Under Pressure

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The United States is a society under pressure. According to a 2006 survey by the American Psychological Association (APA; Washington, DC), 43% of all adults suffer adverse health effects from stress, such as hypertension, anxiety, depression, and obesity. Making matters worse, Americans are using unhealthy behaviors like comfort eating and smoking to combat their stress. While these activities may alleviate stress in the short run, in the long run they could exacerbate stress by causing serious health problems.

Techniques like physical exercise and meditation are productive ways to address stress, and adopting a healthy diet can help provide nutritional support that keeps bodies and minds in working order. However, some researchers believe that dietary supplements can also make important contributions to mental and cognitive health.

“The future for cognitive-enhancing nutraceuticals remains very, very bright, and every month, more and more innovative natural products are launched to receptive consumers who are reacting to their mental, stress, and mood challenges,” says Scott Hagerman, president and CEO of Chemi Nutra (White Bear Lake, MN). “Obviously, the medical community is concerned about the safety and efficacy of any natural product to maintain and improve healthy minds and moods. We live in a time when the number of safe, natural, and effective ingredient compounds is vast, and this provides the ability for companies to formulate and market truly effective, proprietary mental performance products.”


Phospholipids are a family of lipids that possess one of three kinds of molecular backbones that are attached to fatty acids and a phosphate group. Because they are a major component of cell membranes, several phospholipids are of interest to nutraceutical manufacturers.

In 2003, FDA approved a qualified health claim stating that the phospholipid phosphatidylserine (PS) may reduce the risk of dementia or cognitive dysfunction in the elderly. However, the agency added that the evidence was “very limited and preliminary” and stated that it had concluded “there is little scientific evidence supporting this claim.”

Despite FDA’s reservations, many scientists and manufacturers are optimistic about PS’s potential, particularly as it relates to the stress hormone cortisol. “A number of research studies, involving both exercising and nonexercising subjects, have shown that PS, when taken as a nutritional supplement, suppresses the release of cortisol under conditions where its release would have otherwise increased,” Hagerman says. “Elevated cortisol is very destructive, as cortisol is a potent catabolic stress hormone that breaks down the body’s muscle protein into amino acids, which are converted to glucose in the liver. Perhaps more importantly, research has shown that prolonged exposure to elevated cortisol levels disrupts the energy stores of neurons and can lead to neurological damage to the hippocampus region of the brain. This can contribute to accelerated brain aging and to further loss of valuable cognitive functions.”

One novel application for PS involves menopause. “Over the past several years, the medical community has been looking at the association of hormone replacement therapy (HRT), primarily in women, and the impairment of mental performance that often accompanies HRT,” Hagerman says. “Recently, Chemi Nutra’s SerinAid PS was evaluated in a research study at the University of Guadalajara in Mexico involving PS and its ability to reduce the incidence of memory loss that accompanies HRT in women. The one-year study concluded in 2006, and thus far, the researcher has commented that PS did improve various emotional aspects related to HRT.” Hagerman adds that although there are only a handful of studies involving children and PS, some researchers believe that the ingredient may also help children with behavioral problems and stress-related challenges.

Research also suggests that PS, working in conjunction with a related compound called phosphatidic acid (PA), may help dampen the physiological effects of mental or emotional stress. In a study published in the June 2004 issue of the journal Stress, researchers from the University of Trier in Germany tested the effects of a PS/PA complex called PAS on 80 healthy volunteers who underwent the Trier Social Stress Test, which enables scientists to measure stress under laboratory conditions.

Using materials supplied by Lipogen Ltd. (Haifa, Israel), the researchers divided the volunteers into four groups. Each group took either a placebo or 400, 600, or 800 mg per day of PAS for three weeks prior to the experiment. One hour before the experiment began, the researchers took saliva samples to establish baseline levels of cortisol. The researchers also took saliva and blood samples several times throughout the experiment to obtain ACTH and cortisol measurements, concluding that the 400-mg dose reduced ACTH and cortisol responses.

“Ever since we started, we’ve been working with a mixture of phospholipids because we know the mixture is, by far, more effective,” says David Rutenberg, CEO of Lipogen, who explains that PA affects the rigidity of cell membranes, making the cells more flexible and facilitating intercellular communication. “We were the first company to put PS onto the market, and we also include PA in our materials. After 15 years with just PS on the market, it’s high time to start something new with more science behind it.” He adds that Lipogen’s materials are manufactured using vegetable, rather than bacterial, enzymes and are generally recognized as safe (GRAS) for use in foods and beverages.

Another phospholipid, phosphatidylcholine (PC), is found in lecithin and is a major source of choline, a component of the neurotransmitter acetylcholine. A recent article in the May issue of the American Journal of Clinical Nutrition suggested that the current recommended adequate intake (AI) levels of choline are too low and advised the Institute of Medicine to revise the dietary reference intake (DRI) for choline.

A third compound related to phospholipids is the choline precursor L-alpha glycerylphosphorylcholine (A-GPC). “A-GPC is a very novel soy-derived choline compound, which has been proven to be the most potent choline compound in existence, especially as it relates to boosting acetylcholine in the brain and muscle nerve cells,” says Hagerman. He notes that while A-GPC is used in the United States as a supplement and in Europe and Asia as a prescription and OTC drug for a variety of conditions related to cognitive health, it also has applications in sports nutrition. “A-GPC is the true mind-to-muscle ingredient, and theoretically, it will enhance brain and muscle activity together quite significantly. A-GPC continues to grow in use, and Chemi Nutra is currently involved in continuing research with it.”

New Closure Technology Tops Cognitive Health Drink



Talk about putting on their thinking caps. Kyowa Hakko USA (New York City) and Liquid Health Labs (Deerfield, NH) recently came up with a novel way to package Kyowa’s Cognizin brand of citicoline, a precursor of the neurotransmitter phosphatidylcholine.

The two companies packaged the drink using PowerCap technology, a new closure that lets consumers mix dry powders and liquids together with a twist of the wrist. The PowerCap contains an internal cavity that can hold about 2 g of powder and 1.7 cm3 of liquid. Kyowa Hakko and Liquid Health Labs unveiled the functional beverages May 1–2 at this year’s SupplySide East show in Secaucus, NJ. The pomegranate-flavored drink, part of a beverage line called Healthy Twist, contains 250 mg of Cognizin.

“It offers a new and unique concept to employ Kyowa-branded ingredients and give our customers the opportunity to try the products in a delivery system other than a standard tablet or capsule,” says Karen Todd, RD, director of marketing for Kyowa Hakko. “We think this approach will open a pathway of new ideas for supplement and food manufacturers.”


The science of phospholipids is still evolving and can be a considerable source of confusion to researchers, manufacturers, and, perhaps most importantly, consumers. “Consumers are to a large extent not yet aware of the benefits of these nutrients,” says Peter Rohde, CEO of Science & Ingredients Inc. (Carlsbad, CA). “As an example, many consumers are still using simple 1200-mg lecithin softgels for the wrong reasons and are underdosed, unaware that new science has evolved and these products have been replaced by specialized and more-potent supplements.”

Because consumers as well as product developers and marketing executives need more information about phospholipids, Science & Ingredients is publishing a series of books on the subject written by Parris Kidd, PhD. The first in the series, PS: Nature’s Brain Booster, was released last year, and this year, the company published GPC: Mind-Body Power for Active Living and Healthy Aging. “Our next book is already in preparation and will deal with omega-3 phospholipids, including PC from krill and docosahexaenoic acid (DHA) conjugated to PS,” Rohde says.


Aside from phospholipids, another area of interest to researchers and manufacturers is the omega-3 family of essential fatty acids (EFA), particularly eicosapentaenoic acid (EPA) and DHA. There is a growing body of research that shows omega-3s may play an important role in mood and cognitive health. Emerging research also suggests that they may be helpful for related areas, such as stress and problems with impulse control. However, large-scale clinical studies are still needed to confirm the potential of omega-3s.

In the February 27 issue of the British Journal of Psychiatry, Malcolm Garland, MD, a Dublin-based consultant psychiatrist, found that low plasma levels of essential fatty acids in combination with low cholesterol levels are associated with self-harm. In the study, Garland gave either omega-3 supplements or a placebo for 12 weeks to 49 psychiatric patients who engaged in self-harming behavior. By the end of the study, the patients in the omega-3 group experienced improvements in depression and daily stress. EPAX 5500 TG supplements containing 305 mg of EPA and 227 mg of DHA from EPAX AS (Aalesund, Norway) were used in the study.

“We were very pleased with the outcome of this study,” says Garland. “Although we were financially constrained in terms of the number of subjects we could recruit, we achieved acceptable levels of statistical significance. At the end of the study, when we were decoding those patients on placebo and on supplementation, our ‘wish’ for those patients we knew were doing well was for them to be in the supplementation group, and it was almost always fulfilled.”

Omega-3s are also the subject of a major trial involving Alzheimer’s disease sponsored by the National Institutes of Health’s (Bethesda, MD) National Institute on Aging (NIA). The 18-month double-blind trial, conducted by the Alzheimer’s Disease Cooperative Study (ADCS) at 51 sites across the country, will examine whether DHA supplements can slow the progression of cognitive and functional decline. The NIA researchers will assign either 2 g of DHA or a placebo per day to 400 people with mild-to-moderate Alzheimer’s disease. Martek Biosciences Corp. (Columbia, MD) will supply the DHA.

“The evidence to date in observational and animal studies on omega-3 fatty acids and Alzheimer’s disease warrants further evaluation in a rigorous clinical trial,” says Richard Hodes, MD, NIA director. “This study is one of a number we are undertaking in the next few years through the ADCS to test compounds that might play a role in preventing or delaying the symptoms of this devastating disease.”


One growing trend for manufacturers of cognitive-health supplements is the use of ingredients that combine phospholipids with omega-3 fatty acids. For instance, at the 2007 Annual Meeting of the Pediatric Academic Societies (The Woodlands, TX) held May 5–8 in Toronto, researchers presented a study funded by Enzymotec Corp. (Migdal HaEmeq, Israel) that tested the effects of Sharp-PS Platinum, a PS/DHA/EPA conjugation, on more than 60 schoolchildren with attention deficit and hyperactivity disorder (ADHD).

Feeling Your Oats



While many manufacturers are looking to the seas to find their latest cognitive-health ingredients, some may actually find them in fields of oats. At this year’s Natural Products Expo West in Anaheim, CA, Frutarom Inc. (North Bergen, NJ) presented preliminary research suggesting that Neuravena EFLA 955, a wild green oat (Avena sativa L.) extract, seems to stimulate the dopaminergic transmitter system.

According to Frutarom, the company’s choice of raw materials was based on the results of bioassays carried out at its state-of-the-art production site.

“This is exciting research with high consumer interest for effective and safe ingredients to improve memory, sharpen focus, and increase brain power,” says Laurent Leduc, vice president of Frutarom.


“Providing Sharp-PS Platinum to these children had a pronounced impact on their Test of Variables of Attention scores,” says Dori Pelled, PhD, Enzymotec’s chief technical officer. Using a computerized attention-testing system called the Test of Variables of Attention (TOVA), the researchers found that about 60% of the subjects presented asymptomatic scores by the end of the study. “We find it very reassuring that the alleviated TOVA results were highly correlated with the incorporation of this product into the blood components,” Pelled says. “It seems that conjugation of omega-3s to phospholipids has a significant beneficial effect on cognitive performance.”

Along the same lines, the shrimp-like crustacean krill is becoming an increasingly important source of phospholipids because of its high EFA content. “Krill yield a highly potent phospholipid preparation consisting mostly of PC,” says Rohde, adding that the PC from krill is also enriched with DHA and EPA.

“Through animal research, it has been discovered that, as dietary supplements, DHA and EPA are better delivered to the tissues when they are part of phospholipids than as triglycerides,” Rohde says. “Considering the impressive clinical track record of krill phospholipids in supporting mood management in women and blood cholesterol and triglyceride content in both genders, the advent of a full-potency, authentic krill dietary supplement raw material has to be considered a breakthrough for the consumer.”


Vinpocetine, a compound synthesized from the periwinkle (Vinca minor) plant, is sold as a drug in Europe and as a dietary supplement in the United States. Vinpocetine has been used overseas for more than 20 years, and although some researchers believe that it may have positive effects on cognitive health by increasing blood flow to the brain, a Cochrane Review (Oxford, UK) of studies examining the relationship between vinpocetine and dementia found the evidence inconclusive. One recent development that may spur more interest in vinpocetine was the publication in 2006 of a new high-performance liquid chromatography–mass spectrometry (HPLC-MS) method for detecting a vinpocetine metabolite in human plasma. The validated method, described in the September 2006 issue of the Journal of Separation Sciences, requires only a 3-minute run time to quantify apovincaminic acid.

According to Charlene Lee, executive vice president of Cyvex Nutrition (Irvine, CA), which sells BioVinca vinpocetine, the purity of vinpocetine extracts is a major concern for manufacturers. BioVinca is produced under a patent from the Hungarian pharmaceutical company Gedeon Richter (Budapest). “From Cyvex’s perspective, we believe in the efficacy of BioVinca vinpocetine,” Lee says. “It’s the only pharmaceutical-grade pure vinpocetine on the market that has its own portfolio of clinical studies demonstrating its mechanism of action to promote healthy brain function, and hence, cognition activities.”

Lee adds that manufacturers are also aware of consumer doubts about the quality of cognitive-health supplements. “There continues to be some consumer mistrust about all dietary supplements for health, and this comes straight from increasingly sensationalistic mass media, to which consumers are plugged in,” Lee says. “This is a fight for the entire industry to try to win, and it’s not easy. Within this context, proper, aggressive, and cohesive educational efforts must be made without fail.”


Will cognitive-health supplements rise to the challenge? As researchers continue to look into the effects of supplements and manufacturers continue to educate consumers about their potential benefits and limitations, the future looks bright and, not surprisingly, less stressful.

“There are many existing and new health applications for safe, natural brain support dietary supplements, including PS,” says Hagerman. “Considering these interesting and exciting new uses, which go well beyond the established uses for cognitive enhancement and for preventing cognitive decline, the future remains wide open for safe and effective ingredients. Collectively, formulators, marketers, and consumers must simply open their eyes to this potentially huge market that shows every sign of further expansion.”