equivalents, 250 mg vitamin C, 34 mg vitamin E, 10 mg zinc and 0.5 mg copper on contrast sensitivity measured using the Pelli-Robson chart (Clement Clarke International, Edinburgh Way, Harlow, Essex, CM20 2TT, UK) in ARM affected eyes. Contrast sensitivity (CS) is a particularly relevant outcome measure for those with ocular disease as it provides a measure of real-world visual function (Hyvarinen, 1995). CS may help to provide a more complete assessment of visual function in macular disease, and it has been suggested that the test may be a superior predictor of daily living activities and mobility than visual acuity (VA) alone (Jin et al., 1992; Mones and Rubin, 2005). CS is reported to be a better measure of the ability to judge distances (Rubin et al., 1994) and discriminate between objects (Scott et al., 2002), and has also been reported to detect vision loss due to AMD before VA testing (Hyvarinen et al., 1983). Although there is a moderate correlation between VA and CS (Rubin et al., 1994, 1997), these two measures are not interchangeable (Haegerstrom-Portnoy et al., 2000). The effect, however, of a six letter loss of CS has been reported to have a similar impact on self-reported visual disability as a 15 letter loss of VA (Rubin et al., 2001). The inclusion of CS in visual assessment of macular disease patient may be useful in monitoring disease progression, evaluating the benefit of treatment and designing appropriate rehabilitation strategies (Fletcher and Schuchard, 2006).

During the design of the trial, 6 mg daily intake of lutein had been reported to be associated with a reduced risk of AMD (57% lower risk for the highest quintile of lutein intake, 6 mg/day, relative to the lowest quintile, 0.5 mg/day) (Seddon et al., 1994). The reasons for using a multi-ingredient formulation include the fact that ARM has a multifactorial aetiology, and so may be affected by more than one nutrient, and also that nutrients are thought to work synergistically together. A relevant example of this synergism is the facilitation of vitamin A transport from the liver by zinc (Newsome et al., 1994). A review of the nutrients considered suitable for inclusion in an ocular nutritional supplement has been published (Bartlett and Eperjesi, 2004).



The study was approved by the Aston University Human Sciences Ethical Committee (code 02/M). The tenets of the Declaration of Helsinki were followed (World Medical Association, 1997). The trial was registered for an International Standard Randomised Controlled Trial Number (ISRCTN 78467674), and the method has been published (Bartlett and Eperjesi, 2003). Reporting of this RCT adheres to the guidelines set out in the revised CONSORT statement (Moher et al., 2001).


Recruitment methods employed included sending study information to local optometrists, ophthalmologists and a specialist centre for rehabilitation of people with sight loss. Enrolment was carried out by HB, who, along with FE, was masked to group assignment.

The main research centre was Aston University, Birmingham. A secondary research centre was a UK optometric clinical practice.

Inclusion/exclusion criteria

For inclusion participants had to (1) provide written informed consent, (2) be available to attend one of the research centres, (3) present with no ocular pathology in at least one eye, or no ocular pathology other than ARM, identified using the International Classification and Grading System for Age-Related Maculopathy and Age-Related Macular Degeneration (Bird et al., 1995). This definition of ARM includes soft or hard drusen, and areas of increased or decreased pigment associated with these drusen. Fundus examination was used to determine the presence of ARM. Exclusion criteria included type I and II diabetes, prescribed anti platelet or anti coagulant medication because of possible interaction with vitamin E (The ATBC Cancer Prevention Study Group, 1994), and concurrent use of nutritional supplements that potentially raised vitamin and mineral intake above the recommended safe limits (Bartlett and Eperjesi, 2005). Those with AMD in one or both eyes were excluded.


Only one investigator (HB) was involved in the randomization process, which employed the random number generator in Microsoft Excel for Windows XP. Odd and even numbers were used to identify group.

Outcome measure

CS was measured using a Pelli-Robson chart (Clement Clarke International, Edinburgh Way, Harlow, Essex, CM20 2TT, UK) and scored per letter.


The study formulation and placebo tablets were produced by Quest Vitamins Ltd, and were identical in external and internal appearance, and taste. The manufacturer allocated distinguishing symbols, μ and λ, to the outer packaging, which was otherwise identical. The code for the symbols was withheld by the manufacturer until all data had been collected and analysed. Throughout this report, the letters P and A will be used to refer to the placebo and active formulation respectively.

The study formulation contained the following:

lutein esters:

6 mg,


750 μg,

vitamin C:

250 mg,

vitamin E:

34 mg,


10 mg,


0.5 mg.

The placebo tablets contained cellulose.

Participants in both groups were instructed to take one tablet, at the same time every day, with food. They were encouraged not to alter their diets, or to change their current supplementation regime.


Data collection took place at baseline and 9 months and was carried out by HB. Data were collected between March 2003 and December 2004.

Statistical analysis

The change between baseline and 9-month values was calculated. SPSS software (version 11) for Microsoft Windows XP was used for analysis. The non-parametric Mann–Whitney U test was used to determine whether the means of these values differed at the 5% significance level between the two groups.

Sample size calculation

A group size of nine was calculated to be sufficient to provide 80% power at the 5% significance level for CS based on an effect size of 0.3 log units, and mean and standard deviation (s.d.) values taken from a sample of 50 ARM and atrophic AMD patients of the University optometry clinic (1.39±0.22 log CS).

Participant flow

Out of the 36 people who completed enrolment questionnaires, six did not meet the inclusion criteria or decided not to enrol. The remaining 30 individuals were randomized into the treatment or placebo group; a breakdown is shown in Table 1.

Table 1 Summary of enrollment and follow-up figures

Statistical analysis was carried out on a per protocol basis. Compliance was assessed by counting remaining tablets at the follow-up visits, and averaged 94.4%. There was no significant difference in compliance between groups.

Baseline characteristics

Although it is not correct to test for differences between two randomly allocated groups using conventional statistical tests, as any differences will have arisen by chance alone, we acknowledge that the small sample size means that there could be differences between the groups. For this reason, we have reported this information. The cohort ranged in age from 55 to 82 years (mean±s.d.: 69.2±7.8) and 53% were female subjects. There was no significant difference in age or gender between groups. There was no significant difference in baseline VA between active (0.20±0.28) and placebo (0.08±0.15) groups (t=1.229, P=0.229). All participants were White British. There was no significant difference in iris colour between groups. The baseline CS scores were 1.43±0.20 and 1.36±0.20 log units for the placebo and active groups respectively. Both groups fell below the normal CS score reported for this age group, which is 1.65 log units and is repeatable to within±0.15 log units (Elliott et al., 1990).

There was no significant difference between groups for age, smoking history (pack years) and years spent living abroad. Dietary intake of lutein, vitamins C and E, retinol equivalents, and zinc was assessed using food diaries and food frequency questionnaires. Analysis of food diaries was carried out using FoodBase 2000 (The Institute of Brain Chemistry and Human Nutrition, London, UK) for Microsoft Windows XP. There was no difference between groups except that the P group consumed significantly more vitamin C (161.1±71.0 mg) than the A group (88.0±53.7 mg: t=3.04, P=0.005). There was no difference in nutritional supplementation habits between P and A groups.

Adverse effects

There were no reported adverse effects from any of the study participants.


Masking success

End of trial assessment using questionnaires indicated masking success. Out of those participants taking the placebo tablet, 10% correctly guessed which tablet they were taking, and 10% incorrectly guessed. Out of those taking nutritional supplement, 13% guessed correctly which tablet they were taking, and 7% incorrectly guessed. The remaining participants did not know which group they were randomized to.

Assessment of change in baseline characteristics

All participants were asked to fill out end-of-trial food diaries and food frequency questionnaires in order to assess any change in dietary habits over the trial period. Eighty percent of the end-of-trial food frequency questionnaires and food diaries were returned by the P group and 90% by the A group.

There was no change in dietary lutein, vitamin C, vitamin E or retinol for any of the groups. However, there was a significant change in mean zinc intake from 9.17±2.44 mg to 11.41±3.64 mg (t=−2.912, df=19, P=0.04) in the A group. There was no change in ocular health in either group.

Main outcome

The mean CS score increased by 0.07±0.07 log units in the P group and decreased by 0.02±0.18 log units in the A group. A Mann–Whitney test was used to compare groups because the P group data set was not normally distributed (Kolmogorov–Smirnov=0.320, P=0.004). There was no significant difference between the P and A group in the change in CS over 9 months (z=−0.903, P=0.366). There was an improvement in CS over 9 months in the P group (P=0.03, η2=0.21), although this is not clinically significant (Elliott, Sanderson and Conkey, 1990).


The results suggest that supplementing for 9 months with a formulation containing 6 mg lutein, 750 μg retinol equivalents, 250 mg vitamin C, 34 mg vitamin E, 10 mg zinc and 0.5 mg copper does not have an effect on CS in ARM-affected eyes. This is the only RCT to investigate the effect of nutritional supplementation on visual function in people with ARM.

Other RCTs have looked at the effect of nutritional supplementation on ARM and AMD. The age-related eye disease study (AREDS) found that a formulation containing 500 mg vitamin C, 273 mg vitamin E, 15 mg β-carotene and 80 mg zinc was moderately effective in preventing progression to advanced AMD. This effect was only seen in those subjects with extreme intermediate drusen, large drusen or non-central geographic atrophy without advanced AMD (The AREDS Research Group, 2001). The lutein and antioxidant supplement trial was a 12-month RCT designed to evaluate the effect of 10 mg lutein alone or 10 mg lutein combined with additional carotenoids and antioxidants/minerals on MP optical density and objective visual outcome measures in 90 subjects with AMD. Glare recovery and contrast sensitivity significantly improved with both interventions, although it is worth noting that the study population was 95.6% male (Richer et al., 2004).

Although no positive effect of supplementation was shown in this case, the study did have 80% power at the 5% significance level to detect a change of 0.3 log units. This effect size was selected because the measurement of CS using the Pelli–Robson chart has been shown to be reliable to ±0.15 log units, which means that a change of 0.3 log units can be classed as clinically significant. A change of this size would also have brought both placebo and active groups into the normal range (1.50–1.80 log units) (Elliott et al., 1990) for their age.

Research into the role of xanthophylls for retinal health is ongoing. There is evidence for selective deposition of lutein in the retina (Rapp et al., 2000, Bernstein et al., 2001), increase of retinal and serum levels of lutein with supplementation (Hammond et al., 1997; Landrum et al., 1997; Berendschot et al., 2000), and an increased risk of ARMD with low serum (EDCCS Group, 1993) and retinal (Beatty et al., 2001; Bone et al., 2001) lutein levels. Lutein/zeaxanthin supplementation has been linked with improved visual function in patients with congenital retinal degenerations (Dagnelie et al., 2000) and with AMD (Richer, 1999).

The lack of positive effect shown by this RCT may be explained by the selected lutein dosage level. When the study was designed, the recommended daily intake of lutein was 6 mg, based on an epidemiological study that determined a 57% reduced risk for AMD in those consuming 6 mg lutein/zeaxanthin per day compared with those consuming 0.5 mg/day) (Seddon et al., 1994).

More recent work has demonstrated a general increase in macular pigment optical density (MPOD– retinal levels of lutein/zeaxanthin) response with dose (Chew et al., 2003; Landrum et al., 2004). In one study, those supplementing with 10 mg or 20 mg of lutein, but not 5 mg lutein, for 120 days had an increased response compared with those taking a placebo (Landrum et al., 2004). Another study showed that, in patients with varying stages of ARM and AMD, doses of 2.5, 5 and 10 mg lutein all induced an increase in serum levels by 1 month, and a peak by 3 months. Three-month levels ranged from 104 to 339% change from baseline. Macular pigment optical density levels, however, remained largely unchanged over the six-month supplementation period. In other studies the retinal response has been reported to occur after 15 weeks with increased dietary levels of corn and spinach (Hammond et al., 1997), 140 days with 30 mg/day supplemental lutein or zeaxanthin, and 6 months with 2.4 mg/day supplemental lutein or zeaxanthin (Landrum, Bone et al., 1997). The response rates appear to be variable, and this may explain why we did not find an effect on CS. Our dosage of 6 mg/day lutein may not have increased MPOD.

A putative lutein-binding protein has been found in the retinae of human eyes (Yemelyanov et al., 2001), which binds with high affinity and specificity to lutein and other xanthophylls. It has been suggested that people who are less responsive to xanthophyll supplementation may be so because of genetic differences that result in reduced or less efficient binding proteins (Landrum and Bone, 2004). This factor may have had an effect on the outcome of this trial. The protein may also act as an enzyme for the conversion of lutein to meso-zeaxanthin, which predominates over lutein and zeaxanthin at the fovea. There is no current evidence to support the suggestion that people with ARM or AMD have a reduced ability to absorb lutein or zeaxanthin at the macula.

The formulation also contained lutein esters extracted from marigold flowers, rather than pure lutein. It could be argued that this affected the results of this study. In flower petals, the pigments are stored as diesters, whereas they are found unesterified in most fruits and vegetables (Goodwin, 1980). In fact, industrial research showed that 93% of the lutein and zeaxanthin found in fruits, vegetables and eggs is found as lutein, rather than lutein esters (DeFreitas, 2004). Lutein esters contain two fatty acid groups that must be cleaved off before the body can use the lutein (Noy, 2000). The efficacy of this hydrolysis of lutein esters into lutein occurs with an efficacy that is well below 5% (Breithaupt et al., 2002; Granado et al., 2002). Furthermore, a negative correlation between age and serum lutein levels in individuals consuming lutein esters has been reported that was not found in people supplementing with lutein (Chung et al., 2004). This may suggest that the ability to hydrolyse lutein esters declines with age.

These factors have been used to support the argument that lutein esters are less bioavailable than pure lutein. Studies carried out to investigate differences in bioavailability between pure and esterified lutein do not support this hypothesis. One study reported no significant difference in serum lutein response between 6 mg lutein from spinach, 6 mg pure lutein and 10.23 mg lutein esters (Chung et al., 2004). In another study, serum response was greater from lutein esters than pure lutein (Bowen et al., 2002). Although these studies suggest that the use of lutein esters in our formulation should not have hindered bioavailability, it is important to note that they recorded serum response rather than retinal response. Although the retinal response is related to serum response, and dietary modification affects both, the retinal response is reported to be slower than the serum response.

Although serum antioxidant checks were considered during the design of the trial, this evidence suggested that it would only provide a short-term indication of blood antioxidant levels, and so would not provide any additionally useful information about compliance. The inclusion of blood testing in the protocol may also have hindered recruitment.

All participants were White British, and so the results cannot be applied to other ethnic groups.

It is difficult to explain the counterintuitive improvement in mean CS score over the trial period within the P group, although this change was not clinically significant. The trial results could have been confounded by the fact that the P group consumed almost twice as much as vitamin C than the A group. The increase in dietary intake of zinc in the A group is also worth mentioning, although it could be argued that, if anything, this change would increase rather than decrease the likelihood of finding a treatment effect based on the results of trials such as AREDS (The AREDS Research Group, 2001).

The mixed antioxidant and mineral formulation does not permit investigation of the effect of specific nutrients on visual function. The rationale for using a mixed formulation is that nutrients are thought to work synergistically together. A relevant example of this synergism is the facilitation of vitamin A transport from the liver by zinc (Newsome et al., 1994).

Although this study investigated the effect of nutritional supplementation in eyes affected by ARM, there is also interest in lutein supplementation for healthy eyes. It has been hypothesized that the blue-light filter effect of lutein/zeaxanthin may reduce longitudinal chromatic aberration (Wald, 1945) The acuity hypothesis states that retinal lutein may improve visual acuity for images that are illuminated by white light by absorbing poorly focussed short wavelengths before this light is processed by the retina (Hammond et al., 2001). The findings of a study by the authors that investigated the effect of lutein and antioxidant supplementation on visual function in healthy eyes has yet to be published. Despite a lack of empirical evidence, lutein/zeaxanthin supplements are being taken by the public in an attempt to improve retinal health and vision in the absence of disease (Mares-Perlman, 1999). We are not aware of any currently published trials that have investigated this hypothesis.

The finding of no evidence of effect of 9 months of nutritional supplementation on CS adds to the literature, and may suggest that daily intake of 6 mg lutein or less does not have a beneficial effect on ARM. Further clinical trials are required to investigate optimum lutein dosage levels, and we await the results of a large multicentred RCT.


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The project was sponsored by the UK College of Optometrists. Intervention and placebo tablets were provided by Quest Vitamins Ltd UK.

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Corresponding author

Correspondence to H E Bartlett.

Additional information

Guarantor: HE Bartlett.

Contributors: HEB and FE contributed to the design of the trial, statistical analyses, and preparation of the manuscript. HEB collected the data. HEB and FE read and approved the final manuscript.

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Bartlett, H., Eperjesi, F. Effect of lutein and antioxidant dietary supplementation on contrast sensitivity in age-related macular disease: a randomized controlled trial. Eur J Clin Nutr 61, 1121–1127 (2007).

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  • age-related macular disease
  • lutein
  • randomized controlled trial
  • nutrition
  • antioxidants

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