Herbs & Dietary Supplements Database : Age-Related Macular Degeneration Treatment with Herbs & Supplements

Dr. James Manos (MD)
July 5, 2019

Age-Related Macular Degeneration (AMD) prevention and treatment with herbs and dietary supplements

Age-related macular degeneration (AMD) is a chronic eye disease. It is the leading cause of vision loss in people over 60 in the United States, and the number of people with AMD rises as they age. Macular degeneration affects tissue in the part of your retina responsible for central vision, called the macula. It causes blurred vision or a blind spot in the center of the vision and can interfere with reading, driving, or other daily activities. Patients may first notice symptoms when they need more light to see up close. There are two forms of AMD. Dry AMD affects about 85% of those with the disease and causes a gradual loss of central vision, sometimes starting in one eye. Wet AMD, which accounts for 90% of all severe vision loss from the disease, often involves a sudden loss of central vision. Most people with the wet form of AMD previously had the dry kind (3).

Forms of macular degeneration: a) Dry Macular Degeneration. The dry form is the most common type of macular degeneration. This form, in which the photosensitive cells of the macula slowly break down, is diagnosed in 85-90 percent of cases. Yellow deposits called drusen (extracellular waste products from metabolism) form and accumulate under the retina between the retinal pigmented epithelium (RPE) layer and the Bruch’s membrane, which supports the retina. Drusen are often found in the eyes of older people, but an increase in the size and number of these deposits is frequently the first sign of macular degeneration. Over time, drusen are associated with deterioration of the macula and the death of RPE and photoreceptor cells, resulting in a blurring or spotty loss of clear, straight-ahead vision. This process does not cause any pain. In the preliminary stages of the disease, the patient may notice slightly blurry vision. However, as more cells die, central vision worsens. In its most severe form, dry age-related macular degeneration can cause profound vision loss, severely affecting a person’s quality of life.

The dry form of macular degeneration has three stages: 1) Early – patients have several small drusen or a few medium-sized drusen. There is no vision loss or symptoms at this stage. 2) Intermediate - patients have many medium-sized drusen or one or more large drusen. Some people may need more light for tasks such as reading. A blurry spot may appear in the center of the visual field. 3) Advanced – patients exhibit a large number of drusen deposits and a breakdown of RPE, photoreceptor (light-sensitive) cells, and supporting tissue in the retina. A large blurry spot occurs in the center of the visual field and can become more extensive and darker, eventually causing a complete loss of central vision. b) Wet Macular Degeneration. Wet macular degeneration occurs when abnormal blood vessels grow behind the macula as RPE and photoreceptor cells die. The Bruch's membrane begins to break down, usually near drusen deposits, and new blood vessels grow. This growth is called neovascularization. These vessels are very fragile and can leak fluid and blood, resulting in scarring of the macula and the potential for rapid, severe damage. Straight-ahead vision can become distorted or lost entirely in a short period of time, sometimes within days or weeks. Wet macular degeneration accounts for approximately 10 percent of age-related macular degeneration cases, but it results in 90 percent of the cases of legal blindness. All wet macular degeneration is considered advanced (15).

Suggested herbs and dietary supplements for AMD prevention

Age-related macular degeneration (AMD) is an eye condition that affects the central area of the retina (the light-sensitive tissue at the back of the eye). AMD is associated with a loss of detailed vision and adversely affects reading, driving, and face recognition tasks. In the absence of a cure, there has been considerable interest in the role of modifiable risk factors in preventing or slowing down the progression of AMD (16).

Some herbs & dietary supplements that have been studied for preventing AMD include carotenoids, such as beta–carotene, lutein & zeaxanthin, astaxanthin, lycopene; bilberry (rich in flavonoids, and anthocyanidins); fish oil (contains omega – 3 fatty acids); Ginkgo biloba; goji berry (wolfberry); Saffron (dried stigmas of the plant Crocus sativus); melatonin (it actually is a hormone), grape seed extract and dark leafy greens. The studied vitamins include the AREDS 1 formula (vitamin C, vitamin E, beta–carotene, zinc, and copper), folic acid, and vitamin B complex.

The University of Maryland suggests the following herbs and dietary supplements for AMD prevention: a) Ginkgo biloba (suggested dose for AMD is 160 mg – 240 mg per day) contains flavonoids, which researchers think may also help AMD. Two studies showed that people with AMD who took ginkgo were able to slow their vision loss. Ginkgo can increase the risk of bleeding, so people who take blood thinners such as warfarin (Coumadin), clopidogrel (Plavix), or aspirin should not take ginkgo without talking to their doctor. b) Bilberry (Vaccinium myrtillus, suggested dose for AMD is 120 – 240 mg 2 times per day) and grape seed (Vitis vinifera, recommended dose 50 – 150 mg per day) are also high in flavonoids, so researchers think that they may help prevent and treat AMD. However, no studies have looked at using bilberry or grapeseed to treat AMD.

Bilberry and grape seed may increase the risk of bleeding, so people who take blood thinners such as warfarin (Coumadin), clopidogrel (Plavix), or aspirin should not take either bilberry or grape seed without talking to their doctor. People with low blood pressure, heart disease, diabetes, or blood clots should not take Bilberry without first talking to their doctor. Also, pregnant or breastfeeding women should not take bilberry. c) Leafy greens. People who eat dark, leafy greens such as spinach, kale, collard greens, and watercress tend to have a lower risk of AMD. d) Vitamins B6, B12, and folic acid. One study found that taking vitamins B6, B12, and folic acid reduced the risk of AMD in women over 40 with a history of or risk factors for heart disease. The doses used were Vitamin B6 (50 mg daily), Vitamin B12 (1 000 mcg per day), and Folic acid (2 500 mcg per day). Folic acid can mask a vitamin B12 deficiency. Before someone takes these vitamins at these doses, he/she should ask a doctor. e) Omega-3 fatty acids (fish oil). In a study of more than 3,000 people over the age of 49, those who ate more fish were less likely to have AMD than those who ate less. Other studies show that eating fatty fish at least once a week halts the risk of AMD. Another larger study found that consuming docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), two types of omega-3 fatty acids found in fish 4 or more times per week, may reduce the risk of developing AMD.

However, this study suggests that alpha-linolenic acid (another type of omega-3 fatty acid) may increase the risk of AMD. It is safe for people to eat more fish, although someone may want to eat fish with lower levels of mercury, such as shrimp, canned light tuna, salmon, catfish, and pollock. Pregnant or breastfeeding women are advised to eat up to 12 ounces a week of a variety of fish and shellfish that are lower in mercury. People should talk to their doctor before taking fish oil supplements if they are at risk for AMD. Fish oil may increase the risk of bleeding, especially in patients already taking blood thinners such as warfarin (Coumadin) or aspirin (3).

Omega – 3 fatty acids

Evidence from population studies suggests that people who have a diet with relatively high levels of omega-3 fatty acids are less likely to develop AMD. However, people who consume higher levels of omega-3 fatty acids could differ in many ways from those who do not. This means that these population studies do not provide conclusive evidence that higher levels of omega-3 fatty acids in the diet prevent AMD or slow its progression. A Cochrane review found no published randomized clinical trials investigating the use of increasing dietary omega 3 (either by eating more foods rich in omega 3 or by taking nutritional supplements) in preventing or treating AMD. However, data from a large, ongoing, multi-center trial based in the USA will soon be available (16).

Ginkgo biloba

Age-related macular degeneration (AMD) affects the retina's central area (the back of the eye). The retina can deteriorate with age, and some people get lesions that lead to loss of central vision. Gingko biloba, extracted from the leaves of the maidenhair tree, is used in Chinese herbal medicine to treat a variety of medical conditions, in particular, circulatory problems. Ginkgo biloba extract contains two constituents (flavonoids and terpenoids) with antioxidant properties. It is believed these may help to slow down the progression of AMD. The author of a Cochrane review identified two small randomized controlled studies (with a total of 119 participants); one in France and one in Germany. One trial compared Gingko biloba to a placebo, and the other compared two different doses of the extract. Although both trials reported some positive effects of Ginkgo biloba on vision, the trials were small and of short duration. Adverse effects and quality of life were not assessed. The overall conclusion of this review is that current research has not answered the question as to whether Ginkgo biloba is of benefit to people with AMD. Future trials need to include a more significant number of participants and be conducted over a longer time (17).

Suggested herbs/ dietary supplements for AMD treatment

Lutein & Zeaxanthin

Elevated levels of these two antioxidants that give plants orange, red, or yellow color may help protect against AMD, either by acting as antioxidants or by protecting the macula from damage from light. One study found that people with AMD who took lutein alone or in combination with other antioxidants had less vision loss, while those who received a placebo had no change. However, another study failed to find any benefit from lutein. Egg yolks, spinach, and corn have high concentrations of lutein and zeaxanthin (3).

The AREDS 1 study

The National Eye Institute’s Age-Related Eye Disease Study (AREDS) found that taking a specific high–dose formula of antioxidants and zinc (the daily dose is: 500 milligrams of vitamin C; 400 International Units of vitamin E; 15 milligrams of beta-carotene; 80 milligrams of zinc as zinc oxide; and two milligrams of copper as cupric oxide) may delay or prevent intermediate age-related macular degeneration from progressing to the advanced stage. The antioxidant vitamins and minerals in the AREDS formula help maintain healthy cells and tissues and may prevent damage to the macula. There is no evidence, however, that the AREDS formula provided any benefit to people with early-stage age-related macular degeneration. Patients with intermediate age-related macular degeneration in one or both eyes or advanced age-related macular degeneration (dry or wet) in one eye but not the other eye should consider taking the formula (4).

Age-related macular degeneration (AMD) affects the retina's central area (back of the eye). The retina can deteriorate with age, and some people get lesions that can lead to the loss of central vision. It has been suggested that the progression of the disease may be slowed down in people who eat a diet rich in antioxidant vitamins (carotenoids, vitamins C and E) or minerals (selenium and zinc). A Cochrane review identified 13 randomized controlled trials that included 6 150 participants; five trials were based in the USA, two in the UK, two in Austria, and one in each of a further four countries (Australia, China, Italy, and Switzerland). Over half the participants (3 640) were randomized in one trial (AREDS in the USA), which found a beneficial effect of the antioxidant (beta-carotene, vitamin C, and vitamin E) and zinc supplementation on the progression to advanced AMD over an average of 6.3 years. People taking supplements were less likely to lose 15 or more letters of visual acuity. The other trials generally had a shorter follow-up (less than two years). No evidence for an effect of supplementation was seen in these smaller trials of shorter duration. In conclusion, the review of trials found that supplementation with antioxidants and zinc may be of modest benefit in people with Age-related macular degeneration (AMD). This was mainly seen in one large trial that followed up participants for an average of six years. The other smaller trials with shorter follow-ups do not provide evidence of any benefit. Large, well-conducted trials in various populations and with different nutritional statuses are required. Although generally regarded as safe, vitamin supplements may have harmful effects. A systematic review of the evidence on the harms of vitamin supplements is needed (5).

Age-related macular degeneration (AMD) affects the retina's central area (back of the eye). The retina can deteriorate with age, and some people get lesions that can lead to the loss of central vision. Some studies have suggested that people who eat a diet rich in antioxidant vitamins (carotenoids, vitamins C and E) or minerals (selenium and zinc) may be less likely to get AMD. The authors of a Cochrane review identified four large, high-quality, randomized controlled trials, including 62,520 people. The trials were conducted in Australia, Finland, and the USA and investigated the effects of vitamin E and beta-carotene supplementation. These trials provide evidence that taking vitamin E and beta-carotene supplements are unlikely to prevent the onset of AMD. There was no evidence for other antioxidant supplements and commonly marketed combinations. Although generally considered safe, vitamin supplements may have harmful effects, and clear evidence of benefit is needed before they can be recommended (2).

The problems with the vitamins & elements toxicity in the AREDS 1 study

The National Eye Institute’s Age-Related Eye Disease Study (AREDS) formula of antioxidants and daily zinc dose is 500 milligrams of vitamin C; four hundred International Units of vitamin E; 15 milligrams of beta-carotene; 80 milligrams of zinc as zinc oxide; and two milligrams of copper as cupric oxide). People should always consult a physician before taking any supplements. The AREDS formula may be contraindicated due to other medical conditions or medications (4).

People who already take multivitamins should let their doctor know before taking the AREDS formulation (3).

Beta carotene (see also studies below on Vitamin E)

The dose of the AREDS 1 formula for beta–carotene is 15 mg (4). Generally, the University of Maryland Medical Center recommends the following dosages of beta–carotene for adults: for general health, 15 – 50 mg (25 000 – 83 000 IU) per day (9).

Beta-carotene is likely safe when used for certain specific medical conditions and taken in appropriate amounts. However, beta-carotene supplements are not recommended for general use. Beta-carotene is possibly unsafe in high doses, especially when taken long-term (10). Beta-carotene supplements may increase the risk of heart disease and cancer in those who smoke or drink heavily. Heavy smokers or drinkers should not use this supplement except under a doctor's supervision (9). There is growing concern that taking high doses of antioxidant supplements such as beta-carotene might do more harm than good. Some research shows that taking high doses of beta-carotene supplements might increase the chance of death from all causes and possibly other serious side effects. There is also concern that taking large amounts of a multivitamin plus a separate beta-carotene supplement increases the chance of developing advanced prostate cancer in men. Beta-carotene supplements might increase the risk of lung and prostate cancer in people who smoke. People who smoke should not take beta-carotene supplements. In people who have been exposed to asbestos, beta-carotene supplements might increase the risk of cancer. People who have been exposed to asbestos should not take beta-carotene supplements. There is also some concern that when antioxidant vitamins, including beta-carotene, are used together, they might have harmful effects after angioplasty. They can interfere with healing. People should not use beta-carotene and other antioxidant vitamins before or after angioplasty without a doctor's recommendation (10).

A Cochrane systematic review included 78 randomized clinical trials. In total, 296,707 participants were randomized to antioxidant supplements (beta-carotene, vitamin A, vitamin C, vitamin E, and selenium) versus placebo or no intervention. A total of 21 484 of 183 749 participants (11.7%) were randomized to antioxidant supplements, and 11 479 of 112 958 participants (10.2%) randomized to placebo or no intervention died. The increased risk of mortality was associated with beta-carotene and possibly vitamin E and vitamin A but was not related to the use of vitamin C or selenium. The current evidence does not support using antioxidant supplements in the general population or in patients with various diseases (27).

The Beta-Carotene and Retinol Efficacy Trial (CARET) tested the combination of 30 mg beta-carotene and 25 000 IU retinyl palmitate (vitamin A) taken daily against placebo in 18 314 men and women at high risk of developing lung cancer. The CARET intervention was stopped 21 months early because of clear evidence of no benefit and substantial evidence of possible harm; there were 28% more lung cancers and 17% more deaths in the active intervention group. The study concluded that CARET participants receiving the combination of beta-carotene and vitamin A had no chemopreventive benefit and had excess lung cancer incidence and mortality. The results are highly consistent with those found for beta-carotene in the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study in 29 133 male smokers in Finland. Individuals at elevated risk of developing lung cancer, i.e., current smokers and asbestos-exposed workers, should be discouraged from taking supplemental beta-carotene (and the combination of β-carotene with vitamin A). Safety and efficacy should be demonstrated before recommending the use of vitamin supplements in any population (28).

Vitamin C (L- ascorbic acid)

The dose of the AREDS 1 formula for vitamin C is 500 mg (4). Generally, for adults, the recommended daily allowances (RDA) for Vitamin C are for adult males 90mg and adult females 75 mg. The tolerable upper intake levels (ULs) for vitamin C are for adult males and females, 2,000 mg (2 gr) (8).

Vitamin C has low toxicity and is not believed to cause serious adverse effects at high intakes. The most common complaints are diarrhea, nausea, abdominal cramps, and other gastrointestinal disturbances due to the osmotic effect of unabsorbed vitamin C in the digestive tract. In postmenopausal (after menopause) women with diabetes who participated in the Iowa Women’s Health Study, supplemental (but not dietary) vitamin C intake (at least 300 mg/day) was significantly associated with an increased risk of cardiovascular disease mortality. This finding is from a subgroup of patients in an epidemiological study. No such association has been observed in any other epidemiological research, so the significance of this finding is uncertain. High vitamin C intake also has the potential to increase urinary oxalate and uric acid excretion, which could contribute to the formation of kidney stones, especially in individuals with renal disorders. However, studies evaluating the effects on urinary oxalate excretion of vitamin C intakes ranging from 30 mg to 10 g/day have had conflicting results, so it is unclear whether vitamin C plays a role in the development of kidney stones. The best evidence that vitamin C contributes to kidney stone formation is in patients with pre-existing hyperoxaluria. Also, in individuals with hereditary hemochromatosis, chronic consumption of high doses of vitamin C could exacerbate iron overload and result in tissue damage. Under certain conditions, vitamin C can act as a pro-oxidant, potentially contributing to oxidative damage. A few studies in vitro have suggested that by working as a pro-oxidant, supplemental oral vitamin C could cause chromosomal and/or DNA damage and possibly contribute to the development of cancer. However, other studies have not shown increased oxidative damage or cancer risk with high intakes of vitamin C. Other reported effects of high intakes of vitamin C include reduced vitamin B12 and copper levels, accelerated metabolism or excretion of ascorbic acid, erosion of dental enamel, and allergic responses. However, at least some of these conclusions were a consequence of assay artifacts, and additional studies have not confirmed these observations. Long-term intakes of vitamin C above the tolerable upper intake levels (UL) may increase the risk of adverse health effects (8).

The recommended upper limit for ascorbic acid (AA) (vitamin C) intake is 2,000 mg/day. However, because AA is endogenously converted to oxalate and appears to increase the absorption of dietary oxalate, supplementation may increase the risk of kidney stones. The effect of AA supplementation on urinary oxalate was studied in a randomized, crossover, controlled design in which subjects consumed a controlled diet in a university metabolic unit. Stone formers (n = 29 subjects; SF) and age- and gender-matched non-stone formers (n = 19 subjects; NSF) consumed 1 000 mg AA twice each day with each morning and evening meal for 6 days (treatment A) and no AA for 6 days (treatment N) in random order. The study showed that the 1 000 mg ascorbic acid (AA) (vitamin C) twice each day increased urinary oxalate and Tiselius Risk Index (TRI) for calcium oxalate kidney stones in 40% of participants, both stone formers and non-stone formers (25).

Vitamin C is a potent antioxidant but can also be a pro-oxidant and glycated protein under certain circumstances in vitro. These observations led the authors to hypothesize that a high intake of vitamin C in diabetic persons might promote atherosclerosis. A study examined the relationship between vitamin C intake and mortality from cardiovascular disease. The study investigated the relationship between vitamin C intake and mortality from total cardiovascular disease (n = 281 subjects), coronary artery disease (n = 175 subjects), and stroke (n = 57 subjects) in 1 923 post-menopausal (after menopause) women who reported being diabetic at baseline. When dietary and supplemental vitamin C were analyzed separately, only supplemental vitamin C showed a positive association with mortality endpoints. Vitamin C intake was unrelated to mortality from cardiovascular disease in the non-diabetic subjects at baseline. In conclusion, a high vitamin C intake from supplements is associated with an increased risk of cardiovascular disease mortality in post-menopausal (after menopause) women with diabetes (26).

Vitamin E (alpha-tocopherol)

The dose of the AREDS 1 formula for vitamin E is 400 International Units (4). Generally, for adults (males and females), the recommended daily allowance (RDA) for Vitamin E is 15 mg (22.4 IU). The tolerable upper intake levels (ULs) for vitamin E are for adult males and females 1 000 mg (1 500 IU) (11).

Research has not found any adverse effects from consuming vitamin E in food. However, high doses of alpha-tocopherol supplements can cause hemorrhage and interrupt blood coagulation in animals, and in vitro data suggest that high doses inhibit platelet aggregation. Two clinical trials have found an increased risk of hemorrhagic stroke in participants taking alpha-tocopherol; one trial included Finnish male smokers who consumed 50 mg/day for an average of 6 years, and the other trial involved a large group of male physicians in the United States who consumed 400 IU every other day for 8 years. Because most physicians in the latter study were also taking aspirin, this finding could indicate that vitamin E tends to cause bleeding. The FNB has established ULs for vitamin E based on potential hemorrhagic effects. The ULs apply to all forms of supplemental alpha-tocopherol, including the eight stereoisomers present in synthetic vitamin E. Doses of up to 1 000 mg/day (1 500 IU/day of the natural form or 1 100 IU/day of the synthetic form) in adults appear to be safe. However, the data are limited and based on small groups taking at least 2,000 IU for a few weeks or months. Long-term intakes above the UL increase the risk of adverse health effects. Vitamin E ULs for infants have not been established. Two meta-analyses of randomized trials have also raised questions about the safety of large doses of vitamin E, including doses lower than the UL. These meta-analyses linked supplementation to small but statistically significant increases in all-cause mortality. One analysis found an increased risk of death at 400 IU/day doses, although the risk began to rise at 150 IU. In the other review of studies of antioxidant supplements for disease prevention, the highest quality trials revealed that vitamin E, administered singly (dose range 10 IU–5 000 IU/day; mean 569 IU) or combined with up to four other antioxidants, significantly increased mortality risk. The implications of these analyses for the potential adverse effects of high-dose vitamin E supplements are unclear. Participants in the studies included in these analyses were typically middle-aged or older and had chronic diseases or related risk factors. These participants often consumed other supplements in addition to vitamin E. A review of the subset of studies in which vitamin E supplements were given to healthy individuals for the primary prevention of chronic disease found no convincing evidence that the supplements increased mortality. However, results from the recently published, large SELECT trial show that vitamin E supplements (400 IU/day) may harm adult men in the general population by increasing their risk of prostate cancer (11).

A randomized, double-blind, placebo-controlled primary prevention trial was conducted to determine whether daily supplementation with alpha-tocopherol (vitamin E), beta-carotene, or both would reduce the incidence of lung cancer and other cancers. A total of 29 133 male smokers 50 to 69 years of age from southwestern Finland were randomly assigned to one of four regimens: alpha-tocopherol (50 mg per day) alone, beta carotene (20 mg per day) alone, both alpha-tocopherol and beta–carotene, or placebo. Follow-up continued for five to eight years. Among the 876 new cases of lung cancer diagnosed during the trial, no reduction in incidence was observed among the men who received alpha-tocopherol. Unexpectedly, the authors noted a higher rate of lung cancer among the men who received beta carotene than those who did not. The authors found no evidence of an interaction between alpha-tocopherol and beta–carotene concerning the incidence of lung cancer. Fewer cases of prostate cancer were diagnosed among those who received alpha-tocopherol than those who did not. Beta–carotene had little or no effect on the incidence of cancer other than lung cancer. Alpha-tocopherol had no apparent effect on total mortality, although more deaths from hemorrhagic stroke were observed among the men who received this supplement than among those who did not. Overall mortality was 8 percent higher among the participants who received beta–carotene than among those who did not, primarily because there were more deaths from lung cancer and ischemic heart disease. In conclusion, the authors found no reduction in the incidence of lung cancer among male smokers after five to eight years of dietary supplementation with alpha-tocopherol or beta-carotene. In fact, this trial raises the possibility that these supplements may have harmful and beneficial effects (21).

A population-based, randomized, double-blind, placebo-controlled, 2 x 2 factorial design trial (the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study) determined if vitamin E (dl-alpha-tocopherol) and beta–carotene supplementations could be used in the prevention of stroke in men at high risk for hemorrhagic or ischemic events. The investigators used alpha tocopherol (vitamin E), 50 mg; beta carotene, 20 mg; both; or placebo. From the total male population aged 50 through 69 years in southwestern Finland (n = 290 406 subjects), 29 133 male smokers were randomized to 1 of 4 treatment regimens. The authors excluded 614 men because of the previous stroke at baseline, leaving 28 519. The results showed that stroke occurred in a total of 1057 men: 85 had subarachnoid, 112 had an intracerebral hemorrhage, 807 had cerebral infarction, and 53 had an unspecified stroke. Within 90 days from onset, 160 men died of a stroke. Vitamin E supplementation increased the risk of subarachnoid hemorrhage and decreased the risk of cerebral infarction in hypertensive men but did not affect normotensive men. Furthermore, it reduced the risk of cerebral infarction, without elevating the risk of subarachnoid hemorrhage, among hypertensive men with concurrent diabetes. Beta–carotene supplementation increased the risk of intracerebral hemorrhage and modestly decreased cerebral infarction among men with higher alcohol consumption. In conclusion, vitamin E supplementation may prevent ischemic stroke in high-risk hypertensive patients, but further studies are needed (23).

Vitamin E can inhibit platelet aggregation and antagonize vitamin K-dependent clotting factors. As a result, taking large doses of anticoagulant or antiplatelet medications, such as warfarin (Coumadin (R)), can increase the risk of bleeding, especially in conjunction with low vitamin K intake. The amounts of supplemental vitamin E needed to produce clinically significant effects are unknown but probably exceed 400 IU/day (11).

A systematic review and meta-analysis of randomized, placebo-controlled trials evaluated the effect of vitamin E supplementation on incident total, ischemic, and hemorrhagic stroke. Nine trials investigating the effect of vitamin E on incident stroke were included, with a total of 118765 participants (59357 randomized to vitamin E and 59408 to placebo). Among those, seven trials reported data for total stroke and five trials for hemorrhagic and ischemic stroke. In conclusion, in this meta-analysis, vitamin E increased the risk of hemorrhagic stroke by 22% and reduced the risk of ischemic stroke by 10%. This differential risk pattern is obscured when looking at a total stroke. Given the relatively small risk reduction of ischemic stroke and the generally more severe outcome of hemorrhagic stroke, widespread indiscriminate use of vitamin E should be cautioned against (22).

Experimental models and observational studies suggest vitamin E supplementation may prevent cardiovascular disease and cancer. However, several high-dosage vitamin E supplementation trials showed non-statistically significant increases in total mortality. A meta-analysis of the dose-response relationship between vitamin E supplementation and total mortality by using data from randomized, controlled trials was conducted. It involved 135,967 participants in 19 clinical trials. Of these trials, 9 tested vitamin E alone, and 10 tested vitamin E combined with other vitamins or minerals. The dosages of vitamin E ranged from 16.5 to 2000 IU/d (median, 400 IU/d). The meta-analysis concluded that high-dosage (equal to or more than 400 IU/day) vitamin E supplements may increase all-cause mortality and should be avoided (14).

Antioxidant supplements are used for the prevention of several diseases. A review assessed the effect of antioxidant supplements on mortality in randomized primary and secondary prevention trials. The authors included 68 randomized trials with 232 606 participants (385 publications). The review concluded that beta–carotene, vitamin A, and vitamin E treatment may increase mortality. Vitamin C and selenium's potential role in mortality need further study (29).

Another review assessed the effect of antioxidant supplements on mortality in primary or secondary prevention randomized clinical trials. Sixty-seven randomized trials with 232 550 participants were included. The authors found no evidence to support antioxidant supplements for primary or secondary prevention. Vitamin A, beta-carotene, and vitamin E may increase mortality. Future randomized trials could evaluate the potential effects of vitamin C and selenium for primary and secondary prevention. Such trials should be carefully monitored for possible harmful effects. Antioxidant supplements must be considered medicinal products and undergo sufficient evaluation before marketing (30).

Zinc

The dose of the AREDS 1 formula for Zinc is 80 mg (4). Generally, for adults, the recommended daily allowances (RDA) for Zinc are 11 mg for males and 8 mg for females. The tolerable upper intake levels (ULs) for Zinc are for adult males and females 40 mg (12). That means the dose of Zinc in the AREDS 1 formula is above the tolerable upper intake levels (ULs) for adults.

Zinc can be harmful at a dose of 80 mg, so people should be sure to take this combination only under their doctor’s supervision. Zinc can cause copper deficiency, so a small amount of copper is added to the nutrients. In the AREDS study, 7.5% of people who took zinc had problems, including urinary tract infections, enlarged prostate, and kidney stones, compared to 5% of those who did not receive zinc (3).

Zinc toxicity can occur in both acute and chronic forms. Acute adverse effects of high zinc intake include nausea, vomiting, loss of appetite, abdominal cramps, diarrhea, and headaches. One case report cited severe nausea and vomiting within 30 minutes of ingesting 4 g of zinc gluconate (570 mg elemental zinc). Intakes of 150–450 mg of zinc daily have been associated with chronic effects such as low copper status, altered iron function, reduced immune function, and reduced levels of high-density lipoproteins. Reductions in a copper-containing enzyme, a marker of copper status, have been reported with even moderately high zinc intakes of approximately 60 mg/day for up to 10 weeks. The doses of zinc used in the AREDS study (80 mg per day of zinc in the form of zinc oxide for 6.3 years, on average) have been associated with a significant increase in hospitalizations for genitourinary causes, raising the possibility that chronically high intakes of zinc adversely affect some aspects of urinary physiology. Long-term intakes of Zinc above the tolerable upper intake levels (ULs) increase the risk of adverse health effects (12).

Zinc is a common dietary supplement widely believed to have beneficial health effects. To assess the impact of high-dose supplemental zinc on genitourinary diseases, the authors analyzed a recent randomized trial comparing zinc, antioxidants, and their combination with placebo for complications related to the genitourinary tract. In a further analysis of the recent Age-related Eye Disease Study (AREDS), the authors examined the data pool for the primary International Classification of Diseases, 9th revision codes given for hospital admissions related to urological problems. The authors found a significant increase in hospital admissions due to genitourinary causes in patients on zinc vs. non-zinc formulations (11.1% vs. 7.6%). The risk was most notable in male patients. In the study group of 343 patients requiring hospital admission the most common primary International Classification of Diseases, 9th revision codes included benign prostatic hyperplasia/urinary retention (benign prostatic hyperplasia), urinary tract infection, urinary lithiasis (kidney stones), and renal failure. When comparing zinc to placebo, significant increases in urinary tract infections (UTIs) were found, especially in females (2.3% vs. 0.4%). Admissions for urinary lithiasis approached significance in men on zinc compared to placebo (2.0% vs. 0.5%). The study concluded that zinc supplementation at high levels results in increased hospitalizations for urinary complications compared to a placebo. These data support the hypothesis that high–dose zinc supplementation adversely affects select aspects of urinary physiology (13).

The AREDS 2 study

The Age-Related Eye Disease Study (AREDS) demonstrated the beneficial effects of oral supplementation with antioxidant vitamins and minerals on the development of advanced age-related macular degeneration (AMD) in persons with at least intermediate AMD (large bilateral drusen with or without pigment changes). Observational data suggest that other oral nutrient supplements might further reduce the risk of progression to advanced AMD. The primary purpose of the Age-Related Eye Disease Study 2 (AREDS2) is to evaluate the efficacy and safety of lutein plus zeaxanthin (L+Z) and/or ω-3 long-chain polyunsaturated fatty acid (LCPUFA) supplementation in reducing the risk of developing advanced AMD. The study also assesses the reduction in zinc and the omission of beta-carotene from the original AREDS formulation. The AREDS 2 is a multicenter, phase III, randomized, controlled clinical trial. Persons aged 50 to 85 with bilateral intermediate AMD or advanced AMD in 1 eye participated in the study. All participants were randomly assigned to placebo (n = 1 012 subjects), L+Z (10 mg/2 mg; n = 1 044 subjects), ω-3 LCPUFAs (ω-3 long-chain polyunsaturated fatty acids) (eicosapentaenoic acid (EPA) +docosahexaenoic acid (DEA) [650 mg/350 mg]; n = 1 069 subjects), or the combination of L+Z and ω-3 LCPUFAs (n = 1 078 subjects). All participants were offered secondary randomization to 1 of 4 variations of the original AREDS formulation keeping vitamins C (500 mg) and E (400 IU) and copper (2 mg) unchanged while varying zinc and β-carotene as follows: Zinc remains at the original level (80 mg), lower only zinc to 25 mg, omit β-carotene only, or lower zinc to 25 mg and omit beta-carotene. The main outcome measure is the progression to advanced AMD determined by centralized grading of annual fundus photograph. In a study, 4, 203 participants were enrolled at 82 clinical centers located in the United States (7).

The National Eye Institute (NEI) is conducting the AREDS-2 clinical trials focused on the addition of lutein, zeaxanthin, and omega-3 fatty acids to the original AREDS formula. Participants will also be offered variations on beta carotene and zinc levels included in the original AREDS formula. This adjustment was because zinc was thought to cause genitourinary problems that required hospitalization in a small percentage of the original AREDS trial participants, and beta-carotene supplementation is not recommended for consumption by smokers or ex-smokers due to the increased risk of lung cancer. The estimated AREDS2 trial data collection and the primary outcome measure completion date is December 2012. Scientists will follow up for at least five years (1).

About lutein FloraGlo (R)

FloraGLO (R) Lutein is a well-known patented, purified lutein (18), sourced from marigold flowers and purified from marigold flower oleoresin. Kemin Industries is a nutritional ingredients manufacturer headquartered in Des Moines, Iowa, USA. It has developed high-quality science-based dietary antioxidant supplements such as FloraGLO Brand Lutein (20).

Different formulations of lutein & zeaxanthin

Lutein and zeaxanthin are macular pigments with a protective function in the retina (of the eye). These xanthophylls must be obtained from the diet or added to foods or supplements via easy-to-use, stable formulations. The technique employed to produce these formulations may affect the bioavailability of the xanthophylls. Forty-eight healthy volunteers were randomized into a double-blind, cross-over study investigating the plasma kinetics of lutein provided as two different beadlet formulations. Subjects (n = 48 subjects) received a single dose of 20 mg of lutein as either a starch-matrix ("SMB",FloraGLO (R)) Lutein 5 %) or as a cross-linked alginate-matrix beadlet ("AMB", Lyc-O-Lutein 20 %) formulation. In conclusion, these findings confirm that the bioavailability of lutein and zeaxanthin critically depends on the formulation used and documents the superiority of the starch-based over the alginate-based product in this study (19).

Observed Safe Levels (OSL) of lutein & lycopene

Lutein and lycopene, two common carotenoids in the human diet, have become increasingly popular ingredients in dietary supplements. A large body of human and animal research suggests that oral forms of these carotenoids may provide benefits in the areas of the eye, prostate, skin, and cardiovascular health. The increased awareness and use of these ingredients in dietary supplements warrant a comprehensive review of their safety. Systematic evaluation of the research designs and data provides a basis for risk assessment and the usual tolerable Upper Level of Intake (UL) derived from it if the newer methods are described as the Observed Safe Level (OSL) or Highest Observed Intake (HOI) are utilized. The OSL risk assessment method indicates that the evidence of safety is strong at intakes up to 20mg/day for lutein and 75 mg/day for lycopene, and these levels are identified as the respective OSL. Although much higher levels have been tested without adverse effects and may be safe, the data for intakes above these levels is insufficient for a confident conclusion of long-term safety (24).

Drug & surgical therapies

The dry form of AMD can progress to the wet form. People with dry AMD need to test their eyes daily at home using an Amsler grid and let their doctor know immediately if there is any change in their vision. Drug & surgical therapies include a) Drug Therapies. For wet AMD, an anti-vascular endothelial growth factor (anti-VEGF) can be injected into the patient’s eye to stop new blood vessels from growing. Two such drugs are approved to treat AMD: Pegaptanib (Macugen (R)) and Ranibizumab (Lucentis (R)). b) Surgical and Other Procedures. Surgical and other procedures may help some cases of wet macular degeneration. 1) Photocoagulation (laser surgery). In photocoagulation, doctors use a laser to seal off blood vessels that have grown under the macula. Whether this procedure is used depends on where the blood vessels are located, how much fluid or blood has leaked out, and how healthy the macula is. 2) Photodynamic therapy. It is often used to seal off blood vessels under the macula's center. Using photocoagulation in that location would result in permanent central vision loss. With photodynamic therapy, the doctor gives the patient a drug that stays in the blood vessels under the macula. When a light is shined in the patient’s eye, the drug closes them off without damaging the rest of the macula. Photodynamic therapy slows vision loss but doesn’t stop it (3)

Antiangiogenic therapy with anti-vascular endothelial growth factor (anti-VEGF)

Age-related macular degeneration (AMD) is a common cause of severe vision loss in people 55 years and older. Neovascular AMD, which involves abnormal growth of blood vessels in the back of the eye, accounts for most AMD-related severe vision loss. Medications such as pegaptanib and ranibizumab that block this abnormal growth of blood vessels in the back of the eye are one way to treat this condition. Fewer patients treated with pegaptanib lost 15 or more letters of visual acuity in one year. Ranibizumab alone and combined with verteporfin photodynamic therapy (PDT) resulted in fewer patients losing 15 or more letters of visual acuity in one year. Approximately seven patients need to be treated with 0.3 mg or 0.5 mg pegaptanib to prevent one patient's loss of fifteen or more letters of visual acuity. This number is about 14 for 3 mg pegaptanib. In contrast, just over three patients need to be treated with either 0.3 mg or 0.5 mg of ranibizumab to prevent loss of fifteen or more letters of visual acuity. Very few patients treated with pegaptanib gained visual acuity. A higher proportion of patients treated with ranibizumab increased fifteen or more letters of visual acuity in one year compared with sham or verteporfin PDT. No trial directly compared pegaptanib and ranibizumab. Pegaptanib and ranibizumab are beneficial for the treatment of neovascular AMD, and their use is associated with few adverse effects. Trials of other agents that block the abnormal growth of blood vessels in this condition are ongoing and will be included in updates of the Cochrane review (6).

Thanks for reading!

Reference (links)

1.http://www.ahaf.org/macular/about/risk.html

(Retrieved:24 February 2013)

2.http://summaries.cochrane.org/CD000253/antioxidant-vitamins-and-

mineral-supplements-to-prevent-the-development-of-age-related-macular-degeneration

3.http://www.umm.edu/altmed/articles/macular-degeneration-000104.htm

(Retrieved:24 February 2013)

4.http://www.ahaf.org/macular/about/risk.html

(Retrieved:24 November 2012)

5.http://summaries.cochrane.org/CD000254/antioxidant-vitamins-and-

mineral-supplements-to-slow-down-the-progression-of-age-related-macular-degeneration