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Scientific Name(s): Cytidine 5′-diphosphocholine, Cytidine diphosphate-choline
Common Name(s): CDP-choline, Citicoline
Drug class: Oral nutritional supplements

Medically reviewed by Last updated on Feb 15, 2021.

Clinical Overview


There is mounting evidence for choline's place in therapy for stroke, brain and spinal cord injury, cognitive deficits, and glaucoma; however, results in clinical trials have been inconsistent.


Oral dosages of 250 to 2,000 mg daily have been evaluated in adolescents and adults in clinical trials. Lower doses (100 mg twice daily) have been used in short-term trials (6 weeks) with combination therapy in patients with major depressive disorder.


Contraindications have not been identified.


Information regarding safety and efficacy in pregnancy and lactation is lacking at dosages above those usually taken nutritionally.


None well documented.

Adverse Reactions

Citicoline was well tolerated in clinical trials. Adverse effects may include GI disturbances, transient headaches, hypotension, tachycardia, bradycardia, and restlessness.


Studies in humans are limited.


Citicoline is found in all animal and plant cell membranes. It is available commercially in its free-base form or as a sodium salt.1


Citicoline is widely available internationally as a supplement, which was originally developed in Japan for the treatment of cerebrovascular disorders. Use of citicoline has been extended to include treatment of chronic conditions, although further research is needed.2


Citicoline is a phospholipid composed of ribose, pyrophosphate, cytosine, and choline. It is water-soluble and highly bioavailable.3 Citicoline is produced endogenously as an intermediate in the production of phosphatidylcholine from choline and is then hydrolyzed in the small intestine to make choline and cytidine available for further biosynthesis.4

Uses and Pharmacology

Supplementation with citicoline increases choline stores available for other biosynthetic pathways. Citicoline appears to decrease glutamate levels in the brain and increase adenosine triphosphate, which in turn offers protection against ischemic neurotoxicity. Increased glucose metabolism in the brain and cerebral blood flow has also been demonstrated, as well as increased availability of the neurotransmitters acetylcholine, norepinephrine, and dopamine.4, 5

Cocaine dependence

Clinical data

Studies have investigated a role for citicoline in substance addiction and among patients with bipolar disorder.25, 26 A 12-week, double-blind, parallel-group, randomized, placebo-controlled trial (n = 130) in adults with bipolar disorder and cocaine dependence reported a significant early treatment effect in favor of citicoline (500 mg/day titrated up every 2 weeks to 2,000 mg/day by week 6) compared to placebo.34


Animal data

Accelerated resynthesis of phospholipids and subsequent protection of cell membranes in the presence of citicoline have been suggested as a possible mechanism of action, based on animal studies. Labeled phospholipid from radioactively labeled citicoline has been shown to cross the blood-brain barrier. Studies in rats with cognitive impairment have been conducted, and improved memory and learning have been demonstrated in older rats and those with induced memory deficits. Citicoline has also demonstrated enhanced learning ability in dogs.2, 6, 7 Limited animal studies suggest that citicoline may counteract the deposition of beta-amyloid involved in Alzheimer disease.6

Clinical data

A Cochrane meta-analysis of clinical trials up to 2004 found some evidence of supplemental citicoline's positive effect on memory and behavior in the short- to medium-term versus placebo. Effect size for memory measures (N = 884) was 0.19 (95% confidence interval [CI], 0.06 to 0.32), and for the measure of positive Global Clinical Impression (N = 217), an odds ratio (OR) of 8.89 was found (95% CI, 5.19 to 15.22).2 The report further suggests that the effect of citicoline (oral or intravenous) on memory in the included studies did not appear to depend on the pathogenesis of the cerebral disorder. Trials included in the meta-analysis enrolled participants with mild to moderate dementia and Alzheimer disease, as well as those with cerebrovascular disorders.2, 8, 9 An open-label IDEALE study in Italy administered citicoline 1 g daily in 2 divided doses over 9 months to 265 patients with mild age-related vascular cognitive impairment. Mini-Mental State Examination scores remained essentially unchanged over time for the treatment arm, while a decline was evident in the control patients.10 Another open-label, parallel study of citicoline versus usual treatment was conducted in 347 poststroke patients in Spain. Improved cognitive outcomes were reported for the citicoline-treated group in attention, temporal orientation, and functional outcome measures.11


Clinical data

Depression scores improved significantly at 2, 4, and 6 weeks from baseline in patients diagnosed with major depressive disorder who received 6 weeks of citicoline (100 mg every 12 hours) in combination with citalopram (20 mg/day × 7 days, then 40 mg/day) compared to citalopram alone (P<0.03, P=0.032, and P=0.021, respectively) in a randomized, double-blind, placebo-controlled, parallel-group study (n=50). Additionally, the "depressed mood" item improved significantly at the end of the trial (P=0.04). Remission rate was also significantly greater with citicoline combination therapy (72%) compared to citalopram only (44%; P=0.045). No significant differences were noted in adverse events between groups.36


Animal data

Studies in animals suggest that citicoline stimulates dopamine in the retina.12

Clinical data

Limited trials have been conducted.4, 12 However, an 8-year follow-up of patients with glaucoma included in an earlier trial showed improvement in retinal and visual function.13 An open-label study showed similar effects following 2 weeks of treatment with oral citicoline 1 g daily.14

Head injury

Animal data

Antioxidant and anti-inflammatory mechanisms of citicoline have been evaluated in experimental studies in rats.15, 16

Clinical data

A 2008 systematic review of the effect of cholinomimetic agents on head injury included trials using citicoline and case reports, all with some limitations in the methodology (eg, small sample size, single blinding).17 Positive findings have been reported in these studies; however, in the larger Citicoline Brain Injury Treatment Trial published in 2012, a 90-day regimen of enteral or oral citicoline 2,000 mg daily did not result in improvement in functional and cognitive status versus placebo (global OR, 0.87 [95% CI, 0.72 to 1.04]).18

Psychomotor function

Clinical data

Attention and psychomotor speed (of the dominant hand) improved significantly in healthy adolescent males (13 to 18 years of age) after 28 days of supplementation with citicoline 250 and 500 mg/day compared with placebo in a randomized, double-blind trial (n = 75). Changes in scores were predicted significantly more by a weight-adjusted dose with greater improvements in accuracy, detectability, and commission errors following higher weight-adjusted doses.33


Animal data

Positive findings have been reported in experiments using rats with induced cerebral insufficiency and models of hypoxia.19, 20

Clinical data

A meta-analysis of pooled individual results of studies evaluating adjunctive citicoline 500 to 2,000 mg/day in moderate to severe acute ischemic stroke found a positive OR of 1.33 (95% CI, 1.10 to 1.62) for citicoline.14 Further reviews have also suggested citicoline's promise in improving outcomes at 3 months following ischemic stroke.6, 20, 21, 22, 23

Findings have been published from a large multicenter study (N = 2,298) in ischemic stroke patients conducted between 2006 to 2011 using citicoline 1 g IV every 12 hours for 3 days, then orally for 6 weeks. Using a global score combining the National Institutes of Health Stroke Scale, modified Rankin score, and Barthel Index, the ICTUS trial found no significant difference at 90 days for citicoline over placebo (OR, 1.03 [95% CI, 0.86 to 1.25; P = 0.364]). Similarly, there were no significant differences for adverse events.24 Likewise, results were reported in a meta-analysis that reviewed randomized controlled trials published until May 2015 investigating administration of citicoline within 24 hours of acute ischemic (n=6 studies) or hemorrhagic (n=1 study) stroke. Dosing in the 7 studies (N=4,039) ranged from 500 to 2,000 mg/day given for a minimum of 3 months. No significant difference was found in mortality, outcome dependency, effectiveness, or safety between citicoline and controls.35


Citicoline is water-soluble and highly bioavailable, with very little drug excreted in the feces.3 Citicoline exhibits biphasic plasma peak concentrations at 1 and 24 hours, as well as biphasic elimination.28

Oral dosages of 250 to 2,000 mg daily have been evaluated in adolescents and adults in clinical trials.5, 7, 14, 33 Citicoline 100 mg every 12 hours was used in combination with citalopram (20 mg/day for 7 days, then 40 mg/day) for 6 weeks in patients with major depressive disorder.28 (36)

Pregnancy / Lactation

Information regarding safety and efficacy in pregnancy and lactation is lacking at dosages above those usually taken nutritionally. The effects of citicoline have been studied in rats during pregnancy for a potential role in the protection of dendrites in the cortex and fetal lung development, as well as in pregnant women in their third trimesters. However, information is limited on the safety of supplemental citicoline.29, 30


None well documented.4

Adverse Reactions

Citicoline was well tolerated in clinical trials.2 Adverse effects may include GI disturbances, transient headaches, hypotension, tachycardia, bradycardia, and restlessness.3, 4, 10, 31

Citicoline may exacerbate adrenocorticotropic hormone– or cortisol hypersecretion–related disorders, including type 2 diabetes and major depressive disorder.32


Studies in humans are limited. The IV median lethal dose in rodents was suggested to be around 4 g/kg. A 30-day study in rats found no toxicity at 150 mg/kg/day. In dogs given oral citicoline 1.5 g/kg daily for 6 months, no biochemical, neurological, or histological toxicity was found.1


1. Schauss AG, Somfai-Relle S, Financsek I, et al. Single- and repeated-dose oral toxicity studies of citicoline free-base (choline cytidine 5′-pyrophosphate) in Sprague-Dawley rats. Int J Toxicol. 2009;28(6):479-487.19966140
2. Fioravanti M, Yanagi M. Cytidinediphosphocholine (CDP-choline) for cognitive and behavioural disturbances associated with chronic cerebral disorders in the elderly. Cochrane Database Syst Rev. 2005;(2):CD000269.15846601
3. Dávalos A, Secades J. Citicoline preclinical and clinical update 2009-2010. Stroke. 2011;42(suppl 1):S36-S39.21164116
4. Secades JJ, Lorenzo JL. Citicoline: pharmacological and clinical review, 2006 update. Methods Find Exp Clin Pharmacol. 2006;28(suppl B):1-56.17171187
5. Arenth PM, Russell KC, Ricker JH, Zafonte RD. CDP-choline as a biological supplement during neurorecovery: a focused review. PM R. 2011;3(6 suppl 1):S123-S131.21703569
6. Conant R, Schauss AG. Therapeutic applications of citicoline for stroke and cognitive dysfunction in the elderly: a review of the literature. Altern Med Rev. 2004;9(1):17-31.15005642
7. García-Cobos R, Frank-García A, Gutiérrez-Fernández M, Díez-Tejedor E. Citicoline, use in cognitive decline: vascular and degenerative. J Neurol Sci. 2010;299(1-2):188-192.20875651
8. Fioravanti M, Buckley AE. Citicoline (Cognizin) in the treatment of cognitive impairment. Clin Interv Aging. 2006;1(3):247-251.18046877
9. Alvarez-Sabín J, Ortega G, Jacas C, et al. Long-term treatment with citicoline may improve poststroke vascular cognitive impairment. Cerebrovasc Dis. 2013;35(2):146-154.23406981
10. Cotroneo AM, Castagna A, Putignano S, et al. Effectiveness and safety of citicoline in mild vascular cognitive impairment: the IDEALE study. Clin Interv Aging. 2013;8:131-137.23403474
11. Alvarez-Sabín J, Román GC. Citicoline in vascular cognitive impairment and vascular dementia after stroke. Stroke. 2011;42(suppl 1):S40-S43.21164117
12. Grieb P, Rejdak R. Pharmacodynamics of citicoline relevant to the treatment of glaucoma. J Neurosci Res. 2002;67(2):143-148.11782957
13. Parisi V, Coppola G, Centofanti M, et al. Evidence of the neuroprotective role of citicoline in glaucoma patients. Prog Brain Res. 2008;173:541-554.18929133
14. Saver JL. Citicoline: update on a promising and widely available agent for neuroprotection and neurorepair. Rev Neurol Dis. 2008;5(4):167-177.19122569
15. Menku A, Ogden M, Saraymen R. The protective effects of propofol and citicoline combination in experimental head injury in rats. Turk Neurosurg. 2010;20(1):57-62.20066623
16. Bian XX, Yuan XS, Qi CP. Effect of recombinant human erythropoietin on serum S100B protein and interleukin-6 levels after traumatic brain injury in the rat. Neurol Med Chir (Tokyo). 2010;50(5):361-366.20505289
17. Poole NA, Agrawal N. Cholinomimetic agents and neurocognitive impairment following head injury: a systematic review. Brain Inj. 2008;22(7-8):519-534.18568705
18. Zafonte RD, Bagiella E, Ansel BM, et al. Effect of citicoline on functional and cognitive status among patients with traumatic brain injury: Citicoline Brain Injury Treatment Trial (COBRIT). JAMA. 2012;308(19):1993-2000.23168823
19. Hurtado O, Lizasoain I, Moro MÁ. Neuroprotection and recovery: recent data at the bench on citicoline. Stroke. 2011;42(suppl 1):S33-S35.21164125
20. Clark WM. Efficacy of citicoline as an acute stroke treatment. Expert Opin Pharmacother. 2009;10(5):839-846.19351232
21. Adibhatla RM, Hatcher JF. Citicoline mechanisms and clinical efficacy in cerebral ischemia. J Neurosci Res. 2002;70(2):133-139.12271462
22. Adibhatla RM, Hatcher JF. Cytidine 5′-diphosphocholine (CDP-choline) in stroke and other CNS disorders. Neurochem Res. 2005;30(1):15-23.15756928
23. Overgaard K, Meden P. Citicoline—the first effective neuroprotectant to be combined with thrombolysis in acute ischemic stroke? J Neurol Sci. 2006;247(2):119-120.16765988
24. Dávalos A, Alvarez-Sabín J, Castillo J, et al. Citicoline in the treatment of acute ischaemic stroke: an international, randomised, multicentre, placebo-controlled study (ICTUS trial). Lancet. 2012;380(9839):349-357.22691567
25. Brown ES, Gabrielson B. A randomized, double-blind, placebo-controlled trial of citicoline for bipolar and unipolar depression and methamphetamine dependence. J Affect Disord. 2012;143(1-3):257-260.22974472
26. Licata SC, Penetar DM, Ravichandran C, et al. Effects of daily treatment with citicoline: a double-blind, placebo-controlled study in cocaine-dependent volunteers. J Addict Med. 2011;5(1):57-64.21769048
27. Jambou R, El-Assaad F, Combes V, Grau GE. Citicoline (CDP-choline): What role in the treatment of complications of infectious diseases. Int J Biochem Cell Biol. 2009;41(7):1467-1470.19401146
28. Sarkar AK, Ghosh D, Haldar D, et al. A rapid LC–ESI-MS/MS method for the quantitation of choline, an active metabolite of citicoline: Application to in vivo pharmacokinetic and bioequivalence study in Indian healthy male volunteers. J Pharm Biomed Anal. 2012;71:144-147.22951317
29. Rema V, Bali KK, Ramachandra R, Chugh M, Darokhan Z, Chaudhary R. Cytidine-5-diphosphocholine supplement in early life induces stable increase in dendritic complexity of neurons in the somatosensory cortex of adult rats. Neuroscience. 2008;155(2):556-564.18619738
30. Yan J, Jiang X, West AA, et al. Pregnancy alters choline dynamics: results of a randomized trial using stable isotope methodology in pregnant and nonpregnant women. Am J Clin Nutr. 2013;98(6):1459-1467.24132975
31. Cho HJ, Kim YJ. Efficacy and safety of oral citicoline in acute ischemic stroke: drug surveillance study in 4,191 cases. Methods Find Exp Clin Pharmacol. 2009;31(3):171-176.19536360
32. Cavun S, Savci V. CDP-choline increases plasma ACTH and potentiates the stimulated release of GH, TSH and LH: the cholinergic involvement. Fundam Clin Pharmacol. 2004;18(5):513-523.15482372
33. McGlade E, Agoston AM, DiMuzio J, et al. The effect of citicoline supplementation on motor speed and attention in adolescent males [published online ahead of print July 15, 2015]. J Att Dis.26179181
34. Brown ES, Todd JP, Hu LT, Schmitz JM, Carmody TJ, Nakamura A, Sunderajan P, Rush AJ, Adinoff B, Bret ME, Holmes T, Lo A. A randomized, double-blind, placebo-controlled trial of citicoline for cocaine dependence in bipolar 1 disorder. Am J Psychiatry. 2015;172:1014-1021.25998279
35. Shi PY, Zhou XC, Yin XX, Xu LL, Zhang XM, Bai HY. Early application of citicoline in the treatment of acute stroke: a meta-analysis of randomized controlled trials. J Huazhong Univ Sci Technol Med Sci. 2016;36(2):270-277.27072975
36. Roohi-Azizi M, Arabzadeh S, Amidfar M, et al. Citicoline combination therapy for major depressive disorder: a randomized, double-blind, placebo-controlled trial. Clin Neuropharm. 2017;40:1-5.2885707


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