The AREDS2 Formula Side Effects: The Risks Doctors Don’t Tell You

The Age-Related Eye Disease Study (AREDS) and its successor, AREDS2, sponsored by the National Eye Institute, have played a pivotal role in understanding how specific nutritional supplements help support macular health.

The AREDS2 formula has become incredibly popular, with numerous companies selling supplements based on this research. The widespread acceptance of AREDS2 underscores its perceived benefits; however, the potential risks and shortcomings are often under-discussed.

Many consumers and even eyecare professionals are not fully aware of AREDS2 side effects and limitations, leading to a knowledge gap that needs to be bridged.

The purpose of this blog post is to revisit the origins of AREDS / AREDS2 and provide insight into their potential pitfalls.

The Original AREDS Formula

The original AREDS study used a specific combination of vitamins and minerals that showed promise in reducing the risk of progression to advanced macular degeneration (AMD) in individuals with intermediate stages of the disease. This formulation included vitamin A or beta-carotene, vitamin C, vitamin E, zinc, and copper. 

However, subsequent research revealed a significant lung cancer risk associated with beta-carotene, particularly among smokers. Separate trials funded by the National Cancer Institute found that beta-carotene increased the risk of lung cancer, leading to a necessary revision of the original AREDS formula.

Evolution to the AREDS2 Formula

In response to these findings, the AREDS2 study modified the original formulation, replacing beta-carotene with the macular carotenoids lutein and zeaxanthin. The updated formula includes lutein, zeaxanthin, vitamin C, vitamin E, zinc, and copper.

This revised AREDS2 formula significantly reduced the risk of intermediate AMD progressing to advanced stages, without any increased risk of lung cancer. 

However, it's crucial to note that AREDS2 did not show any preventative effect or significant benefits for those with early AMD, highlighting a limitation as many people take it for preventative measures without evidence supporting its efficacy in prevention.

AREDS2 Side Effects and Risks

While the AREDS2 vitamins for macular degeneration are very popular, their risks and limitations are often overlooked.

These concerns are not frequently discussed by eye care professionals and doctors, who themselves may not be fully aware of the potential side effects associated with the vitamin C, vitamin E, and zinc content in the AREDS2 formula.

Vitamin C

While vitamin C is a well-known antioxidant, high doses (500 mg or more daily) may have an opposite, pro-oxidant effect on the lens, potentially increasing the risk of cataract development. Among women aged 65 and above, vitamin C supplement use has been reported to increase the risk of cataract by up to 38%.

The recommendation is to take a small-to-moderate dose of vitamin C daily (less than 100 mg daily) preferably as part of a healthy and balanced diet rather than in the form of supplements. 

Vitamin E

Some studies have found that supplemental vitamin E at the AREDS2 daily dose of 400 IU or above is linked with a small but significant increase in death from all causes.

Prostate cancer risk may also be a concern, based on results from the 2011 Selenium and Vitamin E Cancer Prevention Trialwhich found a 17% increase in prostate cancer risk among men taking 400 IU of vitamin E daily after seven years.

Zinc 

The dose of zinc in the AREDS2 formula is 80 mg, double the tolerable upper intake level (40 mg daily for adults) set by most health authorities. A study published in the Journal of Urology found that individuals taking the AREDS formula with 80 mg of zinc were more likely to be hospitalised for urinary complications compared to placebo.

Of potentially greater consequence are the results from the Health Professionals Follow-up Study, which reported that zinc supplementation of more than 75 mg daily or over 15 years may almost double the risk of lethal and aggressive prostate cancer.

Finally, the presence of zinc in the AREDS2 formula can in fact increase progression to advanced AMD in those with immune gene variations (CFH and ARMS2 genetic polymorphisms) that make the macula particularly sensitive to zinc.

For those who are sensitive to zinc based on genetic testing, the recommended intake of zinc is no more than 8–11 mg daily. At this low dose, no adverse effects were observed with any of the gene variations. 

Limited efficacy for prevention 

The AREDS2 formula does not benefit individuals with early AMD or prevent its onset, despite its widespread use for this purpose.

Alternative Nutrients for Macular Health

The AREDS2 study has firmly established lutein and zeaxanthin as the key essential nutrients for supporting macular health.

However, due to the potential ocular and general health risks associated with other components of the AREDS2 formulation - namely vitamin C, vitamin E, and zinc - alternative nutrient combinations may offer a safer and more comprehensive approach to macular health support.

Vitamin B12 and Folate

Randomised trial data from the Women's Antioxidant and Folic Acid Cardiovascular Study demonstrated that long-term daily supplementation with vitamin B12, folate, and vitamin B6 (averaging 7.3 years) significantly reduced the risk of developing AMD by 35-40%.

The beneficial effect of treatment began to emerge at approximately 2 years of follow-up and persisted throughout the study duration. This trial provides evidence of actually preventing the onset of AMD, unlike the AREDS2 study. 

Ginkgo biloba

Ginkgo biloba leaf extract contains over 60 bioactive compounds, including a high concentration of flavonoids and terpenoids, which reduce blood viscosity, inhibit platelet aggregation and improve blood circulation. Studies suggest that ginkgo biloba can enhance retinal blood flow and improve visual acuity in dry AMD.

There has been concern regarding the potential bleeding risk with ginkgo biloba, but this is not supported by results from randomised clinical trials and meta-analyses.

Grape seed

Grape seed extract is the richest source of procyanidins, potent natural antioxidants that protect the retinal ganglion cells against oxidative damage.

Research has shown that the antioxidant activity of procyanidins is much greater than vitamins C and E (50 times greater than vitamin C and 20 times greater than vitamin E), potentially making procyanidins a superior alternative to traditional antioxidants found in the AREDS2 formula.

Saffron

Saffron, derived from the Crocus sativus flower, is increasingly recognised for its potential benefits in treating AMD.

Rich in carotenoids like crocin and crocetin, saffron has been shown to improve retinal function and enhance visual acuity and sensitivity in mild to moderate AMD, potentially slowing its progression.

The benefits of saffron extend to improving visual function in diabetic maculopathy.

The Way Forward for Macular Health

While the AREDS and AREDS2 formulations have significantly advanced our understanding of nutritional interventions for macular health, their potential side effects and risks must be acknowledged. 

By retaining the core nutrients lutein and zeaxanthin and incorporating additional nutrients such as ginkgo biloba, grape seed extract, methylcobalamin (active vitamin B12), and L-methylfolate (active folate), these shortcomings can be mitigated and potentially provide more comprehensive macular health support across all stages of AMD.

This is the basis of the Nutravision formula. It is designed to support macular health and optic nerve function over the long term, without the potential side effects associated with AREDS2.

Try Nutravision today - the safe, modern approach to support your vision and macular health with confidence.