Cit8.5

Citicoline Research

40 peer-reviewed studies · Evidence score: 8.5/10

Ketamine and other glutamate receptor modulators for depression in adults with unipolar major depressive disorder

Dean RL et al. • The Cochrane database of systematic reviews (2021)

Our findings show that ketamine and esketamine may be more efficacious than placebo at 24 hours.

The evidence suggests that ketamine may result in an increase in response and remission compared with placebo at 24 hours odds ratio (OR) 3.94, 95% confidence interval (CI) 1.54 to 10.10; n = 185, studies = 7, very low-certainty evidence).
Ketamine may reduce depression rating scale scores over placebo at 24 hours, but the evidence is very uncertain (standardised mean difference (SMD) -0.87, 95% CI -1.26 to -0.48; n = 231, studies = 8, very low-certainty evidence).
There was no difference in the number of participants assigned to ketamine or placebo who dropped out for any reason (OR 1.25, 95% CI 0.19 to 8.28; n = 201, studies = 6, very low-certainty evidence).

Systematic Reviewn=5,299

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Citicoline for treating people with acute ischemic stroke

Martí-Carvajal AJ et al. • The Cochrane database of systematic reviews (2020)

This review assessed the clinical benefits and harms of citicoline compared with placebo or any other standard treatment for people with acute ischemic stroke.

A pooled analysis of eight trials indicates there may be little or no difference in all-cause mortality comparing citicoline with placebo (17.3% versus 18.5%; RR 0.94, 95% CI 0.83 to 1.07; I² = 0%; low-quality evidence due to risk of bias).
Four trials found no difference in the proportion of patients with disability or dependence in daily activities according to the Rankin scale comparing citicoline with placebo (21.72% versus 19.23%; RR 1.11, 95% CI 0.97 to 1.26; I² = 1%; low-quality evidence due to risk of bias).
Meta-analysis of three trials indicates there may be little or no difference in serious cardiovascular adverse events comparing citicoline with placebo (8.83% versus 7.77%; RR 1.04, 95% CI 0.84 to 1.29; I² = 0%; low-quality evidence due to risk of bias).

Meta-Analysisn=4,281

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Early application of citicoline in the treatment of acute stroke: A meta-analysis of randomized controlled trials

Shi PY et al. • Journal of Huazhong University of Science and Technology. Medical sciences = Hua zhong ke ji da xue xue bao. Yi xue Ying De wen ban = Huazhong keji daxue xuebao. Yixue Yingdewen ban (2016)

In conclusion, citicolne cannot reduce long-term mortality and dependence rate in the treatment of acute stroke, and the effective rate of citivoline may be not better than that of controls but with reliable safety.

The overall rate of adverse events in citicoline group was not significantly different from that in control group (P=0.30).
The quality of included articles reached moderate-low level.
In conclusion, citicolne cannot reduce long-term mortality and dependence rate in the treatment of acute stroke, and the effective rate of citivoline may be not better than that of controls but with reliable safety.

Meta-Analysisn=4,039

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Medical and surgical interventions for neurotrophic keratopathy

Kruoch Z et al. • The Cochrane database of systematic reviews (2025)

Neurotrophic keratopathy is a rare condition with an array of etiologies, which poses challenges for research in terms of study design, participant recruitment, and consensus on objective outcome measures.

Meta-analysis of two studies showed that rhNGF may slightly improve corneal re-epithelialization (defined as < 0.5 mm of corneal staining) (RR 1.88, 95% CI 1.37 to 2.58; I2 = 0%; 148 participants; low-certainty evidence).
The same two studies assessed complete corneal re-epithelialization (defined as < 0.1 mm of corneal staining) and found similar results but with substantial heterogeneity in the meta-analysis (RR 2.75, 95% CI 1.82 to 4.16; I2 = 72%; 148 participants; low-certainty evidence).
Meta-analysis of two studies showed that rhNGF may not improve visual acuity (RR 0.07, 95% CI -0.58 to 0.71; I2 = 0%; 151 participants; low-certainty evidence).

Meta-Analysisn=494

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Nutraceuticals and phytoceuticals in the treatment of schizophrenia: a systematic review and network meta-analysis "Nutra NMA SCZ"

Fornaro M et al. • Molecular psychiatry (2025)

The Author(s), under exclusive licence to Springer Nature Limited.

Change (Standardized Mean Difference = SMD) in total symptomatology and acceptability (Risk Ratio = RR) were co-primary outcomes.
High heterogeneity (tau2 = 0.10, I2 = 55.9%) and global inconsistency (Q = 40.79, df = 18, p = 0.002) emerged without publication bias (Egger's test, p = 0.42).
Sarcosine improved negative symptoms (SMD = -0.65, 95%CI = -1.10; -0.19).

Meta-Analysisn=50

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Lifestyle-based interventions targeting neurocognition in bipolar disorders - a systematic review of randomized controlled trials

Balanzá-Martínez V et al. • Psychiatry research (2025)

Specific nutraceuticals may offer pro-cognitive effects for BD.

Specific nutraceuticals may offer pro-cognitive effects for BD.
However, the evidence is limited by the small number of included studies and substantial heterogeneity in populations, interventions, and cognitive assessments.
Future studies should examine whole-diet, physical activity/exercise and multimodal LBIs.

Systematic Review

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Pharmacologic neuroprotective agents for the treatment of perinatal asphyxia in low-income and lower-middle-income countries: A systematic review and meta-analysis of randomised controlled trials

Ayeni VA et al. • PloS one (2025)

Pharmacologic neuroprotective agents show promise in improving survival and neurological outcomes in neonates with PA in LILMICs.

The majority (91.7%) of studies were conducted in Asia, with only one study from Africa.
Magnesium sulphate was the most frequently evaluated agent (66.7% of studies), followed by melatonin, topiramate, erythropoietin, and citicoline.
Pharmacologic neuroprotective agents show promise in improving survival and neurological outcomes in neonates with PA in LILMICs.

Meta-Analysis

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Efficacy of citicoline as a supplement in glaucoma patients: A systematic review

Prinz J et al. • PloS one (2023)

There is a lack of sufficient evidence to support that citicoline slows the progression of glaucoma.

There is a lack of sufficient evidence to support that citicoline slows the progression of glaucoma.
Further research warranted to confirm findings

Systematic Reviewn=424

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Is Citicoline Effective in Preventing and Slowing Down Dementia?-A Systematic Review and a Meta-Analysis

Bonvicini M et al. • Nutrients (2023)

The overall quality of the studies was poor.

Overall, citicoline improved cognitive status, with pooled standardized mean differences ranging from 0.56 (95% CI: 0.37-0.75) to 1.57 (95% CI: 0.77-2.37) in different sensitivity analyses.
Further research warranted to confirm findings

Meta-Analysis

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Exploring the efficacy of cholinergic agents for the treatment of psychostimulant use disorder: a systematic review

Salloum N et al. • Psychopharmacology (2024)

This review does not support the current prescription of cholinergic agents to treat PUD.

Only two studies on galantamine (AChEI) and citicoline, reported a significant reduction of cocaine consumption. «Proof-of-concept» laboratory trials showed no evidence of efficacy on the selected outcomes, notably on craving.
This review does not support the current prescription of cholinergic agents to treat PUD.
Replication clinical trials notably on galantamine or other AChEI, and proof-of-concept trials on comedown symptoms will be necessary to identify a potential therapeutic indication for cholinergic agents in PUD.

Systematic Review

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A meta-analysis of the effect of different neuroprotective drugs in management of patients with traumatic brain injury

El Sayed I et al. • Neurosurgical review (2018)

Further research with high validity is needed to reach a solid conclusion about the use of neuroprotective drugs in cases of brain injury.

Patients treated with cerebrolysin (n = 112) had favorable GOS three times more than controls (OR 3.019; 95 % CI 1.76 to 5.16; p = 0.003*).
The odds of cognition improvement in the treatment group was 3.4 times more than controls (OR 3.4; 95 % CI 1.82 to 5.21; p < 0.001*).
Survival of cerebrolysin-treated patients did not differ from controls (103 patients; OR = 2.81; 95 % CI 0.905 to 8.76).

Meta-Analysisn=103

DOI

Citicoline for Acute Ischemic Stroke: A Systematic Review and Formal Meta-analysis of Randomized, Double-Blind, and Placebo-Controlled Trials

Secades JJ et al. • Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association (2016)

This systematic review supports some benefits of citicoline in the treatment of acute ischemic stroke.

This systematic review supports some benefits of citicoline in the treatment of acute ischemic stroke.
But, on top of the best treatment available (rtPA), citicoline offers a limited benefit.
Further research warranted to confirm findings

Meta-Analysis

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Citicoline as Adjuvant Therapy in Parkinson's Disease: A Systematic Review

Que DS et al. • Clinical therapeutics (2021)

However, due to the heterogeneity of the studies, there is a need for more high-quality studies.

Systematic review examining Citicoline efficacy
Further research warranted to confirm findings

Systematic Review

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Application of Citicoline in Neurological Disorders: A Systematic Review

Jasielski P et al. • Nutrients (2020)

Its positive impact on learning and cognitive functions among the healthy population is also worth noting.

In an animal model of nerve damage and neuropathy, citicoline stimulated regeneration and lessened pain.
Among patients who underwent brain trauma, citicoline has an unclear clinical effect.
Citicoline has a wide range of effects and could be an essential substance in the treatment of many neurological diseases.

Systematic Review

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Stroke management

Warburton E et al. • BMJ clinical evidence (2011)

We performed a GRADE evaluation of the quality of evidence for interventions.

Systematic review examining Citicoline efficacy
Further research warranted to confirm findings

Systematic Review

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CDP-choline for cognitive and behavioral disturbances

Fioravanti M, Buckley AE • Cochrane Database of Systematic Reviews (2006)

There is some evidence that CDP-choline has positive effects on memory and behavior in cognitive impairment.

Positive effects on memory
Benefits in cognitive impairment
Improvement in behavioral measures

Systematic Reviewn=4,000

DOI

Effects of Citicoline as an Adjunct Treatment for Alzheimer's Disease: A Systematic Review

Piamonte BLC et al. • Journal of Alzheimer's disease : JAD (2020)

Limited evidence from pooled data of two observational studies suggests that CC used in adjunct with AChEIs in the treatment of AD was well-tolerated and showed improvement in cognition, mood, and behavioral symptoms compared to treating with AChEIs alone.

Limited evidence from pooled data of two observational studies suggests that CC used in adjunct with AChEIs in the treatment of AD was well-tolerated and showed improvement in cognition, mood, and behavioral symptoms compared to treating with AChEIs alone.
Further research warranted to confirm findings

Systematic Review

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Is aura around citicoline fading? A systemic review

Agarwal S et al. • Indian journal of pharmacology (2017)

Functional outcomes were significantly improved by citicoline, but the positive role of this drug in neurological recovery, domestic adaptation, and cognitive outcomes is still a topic of discussion for future.

In neurological evaluation, domestic adaptation evaluation, and cognitive outcomes, there was no significant difference in both the citicoline and placebo groups (odds ratio [OR] = 1.04 [0.9-1.2, P = 0.583]; OR = 1.1 [0.94-1.27, P = 0.209]; OR = 0.953 [0.75-1.2, P = 0.691]).
In evaluation of functional outcomes, there was significant difference in both groups and OR was 1.18 (1.04-1.34, P = 0.01).
Functional outcomes were significantly improved by citicoline, but the positive role of this drug in neurological recovery, domestic adaptation, and cognitive outcomes is still a topic of discussion for future.

Meta-Analysis

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Citicoline in pre-clinical animal models of stroke: a meta-analysis shows the optimal neuroprotective profile and the missing steps for jumping into a stroke clinical trial

Bustamante A et al. • Journal of neurochemistry (2012)

In conclusion, this meta-analysis provides evidence of citicoline efficacy in stroke animal models and shows the optimal neuroprotective profile and the missing experimental requirements before jumping into clinical trials.

Weighted mean difference meta-analysis showed citicoline to reduce infarct volume by 27.8% [(19.9%, 35.6%); p < 0.001].
Citicoline improved neurological deficit by 20.2% [(6.8%, 33.7%); p = 0.015], but only four studies including 176 animals reported these data.
In the stratified analysis, citicoline effect on reducing infarct volume was higher in proximal occlusive models of middle cerebral artery (MCA) compared with distal occlusion.

Meta-Analysisn=14

DOI

Efficacy of citicoline as an acute stroke treatment

Clark WM • Expert opinion on pharmacotherapy (2009)

A citicoline supplement is now available from several sources on the internet.

Citicoline has been studied worldwide in both ischemic and hemorrhagic clinical stroke with excellent safety and possibly efficacy found in several trials.
A meta-analysis of four randomized US clinical citicoline trials concluded that treatment with oral citicoline within the first 24 h after a moderate to severe stroke is safe and increases the probability of complete recovery at 3 months.
Citicoline clinical efficacy trials are now continuing outside of the US in both ischemic and hemorrhagic stroke.

Meta-Analysis

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