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Citicoline

  • Food & Drink
  • Updated January 4, 2024

Citicoline (also known as CDP-choline; cytidine 5'-diphosphocholine) is a naturally occurring compound that serves as a precursor for essential cellular nutrients, including choline, which is used in the production of cell membranes, and acetylcholine, a brain chemical important for memory. Insufficient brain levels of choline may contribute to memory loss and the breakdown of cell membranes in Alzheimer’s disease. Citicoline is considered the form of choline best absorbed by the brain. It is a common ingredient in supplements marketed for brain support, but there is no evidence to date that it can prevent dementia. No serious safety issues have been reported with citicoline treatment. 

Evidence

Clinical trials testing citicoline have been small with possible benefits depending on different factors.  Large confirmatory randomized clinical trials are needed.  

Our search identified:

  • 1 meta-analysis of randomized controlled trials in patients with vascular cognitive impairment, vascular dementia, and senile dementia
  • 3 meta-analyses of randomized controlled clinical trials in patients with acute ischemic stroke
  • 1 meta-analysis of clinical trials in traumatic brain injury
  • 1 systematic review of clinical studies in Parkinson’s disease
  • 5 case-control observational studies in Alzheimer’s patients
  • 1 prospective observational study in vascular cognitive impairment
  • 1 randomized controlled clinical trial in patients with Alzheimer’s disease
  • 1 randomized controlled clinical trial in patients with mild vascular cognitive impairment
  • 7 small clinical trials in healthy individuals (young, middle age, and elderly)
  • 1 randomized controlled clinical trial in traumatic brain injury
  • 4 small open label, non-controlled studies in Alzheimer’s patients

Potential Benefit

Short-term treatment with citicoline has shown benefits in individuals with lower cognition at the beginning of studies, but due to discrepancies across studies, there is insufficient evidence that it is beneficial in healthy people with otherwise good cognition. 

Citicoline supplementation improved speed in cognitive tasks in teenage boys [1], and reaction time in young adults in their 20s [2; 3]. However, another small study in young men found that while performance on measures of processing speed, memory, and executive function improved following supplementation in low performers, it declined slightly in those with high performance at baseline [4]. Similarly, improvements in memory in healthy elderly adults have primarily been observed in those with memory problems [5]. One study in healthy middle-aged women reported that citicoline improved attention [6], while another study in healthy middle age to older adults found a small effect on memory but no effects on attention [7]. Reduction in markers of oxidative stress have also been observed with citicoline supplementation [3].  

No studies have examined whether citicoline can prevent dementia, but studies to date have shown little to no benefit regarding protection against stroke or brain injury-related cognitive impairment. Citicoline has not shown benefits in ischemic stroke relative to the current standard of care [8; 9; 10]. In traumatic brain injury, modest neuroprotection has been observed with intravenous citicoline, while no clear benefits have been observed with other forms of administration [11]. 

APOE4 CARRIERS:

The impact of APOE4 on the effects of citicoline is unclear. One small pilot study in people with the APOE4 variant reported that citicoline treatment for three months improved cognition compared to patients on a placebo [12], another study reported that APOE4 carriers showed less benefit [13], while a third study indicated that cognitive benefits were independent of APOE4 status [14]. For more information on what the APOE4 gene allele means for your health, read our APOE4 information page.

For Dementia Patients

Pilot studies suggest that citicoline may provide cognitive benefits in patients with Alzheimer's disease, but no large randomized controlled trials have been conducted  [12; 15; 16; 17]. Five case-control observational studies reported cognitive benefits when citicoline is added to standard-of-care symptomatic treatments for Alzheimer’s disease relative to those receiving the standard-of-care alone. The modest effects on cognition generally required citicoline treatment for at least nine to 12 months [18; 19; 20; 21; 22]. Some studies also suggest citicoline may be beneficial for patients with vascular cognitive impairment [14; 23; 24], and may allow for lower levodopa doses in patients with Parkinson’s disease [25]. 

Safety

No serious safety issues have been reported with citicoline treatment [26]. In a meta-analysis of trials for cerebral dysfunction in elderly people, citicoline tended to be more tolerable than the placebo [23]. Longer term treatment, up to three years, shows a similar safety profile as short-term supplementation. Drug interactions with citicoline are not well studied, though it may interact with Parkinson's drugs such as levodopa (drugs.com).

NOTE: This is not a comprehensive safety evaluation or complete list of potentially harmful drug interactions. It is important to discuss safety issues with your physician before taking any new supplement or medication.

How to Use

Citicoline is available as a single supplement or as one ingredient in some supplements marketed to promote brain health. Typical doses are 250–1,000 mg/day. According to the European Food Safety Authority, the recommended maximum daily dose of citicoline is 500 mg/day for supplements and 1,000 mg/day for medical foods in middle-aged to elderly adults [27]. For healthy individuals, lower doses (e.g. 250 mg/day) may provide more benefit than higher doses [6], while most clinical studies in patients with neurological disease used doses of 1,000 mg/day. In dementia patients, treatment for at least 12 months was generally required to see evidence of cognitive benefit.

Learn More

Full scientific report (PDF) on Cognitive Vitality Reports

Check for drug-drug and drug-supplement interactions on Drugs.com.

References

  1. McGlade E, Agoston AM, DiMuzio J et al. (2019) The Effect of Citicoline Supplementation on Motor Speed and Attention in Adolescent Males. Journal of attention disorders 23, 121-134.
  2. Bruce SE, Werner KB, Preston BF et al. (2014) Improvements in concentration, working memory and sustained attention following consumption of a natural citicoline-caffeine beverage. International journal of food sciences and nutrition 65, 1003-1007.
  3. Al-Kuraishy HM, Al-Gareeb AI (2020) Citicoline Improves Human Vigilance and Visual Working Memory: The Role of Neuronal Activation and Oxidative Stress. Basic and clinical neuroscience 11, 423-432.
  4. Knott V, de la Salle S, Choueiry J et al. (2015) Neurocognitive effects of acute choline supplementation in low, medium and high performer healthy volunteers. Pharmacology, biochemistry, and behavior 131, 119-129.
  5. Spiers PA, Myers D, Hochanadel GS et al. (1996) Citicoline improves verbal memory in aging. Archives of neurology 53, 441-448.
  6. McGlade E, Locatelli A, Hardy J et al. (2012) Improved Attentional Performance Following Citicoline Administration in Healthy Adult Women. Food and Nutrition Sciences 3, 769-773.
  7. Nakazaki E, Mah E, Sanoshy K et al. (2021) Citicoline and Memory Function in Healthy Older Adults: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial. The Journal of nutrition 151, 2153-2160.
  8. Secades JJ, Alvarez-Sabín J, Castillo J et al. (2016) Citicoline for Acute Ischemic Stroke: A Systematic Review and Formal Meta-analysis of Randomized, Double-Blind, and Placebo-Controlled Trials. Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association 25, 1984-1996.
  9. Martí-Carvajal AJ, Valli C, Martí-Amarista CE et al. (2020) Citicoline for treating people with acute ischemic stroke. The Cochrane database of systematic reviews 8, Cd013066.
  10. Sagaro GG, Amenta F (2023) Choline-Containing Phospholipids in Stroke Treatment: A Systematic Review and Meta-Analysis. Journal of clinical medicine 12.
  11. Secades JJ, Trimmel H, Salazar B et al. (2023) Citicoline for the Management of Patients with Traumatic Brain Injury in the Acute Phase: A Systematic Review and Meta-Analysis. Life (Basel, Switzerland) 13.
  12. Alvarez XA, Mouzo R, Pichel V et al. (1999) Double-blind placebo-controlled study with citicoline in APOE genotyped Alzheimer's disease patients. Effects on cognitive performance, brain bioelectrical activity and cerebral perfusion. Methods and findings in experimental and clinical pharmacology 21, 633-644.
  13. Selezneva ND, Gavrilova SI, Roshchina IF et al. (2021) [Citicoline in the treatment of cognitive impairment in first-degree relatives of AD patients: the influence of the ApoE genotype]. Zhurnal nevrologii i psikhiatrii imeni SS Korsakova 121, 30-36.
  14. Almeria M, Alvarez I, Molina-Seguin J et al. (2023) Citicoline May Prevent Cognitive Decline in Patients with Cerebrovascular Disease. Clinical interventions in aging 18, 1093-1102.
  15. Cacabelos R, Alvarez XA, Franco-Maside A et al. (1993) Effect of CDP-choline on cognition and immune function in Alzheimer's disease and multi-infarct dementia. Annals of the New York Academy of Sciences 695, 321-323.
  16. Caamaño J, Gómez MJ, Franco A et al. (1994) Effects of CDP-choline on cognition and cerebral hemodynamics in patients with Alzheimer's disease. Methods and findings in experimental and clinical pharmacology 16, 211-218.
  17. Cacabelos R, Caamaño J, Gómez MJ et al. (1996) Therapeutic effects of CDP-choline in Alzheimer's disease. Cognition, brain mapping, cerebrovascular hemodynamics, and immune factors. Annals of the New York Academy of Sciences 777, 399-403.
  18. Gareri P, Castagna A, Cotroneo AM et al. (2017) The Citicholinage Study: Citicoline Plus Cholinesterase Inhibitors in Aged Patients Affected with Alzheimer's Disease Study. Journal of Alzheimer's disease : JAD 56, 557-565.
  19. Castagna A, Cotroneo AM, Ruotolo G et al. (2016) The CITIRIVAD Study: CITIcoline plus RIVAstigmine in Elderly Patients Affected with Dementia Study. Clinical drug investigation 36, 1059-1065.
  20. Castagna A, Manzo C, Fabbo A et al. (2021) The CITIMERIVA Study: CITIcoline plus MEmantina plus RIVAstigmine in Older Patients Affected with Alzheimer's Disease. Clinical drug investigation 41, 177-182.
  21. Castagna A, Fabbo A, Manzo C et al. (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 : JAD 79, 1509-1515.
  22. Gareri P, Cotroneo AM, Orsitto G et al. (2021) The Importance of Citicoline in Combined Treatment in Dementia: What did the Citimem Study Teach us? Reviews on recent clinical trials 16, 126-130.
  23. Fioravanti M, Yanagi M (2004) Cytidinediphosphocholine (CDP choline) for cognitive and behavioural disturbances associated with chronic cerebral disorders in the elderly. The Cochrane database of systematic reviews, Cd000269.
  24. Cotroneo AM, Castagna A, Putignano S et al. (2013) Effectiveness and safety of citicoline in mild vascular cognitive impairment: the IDEALE study. Clinical interventions in aging 8, 131-137.
  25. Que DS, Jamora RDG (2021) Citicoline as Adjuvant Therapy in Parkinson's Disease: A Systematic Review. Clinical therapeutics 43, e19-e31.
  26. Grieb P (2014) Neuroprotective properties of citicoline: facts, doubts and unresolved issues. CNS drugs 28, 185-193.
  27. EFSA Panel on Dietetic Products N, Allergies (2013) Scientific Opinion on the safety of “citicoline” as a Novel Food ingredient. EFSA Journal 11, 3421.