Oral citicoline improves brain health

Katie Emerson’s presentation on Cognizin® Citicoline

This helps improve cognitive functions such as memory, attention and mental energy. In this pathway, choline is converted to choline phosphate, then to CDP-choline (citicoline), and finally to phosphatidylcholine.

The mechanism of Cognizin

Cognizin works through the Kennedy pathway, supporting the production of phospholipids, which are essential for healthy neuron cell membranes. This pathway is also known as the CDP-choline pathway, which was discovered by Eugene Kennedy in 1956, hence the name.

Katie presented multiple studies demonstrating the effectiveness of Cognizin.

Key findings include:

Increase mental energy and improve the production of phospholipids in the brain.
Improve the accuracy and reduce errors of cognitive tests for both men people and women people.
Improve motor function and reaction time in healthy adolescents,
This helps improve athletic performance.

The combined benefits of Cognizin on cognitive and motor performance

When choline is used to make phosphatidylcholine to support cell membranes, in the first conversion from choline to choline phosphate, we sacrifice an ATP molecule back to ADP.

By supplementing citicoline (the direct precursor of phosphatidylcholine), is it possible that we save ATP because we don’t need to produce as much endogenous citicoline through this pathway?

If so, this could be another explanation for why citicoline “feels good.” We often attribute the experiential effects of this ingredient to its potential ability to increase dopamine,

But maybe it also contains an ATP-saving component that keeps cell energy higher for other things we need.

We are not sure of the answer to this question, but it is worth exploring and considering in more detail.

Brain benefits of citicoline

According to the latest research, citicoline has been shown to:

• Activation of neuronal membrane phospholipid biosynthesis
• Accelerated neurometabolism
• Upregulates neurotransmitters such as dopamine, norepinephrine and acetylcholine
• Protective nervous tissue
• Alleviating age-related cognitive deficits
• Restore neuron mitochondrial function
• Inhibition of neurodegenerative apoptosis
• Improve neuroplasticity

Choline deficiency, on the other hand, can be catastrophic – it can lead to cognitive dysfunction, organ and muscle damage, and more specifically, non-alcoholic fatty liver disease (NAFLD).

Citicoline, cytidine and phosphatidylcholine

As mentioned above, Cognizin is more than just ordinary choline – it is a chemical combination of choline and cytidine nucleotide, the latter of which provides its own additional supporting properties:

Both parts of the citicoline molecule – choline and cytidine – are necessary for phosphatidylcholine (PC) synthesis.

Citicoline is the rate-limiting step, so it’s more important than just having choline and cytidine – you need citicoline to make PC.

Taking citicoline can help increase the body’s PC production by providing these two precursors. Citicoline is one of the two main phospholipids that the body absorbs into cell membranes

It is reasonable to take citicoline instead of regular choline. Although they are all forms of choline, only citicoline contains all the substances the body needs to make phospholipids. Cytidine also seems to have some health benefits of its own.

One animal study found that cytidine supplementation can alter the composition of gut bacteria and improve certain aspects of metabolic health, such as lipid levels and liver function.

Phospholipid synthesis: activities in the central nervous system

Perhaps more interesting is the ability of cytidine to cross the blood-brain barrier, which makes it highly active in the central nervous system.

This property may be the reason why citicoline is often referred to as the most experienced puzzle form of choline.

As we will see, there are numerous studies showing that citicoline has benefits for brain health that far exceed those of plain choline.

One of the first important things to note is that the natural availability of citicoline can hinder the synthesis of phosphatidylcholine.

In other words, the body’s limited supply of citicoline limits the amount of PC it can produce on its own.

A rate-limiting step for any metabolic process is usually the most effective strategy for optimizing it.

This little thing really goes a long way to explaining why citicoline supplementation has such strong evidence for brain health.

Importantly, the effect of citicoline on phospholipid synthesis in the human brain is not just theoretical.

A 2002 study looking at humans using MRI imaging found a significant increase in phosphodiesters directly related to PC synthesis.

Dietary sources of cytidine?

While it is difficult to find a comprehensive quantitative analysis of cytidine levels in foods, the foods that are commonly recommended for cytidine consumption – sweet potatoes, arugula salad, jalapenia berries, cinnamon – are not common in the diet.

While it’s hard to say exactly, given the current state of research on this topic, we think this means that most people could probably benefit from cytidine containing supplements such as citicoline.

Assuming that you do not consume enough cytidine due to a lack of the above foods in your diet, supplementation with common choline may still not yield all the benefits you are hoping for.

All the choline you want can be ingest, but without enough cytidine or uridine, the body cannot convert most of the choline into phospholipids needed to maintain vital cell membranes.

Cytidine and uridine – citicoline can enhance both

It is true that uridine is abundant in most common foods, but take a look back at our illustration – you can see that there is an intermediate step in the conversion of uridine to phosphatidylcholine.

In general, longer conversion pathways are less efficient, so we think it might make more sense to increase your cytidine intake if you want to optimize your body’s phospholipid production.

That being said, citicoline supplementation has been shown to be effective in raising blood cytidine and blood uridine levels.

In one study, a 2,000 mg dose of citicoline increased uridine levels by about 100%.

But one animal study found that a roughly equivalent dose of citicoline (about 1,600 mg if translated into humans) resulted in a substantial increase in blood cytidine levels – up to 5.4-fold.

Cognizin – Human studies

Now that we understand the mechanism of action of citicoline, let’s see what the research literature has to say about the efficacy of Cognizin in human subjects.

Note that we mention Cognizin here because researchers specifically used a trusted and tested ingredient: psychomotor speed – The Cognizin Study (2015) Psychomotor speed is an important part of everyday functioning.

It is defined as the time it takes for the mind and body to respond to a stimulus.

In other words, it’s the speed of connection between your brain and your muscles.

As we age, mental motor speed slows down, and nutritional strategies can counteract this decline and help us maintain control of our physical environment as we age.

Given the critical role that neuron membranes play in cognitive function, citicoline may help improve psychomotor processing. That’s exactly what a 2015 study of adolescent males examined.

In this double-blind, randomized, placebo-controlled study, 75 young men between the ages of 13 and 18 were treated with 250 mg citicoline, 500 mg citicoline, or placebo over 28 days.

Memory function in healthy older people

Aging is a major factor in cognitive decline, and we should mitigate its effects as much as possible. A randomized, double-blind, placebo-controlled study in 2021 was designed to examine the effects of Cognizin supplements on 100 healthy adults between the ages of 50 and 85.

Healthy meant that the volunteers’ cognitive deficits did not exceed expectations for their age – potential subjects with scores below a certain threshold on key cognitive tests were excluded from the study.

The real purpose of the study was to test whether Cognizin could help manage normal cognitive aging.

Participants were randomly assigned to receive either a placebo or 500 mg of Cognizin daily.

The treatment period lasted 12 weeks, with cognitive testing at the beginning and end of the study.

Subjects were instructed to maintain as normal diet and lifestyle habits as possible to avoid the introduction of any confounding variables.

Analysis of the study results showed that older adults taking Cognizin showed statistically significant improvements in visuospatial working memory (spatial span), episodic memory (paired association test), and overall memory performance (integrated memory).

The study authors reported that older adults who took Cognizin citicoline performed significantly better on tests of visuospatial working memory, episodic memory, and overall memory performance.

Working memory refers to the amount of information you can process in your head at any given moment – it’s a major determinant of fluid intelligence.

Episodic memory is basically time-spatial sequential memory. It refers to a person’s ability to recall not only an object, but also when and where it appeared.

Visuospatial working memory is measured by a spatial span test, which shows subjects a spatial sequence (i.e. illuminating squares on a grid in a specific order) and then asks them to accurately recall it.

Episodic memory is measured by the paired association test, which is learning to pair one test item with another and accurately recall pairs of test items.

According to the study authors, the most likely mechanisms of action for cognitive improvement are phosphatidylcholine upregulation and frontal lobe activation.

CPT-II performance improved in middle-aged women

In previous studies, the researchers found no significant performance differences between the placebo and Cognizin groups on the Continuous Performance Test II (CPT-II), a test designed to measure an individual’s ability to maintain attention.

An earlier study in 2012 found a very different picture. In the study, 60 healthy adult women between the ages of 40 and 60 were randomly assigned to receive 250 mg of citicoline, 500 mg of citicoline, or placebo for 28 days.

The study describes the CPT-II test as follows:

“CPT-II was done on an IBM-compatible laptop. The task starts with a short exercise and then moves into a full test, lasting 14 minutes.

For both the practice test and the full test, participants were asked to press the space bar as quickly and accurately as possible when any letter other than X appeared on the screen. Letters appear on the computer screen one letter at a time for 250 milliseconds.

The stimulus intervals between the letters displayed varied between 1, 2, and 4 seconds.

The measurements provided by the CPT-II assessment include errors of omission and errors of delegation.

Omission errors occur when participants do not respond when they should (i.e., they do not press the space bar when a letter other than X appears), and delegation errors occur when participants fail to suppress a response (i.e., they press the space bar when the letter X appears).”

The basic idea behind the CPT-II test is that if your mind wanders – for example, you press the space bar when you shouldn’t, or you don’t press it when you should – it means you’re not actually paying attention to what’s on the screen.

Improve the function of neuron mitochondria

When the study authors analyzed the MRS Data, they found that the Cognizin group had significantly higher levels of creatine phosphate (PCr, +7%), beta-nucleotide triphosphate (b-NTP, +14%), and phosphoethanolamine (PE, +26%) – all of which are high-energy phosphate metabolites. It indicates enhanced metabolic function (i.e., mitochondrial function).

Enhancing brain potential with citicoline

We’ve been reporting on choline-based dietary supplements for over a decade and have come to the same conclusion time and time again: Citicoline is the source of choline we most commonly feel.

Now that we’ve finally delved into the mechanisms behind citicoline and related research, the experience you get when taking Cognizin makes perfect sense.

Our next hope is that in the next year or two we’ll see more pre-workout supplements with 250 mg or even 500 mg doses of Cognizin – then we can really get into it.

Due to its ability to up-regulate dopamine and provide cytidine, it is not surprising that we continue to use citicoline… And when it comes to trusted and tested sources of citicoline, Cognizin is the form to try.

References:

• Tartar, Jaime L., et al. “A Functional Adenosine Deaminase Polymorphism Associates with Evening Melatonin Levels and Sleep Quality.” Journal of Circadian Rhythms, vol. 19, no. 1, 28 Apr. 2021, p. 5, doi:10.5334/jcr.209. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8086720/
• Thompson, Kayla I., et al. “Acute Sleep Deprivation Disrupts Emotion, Cognition, Inflammation, and Cortisol in Young Healthy Adults.” Frontiers in Behavioral Neuroscience, vol. 16, 23 Sept. 2022, doi:10.3389/fnbeh.2022.945661. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9538963/
• Sims, Stacy T, et al. “International Society of Sports Nutrition Position Stand: Nutritional Concerns of the Female Athlete.” Journal of the International Society of Sports Nutrition, vol. 20, no. 1, 24 May 2023, doi:10.1080/15502783.2023.2204066. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10210857/
• Gonzalez, Drew E., et al. “International Society of Sports Nutrition Position Stand: Tactical Athlete Nutrition.” Journal of the International Society of Sports Nutrition, vol. 19, no. 1, 23 June 2022, pp. 267–315, doi:10.1080/15502783.2022.2086017. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9261739/
• Antonio, et al. “The Effects of an Energy Drink on Psychomotor Vigilance in Trained Individuals.” Journal of Functional Morphology and Kinesiology, vol. 4, no. 3, 22 July 2019, p. 47, doi:10.3390/jfmk4030047. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7739368/
• Gibellini, Federica, and Terry K. Smith. “The Kennedy Pathway-de Novo Synthesis of Phosphatidylethanolamine and Phosphatidylcholine.” IUBMB Life, 2010, p. n/a-n/a, doi:10.1002/iub.337. https://iubmb.onlinelibrary.wiley.com/doi/10.1002/iub.337
• Kennedy, E. P., and S. B. Weiss. “The Function of Cytidine Coenzymes in the Biosynthesis of Phospholipides.” The Journal of Biological Chemistry, vol. 222, no. 1, 1 Sept. 1956, pp. 193–214. https://www.jbc.org/article/S0021-9258(19)50785-2/pdf
• Babb, S M et al. “Chronic citicoline increases phosphodiesters in the brains of healthy older subjects: an in vivo phosphorus magnetic resonance spectroscopy study.” Psychopharmacology vol. 161,3 (2002): 248-54. doi:10.1007/s00213-002-1045-y; https://link.springer.com/article/10.1007/s00213-002-1045-y
• Secades, Julio J., and José Luis Lorenzo. “Citicoline: Pharmacological and Clinical Review, 2006 Update.” Methods and Findings in Experimental and Clinical Pharmacology, vol. 28 Suppl B, 1 Sept. 2006, pp. 1–56; https://pubmed.ncbi.nlm.nih.gov/17171187/
• Silveri, M M et al. “Citicoline enhances frontal lobe bioenergetics as measured by phosphorus magnetic resonance spectroscopy.” NMR in biomedicine vol. 21,10 (2008): 1066-75. doi:10.1002/nbm.1281; https://analyticalsciencejournals.onlinelibrary.wiley.com/journal/10991492
• Stork, C, and P F Renshaw. “Mitochondrial Dysfunction in Bipolar Disorder: Evidence from Magnetic Resonance Spectroscopy Research.” Molecular Psychiatry, vol. 10, no. 10, 12 July 2005, pp. 900–919, doi:10.1038/sj.mp.4001711; https://pubmed.ncbi.nlm.nih.gov/16027739/
• McGlade, Erin, et al. “Improved Attentional Performance Following Citicoline Administration in Healthy Adult Women.” Food and Nutrition Sciences, vol. 03, no. 06, 2012, pp. 769–773. doi:10.4236/fns.2012.36103; https://www.scirp.org/html/8-2700397_19921.htm
• McGlade, Erin et al. “The Effect of Citicoline Supplementation on Motor Speed and Attention in Adolescent Males.” Journal of attention disorders vol. 23,2 (2019): 121-134. doi:10.1177/1087054715593633; https://journals.sagepub.com/doi/10.1177/1087054715593633
• Nakazaki, Eri et al. “Citicoline and Memory Function in Healthy Older Adults: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial.” The Journal of nutrition vol. 151,8 (2021): 2153-2160. doi:10.1093/jn/nxab119; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8349115/
• Conant, Richard, and Alexander G. Schauss. “Therapeutic Applications of Citicoline for Stroke and Cognitive Dysfunction in the older people: A Review of the Literature.” Alternative Medicine Review: A Journal of Clinical Therapeutic, vol. 9, no. 1, 1 Mar. 2004, pp. 17–31; https://pubmed.ncbi.nlm.nih.gov/15005642/
• Sanders LM, Zeisel SH; “Choline: Dietary Requirements and Role in Brain Development;” Nutrition today; 2007;42(4):181-186; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2518394/
• Purves D, Augustine GJ, Fitzpatrick D, et al.; “Neuroscience;” 2nd edition. Sunderland (MA): Sinauer Associates; 2001. Acetylcholine. https://www.ncbi.nlm.nih.gov/books/NBK11143/
• Hasselmo ME; “The role of acetylcholine in learning and memory;”Curr Opin Neurobiol. 2006;16(6):710–715; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2659740/
• Jones BE; “From waking to sleeping: neuronal and chemical substrates”. Trends Pharmacol. Sci.; 2005; 26 (11): 578–86; https://www.ncbi.nlm.nih.gov/pubmed/16183137
• Secades, Julio J, and José Luis Lorenzo. “Citicoline: pharmacological and clinical review, 2006 update.” Methods and findings in experimental and clinical pharmacology vol. 28 Suppl B (2006): 1-56; https://www.researchgate.net/publication/6629277_Citicoline_Pharmacological_and_clinical_review_2006_update
• McGlade, Erin et al. “The Effect of Citicoline Supplementation on Motor Speed and Attention in Adolescent Males.” Journal of attention disorders vol. 23,2 (2019): 121-134. doi:10.1177/1087054715593633; https://journals.sagepub.com/doi/10.1177/1087054715593633
• Ueland, P. M.; “Choline and betaine in health and disease;” Journal of Inherited Metabolic Disease; 2010; 34(1), 3–15; https://onlinelibrary.wiley.com/doi/abs/10.1007/s10545-010-9088-4
• Wurtman, Richard J., et al. “Administration of Docosahexaenoic Acid, Uridine and Choline Increases Levels of Synaptic Membranes and Dendritic Spines in Rodent Brain.” World Review of Nutrition and Dietetics, vol. 99, 2009, pp. 71–96, doi:10.1159/000192998; https://pubmed.ncbi.nlm.nih.gov/19136840/
• Kennedy, Eugene P., and Samuel B. Weiss. “The Function of Cytidine Coenzymes in the Biosynthesis of Phospholipides”. Journal of Biological Chemistry, vol. 222, no. 1, Sept. 1956, pp. 193–214, https://doi.org/10.1016/s0021-9258(19)50785-2; https://www.sciencedirect.com/science/article/pii/S0021925819507852
• Hadley, Kevin B et al. “An assessment of dietary docosahexaenoic acid requirements for brain accretion and turnover during early childhood.” World review of nutrition and dietetics vol. 99 (2009): 97-104. doi:10.1159/000193000; https://karger.com/books/book/2641/chapter-abstract/5750078/An-Assessment-of-Dietary-Docosahexaenoic-Acid
• Cansev, Mehmet. “Uridine and cytidine in the brain: their transport and utilization.” Brain research reviews vol. 52,2 (2006): 389-97. doi:10.1016/j.brainresrev.2006.05.001; https://www.sciencedirect.com/science/article/abs/pii/S0165017306000439
• National Institutes of Health. “Office of Dietary Supplements – Choline.” National Institutes of Health, Office of Dietary Supplements; https://ods.od.nih.gov/factsheets/Choline-HealthProfessional/
• Niu, Kaixia et al. “Cytidine Alleviates Dyslipidemia and Modulates the Gut Microbiota Composition in ob/ob Mice.” Nutrients vol. 15,5 1147. 24 Feb. 2023, doi:10.3390/nu15051147; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10005144/
• Rao, A M et al. “CDP-choline: neuroprotection in transient forebrain ischemia of gerbils.” Journal of neuroscience research vol. 58,5 (1999): 697-705; https://onlinelibrary.wiley.com/doi/10.1002/(SICI)1097-4547(19991201)58:5%3C697::AID-JNR11%3E3.0.CO;2-B
• Babb, S M et al. “Chronic citicoline increases phosphodiesters in the brains of healthy older subjects: an in vivo phosphorus magnetic resonance spectroscopy study.” Psychopharmacology vol. 161,3 (2002): 248-54. doi:10.1007/s00213-002-1045-y; https://link.springer.com/article/10.1007/s00213-002-1045-y
• “Showing Compound Cytidine (FDB021809) – FooDB.” Foodb.ca; https://foodb.ca/compounds/FDB021809
• Wurtman, Richard J. “A nutrient combination that can affect synapse formation.” Nutrients vol. 6,4 1701-10. 23 Apr. 2014, doi:10.3390/nu6041701; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4011061/
• López-Coviella, I et al. “Evidence that 5′-cytidinediphosphocholine can affect brain phospholipid composition by increasing choline and cytidine plasma levels.” Journal of neurochemistry vol. 65,2 (1995): 889-94. doi:10.1046/j.1471-4159.1995.65020889.x https://onlinelibrary.wiley.com/doi/abs/10.1046/j.1471-4159.1995.65020889.x
• Wurtman, R J et al. “Effect of oral CDP-choline on plasma choline and uridine levels in humans.” Biochemical pharmacology vol. 60,7 (2000): 989-92. doi:10.1016/s0006-2952(00)00436-6; https://linkinghub.elsevier.com/retrieve/pii/S0006-2952(00)00436-6
• “Psychomotor Activity – an Overview | ScienceDirect Topics”. https://www.sciencedirect.com/topics/medicine-and-dentistry/psychomotor-activity
• “Finger Tapping Test – an Overview | ScienceDirect Topics”. https://www.sciencedirect.com/topics/medicine-and-dentistry/finger-tapping-test
• Picillo, Marina et al. “Learning More from Finger Tapping in Parkinson’s Disease: Up and Down from Dyskinesia to Bradykinesia.” Movement disorders clinical practice vol. 3,2 184-187. 27 Oct. 2015, doi:10.1002/mdc3.12246; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6353362/
• Nadri, Mahsa, et al. “Analysis of the Ruff 2 & 7 Test of Attention with the Rasch Poisson Counts Model.” The Open Psychology Journal, vol. 12, no. 1, 31 Jan. 2019; https://openpsychologyjournal.com/VOLUME/12/PAGE/7/
• Fasmer, Ole Bernt et al. “Linear and non-linear analyses of Conner’s Continuous Performance Test-II discriminate adult patients with attention deficit hyperactivity disorder from patients with mood and anxiety disorders.” BMC psychiatry vol. 16,1 284. 11 Aug. 2016, doi:10.1186/s12888-016-0993-4; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4982130/
• Nakazaki, Eri et al. “Citicoline and Memory Function in Healthy Older Adults: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial.” The Journal of nutrition vol. 151,8 (2021): 2153-2160. doi:10.1093/jn/nxab119; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8349115/
• Jaeggi, Susanne M et al. “Improving fluid intelligence with training on working memory.” Proceedings of the National Academy of Sciences of the United States of America vol. 105,19 (2008): 6829-33. doi:10.1073/pnas.0801268105; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2383929/
• Spiers, P A et al. “Citicoline improves verbal memory in aging.” Archives of neurology vol. 53,5 (1996): 441-8. doi:10.1001/archneur.1996.00550050071026; https://jamanetwork.com/journals/jamaneurology/article-abstract/594018
• McGlade, Erin, et al. “Improved Attentional Performance Following Citicoline Administration in Healthy Adult Women.” Food and Nutrition Sciences, vol. 03, no. 06, 2012, pp. 769–773; https://www.scirp.org/html/8-2700397_19921.htm
• Silveri, M M et al. “Citicoline enhances frontal lobe bioenergetics as measured by phosphorus magnetic resonance spectroscopy.” NMR in biomedicine vol. 21,10 (2008): 1066-75. doi:10.1002/nbm.1281; https://analyticalsciencejournals.onlinelibrary.wiley.com/journal/10991492
• Synoradzki, Kamil, and Paweł Grieb. “Citicoline: A Superior Form of Choline?.” Nutrients vol. 11,7 1569. 12 Jul. 2019, doi:10.3390/nu11071569; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6683073/