Therapeutic Application of Citicoline

8/12/2019 Therapeutic Application of Citicoline

1/15Copyright2004 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission

Alternative Medicine ReviewVolume 9, Number 12004 Page 17

Review Citicoline

Abstract

Citicoline (CDP-choline; cytidine 5-

diphosphocholine), a form of the essential

nutrient choline, shows promise of clinical

efficacy in elderly patients with cognitive

deficits, inefficient memory, and early-stage

Alzheimers disease. Citicoline has also been

investigated as a therapy in stroke patients,

although the results of trials to date are

inconclusive. Produced endogenously,

citicoline serves as a choline donor in the

metabolic pathways for biosynthesis of

acetylcholine and neuronal membrane

phospholipids, chiefly phosphatidylcholine.

The principal components of citicoline, cholineand cytidine, are readily absorbed in the GI tract

and easily cross the blood-brain barrier.

Exogenous citicoline, as the sodium salt, has

been researched in animal experiments and

human clinical trials that provide evidence of

its cholinergic and neuroprotective actions. As

a dietary supplement, citicoline appears useful

for improving both the structural integrity and

functionality of the neuronal membrane that

may assist in membrane repair. This review,

while not intended to be exhaustive, highlights

the published, peer-reviewed research onciticoline with brief discussions on toxicology

and safety, mechanisms of action, and

pharmacokinetics.

(Altern Med Rev2004;9(1):17-31)

Therapeutic Applications ofCiticoline for Stroke and

Cognitive Dysfunction in the Elderly:A Review of the Literature

Richard Conant, MAc, CN, and

Alexander G. Schauss, PhD

IntroductionCiticoline is a complex organic molecule

(Figure 1) that functions as an intermediate in thebiosynthesis of cell membrane phospholipids.Citicoline is also known as CDP-choline and cy-tidine diphosphate choline (cytidine 5-diphosphocholine). CDP-choline belongs to thegroup of biomolecules in living systems knownas nucleotides that play important roles in cel-lular metabolism. The basic structure of a nucle-otide contains ribose with a nitrogenous base anda phosphate group. CDP-choline is composed ofribose, pyrophosphate, cytosine (a nitrogenousbase), and choline.1

Grouped with the B vitamins, choline is atrimethylated nitrogenous base that enters threemajor metabolic pathways: (1) phospholipid syn-thesis via phosphorylcholine; (2) acetylcholinesynthesis; and (3) oxidation to betaine, whichserves as a methyl donor. Endogenously, forma-tion of citicoline is the rate-limiting step in thesynthesis of phosphatidylcholine, a key membrane

Alexander G. Schauss, PhD, FACN Director of the LifeSciences Division of the American Institute for Biosocialand Medical Research, Inc. (AIBMR) in Puyallup, WA;

adjunct research professor of botanical medicine NationalCollege of Naturopathic Medicine in Portland, Oregon.Correspondence address: 4117 S. Meridian, Puyallup, WA98373Email: [email protected]

Richard Conant, MAc, CN Vice President of Technicaland Regulatory Affairs in the Life Sciences Division of the

American Institute for Biosocial and Medical Research, Inc.(AIBMR); Masters degree in acupuncture from theNorthwest Institute of Acupuncture and Oriental Medicine.

AIBMR has coordinated nonclinical toxicology studies forKyowa Hakko USA, a manufacturer of citicoline.


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Page 18 Alternative Medicine ReviewVolume 9, Number 12004

Citicoline Review

Copyright2004 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission

phospholipid, from choline. Exogenous citicoline,which is hydrolyzed in the small intestine andreadily absorbed as choline and cytidine, entersthe various biosynthetic pathways that utilizeciticoline as an intermediate. Citicoline thus has asparing effect on systemic choline reserves, as wellas inhibiting the breakdown of membrane phos-pholipids.2

Citicoline is produced from choline chlo-ride and orotic acid by an enzymatic process. Free-base citicoline is the form marketed as a dietarysupplement in the United States and as a drug inJapan. The sodium salt of citicoline, the form usedin clinical trials, is sold as a drug in Europe.

Pharmacokinetics and MetabolismCiticoline is a water-soluble compound

with greater than 90-percent bioavailability.3Phar-macokinetic studies on healthy adults have shownoral doses of citicoline are rapidly absorbed, withless than one percent excreted in feces. Plasmalevels peak in a biphasic manner, at one hour afteringestion followed by a second larger peak at 24hours post-dosing. Citicoline is metabolized in thegut wall and liver. The byproducts of exogenousciticoline formed by hydrolysis in the intestinal

wall are cholineand cytidine. Fol-lowing absorp-tion, choline andcytidine are dis-persed through-out the body, en-ter systemic cir-culation for utili-zation in variousbiosynthetic path-ways, and crossthe blood-brainbarrier for re-syn-thesis into

citicoline in thebrain.4

Pharma-cokinetic studiesusing 14Cciticoline showciticoline elimi-

nation occurs mainly via respiratory CO2and uri-

nary excretion, in two phases mirroring thebiphasic plasma peaks. The initial peak in plasmaconcentration is followed by a sharp decline,which then slows over the next 4-10 hours. In the

second phase, an initially rapid decline after the24-hour plasma peak is similarly followed by aslower elimination rate. The elimination half-lifeis 56 hours for CO

2and 71 hours for urinary ex-

cretion.5

Endogenous citicoline serves as an inter-mediate in the biosynthesis of phospholipids, in-cluding phosphatidylcholine, the primary phos-pholipid in cell membranes.6 Cytidine, a majorcomponent of RNA, undergoes cytoplasmic con-version to cytidine triphosphate (CTP). In the

citicoline metabolic pathway, choline is phospho-rylated by the enzyme choline kinase; the result-ing phosphorylcholine combines with CTP to formciticoline. 7 Citicoline then combines withdiacylglycerol (DAG), forming phosphatidylcho-line, with choline phosphotransferase serving asthe enzyme catalyst in this reaction.3

Oral administration of citicoline raisesplasma levels of cytidine and choline in rats within

Figure 1.Structure of Citicoline

CH3

NH2

NO

OH OH

O O

P

O

OH

N

O

O

P

O

O-

N+

CH3

CH3

From: Secades JJ, Frontera G. Meth Find Exp Clin Pharmacol 1995;17(Suppl. B):1-54.


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Review Citicoline


six to eight hours. Prolonged administration for42 and 90 days increases brain concentrations ofphosphatidylcholine, phosphatidylethanolamine,and phosphatidylserine the three major phospho-lipids in brain cell membranes. Evidence for therole of these metabolites as substrates for phos-phatidylcholine synthesis was found in a studygiving rats daily oral doses of citicoline for 90days. At a dose of 500 mg/kg per day phosphati-dylcholine levels increased by 25 percent, phos-phatidylethanolamine by 17 percent, andphosphatidylserine by 42 percent.8

Administration of citicoline to aged ratsactivates CTP:phosphocholine cytidylyl-transferase, the rate-limiting enzyme in the

citicoline pathway of phosphatidylcholine synthe-sis in the brain cell membrane.9Choline and cyti-dine are the major metabolites released via hy-drolysis of citicoline during absorption.

A single oral dose of citicoline raisesplasma choline levels in both younger and oldersubjects. Using protein magnetic resonance spec-troscopy, it was found that brain choline levels inolder subjects decreased after citicoline adminis-tration, but increased in younger subjects. Thepostulated explanation is that the cytidine moietyof citicoline may be taken up by brain cells in older

adults more rapidly than choline. Based on thisfinding, it is suggested that cytidine is the citicolinecomponent primarily responsible for stimulatingphosphatidylcholine synthesis in older subjects.10

Using protein-decoupled phosphorus magneticresonance spectroscopy, it has been shown thatciticoline administration to older subjects for sixweeks increases brain levels of phosphodiesters,byproducts of phospholipid metabolism. This isseen as evidence that citicoline increases phospho-lipid synthesis and turnover, which may help re-

verse cognitive functional deficits associated withaging.11

In clinical trials, citicoline has been ad-ministered orally and by intramuscular injection.

Mechanisms of Action

Phospholipid PrecursorThe pharmacological action of citicoline

appears to involve mechanisms that extend beyondphospholipid metabolism. Citicoline metabolites choline, methionine, betaine, and cytidine-de-rived nucleotides enter a number of metabolicpathways. Evidence of citicolines role as a phos-phatidylcholine precursor has been found in ani-mal studies.12

Biochemical markers of cholinergic nervetransmission are known to be deficient in condi-tions characterized by degeneration of cholinergicneurons, such as Alzheimers disease (AD).Citicoline modestly improves cognitive functionin AD by serving as an acetylcholine precursor.13

The brain uses choline preferentially for acetyl-choline synthesis, which can limit the amount ofcholine available for phosphatidylcholine produc-tion.

When the demand for acetylcholine in-creases or choline stores in the brain are low, phos-pholipids in the neuronal membrane may becatabolized to supply the needed choline.3Exog-enous citicoline may thus help preserve the struc-tural and functional integrity of the neuronal mem-

brane. In an in vitrostudy, citicoline at high con-centrations stimulated brain acetylcholinesterase(AChE), along with Na+/ K+-ATPase.14The pos-tulated mechanism involves bioconversion ofciticoline to phosphatidylcholine in the externalleaflet of the neuronal membrane, the site of AChEactivity. Citicoline is not known to function as anAChE inhibitor in humans, however. Thus, thesignificance of this finding with regard tociticolines therapeutic mechanisms in cognitivedisorders is unknown.

Neuronal Membrane RepairCiticoline has been investigated as a

therapy for stroke patients. Three mechanisms arepostulated: (1) repair of the neuronal membranevia increased synthesis of phosphatidylcholine; (2)repair of damaged cholinergic neurons viapotentiation of acetylcholine production; and (3)


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Citicoline Review


reduction of free fatty acid buildup at the site ofstroke-induced nerve damage.3

Citicoline protects cholinergic neuronsfrom autocannibalism, a process in which mem-brane phospholipids are catabolized to providecholine for synthesis of acetylcholine. This occurswhen choline supplies are depleted, necessitatingsacrifice of membrane phospholipids to maintainneurotransmission. As an exogenous source ofcholine for acetylcholine production, citicolinethus spares membrane phospholipids (in particu-lar, phosphatidylcholine) and prevents neuronalcell death.15

In addition to phosphatidylcholine,citicoline serves as an intermediate in the synthe-

sis of sphingomyelin, another neuronal membranephospholipid component. Citicoline has shownability to restore post-ischemic sphingomyelin lev-els.16Sphingomyelin is formed from ceramide, alipid synthesized in the endoplasmic reticulum thatappears to function as an intracellular second mes-senger and is a byproduct of an intramembranalreaction between ceramide and phosphatidylcho-line.17

Citicoline also restores levels of cardio-lipin, a phospholipid component of the inner mi-tochondrial membrane. The mechanism for this is

unknown, but data suggest citicoline inhibits en-zymatic hydrolysis of cardiolipin by phospholi-pase A

2. Citicoline inhibits release of arachidonic

acid, which serves as substrate for phospholipaseA

2. The arachidonic acid content of phosphatidyl-

choline is decreased following post-ischemicreperfusion due to hydrolysis of the phospholipid.Because citicoline replenishes the arachidonic acidcontent of phosphatidylcholine, it is suggested thatciticoline prevents activation of phospholipase A

2,

rather than inhibiting its activity.18Recent inves-

tigative work has shown citicoline is not an in vivophospholipase A2 inhibitor. In an animal study,

citicoline was found to decrease the formation ofhydroxyl radicals following ischemia and perfu-sion, again suggesting citicoline acts to decreasephospholipase stimulation.19

Citicolines effect on phospholipase A2

may account for the observation that citicolinerestores sphingomyelin levels after ischemia/

reperfusion, protecting hippocampal neurons in theprocess.15Tumor necrosis factor, which is releasedduring ischemia, stimulates sphingomyelinase,resulting in hydrolysis of sphingomyelin. Evidencesuggests that this process is mediated by the phos-pholipase/arachidonic acid pathway.20Modulationof phospholipase activity by citicoline and con-comitant inhibition of sphingomyelinase could beanother route by which citicoline providesneuroprotection.

Effect on beta-AmyloidEvidence has surfaced that citicoline may

counteract the deposition of beta-amyloid, a neu-rotoxic protein believed to play a central role in

the pathophysiology of AD. The characteristic le-sion in AD is the formation of plaques and neu-rofibrillary tangles in the hippocampus. The de-gree of cognitive dysfunction andneurodegeneration in AD is proportional to thebuildup of beta-amyloid.21,22 Citicoline counter-acted neuronal degeneration in the rat hippocam-pus induced by intrahippocampal injection of beta-amyloid protein. The number of apoptotic cellswas also reduced. Memory retention, as measuredby a passive-avoidance learning task, improved

in the rats.23

In an in vitrostudy showing increases inphospholipid levels of rat brain cells induced bycholine plus cytidine (citicoline components), ex-cretion of amyloid precursor protein (APP) wasalso stimulated. Found in the lipid bilayer of neu-ronal membranes, APP contains a peptide thatforms amyloid deposits in Alzheimers patients.This follows abnormal cleavage of APP that oc-curs due to decreased phospholipid content (phos-phatidylcholine and phosphatidylethanolamine)with resulting destabilization of the cell mem-

brane. This formation of amyloidogenic APP frag-ments is an abnormal occurrence that takes placeas a result of aging or neuron damage. Under nor-mal conditions, APP is cleaved in such a way thatthe amyloidogenic peptide is broken down, result-ing in the extracellular secretion of nonplaque-forming APP fragments. Because citicoline re-stores membrane phospholipids, it may thus pro-mote this normal cleavage process. Choline plus


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cytidine were found to stimulate secretion of in-tact, neurotrophic APP from rat brain cells. Thesefindings suggest citicoline may promote neuronalregeneration in Alzheimers patients.24

Effect on NeurotransmittersCiticoline increased brain levels of neu-

rotransmitters in rats at a dose of 100 mg/kg, ad-ministered daily for seven days. Norepinephrineincreased in the cerebral cortex and hypothalamus,dopamine increased in the corpus striatum, andserotonin increased in the cerebral cortex, stria-tum, and hypothalamus.25

An earlier study foundsomewhat differ-ent results. Intravenous administration of citicoline

to rats increased dopamine synthesis in the cor-pus striatum; tyrosine levels also increased. Theauthors suggested citicoline may stimulate tyrosinehydroxylase activity, thus potentiating dopaminesynthesis. Norepinephrine levels increased slightlyin the cerebral cortex; no change was observed inthe brain stem. However, serotonin levels and rateof synthesis in the midbrain and hypothalamusdecreased in this study. This effect was seen withdoses ranging from 10-100 mg/kg. Serotonin syn-thesis in the cortex was unchanged. This effect of

activating dopamine while inhibiting serotonin issuggested as a mechanistic explanation for thereported anti-parkinsonism and central nervoussystem (CNS) stimulation by citicoline.26

Another investigation by the same re-search team found citicoline inhibits synapticdopamine uptake in the corpus striatum of rats,leading the researchers to propose this as a pos-sible explanation for the therapeutic effect ofciticoline in Parkinsons disease (see below).27

Evidence of citicolines ability to enhance nore-pinephrine release in humans was found in a study

showing that citicoline raised urinary levels of 3-methoxy-4-hydroxyphenylglycol (MHPG), anorepinephrine metabolite.28

Rat studies have found evidence thatciticoline potentiates dopamine release in thebrain, presumably by stimulating release of ace-tylcholine.29

Animal Studies

Cerebro-protectionCiticoline injected experimentally into the

cerebrum of gerbils shortly before artificially-in-duced ischemia has demonstrated an ability topartially restore phosphatidylcholine levels whileinhibiting free fatty acid release, suggesting sta-bilization of the neuronal membrane.15

In another gerbil study, citicoline restoredischemia-depleted levels of phosphatidylcholine,sphingomyelin, and cardiolipin after one day ofreperfusion. In addition, this study found that af-ter three days of reperfusion, citicoline increasedboth glutathione levels and glutathione reductaseactivity, suggesting citicoline may contribute toreduction of oxidative stress.30

Traumatic injury damages the brain innumerous ways, including cell death due to edema,disruption of the blood-brain barrier, ischemia, andshear stress. Three underlying pathologies arethought to be at work at the site of brain injury:(1) breakdown of phospholipids in the cell mem-brane, resulting in decreased phosphatidylcholinecontent; (2) release of free fatty acids from thedegraded membrane, which causes local edemadue to accumulation of inflammatory arachidonic

acid metabolites such as prostaglandins andleukotrienes; and (3) decreased release of acetyl-choline, resulting in impaired cholinergic nervetransmission.

The ability of citicoline to reverse the ef-fects of brain injury has been tested in animalmodels of cerebral ischemia. Administered intra-peritoneally, citicoline was found to reduce brainedema and decrease breakdown of the blood-brainbarrier in rats at a dose of 400 mg/kg.31

Citicoline has been shown to delay braincell membrane damage and behavioral dysfunc-

tion in spontaneously hypertensive rats with is-chemia caused by artificially-induced occlusionof the lateral middle cerebral artery.32This effectof citicoline was greatest in rats with mild cellinjury due to lack of oxygen.

In another similar study, citicoline wastested in an animal stroke model. Temporary fo-cal ischemia was artificially induced in rats viablockage of the right middle cerebral artery and


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in the hippocampus were observed in theciticoline-treated animals. Based on previous find-ings of increased free radical production in hip-pocampal neurons following reperfusion, it is theo-rized citicoline inhibits oxygen free radical pro-duction that accompanies arachidonic acid me-tabolism.

In vitro studies using neuronal culturesfrom chick embryos have shown that citicolinemay protect the hippocampus from injury. Addi-tion of citicoline to the cultures both before andafter experimentally induced hippocampal injuryresulted in a protective effect.34

Memory and Learning

Brain aging may be associated with de-creased membrane phospholipid content, leadingto impaired membrane biofunction along with lossof cholinergic neurons. Memory and cognitiondepend on normal neuron-to-neuron communica-tion via transmission of nerve impulses along theneuronal membrane.

In one experiment citicoline was admin-istered intraperitoneally to aged rats with cogni-tive and motor impairment.35Using tests of activeand passive avoidance behavior, it was shown that

citicoline improved learning and memory capac-ity. Motor performance also improved. Citicolinealso improved cognitive function in rats injectedwith scopolamine, an amnesia-inducing anticho-linergic drug, supporting the conclusion thatciticoline exerts cholinergic action.35

The effects of citicoline on retention oflearned behavior in rats were observed in a seriesof experiments.36Memory deficits were artificiallyinduced in young adult and aged rats via oxygendeprivation (hypoxia), electric shock, and admin-istration of scopolamine. Citicoline improved

memory performance in older but not younger rats,which is consistent with the notion that citicolinecorrects impaired phospholipid metabolism.Citicoline prevented amnesia induced by scopo-lamine and by electric shock. Citicoline preventedmemory impairment in rats caused by sodium ni-trate-induced hypoxia. Additional experimentsshowed citicoline improved learning ability in ratswith fetal alcohol syndrome induced by feeding

alcohol to dams during pregnancy. The overallconclusion drawn from these studies is thatciticoline improves memory only in animals withmeasurable memory deficits.

Citicoline, however, has demonstrated theability to facilitate learning and memory in young,normal dogs.37Ten one-year old dogs were putthrough a series of operant conditioned-learningexperiments over a 42-day period. Compared tocontrol animals, dogs administered citicoline dailyprior to repetition of these procedures exhibitedsuperior memory processes including acquisition,retention, and retrieval.

Citicoline as Adjunctive Therapy in

an Animal Model of Embolic StrokeCiticoline has been tested in rats as a pos-

sible adjunct to thrombolytic therapy in embolicstroke. In one experiment, embolism was artifi-cially created in the carotid arteries of 83 Sprague-Dawley rats.38The rats were then divided into sixtreatment groups, including a saline-treated con-trol group, using citicoline at two different doses(250 mg/kg; 500 mg/kg) with or without theantithrombotic agent recombinant tissue plas-minogen activator (rtPA). Size of the cerebral in-

farction caused by an embolism was significantlyreduced in the citicoline-plus-rtPA groups. Func-tional recovery occurred in both the rats that re-ceived citicoline plus rtPA and rats on citicolinealone at the higher dose.

In another similar experiment, citicoline,alone or in combination with the thrombolyticagent urokinase, was injected into rats followingocclusion of the middle cerebral artery. This pro-cedure causes focal ischemia and infarction in thecerebral cortex. Saline-treated rats were used ascontrols. Citicoline, injected as a single dose or

intermittently, significantly reduced neuronal dam-age. Enhanced neuroprotection was seen in the ratstreated with citicoline plus urokinase.39


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Citicoline Review


Human Clinical Trials

Stroke TherapyCiticoline has been tested on stroke pa-

tients in controlled trials. A multicenter, double-blind, placebo-controlled trial evaluated the effectof citicoline on 272 stroke patients in the acutestage of moderate-to-severe cerebral infarctionwith mild-to-moderate disturbances in conscious-ness.40 In the treatment group, 133 patients re-ceived 1,000 mg citicoline by daily intravenousadministration for 14 days. Compared to the re-maining 139 patients on placebo, the level of con-sciousness improved significantly in the citicolinegroup. By day 14, 54 percent of patients onciticoline showed improvement, compared to 29percent of placebo patients. The results suggestintravenous citicoline promotes recovery fromreversible tissue damage in the acute stages ofstroke, while mitigating the aggravation of post-stroke symptoms.

Other trials have administered citicolineto post-stroke patients, demonstrating similar re-sults to the above study, including enhancementof recovery with improvements in parameters ofneurological function, such as muscle strength,ambulation, and cognition. According to a recent

analysis of these trials, initiating citicoline withinthe first 24 hours after stroke onset increases theprobability of complete recovery at threemonths.41

A multicenter, double-blind controlledtrial, conducted by the Citicoline Stroke StudyGroup, examined the effects of oral citicoline on259 stroke patients.42Three doses of citicoline (500mg; 1,000 mg; or 2,000 mg) were administered tothree groups of 65 patients each, within 24 hoursof stroke onset, while a fourth group received pla-cebo. Treatment was continued for six weeks, with

a six-week follow-up period. The primary clini-cal endpoint was a change in the Barthel Index ofNeurological Function. The baseline NIH StrokeScale (NIHSS) score was assessed as a secondvariable to decrease the effect of baseline differ-ences in stroke severity. After 12 weeks, patientsin the groups receiving 500 mg or 2,000 mgciticoline were found to have twice the chance ofstroke recovery compared to patients on placebo.

Curiously, no differences were seen between the1,000-mg citicoline group and the placebo group.No clear explanation was found for this apparentanomaly, other than a difference in patient weightin this group. Because the 2,000-mg group had ahigher incidence of dizziness and accidental in-

jury, the researchers concluded 500 mg per daymight be the optimum citicoline dose.

The Citicoline Stroke Study Group sub-sequently conducted a second double-blind studysimilar to the above trial.43This multicenter trialenrolled 394 patients suffering from acute is-chemic stroke, randomly assigning patients to thetreatment and placebo groups on a two-to-onebasis. Based on the previous results, 500 mg was

selected as the daily citicoline dose; the BarthelIndex and NIHSS score were used to assess effi-cacy. No differences were found between the treat-ment and placebo groups after six weeks of treat-ment and follow-up. However, an inequality inbaseline stroke severity between treatment andplacebo groups was discovered; 34 percent of pa-tients in the placebo group had had mild strokescompared to 22 percent in the treatment group.As reported, This baseline imbalance may haveimpacted the overall efficacy results in this trial.

The most recent investigative effort as-

sessing the effect of citicoline in acute ischemicstroke was a double-blind, multicenter trial of 899patients. The study enrolled patients with acuteischemic stroke in the region of the middle cere-bral artery. The subjects received either 2,000 mgoral citicoline (1,000 mg twice daily) or placebofor six weeks. A six-week, post-treatment follow-up period then ensued. The primary study end-point was the proportion of patients showing aseven-point or greater improvement from baselinein the NIHSS score. The outcome was virtually

the same for both groups: 52 percent of patientsin the citicoline group and 51 percent in the pla-cebo group reached this level of improvement. Theresearchers concluded: Citicoline was safe butineffective in improving the outcome of patientswith acute ischemic stroke as measured by theplanned analyses. The citicoline group did havea significantly higher proportion of patients show-ing improvement after six weeks, as measured by


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the Barthel Index, but this disappeared at the week-12 analysis.44

Cognition in the ElderlyCiticolines potential as a treatment formemory impairment associated with aging wasstudied in a 1989 double-blind trial of 84 elderlypatients with mild-to-moderate memory loss.45

Based on the role of citicoline as an intermediateof phosphatidylcholine biosynthesis, it was hy-pothesized citicoline could reverse age-dependenthistopathological changes within the brain neu-ronal membrane, thereby restoring memory func-tion. The subjects, who all exhibited memory lossas assessed by scores on the Mini Mental State

Examination (MMSE), took 1,000 mg citicolinedaily or placebo for six weeks. The Randt MemoryTest was administered after three weeks and at theend of the treatment period. In addition to memoryfactors such as immediate recall, delayed recall,and global memory efficiency, the Randt test mea-sures three cognitive function parameters: encod-ing and organization (E-O), cognitive efficiency(CE), and acquisition efficiency (AE). The resultsshowed AE improved while E-O and CE remainedunchanged. Because AE is specifically related to

attention, the researchers postulated this findingevidenced a dopaminergic effect of citicoline,based on an association between dopaminergicstimulation and improvement in attention-relatedcognitive mechanisms. Improvements in globalmemory efficiency were also observed.

The effect of citicoline on verbal memoryin the elderly was tested in a double-blind trialusing 95 healthy volunteers ages 50-85.46Thisstudy took place in two phases. In the initial phase,all subjects took 1,000 mg citicoline or placebodaily for three months. Analysis of the data re-

vealed a subgroup with relatively poor memory.These subjects were recruited for the second cross-over trial phase and given either placebo or 2,000mg citicoline daily for three months. After the ini-tial phase, improvement with citicoline occurredonly in the poor-memory subgroup, which showedgains in delayed recall and logical memory. At theend of the second phase, greater improvementsoccurred in the citicoline group, suggesting that

2,000 mg per day is a more effective dose for age-associated memory impairment.

In a double-blind, crossover trial,citicoline was administered orally to 24 memory-impaired elderly subjects for four weeks.Citicoline was given alone at 500 or 1,000 mgdoses, or combined with nimodipine, a calciumchannel blocker used to treat neurological defi-cits in brain hemorrhage patients (citicoline 300mg/day plus nimodipine 90 mg/day). Pre- andpost-treatment memory performance was evalu-ated. The results showed that citicoline improvedthe ability to recall words and objects after view-ing them for two seconds each. In tests of recog-nition, where subjects attempt to identify previ-

ously viewed words and objects randomly mixedwith non-viewed items, no improvement was ob-served. Positive results occurred in all three treat-ment groups.47

A recent meta-analysis looked at data frompublished, double-blind, randomized human tri-als on citicoline and cognitive impairment in pa-tients with chronic cerebral disorders. It was con-cluded that citicoline modestly improves memoryand behavioral outcomes.48

Effect on Brain Wave ActivityCiticoline appears to reverse abnormali-

ties in brain electrical patterns that occur with ag-ing. Age-related cognitive disorders are typicallyassociated with increases in the delta, theta, andfast beta ranges, while the alpha and slow betafrequencies decrease. In an uncontrolled study, 24patients with organic brain syndrome (charac-terized by symptoms such as disorientation, cog-nitive impairment, and emotional lability in pa-tients suffering from cerebrovascular or degenera-tive brain disease) were administered intravenous

citicoline at a dose of 500 mg daily. As measuredby EEG, statistically significant increases in al-pha frequencies were observed, along with de-creases in delta frequencies. Insignificant reduc-tions in theta and slow beta frequencies were alsoseen; clinical parameters improved.49

In another study analyzing changes inbrain mapping with citicoline administration, 19Alzheimers disease patients received 100 mg oral


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Citicoline Review


citicoline daily for one month. Thirteen subjectswere early-onset (EOAD) Alzheimers patients;the remaining six were late onset (LOAD). Thetaband decreases in the frontal-temporal region wereobserved, along with frontal decreases of betabands. A moderate increase in the alpha frequencywas noted in the occipital regions of LOAD pa-tients. No other changes occurred in the relativepower of other frequencies. Cerebral hemodynam-ics also improved, measured by increases in bloodflow velocities. Immunological changes andslightly reduced serum cytokine levels were ob-served. EOAD patients, who are known to havehigher histamine levels than LOAD patients,showed lowered histamine levels after one month

on citicoline.50

Brain InjuryBrain injury results in depletion of cell

membrane phospholipids, followed by intracellu-lar cerebral edema due to breakdown of the so-dium-potassium pump.51 In a single-blind, ran-domized trial, 216 head injury patients were as-signed to two treatment groups. One group re-ceived conventional treatment as control while theother received conventional treatment plus intra-

venous citicoline at a dose of 1,000 mg daily. Theproportion of patients showing improvements incognitive and motor symptoms was greater in theciticoline group; there were no differences in deathrate between the two groups.52

Other studies have shown citicoline facili-tates memory rehabilitation in brain trauma pa-tients by restoring blood flow to the lesion site.53

In a small double-blind study,one month on 1,000mg oralciticoline daily significantly improved theability to recall designs in patients with concus-sion, as compared to placebo. There were no sig-

nificant differences between the two groups inother tests of cognitive function, such as word orlocation recall or verbal fluency. In the placebogroup, a greater trend toward complaints of post-concussional symptoms such as headache, dizzi-ness, and tinnitus was observed at follow-up.54

Alzheimers DiseaseCiticoline has demonstrated a possible

ability to improve cognitive performance in

EOAD. A 1994 double-blind study examined theeffect of one-month treatment with citicoline oncognition in 20 Alzheimers patients. Followingciticoline treatment (1,000 mg/day orally), cogni-tive function assessed using MMSE improvedslightly in an EOAD patient subgroup, as shownby small, but statistically significant (p


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at an oral dose of 1,000 mg daily, was adminis-tered to three groups: EOAD patients, LOAD pa-tients, and patients with multi-infarct dementia; afourth group served as control. Increased levelsof interleukin-1 were normalized after threemonths on citicoline.57

Other Therapeutic EffectsGlaucoma/Amblyopia

Results fromtwo open trials suggest thatciticoline repairs damage to the optic nerve thatoccurs in glaucoma.58Citicoline appears to pro-vide neuroprotection to the retina by enhancingphosphatidylcholine synthesis. Glaucoma, a lead-ing cause of blindness in the elderly, is aneurodegenerative disease characterized byapoptosis of retinal ganglion cells. Damage to theretina may occur before detectable vision loss.59

In a short-term, double-blind, placebo-controlledtrial, citicoline administered by intramuscular in-

jection (1,000 mg/day) improved retinal and vi-sual function in open-angle glaucoma patients.60

It is postulated that dopaminergic stimulation is amajor mechanism for citicolines effect on theretina.58This hypothesis is bolstered by a recentanimal study showing that citicoline raises the

retinal dopamine concentration in rabbits.61

Citicoline, at a dose of 1,000 mg dailyadministered by intramuscular injection was foundto significantly improve visual acuity in patientswith amblyopia.62,63

Parkinsons DiseaseBased on citicolines hypothetical ability

to improve dopaminergic function, a double-blindcrossover trial was conducted on Parkinsons dis-ease patients who were undergoing treatment withL-dopa plus a decarboxylase inhibitor. Improve-ments in bradykinesia and rigidity were seen insubjects administered citicoline (500 mg daily viaintramuscular injection) when compared to pla-cebo subjects; tremor was unchanged.64

Vascular DementiaA small, double-blind clinical trial found

no effect of citicoline treatment in 30 patients age

55 or older with moderate-to-severe vascular de-mentia (VaD). This study excluded patients withAD, stroke, head injury, or other severe neurologi-cal disorders. The diagnosis of VaD was based onbrain abnormalities measured by MRI, along witha battery of neuropsychological tests assessingcognitive and psychomotor function. Fifteen sub-

jects were administered a 500 mg citicoline tablettwice daily, while 15 took placebo tablets. Out-comes were assessed after six and 12 months. Nodifferences were found between treatment and pla-cebo groups in neuropsychological performanceat baseline and at the study end. MRIs showedexacerbation of brain pathology in both groups asthe study progressed.65

ToxicologyThe LD

50of a single intravenous dose of

citicoline was 4,600 mg/kg and 4,150 mg/kg inmice and rats, respectively. An oral LD

50 could

not be determined as no deaths occurred at themaximum possible oral dose.66

No toxic effects were observed in 30-daysubacute toxicity studies of oral citicoline to twogroups of rats at doses of 100 mg/kg and 150 mg/kg. No changes occurred in blood chemistry, or-

gan histology, or urinary parameters.

67

The effect of chronic oral consumption ofciticoline was studied in dogs who were fed asingle 1.5 g/kg dose daily for six months. No toxiceffects were seen nor did any physiological, bio-chemical, neurological, or morphological abnor-malities occur.68

Citicoline exhibits a very low toxicity pro-file in humans. In a short-term, placebo-controlled,crossover study, 12 healthy adults took citicoline,at daily doses of 600 and 1,000 mg, or placebo forconsecutive five-day periods. Transient headaches

occurred in four subjects on the 600 mg dose, fiveon the 1,000 mg dose, and one on placebo. Nochanges or abnormalities were observed in hema-tology, clinical biochemistry, or neurologicaltests.69

In an unpublished GLP acute toxicologystudy, free-base citicoline was administered tomale and female rats at a dose of 2,000 mg/kgbody weight for 14 days. No changes in body


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Citicoline Review


weight, deaths, clinical symptoms or gross patho-logical changes were observed. A GLP, sub-acute,90-day toxicology study on free-base citicoline isunderway, with results slated for release in early2004.

Clinical SafetyCiticoline has an excellent track record of

clinical safety. A large drug surveillance studyanalyzed the results of citicoline treatment in 2,817patients ages 60-80 suffering from senility andcerebral vascular insufficiency. A total of 151 in-cidents of side effects were recorded, represent-ing five percent of the patient sample. The mostcommon adverse effects were transient in nature

and included stomach pain and diarrhea in 102cases. Vascular symptoms of hypotension, tachy-cardia, or bradycardia occurred in 16 cases.70

Conclusion and Future DirectionsCiticoline is a form of the B-vitamin cho-

line that serves as a choline donor and intermedi-ate in the biosynthesis of phospholipids and ace-tylcholine. Citicoline reduces ischemic injury inthe CNS by preserving membrane phospholipids,chiefly phosphatidylcholine. As a therapeutic in-

tervention in acute stroke the studies have yieldedmixed results. It is possible exogenous citicolinemay increase the possibility of complete recoverywhen treatment is started within 24 hours of strokeonset. Citicoline therapy might improve cognitivefunction in elderly patients with memory deficits,mild cognitive impairment, and senile dementiaof the Alzheimers type. Citicoline exhibits a verylow toxicity profile, and appears to be safe forlong-term clinical use and consumption as a di-etary supplement. A human clinical trial is soonto begin that will assess the effect of free-base

citicoline on memory in 50-75 year-olds.

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Therapeutic Application of Citicoline