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Common Name(s): CDP-choline, Citicoline, Cytidine 5′-diphosphocholine, Cytidine diphosphate-choline

Medically reviewed by Last updated on Nov 1, 2022.

Clinical Overview


Citicoline has been investigated for the treatment of depression, schizophrenia, stroke, Parkinson disease, brain injury, and cognitive deficits (ie, mild to moderate dementia and Alzheimer disease, cerebrovascular disorders), as well as for its ophthalmologic effects. However, clinical trial results have been inconsistent; therefore, citicoline cannot be recommended for any indication.


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 consumed 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.


No data.


Citicoline is found in all animal and plant cell membranes. 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.(Nakazaki 2021, Secades 2006) Citicoline is available commercially in its free-base form or as a sodium salt.(Schauss 2009)


Citicoline is widely available internationally as a supplement, which was originally developed in Japan for the treatment of acute cerebrovascular disorders. After introduction in some European markets, use has shifted from treatment of acute to treatment of chronic cerebrovascular disorders, although further research is needed.(Fioravanti 2005)


Citicoline is a phospholipid composed of ribose, pyrophosphate, cytosine, and choline. It is water soluble and highly bioavailable.(Nakazaki 2021, Nashine 2020, Shi 2016)

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.(Arenth 2011, Secades 2006)

Antioxidant effects

Animal and in vitro data

Antioxidant effects of citicoline have been demonstrated in several models, including brain, renal, and hepatic injury.(Bian 2010, Buelna-Chontal 2017, Kocaturk 2021, Menku 2010, Zazueta 2018)

CNS effects


Clinical data

Studies have investigated a role for citicoline in substance addiction, including in patients with bipolar disorder.(Brown 2012, Licata 2011) A 12-week, double-blind, parallel-group, randomized, placebo-controlled trial in 130 adults with bipolar disorder and cocaine dependence reported a significant early treatment effect with citicoline (500 mg/day titrated up every 2 weeks to 2,000 mg/day by week 6) compared with placebo.(Brown 2015)

In methamphetamine-dependent adults enrolled in a double-blind, randomized, placebo-controlled trial (N=74), administration of citicoline 1 g orally twice daily for 8 weeks significantly increased the volume of grey matter (ie, left middle frontal gyrus, right hippocampus, left precuneus) compared with baseline (P<0.01 each) and compared with placebo-treated methamphetamine-dependent patients as well as healthy controls. Although cravings for methamphetamine decreased significantly in the citicoline group (P=0.01), the changes were not statistically significantly different from placebo. Citicoline was well tolerated, with 13 adverse events reported compared with 28 events with placebo.(Jeong 2021)

In another double-blind, randomized, placebo-controlled trial in patients with alcohol use syndrome (N=62), effects of a 12-week citicoline regimen on alcohol use and craving and cognitive parameters were explored. No differences were observed between groups regarding number of drinking days, alcohol craving, or cognitive outcome scores. Tolerability was similar between groups.(Brown 2019)


Animal data

Based on 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 in treating cognitive impairment. Labeled phospholipid from radioactively labeled citicoline has been shown to cross the blood-brain barrier. In studies in rats with cognitive impairment, 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.(Conant 2004, Fioravanti 2005, García-Cobos 2010) Limited animal studies suggest that citicoline may counteract the deposition of beta-amyloid involved in Alzheimer disease.(Conant 2004)

Clinical data

A Cochrane meta-analysis of clinical trials (from 1970s to 2003) 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% CI, 0.06 to 0.32); measure of positive Global Clinical Impression (n=217) showed an odds ratio (OR) of 8.89 (95% CI, 5.19 to 15.22).(Fioravanti 2005) The report further suggests that the effect of citicoline (oral or intravenous [IV]) on memory 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.(Alvarez-Sabín 2013, Fioravanti 2005, Fioravanti 2006) In the open-label IDEALE Italian study in patients with mild age-related vascular cognitive impairment (N=349), 265 patients received citicoline 1 g daily in 2 divided doses over 9 months. Mini-Mental State Examination scores remained essentially unchanged over time for the treatment arm, while a decline was evident in control patients (no treatment).(Cotroneo 2013) A placebo-controlled study of 100 patients with age-associated memory impairment used a citicoline dosage of 500 mg daily for 12 weeks. Treated patients significantly improved from baseline to end point in 3 of the 8 outcomes: Spatial Span, Composite Memory, and Feature Match assessments.(Nakazaki 2021) Another open-label, parallel study of citicoline versus usual treatment was conducted in 347 poststroke patients in Spain. Improved cognitive outcomes (attention, temporal orientation, and executive function) were reported for the citicoline-treated group.(Alvarez-Sabín 2011)

In healthy volunteers (N=40), a 2-week trial of citicoline 500 mg daily showed significant changes compared with placebo in cognitive outcome measures, such as processing time, working memory, and vigilance. Serum malondialdehyde levels, which normally increase during psychomental stimulus, were also reduced compared with placebo.(Al-kuraishy 2020)


Clinical data

In a randomized, double-blind, placebo-controlled, parallel-group study in patients diagnosed with major depressive disorder (N=50), depression scores improved significantly at 2, 4, and 6 weeks from baseline with 6 weeks of citicoline (100 mg every 12 hours) in combination with citalopram (20 mg/day for 7 days, then 40 mg/day) compared with citalopram alone (P<0.03, P=0.032, and P=0.021, respectively). Additionally, a significant difference in the "depressed mood" item of the Hamilton Depression Rating Scale was observed between the 2 groups at the end of the trial (P=0.04). Remission rate was also significantly greater with citicoline combination therapy (72%) compared with citalopram only (44%) (P=0.045). No significant differences were noted in adverse events between groups.(Roohi-Azizi 2017)


Animal data

In 2 organophosphate-induced seizure rat models, administration of citicoline did not demonstrate anticonvulsant or neuroprotective effects.(Barker 2020)

Head injury

Animal data

Antioxidant and anti-inflammatory mechanisms of citicoline have been evaluated in experimental studies of rats with head injury.(Bian 2010, Menku 2010)

Clinical data

A 2008 systematic review of the effects of cholinomimetic agents on head injury included trials and case reports using citicoline, all with some limitations in methodology (eg, small sample size, single blinding).(Poole 2008) 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]).(Zafonte 2012)

Neuroprotective effects

Clinical data

Hospitalized children (N=80) who had experienced cardiac arrest were treated with citicoline 10 mg/kg added to conventional therapy for 6 weeks or conventional therapy alone. Patients in the citicoline group had improved Glascow coma and disability scores and reduced seizure frequency and duration, as well as shorter pediatric intensive care unit stays and a lower mortality rate compared with the conventional therapy group.(Salamah 2021)

Parkinson disease

Clinical data

A systematic review of literature published through 2019 evaluated citicoline as an adjuvant to levodopa therapy in adults with Parkinson disease. The 7 included studies were randomized controlled (n=3), crossover (n=2), and open-label prospective (n=2). The studies enrolled a total of 335 patients (individual study range, 10 to 85 patients) 31 to 82 years of age. Duration of disease ranged from 1 month to 30 years, and disease severity encompassed all stages. Overall, results suggested that the addition of citicoline to levodopa may offer benefit over levodopa alone, including up to a 50% reduction in levodopa dose noted by 2 studies and significant improvement in global and/or individual symptoms (eg, rigidity, akinesia, motor tasks, balancing upper extremities, speech) documented in all 7 studies.(Que 2021)

Psychomotor function

Clinical data

Attention and psychomotor speed (of the dominant hand) improved significantly in 75 healthy adolescent males (13 to 18 years of age) after 28 days of supplementation with citicoline 250 mg/day or 500 mg/day compared with placebo in a randomized, double-blind trial. Higher weight-adjusted doses were associated with greater improvements in accuracy, signal detectability, and commission errors.(McGlade 2019)


Clinical data

In an 8-week double-blind, randomized, placebo-controlled trial in 73 patients with stable schizophrenia, adjunctive use of citicoline with risperidone significantly improved mean negative symptom scores (on Positive and Negative Syndrome Scale [PANSS]) compared with placebo plus risperidone (adjusted P=0.013). Patients in the citicoline group experienced a significantly (both statistically and clinically) greater reduction (11%) from baseline in PANSS negative subscale score compared with those receiving placebo. General psychopathology (P=0.013) and total PANSS scores (P<0.001) were also better in the citicoline group. Scores for positive symptoms, extrapyramidal symptoms, and depression remained similar between treatment groups. No significant difference in frequency of adverse events was observed between the groups.(Ghajar 2018)

Citicoline's effects in schizophrenia may be related to improvements in sensory processing associated with impact on the alpha7 nicotinic acetylcholine receptor system.(Aidelbaum 2022)

Tremor/ataxia syndrome

Clinical data

An open-label phase 2 pilot study explored the safety and efficacy of citicoline in 10 patients with fragile X-associated tremor/ataxia syndrome, specifically in terms of motor and cognitive function. Overall, citicoline 1,000 mg/day for 12 months did not significantly improve the severity of motor signs, and results were inconclusive regarding whether improvements in cognitive scores and anxiety were due to study medication. Citicoline was safe and well tolerated in this small patient population.(Hall 2020)

Endotoxic shock

Animal data

In a study of mongrel dogs, administration of citicoline reduced or blocked endotoxin-induced changes in blood pressure (P<0.001), heart rate (P<0.001), echocardiographic parameters, cardiac injury markers, respiratory rate, PO2, pH (P<0.001), and bicarbonate versus baseline, without altering sinus cardiac rhythm. Additionally, citicoline suppressed endotoxin-induced increases in tumor necrosis factor alpha and nitric oxide but also enhanced catecholamine levels in both control and endotoxin-treated animals.(Kocaturk 2021)

Hepatoprotective effects

Animal data

In mice, citicoline provided hepatoprotective effects against ischemic-reperfusion liver damage via preservation of mitochondrial function and a reduction in oxidative stress, but did not show an effect on inflammatory mediators.(Zazueta 2018)

Ophthalmologic effects

Animal data

Studies in animals suggest that citicoline stimulates dopamine in the retina.(Grieb 2002) In rats with chronically elevated intraocular pressure (IOP), oral citicoline treatment (500 mg/kg) was associated with reduced degradation of visual acuity and "visual brain integrity loss" without lowering IOP, suggesting neurological benefits beyond IOP control.(van der Merwe 2021)

Clinical data

An 8-year follow-up of patients with glaucoma who were included in an earlier trial showed improvement in retinal and visual function.(Parisi 2008) An open-label study showed similar effects following 2 weeks of treatment with oral citicoline 1 g daily.(Saver 2008) In patients with mild to moderate progressive open-angle glaucoma (IOP <18 mm Hg) enrolled in a double-blind, randomized, placebo-controlled study (N=80), topical citicoline application for 3 years did not significantly reduce the 3-year progression rate compared with placebo (−1.03 dB vs −1.92 dB, respectively) based on the 24-2 standard strategy assessment. In contrast, significant improvement in visual field progression was observed with citicoline compared with placebo using the 10-2 strategy assessment (3-year progression rate, −0.41 dB vs −2.22 dB, respectively; P=0.02). The rate of retinal nerve fiber layer loss was also significantly less on average at year 3 with citicoline eye drops (−1.86 mcm) compared with placebo (−2.99 mcm) (P=0.02). Humphrey field analyzer mean deviation progression was significantly associated with age but not IOP. Citicoline eye drops were well tolerated, and no local or systemic adverse events were reported.(Rossetti 2020)

In a single-blind, randomized, prospective pilot study of adults with nonarteritic anterior ischemic optic neuropathy (NAION) (N=60), 6-month administration of oral citicoline solution significantly improved functional and morphological parameters (P<0.01 each) compared with no treatment. Improvements were significantly and positively correlated with greater impairment at baseline (P<0.01 each). Additionally, visual acuity was significantly better in the citicoline group, with only 5.27% of eyes experiencing a reduction in visual acuity at month 6 compared with 29.41% of eyes in the untreated group (P<0.01). After a 3-month citicoline washout period, significant improvements were maintained for all 3 assessments in treated compared with untreated controls (P<0.01 for all) at month 9. Reduced visual acuity was still present in only 5.26% of eyes previously treated with citicoline compared with 41.18% of eyes in the untreated group. No adverse events were reported in either group.(Parisi 2019)

Based on success with citicoline treatment in adult patients with amblyopia, researchers performed a retrospective study evaluating success rates in pediatric patients treated with citicoline for refractive amblyopia. All eyes showed clinical improvement in visual acuity after 3 to 6 months of treatment, but only eyes with mild or moderate amblyopia reached statistically significant improvement.(Loebis 2021)

In a prospective, controlled study in 78 patients who underwent LASIK surgery, post-LASIK treatment with either conventional lubricant (hyaluronic acid 15% eye drops) or citicoline eye drops was compared. Corneal sensitivity measurements were significantly better with citicoline at postsurgical weeks 1, 2, 3, 4, and 6; measurements were not significantly different between groups at weeks 8 and 12.(Cinar 2019)

Renal dysfunction

Animal data

Citicoline offered nephroprotection against mercury-induced renal damage in rats, specifically via preservation of calcium accumulation in the renal mitochondria. This allowed for continued transmembrane potential and adenosine triphosphate production. Reductions in oxidative stress were also reported, including lower interleukin 1 (IL-1) and IL-6 levels.(Buelna-Chontal 2017)

Respiratory distress syndrome

Animal data

In mice infected with an acutely lethal dose of H1N1 influenza A virus, administration of citicoline within 4 days postinoculation significantly reduced hypoxemia, bradycardia, pulmonary edema, and bronchoalveolar lavage fluid protein levels. Static lung compliance and alveolar fluid clearance rates were also restored to normal.(Rosas 2021)


Animal data

Positive findings with citicoline have been reported in experiments using rats with induced cerebral insufficiency and models of hypoxia.(Clark 2009, Hurtado 2011)

Clinical data

A meta-analysis of pooled individual results from studies evaluating adjunctive use of citicoline 500 to 2,000 mg/day in moderate to severe acute ischemic stroke showed a positive OR of 1.33 (95% CI, 1.1 to 1.62) for citicoline.(Saver 2008) Further reviews of citicoline treatment following ischemic stroke have also suggested improved outcomes, including complete recovery, at 3 months.(Adibhatla 2002, Adibhatla 2005, Clark 2009, Conant 2004, Overgaard 2006) However, in a meta-analysis of randomized controlled trials (published up to May 2015) in which citicoline was administered within 24 hours of acute ischemic (n=6 studies) or hemorrhagic (n=1 study) stroke, no significant difference was found between citicoline and controls regarding mortality, outcome dependency, effectiveness, or safety. Citicoline dosing in the 7 studies (N=4,039) ranged from 500 to 2,000 mg/day given for a minimum of 3 months.(Shi 2016)

Findings from the large multicenter ICTUS study in ischemic stroke patients (N=2,298; conducted between 2006 and 2011) using citicoline 1 g IV every 12 hours for 3 days, then orally for 6 weeks have been published. Using a global score combining the National Institutes of Health Stroke Scale, modified Rankin score, and Barthel Index, no significant difference at 90 days between citicoline and placebo was observed (OR, 1.03 [95% CI, 0.86 to 1.25]; P=0.364). Similarly, there were no significant differences regarding adverse events.(Dávalos 2012)

A 2020 Cochrane review of citicoline use in acute ischemic stroke (10 studies) concluded that there may be "little or no difference" in mortality, disability reduction, cardiovascular adverse events, or physical recovery for citicoline treatment compared with placebo.(Martí-Carvajal 2020) A placebo-controlled study evaluating citicoline 1 g twice daily in patients undergoing recanalization after acute ischemic stroke showed no difference from placebo in clinical outcomes at 3 months.(Agarwal 2022) A study of conventional therapy alone versus conventional therapy plus citicoline 1 g daily showed no differences in clinical outcomes at 8 weeks, but did note an improvement in short-interval intracortical inhibition in the citicoline group compared with placebo.(Premi 2022)


In clinical studies evaluating various neurological effects of citicoline, oral dosages ranged from 250 to 2,000 mg daily; treatment durations varied.(Brown 2015, Cotroneo 2013, McGlade 2019, Nakazaki 2021) Citicoline 100 mg every 12 hours was used in combination with citalopram for 6 weeks in a study of patients with major depressive disorder.(Roohi-Azizi 2017, Sarkar 2012)

Citicoline is water-soluble and highly bioavailable, with very little drug excreted in the feces.(Dávalos 2011) Citicoline exhibits biphasic plasma peak concentrations at 1 and 24 hours, as well as biphasic elimination.(Sarkar 2012)

Pregnancy / Lactation

Information regarding safety and efficacy in pregnancy and lactation is lacking at dosages above those usually consumed 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 individuals during the third trimester. However, information is limited regarding the safety of supplemental citicoline.(Rema 2008, Yan 2013)


None well documented.(Secades 2006) Animal data indicate synergism between citicoline and imipramine; a pharmacodynamic interaction may be possible.(Khakpai 2021)

Adverse Reactions

Citicoline was well tolerated in clinical trials.(Fioravanti 2005) Adverse effects may include GI disturbances, transient headaches, hypotension, tachycardia, bradycardia, and restlessness.(Cho 2009, Cotroneo 2013, Dávalos 2011, Secades 2006)

Citicoline may exacerbate adrenocorticotropic hormone– or cortisol hypersecretion–related disorders, including type 2 diabetes and major depressive disorder.(Cavun 2004)


Clinical data regarding toxicity are limited. The IV median lethal dose in rodents was suggested to be approximately 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.(Schauss 2009)



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