The robust cognitive health segment of the nutraceuticals industry is fueled by continued intrigue into the role that natural ingredients and dietary patterns can play in performing one’s best. For athletes, people in academia, or people in demanding work environments, gaining an edge in focus, decision-making, mood, and stress management is highly appealing. Older people, many of whom are working well into their golden years, are considering the role that nutrition can play in preserving their acuity and maintaining resilience against age-related cognitive decline.

“Interest in cognitive health has grown steadily over the last decade,” said Sébastien Bornet, vice president of global sales and marketing at Horphag Research. “That interest is rooted in being proactive—take care of your cognitive health earlier in life for better performance throughout your life. Successful product differentiation and marketing strategies heavily rely on how the science behind the ingredient is communicated to consumers.”

Today, while some consumers are looking for short-term, performance-based active ingredients, others are looking for permanent fixtures in their diet that promise dividends in cognitive health years down the road. As research advances, and mainstream interest in cognitive health benefits grows, brands will differentiate products to apply to a range of applications. At the same time, many consumers understand that various facets of health are tied to cognitive health, such as sports performance, weight management, cardiovascular health, mood, sleep, and more.

“In recent years, the cognitive support supplement market has transformed from a specific target category to a large, holistic concept that involves complex interlinked issues such as stress, anxiety, sleep, relaxation, fatigue, and memory,” said Aditya Kulkarni, overseas business development manager at Pharma Foods International. “Today, consumers are becoming increasingly aware of how these factors are interlinked and affect one’s overall cognitive health.”

While the dietary supplements market is beginning to see sales normalize following a boom associated with the COVID-19 pandemic, data technology company SPINS noted that cognitive health supplements have rapidly ascended in sales for the 52-week period ending in September 2021. The company reported that condition-specific cognitive supplements have increased 67% over the past year, bringing in an estimated $345.9 million in sales, while general health supplements with cognitive health claims have risen 59% to $386.2 million.

According to SPINS, ongoing effects of the pandemic are still contributing to feelings of distractibility and brain fog. Nootropics (an industry term for performance-based cognitive health ingredients) have been on the rise, especially in shelf-stable beverages compared to more conventional, condition-specific supplement formats.

Ingredients seeing healthy sales increases include certain neurochemicals or precursors to neurotransmitters; and there has been a groundswell of popularity for herbs and botanicals. Some star ingredients in the category include valerian (up 106%), phosphatidylserine (up 105%), Bacopa monnieri (up 98%), and DMAE (up 77%), SPINS reported.

The cognitive health category is diversifying at a faster rate than the overall supplements market. Product development is branching out from the central focus of stimulation that the category was known for in the past, according to Laurentia Guesman, business manager for food and supplement ingredients at AIDP.

“The cognition space has evolved to support focus, calm, sleep, and memory, which appeals to a broader audience,” she said. “Inevitably, the brain changes as we age. Even children can experience cognitive-related difficulties such as ADHD or learning disabilities. However, what we are now learning is that the brain is capable of slowing the rate of decline through a variety of life choices, whether it be through diet, clinically-supported supplements, brain exercises, or exercise in general. This is an exciting new frontier for science.”

Certain qualities are universally appealing to consumers in this category, noted Maria Stanieich, marketing manager for Kyowa Hakko USA, such as clean label functionality. The company’s citicoline ingredient, Cognizin, which is featured in 200 products, is made via a fermentation process rather than chemical synthesis, is vegetarian, allergen-free, and Generally Recognized As Safe (GRAS)—all important boxes to check with consumers seeking easy-to-understand, natural ingredients, she said.

For some ingredients, overarching clean-label concerns make transparency essential. “Bacopa has been used for centuries,” noted Kristen Marshall, digital marketing manager at Verdure Sciences. “Plagued by clean label concerns, bacopa has robust offerings backed by traditional use and modern clinical evidence. Thus, a reliable ingredient and supply chain are of paramount concern when choosing a bacopa extract. Bacognize is not only backed by clinical support in numerous demographics/ages, but is also supported by rigorous supply chain mitigation and quality assurance.”

Research Targets & Trends
Research in the cognitive health market comes with a unique set of challenges. Scientific understanding about how diet and nutrition impact lifelong cognition is still in its nascent stages.

“There are some relationships that scientists are trying to correlate between brain/body biomarkers and cognitive function,” said Sid Shastri, director of marketing for Kaneka Probiotics. “However, they are not as well-established as, say, correlating blood lipids and cardiovascular health.”

AIDP’s investments in research have confirmed that its magnesium L-threonate ingredient, Magtein, is the most effective form of magnesium at crossing the blood-brain barrier, Guesman said.

Highlighting mechanisms of action for citicoline, which offers benefits for energy, memory, focus, and attention, has been especially important to the success of Kyowa Hakko’s Cognizin, according to Stanieich. “Cognizin facilitates membrane fluidity and plasticity, fortifies cell membrane structures, and enhances neuron communication.”

Further, research on proprietary ingredients can establish a credible reputation, she added. “Consumers are seeking out branded ingredients because of their trust in the efficacy and safety of those ingredients. Studies that contribute to a growing body of evidence that demonstrates clear value to cognitive function will continue to attract a consumer.”

PharmaGABA research has expanded upon GABA’s connection to not just stress, fatigue, and anxiety, but also relaxation and sleep quality as well as global cognitive function. “All of these functionalities of PharmaGABA are supported by scientific research and published in peer-reviewed journals,” said Kulkarni.

Specifically, clinical trials on PharmaGABA supplementation have studied global test batteries of cognitive function, memory, and sleep quality, as well as biomarkers of stress such as heart rate, hormonal changes, and inflammatory cytokines.

Especially in the role of developmental nutrition, research is still making leaps and bounds on core nutrients. “Choline’s role in brain health has been known for a long time, given that it is a building block for the neurotransmitter acetylcholine,” said Tom Druke, marketing director for VitaCholine at Balchem Corporation. “One of the most significant research developments in recent years took place at Cornell University, where Dr. Marie Caudill was exploring the impact of supplemental choline during pregnancy (Caudill et al., 2017). Moms participating in the randomized controlled trial study received dietary choline and supplemental VitaCholine at a total dose of either 480 mg for the control group and 930 mg for the test group. Initial findings suggested benefits to mom and baby related to DHA delivery, placental function, and lowered cortisol levels. Subsequent research has shown that the children born to the moms who received higher choline levels had significantly faster cognitive processing speeds as infants (Boeke, et al., Amer. Journal of Epidemiology), an improvement that researchers believe could have enduring benefits for lifelong cognition.”

At Vitafoods Europe 2021, held in Geneva, Switzerland, Louise Dye, a psychologist and researcher at the University of Leeds, pointed out a number of best practices and key considerations for those investigating the role that food can have in the cognitive health space across life’s stages.

“Measuring cognitive function in a laboratory on a day-by-day basis is highly variable, and we need to think about highly sensitive measures as a means of evaluating cognitive function,” Dye said. “Valid, reliable, sensitive measurements of cognitive function with specificity are needed, and people can’t be able to improve on these tests based on repetitive performance. Tests also need to be appropriate for the sample population.”

Establishing credibility is no small undertaking in these studies, she added. “Studies like these need to be long-term, and there’s a risk of losing participants due to dropouts or a lack of adherence over a long time. There’s also a good deal of mistrust when it comes to industry-supported health research. We need very strong evidence that stands up to scrutiny and there is a hierarchy of acceptability when it comes to analysis.” 

There is heightened scrutiny coming from both the industry and regulators in the cognitive health space, Bornet said.

When it comes to establishing versatility of an ingredient, researching a variety of age groups is a great place to start, he added. Pycnogenol, a proprietary extract of French maritime pine bark, has been shown over 40 years to exert strong antioxidant effects and benefits to cardiovascular health. Throughout over 160 clinical trials involving more than 12,000 patients it has been associated with a host of cognitive health benefits at a variety of ages. A 2018 study (Lamm et al., Minerva Medica), found the ingredient helped improve mild cognitive impairment, with an 18% average improvement on Mini-Mental State Examination scores. Two studies in 2015 found that Pycnogenol improved attention span, decision making, memory, and overall cognitive function in people over the age of 55 (Belcaro et al., Journal of Neurosurgical Sciences) and improved overall cognitive function in the workplace in people between the ages of 35 and 55. Lastly, a study published in 2011 showed Pycnogenol improved memory and test scores in college students (Luzzi et al., Panminerva Medica, 2011).

A wide range of cognitive tests can help establish an ingredient is versatile across different applications, said Marshall. For example, researchers have linked Verdure’s Bacopa monnieri ingredient, Bacognize, to significant benefits across 15 unique cognitive testing batteries. While biomarkers alone are good preliminary details, “clinical substantiation should encompass a mechanistic understanding, such as Bacognize’s ability to modulate serotonergic pathways, in addition to repeatable efficacy studies. In the case of Bacognize, we also looked at stress hormone biomarkers as additional supporting evidence as a response to psychological stress. This allows for repeatable evidence in addition to more subjective markers for a robust understanding of the outcomes and tangible benefits.”

Innovation in areas of mechanistic research are also important, Marshall added. In addition to utilizing Lipinski’s Rule of Five to establish blood-brain barrier permeability for its curcumin ingredient Longvida, researchers were able to use a non-invasive approach to detect and monitor retinal amyloid deposits (Koronyo Y et al., 2017), a first-of-its-kind approach to curcumin bioavailability assessment.

Research is trending toward trying to establish short-term benefits for the sought-after “experiential effect,” according to Steve Fink, vice president of marketing for PLT Health Solutions. “This produces positive reinforcement, better compliance, and a virtuous reorder cycle on an ongoing basis. Additionally, there is exciting new research and significant customer interest in ingredients that can provide results on a short-term or acute basis in addition to longer-term use.”

Research to establish patents, approvals, and novel benefits is crucial to product differentiation, Guesman said. AIDP’s two main cognitive health ingredients, Magtein and BacoMind, have been subject to long-term clinical trials across diverse age groups, with patents and GRAS status established. Based on global cognitive test improvements, Magtein is linked to a reduction in brain age by 9 years, Guesman said. Unique to BacoMind is a study on children between the ages of 6-12 which demonstrated reduced restlessness, improved self-control, and improved attention.

“All suppliers need to meet quality and safety standards; those are table stakes,” said Druke. “As the market evolves and traceability and sustainability become broad market expectations, those will be less important to finished goods manufacturers because they’ll be assumed. In my view, the most important thing is having the claims and the science to back them. Not all companies are willing or able to make the investment that is required to substantiate claims. That’s what sets branded ingredients apart.”


The E-Sports Market
“E-sports is a quietly burgeoning niche in the larger sports performance category,” according to Elyse Lovett, vice president of marketing for Nutrition21. “In fact, tens of millions of dollars in scholarships are now being awarded to college athletes involved in e-sports. According to a recent 2021 KemperLesnik trend report, not only will more colleges invest in their own collegiate e-sports programs, more professional e-sports organizations will partner with universities.”

Products that offer a jitter-free, natural alternative to caffeine, but promise attention, focus, accuracy, reaction time, mental endurance, and energy will be clear winners, Lovett said. Nutrition21’s flagship e-sports ingredient, nooLVL, a bonded arginine silicate complex, has been put to the test in clinical trials on gamers, including a new study performed at Texas A&M University that is slated for publication in the Journal of the International Society of Sports Nutrition.

“This new data found evidence of enhanced short-term memory, reaction time, reasoning, and concentration among gamers following nooLVL supplementation,” Lovett said. “The new data also strengthens previous studies on nooLVL for improving cognitive benefits for e-sports gamers, who rely on quick reactions, focus, memory, and fine motor skills to excel during competition.”

“With the uptick in e-sports players turning to natural and healthy alternatives for cognitive support, Bacopa monnieri extract, Bacognize, offers multiple benefits to support focus, memory, and overall mood for improving game play,” according to Marshall. Natural ingredients are favorable in these high-level events, where heightened attention is given to clean-label supplements and anti-doping rules, she added.

There has been notable demand for ready-to-drink products within the e-sports community, according to Stanieich. “The emergence of quick-to-consume forms like gummies, jellybeans, fast chews, or easy melts are on the rise. This sizeable audience of PC gamers, Mobile gamers, etc. is made up of a lot of different types of consumers.”

More consumers are avoiding caffeine and sugar to skip the crash once effects diminish. “In particular, we identified a target opportunity among what we call ‘serious gamers,’” said Druke. “Certain ingredients are well-positioned to meet the needs of this consumer target. In a 2015 randomized controlled study published in Nature: Scientific Reports, healthy young students in the Netherlands received either a placebo or the equivalent of 800 mg of choline as choline bitartrate.

The researchers examined the data and found that the choline group showed a reduction in pupil size within 20 minutes on average, an effect that lasted for two hours. Pupil constriction is a well-accepted measure of cholinergic network activation, so the choline was having a quick impact in the brain. Even more interesting, the choline group showed better targeting, with hits that were 9% closer to the center of the target and increased accuracy.”

Among the most skilled players, Druke continued, “the choline group was, on average, nearly 2.5 times more accurate than those receiving the placebo. This suggests that choline may actually be providing the greatest benefit to skilled players, those who are actively seeking a performance edge.”

The eye is a direct extension of the brain, and prolonged screen time can lead to inflammation. “Another novel ingredient from Kyowa Hakko, Eyemuse, the first postbiotic for eye health is also a complementary ingredient in the e-sports community,” Stanieich said. “Gamers are spending 14 hours a week playing video games, up from 12 hours a week in 2018. Eyemuse is the perfect ingredient to help gamers continue their relentless pursuit of leveling up and may help gamers support eye health and promote healthy eye function.”

Fink noted that reaction time (RT) can be critical in e-sports. Among other clinical benefits, Zynamite, PLT’s Mangifera indica extract, was able to reduce standard reaction times by 50 milliseconds. “To put that in perspective, the mean RTs for sprinters at the Beijing Olympics were 166 milliseconds for males and 189 milliseconds for females; but in one out of 1,000 starts they can achieve 109 milliseconds and 121 milliseconds, respectively. The average driver makes about 20 major decisions during each mile driven, and often has less than 500 milliseconds to react to avoid a potential collision. The blink of an eye is 100-400 milliseconds. A 95-mile-per-hour baseball pitch reaches the batter in 434 milliseconds. Think about what a 10% advantage would mean to hitters of your favorite baseball team,” he said. 

“One of the differentiators in the brain health market is the time it takes for someone to ‘feel the benefit,’” Lovett concurred. “For products to be successful they ideally need to produce a benefit quickly. Nutrition21’s nooLVL has been shown to work within 15 minutes to increase energy, focus, and reaction time. Another unique advantage for gamers is that nooLVL is stimulant-free, safely increasing energy without negatively affecting heart rate or blood pressure.”

Stress and Sleep
The U.S. has a stress problem, “and it’s getting worse,” according to Fink. “According to the American Institute of Stress, U.S. businesses lose over $300 billion a year because of workplace stress.”

“From radio to television to the internet and virtual reality tech, the changes in the amount of sensory input we are exposed to and the complexity of that input is certainly taxing our brains and contributing to information overload,” Druke said. “When you add in the pressures of a global pandemic and the numerous impacts on our everyday routine, it’s no wonder that people are seeking solutions for relief from stress, anxiety, and difficulty sleeping. One of the more important things we’ve seen from our market research is that consumers aren’t necessarily seeking a magic bullet.”

Unprecedented levels of stress, as shown in surveys conducted by health organizations, and overdue discussions on mental health issues are encouraging people to keep their mental well-being in mind, Bornet said. “Quality sleep and stress management have always factored into cognitive health, and those factors have become magnified during the global pandemic. A recent survey by the American Psychological Association found that two in three Americans (67%) said that they are sleeping more or less than they wanted to since the start of the pandemic, and nearly half of parents (48%) said the level of stress in their life has increased compared to before the pandemic. Long-term stress and disrupted sleep can also impact other areas of health, and are specifically a risk factor for cardiovascular health.”

An increased interest in tackling stress and sleep disruptions naturally has led to a 33% sales increase in calmative, mood support, and sleep supplements over the past year, SPINS reported.

“Unfortunately, many Americans suffer from inadequate intake of nutrients, with recent studies suggesting that as many as 40% of adults are not getting enough magnesium in their diet,” noted Druke. “For people who are already stressed, sometimes restoring nutrient levels is enough to help them gain back balance in their sleep cycle.”

Both well-established and novel ingredients have an opportunity to respond to the call for stress solutions, Guesman said. “We see the addition of other natural ingredients used in synergy with other compounds for improved cognitive support, specifically adaptogens. Consumers want something they can notice.”

Fast-acting formulas can be key in the stress supplements market, said Fink. “These launches are bringing fast-acting mood enhancement and stress relief to the mainstream. We think this means that stress management via supplements is here to stay—provided that we maintain trust with the consumer.”

Branching Out
The industry is meeting consumer demand for condition-specific formulations and a variety of delivery platforms. While long-term dietary habits, exercise, and supplements are all needed to tackle chronic issues of obesity, systemic inflammation, and metabolic conditions, novel ingredients will continue to offer support in areas such as developmental nutrition, mood and sleep, stress, sports, and more.

In sports/active nutrition, formulations are using cognitive ingredients to improve focus and reaction times for workout and overall performance. In weight management, cognitive support ingredients are helping to reduce cravings and make dieting less stressful. PLT Health Solutions offers Zembrin, a Sceletium tortosum extract, positioned as a botanical with cognitive health effects that also help to improve workouts. “The idea is that the use of an experiential ingredient like Zembrin—whose effects can be experienced as quickly as 30 minutes—can give immediate positive reinforcement and enhanced mood every day over months and months of training,” Fink said.

Magnesium is a staple in the sports nutrition world, and will likely benefit from its ties to stress management among active consumers, Druke said. “We see a lot of potential for Albion chelated magnesium to fit this need because it combines the relaxation properties of magnesium with the sleep support benefits of glycine. One of the barriers for magnesium is that many consumers experience digestive discomfort with the salt forms. With chelated forms, the mineral is surrounded by an amino acid which helps it pass further down the digestive tract to the optimal point of absorption. Because chelated minerals are protected, they are less prone to interactions in the digestive tract and are generally better-tolerated.”

On experimenting with new, convenient delivery applications, formulators in the herbs and botanicals space may have some trouble with the issues of taste and organoleptics, Fink noted. Advances in food technology will continue to change the trajectory for difficult ingredients.

“Usually, functional ingredients have their own flavor, taste, odor, color, and mouthfeel, which could lead to formulation challenges when incorporating them into various product applications,” Kulkarni added. “In addition, poor solubility in water, poor stability to pH, and temperature are some other common challenges faced by formulators. PharmaGABA is readily soluble in water, very stable at high temperatures and a wide range of pH. It has no taste and color on its own and therefore can be easily used in any product formulation.

SPINS reported that consumers are taking an exploratory approach to cognitive health solutions today, creating a prime opportunity for lesser-known ingredients. “With the growth seen in mushrooms, lion’s mane specifically is one to look out for. Pulling from other categories that emphasize focus, we expect different ingredients in products such as performance nutrition to gain popularity as either standalone cognitive support or as a part of brain-boosting blends. Some to keep an eye out for are phosphatidyl serine, huperzine A, and even lesser-utilized caffeine alternatives such as synephrine. Other ingredients to look out for include L-theanine, acetyl L-carnitine, and other mushrooms.”

Gut Feelings
While research in the probiotics category advances, there is still much to uncover regarding how the gut microbiome influences different areas of health, including mental well-being. Enzymes, hormones, and the activities of several neurotransmitters are modulated by gut microbes. Gains in published clinical studies over the past decade have created a breakthrough segment of probiotics focused on cognitive benefits by way of modulating the gut, known as the gut-brain axis.

“One of the major factors driving momentum into the cognitive support field comes from the massive amount of research being conducted in the gut-brain axis field,” said Kaneka’s Shastri. “In our industry, nothing strengthens the foundation of a product more than published science. The recent spike in research related to the gut-brain axis is dramatic: 32 publications mentioned the gut-brain axis in 2011, versus 730 publications in 2021. This acceleration in scientific publications shows how far we’ve come from the initiation of gut-brain axis science in 1988.”

Reviews specifically covering the gut-brain axis have grown 291% between 2017 and 2020, Shastri added, showing that scientific intrigue in this field is hot, especially in areas of mood and sleep. It isn’t commonly known, but is a clear target of probiotic researchers, that 95% of the body’s serotonin is produced in the gut, said Shastri, and strains such as Kaneka’s Lactobacillus plantarum DR7 have been shown to enhance serotonin pathways by expressing an enzyme tryptophan hydroxylase, which converts tryptophan into serotonin.

“These modifications of the GBA showed Kaneka’s DR7 enhanced memory and cognitive traits in a 12-week clinical trial,” said Shastri. “For our studies, we wanted to take a broad perspective by including mechanisms of action (i.e., tryptophan pathway enzymes) as well as cognitive tests such as the Cogstate Brief Battery.” Additionally, DR7 was shown to modulate pro-inflammatory cytokines in adults with upper respiratory tract infections, and reduce the severity and duration of respiratory symptoms. 
 

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Mike Montemarano has been the Associate Editor of Nutraceuticals World since February 2020. He can be reached at MMontemarano@RodmanMedia.com.