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Citicoline (CDP-Choline): A Comprehensive Reference

1. Identity and Chemical Nature

Citicoline is the generic name — and the International Nonproprietary Name (INN) — of the pharmaceutical substance that chemically is cytidine-5′-diphosphocholine (CDP-choline), which is identical to the natural intracellular precursor of phospholipid phosphatidylcholine. It is also known by the names CDPCho and cytidine-5′-diphosphocholine; it is classified as a nootropic agent and central stimulant, and has a molecular weight of 488 g/mol with the chemical formula C₁₄H₂₆N₄O₁₁P₂.

Citicoline (cytidine-5′-diphosphocholine; CDP-choline) is an endogenous mononucleotide, composed of ribose, cytosine, pyrophosphate, and choline, and an essential precursor for the synthesis of neuronal plasma membrane phospholipids, important as a rate-limiting step in phosphatidylcholine synthesis.

CDP-choline is a natural metabolite present in minute amounts inside every living cell, playing a crucial role in the synthesis of cellular phospholipids. The work of Kennedy and collaborators in the 1950s showed that this phosphorylated choline nucleotide is a precursor of glycerophospholipid phosphatidylcholine (PC). Kennedy and colleagues first identified citicoline in 1955 and synthesized it in 1956.

Natural Sources and Endogenous Synthesis

Citicoline is a natural metabolite present in all living cells. Although citicoline is not a natural part of the diet in substantial amounts, the body makes citicoline from other nutrients, such as choline, that are found in the diet. Dietary supplements that contain citicoline are made in a laboratory (synthetic).

Phosphatidylcholine (PC) and its twin compound phosphatidylethanolamine (PEt) are the two most abundant phospholipids in eukaryotic cells, accounting for more than half of the total phospholipid content in membranes.

Commercial Forms and Preparations

Citicoline is available commercially in several forms. One of its variants — citicoline inner salt — was pronounced a food constituent in the major world markets (USA, European Union), and therefore citicoline became freely available over the counter as a food supplement considered a memory enhancer. The sodium salt form is used extensively in pharmaceutical preparations. Citicoline is water-soluble and highly bioavailable, with very little drug excreted in the feces, and it exhibits biphasic plasma peak concentrations at 1 and 24 hours, as well as biphasic elimination. Dosage forms include oral tablets, oral solutions, and injectable (intravenous and intramuscular) preparations used in clinical and pharmaceutical settings.

2. Historical and Regulatory Context

CDP-choline from an exogenous source, known as citicoline, has been used in medicine since the 1970s as a prescription drug displaying neuroprotective effects, indicated for various chronic and acute neurological diseases (e.g., Parkinson's disease, stroke, brain and spinal cord injury, glaucoma).

The use of citicoline arose in the early 1970s with a view that it might be a substance for treating drug abuse. It is a member of the group of molecules that play important roles in cellular metabolism, and since its identification it has been studied extensively in Europe, Japan, and the United States.

Before citicoline (inner salt) was accepted as a food constituent, citicoline (both inner salt and sodium salt) had been extensively used as a prescription drug to treat neurological diseases, both acute (ischemic brain stroke, brain trauma) and chronic (dementias, Parkinson's disease). CDP-choline (cytidine-5′-diphosphate choline), also called citicoline, is one of the most frequently prescribed drugs for cognitive impairment in several European countries and worldwide.

Unlike botanicals and herbals that have long ethnomedical traditions, citicoline has no pre-modern traditional use. Its clinical history begins entirely in the modern pharmaceutical era. Citicoline is approved in some countries for the treatment of acute ischaemic stroke. Its development and regulatory approval as a prescription drug occurred predominantly in Europe and Japan from the 1970s onward, after laboratory identification of the compound in the 1950s.

3. Key Constituents and Mechanisms of Action

Metabolic Fate After Ingestion

Following injection or ingestion, citicoline is believed to undergo quick hydrolysis and dephosphorylation to yield cytidine and choline, which then enter the brain separately and are used to resynthesize CDP-choline inside brain cells. Administered by both oral and intravenous routes, citicoline is converted into two major circulating metabolites, cytidine and choline. It is metabolized in the gut wall and liver. CDP-choline is a water-soluble compound with greater than 90% bioavailability.

The principal components of citicoline — choline and cytidine — are readily absorbed in the GI tract and easily cross the blood-brain barrier. Following administration by both the oral and parenteral routes, citicoline releases its two main components, cytidine and choline. Absorption by the oral route is virtually complete, and bioavailability by the oral route is therefore approximately the same as by the intravenous route. Once absorbed, citicoline is widely distributed throughout the body, crosses the blood-brain barrier and reaches the central nervous system (CNS), where it is incorporated into the membrane and microsomal phospholipid fraction.

Phospholipid Synthesis

Produced endogenously, citicoline serves as a choline donor in the metabolic pathways for biosynthesis of acetylcholine and neuronal membrane phospholipids, chiefly phosphatidylcholine. Citicoline, as an endogenous metabolite, serves as a synthetic precursor for essential structural and functional components of the cell membrane, such as phosphatidylcholine and sphingomyelin, and for the neurotransmitters dopamine and acetylcholine.

Choline is a precursor of acetylcholine and phospholipids — a neurotransmitter pivotal for learning and memory and important constituents of neuronal membranes and myelin sheaths, respectively. Cytidine in humans is readily converted to uridine, which exerts a positive effect on synaptic function and supports the formation of synaptic membranes.

Neuroprotective and Neurochemical Actions

Citicoline activates biosynthesis of structural phospholipids of neuronal membranes, increases brain metabolism, and acts upon the levels of different neurotransmitters. Citicoline has been shown to restore the activity of mitochondrial ATPase and membrane Na+/K+ATPase, to inhibit activation of certain phospholipases, and to accelerate reabsorption of cerebral edema in various experimental models. Owing to these pharmacological mechanisms, citicoline has a neuroprotective effect in hypoxic and ischemic conditions, decreasing the volume of ischemic lesion, and also improves learning and memory performance in animal models of brain aging.

Citicoline has also been shown to be able to inhibit mechanisms of apoptosis associated with cerebral ischemia and in certain neurodegeneration models, and to potentiate neuroplasticity mechanisms. The action of citicoline involves its modulation of N-methyl-d-aspartate (NMDA) receptors and the regulation of glutamate neurotransmission. Citicoline appears to decrease glutamate levels in the brain and increase adenosine triphosphate, which in turn offers protection against ischemic neurotoxicity.

Citicoline increases dopamine synthesis and inhibits dopamine uptake. It can also modulate the activity/expression of some protein kinases involved in neuronal death and increases SIRT1 expression in the central nervous system.

Upon intake, citicoline and its metabolites are presumed to fuel biosynthetic pathways that stimulate neuron homeostasis, synaptic transmission, and plasticity, thereby promoting cognitive and visual performance.

Acknowledged Mechanistic Limitations

It is concluded by some researchers that at present, there is no adequate description of the mechanism(s) of the pharmacological actions of this substance. Much remains to be learned of citicoline's mechanisms of action and biotransformation; much of the evidence shows that citicoline is sequentially hydrolyzed and dephosphorylated to uridine (in humans) and choline. The question of whether the intact citicoline molecule itself, or specific phosphorylated intermediates, may exert direct pharmacological effects remains under investigation.

4. Scientific Evidence by Area of Use

4.1 Ischemic Stroke

Stroke has been the most intensively studied indication for citicoline. A large number of experimental studies have explored the protective effects of citicoline in stroke models. At the experimental level, citicoline has been reported to reduce infarct volume and brain edema, leading to an improvement of neurologic deficits either when used as a single therapy or in combination with other agents.

In early US clinical trials, a randomized (3 doses of citicoline to 1 placebo), vehicle-controlled, double-blind trial was conducted at 21 US centers, in which, when the baseline NIH stroke scale was used as a covariate, both the 500-mg citicoline group and the 2,000-mg citicoline group had a significant improvement in terms of the percent of patients who had a favorable outcome on the Barthel Index at 90 days. There were no drug-related serious adverse events or deaths in this study. The study suggests that oral citicoline can be used safely with minimal side effects in acute stroke treatment. Citicoline appeared to improve functional outcome and reduce neurologic deficit, with 500 mg of citicoline appearing to be the optimal dose.

A pooled data analysis suggested benefit in moderate-to-severe acute ischemic stroke. In a pooled data analysis, the odds ratio of complete functional and neurological recovery in patients with moderate-to-severe acute ischemic stroke treated with oral citicoline for 6 weeks was 1.33 (95% confidence interval [CI] = 1.10–1.62) when compared with placebo. A further updated meta-analysis of tabulated data confirmed these previous results, with a reduction in death or dependency (OR 0.65, 95% CI = 0.54–0.77; P = 0.00001; Number Needed to Treat 9.5).

However, the definitive large-scale trial produced negative results. The ICTUS trial was a randomised, placebo-controlled, sequential trial in patients with moderate-to-severe acute ischaemic stroke admitted at university hospitals in Germany, Portugal, and Spain. Patients were randomly assigned in a 1:1 ratio to receive citicoline or placebo within 24 hours after the onset of symptoms (1000 mg every 12 hours intravenously for 3 days, followed by oral administration). Under the circumstances of the ICTUS trial, citicoline was not efficacious in the treatment of moderate-to-severe acute ischaemic stroke.

A subsequent 2022 randomized controlled trial examining citicoline administered immediately after recanalization therapy also found negative results: the study aimed to find out whether administration of citicoline immediately after recanalization therapy for acute stroke would improve both radiological (decrease in infarct volumes at six weeks) and clinical outcomes; however, it was found not to meet any of these primary or secondary endpoints.

A 2016 systematic review and formal meta-analysis examined 10 randomized clinical trials: citicoline is a drug approved for the treatment of acute ischemic stroke in some countries; although evidence of its efficacy has been reported, the results of a large placebo-controlled clinical trial did not show differences. Overall, evidence for citicoline in acute ischemic stroke is mixed. Earlier trials and meta-analyses showed modest benefit, but the large, well-powered ICTUS trial did not confirm efficacy. The evidence in this indication is therefore currently inconclusive.

A large Korean drug surveillance study involving 4,191 patients with acute ischemic stroke reported that all measured outcomes, including NIHSS, Barthel Index, and modified Rankin Scale, were improved after 6 weeks of therapy (P < 0.05). Further improvement was observed in 125 patients who continued citicoline therapy for more than 12 weeks, and improvements were more significant in the higher dose group (≥ 2000 mg/day). Citicoline safety was excellent; 37 side effects were observed in 31 patients (0.73%). The most frequent findings were nervous system-related symptoms (8 of 37, 21.62%), followed by gastrointestinal symptoms (5 of 37, 13.5%). This study was observational and not placebo-controlled, limiting its conclusions.

4.2 Traumatic Brain Injury (TBI)

The Citicoline Brain Injury Treatment Trial (COBRIT) was a Phase III, double-blind, randomized, clinical trial conducted between 2007 and 2011 among 1,213 patients at eight US level-1 trauma centers, investigating the effects of citicoline vs. placebo in patients with traumatic brain injury (TBI) classified as complicated mild, moderate, or severe. The study lasted 90 days and patients were administered oral citicoline (2 g) or placebo. The citicoline and placebo groups did not differ significantly at the 90-day evaluation (global odds ratio [OR], 0.98 [95% CI, 0.83–1.15]).

Despite the negative COBRIT result, a subsequent 2023 systematic review and meta-analysis reached different conclusions. In total, 11 clinical studies enrolling 2,771 patients were identified. Under the random-effects model, treatment with citicoline was associated with a significantly higher rate of independence (RR, 1.18; 95% CI = 1.05–1.33; I², 42.6%). The dose of citicoline or the administration route had no effect on outcomes. No significant effects on mortality were found, and no safety concerns were noticed. The meta-analysis indicates some beneficial effects of citicoline in increasing the number of independent patients with TBI. The most important limitation was the presumed heterogeneity of the studies included.

The overall picture for TBI is mixed: the largest single RCT (COBRIT) showed no benefit, while a subsequent meta-analysis incorporating 11 trials showed modest benefit on functional independence. Evidence strength is currently low to moderate and inconsistent.

4.3 Cognitive Impairment, Vascular Dementia, and Alzheimer's Disease

A final version of the Cochrane review concerning citicoline for cognitive and behavioral disturbances associated with chronic cerebral disorders in the elderly included the analysis of 14 randomized, placebo-controlled studies on aged individuals with symptoms ranging from memory disorders to vascular mild cognitive impairment, vascular dementia, or senile dementia. Duration of studies ranged between 20 and 30 days; one study lasted 6 weeks, four studies lasted 2 and 3 months, and one study lasted 12 months.

Overall results (884 patients) showed evidence of benefit of citicoline on memory and behavior, but not on attention. There was significant improvement in the global impression of change in comparison with the placebo group. A Cochrane meta-analysis of 14 RCTs in patients with vascular cognitive impairment, vascular dementia, and senile dementia reported no benefit of attention with citicoline. However, citicoline provided small benefits in memory, behavior, and on the clinical global impression scale.

A 2023 systematic review and meta-analysis searched the PubMed and Cochrane Library databases for articles published between 2010 and 2022. Seven studies were selected, including patients with mild cognitive impairment, Alzheimer's disease, or post-stroke dementia. All the studies showed a positive effect of citicoline on cognitive functions. Six studies could be included in the meta-analysis; 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. The overall quality of the studies was poor. Available data indicate that citicoline has positive effects on cognitive function; however, the general quality of the studies is poor, with significant risk of bias in favor of the intervention.

In the CITIMEM study, supplementing memantine with citicoline for 9 months resulted in improvement of the average MMSE score from 16.2 to 17.7, whereas treatment with memantine alone resulted in the average MMSE score deteriorating from 16.6 to 14.6. Such data are indicative of a citicoline effect being larger than the suggested threshold of a minimal clinically important difference in an Alzheimer's disease clinical trial.

The Italian IDEALE study was one of the few trials conducted for a period exceeding 6 months. Its aim was to assess the effectiveness and safety of oral citicoline in elderly people with mild vascular cognitive impairment; of note is that the authors considered citicoline as a dietary supplement. Citicoline appears to be a promising agent to improve cognitive impairment, especially of vascular origin.

A number of evidence pieces show that CDP-choline provides modest but consistent improvement in memory and behavior in cognitively impaired patients. One of the most critical points regards the relatively short term of clinical controlled observations, which in all studies but one lasted for no more than 3 months — too short a time for getting the best effects of citicoline; 6 months is the reported recommendation for getting the best outcomes.

Overall, the evidence for cognitive impairment is promising but limited by short study duration, small sample sizes, and methodological heterogeneity. There is no evidence to date that citicoline can prevent dementia.

4.4 Memory in Healthy and Aging Adults

Supplementation of citicoline (CDP-choline), a naturally occurring mononucleotide, has shown beneficial effects on memory function and behavior in populations with a wide range of impairments. A total of 100 healthy men and women aged between 50 and 85 years with age-associated memory impairment (AAMI) participated in a randomized, double-blind, placebo-controlled trial; participants were randomized to receive placebo (n = 51) or citicoline (n = 49; 500 mg/day) for 12 weeks.

After the 12-week intervention, participants supplemented with citicoline showed significantly greater improvements in secondary outcomes of episodic memory (assessed by the Paired Associate test), compared with those on placebo (mean: 0.15 vs. 0.06, respectively, P = 0.0025). Composite memory (secondary outcome), calculated using the scores of 4 memory tests, also significantly improved to a greater extent following citicoline supplementation (mean: 3.78) compared with placebo (mean: 0.72, P = 0.0052).

Dietary supplementation of citicoline for 12 weeks improved overall memory performance, especially episodic memory, in healthy older males and females with AAMI. The findings suggest that regular consumption of citicoline may be safe and potentially beneficial against memory loss due to aging. This trial was funded by Kyowa Hakko Bio Co., Ltd., and the funder participated in study design, which should be considered when evaluating the results.

Magnetic resonance spectroscopy studies showed that citicoline intake improves brain uptake of choline in older persons, suggestive of helping to reverse early age-related cognitive changes. In randomized, placebo-controlled trials of cognitively normal middle-aged and elderly persons, positive effects of citicoline on memory efficacy were found.

4.5 Attention and Psychomotor Speed

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.

Evidence for citicoline's effects on attention in healthy populations is preliminary and based on small trials. Effects in clinical ADHD populations remain uncertain: citicoline is an endogenous molecule that has beneficial effects on attention, impulsivity, and memory and is a potential treatment for ADHD; a randomized, crossover, double-blind, placebo-controlled clinical trial included patients aged 7–12 years diagnosed with ADHD; however, no statistically significant difference was noted between the use of citicoline and placebo in the evaluated parameters.

4.6 Glaucoma and Ophthalmic Neuroprotection

Citicoline (cytidine-5′-diphosphocholine, CDP-choline) is a naturally occurring endogenous precursor of the neurotransmitter acetylcholine and neuronal membrane components such as phosphatidylcholine or sphingomyelin. Citicoline was demonstrated to delay cognitive decline in patients with Alzheimer's and Parkinson's disease, multiple sclerosis, cerebral ischemia, and traumatic brain injury. Recently, the role of citicoline as a neuroprotective agent in various ophthalmologic conditions, including amblyopia, non-arteritic ischaemic optic neuropathy, corneal oxidative damage, and glaucoma, has been investigated.

Glaucoma is a leading cause of irreversible blindness worldwide. Retinal ganglion cells (RGC), the neurons that connect the eyes to the brain, specifically die in glaucoma. Elevated intraocular pressure (IOP) is the only modifiable risk factor; however, many patients progress despite excellent IOP control. Thus, alternative treatment strategies to prevent glaucoma progression are an unmet need.

A 2023 systematic review (PRISMA 2020), conducted by Prinz et al. and published in PLOS ONE, searched PubMed, Web of Science, Google Scholar, and Embase. Ten studies were eligible, including 424 patients. The mean length of follow-up was 12.1 ± 11.6 months. The overall risk of bias was low to moderate. The mean age of the patients was 56.7 years. There were no significant differences in the IOP, MD 24–2, RNFL, or PERG P50-N95 amplitude between patients receiving citicoline and the control group. Conclusive evidence of the effect of citicoline on glaucoma progression is missing.

Despite the negative pooled analysis on objective parameters, some earlier individual studies and narrative reviews have reported improvements in electrophysiological measures such as PERG amplitudes with citicoline. The evidence base for glaucoma is promising but currently insufficient to establish clinical benefit definitively.

4.7 Parkinson's Disease

Citicoline plays a role in synthesis of phospholipids and has neuroprotective properties in animals and humans. The mechanisms of action include inhibiting apoptosis associated with cerebral ischemia and models of neurodegeneration. A systematic review found that citicoline adjuvant therapy has positive effects on the improvement of motor function, delay of the progression of cognitive impairment, and reduction of bradykinesia, rigidity, and, to some extent, tremor in patients with PD.

A systematic review on the role of citicoline as an adjuvant drug for Parkinson's disease (PD) included a total of 7 studies with 355 participants. The methodology and outcomes were varied. Citicoline was reported to be effective in reducing levodopa by up to 50%, with improvement in the patient's rigidity, akinesia, tremor, handwriting, and speech. While the available evidence is still limited and there is a need for more high-quality trials, adjuvant citicoline may be considered.

4.8 Schizophrenia

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 the Positive and Negative Syndrome Scale [PANSS]) compared with placebo plus risperidone (adjusted P = 0.013). This is a single study with a small sample and requires replication.

4.9 Substance Use and Addiction

The use of citicoline arose in the early 1970s with a view that it might be a substance for treating drug abuse. Citicoline had no effect on cocaine use or self-reported craving for cocaine relative to placebo in a PMC-published double-blind placebo-controlled study in cocaine-dependent volunteers. Citicoline has also been shown to be effective in Parkinson disease, drug addictions, and alcoholism, as well as in amblyopia and glaucoma, according to one comprehensive pharmacological review, though the evidence quality varies considerably across these indications.

5. Body Systems and Health Areas

• Central nervous system: The primary area of investigation. Citicoline has been shown to be effective in a variety of experimental and clinical disorders of the CNS, including acute and chronic cerebral ischemia, intracerebral hemorrhage, global cerebral hypoxia, and neurodegenerative diseases. Pharmacological actions of citicoline in the CNS are pleiotropic, affecting various cell structures and biochemical pathways, and include neuroprotective and neuroregenerative effects.
• Neuronal membranes: As a dietary supplement, citicoline appears useful for improving both the structural integrity and functionality of the neuronal membrane, which may assist in membrane repair.
• Dopaminergic system: Citicoline increases dopamine synthesis and inhibits dopamine uptake.
• Cholinergic system: Choline derived from citicoline is a precursor of acetylcholine, a neurotransmitter pivotal for learning and memory.
• Visual system/retina: Citicoline is beneficial in glaucoma and amblyopia, based on its neuroprotective effects on retinal ganglion cells.
• Neuroenergetics: Citicoline has been shown to enhance frontal lobe bioenergetics as measured by phosphorus magnetic resonance spectroscopy, supporting ATP production in brain tissue.
• Synaptic and membrane integrity: Cytidine derived from citicoline is readily converted to uridine in humans, which exerts a positive effect on synaptic function and supports the formation of synaptic membranes.

6. Dosage Forms and Dosages Reported in Studies

The usual daily therapeutic dosage of citicoline in humans is 500–2,000 mg — that is, 7–28 mg/kg in a person of average body weight (70 kg).

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.

Specific dosages used across key trials:

• In the healthy older adults memory trial (Cognizin), participants received 500 mg/day of citicoline for 12 weeks.
• In the COBRIT TBI trial, patients were administered oral citicoline 2 g/day or placebo for 90 days.
• In the Citicoline Stroke Study Group dose-response trial, three doses were compared (500 mg, 1,000 mg, and 2,000 mg/day) against placebo. Treatment was started within 24 hours of stroke onset and continued orally for 6 weeks, with final outcome assessments at 12 weeks.
• In a Korean drug surveillance study, oral citicoline (500–4,000 mg/day) was administered within 24 hours after acute ischemic stroke for at least 6 weeks.
• In the adolescent attention trial, citicoline was given at 250 mg/day or 500 mg/day for 28 days.
• The VITA study evaluated citicoline administered intravenously at 2 g/day in geriatric patients with clinical confusion.

7. Safety Considerations and Interactions

General Safety Profile

Citicoline is a safe drug, as shown by toxicological tests, that has no significant systemic cholinergic effects and is a well-tolerated product. Data from clinical trials have corroborated preclinical toxicological findings, revealing a favourable safety profile, with only a few reports of adverse events, mostly related to digestive disturbances following oral intake.

No serious safety issues have been reported with citicoline treatment. Safety measures indicated no differences between treatment groups in terms of general health, blood chemistry, urinalysis, or vital signs, and there were no serious adverse events in a 12-week placebo-controlled trial.

Observed Adverse Effects

In clinical trials, adverse events have been infrequent and mostly mild. In a large drug surveillance study, 37 side effects were observed in 31 out of 4,191 patients (0.73%). The most frequent findings were nervous system-related symptoms (8 of 37, 21.62%), followed by gastrointestinal symptoms (5 of 37, 13.5%). There were no drug-related serious adverse events or deaths in a multi-center US stroke trial. The study suggests that oral citicoline can be used safely with minimal side effects.

Pregnancy and 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. However, information is limited regarding the safety of supplemental citicoline.

Drug Interactions

No interactions are well documented. Animal data indicate synergism between citicoline and imipramine; a pharmacodynamic interaction may be possible. Contraindications have not been identified in the available literature, though this reflects a lack of systematic investigation rather than a confirmed absence of interactions.

Pediatric Considerations

Citicoline seems to be a safe molecule to administer in the pediatric age group; however, further studies are required to assess the therapeutic potential of citicoline in ADHD.

Long-Term Safety

Long-term safety data remain limited. Most trials are of 3 months or shorter duration. Citicoline has been demonstrated to be safe during short-term treatment (i.e., 14 days), and to reduce scores on the Somatic Symptom Scale during a longer trial (i.e., 12 weeks). Data on safety beyond 3 months are sparse, and the safety of long-term use has not been comprehensively established in controlled trials.

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