CDP Choline

Ingredient Overview

Citicoline is the common name for cytidine-5′-diphosphocholine (CDP-choline), a water-soluble compound that serves as a source of the nutrient choline and the nucleoside cytidine. It is chemically identical to an intermediate naturally formed in human cells during the synthesis of phosphatidylcholine, a major component of cell membranes³. First identified in the 1950s by scientist Eugene Kennedy as a precursor in phospholipid biosynthesis, citicoline later gained attention as a neuroactive substance. By the 1970s, it was introduced as a prescription nootropic drug in some countries for neurological disorders. Today, citicoline is available as a dietary supplement in many parts of the world, including the EU and US, where it is used without prescription. Importantly, no health or cognitive benefit claims for citicoline are officially approved in Europe⁴, and its use is intended to provide biochemical precursors rather than to treat any disease.

Chemical Classification and Structure

Citicoline is classified as a pyrimidine ribonucleoside diphosphate⁵ – essentially a nucleotide composed of the pyrimidine base cytosine attached to a ribose sugar, which is esterified with pyrophosphate and linked to choline (a quaternary ammonium alcohol)⁶. In other words, the molecule consists of cytidine diphosphate (CDP) attached to a choline moiety, hence the name CDP-choline⁶. Its molecular formula is C₁₄H₂₆N₄O₁₁P₂, and it has a molecular weight of about 488.3 g/mol. The structure includes a cytidine (cytosine + ribose) segment on one end and a choline group on the other, bridged by two phosphate groups in sequence⁶. Figure: Ball-and-stick model of the citicoline (CDP-choline) molecule, showing the cytidine portion (right, containing the cytosine ring with nitrogen atoms in blue) connected via diphosphate linkage (orange and red) to the choline group (left, with the trimethylammonium head in blue). The IUPAC name of citicoline is lengthy (“5′-O-[hydroxy({hydroxy[2-(trimethylammonio)ethoxy]phosphoryl}oxy)phosphoryl]cytidine”), reflecting its multiple functional groups. Citicoline is usually isolated as an inner salt (zwitterion) or as a sodium salt; both forms are white, water-soluble crystalline powders of high purity (typically ≥98%)⁷. As a nucleotide-derived molecule, citicoline is stable and highly polar, and it readily dissociates in solution into ionic forms.

Dietary Sources

Citicoline itself is not a common dietary constituent – natural foods do not contain significant amounts of preformed CDP-choline. This is because citicoline primarily exists as an intermediate inside living cells rather than as a storage or transport form of nutrients. In the human diet, the body obtains citicoline’s building blocks (choline and cytidine) from other sources. Choline is an essential nutrient found abundantly in animal products such as liver, eggs, beef, fish, and poultry¹⁰. For example, egg yolks and organ meats are among the richest sources of choline in foods¹⁰. In these foods, choline mostly occurs as part of phosphatidylcholine (lecithin) in cell membranes, which the body can digest to release free choline¹⁰. Cytidine, on the other hand, can be supplied through dietary nucleotides (such as RNA) present in foods or is synthesized in the body from other precursors. Because of these metabolic pathways, the body can endogenously produce citicoline by combining choline (from diet or liver stores) with cytidine triphosphate inside cells. However, there is no substantial direct intake of citicoline from ordinary foods, and thus it is mainly obtained through supplementation when a concentrated source is desired.

Biochemical Role and Presence in the Body

In human physiology, citicoline plays a pivotal biochemical role as an intermediate in the “Kennedy pathway,” the major route for de novo synthesis of phosphatidylcholine (PC) in cell membranes³. Choline from the diet or released from phospholipid turnover is first phosphorylated to phosphocholine, which then reacts with cytidine triphosphate (CTP) to form CDP-choline (citicoline) via the enzyme CTP-phosphocholine cytidylyltransferase (the rate-limiting step of the pathway)⁶. Finally, the CDP-choline donates its choline component to diacylglycerol to produce phosphatidylcholine, releasing cytidine monophosphate³. Through this sequence, citicoline is constantly generated and consumed inside cells to maintain membrane phospholipid levels. Citicoline exists naturally in all eukaryotic organisms from yeast to humans as a transient metabolic intermediate⁵. In the human body, it is present at low concentrations in tissues with active phospholipid metabolism, notably the brain, liver, and other organs, reflecting its role in membrane maintenance⁶. Besides its structural role, citicoline (via its choline component) is biochemically linked to the synthesis of the neurotransmitter acetylcholine⁶. Neurons can utilize the free choline derived from citicoline for acetylcholine production, which is critical for nerve signal transmission⁶. Additionally, choline from citicoline can be oxidized to form betaine in the liver, serving as a methyl donor in one-carbon metabolism (important for processes like homocysteine remethylation)⁶. Cytidine from citicoline is converted to uridine in the bloodstream, which can be taken up by the brain and incorporated into nucleic acids and membrane components³. Through these pathways, citicoline’s components support several physiological functions: building cell membranes, enabling neurotransmitter synthesis, and contributing to methylation reactions. Notably, citicoline itself does not accumulate to high levels in blood or tissues because it is rapidly utilized in these biochemical processes.

Metabolism and Excretion

When taken orally, citicoline is very well absorbed and undergoes extensive first-pass metabolism. Oral bioavailability is high (approximately 90%), as evidenced by human and animal studies³. Rather than circulating largely as an intact molecule, ingested citicoline is quickly hydrolyzed in the gastrointestinal tract and liver to yield two primary metabolites: choline and cytidine³. These metabolites enter the bloodstream separately and are distributed to tissues³. The cytidine is rapidly converted to uridine in the plasma³, which along with choline can cross the blood–brain barrier³. Once inside the brain and other cells, these components are reassembled into CDP-choline as needed for phospholipid synthesis³. It has been observed that blood levels of choline and uridine rise after citicoline ingestion, often peaking a few hours post-dose³. The intact citicoline molecule itself is transient – only a small fraction may appear in circulation unmetabolized, and most of it is present as its breakdown products. Citicoline’s metabolites are incorporated into various pathways: choline into cell membranes or acetylcholine, and uridine into nucleotide pools. Because of this efficient utilization, very little of an oral dose is wasted.

The excretion of citicoline’s components occurs through both renal and respiratory routes. Any choline that is not used for biosynthesis can be oxidized to carbon dioxide and eliminated via respiration (exhaled as CO₂). Remaining metabolites are excreted in urine and, to a lesser extent, in feces. Studies with radiolabeled citicoline have shown that a significant portion of the dose is recovered as CO₂, indicating extensive metabolic breakdown, and the rest is primarily recovered in urine over the next 24–48 hours⁷. Only a tiny amount is eliminated unchanged. Overall, citicoline is almost completely absorbed and utilized, with rapid uptake into tissues and minimal excretion of the intact compound. This metabolic fate differentiates citicoline from some other choline sources: for example, there is evidence that citicoline’s choline is less prone to be converted by gut microbes into trimethylamine (a precursor of TMAO) compared to choline from phosphatidylcholine or choline chloride⁴. This may result in a lower production of TMAO, a metabolite implicated in cardiovascular risk, though this is an area of ongoing research. In summary, citicoline is efficiently absorbed and broken down into natural metabolites that are either incorporated into physiological pathways or harmlessly excreted as common metabolic end-products.

Industrial Production Methods

Manufacturing of citicoline for supplement and pharmaceutical use is typically carried out through specialized chemical or biotechnological processes under Good Manufacturing Practice (GMP) conditions⁷. One common production method uses enzymatic synthesis: starting from choline chloride and orotic acid (a pyrimidine precursor), enzymatic catalysts are employed to build the cytidine diphosphocholine structure in vitro⁷. In a proprietary process developed by at least one manufacturer, non-pathogenic strains of microbes (e.g., Corynebacterium ammoniagenes and E. coli) are cultivated to produce the necessary enzymes, which are then harvested and added to a reaction mixture of choline chloride and orotic acid⁷. These enzymes catalyze the sequential formation of the CDP-choline molecule. After the reaction, the mixture undergoes multiple purification steps – including filtration, ion-exchange resin purification, and crystallization – to isolate high-purity citicoline⁷. The final product is obtained as a white crystalline powder, which is dried and milled to specification. This enzymatic route is efficient and yields a highly pure product with minimal organic solvent residues.

Alternative production routes have also been developed. Citicoline can be synthesized via chemical steps by combining cytidine derivatives with phosphorylated choline intermediates, although purely chemical synthesis is complex due to the need to control multiple chiral centers and charged groups. Fermentation-based methods have been explored as well, leveraging engineered microorganisms that can accumulate CDP-choline from simpler nutrients, but such methods are less common commercially. In pharmaceutical contexts, citicoline is often provided as the sodium salt (citicoline sodium), especially for injectable or intravenous formulations, since the salt form enhances stability and solubility. For dietary supplements, the free-base (inner salt) form – which is essentially citicoline in its zwitterionic form – is commonly used⁷. Both forms have equivalent bioavailability and are converted to the same active components in the body. The industrial products are typically >98% pure and are tested to ensure low levels of impurities (such as free phosphoric acid or cytosine compounds) and microbial contaminants⁷. Major producers, such as Kyowa Hakko Bio (the company that pioneered citicoline’s novel food approval in the EU), have dedicated production facilities where citicoline manufacturing is integrated from fermentation or enzymatic reaction through to final purification. These careful production methods ensure that the citicoline used in supplements is chemically identical to the naturally occurring compound and meets safety and quality standards for human consumption.

Regulatory and Historical Background

Citicoline has an interesting regulatory history that reflects its dual identity as both a naturally occurring metabolite and a man-made supplement ingredient. It was first synthesized and characterized in the mid-20th century (synthesized around 1956 following its discovery in 1955). In subsequent decades, citicoline became a licensed medicine in several countries. For example, Japan and many European and Latin American countries introduced citicoline (under brand names like Somazina, CerAxon, etc.) as a prescription drug for neurological conditions such as stroke recovery or cognitive impairment in the 1970s and 1980s. Because of its role in brain chemistry, it was classed as a nootropic or psychostimulant drug and could only be obtained with medical supervision in those regions. Meanwhile, in the United States, citicoline was not approved as a drug but was later marketed as a dietary supplement⁴. The U.S. Dietary Supplement Health and Education Act (DSHEA) of 1994 allowed citicoline to be sold in supplements, and in 2009 a leading manufacturer self-affirmed citicoline (as the free base form, often branded as Cognizin®) as Generally Recognized As Safe (GRAS) for use in foods and supplements⁴. This GRAS notice, submitted to the FDA, meant that expert review found no safety concerns at intended usage levels, paving the way for its broader use in fortified foods and beverages in addition to pills. Since then, citicoline has been available OTC (over-the-counter) in the US, with typical supplement dosages ranging from 250 mg to 500 mg per serving.

In the European Union, citicoline was not historically used in supplements and thus fell under the Novel Food regulation when companies sought to introduce it as an ingredient⁷. A Novel Food application was submitted by Kyowa Hakko Europe, and the European Food Safety Authority (EFSA) conducted a thorough safety assessment⁷. In 2013, EFSA’s Panel on Dietetic Products, Nutrition and Allergies issued a scientific opinion concluding that citicoline is safe for use in food supplements under the proposed conditions⁷. Following EFSA’s positive evaluation, the European Commission published Implementing Decision 2014/423/EU authorising citicoline as a novel food ingredient⁸. This decision allows citicoline to be added to food supplements in the EU with certain restrictions: it is permitted at a maximum level of 500 mg per day in supplements for the general adult population, and up to 250 mg per serving (and no more than 1000 mg per day) in foods for special medical purposes (intended for patients under medical care)⁸. The Decision also specifies that products containing citicoline should be labeled as not intended for children⁸. Since 2014, citicoline has been legally sold across the EU as an ingredient in dietary supplements, and several companies market it in capsules, tablets, or powder forms. Notably, despite its approval for use as a supplement, citicoline can still be considered a drug in certain contexts. EU law allows Member States to regulate a substance as a medicinal product if it is presented as having properties for treating or preventing disease. Thus, if citicoline supplements are marketed with medicinal claims in Europe, national authorities could choose to treat them as drugs and restrict sales accordingly⁴. However, when sold purely as a source of choline/cytidine with no health claims, citicoline is treated as a normal supplement ingredient.

Importantly, no health claims for citicoline have been approved under EU nutrition and health claim regulations⁴. EFSA has not authorized any claims linking citicoline itself to health benefits such as cognitive function or vision improvement⁴. (While choline as a nutrient has approved claims – e.g., “choline contributes to normal homocysteine metabolism” – these claims cannot be transferred to citicoline without specific authorization⁴.) This means that in the EU, marketing materials for citicoline supplements must not state or imply any medical or physiological benefits beyond its role as a source of choline. The regulatory stance is strictly focused on safety and nutritional rationale, not efficacy for any health condition. Nonetheless, citicoline continues to be investigated in clinical research for its potential neuroprotective and cognitive effects. Globally, it occupies a unique space as both an established prescription drug in some countries and a nutraceutical in others. As of 2025, consumers can purchase citicoline as a supplement in the EU, US, Canada, and dozens of other countries without a prescription, but they should do so with the understanding that its purported benefits are not officially verified. The historical evolution from a laboratory discovery, to a prescription drug, and finally to an EU-approved novel nutrient ingredient underscores citicoline’s safety record but also the caution around health claims that regulators maintain.

Safety and Recommended Dosages

Citicoline is generally regarded as a very safe substance. Extensive toxicological testing in animals and ongoing observations in humans have not identified serious risks at the dosages used. In acute toxicity studies, citicoline demonstrated low toxicity – rodents showed no lethal effects at oral doses well above 2,000 mg per kilogram of body weight. (For perspective, an oral LD₅₀ in rats is estimated to be greater than 2 g/kg, indicating that only extraordinarily large doses would be harmful, far exceeding any normal intake.¹) No evidence of mutagenicity or genotoxicity has been found in standard assays: citicoline was negative in bacterial Ames tests at high concentrations and caused no chromosomal aberrations in mammalian cell tests or micronucleus formation in live mice⁹. These results suggest it does not damage DNA or have carcinogenic potential. Subchronic toxicity studies have also shown a wide margin of safety. In a 90-day repeated-dose study in rats, daily doses of 100, 350, and even 1000 mg/kg caused no mortality or major organ damage⁹. Only mild, dose-dependent changes were noted – for example, at the highest dose some rats had minor renal tubular mineralization (calcium deposits in the kidney) without any signs of kidney injury or dysfunction⁹. This finding was attributed to the high phosphate content of very large citicoline doses rather than an intrinsic toxicity of citicoline itself⁹. Overall, the rodent studies established a No-Observed-Adverse-Effect Level (NOAEL) at the highest tested doses, supporting citicoline’s safety even at intake levels vastly above those used by humans⁹.

Human data likewise indicate that citicoline is well-tolerated. Clinical trials and consumer use have not flagged significant adverse effects. Typical supplemental doses (e.g., 250–1000 mg per day) produce minimal side effects – at most, some individuals might experience mild transient symptoms like stomach upset, nausea, or headache, but these are infrequent. In controlled studies, even doses up to 2000 mg daily for several weeks were reported to be tolerated without serious events³. Unlike some choline sources, citicoline at recommended dosages does not appear to cause fishy body odor or gastrointestinal distress in most users (issues that can occur when large doses of choline are metabolized to trimethylamine). Post-market surveillance in Europe (where citicoline has been used in patients for decades as a drug) indicates a very low incidence of side effects. For example, a review of thousands of patients on citicoline therapy noted no significant differences in adverse event frequency compared to placebo³. The safety profile is comparable in children in the limited cases where it has been studied, though citicoline supplements are generally not intended for pediatric use unless under medical advice.

Based on both clinical experience and regulatory evaluations, authorities have provided guidance on citicoline’s acceptable intake. EFSA’s novel food approval specifies 500 mg per day as the maximum level for general supplement use in adults⁸. This level is considered safe with a large safety buffer². For special medical purposes, under healthcare supervision, up to 1000 mg per day is allowable (typically divided into two 250 mg servings in fortified foods)⁸². In the United States, there is no formal upper limit set by regulators, but the self-affirmed GRAS status was likewise based on an intended use of around 500 mg per serving. Many supplement manufacturers recommend daily dosages in the range of 250 mg to 1000 mg for cognitive support or overall health, which aligns with these safety guidelines. Common retail products contain 250 mg or 500 mg per capsule, with directions to take one or two per day. It is noteworthy that in clinical settings (particularly in some countries where citicoline is used as a drug), higher doses such as 1–2 grams per day have been used for acute cases (like stroke recovery), still without significant safety issues³. However, such high intakes are typically short-term and under medical oversight. For normal supplemental purposes, exceeding 1000 mg daily is not generally necessary and may not confer additional benefit, and it would remain well below any known toxicity threshold in any case.

In summary, citicoline is a very safe nutritional supplement ingredient when used at recommended dosages. Its metabolites (choline and cytidine/uridine) are normal constituents of the body, and the compound does not introduce unusual toxicological risks. Regulatory agencies have examined citicoline and found it acceptable for daily consumption in moderate amounts. Consumers using citicoline within the suggested dose range can be confident in its safety profile. Of course, it is still prudent to adhere to labeled dosages and to consult with a healthcare provider if combining citicoline with any medications. (Notably, EFSA did mention that citicoline could interact with certain medications, such as some blood-thinners or neuroactive drugs, so individuals on prescription meds should seek medical advice⁷.) No upper limit of intake has been definitively established by authorities, but the absence of toxicity up to very high doses in studies provides reassurance. As with any supplement, sensible use is advised: citicoline should be used to complement the diet (especially if one needs additional choline) rather than to replace any essential nutrients. Overall, the compound’s safety, coupled with its biochemical role, is the basis for its inclusion in supplements — providing a convenient and safe source of choline and cytidine for those who might benefit from an increased intake of these nutrients.

Conclusion

Citicoline is a well-characterized dietary supplement ingredient that serves as a source of choline and cytidine, molecules vital for cell membranes and numerous metabolic processes. Chemically, it is a nucleotide-derived compound (CDP-choline) and is identical to an intermediate naturally used by the body to form phospholipids. While not found in significant amounts in foods, citicoline can be synthesized endogenously and is now produced industrially for use in supplements. It is efficiently absorbed and split into choline and uridine (from cytidine), which integrate into normal physiology – supporting the structural integrity of cell membranes and contributing to neurotransmitter synthesis and methylation biochemistry. Citicoline’s introduction as a supplement has been backed by safety evaluations: it has an excellent safety profile with no serious adverse effects noted at recommended intakes. Historically used as a drug in some countries, it is now available over-the-counter in the EU, US, and elsewhere, but its marketing is carefully regulated to avoid unsubstantiated health claims. Consumers and health professionals view citicoline as a scientifically interesting nutrient compound, given its role in the nervous system, yet it is important to approach it as a source of essential nutrients rather than a cure-all. Ongoing research continues to explore any potential benefits of citicoline for cognitive or neurological function, but until clear evidence and regulatory approval are established, no health claims can be made. In essence, citicoline offers a safe and biologically active means to boost choline intake and support phospholipid metabolism, fitting into the supplement category as a chemical and nutritional tool rather than a therapeutic drug.

This scientific overview has presented chemical, biochemical, and regulatory context without any health claims. The European Food Safety Authority (EFSA) has not approved any health or physiological claims associated with Citicoline⁴. Consumers should not interpret this educational information as medical advice or a basis for health decisions. Always consult a healthcare professional before starting dietary supplements or making significant dietary changes. Supplements should complement, not replace, a varied and balanced diet or a healthy lifestyle.

1. Fisher Scientific (2021). Safety Data Sheet – Citicoline. Thermo Fisher Scientific, SDS P03299. (Reports oral LD₅₀ in rat > 2000 mg/kg, indicating low acute toxicity.)

2. Grieb, P. et al. (2016). “Citicoline: A Food Beneficial for Patients Suffering from or Threatened with Glaucoma – Or Is It?” Frontiers in Aging Neuroscience 8:73. (Notes EFSA’s safe intake of 500–1000 mg/day and discusses the supplement’s neuroprotective research.)

3. Celia, A., Filip, A. et al. (2017). “Citicoline – a neuroprotector with proven effects on glaucomatous disease.” Journal of Medicine and Life 10(3): 112–116. (Overview of citicoline’s pharmacology, including its role in phospholipid synthesis, metabolism to choline/uridine, and safety profile.)

4. Troncoso, C., Berlanga, J. et al. (2019). “Citicoline: A Superior Form of Choline?” Nutrients 11(7): 1568. (Reviews regulatory status: citicoline as a novel food in EU with no authorized health claims; compares toxicity of citicoline vs choline and notes lower TMAO conversion.)

5. Yeast Metabolome Database (2016). Entry YMDB00090 – Citicoline. (Classifies citicoline as a pyrimidine ribonucleoside diphosphate and notes it exists in all eukaryotes from yeast to humans.)

6. Qureshi, I. (2015). “Citicoline: A Novel Therapeutic Agent with Neuroprotective, Neuromodulatory, and Neuroregenerative Properties.” Natural Medicine Journal 7(8). (States that citicoline is a mononucleotide composed of ribose, cytosine, pyrophosphate, and choline, and outlines its role in cell membranes, acetylcholine synthesis, and as a methyl donor via betaine.)

7. European Food Safety Authority (2013). Scientific Opinion on the safety of “citicoline” as a Novel Food ingredient. EFSA Journal 11(10):3421. (EFSA’s assessment concluding citicoline is safe at 500 mg/day in supplements; describes the production process using enzymatic synthesis with microbial enzymes under GMP.)

8. European Commission (2014). Commission Implementing Decision 2014/423/EU of 1 July 2014 authorising the placing on the market of citicoline as a novel food ingredient under Regulation (EC) No 258/97. Official Journal of the EU L196: 22–26. (Authorizes citicoline in EU supplements, max 500 mg/day, and in medical foods up to 1000 mg/day; stipulates labeling and use conditions.)

9. Food Safety Authority of Ireland (2012). Safety Assessment of Citicoline (Novel Food Dossier Initial Assessment). FSAI, June 2012. (Summarizes toxicology: LD₅₀ > 2000 mg/kg; no genotoxicity in Ames, CHO and mouse micronucleus tests; 90-day rat study found no adverse effects up to 1000 mg/kg/day aside from minor, non-toxic changes.)

10. Blusztajn, J.K. & Zeisel, S.H. (2018). “Dietary Choline Intake: Current State of Knowledge Across the Life Cycle.” Nutrients 10(10): 1153. (Provides data on choline nutrition; notes that the richest dietary sources of choline are liver, eggs, meats, fish, etc., mostly as phosphatidylcholine in foods.)