what is the best form of choline to take?
Nutrients. 2019 Jul; 11(7): 1569.
Citicoline: A Superior Course of Choline?
Received 2019 Jun 11; Accustomed 2019 Jul 10.
Abstract
Medicines containing citicoline (cytidine-diphosphocholine) as an active principle have been marketed since the 1970s every bit nootropic and psychostimulant drugs available on prescription. Recently, the inner salt variant of this substance was pronounced a nutrient ingredient in the major globe markets. All the same, 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 non have whatsoever wellness claim authorized either, but there are claims authorized for choline, apropos its contribution to normal lipid metabolism, maintenance of normal liver office, and normal homocysteine metabolism. The applicability of these claims to citicoline is discussed, leading to the determination that the effect is not a trivial 1. Intriguing data, showing that on a molar mass basis citicoline is significantly less toxic than choline, are also analyzed. Information technology is hypothesized that, compared to choline moiety in other dietary sources such equally phosphatidylcholine, choline in citicoline is less decumbent to conversion to trimethylamine (TMA) and its putative atherogenic Northward-oxide (TMAO). Epidemiological studies have suggested that choline supplementation may better cerebral performance, and for this awarding citicoline may exist safer and more efficacious.
Keywords: citicoline, choline, wellness claims, toxicity, trimethylamine oxide, procognitive furnishings
1. Introduction
Citicoline is the international nonproprietary proper name (INN) for cytidine-diphosphocholine (CDP-Cho). The substance is commercially available in two forms, sodium table salt and inner table salt. Citicoline sodium salt, classified as a nootropic and psychostimulant [1], is an active principle of a diversity of prescription drugs, either injectables or oral formulations. In 2009 in the U.s.a., citicoline (inner salt) was cocky-affirmed by the Japanese visitor Kyowa-Hakko every bit GRAS (generally regarded as safety) [two], and in 2014 it was announced as a novel nutrient ingredient by the appropriate Implementing Conclusion 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 centre-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 Event of Wellness Claims
Classifying citicoline every bit a food ingredient suitable for food supplements should make information technology widely available, just in the highly regulated marketplace 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 nutrient supplements must be formally authorized following scientific cess performed by the European Food Safety Agency (EFSA). Citicoline does not have any nutrition or health claim authorized up to engagement. Moreover, application for authorization of a health claim (related to citicoline and maintenance of normal vision) was turned down by the EFSA considering it was concluded that a crusade and effect human 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 European union market in a food supplement, information provided most this supplement should not contain any information most its specific nutritional and/or functional value?
Looking through the positive EFSA Scientific Opinion on citicoline issued prior to the aforementioned implementing determination [six], we find the reference to the observation that, both in humans and in rats, upon ingestion citicoline undergoes quick hydrolysis, breaking downwards to choline and cytidine [7], which then undergo farther metabolism and incorporation into normal pathways of metabolism [8]. Cytidine, a pyrimidine nucleoside which in humans interconverts with uridine [nine], undergoes intracellular phosphorylations to cytidine triphosphate (CTP), which participates in phospholipids synthesis via the Kennedy pathway, and may also exist 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. As well, in cholinergic neurons, choline is acetylated to form the neurotransmitter acetylcholine.
Nosotros 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 then-called functional claims relating to the benign 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 accustomed 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-gratuitous total parenteral nutrition solutions, whose effects tin be reversed by the assistants of dietary choline [10,eleven]. 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,xiv] as well as intervention [xv] studies supported the inverse clan 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 office and normal cognitive function were rejected by the EFSA because cause and outcome relationships have not been established between the consumption of choline and the claimed effects [xvi]. 1 of the reasons was that some references that presented back up 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 engagement of issuing scientific opinion on the wellness claims apropos choline (i.east., year 2011), citicoline was non all the same appreciated by EFSA experts as the dietary source of choline. Indeed, natural foods practise non contain any meaning amount of this substance.
There is no direct proof that citicoline intake can opposite either elevated serum alanine aminotransferase activity or the development of fatty liver in people who are choline-deficient. In that location is too no directly 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 increment of plasma homocysteine, merely 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 safety and efficient method of delivery of choline to the human body.
It might perhaps be ended that the upshot of the applicability to citicoline of health claims pertaining to choline (and apparently also to some of its derivatives, such as phosphatidylcholine) is but a legal problem that shall be settled accordingly by the appropriate authorities. On the other mitt, a health claim authorized almost a decade ago may not exist supported in its entirety by the contemporary scientific data. Electric current guidelines for the management of fatty liver do not mention supplementation with choline or its derivatives [xviii]. Besides, folic acid, vitamin Bvi, vitamin B12, and betaine, simply not cholines, are listed amidst nutrients that may counteract hyperhomocysteinemia [19].
3. Citicoline every bit a Source of Choline: The Event of Acute Toxicity
It is well established that following ingestion citicoline is fully absorbed and catabolized to cytidine and choline, which enter their corresponding metabolic pools in the body [xx,21,22]. However, the particulars of its absorption, hydrolysis, and dephosphorylation(south) are a chip unclear. Citicoline contains equimolar amounts of choline and cytidine. Following citicoline ingestion in rats, the increment in both plasma cytidine and choline occurred chop-chop, but the molar increment in plasma choline was markedly smaller [23]. In a homo study [24], oral citicoline resulted in increases in plasma choline and uridine that were like in timing and magnitude, simply in the other human written report, the increase in plasma choline post-obit citicoline ingestion was biphasic and delayed [25]. Information technology has been suggested that citicoline is captivated intact and its hydrolysis occurs in the liver and is coupled with a selective withdrawal of choline from blood [26]. Post-obit oral citicoline intake in humans, the quantitative transformation of cytidine to uridine occurring in the intestine or liver was too postulated [24].
Assimilation of intact citicoline molecules from the intestine to blood could as well be helpful for explaining differences of acute toxicity of citicoline versus choline upon dissimilar routes of administration (Effigy 1).
Median lethal dose of choline chloride and citicoline in mice (A,B) and rats (C,D) expressed in milligrams (A,C) or in millimoles (B,D) per kilogram torso weight, depending on the route administration. Data compiled from refs. [27,28,29,30,31]. Abbreviations used: i.v., intravenous; i.p., intraperitoneal; ND, no data available.
The classical measure of acute toxicity is LD50, the median lethal dose of the tested chemical compound expressed in milligrams per kilogram trunk weight. The lower the LDl value, the more toxic the substance. For whatever road 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 departure is certainly not unexpected when nosotros consider that the molecular weight of choline moiety (MW = 104) contributes less than 30% to the molecular weight of citicoline (MW = 489), whereas the astute toxicity of cytidine is probably lower than that of choline. However, when nosotros express the same LD50 values on a tooth basis, citicoline is withal substantially less toxic than choline. The difference in molar toxicity between citicoline and choline is more than than 20-fold when the substances are applied intravenously. Manifestly intact citicoline molecules do non evoke acute cholinergic toxicity, probably because they are non substrates for acetylcholine synthesis.
When the compounds are given per bone, the departure in toxicity is several times lower, but it withal is quite significant. Two possible explanations can be proposed for the aforementioned differences. I could exist that when cytidine appears in claret concomitantly with choline, it somehow attenuates acute choline toxicity. The other, which seems more plausible, could be that upon oral application choline is non liberated from citicoline in the abdominal lumen, preventing its conversion to TMA. Compared with phosphatidylcholine and other choline derivatives encountered in food (east.g., carnitine, glycerophosphocholine), citicoline may exist less prone to enzymatic hydrolysis within the abdominal lumen because it is the only compound containing pyrophosphate group (it should, yet, be noted that according to one study [32], the distribution of radioactive decay in tissues, urine, and expired air post-obit 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 assimilation).
4. Does Resistance to Hydrolysis in the Intestine Brand 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 diverse diseases, such equally kidney failure, diabetes, and cancer [33]. There is a big 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 college plasma TMAO correlates with a 23% increase in take chances for cardiovascular events and a 55% increment in all-cause mortality [35]. Two recent reports showed that college TMAO levels were associated with increased chance of offset 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 non 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 exist dangerous to human health [39].
On the other hand, several observations cast dubiety on the pivotal part of TMAO in atherosclerosis. Kickoff of all, nutritional intakes of TMAO and its precursors do not always correlate with cardiovascular disease take chances. For case, high fish intake increases TMA/TMAO while existence cardioprotective. Some hypotheses take 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].
Even so, many authors still take information technology as having been proven that TMAO is a causative cistron in the development of atherosclerosis and cardiovascular diseases. For case, 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 mark for this disease, and bespeak 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.
Information technology may exist concluded that until the place of TMAO in the chain of events leading to cardiovascular diseases and bloodshed is ultimately antiseptic, citicoline could exist a more than 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 betwixt choline intake or complimentary 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] (Figure ii). In some other cantankerous-sectional study (2195 subjects aged lxx–74 years), low plasma gratis 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 knowledge [44].
Dose–response relationship between the average daily choline intake and verbal and visual memory performance in non-demented adults. Black lines point the mean score and red lines indicate 95% conviction interval. Figure reproduced from [44].
Therefore, it might exist expected that supplementation with choline will ameliorate cognitive functioning. However, trials in which the effects of oral supplementation of humans with choline or phosphatidylcholine on cognition were investigated yielded mixed, mostly negative results (run across [45] and references cited therein). On the other hand, in a recent small placebo-controlled study, adolescent males treated with citicoline showed improved attending and psychomotor speed and reduced impulsivity [46]. In other recent controlled studies, citicoline seemed to be efficacious in developed patients suffering from cognitive impairments, particularly of vascular origin [47]. These newer studies corroborated results obtained previously when citicoline equally a prescription drug had been tested in several placebo-controlled trials for cognitive harm due to chronic cerebral disorders in the elderly. The review of those early on trials led to the determination 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
Birthday, whereas the jury may even so exist 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.Due south. wrote the paper.
Funding
This inquiry received no external funding.
Conflicts of Involvement
The authors declare no conflict of interest.
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Articles from Nutrients are provided here courtesy of Multidisciplinary Digital Publishing Plant (MDPI)
Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6683073/
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