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Department of Experimental Pharmacology, Mossakowski Medical Research Centre, Polish Academy of Sciences, 5 Pawinskiego str., 02-106 Warsaw, Poland
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Citicoline is the generic name of the pharmaceutical substance that chemically is cytidine-5&#;-diphosphocholine (CDP-choline), which is identical to the natural intracellular precursor of phospholipid phosphatidylcholine. Following injection or ingestion, citicoline is believed to undergo quick hydrolysis and dephosphorylation to yield cytidine and choline, which then enter the brain separately and are used to resynthesize CDP-choline inside brain cells. Neuroprotective activity of citicoline has been repeatedly shown in preclinical models of brain ischaemia and trauma, but two recent, large, pivotal clinical trials have revealed no benefits in ischaemic stroke and traumatic brain injury. However, the substance seems to be beneficial in some slowly advancing neurodegenerative disorders such as glaucoma and mild vascular cognitive impairment. This paper critically discusses issues related to the clinical pharmacology of citicoline, including its pharmacokinetics/biotransformation and pharmacodynamics/mode of action. It is concluded that at present, there is no adequate description of the mechanism(s) of the pharmacological actions of this substance. The possibility should be considered and tested that, in spite of apparently fast catabolism, the intact citicoline molecule or the phosphorylated intermediate products of its hydrolysis, cytidine monophosphate and phosphocholine, are pharmacologically active.
Citicoline is chemically identical to CDP-choline, the natural precursor of the major cell membrane phospholipid phosphatidylcholine.Given orally or by injection, citicoline is non-toxic and very well tolerated.Preclinical experiments with various models of central neurodegenerative diseases have shown that citicoline displays significant neuroprotective properties.However, recent large and well-controlled data have shown no benefit from citicoline in acute ischaemic stroke and traumatic brain injury.The pharmacological actions of citicoline in the central nervous system seem to be pleiotropic and involve, amongst other things, modulation of some kinases and sirtuin-1. However, our understanding of the mechanisms involved is, at most, fragmentary.Open in a separate window
Citicoline is the generic name, or the International Nonproprietary Name (INN) of cytidine-5&#;-diphosphocholine (CDP-choline, CDPCho), a pharmaceutical substance that is chemically identical to the naturally occurring metabolite, which plays crucial role in the synthesis of phospholipids. The work of Kennedy and collaborators in the s showed that this phosphorylated choline nucleotide is a precursor of glycerophospholipid phosphatidylcholine (PC) [1]. PC and its twin compound phosphatidylethanolamine (PEt) are the two most abundant phospholipids in eukaryotic cells, accounting for more than half of the total phospholipid content in membranes. The pathway of de novo synthesis of PC, the CDP-choline pathway (Fig. ), includes the enzymes cytidine kinase (CK), choline phosphate cytidilyltransferase (CCT) and CDP-choline:1,2-diacylglycerol choline phosphotransferase (CPT) [2]. These enzymes are located intracellularly, in the endoplasmic reticulum and cell nucleus [3]. Choline that is used for synthesis of phosphatidylcholine through the CDP-choline pathway is derived from transport of exogenous choline into the cell or from phospholipase D-mediated turnover of PC [4].
Open in a separate windowThe search for relevant literature&#;non-clinical as well as clinical&#;was performed in the PubMed, Scopus and Web of Science databases, using the term &#;CDP-choline&#;, its variants (&#;CDPcholine&#;, &#;cytidine-diphosphocholine&#;, etc.) and &#;citicoline&#;. Whereas &#;CDP-choline&#; designates the natural metabolite synthesized inside the cells (a substance of endogenous origin), the term &#;citicoline&#; did not exist until the substance became used as the drug, which occurred in the s. Notwithstanding, some papers currently indexed under the term &#;citicoline&#; are dated earlier; some of them (e.g. the paper by Berger and Gimenez [5], describing crystallization of CDP-choline from yeast) could be qualified as concerning citicoline (the compound synthesized exogenously), but others (e.g. the paper by Ansell and Bayliss [6], reporting on the concentration of endogenous CDP-choline in the rat brain) undoubtedly concern CDP-choline (the compound synthesized endogenously). The difference between CDP-choline (synthesized endogenously) and citicoline (synthesized exogenously) is not trivial, as will be discussed later.
In the Anglophone medical literature, the use citicoline as a drug was advocated as early as , by Manaka et al. [7] from Japan, for the treatment of Parkinson&#;s disease. A few years later, the idea of using it as a neuroprotectant stemmed from the observation, made by Horrocks and collaborators [8], of the reversibility of phosphotransferase enzymes in the brain. The first patent for the use of CDP-ethanolamine, alone or in combination with CDP-choline, to reverse neurodegenerative diseases was issued in [9]. Since that time, hundreds of studies concerning various aspects of the preclinical and clinical pharmacology of citicoline have been published. Several relevant reviews have also appeared in high-ranking journals, including at least five during the last 4 years [10&#;14]. However, the subject of citicoline&#;s mode of action is far from being clarified. The present review is an attempt to classify the major issues concerning the neuroprotective properties of citicoline into three categories: facts, i.e. those that are solved with an acceptable degree of certainty; doubts, i.e. those that are likely misinterpreted; and unresolved issues, i.e. those that remain unexplained. Needless to say, such classification is subjective: facts, doubts and unresolved issues are, in many cases, intermingled.
Citicoline displays negligible toxicity. The compound is quickly catabolized (Fig. ), 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.
Open in a separate windowThe 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.
Where is citicoline catabolized? While it seems reasonable to assume that, at least in rodents, citicoline given systemically is quickly hydrolysed and further dephosphorylated, the particulars of this decomposition process are uncertain. Does it take place in blood plasma or in other location(s)? Of note is that, following injection or ingestion of citicoline in the rat, the increase in plasma cytidine was, on a molar basis, several times larger than the concomitant increase in plasma choline [20]. What happened to the &#;surplus&#; choline? Was it taken up by the liver? Does the several-fold &#;domination&#; of the cytidine increase over the choline increase provide an explanation for the lack of cholinergic toxicity of citicoline versus the toxic effects of equimolar choline (see below)?
How is citicoline catabolized? In humans, an oral challenge with citicoline was accompanied by an increase in plasma uridine instead of cytidine [53]. In this last study, the participants took oral citicoline doses of up to 4 g (still much less per kilogram of bodyweight than the doses used in most rodent experiments), and significant dose-related increases in blood plasma uridine were observed. The data resembled the rat data reported previously by the same laboratory [20] in that the magnitude of the choline increases was several times smaller than the magnitude of the pyrimidine increase. Choline increments obtained after 2 or 4 g doses were comparable, on a molar basis, to those seen after similar doses of choline chloride, although the peaks were delayed by one or more hours. The authors failed, however, to detect any significant quantities of cytidine in human blood, either before or after citicoline intake. They interpreted this finding as evidence that the human gastrointestinal tract and liver quantitatively transform cytidine liberated from citicoline to circulating uridine. Would this indicate that hydrolysis of citicoline to CMP and PCho and consecutive dephosphorylations of these products to cytidine and choline occur almost immediately, followed by conversion of cytidine to uridine? But why is the final effect&#;namely, an increase in circulating choline&#;delayed by one or more hours?
Resynthesis of CDP-choline in the brain following citicoline intake and the pharmacodynamics of citicoline. It is usually assumed that following citicoline intake, cytidine and choline enter brain cells separately and are used for intracellular synthesis of CDP-choline [36]. For example, in a recent paper, Ramos-Cabrer et al. [54] stated &#;It is believed that when citicoline is exogenously administered as sodium salt, it is hydrolysed into choline and cytidine to be re-synthesized later in the brain&#;&#;. These statements seem to imply that resynthesis of citicoline from cytidine and choline in the brain is the only event&#;or at least the most important event&#;of systemic citicoline application.
At this point, the difference between citicoline (synthesized exogenously) and CDP-choline (synthesized endogenously) acquires its key importance, for at least three reasons. First, it must be appreciated that only a minor fraction of the choline dose administered as citicoline enters the brain. Tolvanen et al. [55] investigated the biodistribution and biokinetics of [11C]choline (a radio-pharmaceutical used for oncological positron emission tomography [PET] studies) in rats and humans following intravenous injection. They found that the highest uptake of the tracer was by the kidney, lung and adrenal glands, whereas the brain cortex and cerebellum were the organs taking up less than 0.1 % of the tracer dose. Second, stimulation following citicoline intake of at least two other major synthetic pathways of choline in the brain, one leading to betaine (an important donor of methyl groups) and the other leading to acetylcholine (an important CNS neurotransmitter), should also be taken into account [56]. Third, the ischaemic heart is the source of increased choline in the blood of patients with an acute coronary syndrome related to coronary plaque instability [57]. Moreover, the authors mention small unpublished pilot studies in which elevated levels of whole blood choline were also found in patients with stroke or cerebral ischaemia in combination with advanced plaques in the carotid artery. It is reasonable to assume that degradation of membrane phospholipids and elevation of blood choline levels occur in all cases of brain ischaemia, i.e. ischaemic stroke. Is there any difference between the metabolic effects of choline increases in plasma consequential to citicoline intake and those resulting from a heart attack or stroke?
Why were preclinical results with citicoline for stroke not reproduced in the clinical setting? The systematic review and meta-analysis of data obtained with preclinical models of embolic stoke [58] provided evidence that citicoline does indeed deliver some neuroprotection; however, the effect is stronger for infarct volume reduction and more limited for neurological outcome. The authors concluded that factors shown to be important for translation into human studies are multiple-dose administration, large infarct size and/or neurological deficit. However, the most important cause of the irreproducibility of preclinical results in a clinical setting may be the use of excessively large doses of citicoline in most animal experiments. For example, in a series of papers authored by Savci and collaborators (see the paper by Eyigor et al. [59] and the references quoted therein), various cardiovascular and endocrine effects of large, although subtoxic, doses of citicoline (0.5&#;2 g/kg) given intravenously were described. Among them were an increase in blood pressure and large rises in plasma levels of catecholamines and several pituitary hormones, including vasopressin and oxytocin. Evidence of histaminergic system involvement in the responses to citicoline has also been presented [60]. Can these effects be of potential benefit, e.g. in hypovolaemic shock (as suggested by Savci et al. [61]), or are they instead an early sign of toxicity? (On the other hand, it would be of importance to find an explanation for the observation that in rats&#;both normotensive and haemorrhagic&#;these massive doses of citicoline increased blood pressure, whereas no such effect occurred following equivalent doses of either cytidine or choline.)
Similar doubts may be raised against the recent report by Gutiérrez-Fernández et al. [62], who compared the effects of citicoline (1,000 mg/kg intraperitoneally) and recombinant tissue plasminogen activator [rt-PA] (5 mg/kg intravenously) in a rat model of embolic stroke. The problem with this paper was that whereas the rt-PA dose used per kg of bodyweight was 5 to 8 times the dose used in the treatment of human embolic stroke (0.6&#;1.1 mg/kg intravenously; see Wardlaw et al. [63]), the citicoline dose was 15 to 30 times the dose used in clinical trials of citicoline in stroke. The rationale for investigating the effects of injecting citicoline in doses corresponding to 30&#;150 g per person (assuming an average human bodyweight of 70 kg) is doubtful.
Why is citicoline so much less toxic than choline? The acute toxicity of citicoline and choline after oral and intravenous application was compared by Agut et al. [64]. These authors concluded that CDP-choline given either orally or intravenously did not cause any cholinergic intoxication in the treated groups, whereas such toxic effects were observed after administration of an equimolar dose of choline. Apparently, CDP-choline given by the oral or intravenous route yields toxicological consequences that are different from those yielded by choline. A mechanistic interpretation of the substantially lower toxicity of citicoline compared with that of choline is lacking to date.
Can intact citicoline be delivered orally? Yashima et al. [65] used citicoline doubly-labelled with carbon-14 at the methyl groups of choline and tritium at C5 of pyrimidine, and obtained evidence of CDP-choline being broken down in the intestine, resulting in release of choline and cytidine, likely due to the actions of intestinal esterases and pyrophosphatases. However, the authors concluded that &#;these split compounds as well as the original CDP-choline may be absorbed from the intestinal mucosa as such&#;. Apparently, they could not rule out the possibility that following oral intake, some fraction of intact citicoline is absorbed.
Is citicoline a prodrug or an active compound? The consequences of the assumed fast hydrolysis and subsequent dephosphorylation of citicoline after injection or oral intake are usually interpreted in terms of a prodrug, which is administered in an inactive or less than fully active form and is subsequently metabolically converted (bioactivated) to the active pharmacological agents, cytidine and choline. However, one may assume that the reverse is true, i.e. the most active form is unhydrolysed (intact) citicoline, whereas cytidine and choline are its pharmacologically less active metabolites. Although the prodrug concept clearly prevails in the scientific literature, several observations may indicate that intact citicoline molecules, or perhaps CMP and/or PCho intermediates, display their own activities, which are different from and/or more potent than the actions of cytidine and choline.
One reason for not discarding the idea of intact citicoline being significantly neuroprotective is the magnitude of the protective effect of citicoline in vitro versus in vivo. Neuroprotective effects in vitro occurred upon exposure of retinal cells or brain neurons to citicoline concentrations as low as submicromolar to micromolar [66, 67], whereas in the in vivo (animal) experiments, the minimal doses necessary to produce appreciable neuroprotection were within the range of 0.3&#;1 g/kg [68], an amount that could be equivalent to 0.6&#;2 mmol/kg, assuming even distribution throughout the body. Thus, citicoline seems to be a neuroprotectant that acts weakly in vivo but is much more potent in vitro.
The other reason concerns the activity of liposomal citicoline. A few studies have indicated that in experimental ischaemic stroke, liposomal formulations of citicoline are significantly more neuroprotective (i.e. by means of decreasing the ischaemic infarct volume) than equivalent doses of free citicoline (see, for example Fresta and Puglisi [69, 70] and Adibhatla et al. [69, 70]). The most recent study of this kind [54] indicated that liposomal citicoline is more neuroprotective than the equivalent intravenous dose of the free drug which, in turn, is more neuroprotective than the equivalent intraperitoneal dose. Although other explanations may be speculated upon, the aforementioned result is compatible with the idea that intact citicoline is pharmacologically more active than its metabolites.
Does intact citicoline modulate some kinases? Interesting observations have been reported on the modulation by citicoline of the activity/expression of some protein kinases involved in neuronal death&#;namely, MAPKs&#;in the postischaemic brain [40] and extracellular signal-regulated kinase 1/2 (ERK1/2) in the rat retina after kainic acid (KA) treatment [71]. Modulation of activity of cellular kinases and, in particular, members of the ERK/MAPK family, occurs through transduction of extracellular signals [72, 73]. Perhaps the neuroprotective actions of citicoline are exerted not by its hydrolysis products but by the unhydrolysed molecules acting extracellularly as signalling molecules. In this context, one should consider the possibility of binding of citicoline to plasma proteins such as albumin. Albumin binding has been reported for cytidine [74] and also for sphingosylphosphorylcholine [75], a compound remotely similar to citicoline. If intact citicoline binds to albumin, its hydrolysis could be retarded and its action as a signalling molecule could be prolonged.
In spite of the negative results of recent pivotal studies in acute ischaemic stroke and traumatic brain injury, there is continuing interest in the neuroprotective properties of citicoline. The drug is non-toxic, and numerous preclinical data support the view that it displays neuroprotective properties. However, no adequate mechanistic explanation for these observations has ever been provided.
The most frequently presented explanation for the neuroprotective effects of citicoline on the brain is based on the assumption that it is a prodrug which, following injection or ingestion, is sequentially hydrolysed and dephosphorylated, finally, to cytidine (or uridine in humans) and choline. Then these two metabolites separately enter the brain tissues and are used to resynthesize CDP-choline, which exerts neuroprotection intracellularly by supporting biosynthesis of cellular phospholipids. An alternative explanation&#;i.e. that unhydrolysed citicoline, or perhaps phosphocholine and/or cytidine monophosphate, are pharmacologically active metabolites of citicoline&#;has never been considered.
Dr Grieb has no conflicts of interest that are directly relevant to the content of this review. No sources of funding were used in the preparation of the review.
By Dr. Ramon Velazquez Ph.D.
&#;
Last updated: Sep 27, 24&#;
Citicoline is a brain supplement (also known as a nootropic) linked to multiple cognition-enhancing effects in human randomized controlled trials. Its benefits may include support for focus, recall, attention and overall brain health. It is one of the best nootropics known to science. In this article we explain why as well as give recommendations on the best supplements that supply this nutrient.
Citicoline (also known as cytidine-5-diphosphocholine, cytidine diphosphate choline or CDP-choline) is a naturally occurring compound in the human body. Citicoline is a 2-in-1 brain booster because after it is consumed, it breaks down into two distinct nootropic compounds:
Choline, a nutrient related to "good fats" and B-vitamins that is regarded as one of the most important nootropics for brain health and sharp cognition;(1)
Cytidine, a compound that is metabolized into uridine, which is another nootropic associated with memory function, brain plasticity, and healthy brain cell membranes (2)
Citicoline&#;s two nootropic compounds promote brain health in several pathways. The end result is a single whole-brain optimizer nootropic that can boost brainpower across all age groups and lifestyles -- making it the ideal core ingredient for a brain supplement called Mind Lab Pro.
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250 mg of citicoline per serving
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Citicoline's benefits as a supplement can be broadly placed into two categories: brain health support, and nootropic cognitive enhancement.
The following lists show some of the evidence-backed benefits associated with citicoline.
Optimizes brain cells' mitochondria for healthy energy metabolism
Raises brain levels of neural building-block phosphatidycholine
Supports brain chemicals acetylcholine, dopamine and norepinephrine
Helps create and repair brain cell membranes and DNA.
Protects brain cells from the damaging effects of free radicals and aging
Energizes brain cells
Enhances memory and recall
Promotes focus and attention
Supports overall cognitive function
We will cover some of the research backing these beneficial CDP choline effects a little later in this article. We'll also discuss its potential in another central nervous system pathway: the eyes. Beyond the brain, citicoline is suggested as a vision enhancer.
Next let's take a look at some citicoline bioactivities believed to account for its various benefits.
Citicoline has been suggested to help the brain generate electrical impulses by supporting proper function of mitochondria: the powerhouses that generate cell energy.
For more Buy Citicoline In Bulksinformation, please contact us. We will provide professional answers.
Healthy mitochondrial function results in higher levels of ATP energy in brain cells, which in turn powers not only mental energy, but also the demanding tasks of higher-order cognition and brain regeneration. One human research study found that Cognizin® Citicoline increased frontal lobe brain energy levels by 13.6%.
In addition to supporting the energy that fuels brain regeneration, Citicoline promotes formation and healthy function of brain cell membranes as a cholinergic compound that raises brain levels of phosphatidylcholine.
Phosphatidylcholine is one of the phospholipid building block compounds that makes up about 30% of all brain tissue. Due to its ability to affect brain phospholipid composition, Citicoline may help with brain renewal, support efficient formation of new brain cells and promote brain cell membrane integrity.(5)
Citicoline helps to form acetylcholine, which is the brain's most important executive neurotransmitter.(6) Acetylcholine is largely responsible for the function of working memory, learning and information processing, as well as muscle contraction and speech.
Since acetylcholine levels decline with age, and low acetylcholine is linked to brain degeneration, researchers have suggested that Citicoline (as Cognizin) may be a useful potential therapy for age-related cognitive decline.(7)
Citicoline may also support brain chemical dopamine and norepinephrine production, which are associated with more immediate benefits for mood and performance-driven cognition. Its far-reaching impact on brain chemicals position citicoline as one of the best nootropics for neurotransmitters.
Citicoline in supplement form has been suggested to promote healthy cerebral circulation. In one study of patients with brain degeneration and memory problems, researchers reported that left temporal cerebral blood flow appeared to normalize after supplementation with citicoline.(8) This may suggest potential to help with cerebrovascular disorders in general.
Other brain-protective nootropic supplements supply antioxidant activity that helps to neutralize the brain cell-damaging effects of toxic free radicals. Citicoline adds another level of neuroprotective activity that may be even more important: Citicoline protects hippocampal neurons in the brain via phosphatidylcholine synthesis, helping to strengthen brain cell membranes and enhance neural repair.(9)
So what about the research behind citicoline? There have been a few human clinical trials on this brain nutrient, along with several animal research and "petri dish" style studies. Let's take a look at a few that focus on citicoline's potential roles in brain performance.
Citicoline may help brain energy and brain cell regeneration
In a randomized controlled trial, 16 healthy men and women with an average age of 47 took either 500 mg or 2,000 mg Cognizin® Citicoline every day for 6 weeks and were then evaluated for changes to their brains&#; structure and function.
Researchers reported the Cognizin® Citicoline was associated with a 14% increase in brain ATP (&#;cellular currency&#; for brain energy) and 35% increase in brain cell membrane turnover (repair, rejuvenation & replacement). Researchers suggested these benefits may help counter brain degeneration related to aging and low brain energy levels.(10)
Citicoline improves verbal memory and may help rejuvenate brain cells
In this randomized placebo controlled trial, subjects were given 500 mg of Citicoline daily for six weeks, and then continued with either more Citicoline or placebo for another six weeks.
Researchers reported Citicoline was associated with a 7.3% increase in brain photodiesters, and that subjects&#; performance in verbal learning improved as photodiesters increased. Researchers have suggested that that chronic citicoline increases phosphodiesters, sparks the synthesis and rejuvenation of brain cell membrane phospholipids, and therefore may help with age-related changes in the brain.(11)
While not mentioned in this specific placebo controlled study, these changes may also suggest help for age-related cognitive impairment and other chronic cerebral disorders.
Citicoline may help with attentional performance
In this randomized controlled clinical trial, 60 women age 40 to 60 took 250 mg Cognizin® Citicoline, 500 mg Cognizin® Citicoline, or placebo every day for 28 days, and were then administered cognitive performance testing.
Researchers reported that the testing results of this placebo controlled clinical trial showed both doses of Cognizin® were linked to higher test scores, with the 500 mg serving showing the greatest benefit. Researchers concluded that Citicoline may enhance cognitive function and attentional performance in middle-aged women.(12)
Citicoline may help memory in elderly subjects
Elderly study subjects supplemented with Cognizin® Citicoline CDP Choline (500 mg or mg), placebo, or a drug daily for a span of four weeks prior to mental performance testing.
Researchers reported that, when compared to placebo, Citicoline improved memory, word recall, immediate recall, and delayed recall. Researchers attributed these benefits to Citicoline&#;s neuroregenerative and cerebral circulation-boosting properties, and suggested it may be helpful for memory loss in geriatric populations.(13)
Healthy adolescents may improve attention with Citicoline supplements
75 healthy adolescent males received 250 mg Cognizin® Citicoline, 500 mg Cognizin® Citicoline, or placebo daily for 28 days. Study subjects completed cognitive performance tests at the study&#;s starting point and end point.
Researchers reported that the study subjects who took Citicoline showed improvements in attention and psychomotor speed (versus placebo). The larger dosage of Citicoline was more strongly associated with mental performance benefits, including increased accuracy of attention, improved detection ability during attention tasks, and decreased cognitive and behavioural disturbances.(14)
**Those under age 18 should only take dietary supplements under the direction of a doctor.
This question is a little complicated to answer. In the United States, citicoline is sold as a supplement. As such, its claims relate to supporting healthy brain function, enhancing some aspects of cognition, fighting cognitive decline and assisting with mild cognitive impairment.
In other parts of the world, oral citicoline is considered for more serious health concerns and cognitive deficits. For example, in Europe and Japan, citicoline treatment is used for acute stroke, traumatic brain injury, chronic cerebrovascular diseases and other CNS disorders (central nervous system), along with age-related cognitive dysfunctions. Its use for these concerns reflects citicoline's extensive pharmacological and clinical review.
Let's take a look at some of citicoline's other uses around the world, where it is sometimes administered more like a pharmaceutical drug than a supplement.
In an acute ischaemic stroke, blood flow to the brain is abruptly cut off. Parts of the brain that do not receive blood flow become damaged, as brain cells die. This is known as an ischemic brain injury.
As we mentioned earlier, citicoline breaks down into choline and cytidine. These two compounds are required for the synthesis of phosphatidylcholine, which is a key raw material that is used to repair and create healthy cell membranes, including brain cells. Due in part to these bioactivities:
Brain cell membrane repair and regeneration -- which citicoline is suggested to support -- play a significant role in recovery from acute ischemic stroke.
Researchers have cited data from multiple clinical trials that support the potential of chronic citicoline intake as a safe way to support recovery from issues related to acute stroke.(15)
Mild vascular cognitive impairment refers to mental performance issues brought on by insufficient blood flow to the brain. Vascular cognitive impairment deficits that follow this cerebral disorder include issues with memory (including verbal memory), attention and executive functions.
In a similar vein and related to acute ischemic stroke is vascular dementia: a chronic cerebrovascular disease where these symptoms worsen. Vascular dementia is the second most common form of dementia, caused by poor blood flow to the brain for any reason, including strokes and mini-strokes (transient cerebral ischemia).
In one review, researchers reported that CDP-choline appeared to assist with memory function and behavior in individuals with memory problems, including subjects with mild-to-moderate vascular cognitive impairment, vascular dementia or senile dementia. Researchers concluded some evidence backs CDP-choline's beneficial effects and called for more study, especially in the clinical aspects of vascular dementia and vascular mild cognitive impairment.(16)
Combination therapy refers to when multiple drugs are use together to target a single health concern. One example is a research study that found citicoline and the drug citalopram to be an effective combination therapy for helping with depression. Researchers noted citicoline's influence on mood-related brain chemicals may contribute to its beneficial mood effects.(17)
Research suggests citicoline helps protect neurons. But neurons are not limited to the brain. They include retinal cells required for sharp vision and overall eye health. In one review, researchers have proposed Glaucoma patients may benefit from citicoline supplementation, suggesting that the compound's neuroprotective activity may represent a safe, effective way to support vision.(18) Researchers have also suggested citicoline eyedrops reduce progression of glaucoma.(19)
Now let's take a look at some common questions related to this powerful brain nutrient.
How much Citicoline should you take per day?
The dose of Citicoline that you use ultimately depends on what you are looking to get out of the nootropic.
For serious cases of cognitive dysfunction, brain injury, or other concerns, the usual daily therapeutic dosage of citicoline in humans is 500&#;2,000 mg. In other words, 7&#;28 mg/kg of oral CDP choline per day for a person of average bodyweight (70 kg).
But for day-to-day cognitive enhancement, you don't need to use anywhere near this much Citicoline. The clinical evidence suggests that as little as 150mg of Citicoline per day is sufficient to support focus, learning, and information processing speeds.
There is a dose-dependent relationship up to around 250mg per day. Beyond that point, larger doses of Citicoline do not seem to confer any extra benefits to otherwise healthy people.
Is it safe to take Citicoline every day? Not only is it safe to take CDP choline every day, but you should take it on a daily basis. Citicoline (cytidine 5 diphosphocholine) has multiple different mechanisms of action. One of these is increased brain cell maintenance and development via the donation of cytidine. Long-term, daily CDP choline use has been found to have significant benefits over using it on an infrequent basis due to overall better brain cell development and health. Learn more here.
Since Citicoline is safe to take daily, you may be wondering if you can take it long-term. Well, it may actually be better to take it long-term. How frequently and consistently you take it will depend on you. Read more here.
Citicoline is naturally occurring within the body. Therefore, it is regarded as having low toxicity and little concern for side effects. Most clinical research studies on it report that no side effects were experienced by subjects. However, as with any supplements, individual sensitivities vary. Rarely reported side effects associated with citicoline supplementation may include digestive distress, nausea, sleep problems and blood pressure imbalance. Discover more here.
In one early study, researchers reported that citicoline appeared to have the potential to help ease symptoms of anxiety and major depressive disorder in post-stroke patients.(20) Researchers noted that more clinical study was needed for this therapy, however. Citicoline may indeed have potential to help with anxiety, but other nootropics are backed by stronger and more extensive research. To learn more, read our article on the best nootropics for anxiety.
Some early animal research suggests that citicoline may play a role in regulating brain inflammation.(21) Researchers believe it may regulate enzymes that are involved in the breakdown of cell membranes. While this bioactivity may suggest potential, as with citicoline for anxiety, there are other nutrients with far more research for modulating inflammatory responses, including but not limited to the Omega-3 fatty acid DHA (docosahexaenoic acid), which also happens to be one of the best nootropics for adults overall.
Above we have referenced one research study using Cognizin® that suggested citicoline may benefit adolescent males by improving attention and reducing impulsivity. While the research is early, it does suggest that the Cognizin® form, at least, may assist with attention on some level. This is not necessarily help for attention deficit hyperactivity disorder (ADHD), however. To learn more about some nootropics and brain supplements for ADHD specifically, read our article on the topic here.
Citicoline and choline are not the same. Choline is one component of Citicoline. But citicoline is distinct from choline because it also supplies cytidine. For more information on this topic, check out our article here.
There is actually a distinction between Citicoline and CDP-Choline (cytidine diphosphate choline). When physicians adminster the compound as a therapy (e.g. to help with brain injury recovery), it is called Citicoline. When produced naturally in the brain, it is CDP-Choline. But ultimately, citicoline and CDP choline are structurally the same; one and the same thing.
Citicoline is known to support mental energy, focus, attention, and overall cognitive function. Energy stored in the cells power messages sent around the brain. The process that empowers this is linked to the nutrient citicoline. Read more about it here.
Mind Lab Pro®'s Citicoline optimizes brainpower at a cellular level while nourishing the brain with building block neuronutrients &#; uniquely supporting the healthy brain metabolism, repair, maintenance and regeneration that are crucial for sharp overall cognition.
With additional support for neurotransmitters, brain circulation and brain defenses, Citicoline is the driving-force ingredient of Mind Lab Pro®'s 100% Brainpower&#; effects: A single nootropic that boosts multiple pathways to optimize mental performance and whole-brain health.
Mind Lab Pro® includes 11 brain nutrients:
Stacked together in Mind Lab Pro®, these nootropics support every aspect of peak cognitive performance. It is designed to help with:
Mental clarity and fast processing speed
Concentration, attention and focus
Multitasking and performing under pressure
All forms of memory, including new learning
Mood, stress resistance and motivation
Mind Lab Pro® is also designed to nourish the brain for long range health, helping with age-related cognitive concerns and strengthening antioxidant defenses for healthy brain aging.
Mind Lab Pro® is Backed By Research.
Mind Lab Pro® is one of the only nootropic supplements on the market that has been the subject of rigorous clinical human trials.
In this research, it demonstrated clinical efficacy by improving brain performance across several key cognitive markers.
In one study, researchers reported that subjects taking Mind Lab Pro for 30 days experienced significant improvements (when compared to those taking placebo) in performing information processing tasks involving simple reaction time (SRT), choice reaction time (CRT) and anticipation.(1)
A second study found that subjects taking Mind Lab Pro demonstrated significant improvements across all memory functions that were tested, including auditory, visual, visual working, immediate and delayed recall memory.(2)
In this article, we have referenced citicoline as a generic nutrient along with a patented form called Cognizin® citicoline. This particular form of citicoline has been researched more extensively than any other.
Mind Lab Pro® uses a quality generic citicoline as part of its 11-ingredient nootropic stack.
Performance Lab® Mind, on the other hand, is a more streamlined 4-ingredient nootropic stack that uses patented Cognizin® citicoline. It supplies:
Cognizin® Citicoline, 250 mg
Sharp-PS® Green (Phosphatidylserine), 100 mg
Ajipure® L-Tyrosine, 250 mg
Maritime Pine Bark Extract (95% proanthocyanidins), 75 mg
Where Mind Lab Pro is universal, Performance Lab® Mind is a little more focused as a brain supplement. It promotes mental performance and mental recovery at once, in a brain-healthy formula for the long haul.
Whether you call it cytidine diphosphate choline, CDP Choline, diphosphocholine CDP choline, or simply citicoline, this naturally occurring compound remains one of the best nootropics you can take.
Mind Lab Pro and Performance Lab Mind are two top supplements that supply this powerful brain-booster. Both are high-quality formulations that are sure to deliver citicoline's best benefits for mental performance, brain health and more.
Related Post: Best Choline Supplement
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