Citicoline

Citicoline is a physiological substance that occurs naturally in the human body and plays a central role in the formation of cell membranes and important messenger substances in the brain. The so-called nucleotide derivative consists of two building blocks:

1. Choline – a vitamin-like nutrient, important for the brain and nervous system.
2. Cytidine – a component of RNA, i.e. a basic building block of our genetic information.

The two components are linked by a so-called diphosphate bridge. This is why citicoline is also known as CDP-choline, which stands for “cytidine-5′-diphosphocholine”.

The human body produces citicoline as an intermediate in the so-called Kennedy metabolic pathway. Citicoline is an important intermediate building block for the production of phosphatidylcholine, a main component of cell membranes (see Image 2). These membranes surround all cells in the body and ensure their stability, flexibility and smooth functioning, especially for the cells in the brain and nervous system.

When citicoline is taken as a dietary supplement, it first enters the stomach and then the small intestine. There it is broken down into its two components, choline and cytidine, by the body’s own enzymes. These two substances then enter the bloodstream and are distributed throughout the body. Among other things, both choline and cytidine can cross the blood-brain barrier – a natural protective barrier that protects the brain from harmful substances. In the brain, choline and cytidine are reassembled to form citicoline, where they serve as building blocks for various vital processes. Research shows that some of these mechanisms can have a positive influence on disturbed processes in dementia by inhibiting or even partially reversing pathological changes [13].

While citicoline is classified as a drug in the USA, it is considered a freely available dietary supplement in the European Union, including Germany and Austria [11].

Possible mechanisms of action of citicoline

Image 2

In particular, preclinical studies in animal models and in vitro studies are dedicated to researching the exact mechanisms of action of citicoline in dementia. The focus here is primarily on two approaches: the promotion of phospholipid biosynthesis and the support of neurotransmitter function.

Promotes phospholipidbiosynthesis

In the brain, choline and cytidine are converted back into CDP-choline, which is then assembled into phosphatidylcholine (PC). PC is the main component of neuronal cell membranes and is essential for the integrity, fluidity and repair of neuronal cell membranes. Supplementation with citicoline can therefore increase phospholipid biosynthesis and thus contribute to the regeneration and stabilization of damaged nerve cell membranes and improve neuronal signal transmission. In addition, phosphatidylcholine provides essential building blocks for myelin synthesis and thus supports the maintenance and repair of the protective myelin layer that surrounds and insulates the nerve fibers [9,12].

Promotes neurotransmitter release

Acetylcholine

The choline provided by citicoline serves as a starting material in the brain for the production of acetylcholine – an important neurotransmitter involved in memory, learning and attention. In Alzheimer’s disease, certain nerve cells, known as cholinergic neurons, are lost. As a result, less choline is processed and the production of acetylcholine decreases. This deficiency can lead to cognitive problems such as forgetfulness and difficulty concentrating. If more choline is available as a building material thanks to citicoline, more acetylcholine can be produced again. This improves signal transmission between the nerve cells and can therefore support mental abilities such as memory and attention [9,17].

Dopamine and noradrenaline

Clinical studies and reviews show that citicoline can increase the levels of the neurotransmitters dopamine and noradrenaline in the brain by supporting their formation and release. This effect is particularly relevant as an increase in dopamine levels can have a positive effect on cognitive performance and memory in Alzheimer’s patients [6,9].

Study situation for citicoline in Alzheimer’s patients

In addition to animal and in-vitro studies, numerous human studies also indicate that citicoline can be useful for both the prevention and adjunctive treatment of dementia and mild cognitive impairment (MCI) [1].

As early as 2005, the Cochrane review by Fioravanti & Yanagi included 14 randomized, double-blind, placebo-controlled human trials of citicoline with approximately 1000 older, cognitively impaired people. The analysis showed that citicoline has clear indications of a positive effect on memory function, particularly in the short and medium term in mild and moderate impairment. In contrast, citicoline has no significant effect on attention, but there is a clear positive trend in the global clinical assessment. The tolerability of citicoline was also very good, no noticeable side effects were observed [7].

In the following years, the therapeutic effect of citicoline was primarily investigated as an add-on to existing dementia therapies.

• In a case-control study by Castagna et al. with 104 patients (over 65 years of age), 63 received the standard therapy with memantine and rivastigmine, while 41 additionally received 1000 mg citicoline daily. At the beginning, the groups did not differ in their mental performance. Over time, the citicoline group showed a significant improvement in memory and thinking ability, while the control group remained stable. There were no significant changes in other areas such as daily living skills, mood and behavior in either group [4].
• In another case-control study by Castagna et al. with 170 Alzheimer’s patients (over 65 years of age), 89 patients received memantine and donepezil, rivastigmine or galantamine as standard therapy, while 81 patients additionally received 1000 mg citicoline per day. After twelve months, the citicoline group showed a statistically significant improvement in cognitive abilities as measured by the MMSE test [3].
• An earlier study by Castagna et al. with 174 patients (over 65 years of age) with Alzheimer’s or mixed dementia compared a control group that received rivastigmine with an intervention group that additionally took 1000 mg citicoline daily. After nine months, the citicoline group showed significantly better cognitive function and fewer behavioral abnormalities such as mood swings and agitation. Depression levels were also significantly lower in this group. There were no differences in everyday abilities [2].
• Gareri et al. also examined 448 Alzheimer’s patients (over 65 years of age). The control group (197 patients) received standard therapy with ACHEI, the intervention group (251 patients) additionally received 1000 mg citicoline daily. After nine months, there was a significant improvement in cognitive function in the citicoline group compared to the control group [8].

Study situation for citicoline in mild cognitive impairment (MCI)

Mild cognitive impairment (MCI) refers to a progressive deterioration in mental performance. Those affected usually have no or only minor restrictions in everyday life, but show difficulties with abilities such as learning, memory, language and spatial orientation. It describes the intermediate state between normal ageing and dementia. 10-15% of those affected develop dementia as a result. In comparison, non-affected people only have a 1-2% risk of developing dementia [1].

• Cotroneo et al. conducted a randomized, controlled trial with 265 patients with MCI who had a Mini-Mental Status Examination (MMSE) of over 21. One group received 800 mg citicoline twice daily, the control group a placebo. After nine months, there was a clear difference in the MMSE score in favor of the citicoline group. The results indicate that citicoline stimulates the formation of phospholipids in the nerve cell membranes, increases the metabolism in the brain and raises the levels of the neurotransmitters noradrenaline and dopamine [5].
• Li et al. studied 81 patients with Parkinson’s disease and MCI. The intervention group of 41 patients received 200 mg citicoline three times a day in addition to the usual treatment (L-dopa or pramipexole), while the control group received a placebo. After twelve and eighteen months, the cognitive test results (MoCA and COPA-COG scores) were significantly better in the citicoline group than in the control group. In addition, blood phospholipid levels were lower. The study suggests that citicoline as a complementary therapy can delay cognitive decline in Parkinson’s patients with MCI and have neuroprotective effects [10].

IMPORTANT: What should you bear in mind when taking supplements?

Choline-containing food supplements – including citicoline – are broken down into their components in the small intestine after ingestion, in particular cholineis broken down. Part of the released choline reaches the large intestine, where it is metabolized by certain Intestinal bacteria in trimethylamine (TMA) converted. This is then fed into the liverwhere it is converted to trimethylamine-N-oxide (TMAO) is further processed.

According to several studies, elevated TMAO levels in the blood are associated with an increased risk of cardiovascular diseasesuch as arteriosclerosis, heart attack or strokeas well as with possible kidney damage [15,16].

Compared to other choline-containing supplements, however, citicoline leads to a lower formation of TMAO. This is because citicoline has a stable structure and is quickly absorbed in the small intestine. This means that less free choline reaches the large intestine, where it could be converted to TMA by bacteria. In addition, it is now known from scientific publications that an incorrect colonization of the large intestine in particular can promote the bacterial development of TMA and therefore also TMAO. Supplementation with citicoline should therefore always be discussed with a holistic doctor or therapist. doctor or therapist and adapted to the individual (intestinal) situation [14].

Conclusion

Numerous studies provide positive evidence that citicoline can improve memory function in people with dementia or mild cognitive impairment (MCI). Citicoline is generally considered to be well to very well tolerated and is particularly suitable as a supplement to existing standard therapies. Nevertheless, the individual (intestinal) situation is also decisive for a therapy and should first be discussed with a holistic doctor or therapist.

If you would like to find out more about dementia, its prevention and treatment, click here.

References

1. Bonvicini, M., Travaglini, S., Lelli, D., Antonelli Incalzi, R., & Pedone, C. (2023). Is Citicoline Effective in Preventing and Slowing Down Dementia?-A Systematic Review and a Meta-Analysis. Nutrients, 15(2), 386. https://doi.org/10.3390/nu15020386
2. Castagna, A., Cotroneo, A. M., Ruotolo, G., & Gareri, P. (2016). The CITIRIVAD Study: CITIcoline plus RIVAstigmine in Elderly Patients Affected with Dementia Study. Clinical Drug Investigation, 36(12), 1059-1065. https://doi.org/10.1007/s40261-016-0454-3
3. Castagna, A., Fabbo, A., Manzo, C., Lacava, R., Ruberto, C., & Ruotolo, G. (2021). A Retrospective Study on the Benefits of Combined Citicoline, Memantine, and Acetylcholinesterase Inhibitor Treatments in Older Patients Affected with Alzheimer’s Disease. Journal of Alzheimer’s Disease, 79(4), 1509-1515. https://doi.org/10.3233/JAD-201211
4. Castagna, A., Manzo, C., Fabbo, A., Lacava, R., Ruberto, C., & Ruotolo, G. (2021). The CITIMERIVA Study: CITIcoline plus MEmantina plus RIVAstigmine in Older Patients Affected with Alzheimer’s Disease. Clinical Drug Investigation, 41(2), 177-182. https://doi.org/10.1007/s40261-020-00996-2
5. Cotroneo, A. M., Putignano, S., Fantò, F., Monteleone, F., Lacava, R., Castagna, A., Gareri, P., & Gareri, P. (2012). O4-12-05: Effectiveness and safety of citicoline in mild vascular cognitive impairment: The IDEALE study. Alzheimer’s & Dementia, 8(4S_Part_20), S746–S746. https://doi.org/10.1016/j.jalz.2013.08.031
6. Dahl, M. J., Bachman, S. L., Dutt, S., Düzel, S., Bodammer, N. C., Lindenberger, U., Kühn, S., Werkle-Bergner, M., & Mather, M. (2023). The integrity of dopaminergic and noradrenergic brain regions is associated with different aspects of late-life memory performance. Nature Aging, 3(9), 1128-1143. https://doi.org/10.1038/s43587-023-00469-z
7. Fioravanti, M., & Yanagi, M. (2005). Cytidinediphosphocholine (CDP-choline) for cognitive and behavioral disturbances associated with chronic cerebral disorders in the elderly. The Cochrane database of systematic reviews, (2), CD000269. https://doi.org/10.1002/14651858.CD000269.pub3
8. Gareri, P., Castagna, A., Cotroneo, A. M., Putignano, D., Conforti, R., Santamaria, F., Marino, S., & Putignano, S. (2017). The Citicholinage Study: Citicoline Plus Cholinesterase Inhibitors in Aged Patients Affected with Alzheimer’s Disease Study. Journal of Alzheimer’s Disease, 56(2), 557-565. https://doi.org/10.3233/JAD-160808
9. Gareri, P., Castagna, A., Cotroneo, A. M., Putignano, S., De Sarro, G., & Bruni, A. C. (2015). The role of citicoline in cognitive impairment: Pharmacological characteristics, possible advantages, and doubts for an old drug with new perspectives. Clinical Interventions in Aging, 10, 1421-1429. https://doi.org/10.2147/CIA.S87886
10. Li, Z., Wang, P., Yu, Z., Sun, H., Zhang, J., Zhang, J., Cong, Y., Sun, C., Zhang, Y., & Ju, X. (2016). Effect of citicoline adjuvant therapy on mild cognitive impairment in Parkinson’s disease.
11. Nakazaki, E., Mah, E., Sanoshy, K., Citrolo, D., & Watanabe, F. (2021). Citicoline and Memory Function in Healthy Older Adults: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial. The Journal of Nutrition, 151(8), 2153-2160. https://doi.org/10.1093/jn/nxab119
12. Secades, J. J., & Frontera, G. (1995). CDP-choline: Pharmacological and clinical review. Methods and Findings in Experimental and Clinical Pharmacology, 17 Suppl B, 1-54.
13. Świątkiewicz, M., & Grieb, P. (2023). Citicoline for Supporting Memory in Aging Humans. Aging and Disease, 14(4), 1184-1195. https://doi.org/10.14336/AD.2022.0913
14. Synoradzki, K., & Grieb, P. (2019). Citicoline: A Superior Form of Choline? Nutrients, 11(7), Article 7. https://doi.org/10.3390/nu11071569
15. Wang, M., Tang, W. H. W., Li, X. S., de Oliveira Otto, M. C., Lee, Y., Lemaitre, R. N., Fretts, A., Nemet, I., Sotoodehnia, N., Sitlani, C. M., Budoff, M., DiDonato, J. A., Wang, Z., Bansal, N., Shlipak, M. G., Psaty, B. M., Siscovick, D. S., Sarnak, M. J., Mozaffarian, D., & Hazen, S. L. (2024). The Gut Microbial Metabolite Trimethylamine N-oxide, Incident CKD, and Kidney Function Decline. Journal of the American Society of Nephrology, 35(6), 749. https://doi.org/10.1681/ASN.0000000000000344
16. Wilson Tang, W. H., Wang, Z., Kennedy, D. J., Wu, Y., Buffa, J. A., Agatisa-Boyle, B., Li, X. S., Levison, B. S., & Hazen, S. L. (2015). Gut Microbiota-Dependent Trimethylamine N-oxide (TMAO) Pathway Contributes to Both Development of Renal Insufficiency and Mortality Risk in Chronic Kidney Disease. Circulation research, 116(3), 448-455. https://doi.org/10.1161/CIRCRESAHA.116.305360
17. Zhuravin, I. АNalivaeva, N. N., Kozlova, D. I., Kochkina, E. G., Fedorova, Y. B., & Gavrilova, S. I. (2015). [The activity of blood serum cholinesterases and neprilysin as potential biomarkers of mild-cognitive impairment and Alzheimer’s disease]. Zhurnal Nevrologii I Psikhiatrii Imeni S.S. Korsakova, 115(12), 110–117. https://doi.org/10.17116/jnevro2015115112110-117

Image 1: from Shutterstock from StudioMolekuul

Image 2: from (Świątkiewicz & Grieb, 2023)