Kyowa Hakko’s Cognizin Citicoline shows acute cognitive benefits in proof-of-concept study

A new proof-of-concept research on Kyowa Hakko’s Cognizin Citicoline reveals an acute, single-dose effect of the ingredient on brain wave activity and cognitive performance in healthy adults. 

Nutrition Insight discusses the results and next steps for Kyowa Hakko USA with its senior manager of scientific affairs, Katie Emerson, Ph.D. candidate at the US Rocky Mountain University of Health Professions and registered dietitian. 

Although the study has not yet been published, Emerson presented its outcomes at the ongoing International Society of Sports Nutrition Annual Conference (Jun 17–19) in Florida, US. 

Emerson tells us that Kyowa Hakko set up this preclinical, proof-of-concept human study following its parent company Kirin Holdings’ implementation of a no-animal-testing policy in 2018. 

“We wanted to keep it as clinically relevant as possible,” she details. “We did a double-blind, randomized, placebo-controlled crossover study to strengthen it, since it’s a small sample of 12 healthy adult males, ages 18 to 35.”

The researchers tracked brain waves through an electroencephalogram (EEG) band one and four hours after taking Cognizin. Moreover, Emerson notes that the participants provided a subjective assessment of cognitive parameters, which “paired up with what brain wave was being activated at the time.”

Meanwhile, she notes that Kyowa Hakko will explore these findings in further research and is on the lookout to patent some of its findings as a way to protect the science. 

Boosting focus and attention

Emerson notes that the team expected to see an activation in brain waves associated with focus and attention, as previous studies from Kyowa Hakko demonstrate this impact. She says the company also anticipated that these waves would be activated after four hours because of its pharmacokinetic data. 

Emerson says Cognizin Citicoline activates brain waves linked to focus and attention.While the results were promising, she stresses that Kyowa Hakko treats the research as a preclinical study, meaning that results need to be validated in follow-up testing and that the company doesn’t make claims based on this study. 

“Seeing consistent results at one and four hours was reassuring, that it’s working, not necessarily immediately, and that it’s being sustained. That ability of your brain is being activated, as those bioenergetics are tuned in,” stresses Emerson.

“When you compare it to the placebo group, they did not have nearly the same response. It was a much duller signal.”

Study set-up

Emerson explains that the study participants received an EEG band around their head, which tracks different brain waves while stimulating them with different validated cognitive tests, such as the Wisconsin Card Sorting Test. 

The participants consumed a 500 mg dose of Cognizin or a placebo and were evaluated 60 and 240 minutes post-ingestion to assess the onset and duration of cognitive effects. 

“We wanted to see what happens at baseline, one hour, and then four hours,” says Emerson. “That was based on our pharmacokinetic data that shows us peaks when citicoline is being increased in the bloodstream. We saw increases at around three to four hours, but a lot of products are starting to be in foods and beverages, so I wanted to know what happens within an hour.” 

She adds that the team used three behavioral and mood validated tests to assess the subjective effects of the ingredient. “We wanted to understand what the subject is going to relate to, and what we can take from this study and move it into a bigger study eventually.”

Measuring brain waves

For the brain wave analysis, the researchers collaborated with a neurocognitive science expert. Emerson explains that these waves are patterns of electrical activity that reflect different states of mental activity. 

For example, she highlights delta waves, which are most commonly associated with deep sleep and restoration, while theta waves are linked to relaxed attention. 

The Cognizin group felt more attentive, quick-witted, and social over time.Next, alpha waves are “directly connected to relaxed focus, like a calm alertness,” she details. “Alpha waves in general are when the brain is ready to engage and not overly stressed. It’s like the starting point of being focused.” 

While these waves tend to be more activated when people close their eyes, Emerson says participants in the proof-of-concept study showed activated alpha waves without closing their eyes. 

Emerson notes the most exciting results from the study were in low and high beta waves, which are associated with active thinking, concentration, problem-solving, and task engagement. 

“The Cognizin group stimulated the low beta waves throughout the entire study, which is telling us that they’re actively thinking and being engaged,” says Emerson. 

Meanwhile, high beta waves were stimulated in hour one but not at hour four, she adds. “A high beta wave in the beginning is good, because it’s showing that the problem-solving and task-engagement center is activated, but over time it can show a cognitive overload, almost like you’re stressed.”

“The placebo group had the complete opposite result,” notes Emerson. “They did not stimulate low beta waves high enough to see significance at hour one or four, and the high beta waves were not significant in hour one, but at hour four, they were. Essentially, what this means is they’re trying to focus, and toward the end, they were stressed and in a cognitively demanding state.” 

Pairing objective and subjective assessments

Although subjective measures are more difficult to capture, Emerson notes that these are “equally important.” She highlights the importance of pairing these with objective measures, as participants may behave differently if they know they are being tested, even if they use a placebo. 

“When they align, it gives reassurance that it wasn’t a false positive or negative, that you’re truly seeing changes that were stimulated by the nutrient that you’re given.” 

The placebo group showed signs of cognitive overload at hour four, while Cognizin participants stayed engaged.She highlights some outcomes on the Visual Analog Scale scores, which ask participants to rate how they feel over time on a scale that compares two terms, such as dreamy versus attentive. 

“What we noticed in that particular sense was that the Cognizin group felt more attentive over time, while the placebo group felt more dreamy,” says Emerson. 

“We did the same thing with quick-witted versus mentally slow, showing very similar results. Although the placebo group didn’t necessarily feel slower, they just were very neutral, whereas the Cognizin group showed at hour four that they felt more quick-witted.”

Another aspect the study pointed to is improved social engagement, says Emerson, which she notes is not commonly discussed in the supplement space. 

“When you looked at withdrawn versus social, at hour four, the Cognizin group was significantly more social than the placebo group.” She notes that this highlights that after hours of cognitive demand and tasks, participants may still have social energy to be with family and friends. 

In addition, the placebo group was more bored toward hour four than participants taking Cognizin, says Emerson. 

“It’s telling a fun story that actually pairs nicely with those brain waves at the exact same time,” she highlights. “These were seen at hours one and four, across the board, depending on which endpoint you’re looking at.”

For example, though the findings were not statistically significant, the placebo group was trending toward feeling more tense at hour four, which Emerson notes aligns with the high beta wave identified. 

Cognizin versus generic versions

Although the study is not yet published, it has been third-party reviewed, says Emerson. Kyowa Hakko has decided to only publish its abstract to protect the company’s science and resources used for this study and to prevent generic citicoline products from leveraging its findings, she adds. 

Emerson explains that generic citicoline is made through a synthetic process, which could result in additional unwanted solvents attached to it. As such, these versions are not as “clean and pure” as Kyowa Hakko’s Cognizin. 

Emerson sees research opportunities for Cognizin in mood, sports, gut-brain axis, and women’s health.“We put it through this patented fermentation process that requires machines, resources, and people, and it’s just more expensive, but you get a better product at the end,” she details.

“We have looked at the comparison of density between the two, and we have seen that ours is more dense, compact, and pure.”

At the same time, she notes that generic versions have the same chemical structure and could therefore deliver the same benefits. “But what we’re starting to notice is other researchers in the field coming to us who want to explore citicoline, and they would rather use the pure, clean compound than the synthetic.”

What’s next?

Although the study is preclinical, Emerson notes Kyowa Hakko’s clients are excited about its findings, as these may help them to position their products with Cognizin in a new way. Specifically, she says the study’s insights on acute benefit support the ingredient’s inclusion in functional food formats. 

“When we’re talking about food and beverages, we want to be reassured that the person experiencing it will get those benefits within the day,” she highlights. “Not everybody has the same experience, but at least we know from a validation stance that we can rest assured that they’re hopefully going to feel it.” 

Kyowa Hakko is also conducting new studies with Cognizin in other health areas to help build claims. For example, Emerson says the company is conducting research on mood, has designed a study on sports, and is considering research in the gut-brain axis and women’s health. 

“I don’t think there’s nearly enough research in the women’s space for this,” she details. “We have to explore what’s happening in our brain to help contribute with products that actually work.” 

“For Cognizin specifically, I want to explore dose, duration, and time points,” Emerson concludes. “The pharmacokinetic data is unique as it shows those peaks, but it also has a half-life at around 24 hours, and I think we should test this at a two-day span and look at where it’s going, near the spikes.”