Citicoline: A Superior Form of Choline? - PMC

If you are looking for more details, kindly visit bulk citicolines powders.

Abstract

Medicines containing citicoline (cytidine-diphosphocholine) as an active principle have been marketed since the 1970s as nootropic and psychostimulant drugs available on prescription. Recently, the inner salt variant of this substance was pronounced a food ingredient in the major world markets. However, in the EU no nutrition or health claim has been authorized for use in commercial communications concerning its properties. Citicoline is considered a dietetic source of choline and cytidine. Cytidine does not have any health claim authorized either, but there are claims authorized for choline, concerning its contribution to normal lipid metabolism, maintenance of normal liver function, and normal homocysteine metabolism. The applicability of these claims to citicoline is discussed, leading to the conclusion that the issue is not a trivial one. Intriguing data, showing that on a molar mass basis citicoline is significantly less toxic than choline, are also analyzed. It is hypothesized that, compared to choline moiety in other dietary sources such as phosphatidylcholine, choline in citicoline is less prone to conversion to trimethylamine (TMA) and its putative atherogenic N-oxide (TMAO). Epidemiological studies have suggested that choline supplementation may improve cognitive performance, and for this application citicoline may be safer and more efficacious.

Keywords:

citicoline, choline, health claims, toxicity, trimethylamine oxide, procognitive effects

1. Introduction

Citicoline is the international nonproprietary name (INN) for cytidine-diphosphocholine (CDP-Cho). The substance is commercially available in two forms, sodium salt and inner salt. Citicoline sodium salt, classified as a nootropic and psychostimulant [1], is an active principle of a variety of prescription drugs, either injectables or oral formulations. In 2009 in the USA, citicoline (inner salt) was self-affirmed by the Japanese company Kyowa-Hakko as GRAS (generally regarded as safe) [2], and in 2014 it was announced as a novel food ingredient by the appropriate Implementing Decision of the Commission of the European Union [3].

The aforementioned EU Implementing Decision states that citicoline may be placed on the EU market, where it is intended to be used in food supplements aimed at a target population of middle-aged to elderly adults at a maximum level of 500 mg/day, and in dietary foods for special medical purposes with a maximum dose of 250 mg per serving and with a maximum daily consumption level of 1000 mg from these types of foods.

2. Citicoline in Food Supplements: The Issue of Health Claims

Classifying citicoline as a food ingredient suitable for food supplements should make it widely available, but in the highly regulated market of the European Union its marketing is problematic. According to the EU Regulation EC No 1924/2006 [4], all nutrition and health claims made in commercial communications concerning food supplements must be formally authorized following scientific assessment performed by the European Food Safety Agency (EFSA). Citicoline does not have any nutrition or health claim authorized up to date. Moreover, application for authorization of a health claim (related to citicoline and maintenance of normal vision) was turned down by the EFSA because it was concluded that a cause and effect relationship has not been established between the consumption of citicoline and the maintenance of normal vision [5]. Does this mean that, although it is legal to introduce citicoline to the EU market in a food supplement, information provided about this supplement should not contain any information about its specific nutritional and/or functional value?

Looking through the positive EFSA Scientific Opinion on citicoline issued prior to the aforementioned implementing decision [6], we find the reference to the observation that, both in humans and in rats, upon ingestion citicoline undergoes quick hydrolysis, breaking down to choline and cytidine [7], which then undergo further metabolism and incorporation into normal pathways of metabolism [8]. Cytidine, a pyrimidine nucleoside which in humans interconverts with uridine [9], undergoes intracellular phosphorylations to cytidine triphosphate (CTP), which participates in phospholipids synthesis via the Kennedy pathway, and may also be incorporated into nucleic acids. Choline is either phosphorylated to phosphocholine and participates in phosphatidylcholine synthesis, or oxidized to betaine, which serves as a methyl donor in the betaine-homocysteine methyltransferase reaction. Also, in cholinergic neurons, choline is acetylated to form the neurotransmitter acetylcholine.

We may, therefore, consider citicoline as a source of choline and cytidine. Whereas there is no nutrition or health claim authorized for cytidine either, there are three such claims authorized for choline. These are so-called functional claims relating to the beneficial effects of a nutrient on certain normal bodily functions. The first two state that choline contributes to normal lipid metabolism and to the maintenance of normal liver function. These claims were accepted because they were substantiated by observations that choline deficiency is associated with signs of liver damage (elevated serum alanine aminotransferase activity) and the development of fatty liver (hepatosteatosis) in humans fed choline-free total parenteral nutrition solutions, whose effects can be reversed by the administration of dietary choline [10,11]. The third claim, stating that choline contributes to normal homocysteine metabolism, was substantiated by the observations that choline-depleted diets tend to increase plasma concentrations of homocysteine [12], whereas human observational [13,14] as well as intervention [15] studies supported the inverse association between dietary choline and blood concentrations of homocysteine. Of note is that in the aforementioned intervention study, choline was supplied orally in the form of phosphatidylcholine (lecithin).

At the same time, health claims stating that choline contributes to the maintenance of normal neurological function and normal cognitive function were rejected by the EFSA because cause and effect relationships have not been established between the consumption of choline and the claimed effects [16]. One of the reasons was that some references that presented support for the claimed effects described studies that did not evaluate choline, but, for example, citicoline. A possible explanation of this paradox is that at the date of issuing scientific opinion on the health claims concerning choline (i.e., year 2011), citicoline was not yet appreciated by EFSA experts as the dietary source of choline. Indeed, natural foods do not contain any significant amount of this substance.

There is no direct proof that citicoline intake can reverse either elevated serum alanine aminotransferase activity or the development of fatty liver in people who are choline-deficient. There is also no direct proof that citicoline intake may lower homocysteine in blood. On the contrary, single oral administration of a high dose of citicoline (1 g/kg b.w.) to rats resulted in a transient increase of plasma homocysteine, but when a lower dose was supplemented in the diet for two months, plasma homocysteine remained unchanged [17]. At the same time there is no reasonable doubt that oral intake of citicoline is a safe and efficient method of delivery of choline to the human body.

It might perhaps be concluded that the issue of the applicability to citicoline of health claims pertaining to choline (and apparently also to some of its derivatives, such as phosphatidylcholine) is merely a legal problem that shall be settled accordingly by the appropriate authorities. On the other hand, a health claim authorized almost a decade ago may not be supported in its entirety by the contemporary scientific data. Current guidelines for the management of fatty liver do not mention supplementation with choline or its derivatives [18]. Likewise, folic acid, vitamin B6, vitamin B12, and betaine, but not cholines, are listed among nutrients that may counteract hyperhomocysteinemia [19].

3. Citicoline as a Source of Choline: The Issue of Acute Toxicity

It is well established that following ingestion citicoline is fully absorbed and catabolized to cytidine and choline, which enter their respective metabolic pools in the body [20,21,22]. However, the particulars of its absorption, hydrolysis, and dephosphorylation(s) are a bit unclear. Citicoline contains equimolar amounts of choline and cytidine. Following citicoline ingestion in rats, the increase in both plasma cytidine and choline occurred quickly, but the molar increase in plasma choline was markedly smaller [23]. In a human study [24], oral citicoline resulted in increases in plasma choline and uridine that were similar in timing and magnitude, but in the other human study, the increase in plasma choline following citicoline ingestion was biphasic and delayed [25]. It has been suggested that citicoline is absorbed intact and its hydrolysis occurs in the liver and is coupled with a selective withdrawal of choline from blood [26]. Following oral citicoline intake in humans, the quantitative transformation of cytidine to uridine occurring in the intestine or liver was also postulated [24].

Absorption of intact citicoline molecules from the intestine to blood could also be helpful for explaining differences of acute toxicity of citicoline versus choline upon different routes of administration ( ).

Open in a separate window

The classical measure of acute toxicity is LD50, the median lethal dose of the tested compound expressed in milligrams per kilogram body weight. The lower the LD50 value, the more toxic the substance. For any route of administration (oral, intraperitoneal, intravenous), the LD50 of citicoline is higher than the corresponding LD50 of choline, indicating that citicoline is much less toxic than choline. This difference is certainly not unexpected when we consider that the molecular weight of choline moiety (MW = 104) contributes less than 30% to the molecular weight of citicoline (MW = 489), whereas the acute toxicity of cytidine is probably lower than that of choline. However, when we express the aforementioned LD50 values on a molar basis, citicoline is still substantially less toxic than choline. The difference in molar toxicity between citicoline and choline is more than 20-fold when the substances are applied intravenously. Apparently intact citicoline molecules do not evoke acute cholinergic toxicity, probably because they are not substrates for acetylcholine synthesis.

When the compounds are given per os, the difference in toxicity is several times lower, but it still is quite significant. Two possible explanations can be proposed for the aforementioned differences. One could be that when cytidine appears in blood concomitantly with choline, it somehow attenuates acute choline toxicity. The other, which seems more plausible, could be that upon oral application choline is not liberated from citicoline in the intestinal lumen, preventing its conversion to TMA. Compared with phosphatidylcholine and other choline derivatives encountered in food (e.g., carnitine, glycerophosphocholine), citicoline may be less prone to enzymatic hydrolysis inside the intestinal lumen because it is the only compound containing pyrophosphate group (it should, however, be noted that according to one study [32], the distribution of radioactivity in tissues, urine, and expired air following oral and intravenous administration of methyl-14C-labeled citicoline in rats showed metabolic differences which suggested that the compound is, at least partially, metabolized to TMA prior to its gastrointestinal absorption).

4. Does Resistance to Hydrolysis in the Intestine Make Citicoline a Safer Choline Supplement?

The issue of hypothetical citicoline resistance to intraintestinal hydrolysis is of importance when we consider that the intestinal microbiome metabolizes a significant fraction of choline and its derivatives to trimethylamine (TMA), a gaseous metabolite readily taken up and oxidized in the liver to its N-oxide, TMAO.

TMAO has been implicated in the etiology of various diseases, such as kidney failure, diabetes, and cancer [33]. There is a large and growing amount of literature on the atherogenicity of TMAO resulting in increased incidence of myocardial infarction, stroke, or death [34]. A meta-analysis published recently led to the conclusion that higher plasma TMAO correlates with a 23% increase in risk for cardiovascular events and a 55% increase in all-cause mortality [35]. Two recent reports showed that higher TMAO levels were associated with increased risk of first ischemic stroke and worse neurological deficit [36], and that patients suffering from atrial fibrillation who developed cardiogenic stroke displayed approx. 4 times higher TMAO levels in plasma than patients with atrial fibrillation who did not develop stroke [37]. Another recent report suggested a link between TMAO and Alzheimer’s disease [38]. It has even been suggested that supplementation with choline esters prone to be metabolized to TMA and TMAO, such as phosphatidylcholine, may be dangerous to human health [39].

On the other hand, several observations cast doubt on the pivotal role of TMAO in atherosclerosis. First of all, nutritional intakes of TMAO and its precursors do not always correlate with cardiovascular disease risk. For example, high fish intake increases TMA/TMAO while being cardioprotective. Some hypotheses have been proposed recently to resolve this paradox, employing inter alia a phenomenon of reverse causality, a possible role of insulin resistance and diabetes mellitus in activating N-oxidation of TMA, etc. [40].

Nonetheless, many authors still take it as having been proven that TMAO is a causative factor in the development of atherosclerosis and cardiovascular diseases. For example, in a recent review on TMAO and stroke [41], several reports are quoted that show the importance of TMAO as a risk factor and prognostic marker for this disease, and indicate the pathomechanisms involved. These include increased TMAO generation promoting atherosclerosis, platelet activation, and inflammation. The author concludes that TMAO may be a central molecule in the re­lationship of diet, genetics, the gut microbiota, and cardiovascular disease.

It may be concluded that until the place of TMAO in the chain of events leading to cardiovascular diseases and mortality is ultimately clarified, citicoline could be a more reasonable choice than other choline compounds, when choline supplementation is indicated.

5. Citicoline: A “Procognitive” Form of Choline

In two population studies, significant associations were found between choline intake or free choline level in blood and the cognitive performance of adult and elderly people. In a community-based population of non-demented individuals (1391 subjects, mean age 60.9 years), higher concurrent choline intake was related to better cognitive performance [42] ( ). In another cross-sectional study (2195 subjects aged 70–74 years), low plasma free choline concentrations were associated with poor cognitive performance [43]. A possible explanation for the effect of choline intake on cognition in adults has been sought in its function as a precursor of phosphatidylcholine (PC), a major constituent of all biological membranes, and acetylcholine, a neurotransmitter involved in cognition [44].

Open in a separate window

Therefore, it might be expected that supplementation with choline will improve cognitive performance. However, trials in which the effects of oral supplementation of humans with choline or phosphatidylcholine on cognition were investigated yielded mixed, mostly negative results (see [45] and references cited therein). On the other hand, in a recent small placebo-controlled study, adolescent males treated with citicoline showed improved attention and psychomotor speed and reduced impulsivity [46]. In other recent controlled studies, citicoline seemed to be efficacious in adult patients suffering from cognitive impairments, especially of vascular origin [47]. These newer studies corroborated results obtained previously when citicoline as a prescription drug had been tested in several placebo-controlled trials for cognitive impairment due to chronic cerebral disorders in the elderly. The review of those early trials led to the conclusion that there was some evidence of a positive effect of citicoline on memory and behavior in at least the short to medium term [48]. Moreover, it was recently shown that in patients suffering from dementia concomitant oral intake of citicoline improved the efficacy of cholinesterase inhibitors [49,50].

6. Conclusions

Altogether, whereas the jury may still be out on the issue whether, or to what extent, citicoline taken orally is metabolized to TMA and TMAO, there are reasons to believe that procognitive effects of citicoline supplementation are superior over those of choline or phosphatidylcholine.

Author Contributions

P.G. and K.S. wrote the paper.

Funding

This research received no external funding.

Conflicts of Interest

The authors declare no conflict of interest.

This is a fact sheet intended for health professionals. For a general overview, see our consumer fact sheet.

Introduction

Choline is an essential nutrient that is naturally present in some foods and available as a dietary supplement. Choline is a source of methyl groups needed for many steps in metabolism. The body needs choline to synthesize phosphatidylcholine and sphingomyelin, two major phospholipids vital for cell membranes. Therefore, all plant and animal cells need choline to preserve their structural integrity [1,2]. In addition, choline is needed to produce acetylcholine, an important neurotransmitter for memory, mood, muscle control, and other brain and nervous system functions [1-3]. Choline also plays important roles in modulating gene expression, cell membrane signaling, lipid transport and metabolism, and early brain development [1,2].

Humans can produce choline endogenously in the liver, mostly as phosphatidylcholine, but the amount that the body naturally synthesizes is not sufficient to meet human needs [4]. As a result, humans must obtain some choline from the diet. Premenopausal women might need less choline from the diet than children or other adults because estrogen induces the gene that catalyzes the biosynthesis of choline [4]. When a diet is deficient in folate, a B-vitamin that is also a methyl donor, the need for dietary choline rises because choline becomes the primary methyl donor [1].

The most common sources of choline in foods are the fat-soluble phospholipids phosphatidylcholine and sphingomyelin as well as the water-soluble compounds phosphocholine, glycerolphosphocholine, and free choline [1]. When these choline-containing compounds are ingested, pancreatic and mucosal enzymes liberate free choline from about half of the fat-soluble forms and some water-soluble forms [5]. Free choline, phosphocholine, and glycerophosphocholine are absorbed in the small intestine, enter the portal circulation, and are stored in the liver, where they are subsequently phosphorylated and distributed throughout the body to make cell membranes [1-3]. The remaining fat-soluble phospholipids (phosphatidylcholine and sphingomyelin) are absorbed intact, incorporated into chylomicrons, and secreted into the lymphatic circulation, where they are distributed to tissues and other organs, including the brain and placenta [1,6].

Choline status is not routinely measured in healthy people. In healthy adults, the concentration of choline in plasma ranges from 7 to 20 mcmol/L [2]. According to one study, the range is 7–9.3 mcmol/L in fasting adults [7]. Plasma choline levels do not decline below 50% of normal, even in individuals who have not eaten for more than a week [3]. This may be due to the hydrolysis of membrane phospholipids, a source of choline, to maintain plasma choline concentrations above this minimal level, or to endogenous synthesis [2].

Recommended Intakes

Intake recommendations for choline and other nutrients are provided in the Dietary Reference Intakes (DRIs) developed by the Food and Nutrition Board (FNB) of the Institute of Medicine [2]. DRI is the general term for a set of reference values used for planning and assessing nutrient intakes of healthy people. These values, which vary by age and sex, include the following:

For more information, please visit phosphatidylserine 70%.

Featured content:
Best High Quality Fruit Powder Manufacturer Factory – Licorice ...

• Recommended Dietary Allowance (RDA): Average daily level of intake sufficient to meet the nutrient requirements of nearly all (97%–98%) healthy individuals; often used to plan nutritionally adequate diets for individuals
• Adequate Intake (AI): Intake at this level is assumed to ensure nutritional adequacy; established when evidence is insufficient to develop an RDA
• Estimated Average Requirement (EAR): Average daily level of intake estimated to meet the requirements of 50% of healthy individuals; usually used to assess the nutrient intakes of groups of people and to plan nutritionally adequate diets for them; can also be used to assess the nutrient intakes of individuals
• Tolerable Upper Intake Level (UL): Maximum daily intake unlikely to cause adverse health effects

How to Get Low Price Bulk Beet Root Juice Powder - A Complete Guide

Insufficient data were available to establish an EAR for choline, so the FNB established AIs for all ages that are based on the prevention of liver damage as measured by serum alanine aminostransferase levels [2]. The amount of choline that individuals need is influenced by the amount of methionine, betaine, and folate in the diet; gender; pregnancy; lactation; stage of development; ability to produce choline endogenously; and genetic mutations that affect choline needs [1,2,4,5]. Table 1 lists the current AIs for choline [2].

Table 1: Adequate Intakes (AIs) for Choline [2] Age Male Female Pregnancy Lactation Birth to 6 months 125 mg/day 125 mg/day 7–12 months 150 mg/day 150 mg/day 1–3 years 200 mg/day 200 mg/day 4–8 years 250 mg/day 250 mg/day 9–13 years 375 mg/day 375 mg/day 14–18 years 550 mg/day 400 mg/day 450 mg/day 550 mg/day 19+ years 550 mg/day 425 mg/day 450 mg/day 550 mg/day  

Sources of Choline

Food

Many foods contain choline [4]. The main dietary sources of choline in the United States consist primarily of animal-based products that are particularly rich in choline—meat, poultry, fish, dairy products, and eggs [4,5,8-10]. Cruciferous vegetables and certain beans are also rich in choline, and other dietary sources of choline include nuts, seeds, and whole grains.

About half the dietary choline consumed in the United States is in the form of phosphatidylcholine [8,9]. Many foods also contain lecithin, a substance rich in phosphatidylcholine that is prepared during commercial purification of phospholipids; lecithin is a common food additive used as an emulsifying agent in processed foods, such as gravies, salad dressings, and margarine [1,3]. Choline is also present in breast milk and is added to most commercial infant formulas [3,4]. Precise estimates of the percentage absorption of the different forms of dietary choline in humans are not available [2,3].

Several food sources of choline are listed in Table 2.

Table 2: Choline Content of Selected Foods [11] Food Milligrams
(mg) per
serving Percent
DV* Beef liver, pan fried, 3 ounces 356 65 Egg, hard boiled, 1 large 147 27 Beef top round, separable lean only, braised, 3 ounces 117 21 Soybeans, roasted, ½ cup 107 19 Chicken breast, roasted, 3 ounces 72 13 Beef, ground, 93% lean meat, broiled, 3 ounces 72 13 Fish, cod, Atlantic, cooked, dry heat, 3 ounces 71 13 Potatoes, red, baked, flesh and skin, 1 large potato 57 10 Wheat germ, toasted, 1 ounce 51 9 Beans, kidney, canned, ½ cup 45 8 Quinoa, cooked, 1 cup 43 8 Milk, 1% fat, 1 cup 43 8 Yogurt, vanilla, nonfat, 1 cup 38 7 Brussels sprouts, boiled, ½ cup 32 6 Broccoli, chopped, boiled, drained, ½ cup 31 6 Mushrooms, shiitake, cooked, ½ cup pieces 27 5 Cottage cheese, nonfat, 1 cup 26 5 Fish, tuna, white, canned in water, drained, 3 ounces 25 5 Peanuts, dry roasted, ¼ cup 24 4 Cauliflower, 1" pieces, boiled, drained, ½ cup 24 4 Peas, green, boiled, ½ cup 24 4 Sunflower seeds, oil roasted, ¼ cup 19 3 Rice, brown, long grain, cooked, 1 cup 19 3 Bread, pita, whole wheat, 1 large (6½ inch diameter) 17 3 Cabbage, boiled, ½ cup 15 3 Tangerine (mandarin orange), sections, ½ cup 10 2 Beans, snap, raw, ½ cup 8 1 Kiwi fruit, raw, ½ cup sliced 7 1 Carrots, raw, chopped, ½ cup 6 1 Apples, raw, with skin, quartered or chopped, ½ cup 2 0

*DV = Daily Value. The U.S. Food and Drug Administration (FDA) developed DVs to help consumers compare the nutrient contents of foods and dietary supplements within the context of a total diet. The DV for choline is 550 mg for adults and children age 4 years and older [12]. FDA does not require food labels to list choline content unless choline has been added to the food. Foods providing 20% or more of the DV are considered to be high sources of a nutrient, but foods providing lower percentages of the DV also contribute to a healthful diet.

The U.S. Department of Agriculture’s (USDA’s) FoodData Central [11] lists the nutrient content of many foods and provides a comprehensive list of foods containing choline arranged by nutrient content.

Dietary supplements

Choline is available in dietary supplements containing choline only, in combination with B-complex vitamins, and in some multivitamin/mineral products [13]. Typical amounts of choline in dietary supplements range from 10 mg to 250 mg. The forms of choline in dietary supplements include choline bitartrate, phosphatidylcholine, and lecithin. No studies have compared the relative bioavailability of choline from these different forms.

Choline Intakes and Status

Most people in the United States consume less than the AI for choline. An analysis of data from the 2013–2014 National Health and Nutrition Examination Survey (NHANES) found that the average daily choline intake from foods and beverages among children and teens is 256 mg for ages 2–19 [14]. In adults, the average daily choline intake from foods and beverages is 402 mg in men and 278 mg in women. Intakes from supplements contribute a very small amount to total choline intakes.

According to an analysis of 2007–2008 NHANES data, black males of all ages had lower mean choline intakes than their white and Hispanic counterparts, but choline intakes did not differ substantially among females of different races/ethnicities [10].

Choline Deficiency

Choline deficiency can cause muscle damage, liver damage, and nonalcoholic fatty liver disease (NAFLD or hepatosteatosis) [1,2,4,15]. Although most people in the United States consume less than the AI of choline, frank choline deficiency in healthy, nonpregnant individuals is very rare, possibly because of the contribution of choline that the body synthesizes endogenously [1,5].

Groups at Risk of Choline Inadequacy

The following groups are among those most likely to have inadequate choline status.

Pregnant women

Approximately 90%–95% of pregnant women consume less choline than the AI [16]. Prenatal dietary supplements typically contain little if any choline [17]. The risk of inadequate choline status might be greater in pregnant and lactating women who do not take folic acid supplements, those with low vitamin B12 status, and those with a common variant in methylenetetrahydrofolate dehydrogenase (an enzyme that can affect folate status), all of which reduce the body’s pool of methyl groups needed for metabolism [17-20].

Some evidence indicates that lower plasma or serum choline levels (e.g., serum concentration of 2.77 mmol/L in midpregnancy) are associated with an increased risk of neural tube defects [21,22]. However, other research found no relationship between plasma choline concentrations during pregnancy and neural tube defects in offspring [23].

People with certain genetic alterations

Genes involved in the metabolism of choline, folate, and methionine play a role in the pathways for choline production and use [24,25]. Humans have variations in the DNA sequences for these genes (single nucleotide polymorphisms [SNPs]), and these SNPs can have a strong influence on demands for dietary choline. For example, one common SNP in the PEMT gene reduces endogenous synthesis of choline in women induced by estrogen [26]. The prevalence of SNPs that alter requirements for dietary choline vary by race. In a study of 100 African, Asian, Caucasian, and Mexican Americans, individuals of European ancestry had a higher prevalence of four SNPs that increased the risk of organ dysfunction when these individuals consumed a low-choline diet [27].

Patients requiring total parenteral nutrition

At present, choline is not routinely added to commercial parenteral solutions for infants and adults [28,29]. As a result, adults and infants receiving total parenteral nutrition (TPN) over the long term have low plasma choline concentrations (approximately 5 nmol/ml in adults and 5.7 nmol/ml in infants), which can result in hepatic abnormalities, including NAFLD [30-32]. The American Society for Parenteral and Enteral Nutrition recommends the routine addition of choline to adult and pediatric parenteral nutrition formulations and calls for the development of a commercially available parenteral product that contains choline [28].

Choline and Health

This section focuses on three conditions in which choline might play a role: cardiovascular and peripheral artery disease, neurological disorders, and NAFLD. Choline is involved in functions that overlap with those of folate and other B vitamins. Many studies do not assess the status of all B vitamins, which can confound results and obscure the true relationship between choline and the observed outcome.

Cardiovascular and peripheral artery disease

Some researchers have suggested that choline might protect cardiovascular health by reducing blood pressure, altering lipid profiles, and reducing levels of plasma homocysteine [3]. Other research suggests that higher dietary choline might increase cardiovascular disease risk because some choline and other dietary ingredients, such as carnitine, are converted to trimethylamine (TMA) by intestinal bacteria. The TMA is then absorbed and converted by the liver into trimethylamine-N-oxide (TMAO), a substance that has been linked to a higher risk of cardiovascular disease [33,34].

Despite the hypothesis that choline might affect heart health, several large observational studies have found no significant associations between choline intakes and cardiovascular or peripheral artery disease risk. An analysis of 72,348 women in the Nurses’ Health Study and 44,504 men in the Health Professionals Follow-Up Study showed no association between choline intake and risk of peripheral artery disease in men or women [35]. Similarly, a prospective study in 14,430 middle-age adults in the Atherosclerosis Risk in Communities Study found that over 14 years, risk of coronary heart disease was not significantly different in the highest choline intake quartile compared to the lowest quartile [36]. Choline intakes also had no association with cardiovascular disease risk in a study of 16,165 women participating in the European Prospective Investigation into Cancer and Nutrition [37].

However, a more recent analysis of data on 80,978 women from the Nurses’ Health Study and 39,434 men from the Health Professionals Follow-Up Study found an increased risk of mortality in those consuming higher levels of choline [33]. The authors suggest that the higher risk might be due to increased production of TMAO, although they did not directly measure TMAO.

Additional research is needed to determine the relationship between choline intakes and cardiovascular and peripheral artery disease as well as the potential risks and benefits of choline supplementation to reduce the risk of these diseases.

Neurological disorders

People with Alzheimer’s disease have lower levels of the enzyme that converts choline into acetylcholine in the brain [38]. In addition, because phosphatidylcholine can serve as a phospholipid precursor, it might help support the structural integrity of neurons and thus might promote cognitive function in elderly adults [8]. Some experts have therefore theorized that consuming higher levels of phosphatidylcholine could reduce the progression of dementia in people with Alzheimer’s disease [38]. However, little research conducted to date supports this hypothesis, as described below.

A few observational studies have shown a link between cognitive performance in adults and both higher choline intakes and plasma concentrations. In one observational study in 2,195 adults age 70–74 years in Norway, participants with plasma free choline concentrations lower than 8.4 mcmol/L (20th percentile of concentrations in the study population) had poorer sensorimotor speed, perceptual speed, executive function, and global cognition than those with choline concentrations higher than 8.4 mcmol/L [39]. A second study in 1,391 adults age 36–83 years from the Framingham Offspring study who completed food frequency questionnaires from 1991 to 1995 and again from 1998 to 2001 found that those with higher choline intakes had better verbal memory and visual memory [40]. Furthermore, higher choline intakes during the earlier period were associated with smaller white matter hyperintensity volume (a high volume is a sign of small-vessel disease in the brain).

Some small randomized intervention trials have shown that choline supplements improve cognitive performance in adults [30,41]. However, a 2015 systematic review of 13 studies on the relationship between choline levels and neurological outcomes in adults found that choline supplements did not result in clear improvements in cognition in healthy adults [8]. Similarly, a 2003 Cochrane Review of 12 randomized trials in 265 patients with Alzheimer’s disease, 21 with Parkinsonian dementia, and 90 with self-identified memory problems found no clear clinical benefits of lecithin supplementation for treating Alzheimer’s disease or Parkinsonian dementia [38].

Future studies are needed to clarify the relationship between choline intakes and cognitive function and determine whether choline supplements might benefit patients with Alzheimer’s disease or other forms of dementia.

Nonalcoholic fatty liver disease

NAFLD involves the accumulation of lipids in the livers of people who consume less than 20 g/day ethanol and who have no other known causes of steatosis [42,43]. (A single drink [e.g., 12 oz beer, 5 oz wine, or 1.5 oz hard liquor] contains about 12–14 g alcohol.) It is the most common chronic liver disorder, present in up to 65% of individuals who are overweight and 90% of those with obesity [1]. Although it is often benign, NAFLD can lead to steatohepatitis, fibrosis, cirrhosis, liver failure, and liver cancer [15]. Choline, especially phosphatidylcholine, is essential for transporting lipids from the liver [1]. Therefore, in choline deficiency, fat accumulates in the liver, which can result in NAFLD [44,45]. Although most women of childbearing age are resistant to NAFLD because of their high estrogen levels, at least 40% have a polymorphism that makes them insensitive to activation of the gene by estrogen; adequate consumption of dietary choline is particularly important for this population [46].

Data from a single large observational study support a link between choline deficiency and risk of NAFLD. Specifically, a cross-sectional study of 56,195 Chinese adults age 40–75 years found an inverse relationship between dietary choline intakes and risk of NAFLD based on 24-hour dietary recall [47]. The risk of NAFLD was 32% lower in women in the highest quintile of choline intake (412 mg/day) compared to the lowest (179 mg/day) and 25% lower in men in the highest (452 mg/day) quintile compared to those in the lowest (199 mg/day). However, choline intake was associated with NAFLD in normal-weight women only and not in those with overweight or obesity. This difference by weight status was not observed in men.

In a cross-sectional study of 664 adults and children from the Nonalcoholic Steatohepatitis Clinical Research Network, postmenopausal women who had nonalcoholic steatohepatitis (an extreme form of NAFLD involving liver inflammation and fibrosis) and a choline intake less than 50% of the AI had more severe fibrosis, but the results showed no relationship between choline intake and degree of liver steatosis [48].

Only limited data are available on the use of choline to treat NAFLD. For example, in a study of 57 adults who consumed a diet that included less than 50 mg choline per 70 kg body weight per day (<10% of the AI) for up to 42 days, 37 of the participants developed liver dysfunction [45]. Liver function returned to normal in 29 participants in this study after they were fed a diet containing 25%–75% of the choline AI and in eight who consumed an ad libitum diet. A pilot study in 15 adults on TPN found that NAFLD resolved completely in all patients who received their usual TPN regimen with an additional 2 g choline and in none of the patients who received their usual TPN regimen only [49].

Adequate choline intake is needed for proper liver function and to prevent NAFLD, but more research is needed to further clarify the role of choline in preventing or treating NAFLD [50].

Health Risks from Excessive Choline

High intakes of choline are associated with a fishy body odor, vomiting, excessive sweating and salivation, hypotension, and liver toxicity [1,2]. Choline consumption has been shown to increase production of TMAO, a substance that has been linked to a higher risk of cardiovascular disease, in a dose-dependent manner in adults.

The FNB has established ULs for choline from food and supplements based on the amounts of choline that are associated with hypotension and fishy body odor (see Table 3) [2]. The ULs apply to healthy children and adults but not to those taking high doses of choline under medical supervision. The FNB was unable to establish ULs for infants due to the lack of data on adverse effects in this age group.

Table 3: Tolerable Upper Intake Levels (ULs) for Choline [2] Age Male Female Pregnancy Lactation Birth to 6 months* 7–12 months* 1–3 years 1,000 mg 1,000 mg 4–8 years 1,000 mg 1,000 mg 9–13 years 2,000 mg 2,000 mg 14–18 years 3,000 mg 3,000 mg 3,000 mg 3,000 mg 19+ years 3,500 mg 3,500 mg 3,500 mg 3,500 mg

*Not possible to establish; breast milk, formula, and food should be the only sources of choline for infants.

Interactions with Medications

Choline is not known to have any clinically relevant interactions with medications.

Choline and Healthful Diets

The federal government's 2020–2025 Dietary Guidelines for Americans notes that "Because foods provide an array of nutrients and other components that have benefits for health, nutritional needs should be met primarily through foods. ... In some cases, fortified foods and dietary supplements are useful when it is not possible otherwise to meet needs for one or more nutrients (e.g., during specific life stages such as pregnancy)."

For more information about building a healthy dietary pattern, refer to the Dietary Guidelines for Americans and the USDA's MyPlate.

The Dietary Guidelines for Americans describes a healthy dietary pattern as one that

• Includes a variety of vegetables; fruits; grains (at least half whole grains); fat-free and low-fat milk, yogurt, and cheese; and oils.
  • Many vegetables, fruits, whole grains, and dairy products contain choline.
• Includes a variety of protein foods such as lean meats; poultry; eggs; seafood; beans, peas, and lentils; nuts and seeds; and soy products.
  • ​​​​​​​Fish, beef, poultry, eggs, and some beans and nuts are rich sources of choline.
• Limits foods and beverages higher in added sugars, saturated fat, and sodium.
• Limits alcoholic beverages.
• Stays within your daily calorie needs.

Disclaimer

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.

If you want to learn more, please visit our website yesherb group inc.