Fierce Debate over Zeaxanthin Isomers

Of all the eye-health ingredients known to dietary supplement shoppers, none is more prominent today than lutein. SPINS ranks lutein as eye health’s top seller, citing double-digit, past-year gains of 13.1% and 16.7% in the natural and conventional channels, respectively. Somewhat lesser known is zeaxanthin, another key eye-health carotenoid. But, although consumers may not realize it, they’re already quite familiar with zeaxanthin. Most supplements that contain lutein also include zeaxanthin. Together, the two work hand in hand to protect the eye against oxidative stress and to help maintain macular pigment optical density (MPOD).

A healthy macular pigment is rich in lutein and zeaxanthin. In the macular pigment, lutein and zeaxanthin absorb harmful, high-energy (blue) light, thereby acting as a filter to protect the macula. Lutein is dominant in the periphery of the macula, helping you see in low-light conditions and reducing glare discomfort. Zeaxanthin primarily concentrates in the center of the macula where it helps with sharp central vision and contrast.

Researchers have invested a lot in lutein and zeaxanthin’s study. Most notably, of course, is the National Institutes for Health’s Aged-Related Eye Disease Study 2 (AREDS2), a 4203-patient, five-year phase 3 follow-up study on the ability of supplements to help slow or delay the progression of age-related macular degeneration (AMD), the leading cause of blindness. An AREDS2 subgroup experienced an 18% reduced risk of AMD progression when lutein and zeaxanthin were added to the original AREDS supplement formula of vitamins C and E, zinc, and copper (but minus the original formula’s beta-carotene). Perhaps even more telling of lutein and zeaxanthin’s effectiveness, subgroup subjects (1,055 eyes) with the lowest lutein and zeaxanthin intake (median 0.7 mg/day) had a significant, reduced risk of AMD progression of up to 26% following supplementation.

This subgroup may better represent the level of lutein and zeaxanthin intake in the U.S. population, says ingredients supplier Kemin (Des Moines, IA). AREDS2 used DSM Nutritional Products’ (Parsippany, NJ) OPTISHARP zeaxanthin, as well as Kemin’s FloraGLO lutein, which DSM formulates.

The body must get lutein and zeaxanthin from the diet or from supplementation. Unfortunately, “In the United States, the dietary intake of lutein and zeaxanthin is typically less than 1-2 mg/day. This amount is well below the 10 mg lutein and 2 mg zeaxanthin that the [AREDS2] study has proven to be effective,” Kemin says.

While AREDS2 results build on the positive support around lutein and zeaxanthin for eye health, a recent report out of France raised some questions about one zeaxanthin isomer.

The French Report

Two zeaxanthin stereoisomers are found in the macular pigment, along with lutein: the 3R,3’R isomer (also referred to as “RR-zeaxanthin”) and the 3R,3’S isomer (also called “meso-zeaxanthin”). A third, less-common isomer of zeaxanthin, 3S,3’S, also exists.

“Isomers are molecules with the same molecular formula but different chemical structure (same number of atoms of each element, but arranged differently in space),” explains Lynda Doyle, vice president, global marketing, for ingredients supplier OmniActive Health Technologies (Morristown, NJ). All of these zeaxanthin stereoisomers share the same number of double bonds and similar end rings; however, the direction of one hydroxyl group differentiates them. According to Doyle, “Most nutrients exist in nature and the diet as stereoisomers and are consumed as such and are safe-for example, proteins, amino acids, and sugars. One such example is alpha-lipoic acid, which is commercially available as a 50:50 racemic mix of the R and S isomers (RS).”

Tatania Emmick, technical service manager at Kemin, cautions, however, that “there are certain cases in which the differences between isomers can be 1) ineffective, 2) effective, but in different ways, or 3) toxic. So, that is why chirality really matters.”

In March 2014, French regulatory division the Directorate General of Competition, Consumer Affairs, and Fraud Prevention (DGCCRF) reported that at least 50% of eye-health dietary supplements on the French market that contain lutein and zeaxanthin are “contaminated with meso-zeaxanthin, an unevaluated isomer of zeaxanthin.”

Meso-zeaxanthin is not an authorized dietary ingredient in the European Union because it does not currently have Novel Food approval. (EU Regulation No. 258/97 states that any food not consumed to a significant degree in the EU prior to May 1997 cannot enter the market without first getting Novel Food approved.)

DGCCRF began investigating eye-health supplements-in part as requested by one trade group, the Zeaxanthin Trade Association-following at least 40 reports of adverse events after consumers took eye-health supplements. These events included adverse skin effects or, as DGCCRF stated in its report, “10 reported undesirable cutaneous side effects that were manifested as ‘toxidermia,’ including eight that were allegedly linked to the consumption of four products containing lutein and zeaxanthin.” The adverse events stemmed from products manufactured by various companies, the report added.

French agents subsequently inspected 27 lutein/zeaxanthin finished-products on the French market and found that 14 of them (50%) contained meso-zeaxanthin. They also conducted site inspections of ingredient suppliers, manufacturers, and retailers.

Although the French report initially associated meso-zeaxanthin with adverse side effects, not everyone is convinced there is a link. “Lutein, RR-zeaxanthin, and meso-zeaxanthin were not the only ingredients in the formulations that reportedly caused toxidermia,” Doyle points out. “Have the authorities reviewed the complete ingredient profile and allergenic potential of the products?” If not, she says, it’s hard to definitely attribute adverse effects to any of these three macular carotenoids, “all of which have such strong safety records.”

Doyle adds that “hundreds of supplements around the world containing varying levels of lutein, RR-zeaxanthin, and meso-zeaxanthin have been on the market for some time, with no reported adverse events” and that, to date, there are no adverse events reported in research studies involving meso-zeaxanthin.

Since its initial report in March, DGCCRF followed up with a statement in May saying that the origin of the reported adverse events remains unclear (DGCCRF is uncertain which molecules in the finished-product formulations were responsible for the adverse effects). Still, it reported that the number of adverse-event reports decreased since the investigation began and DGCCRF contacted the supplement manufacturers in question-many of whom DGCCRF initially reported “either modified their formulas or halted distribution” of their products.

Zeaxanthin Isomers

Meso-zeaxanthin may be under fire in France and may lack Novel Food clearance in the EU, but, in the United States, FDA acknowledged a Generally Recognized as Safe (GRAS) notification for an eye-health ingredient that includes meso-zeaxanthin. In 2011, the agency acknowledged OmniActive’s GRAS notification for Lutemax 2020, which contains lutein, RR-zeaxanthin, and meso-zeaxanthin.

FDA’s GRAS database also shows another, pending meso-zeaxanthin submission, dated August 5, 2013, for a “meso-zeaxanthin rich extract” powder called Hi-Fil Z from Mexico-based carotenoid supplier Industrial Organica S.A. de C.V.

Critics on both sides fiercely argue over the value of meso-zeaxanthin supplementation for eye health, especially when comparing meso-zeaxanthin to RR-zeaxanthin.

RR-zeaxanthin­-also often referred to simply as zeaxanthin-is inarguably the most studied zeaxanthin isomer for eye health. It is GRAS affirmed in the United States. Humans obtain the RR-isomer from foods such as dark green leafy vegetables or yellowy-red fruits and vegetables, as well as egg yolk. In the ingredients market, RR-zeaxanthin’s main commercial sources are marigolds (Tagetes erecta)-which is also the commercial source of lutein-or paprika (Capsicum annuum).

Eye-health ingredient suppliers Kemin and OmniActive each have exclusive distribution deals for RR-zeaxanthin. Kemin’s ZeaONE zeaxanthin stems from the company’s exclusive right to a patented, zeaxanthin-rich marigold plant from Chrysantis (Chicago)/Ball Horticultural Corp. (Chicago).¹ OmniActive’s OmniXan zeaxanthin is licensed from Kalsec (Kalamazoo, MI) and comes from pepper/paprika.

A third source of RR-zeaxanthin is chemical synthesis. This is how DSM creates its OPTISHARP synthetic, nature-identical RR-zeaxanthin. FDA had no objections to a New Dietary Ingredient notification for OPTISHARP, which also has self-affirmed GRAS status in the United States as well as Novel Food approval in the EU.

Regardless of whether the RR-isomer is obtained from “natural” sources (marigold or paprika) or is synthesized, “All of the science to date tells you that if you ingest zeaxanthin [RR-zeaxanthin] via supplementation, it’s going to get where it needs to be in the eye, just as it would if you got it from eating food,” says Kemin’s Emmick.

Meso-Zeaxanthin Sources

Some say meso-zeaxanthin also comes from the diet, although the foods that contain meso-zeaxanthin are not eaten as frequently as those that contain RR-zeaxanthin. According to Doyle, meso-zeaxanthin is found in the skin of 21 fish species (including rainbow trout and salmon), shrimp shells, and the fat of sea turtles. In Mexico, meso-zeaxanthin is added to chicken feed in order to enhance the yellow-orange color of egg yolk.^2,3,4

But opinions differ on whether meso-zeaxanthin can be obtained from the diet in amounts significant enough to translate to a presence in the macula.

In a 2012 Journal of Food Composition and Analysis (JFCA) study⁵, researchers looked to quantify the meso-zeaxanthin in fish and seafood and in eggs in the United States (California, Illinois, and Massachusetts) and Mexico. The JCFA-study authors stated that their purpose was to follow up on a 1986 study² by another group of researchers who said meso-zeaxanthin is found in shrimp, fish, and turtles.

The JFCA-study authors said they found no presence of lutein, zeaxanthin, or meso-zeaxanthin in fish and seafood. They did find a small amount of meso-zeaxanthin (0.01 mg/100 g yolk) in a single egg from California, and found a slightly higher ratio of lutein: zeaxanthin: meso-zeaxanthin (1:1:1.3) in eggs from Mexico. They concluded, “In the U.S., the presence of [meso-zeaxanthin] in the macula is not likely due to dietary sources, although this is a possibility when consuming eggs of chickens fed [meso-zeaxanthin].”

According to Kemin, one of the JCFA-study’s authors, Elizabeth Johnson, PhD, of Tufts University’s Jean Mayer USDA Human Nutrition Research Center on Aging, further stated the following in March 2014, based on her ongoing research. In terms of meso-zeaxanthin in salmon, she said, “[W]e only found meso-zeaxanthin detected in salmon skin-that is the only place-in the amount of 0.02 parts per million. To give you an idea of how much that is, if we look at AREDS2, they gave 2 mg of zeaxanthin. You would have to eat…200 lb of salmon skin to get 2 mg of meso-zeaxanthin. I would not consider this a dietary source of macular pigment.”

According to Kemin, Johnson also said that, although the researchers found a small amount of meso-zeaxanthin in the single California egg, “I think…you would have to eat 40 lb of egg yolk to get your 2 mg of meso-zeaxanthin-again, not really to be considered a dietary source.” Regarding the eggs from Mexico, she said, “[W]e found a whopping dose of meso-zeaxanthin,” but, she added, “the reason it is there is not a natural source but a supplemented source. Bottom line is you do not find meso-zeaxanthin in the diet.”

But John M. Nolan, PhD, of the Macular Pigment Research Group at the Waterford Institute of Technology, rebutted the JCFA-study findings, stating in the journal Eye⁶ that the JCFA-study researchers failed to saponify their samples, which he alleges would have “freed” esterified carotenoids in the foods; thus, he says, the researchers underestimated the presence of meso-zeaxanthin.

James Stringham, PhD, a research professor at the Nutritional Neuroscience Laboratory at the University of Georgia, asserts that meso-zeaxanthin does exist in the diet.  ”Although food sources of meso-zeaxanthin are rare (fish skin, shrimp carapace, and turtle fat), they do exist and have been consumed by humans for millennia. In sum, although meso-zeaxanthin might appear to be a novel, perhaps artificial, nutrient, the overwhelming scientific evidence on the matter suggests that it is most certainly not; rather, it has existed for a long time and is actively used by the body to promote health.”

Aside from the dietary-source debate, another place that meso-zeaxanthin may come from is marigolds, as a result of lutein processing. Meso-zeaxanthin can typically occur when lutein esters are converted into a non-esterified form (“free form”). As Doyle explains, “Trace amounts of meso-zeaxanthin are formed during the standard saponification process of converting lutein esters to its free form-a process used by most commercial lutein manufacturers.” According to Doyle, because of this, commercial marigold-derived lutein and RR-zeaxanthin ingredients may contain trace amounts of meso-zeaxanthin.

Specifying Isomers

The DGCCRF report stated that some ingredient suppliers simply sell their ingredients by the general name zeaxanthin, without specifying which zeaxanthin isomers the ingredient contains. The report said that some companies might use marigold-derived meso-zeaxanthin in place of “zeaxanthin”-purportedly RR-zeaxanthin-when trying to achieve the 5:1 ratio (10 mg lutein: 2 mg zeaxanthin) that most studies support for eye health, because meso-zeaxanthin is less expensive. In the EU, not specifying the presence of meso-zeaxanthin is a problem if companies then sell products with meso-zeaxanthin, which isn’t Novel Food approved.

“Having a mixture of meso-zeaxanthin and zeaxanthin [RR-zeaxanthin] in your product is less expensive than doing the due diligence to make sure it is 100% zeaxanthin [RR-zeaxanthin],” says Heather Richardson, Kemin’s FloraGLO lutein and ZeaONE zeaxanthin marketing manager.

In fact, converting lutein to meso-zeaxanthin is even less expensive than synthesizing an RR-isomer like DSM’s OPTISHARP zeaxanthin, confirms Kathy Maurer, DSM’s senior marketing manager in charge of the firm’s eye-nutrition portfolio.

If ingredient suppliers deliberately substitute meso-zeaxanthin in place of RR-zeaxanthin, without specifying that an ingredient includes both isomers, that’s not okay, all three suppliers say.

Kemin’s website states that meso-zeaxanthin “is not a suitable replacement” for RR-zeaxanthin.

OmniActive’s Doyle agrees, and moreover says, “Meso-zeaxanthin should not be considered a substitute for RR-zeaxanthin, nor should RR-zeaxanthin be considered a substitute for meso-zeaxanthin.”

“This should not be a competition between meso-zeaxanthin and RR-zeaxanthin, as some seem to think,” she continues. “It’s simple: the eye needs both isomers, with lutein, for optimal protection and function.”

But whether or not supplementation with meso-zeaxanthin is in fact beneficial to eye health is hotly debated. Some contend that research is still lacking to demonstrate this.

Supplementation Science Still Emerging

DSM and Kemin’s stance is generally that the current evidence is weak on the eye-health efficacy of meso-zeaxanthin supplementation. “Meso-zeaxanthin has not been studied by itself,“ says Richardson. “There are only eight very small human supplementation trials that have been conducted with meso-zeaxanthin, all by the same investigators, but those studies included meso-zeaxanthin in addition to lutein and zeaxanthin [RR-zeaxanthin],” she says, so one can’t pinpoint which benefits came solely from meso-zeaxanthin. “Really, the science is around lutein and zeaxanthin [RR-zeaxanthin].”

Richardson explains that research on supplementation with RR-zeaxanthin is much more robust. “There has been 30 years of study of zeaxanthin [RR-zeaxanthin] and lutein, which include thousands of subjects and was conducted by multiple investigators at different sites around the world, versus eight years of study for meso-zeaxanthin. We have a lot to learn. Moreover, there are over 100 published human clinical studies on zeaxanthin [RR-zeaxanthin] and lutein, 64 of those specifically with FloraGLO brand lutein, versus eight published human clinical trials with meso-zeaxanthin, which was not studied by itself but in combination with dietary lutein and zeaxanthin [RR-zeaxanthin].” DSM’s OPTISHARP RR-zeaxanthin has been studied alone in supplementation, for instance.⁷

But OmniActive’s Doyle contends that studies on RR-zeaxanthin and lutein have also included meso-zeaxanthin as a trace ingredient because it is naturally found in free lutein and RR-zeaxanthin made from marigolds. Although difficult to measure and not typically tested, she says, “Lutein studies invariably had RR-zeaxanthin and some traces of meso-zeaxanthin, as all commercial lutein contains [traces of] RR-zeaxanthin and meso-zeaxanthin. Commercial lutein from virtually any source can sometimes show trace amounts of meso-zeaxanthin if chiral [high-performance liquid chromatography/HPLC] analysis is performed” to detect it. The authors of a 2012 British Journal of Nutrition study⁸, for instance, found a trace amount of meso-zeaxanthin (0.3 mg out of 24.74 mg total carotenoids) in each capsule of Nature’s Plus’s Ultra Lutein supplement, which contained FloraGLO lutein and zeaxanthin.

Doyle futher says that if meso-zeaxanthin has been present in lutein and RR-zeaxanthin studies, “As such, whether as dietary intake, its own supplementation, or part of lutein and RR-zeaxanthin supplementation, meso-zeaxanthin has already been part of studies investigating the nutrition impact on visual performance and AMD risk reduction.”

Regarding OPTISHARP’s nature-identical RR-zeaxanthin, though, Maurer says, “If meso-zeaxanthin is present in OPTISHARP, it is at minimal levels. [It] is an artifact of the manufacturing process and is considered an impurity rather than a nutritional ingredient or component of zeaxanthin [RR-zeaxanthin].”

Emmick maintains that if meso-zeaxanthin is in fact present only at trace levels in studies also including lutein and RR-zeaxanthin, those trace levels aren’t substantial enough to determine, from those trials, meso-zeaxanthin’s efficacy or even safety. “Safety and efficacy cannot be inferred for impurities [of meso-zeaxanthin] that are inadvertently in food at uncertain, de minimis levels.”

And, regarding the aforementioned British Journal of Nutrition Study⁸, which found traces of meso-zeaxanthin, Kemin and OmniActive underline different takeaways. Kemin points out that the study tested all three carotenoids in combination (lutein, meso-zeaxanthin, and RR-zeaxanthin), so it’s doubtful one can isolate any beneficial effects found in the study to a specific ingredient. Emmick also says the study indicated that supplemental meso-zeaxanthin is not as well absorbed by the body as a RR-zeaxanthin supplement is. “In fact, you can give someone significantly more meso-zeaxanthin than zeaxanthin [RR-zeaxanthin] and hardly any of it goes into the bloodstream,” she says.

But Doyle contends that the same study⁸ nevertheless showed meso-zeaxanthin is absorbed and present in blood serum following supplementation. She also points to a study published in Current Eye Research⁹ in which researchers found an increase in both meso-zeaxanthin and lutein (but a higher increase for lutein) following supplementation with a formulation containing meso-zeaxanthin, RR-zeaxanthin, and lutein. Again, however, the researchers did not definitely isolate and attribute the serum increase in meso-zeaxanthin solely to meso-zeaxanthin supplementation alone.

According to Kemin’s Emmick, the bottom line is that the value of meso-zeaxanthin supplementation is still not proven.

“To date, there is no evidence that we should be supplementing with meso-zeaxanthin or any of the stereoisomers. That connection has not been made,” she says.

Ophthalmologist Jodi Luchs, MD, FACS, founder and CEO of the OJO “fortified eye care nectar” eye-health liquid supplement, agrees. “While it may have similar antioxidant and protective effects, the jury is still on out whether supplementation [with meso-zeaxanthin] is helpful.” The larger body of research on RR-zeaxanthin, by comparison, already shows improvements in visual acuity, reduced glare sensitivity, reduced visual fatigue, and increased photo-stress recovery, among other effects.

Doyle maintains that meso-zeaxanthin plays its own, unique role in the eye and that, like RR-zeaxanthin, meso-zeaxanthin is a “potent antioxidant” and a “critical macular carotenoid.” Meso-zeaxanthin, in fact, is a stronger antioxidant than lutein and RR-zeaxanthin when combined with Z-binding protein, Doyle says, citing an in vitro study.¹⁰ (Kemin’s Emmick cautions that this study is in vitro, and not in vivo, and that in vitro results cannot be correlated with effects in humans.)

Doyle says that because meso-zeaxanthin is the stronger antioxidant-although RR-zeaxanthin and lutein are present in the eye in greater amounts-“it’s not surprising, then, that meso-zeaxanthin is primarily concentrated in the very center of the macula, the focal point of vision and where the tissue suffers the most antioxidant stress, compared to RR-zeaxanthin, which is primarily concentrated in the mid-periphery of the macula.”¹¹

Because lutein, RR-zeaxanthin, and meso-zeaxanthin all absorb blue light, OmniActive advises supplementing with all three carotenoids, which is what Lutemax 2020 provides. Doyle calls this “the most failsafe approach to meet the needs of today’s population.”

She cites several in vitro studies, including one published in the Archives of Biochemistry and Biophysics¹², that she says show “it is the combination of the three macular carotenoids-lutein, RR-zeaxanthin, and meso-zeaxanthin-that provides optimal protection and support to the eye. Research suggests that all three macular carotenoids work better together than individually to protect the eye against oxidative damage and filter high-energy blue light.”

Jeffrey Anshel, OD, FAAO, president of the Ocular Nutrition Society, supports OmniActive’s position. “Lutein and the zeaxanthin isomers (RR-zeaxanthin and meso-zeaxanthin)…individually and in combination play a critical role in ocular health. Because of the presence and placement of each of these carotenoids in the eye tissue, we should not underplay the importance of any one of these three macular pigments.” In an article in the magazine Optometry Today¹³, John Nolan, quoted earlier, discussed a meso-zeaxanthin–containing supplement in the UK called Macushield and said “when meso-zeaxanthin is included in the formulation, the response is far greater than what you would get with a lutein-only supplement…”

Regarding meso-zeaxanthin’s research infancy, Doyle says, “Certainly, there are more studies on RR-zeaxanthin specifically, but like meso-zeaxanthin, most are in combination with either lutein or other antioxidants.”

She adds, “It wasn’t that long ago that RR-zeaxanthin was approved for use in European countries. When RR-zeaxanthin first became commercially available, some raised questions about the need for RR-zeaxanthin, since RR-zeaxanthin is naturally present in lutein at approximately 5%. It has since been established through research that higher levels than those found naturally in lutein show benefit. We are now at this point with meso-zeaxanthin.”

According to Doyle, when it comes to meso-zeaxanthin, “The bottom line is that it’s in the diet, it’s safe, and it plays a functional role in eye health alongside RR-zeaxanthin and lutein. If the ingredient can be made available for its benefit, commercial interests shouldn’t block such innovation.”

Manufacturer Options

Given these disparate opinions, supplement manufacturers have a lot of deciding to do when it comes to selecting a zeaxanthin ingredient. Synthetic source or natural? RR-zeaxanthin alone, or meso-zeaxanthin, as well?

The decision comes down to a company’s preference and evaluation of the science. “It really depends on the customer,” says DSM’s Maurer. “Some customers want natural zeaxanthin; some want synthetic. It really just depends on the customer’s needs.”

Kemin’s Richardson agrees. “If the customer prefers a natural source versus a synthetic, then that’s what we want to provide them.” She says DSM and Kemin each offer “a single form of zeaxanthin that can be used in both markets [EU and U.S.], without regulatory concerns.”

OmniActive says its goal is to offer a broad range of ingredients to meet every customer’s need. For markets like the United States, OmniActive can supply Lutemax 2020 with lutein, RR-zeaxanthin, and meso-zeaxanthin. For markets like France where meso-zeaxanthin isn’t currently allowed, OmniActive also offers Lutemax 2020-RR, which contains lutein and only RR-zeaxanthin-no meso-zeaxanthin. And, the company’s OmniXan zeaxanthin is solely RR-zeaxanthin.

Labeling and Transparency

As the DGCCRF report stated, one of the biggest problems is that ingredient suppliers may not disclose whether their zeaxanthin ingredients contain meso-zeaxanthin; they may just call their ingredient generally zeaxanthin. “A genuine lack of transparency exists as to the nature of the preparations of plants that are used in the products and the concentrations of lutein and zeaxanthin that are found in them,” the report said. In the EU, this is a problem, of course, due to meso-zeaxanthin’s prohibited use in commerce. But, even in the United States where meso-zeaxanthin is allowed, ingredient transparency is still a good idea.

“Labeling laws in the United States require all dietary ingredients to be present on the supplement label,” Richardson says. “It’s misleading to label products as zeaxanthin when they in fact contain a mixture of zeaxanthin and meso-zeaxanthin.” To do so, she says, would be “misbranding.”

Yet, more often these days, zeaxanthin “mixtures” are creeping onto the market, without proper disclosure of the isomers present. And, Emmick says, it can “run the gamut.” Some companies may be “misleading, saying that it’s zeaxanthin alone. And then I think there are a lot of other, smaller, no-name suppliers” who are also not disclosing the full makeup of their ingredients, she says. “I’ve seen anywhere from an ingredient that is almost entirely meso-zeaxanthin, to a 50/50 mixture,” she says, adding that these ingredients are usually sold at a cheaper price.

Labeling vagueness is a growing problem, Richardson says-”in fact, maybe more so than we realized. The rising occurrence of mislabeling is coming to light now, which is what we saw in the published French report and now in the U.S. market.”

As mentioned, DGCCRF said most of the manufacturers questioned over their meso-zeaxanthin products were given a chance to reformulate or stop distributing product, and that the adverse events have since declined. The agency took a much harder stance against ingredient suppliers, however-even levying criminal charges. DGCCRF stated that “[T]he suppliers of the extracts […] are obligated to conduct their own quality-control inspections for the manufacturing process and all of their production activities.”

“It’s definitely the responsibility of suppliers to know what they’re selling and to accurately inform their customers,” Emmick says.

“Manufacturers should be confirming the identity of ingredients they use,” Richardson agrees. “There are tests available to distinguish between meso-zeaxanthin and the dietary form [RR-zeaxanthin]”-namely, the aforementioned chiral HPLC analysis. She quotes the DGCCRF report, which said, “nothing exists that might prevent manufacturers of extracts, who also produce dietary supplements, from performing these trials.”

Doyle says that OmniActive makes very clear from the start what its ingredients include. It has always said that Lutemax 2020 includes all three carotenoids: meso-zeaxanthin, RR-zeaxanthin, and lutein. “OmniActive always characterizes the active components of our products,” she says. “Our products that do contain more than one zeaxanthin isomer are clearly labeled to provide full disclosure to our customers.”

Ingredient suppliers need to comply with regulations, she stresses. Regarding meso-zeaxanthin, she maintains, “There are no safety concerns for the consumer in this instance. However, if the lack of transparency were to involve a harmful substance, this would be a completely different story.”

Richardson says the DGCCRF report may inspire other countries to look into the issue of isomers and labeling transparency-if they haven’t already started to. “We do understand that other EU countries are looking into this after the French authorities issued this report.”

The Consumer in Sight

At the end of the day, it’s consumers who deserve to know what they’re buying. “The consumer believes that he or she is getting one ingredient [...] when in fact he or she is getting a different ingredient, or a mixture of isomers without the same level of government authorization, research, and use,” Richardson says. “It’s a truth-in-labeling issue.”

Doyle agrees that “consumers need to have confidence in the supplements they purchase.”

“I think what’s important to bring home is that vitamin manufacturers may just assume that zeaxanthin is zeaxanthin, no matter if they are getting it from marigolds or paprika, or wolfberry, or if it’s synthetic-as long as it’s the same molecule, they assume they are comparing apples to apples,” Richardson says. “But we need to remember that every ingredient supplier has a different manufacturing process, and zeaxanthin ingredients at the end of the day are not all the same.”

“What is important for vitamin manufacturers to look for when sourcing zeaxanthin or lutein is the clinical evidence that proves that this particular ingredient gets absorbed in the body, gets to the eye like it’s supposed to, and increases macular pigment and benefits for eye health,” she concludes.

Increased vigilance is even more crucial as the eye-health supplement market grows. Market researcher Euromonitor predicts that global retail sales for eye-health supplements will grow from US $1.2 billion in 2013 to $1.5 billion by 2017-and from $413 million to $687 million between 2013–2017 in the United States alone. Supplement manufacturers cannot afford to make ingredient choices blindly. They must consider all opinions, study the science, and weigh the evidence themselves.  

References
1. U.S. Patent Nos. 6,784,351, 7,575,766 and 7,033,622. ZeaONE is also licensed under ZeaVision LLC’s Patent Nos. 7,691,406 and RE 38,009 (“Zeaxanthin Formulations for Human Ingestion”).

2. Maoka T et al., “The first isolation of enantiomeric and meso-zeaxanthin in nature,” Comparative Biochemistry and Physiology, vol. 83, no. 1 (1986): 121-124.

3. Schiedt K et al., “Metabolites of astaxanthin and canthaxanthin in the skin of Atlantic salmon (Salmo salar, L.),”Helvetica Chimica Acta, vol. 71 (1988): 887-896.

4. Bone RA et al., “Macular pigment response to a supplement containing meso-zeaxanthin, lutein and zeaxanthin,” Nutrition & Metabolism, May 11, 2007.

5. Rasmussen HM et al., “Lutein, zeaxanthin, meso-zeaxanthin content in egg yolk and their absence from fish and seafood,” Journal of Food Composition and Analysis, vol. 27, no. 2 (September 2012): 139-144.

6. Nolan JM et al., “What is meso-zeaxanthin and where does it come from?” Eye (vol. 27, no. 8 (August 2013): 899-905.

7. Schalch et al., “Xanthophyll accumulation in the human retina during supplementation with lutein or zeaxanthin - the LUXEA (LUtein Xanthophyll Eye Accumulation) study,” Archives of Biochemistry and Biophysics, vol. 458, no. 2 (February 15, 2007): 128-135.

8. Meagher KA et al., “Serum response to supplemental macular carotenoids in subjects with and without age-related macular degeneration,” British Journal of Nutrition, vol. 110, no. 2 (July 28, 2013): 289-300.

9. Connolly EE et al., “Augmentation of macular pigment following supplementation with all three macular carotenoids: an exploratory study,” Current Eye Research, vol. 35, no. 4 (April 2010): 335-351.

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Sidebar: Zeaxanthin Esters versus Non-Esters

Stereoisomer talk is crucial when it comes to zeaxanthin, but so is a discussion of whether a zeaxanthin ingredient is an ester or a non-ester. The companies interviewed for this story-DSM Nutritional Products, Kemin, and OmniActive Health Technologies-say that their dietary 3R,3’R zeaxanthin ingredients are non-esters-meaning that they are non-esterified or what’s known as “free form” zeaxanthin.

The body directly absorbs non-esterified molecules. By contrast, the body must first convert-“de-esterify”-esters into the free form before it can absorb them in the blood stream. The concept of de-esterification is important because there is some evidence-albeit, not yet a lot-that de-esterification, or molecule cleaving, may slow with age or other factors. This would imply that as a person ages and the cleaving process slows, the body may not convert esters with the same efficiency as before, subsequently preventing nutrient absorption.

According to Heather Richardson, Kemin’s marketing manager, 93% of zeaxanthin and lutein obtained from the diet is in the free form, or non-esterified. “This is what the body prefers,” she says.

But suppliers may supply either form-either esters or free form. Even a zeaxanthin ingredient that comes from the same source, such as marigolds, can be esters or non-esters, depending on the supplier, Richardson adds.

Cost often plays a role. “The ester form is cheaper because there’s an extra processing step in manufacturing that’s required to go from an ester to a free form,” says Richardson.

Yet, just as some suppliers may call their ingredient “zeaxanthin,” without specifying whether it contains both dietary zeaxanthin and meso-zeaxanthin, suppliers may likewise provide a zeaxanthin mixture that contains both esters and non-esters-without disclosing this fact, she adds.

Knowing whether an ingredient is an ester or not is important because, Richardson says, the ester form is “not well studied.”

“A lot of the clinical studies that are out there showing improvement in visual performance are on this free form of zeaxanthin, the dietary free form. It’s this free form, not the ester, that is clinically proven,” she says.

Lynda Doyle, OmniActive’s vice president of global marketing, agrees that “The bulk of human clinicals is on free-form” zeaxanthin.

Tatania Emmick, Kemin’s technical service manager, says that there are only absorption studies, not efficacy studies, on the ester form. “To my knowledge, the only study with paprika esters was simply a serum absorption study, and that showed that the ester form does not make it into the serum. But I have not seen any efficacy study as far as benefits to the eye, or anything along those lines, with the esterified forms.”

Jennifer Grebow
Editor-in-Chief
Nutritional Outlook magazine
jennifer.grebow@ubm.com

Correction 6/30/14 2:00 pm PST:

"The authors of a 2012 British Journal of Nutrition study⁸, for instance, found a trace amount of meso-zeaxanthin (0.3 mg out of 22.74 mg total carotenoids) in each capsule of Nature’s Plus’s Ultra Lutein supplement, which contained FloraGLO lutein and zeaxanthin..." The correct measurement should be "...(0.3 mg out of 24.74 mg total carotenoids)..."

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