Cognizin® Citicoline

Introduction (General Overview)

Cognizin® is a proprietary form of citicoline, which is the common name for cytidine-5′-diphosphocholine (CDP-choline)². Citicoline is a naturally occurring compound found in all living cells as an intermediate in phospholipid metabolism¹. It was first identified in the 1950s and by the 1970s was developed as a prescription substance (notably in Japan and parts of Europe) for neurological conditions². In the United States, it later became available as a dietary supplement, and the Cognizin brand was introduced in 2003 by Kyowa Hakko Bio². Chemically, citicoline is water-soluble with molecular formula C₁₄H₂₆N₄O₁₁P₂ (molar mass ≈488.3 g/mol). It is a stable, highly purified (>98%) compound when isolated for supplement use⁷. Importantly, as a dietary ingredient in the EU, Cognizin citicoline is not associated with any authorized health claims and is regulated strictly as a nutrient substance (see Section 7)². All information in this overview is factual and neutral, describing the properties of Cognizin without implying health benefits.

Chemical Classification and Structure

Citicoline is classified as a pyrimidine nucleotide derivative. Structurally, it is a mononucleotide composed of the nucleoside cytidine (which includes the base cytosine attached to a ribose sugar) coupled via a diphosphate bridge to a choline molecule⁴. In biochemical terms, citicoline is essentially cytidine diphosphate-choline, meaning it contains a cytidine 5′-diphosphate group esterified with choline. This structure is similar to other nucleotide cofactors (like CDP-ethanolamine) but with choline as the alcohol component. The IUPAC name for the inner salt form of citicoline reflects its complex structure; one representation is 5′-O-[hydroxy({hydroxy[2-(trimethylammonio)ethoxy]phosphoryl}oxy)phosphoryl]cytidine⁶. In simpler terms, the molecule can be visualized as comprising a cytosine base linked to ribose (forming cytidine), with a pyrophosphate connecting to a choline group. The presence of the positively charged choline (a quaternary ammonium) and the phosphate groups makes citicoline an inner salt (zwitterion) in its purified form⁶. As such, citicoline is highly water-soluble and exists predominantly as a zwitterionic compound. This compound belongs to the class of nucleotide metabolites and is the biochemical equivalent of CDP-choline found in vivo, which distinguishes it from other forms of choline (such as phosphatidylcholine or choline bitartrate) by its nucleotide-linked structure.

Dietary Sources and Natural Occurrence

Citicoline is not widely present in common foods. In nature, it occurs at only trace levels, primarily in animal organ tissues like brain and liver⁵. Typical human diets do not provide significant preformed citicoline; instead, choline is usually consumed in other forms (e.g. phosphatidylcholine in egg yolks or free choline in meats) and then converted within the body to CDP-choline. The richest dietary sources of CDP-choline are organ meats such as liver and brains, but even these contain only small amounts, and such foods are not commonly eaten in large quantities⁵. Cooking or processing is not known to selectively destroy citicoline, but the overall content in foods is so low that diet is generally not considered a meaningful source. Given this scarcity in foods, the body must endogenously synthesize most of its required CDP-choline (see Section 4). It’s worth noting that while related choline compounds are abundant in diet (e.g. lecithin in soy, choline in eggs), citicoline itself is primarily obtained through supplementation or produced internally via metabolic pathways. No significant variation in citicoline content among different diets has been documented, since virtually all diets rely on internal synthesis rather than direct intake⁵. In summary, citicoline does not contribute significantly to typical dietary choline intake, and its presence in the food supply is minimal, prompting its use as a supplemental ingredient rather than as a nutrient derived from whole foods.

Biochemical Role and Physiological Presence

Citicoline plays a key biochemical role as an intermediate in phospholipid synthesis within the body. It is an endogenous compound: humans synthesize CDP-choline as part of the Kennedy pathway (also known as the CDP-choline pathway) for producing phosphatidylcholine, an essential phospholipid of cell membranes². In this pathway, choline obtained from the diet (or from phospholipid turnover) is first phosphorylated to phosphocholine, which then reacts with cytidine triphosphate (CTP) to form CDP-choline (citicoline). The enzyme CTP–phosphocholine cytidylyltransferase catalyzes this step, making citicoline the rate-limiting intermediate in membrane phosphatidylcholine biosynthesis⁴. Because of this central role, citicoline is present in virtually all cells at low concentrations, particularly in tissues with high membrane turnover (such as the brain). Once formed, CDP-choline is incorporated into phosphatidylcholine by combining with diacylglycerol. This means citicoline serves as a donor of two crucial components: the choline headgroup (used not only for building phosphatidylcholine but also for synthesizing the neurotransmitter acetylcholine) and the nucleotide cytidine (which in humans rapidly converts to uridine, a precursor for RNA and phospholipid components)². Thus, physiologically, citicoline provides building blocks for cell membrane repair and maintenance, and supports neurotransmitter synthesis pathways (through choline). It is noteworthy that the body can produce citicoline endogenously from choline; however, endogenous production may be limited, which is why citicoline is sometimes described as a “pool” that can be augmented by supplementation (without making any health claims here, only biochemical context). In the bloodstream and tissues, citicoline primarily exists as its breakdown products (choline and cytidine) rather than as intact CDP-choline, because it undergoes rapid enzymatic hydrolysis³. Nonetheless, under normal conditions, the body maintains a balance between choline availability and CDP-choline synthesis to ensure sufficient phospholipid and acetylcholine production². Citicoline itself is not stored at high levels; rather, it is continuously generated and consumed in metabolic cycles. There is no known distinct “reservoir” of free citicoline in tissues – instead, its components integrate into various metabolic pools. In summary, citicoline’s physiological presence is as a transient but crucial metabolite that links nutritional choline to the structural and signaling molecules (membrane phospholipids and acetylcholine) required for normal cell function.

Metabolism and Excretion

When Cognizin (citicoline) is ingested orally, it is rapidly and almost completely absorbed. Human pharmacokinetic data indicate that citicoline has >90% oral bioavailability⁶. After absorption from the small intestine, the intact molecule undergoes extensive first-pass metabolism: it is hydrolyzed and dephosphorylated into two main constituents, choline and cytidine, before reaching systemic circulation². This breakdown can occur in the intestinal mucosa, blood, and liver enzymes. Once split, the choline and cytidine (as uridine) travel through the bloodstream and readily cross the blood–brain barrier³. About an hour after administration, plasma levels of choline and uridine rise, reflecting the efficient uptake of these metabolites³. Importantly, the separated components are later re-synthesized into citicoline within cells as needed: in the brain, neurons take up choline and uridine to reform CDP-choline for phospholipid synthesis³. In this way, the delivered citicoline is distributed systemically in the form of its building blocks, which are incorporated into normal metabolic pathways. The elimination of citicoline’s metabolites is primarily via oxidation to carbon dioxide and renal excretion. Studies show that a majority of an administered dose is ultimately exhaled as carbon dioxide (reflecting complete metabolism of part of the choline fraction), and the remainder is excreted in the urine within 24–48 hours¹³. Very little, if any, of the intact citicoline molecule is excreted in feces, indicating that absorption is nearly complete and metabolism is thorough. Choline that is not used for biosynthesis can be oxidized to betaine, which donates methyl groups in the liver, and eventually its carbons may enter the one-carbon pool and be released as CO₂¹³. Cytidine (after conversion to uridine) that is not reutilized in nucleotide synthesis may be catabolized as well or excreted in urine¹³. The kidney eliminates the excess free choline and uridine that are not taken up by tissues, with urine measurements showing peak excretion of these metabolites hours after dosing¹³. The metabolic half-life of citicoline’s components in plasma is relatively short; within a day after ingestion, most of the dose has been either incorporated into tissues or eliminated. Notably, the metabolic fate of citicoline appears to avoid formation of certain byproducts associated with other choline sources. For instance, free choline can be converted by gut bacteria into trimethylamine (TMA), which in the liver forms TMA N-oxide (TMAO), a compound linked to cardiovascular risk. Citicoline’s choline moiety, delivered alongside cytidine, may be less prone to generate TMA/TMAO compared to choline salts – one hypothesis is that the cytidine/uridine presence helps channel choline into phospholipid synthesis rather than bacterial degradation². While this is an emerging area of research, it underscores that citicoline’s metabolic profile is distinct in some ways from other choline donors. In all, the ADME (Absorption, Distribution, Metabolism, and Excretion) profile of Cognizin citicoline is well characterized: it is efficiently absorbed, widely distributed as essential nutrients, metabolized into integral physiological pathways, and its excess is safely excreted via natural routes (exhalation and urination)¹³.

Industrial Production Methods

Citicoline (Cognizin) can be produced at industrial scale by two main methods: chemical synthesis and fermentation-based biotechnological processes. Chemical synthesis of citicoline was the original method used when the compound was developed as a pharmaceutical. One common synthetic route involves coupling cytidine 5′-monophosphate (CMP) with an activated form of choline phosphate. For example, early patents describe reacting cytidine-5′-monophosphate (or its amide) with phosphorylcholine (often in the form of a calcium salt) in the presence of a condensing agent like dicyclohexylcarbodiimide (DCC) to form citicoline⁷. The resulting product can be purified by ion-exchange chromatography and crystallization. Modern improvements to this process have focused on simplifying purification; one newer method uses addition of certain dicarboxylic acids to precipitate impurities, allowing production of extremely high purity citicoline (>99% by HPLC) without extensive column chromatography⁷. Chemically synthesized citicoline is typically obtained as the sodium salt (citicoline sodium), which is very water-soluble⁶. The chemical process yields a highly pure, stable product, but it requires multiple steps and careful control of reaction conditions (e.g. strong reagents like concentrated acids or coupling agents) to avoid degradation of the nucleotide components⁶. Fermentation (biotechnological) production is a newer method that has been embraced for producing Cognizin. In 1990, Kyowa Hakko Bio pioneered an industrial fermentation process for citicoline, leveraging its expertise in microbial fermentation technology. This process uses specially engineered microorganisms to biosynthesize citicoline from basic nutrients⁸. In practice, two types of bacteria may be employed simultaneously: one strain optimized to generate the nucleotide intermediate (e.g. CTP or other precursors) and another engineered to produce or couple the choline phosphate, with the fermentation conditions allowing these two microbes to collaborate in creating CDP-choline⁸. Kyowa’s published overview indicates the use of orotic acid (a precursor in nucleotide biosynthesis) and choline chloride as inexpensive raw materials fed into the fermentation, under a controlled bioprocess that yields citicoline efficiently⁸. After fermentation, the broth undergoes purification steps (filtration, crystallization, etc.) to isolate citicoline. This biotech method is considered environmentally friendly and cost-effective, as it runs under milder conditions than chemical synthesis and uses renewable resources (microbial catalysts). Originally, industry-standard fermentation for CDP-choline was a two-step process: cells would be grown, then permeabilized and supplied with substrates to convert into citicoline⁶. More recently, research has developed one-step fermentation processes where live cells secrete citicoline directly, further streamlining production⁶. The advantage of fermentation is a simpler process flow with potentially fewer chemical reagents and byproducts; it can achieve high yields and high purity comparable to synthetic methods⁸. Kyowa Hakko Bio reports that its fermentation technology for Cognizin produces a consistent, pharmaceutical-grade product and that they are the only company with a stable, large-scale supply using this particular dual-fermentation approach⁸. In summary, both production methods result in the same citicoline end product. Chemical synthesis has the benefit of well-understood chemistry and batch consistency, while fermentation offers a bio-based, potentially more sustainable route. The citicoline produced (whether via synthesis or fermentation) is held to high purity standards (typically ≥98% purity)⁷. Industrial producers must also ensure the final product meets quality and safety specifications (e.g. absence of microbial contaminants, solvent residues, etc.). Cognizin citicoline, as marketed, is a highly pure, free-flowing crystalline powder that is soluble in water, making it suitable for incorporation into tablets, capsules, or functional beverages. The choice of production method generally comes down to economic and regulatory considerations, but both pathways yield an equivalent, chemically identical form of citicoline suitable for use in supplements.

Regulatory and Historical Background

Citicoline’s regulatory status has evolved from a drug in some countries to a novel food/supplement ingredient in others. Historically, citicoline was developed and tested as a medication for neurological disorders. It was first approved in Japan in the 1970s for stroke recovery, and subsequently adopted in several European countries as a prescription nootropic or neuroprotective agent². (For example, it has been prescribed under various brand names for cognitive impairment associated with vascular dementia or stroke, though those uses fall under medicinal regulation rather than nutrition.) In the United States, citicoline was never formally approved as a drug; instead, it entered the market as a dietary supplement by the early 2000s. In 2009, the manufacturer (Kyowa) self-affirmed citicoline (Cognizin) as GRAS (“Generally Recognized As Safe”) for use in conventional foods, at levels up to 250 mg per serving¹¹. This GRAS status meant that citicoline could be added to certain foods and beverages in the U.S., in addition to its availability in dietary supplement products. In the European Union, citicoline was treated as a Novel Food when introduced for supplement use. Following a safety evaluation by the European Food Safety Authority (EFSA), the European Commission in 2014 authorized citicoline (Cognizin) to be placed on the EU market as a novel food ingredient¹¹. The authorization (Commission Implementing Decision 2014/423/EU) specified its conditions of use: citicoline is allowed in food supplements for the adult population at a maximum level of 500 mg per day, and in certain specialty foods (foods for special medical purposes) at up to 250 mg per serving (not exceeding 1000 mg total per day in those medical foods)¹¹. These limits were established based on safety data and intended usage levels. Importantly, citicoline’s approval as a novel food was for use as a source of choline/cytidine in the diet and did not confer any health claim authorization. In fact, to date no health or physiological claims for citicoline have been approved in the EU². In 2014, EFSA’s Panel on Dietetic Products, Nutrition and Allergies evaluated a proposed health claim that CDP-choline could help maintain normal vision, and concluded the evidence was not sufficient to establish a cause-effect relationship². More recently, in 2024, EFSA assessed a proprietary claim that citicoline supports memory function in older adults; the panel again found the evidence lacking and rejected the claim that citicoline intake improves or maintains memory, stating that no cause-and-effect relationship could be established⁹. These assessments mean that in Europe, marketing of Cognizin or citicoline cannot include any claims of cognitive or health benefits. Labeling is restricted to factual information (e.g. “source of choline”) in line with approved nutrient claims (notably, choline itself has some permitted claims related to normal metabolism, but citicoline as an ingredient cannot currently claim those without regulatory clearance)². Globally, citicoline’s status varies. It remains a prescription drug in some countries (for example, it’s listed as a pharmacological substance in parts of Asia and Europe for certain neurological indications), whereas in North America and many other regions it is sold as an over-the-counter supplement. Regulatory agencies uniformly advise that any statements about cognitive enhancement or disease treatment with citicoline are not authorized without sufficient scientific agreement. Both the U.S. FDA and EU authorities consider citicoline a dietary ingredient or nutrient rather than a medication when used in supplements. As such, Cognizin must adhere to general food safety and labeling laws (in the EU, under the Novel Food Regulation and Nutrition and Health Claims Regulation; in the US, under DSHEA for supplements and FDA regulations for GRAS substances). No specific maximum daily dose is set in the US by regulation, but common supplement dosages (see Section 8) are used. In the EU, the novel food approval effectively sets 500 mg/day as the recommended upper level for general adult use¹¹. In summary, citicoline has a dual identity in regulatory terms: a former drug now repurposed as a nutraceutical ingredient. Its safety has been vetted by authorities, but no official endorsements of health benefits exist. All communications in the EU must include the requisite disclaimer that no health claims are approved (as provided in the conclusion of this document), ensuring that consumers are not misled about its effects². Cognizin’s manufacturer provides technical data and ensures compliance with these regulations in all markets where it is sold.

Safety and Recommended Dosages

Cognizin citicoline has an excellent safety profile and is generally regarded as safe for consumption. Numerous toxicological and clinical studies have not found serious adverse effects at the doses tested. In toxicology assessments, citicoline demonstrated very low acute toxicity: for example, the median lethal dose (LD₅₀) in animal studies is extremely high (oral LD₅₀ values in rodents have been reported on the order of 18–27 g/kg, indicating a wide safety margin)². Even when administered intravenously, citicoline’s lethal dose in animals is over 20-fold higher (less toxic) on a molar basis than that of simple choline chloride¹². These data underscore that citicoline itself is not inherently toxic. Genotoxicity and mutagenicity assays have been negative, and subchronic animal studies (e.g. 90-day feeding studies in rats up to ~1000 mg/kg body weight per day) showed no organ damage or significant toxic effects⁵. Human studies likewise support citicoline’s safety. Clinical trials and post-marketing surveillance indicate that citicoline is well-tolerated. No serious drug-related adverse events have been conclusively linked to citicoline supplementation in adults¹⁰. In a review of trials as well as a large usage survey (>2,800 patients), the incidence of side effects was very low: only around 5% of people reported any minor, transient adverse effects⁵. The most common mild side effects are gastrointestinal in nature – for instance, some individuals may experience stomach ache, nausea, or diarrhea⁵. These symptoms, when they occur, are usually temporary and resolve on their own. Citicoline does not appear to affect heart rate, blood pressure, or other vital signs, and laboratory tests (liver/kidney function, blood counts) in clinical trials have remained normal, suggesting no clinically significant systemic toxicity⁵. Furthermore, unlike certain choline sources, citicoline at recommended doses has not been associated with the fishy body odor that can occur at very high choline intakes (due to TMA accumulation)⁵. Overall, both the U.S. Institute of Medicine and EFSA have not assigned a specific Tolerable Upper Intake Level to citicoline itself, instead considering it under the general guidance for choline. The absence of notable adverse effects up to 2,000 mg/day in studies is consistent with its status as a natural metabolite⁵. Recommended dosages: In dietary supplement use, typical dosages of Cognizin citicoline range from about 250 mg to 500 mg per day, although higher doses are sometimes used in research settings. A common serving is 250 mg once or twice daily, and many commercial products provide 500 mg per day. Clinical studies have examined doses up to 1,000–2,000 mg/day for several months without safety issues¹⁰. For example, trials in cognitive aging and memory have often used 500 mg/day or 1,000 mg/day of citicoline over 12-week periods¹⁰. These studies found that such doses were well-tolerated, with no significant differences in side effects compared to placebo¹⁰. The 500 mg per day level is also the maximum recommended in the EU for general supplementation (as established by the novel food approval)¹¹. Some specific uses (under medical supervision, e.g. in food for special medical purposes) have gone up to 1,000 mg/day in Europe¹¹, but for over-the-counter purposes, doses usually do not exceed 1 gram per day. It is generally unnecessary to take extremely high doses of citicoline, since lower amounts are effectively utilized by the body (excess choline or uridine will simply be excreted). Consumers should follow the dosage instructions provided by product manufacturers or healthcare professionals. For Cognizin, a typical recommended dose for adults is 250–500 mg daily, with some formulations suggesting 500 mg twice daily for short-term use. No adjustments for gender have been established, and research in older adults has used the same dose range as in middle-aged adults. There is limited data on pediatric use, so citicoline supplements are usually intended for adults unless under medical advice. Because citicoline is a source of choline, it contributes to overall choline intake; however, the doses used (even 500 mg of citicoline) correspond to a moderate amount of choline (about CDP-choline contains ~18% choline by weight, so 500 mg provides ~90 mg choline) – well within normal dietary choline levels. Thus, at recommended intakes, it does not approach the choline Tolerable Upper Intake Level (3.5 g/day of choline for adults, set by the IOM). In terms of interactions and contraindications, citicoline has no known severe interactions. It has been co-administered with common medications in clinical trials without incident, although formal interaction studies are lacking. Because it can slightly affect dopamine levels, caution is sometimes mentioned if combined with L-Dopa or other dopaminergic drugs, but no adverse interaction has been documented in literature². As with any supplement, pregnant or breastfeeding women are advised to consult a doctor before use, as safety data in those populations are insufficient (and because citicoline is a nutrient, prenatal vitamins typically cover choline needs through choline itself). In conclusion, Cognizin citicoline is considered safe when used as directed. The commonly recommended dosages (250–500 mg/day) are well within tested safe ranges¹⁰. Observing the standard precautions – using the product as a supplement to, not a substitute for, a healthy diet, and consulting a healthcare provider if you have underlying medical conditions – will ensure that this ingredient is used appropriately. The next section provides a factual summary and reiterates the regulatory stance, including the required EFSA consumer disclaimer on health claims.

Conclusion

In this overview, we have presented a scientific profile of Cognizin® citicoline, covering its chemistry, natural occurrence, metabolism, production, regulation, and safety. Cognizin is a branded, high-purity form of citicoline (CDP-choline), an endogenous nutrient involved in cell membrane synthesis. We described how citicoline functions biochemically as a source of choline and cytidine, integrates into normal metabolic pathways, and is endogenously produced in the human body. Dietary sources of citicoline are negligible, which is why it is used as a supplement ingredient rather than obtained from foods. The compound’s metabolism and pharmacokinetics are well-understood: it is readily absorbed and distributed as its component nutrients, and excess amounts are excreted harmlessly as CO₂ and in urine. Industrial manufacturing of Cognizin was detailed, noting both chemical synthesis and fermentation methods that yield highly pure citicoline for use in supplements. Regulatory history shows that while citicoline is accepted as a safe food ingredient (GRAS in the US, Novel Food in the EU), no health claims (e.g. for cognitive improvement) are authorized in Europe due to insufficient evidence⁹, which necessitates careful, claims-compliant marketing. Safety assessments indicate that citicoline has a strong safety record with low toxicity and good tolerability at recommended dosages. Typical usage dosages (around 250–500 mg/day for adults) have been studied and found to be safe. All these facts have been presented in a neutral, evidence-based manner without implying any health benefits, in compliance with EU regulatory requirements.

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 Cognizin⁹. 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. ADDF Cognitive Vitality (2017). Citicoline (CDP-choline) – For Researchers. (Source for: CDP-choline is a naturally occurring compound produced by the body and a precursor in phosphatidylcholine synthesis).

2. Synoradzki, K.; Grieb, P. (2019). Citicoline: A Superior Form of Choline? (Source for: notes citicoline (cytidine-5′-diphosphocholine) has been used as a prescription nootropic since the 1970s and recently as a food ingredient, with no nutrition or health claim authorized in the EU).

3. Grieb, P. et al. (2014). Neuroprotective Properties of Citicoline: Facts, Doubts and Unresolved Issues. (Source for: orally administered citicoline is quickly hydrolyzed to choline and cytidine, which cross into the brain and are used to resynthesize CDP-choline in neurons).

4. Natural Medicine Journal (2016). Citicoline – A Novel Therapeutic Agent… – Technical introduction. (Source for: Describes citicoline as a mononucleotide composed of ribose, cytosine, diphosphate, and choline, highlighting its role as an intermediate in phosphatidylcholine synthesis).

5. Kyowa Hakko Bio (2016). Cognizin® Citicoline – Fact Sheet for Health Professionals. (Source for: States that citicoline is present only in very low amounts in foods (highest in liver and brain, which are not commonly consumed)).

6. New Drug Approvals blog (2021). Citicoline. (Source for: Provides chemical and industrial insights. Confirms the IUPAC name… and notes an industry-standard two-step fermentation process, with newer one-step fermentation in development).

7. Google Patents (2013). WO2013128393A1 – Process for preparing pure citicoline. (Source for: Describes a synthetic route reacting cytidine-5′-monophosphate with phosphorylcholine (calcium salt) using DCC, yielding highly pure citicoline (≥99% HPLC purity) after removing impurities with dicarboxylic acid).

8. Kyowa Holdings (2021). The History of Kyowa Hakko Bio and Citicoline (Investor report) – Highlights Kyowa’s fermentation technology. (Source for: Indicates use of nucleic acid–producing and citicoline biosynthesis–enhancing bacteria, inexpensive substrates (orotic acid, choline chloride), and a simple fermentation process to produce citicoline, with two microorganisms controlled simultaneously).

9. EFSA Panel on Nutrition (2024). Scientific Opinion on “Citicoline” and memory (Article 13(5) health claim). EFSA Journal 18(7): 8861. (Source for: Concludes that a cause-and-effect relationship has not been established between citicoline intake and improvement of memory in aging adults).

10. ADDF Cognitive Vitality (2017). Citicoline (CDP-choline) – For Researchers. (Source for: Summarizes that citicoline is well-tolerated with few or no adverse effects and widely used in cognition studies. Also notes that in most clinical studies, citicoline doses ranged from 250 mg to 1,000 mg per day over up to 12 weeks with a good safety profile. Minor GI side effects were the only notable issues in a small percentage of subjects).

11. Cognizin® Citicoline Novel Food Approval – Kyowa Hakko Europe News (2014). (Source for: Confirms EU Commission Decision 2014/423 authorizing citicoline as a novel food ingredient at max 500 mg/day in supplements (1000 mg/day in special medical foods), and notes Cognizin’s GRAS status in the US (self-affirmed in 2009)).

12. Synoradzki & Grieb (2019) – Additional data. (Source for: Reports that citicoline’s toxicity is substantially lower than choline’s: on a molar basis, >20-fold higher LD50 for citicoline vs choline, suggesting a very wide safety margin for citicoline supplementation).

13. New Drug Approvals blog (2021) – Pharmacokinetic excerpt. (Source for: Notes that after oral ingestion of citicoline, the majority is excreted as CO2 (via respiration), and the remaining fraction is excreted in urine within about 24 hours, indicating effective absorption and complete metabolism of the dose).