This is a general overview. For more in-depth information, see our health professional fact sheet.
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Choline is a nutrient that is found in many foods. Your brain and nervous system need it to regulate memory, mood, muscle control, and other functions. You also need choline to form the membranes that surround your body’s cells. You can make a small amount of choline in your liver, but most of the choline in your body comes from the food you eat.
The amount of choline you need each day depends on your age and sex. Average daily recommended amounts are listed below in milligrams (mg).
Life Stage Recommended Amount Birth to 6 months 125 mg Infants 7–12 months 150 mg Children 1–3 years 200 mg Children 4–8 years 250 mg Children 9–13 years 375 mg Teen boys 14–18 years 550 mg Teen girls 14–18 years 400 mg Men 19+ years 550 mg Women 19+ years 425 mg Pregnant teens and women 450 mg Breastfeeding teens and women 550 mgMany foods contain choline. You can get recommended amounts of choline by eating a variety of foods, including the following:
Some multivitamin/mineral supplements contain choline, often in the form of choline bitartrate, phosphatidylcholine, or lecithin. Dietary supplements that contain only choline are also available.
The diets of most people in the United States provide less than the recommended amounts of choline. Even when choline intakes from both food and dietary supplements are combined, total choline intakes for most people are below recommended amounts.
Certain groups of people are more likely than others to have trouble getting enough choline:
Although most people in the United States don’t get recommended amounts of choline, few people have symptoms of choline deficiency. One reason might be that our bodies can make some choline. However, if a person’s choline levels drop too low, he or she can experience muscle and liver damage as well as deposits of fat in the liver (a condition called nonalcoholic fatty liver disease [NAFLD] that can damage the liver).
Scientists are studying choline to better understand how it affects health. Here are some examples of what this research has shown.
Some research shows that getting enough choline might help keep the heart and blood vessels healthy, partly by reducing blood pressure. Other research suggests that higher amounts of choline might increase cardiovascular disease risk. More research is needed to understand whether getting more choline from the diet and supplements might raise or lower the risk of cardiovascular disease.
Some studies have found a link between higher intakes of choline (and higher blood levels of choline) and better cognitive function (such as verbal and visual memory). However, other studies have shown that choline supplements do not improve cognition in healthy adults or in patients with Alzheimer’s disease, Parkinson's disease dementia, or other memory problems. More research is needed to understand the relationship between choline intakes and cognitive function as well as to find out whether choline supplements offer any benefit to patients with dementia.
There may be a link between low intakes of choline and the risk of developing NAFLD. NAFLD is a condition in which fat builds up in the liver of people who do not drink excessive amounts of alcohol. It is a common liver disorder, especially in people who are overweight or have obesity. Getting enough choline is necessary for proper liver function and to prevent NAFLD. However, more research is needed to better understand how choline might help prevent or treat NAFLD.
Getting too much choline can cause a fishy body odor, vomiting, heavy sweating and salivation, low blood pressure, and liver damage. Some research also suggests that high amounts of choline may increase the risk of heart disease.
The daily upper limits for choline include intakes from all sources—food, beverages, and supplements—and are listed below.
Life Stage Upper Limit Birth to 12 months Not established Children 1–3 years 1,000 mg Children 4–8 years 1,000 mg Children 9–13 years 2,000 mg Teens 14–18 years 3,000 mg Adults 3,500 mgCholine is not known to interact with any medications.
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Tell your doctor, pharmacist, and other health care providers about any dietary supplements and prescription or over-the-counter medicines you take. They can tell you if the dietary supplements might interact with your medicines or if the medicines might interfere with how your body absorbs, uses, or breaks down nutrients such as choline.
People should get most of their nutrients from food and beverages, according to the federal government’s Dietary Guidelines for Americans. Foods contain vitamins, minerals, dietary fiber, and other components that benefit health. In some cases, fortified foods and dietary supplements are useful when it is not possible to meet needs for one or more nutrients (for example, during specific life stages such as pregnancy). For more information about building a healthy dietary pattern, see the Dietary Guidelines for Americans and the U.S. Department of Agriculture’s (USDA's) MyPlate.
This fact sheet by the National Institutes of Health (NIH) Office of Dietary Supplements (ODS) provides information that should not take the place of medical advice. We encourage you to talk to your health care providers (doctor, registered dietitian, pharmacist, etc.) about your interest in, questions about, or use of dietary supplements and what may be best for your overall health. Any mention in this publication of a specific product or service, or recommendation from an organization or professional society, does not represent an endorsement by ODS of that product, service, or expert advice.
Citicoline displays negligible toxicity. The compound is quickly catabolized (Fig. 2), and the products arising are subsequently available for diverse biosynthetic pathways and ultimately excreted as carbon dioxide. The lack of acute and chronic toxicity of citicoline has been repeatedly confirmed in rodents and dogs (see the most recent report by Schauss et al. [15] and the references quoted therein). An impressive example is the median lethal dose (LD50) of an acute single intravenous application of citicoline, which equals 4,600 and 4,150 mg/kg in mice and rats, respectively. The LD50 for ingested citicoline is even higher at approximately 8 g/kg in both mice and rats. For comparison, in mice, the LD50 of an acute single intravenous dose of sodium chloride is 645 mg/kg, and that of vitamin C is 518 mg/kg. In a 90-day rat oral toxicity study of 100–1,000 mg/kg daily doses, increases in serum creatinine and in renal tubular mineralization, likely caused by phosphate liberation from citicoline, were found, without concomitant degenerative or inflammatory reactions.
Fig. 2Presumed catabolism of citicoline (Cyt-P-P-Cho) in the rodent intravascular compartment. In the first step, hydrolysis of the pyrophosphate bridge takes place. In the second step, cytidine monophosphate (Cyt-P) and phosphocholine (Cho-P) are dephosphorylated to cytidine (Cyt) and choline (Cho), respectively; supposedly, a large part of the liberated choline is taken up by the liver (which may explain the unexpectedly low cholinergic toxicity of citicoline)
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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 bodyweight (70 kg). 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. In adult and elderly stroke patients, the drug has lacked significant adverse events (see, for example, the study by Cho and Kim [16] in 4,191 Korean stroke patients), and a meta-analysis of placebo-controlled trials has shown that the overall frequency of adverse effects was comparable between groups comprising 1,652 actively treated and 686 placebo-treated subjects [17]. There are no data concerning the effects of liver or kidney insufficiency on the safety profile and pharmacokinetics of citicoline although, on the basis of the aforementioned toxicology data, an enhanced threat of hyperphosphataemia may be predicted in patients with kidney failure.
Upon administration, citicoline is relatively quickly catabolized and is the source of choline that appears in the blood. Administered parenterally or orally, citicoline is relatively quickly (i.e. within minutes rather than hours) converted to its cholinergic and pyrimidinergic catabolites. In the perfused rat liver, citicoline disappeared from the perfusate within 10 min [18, 19]. Since phosphorylated substrates are considered unable to penetrate cell membranes, it is usually assumed that cytidine monophosphate (CMP) and phosphocholine (PCho) yielded from hydrolysis of citicoline are further dephosphorylated by phosphatases in blood plasma. In agreement with this assumption, citicoline given orally to rats produced pronounced increases in plasma cytidine and choline, although it should be noted that the rise of cytidine was several-fold larger than that of choline [20]. A recently published paper [21] reported on the use of a liquid chromatography electrospray ionization tandem mass spectrometry (LC–ESI–MS/MS) method to evaluate the pharmacokinetics of choline in blood from human volunteers following ingestion of 1,000 mg citicoline tablets. Biphasic concentration–time curves of choline in plasma have been recorded, with a large peak of 2 μg/mL at approximately 2 h and a second, slightly smaller but much broader peak with a maximum at approximately 24 h following ingestion. Unfortunately, no data on the initial plasma level of choline were shown, which makes the whole picture a bit unclear. One older source reported an arithmetic mean plasma choline level oscillating around 1.36 μg/mL [22] in a healthy human subject, and this was confirmed recently [23].
Is citicoline carcinogenic? In a wide variety of cancers, choline phospholipid metabolism is altered in such a way that cancer cells display elevated levels of phosphocholine, as well as total choline-containing compounds [24]. One may therefore pose a question as to whether increasing choline exposure doesn’t induce carcinogenesis and/or accelerate cancer growth. However, choline chloride has displayed no mutagenic potential when tested in vitro (using Ames testing, yeast gene conversion, clastogenicity and sister chromatid exchange) [25], and similar negative data have been obtained for citicoline [26]. Moreover, epidemiological data have shown that the associations between choline intake and cancer—if any—are weak. For example, Johansson et al. [27] found that elevated plasma concentrations of choline may be associated with a slightly increased risk of prostate cancer, but a similar (even slightly stronger) association has been found for vitamin B2. On the other hand, Lee et al. [28] did not find any association between choline (or betaine) intake and the risk of colorectal cancer, whereas Xu et al. [29] found that dietary choline intake was inversely associated with breast cancer risk.
Citicoline is neuroprotective in various animal (preclinical) experimental paradigms. The compound has offered marked neuroprotection in several in vitro and in vivo models of acute and chronic brain ischaemic and neurodegenerative diseases, including brain hypoxia, ischaemia and intracerebral haemorrhage (reviewed by Adibhatla and Hatcher [30]), brain and spinal cord trauma [31], in vitro glutamate excitotoxicity [32, 33] and in vivo amyloid toxicity [34]. However, the mechanisms of this neuroprotection are far from being understood.
One major effect of citicoline is believed to be stimulation of the synthesis and increase in the content of brain phospholipids. Increases in brain phospholipids following oral administration of citicoline have also been observed in humans, with use of phosphorous magnetic resonance spectroscopy [35]. The relevant hypothesis assumes that the citicoline breakdown products cytidine and choline enter the brain separately and, inside brain cells, they act as substrates for resynthesis of CDP-choline. This, in turn, is believed to result in slowing down of phospholipid breakdown and acceleration of phospholipid resynthesis necessary for membrane repair [36]. However, since citicoline is devoid of cholinergic toxicity (see below), a significant rise in brain choline following therapeutic doses of citicoline in humans does not seem probable—indeed, a decrease in choline in the brains of older subjects and no change in those of younger subjects have been observed following oral citicoline, with use of proton magnetic resonance spectroscopy (MRS) [37].
The other mechanisms suggested to be involved in the neuroprotective effects of citicoline in stroke models include prevention of activation of phospholipase A2 (PLA2) [38]. The related effects comprise attenuation of the increase in hydroxyl radical generation, preventing loss of cardiolipin (an exclusive inner mitochondrial membrane phospholipid essential for mitochondrial electron transport, which is degraded in response to cellular insults and disrupts the mitochondrial respiratory chain). In aged rats, an increase in the brain level of platelet-activating factor (a bioactive phospholipid implicated in neuronal excitotoxic death) has also been noted [39]. In rats, attenuation of mitogen-activated protein kinases (MAPKs) and caspase activation have been observed following citicoline administration [40, 41]. Last, but not least, according to the most recent report [42], treatment with citicoline has been found to increase sirtuin-1 (SIRT1) protein levels in cultured neurons, in circulating blood mononuclear cells and in the brain. This effect seems to be of critical importance for neuroprotection in experimental stroke because sirtinol, a specific inhibitor of SIRT1 which, by itself, does not influence infarct volume, has been shown to abolish the neuroprotection offered by citicoline. Citicoline displayed a potent synergistic effect with resveratrol (which is known to be a SIRT1 activator), leading to a 60 % reduction in the experimental infarct volume in rats when both drugs were used in doses that were individually ineffective. Moreover, citicoline was ineffective in SIRT1 knock-out homozygotic mice subjected to focal brain ischaemia. However, detailed mechanistic explanations for all of these effects are lacking. For example, there is no explanation as to how citicoline administration leads to attenuation of MAPK activity and increases sirtuin-1 protein content in brain tissues; in particular, does the drug act extracellularly, or is resynthesis of CDP-choline inside brain cells a prerequisite?
Citicoline is not beneficial in patients with stroke and traumatic brain injury. Positive results of preclinical studies with animal models of neurodegenerative diseases have prompted clinical trials with citicoline as a treatment for human brain diseases. Whereas several previous small clinical studies had achieved promising results, two recent large randomized multicenter trials—the COBRIT (Citicoline Brain Injury Treatment) trial performed in 1,213 patients with traumatic brain injury [43], and the international, randomized, multicentre, placebo-controlled sequential ICTUS (International Citicoline Trial on Acute Stroke) trial performed in 2,298 patients with moderate-to-severe acute ischaemic stroke [44]—led to the conclusion that citicoline is not efficacious in these clinical settings. The negative outcomes of these studies were deemed surprising and prompted a few comments, which focused mostly, although not exclusively, on methodological aspects of the evaluation of the clinical effects of the drug [45–47]. What was not commented on was the lack of a mechanistic explanation for the putative neuroprotective properties of citicoline.
Citicoline treatment seems beneficial in some chronic neurodegenerative diseases. Some recent data are suggestive that prolonged intake of citicoline, given orally or by injection, may be significantly effective in certain slowly developing neurodegenerative diseases. One is glaucoma, currently considered a neurodegenerative disease, which involves the entire central visual pathway. In glaucoma patients with moderate visual defects, citicoline treatment improved retinal function and neural conduction, and continuation of treatment for 2–8 years significantly slowed, stabilized or even improved glaucomatous visual dysfunction [48, 49]. The other is mild vascular cognitive impairment. In the open IDEALE (Studio di Intervento nel Decadimento Vascolare Lieve) study [50], oral citicoline taken for up to 9 months significantly improved the Mini-Mental State Examination score and positively influenced mood; the latter effect could have been related to increases in noradrenaline and dopamine levels, which would be expected on the basis of animal experiments (see the paper by Rejdak et al. [51] and the references cited therein).
Also, it has recently been shown that in sub-acute ischaemic cerebrovascular disease, administration of citicoline in an intravenous dose of 2,000 mg for 5 or 10 days improves functional independence and reduces the burden of care [52]. The uniqueness of citicoline may lie not only in its negligible toxicity and virtual lack of side effects but also in the fact that it appears to deliver a significant subjective improvement and mood-enhancing effect.
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