Citicoline

Citicoline

Citicoline

Clinical overview

Use

dosage

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

Contraindications

Contraindications have not been identified.

Pregnancy/breastfeeding

There is a lack of information on safety and effectiveness in pregnancy and breast-feeding at doses above those normally consumed with food.

Interactions

None are well documented.

Side effects

Citicoline was well tolerated in clinical studies. Adverse reactions may include gastrointestinal disorders, transient headache, hypotension, tachycardia, bradycardia, and agitation.

toxicology

No data.

source

Citicoline is found in all animal and plant cell membranes. Citicoline is formed 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 commercially available in its free base form as a sodium salt. (Schauss 2009)

Story

Citicoline is widely used internationally as a dietary supplement and was originally developed in Japan to treat acute cerebrovascular disease. Following introduction in some European markets, use has shifted from treating acute to chronic cerebrovascular disease, although further research is needed. (Fioravanti 2005)

Chemistry

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

Use and Pharmacology

Citicoline supplementation increases choline stores available for other biosynthetic pathways. Citicoline appears to reduce brain glutamate levels and increase adenosine triphosphate levels, which in turn provides protection against ischemic neurotoxicity. Increased brain glucose metabolism and blood flow have also been demonstrated, as well as increased availability of the neurotransmitters acetylcholine, norepinephrine and dopamine. (Arenth 2011, Secades 2006)

Antioxidant effect

Animal and in vitro data

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

CNS effects

Seeks

Clinical data

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

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

In another double-blind, randomized, placebo-controlled study in patients with alcohol use disorder (N=62), the effects of 12 weeks of citicoline therapy on alcohol consumption and craving as well as cognitive parameters were examined. No differences were observed between groups in number of drinking days, alcohol craving, or cognitive outcome scores. Tolerability was similar between groups. (Brown 2019)

knowledge

Animal data

Based on animal data, accelerated resynthesis of phospholipids and subsequent protection of cell membranes in the presence of citicoline has been suggested as a possible mechanism of action in the treatment of cognitive impairment. Labeled phospholipid from radiolabeled citicoline has been shown to cross the blood-brain barrier. In studies of rats with cognitive impairment, improvement in memory and learning has been demonstrated in older rats and those with induced memory deficits. Citicoline has also shown improved learning ability in dogs. (Conant 2004, Fioravanti 2005, García-Cobos 2010) Limited animal studies suggest that citicoline may counteract beta-amyloid deposition, which plays a role in Alzheimer's disease. (Conant 2004)

Clinical data

A Cochrane meta-analysis of clinical trials (from 1970 to 2003) found some evidence of a short- to medium-term beneficial effect of citicoline as a dietary supplement compared to placebo. The effect size for memory measures (n = 884) was 0.19 (95% CI: 0.06 to 0.32); The positive global clinical impression measure (n = 217) showed an odds ratio (OR) of 8.89 (95% CI: 5.19 to 15.22). (Fioravanti 2005) The report also suggests that the effect of citicoline (oral or intravenous [IV]) on memory did not appear to depend on the pathogenesis of the brain disorder. Studies included in the meta-analysis included participants with mild to moderate dementia and Alzheimer's disease, as well as those with cerebrovascular disorders. Due to age-related vascular cognitive impairment (N=349), 265 patients received 1 g of citicoline daily in 2 divided doses for 9 months. Mini-Mental State Examination scores remained essentially unchanged over time in the treatment arm, whereas declines were evident in control (no treatment) patients. (Cotroneo 2013) In a placebo-controlled study involving 100 patients with age-related memory impairment, a citicoline dosage of 500 mg daily for 12 weeks was used. Treated patients significantly improved from baseline to endpoint in 3 of 8 outcomes: spatial span, composite memory, and feature agreement scores. (Nakazaki 2021) Another open-label, parallel study of citicoline compared to usual care was conducted in 347 post-stroke patients in Spain. Improved cognitive outcomes (attention, temporal orientation, and executive function) were reported for the citicoline-treated group. (Alvarez-Sabín 2011)

In healthy subjects (N=40), a two-week study of citicoline 500 mg daily showed significant changes in cognitive outcome measures such as processing time, working memory and alertness compared to placebo. Serum malondialdehyde levels, which normally increase with psychomental stimuli, were also reduced compared to placebo. (Al-kuraishy 2020)

depression

Clinical data

In a randomized, double-blind, placebo-controlled, parallel-group study of patients diagnosed with major depressive disorder (N=50), depression scores significantly improved 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 to citalopram alone (P<0.03, P=0.032 and P=0.021, respectively). Furthermore, at the end of the experiment, a significant difference was observed in the depressed mood category of the Hamilton Depression Rating Scale between the two groups (P = 0.04). The remission rate was also significantly higher with citicoline combination therapy (72%) compared to citalopram alone (44%) (p = 0.045). No significant differences in adverse events were noted between groups. (Roohi-Azizi 2017)

epilepsy

Animal data

In two rat models of organophosphate-induced seizures, citicoline administration showed no anticonvulsant or neuroprotective effects. (Barker 2020)

Head injury

Animal data

Citicoline's antioxidant and anti-inflammatory mechanisms have been investigated in experimental studies in head-injured rats. (Bian 2010, Menku 2010)

Clinical data

A 2008 systematic review of the effects of cholinomimetics on head injury included studies and case reports using citicoline, all with some limitations in methodology (e.g., small sample size, single blinding). (Poole 2008) Positive results were reported in these studies; However, in the larger Citicoline Brain Injury Treatment Trial published in 2012, 90 days of treatment with enteral or oral citicoline 2,000 mg daily did not improve functional and cognitive status compared to placebo (global OR 0.87). [95% CI, 0.72 to 1.04]).(Zafonte 2012)

Neuroprotective effect

Clinical data

Hospitalized children (N=80) who experienced cardiac arrest were treated with citicoline 10 mg/kg in addition to conventional therapy or with conventional therapy alone for 6 weeks. 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 to the conventional therapy group. (Salamah 2021)

Parkinson's disease

Clinical data

A systematic review of literature published through 2019 evaluated citicoline as an adjuvant to levodopa therapy in adults with Parkinson's disease. The 7 included studies were randomized controlled (n=3), crossover (n=2) and open prospective (n=2). A total of 335 patients (individual study range: 10 to 85 patients) aged 31 to 82 years took part in the studies. The duration of the disease ranged from 1 month to 30 years and the severity of the disease included all stages. Overall, the results suggest that the addition of citicoline to levodopa may provide benefits over levodopa alone, including up to 50% reduction in levodopa dose seen in two studies and significant improvement in global and/or individual symptoms (e.g., rigidity, akinesia, motor function). tasks, balancing the upper extremities, speaking) documented in all 7 studies. (Queue 2021)

Psychomotor function

Clinical data

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

schizophrenia

Clinical data

In an 8-week double-blind, randomized, placebo-controlled trial in 73 patients with stable schizophrenia, the addition of citicoline with risperidone significantly improved mean negative symptom scores (on the positive and negative syndrome scale [PANSS]) compared to 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 the negative PANSS subscale score compared to patients 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 the frequency of adverse events was observed between groups. (Ghajar 2018)

The effect of citicoline in schizophrenia may be related to an improvement in sensory processing associated with the effect on the alpha7-nicotinic acetylcholine receptor system. (Aidelbaum 2022)

Tremor/ataxia syndrome

Clinical data

A phase 2 open-label pilot study evaluated the safety and effectiveness of citicoline in 10 patients with fragile X-associated tremor/ataxia syndrome, particularly with regard to motor and cognitive function. Overall, citicoline 1,000 mg/day for 12 months did not significantly improve motor symptom severity and results were inconclusive as to whether improvements in cognitive scores and anxiety were attributable to study medication. Citicoline was found to be safe and well tolerated in this small group of patients. (Hall 2020)

Endotoxic shock

Animal data

In a study in 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 and pH (P <). 0.001) and bicarbonate compared to baseline without changing sinus heart rhythm. Furthermore, citicoline suppressed endotoxin-induced increases in tumor necrosis factor alpha and nitric oxide, but also increased catecholamine levels in both control and endotoxin-treated animals. (Kocaturk 2021)

Hepatoprotective effect

Animal data

In mice, citicoline produced a hepatoprotective effect against liver injury caused by ischemic reperfusion by preserving mitochondrial function and reducing oxidative stress, but had no effect on inflammatory mediators. (Zazueta 2018)

Ophthalmological effects

Animal data

Animal studies 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 deterioration in visual acuity and a "loss of visual brain integrity" without reducing IOP, suggesting neurological benefits beyond IOP control. (van der Merwe 2021)

Clinical data

An 8-year follow-up of patients with glaucoma included in a previous study showed improvement in retinal and visual function. (Parisi 2008) An open study showed similar effects after two 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 trial (N=80), topical citicoline for 3 years had no significant effect on reducing the 3-year progression rate compared to placebo (−1.03 dB vs −1.92 dB, respectively), based on the 24-2 standard strategy rating. In contrast, a significant improvement in visual field progression was observed with citicoline compared to placebo using the 10-2 strategy assessment (3-year progression rate, −0.41 dB and −2.22 dB, respectively; P = 0.02). The rate of retinal nerve fiber layer loss was also significantly lower on average in the third year with citicoline eye drops (−1.86 mcm) compared to placebo (−2.99 mcm) (P = 0.02). Progression of Humphrey field analyzer mean deviation was significantly associated with age but not with 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), administration of an oral citicoline solution for 6 months significantly improved functional and morphological parameters (both P<0.01) compared to no treatment. Improvements correlated significantly and positively with greater impairment at baseline (both P < 0.01). Furthermore, visual acuity was significantly better in the citicoline group, with only 5.27% of eyes showing a decrease in visual acuity at the sixth month compared to 29.41% of eyes in the untreated group (P < 0.01). After a 3-month citicoline washout period, significant improvements were maintained at month 9 in all three assessments in treated eyes compared to untreated controls (P < 0.01 for all). Reduced visual acuity was present in only 5.26% of eyes previously treated with citicoline compared to 41.18% of eyes in the untreated group. No adverse events were reported in either group. (Parisi 2019)

Based on the success of citicoline treatment in adult patients with amblyopia, researchers conducted a retrospective study to evaluate 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 achieved statistically significant improvement. (Loebis 2021)

A prospective, controlled study of 78 patients who had undergone LASIK surgery compared post-LASIK treatment with either traditional lubricant (hyaluronic acid 15% eye drops) or citicoline eye drops. Corneal sensitivity measurements were significantly better with citicoline at weeks 1, 2, 3, 4, and 6 postoperatively; Measurements did not differ significantly between groups at weeks 8 and 12. (Cinar 2019)

Renal dysfunction

Animal data

Citicoline provided nephroprotection against mercury-induced kidney injury in rats, particularly by preserving calcium accumulation in kidney mitochondria. This allowed continuous transmembrane potential and adenosine triphosphate production. Reductions in oxidative stress have also been reported, including lower levels of interleukin-1 (IL-1) and IL-6. (Buelna-Chontal 2017)

Respiratory distress syndrome

Animal data

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

stroke

Animal data

Positive results with citicoline have been reported in experiments with rats with induced brain failure and hypoxia models (Clark 2009, Hurtado 2011).

Clinical data

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

Results of the large multicenter ICTUS study in patients with ischemic stroke (N=2,298; conducted between 2006 and 2011), in which citicoline 1 g i.v. every 12 hours for 3 days and 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 was observed between citicoline and placebo at 90 days (OR: 1.03). [95% CI, 0.86 to 1.25]; P=0.364). There were also no significant differences in adverse events. (Dávalos 2012)

A 2020 Cochrane review on the use of citicoline in acute ischemic stroke (10 studies) concluded that there may be “little or no difference” in mortality, disability reduction, cardiovascular adverse events, or exercise recovery with citicoline treatment compared to placebo (Martí-Carvajal). 2020) A placebo-controlled trial 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 compared to conventional therapy plus citicoline 1 g daily showed no differences in clinical outcomes after 8 weeks, but found an improvement in short-term intracortical inhibition in the citicoline group compared to placebo. (Premier 2022)

dosage

In clinical studies examining various neurological effects of citicoline, oral dosages ranged from 250 to 2,000 mg daily; The duration of treatment 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 of the active ingredient being excreted in the feces. (Dávalos 2011) Citicoline exhibits biphasic peak plasma concentrations at 1 and 24 hours and biphasic elimination. (Sarkar 2012)

Pregnancy/breastfeeding

There is a lack of information on safety and effectiveness in pregnancy and breast-feeding at doses above those normally consumed with food. The effects of citicoline were studied in rats during pregnancy for a possible role in protecting dendrites in the cortex and in fetal lung development, and in pregnant individuals during the third trimester. However, there is limited information regarding the safety of supplemental citicoline. (Rema 2008, Yan 2013)

Interactions

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

Side effects

Citicoline was well tolerated in clinical studies. (Fioravanti 2005) Adverse reactions may include gastrointestinal disorders, transient headache, hypotension, tachycardia, bradycardia and agitation. (Cho 2009, Cotroneo 2013, Dávalos 2011, Secades 2006)

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

toxicology

Clinical data on toxicity are limited. The mean lethal intravenous dose in rodents has been estimated to be approximately 4 g/kg. A 30-day study in rats revealed no toxicity at 150 mg/kg/day. No biochemical, neurologic, or histologic toxicity was noted in dogs administered 1.5 g/kg citicoline orally daily for 6 months. (Schauss 2009)

References

Disclaimer

This information relates to an herbal, vitamin, mineral or other dietary supplement. This product has not been evaluated for safety or effectiveness by the FDA and is not subject to the quality and safety information collection standards that apply to most prescription drugs. This information should not be used to decide whether or not to take this product. This information does not confirm that this product is safe, effective, or approved to treat any patient or medical condition. This is just a brief summary of general information about this product. It does NOT contain all information about the possible uses, instructions, warnings, precautions, interactions, side effects or risks that may apply to this product. This information does not constitute specific medical advice and does not replace the information you receive from your healthcare provider. You should speak to your doctor to get complete information about the risks and benefits of using this product.

This product may interact negatively with certain health and medical conditions, other prescription and over-the-counter medications, foods or other dietary supplements. This product may be unsafe if used before surgery or other medical procedures. It is important to fully inform your doctor about the herbs, vitamins, minerals, or other supplements you are taking before any surgery or medical procedure. With the exception of certain products generally considered safe in normal amounts, including the use of folic acid and prenatal vitamins during pregnancy, this product has not been adequately studied to determine whether it is safe for use during pregnancy, breastfeeding, or in those younger than 2 years of age.

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