Citicoline: A Unique Source of Choline For Brain Health

Summary

Citicoline vs. Choline

Citicoline quickly breaks down into choline and cytidine after oral consumption. Each of these compounds then enters their respective metabolic pathways. That means that citicoline delivers all the benefits of choline. 

The cytidine component, however, gives citicoline unique advantages. Cytidine rapidly metabolizes into uridine, which crosses the blood-brain barrier. Once in the brain, uridine helps to resynthesize choline into phosphatidylcholine for nerve-cell membrane growth.

Although all forms of choline support acetylcholine production, citicoline has been uniquely found to also support the production of dopamine, norepinephrine, and serotonin. And citicoline has the added advantage of supporting mitochondrial function and energy production in the brain. 

Some have suggested that citicoline may have a better safety profile than other forms of choline. In a 2019 article published in Nutrients, researchers proposed that citicoline is less likely than other choline sources to metabolize into trimethylamine (TMA) or its n-oxide (TMAO). Because TMA and TMAO may pose some danger to human health, this could give citicoline a safety advantage.

 

Article

You’ve heard of choline—a micronutrient that supports lipid metabolism and liver health. Choline is also a critical nutrient for brain health because of the many metabolic pathways it feeds into. 

For instance, choline is a precursor for phosphatidylcholine (in cell membranes), acetylcholine (in the brain), sphingomyelin (in the myelin sheath of nerve cells), and betaine (in the methylation cycle).

Eggs, liver and peanuts are especially rich in choline, and the major contributors of choline in the American diet are meat, poultry, fish, dairy foods, pasta, rice, and egg-based dishes. Yet, data from the National Health and Nutrition Examination Survey shows that only 8 percent of Americans consume the recommended amount of this vital nutrient. Consequently, many people could benefit from supplementation to fulfill their metabolic demand for choline.

Most nutritional supplements deliver choline as choline bitartrate or phosphatidylcholine. But there’s also a lesser-known supplemental source called citicoline.

Citicoline is unique because it’s a nutritional source of both choline and cytidine. Emerging research suggests that citicoline provides all of the benefits of choline but also works via unique mechanisms of its own. Because of this, citicoline might be a better option than other forms of supplemental choline in some patients or situations.

Here’s what you need to know to appropriately educate patients on this unique dietary supplement.

 

WHAT IS CITICOLINE?

Citicoline is the ingredient name for a compound that’s chemically identical to cytidine-diphosphocholine (CDP-choline). The only difference is that CDP-choline is naturally occurring in humans, and citicoline is the form found in nutritional supplements.

CDP-choline is a nucleotide composed of choline, cytosine, ribose, and pyrophosphate.

It’s present in every cell of the human body and is naturally occurring in foods. However, the only foods that contain any appreciable amount of CDP-choline are liver, brain, and other organ meats.

CDP-choline was discovered in 1955. Scientists developed the synthetic version of the molecule shortly after that. The earliest form of citicoline was marketed not as a nutritional supplement, but as a prescription medication. Physicians in Europe and Japan have been prescribing citicoline since the 1970s.

Citicoline was introduced in the United States as a dietary supplement in the 1980s. In 2009, it was self-affirmed by the Japanese company Kyowa Hakko as GRAS (generally recognized as safe) in the U.S. Although citicoline had long been available by prescription in Europe, authorities didn’t approve it as a novel food ingredient in Europe until 2014.

 

HOW CITICOLINE WORKS IN THE BRAIN

Citicoline has an oral bioavailability of approximately 92 percent. It’s first broken down in the small intestines and liver to cytidine and choline. Cytidine is then metabolized into uridine. Uridine and choline are both free to cross the blood-brain barrier.

Once inside the central nervous system, uridine and choline can recombine to form CDP-choline. They are also each available to enter other metabolic pathways independently.

The choline component of citicoline accounts for many of its mechanisms. As mentioned earlier, choline is a precursor for acetylcholine—a brain neurotransmitter that supports focus, attention, learning, and memory. Choline is also a precursor for phosphatidylcholine—a structural component of cell membranes of the neurons in the brain.

However, the choline component doesn’t explain all of citicoline’s mechanisms of action. For example, citicoline supports dopamine levels in the brain. It also supports mitochondrial function and brain energy production. And it supports the protein expression of sirtuin 1 (SIRT1), an enzyme that supports the health of nerve cells. 

All of this opens up endless possibilities for brain health. Clinical studies of citicoline continue to unfold, but already show promise for its ability to support attention, memory, craving control, and vision.* 

 

CITICOLINE FOR FOCUS AND ATTENTION 

One relevant result of studies that have found that citicoline supports energy production in the brain is that the increased energy is specific to areas of the frontal lobe that are dedicated to focus and attention.* 

Two double-blind, placebo-controlled trials have evaluated citicoline for focus and attention in healthy subjects. Both were conducted by a team of researchers led by Erin McGlade at the University of Utah. 

The first study involved 60 healthy women, and the second involved 75 teenaged boys. Both studies randomized the participants into three groups for 28 days. One group took 500 mg of citicoline per day, another group took 250 mg of citicoline per day, and the third group took a placebo. 

Results of both studies were positive. Citicoline supported attention and cognition in healthy women, and helped support attention, motor speed and caution in teens.*

 

CITICOLINE FOR MEMORY

Because of its role as a precursor for acetylcholine and as a building block for neuronal cell membranes, citicoline has been studied extensively for its role in memory and cognitive function.* 

Some of the earliest studies of citicoline found that it supports cognition in healthy older adults. In these studies, citicoline was particularly helpful for healthy people who didn’t have any cognitive disorders, but who were beginning to notice some age-­related memory concerns.*

Other studies evaluated citicoline in people with cognitive concerns. A 2005 Cochrane review of 14 of these studies concluded: “There is some evidence that CDP-choline provides modest but consistent improvement of memory and behavior in these patients.” 

One of the most recent clinical trials of citicoline for memory was the IDEALE study. This 2013 study was unique in that it administered citicoline for nine months—significantly longer than earlier studies. Results showed that oral supplementation with 1,000 mg of citicoline per day successfully supported cognitive function.*

 

CITICOLINE FOR CRAVING CONTROL

Many studies have linked dopamine, norepinephrine, and serotonin to human moods and cravings. Citicoline’s ability to support the synthesis of these neurotransmitters has led to research examining its effects in people struggling with addictions and other cravings.

The results of these studies have been mixed. Although citicoline consistently supports memory, attention, and mood in these studies, it doesn’t consistently help to reduce cravings. For example, a study published in 2019 found that citicoline had no effect on alcohol intake in people struggling with unhealthy use of alcohol.

Despite conflicting results in studies of cravings, there may be a potential role for citicoline to support appetite control in healthy adults. A study published by Killgore and colleagues in 2010 showed that oral citicoline supplementation supported healthy brain patterns in response to high-calorie foods and healthy appetite control.* 

 

CITiCoLINE FOR HEALTHY VISION

Until recently, citicoline research has concentrated on memory, focus, and brain health. The eyes, however, are undeniably an extension of the brain. The optic nerve is cranial nerve II, and the retina is packed with specialized nerve cells called retinal ganglion cells.  

Therefore, regardless of the inherent health of a person’s eyes, one foundational way to support healthy vision is to support the healthy structure and function of the retina and optic nerve. Damage to these critical components of eye health can lead to vision loss over time.  

Research on citicoline’s role in supporting eye health and vision is accelerating quickly. Some of the earliest studies evaluated citicoline in children who use an eye patch to improve vision. The combination of citicoline with patching was more effective for supporting healthy vision than patching alone.

In a 2013 study published in Ophthalmologica, researchers showed that oral supplementation with citicoline supported healthy vision in patients with an existing eye condition. A 2019 study published in PLoS ONE reported that oral citicoline supported visual function, retinal ganglion function, and neural conduction along visual pathways. 

Eye drops containing citicoline have been evaluated in Italy, with preliminary evidence suggesting that the topical application of citicoline may also support retinal and visual health.*

 

CITiCoLINE IN PRACTICE

Citicoline is produced in two different forms: citicoline salt and citicoline freebase. Citicoline salt is available by prescription in some countries. Citicoline freebase is available in dietary supplements in the U.S. 

Japanese company Kyowa Hakko produces citicoline freebase by using a patented and natural fermentation process. It goes by the brand name Cognizin and can be found in nutritional supplements sold by numerous manufacturers. 

Citicoline is considered to have an excellent safety profile. Some mild adverse effects have been observed, such as gastrointestinal discomfort or irritability. No serious adverse effects have been reported.   

Citicoline is approved for a maximum intake of 1,000 mg per day by European agencies. U.S. supplements containing citicoline typically provide 250 to 500 mg per day. This amount is consistent with studies of citicoline to support attention or memory in healthy adults and teens.* n

 

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