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Received: 2015.05.20
Accepted: 2015.06.11
Published: 2015.07.04
3467 — — 44
Citicoline: A Food That May Improve Memory
ABCDEF Paweł Grieb
Corresponding Author: Paweł Grieb, e-mail: pgrieb@imdik.pan.pl
Source of support: Self financing
Attempts to improve memory function with drugs affecting the brain have given unimpressive results. Dietary
supplements are more widely available, and there also has been little evidence of their positive effect on mem-
ory. Citicoline may be a valuable exception. In several countries it has been registered as a nootropic drug for
decades, but recently it did not prove effective in treatment of acute ischemic strokes and brain injuries. In the
USA, citicoline attained the status of “generally recognized as safe”, and in the European Union recently it was
qualified as a “novel food”. Small randomized, placebo-controlled trials involving healthy volunteers revealed
that permissible doses of this novel food produce positive effects in the human brain recognized electrophysi
-
ologically, neurochemically, and functionally. Citicoline supplementation may be useful for subjects with mem-
ory disorders of mild-to-moderate intensity, those undergoing neurorehabilitation following brain strokes, and
for healthy subjects facing requirements for enhanced attention and mental effort.
MeSH Keywords: Dietary Supplements • Memory Disorders • Nootropic Agents
Full-text PDF: http://www.medscirev.com/abstract/index/idArt/894711
Authors’ Contribution:
Study Design A
Data Collection B
Statistical Analysis C
Data Interpretation D
Manuscript Preparation E
Literature Search F
Funds Collection G
Department of Experimental Pharmacology, Mossakowski Medical Research Centre,
Polish Academy of Sciences, Warsaw, Poland
e-ISSN 2373-2490
© Med Sci Rev, 2015; 2: 67-72
DOI: 10.12659/MSRev.894711
67
Background
Memory disorders commonly occur in the elderly but they also
may appear in younger people. It is commonly believed that
so-called memory lapses (forgetfulness) are the first symp-
toms of dementia. Fortunately, in most cases they have a dif-
ferent cause [1].
Almost everybody will experience certain deterioration of mem-
ory with age. This is manifested as the above-mentioned for-
getfulness but also as prolongation of time required to mem-
orize new information and to recall information previously
remembered. Cognitive functions are slowed but not impaired.
Progression and a characteristic picture of memory disorders
is the evidence of a syndrome called mild cognitive impair
-
ment (MCI). In comparison with healthy subjects of similar
age, persons suffering from MCI reveal inferior abilities re-
garding short-term memory. Disturbances mainly concern re-
calling recent events, while memory of remote events is usu-
ally well preserved. MCI is often (but not always) a transitory
stage between normal ageing and dementia. The yearly inci
-
dence of dementia among MCI patients is estimated as 3% to
17% [2]. Dementia is characterized by most severe memory
dysfunction, usually associated with concurrent neuropsychi
-
atric symptoms; it is a life-threatening problem with serious
social and medical consequences. However, the issue of de
-
mentia is beyond the scope of the present review.
Treatment of initial memory disorders is a controversial issue.
While there seems to be agreement in the contemporary scien-
tific literature that MCI is a pathologic condition that requires
drug therapy, forgetfulness is not a disease. Moreover, few if
any drugs or food supplements proved useful in this setting.
Citicoline, recently qualified as a new food in the European
Union, may be a valuable exception.
Search Strategy and Selection Criteria
References for this review were selected through PubMed, Web
of Science, and Scopus databases as follows: For general re-
marks on the issue of pharmacotherapy of memory disorders,
few representative reviews and metaanalyses published since
2009 were chosen from those identified through searches of
by the use of terms “memory” and “pharmacotherapy”. To il
-
lustrate the evolution of citicoline from a prescription drug to
a novel food, and to review studies published to date on the
subject of citicoline and memory, the aforementioned data
-
bases were thoroughly reviewed for relevant papers using the
terms “CDP-choline” and its variants (“CDPcholine”, “cytidine-
diphosphocholine”, etc.), and “citicoline”.
Pharmacotherapy of Memory Disorders
In the Anatomical Therapeutic Chemical classification of drugs
(ATC), most medicines indicated to treat memory disorders be-
long to group N 06 B: psychostimulants and nootropics. This
group includes substances with various chemical structures,
which common feature is ability to activate central nervous
system metabolism. Here we encounter centrally acting sym
-
pathomimetics such as amphetamine or pemoline, but also
xanthine derivatives such as caffeine which is actually a food
product. Subgroup N 06 BX contains “other medicines”, with
piracetam and vinpocetine as the majors.
Safety and efficacy of nootropics in pharmacotherapy of mem-
ory disorders is controversial. Some of them (amphetamine,
methamphetamine and methylphenidate) should not be used
due to the risk of causing not only serious behavioral, but also
structural and neurochemical changes [3]. Others are known to
stimulate metabolic processes in the brain, but do not signif-
icantly improve memory and cognitive processes. Piracetam,
which pharmacological activity is associated, inter alia, with
an improvement in functioning of mitochondria in the central
nervous system [4], has only a slight positive effect on mem-
ory disorders [5]. Vinpocetine, which stimulates cerebral cir-
culation, glucose consumption and ATP production, is some-
times advertised as medicine improving memory. There is no
scientific data, however, to confirm such effects of this drug [6].
There have been attempts to treat MCI with agents belong-
ing to group N 06 D, i.e. anti-dementia drugs, but also without
much success. Russ & Morling [7] and Trico et al. [2] present-
ed meta-analyses of clinical trials on the efficacy of rivastig-
mine, donepezil and galantamine – cholinesterase inhibitors
which increase acetylcholine concentration in the brain, and
memantine – NMDA receptor antagonist. The results were neg-
ative, no clinically significant improvement in memory or cog-
nitive functions were observed.
The most popular, and at the same time considered the safest
memory enhancer is another drug of group N 06 D, i.e. Gingko
biloba extract. In ancient times, Gingko seeds were recommend-
ed by traditional Chinese medicine for numerous diseases in-
cluding those of elderly people. In Europe, standardized Gingko
leaf extract was first used in 1965 to treat cerebral and pe-
ripheral circulation insufficiency [8]. This product, EGb761, is
a composite medicine containing numerous pharmacologically
active substances, e.g. flavonoids and terpenoids. Its efficacy
in various neurological diseases, including memory disorders
of different intensity, was assessed in numerous randomized
clinical trials. The drug was used at the doses from 80 to 720
mg daily for the period ranging from 2 weeks to 2 years and the
results were in many cases moderately positive [9]. However,
the largest randomized trial, conducted in 2000–2008 in the
68
Grieb P.
Citicoline and memory
© Med Sci Rev, 2015; 2: 67-72
USA and involving 3,000 subjects aged over 72 without symp-
toms of dementia, where the median follow-up was 6 years,
gave a negative result [10].
Cosmetic Neurology: from Illegal Medicines
to Dietary Supplements
Since forgetfulness is not considered a pathologic condition but
rather a dysfunction, the use of medicines improving memory in
forgetful subjects is a controversial issue. This is part of a wider
problem of approving the use of drugs and substances which re-
inforce (“improve”) cognitive and memory functions by healthy
subjects. Such medicines are called “cognitive enhancers” or
“smart drugs”. One of the initiators of a serious discussion on
this subject is Anjan Chatterjee, who coined the term “cosmet
-
ic neurology” to describe the use of cognitive enhancers to im-
prove memory and cognitive functions in healthy people. Cosmetic
neurology would be a field of medicine analogical to “cosmetic
surgery”, which task is not to cure diseases or correct disabili
-
ties – this is the domain of “plastic surgery” – but to “improve”
and “beautify” people with normal, age-adequate appearance.
Development of cosmetic neurology, although problematic from
the ethical point of view, is according to Chatterjee unavoidable.
One of the reasons is that pharmaceutical companies are seek-
ing to reach a wider group of subjects, including healthy ones
– which is actually already happening in other fields of medi
-
cine. One example is proton pump inhibitors, which are adver-
tised to healthy people as a simple way to avoid heartburn fol-
lowing ingestion of heavy food, such as e.g. pizza pepperoni [11].
At the background of the discussion on the use of cogni-
tive enhancers by subjects considered healthy is the issue of
availability of these substances. Some nootropics are no lon
-
ger used in medicine or their use is marginal, so that they are
available only illegally. One example is the infamous (and not
without a reason) amphetamine, which in the ATC classifica
-
tion is listed in the group of centrally acting sympathomimet-
ics (ATC N06 BA) and is still used as the drug in treatment of
attention deficit hyperactivity disorder (ADHD) and narcolep
-
sy [12]. Others, such as the above-mentioned vinpocetine, are
prescription drugs despite strong efforts of manufacturers to
obtain authorization for non-prescription availability. Still oth-
ers, widely used and considered safe, are already available over
the counter and in some countries have obtained the status
of dietary supplements. An example is Gingko biloba extract.
Another example is piracetam, which still is a prescription drug
in Poland, but in the USA since 2006 it had been temporari-
ly sold as a food supplement, until 4 years later FDA “discov-
ered” that it does not meet the supplement definition [13].
This last example provokes a question about what exactly are
food supplements, alternatively called dietary supplements. The
literature on this subject is abundant. To mention just the two
authoritative sources, I will recall the definition included in the
Encyclopaedia Britannica [14] according to which a dietary sup-
plement is any vitamin, mineral, herbal product, or other in-
gestible preparation that is added to the diet to benefit health.
Dietary supplements must be at the same time differentiated
from medicines and from food. I will also quote the definition
found on the website of the European Union [15], according
to which dietary supplements are concentrated sources of nu-
trients or other substances with a nutritional or physiological
effect whose purpose is to supplement the normal diet. They
are marketed in “dose” forms, i.e. as pills, tablets, capsules,
liquids in measured doses etc. Common rules for all the coun-
tries of the European Union were introduced by the Directive
2002/46/EC of the European Parliament and Council on the
approximation of the laws of Member States relating to food
supplements. This directive established harmonized rules for
introducing food supplements to the EU market, which are as
follows: Agents already present on the market remain to be
dietary supplements in EU, but new substances, called “nov
-
el food”, must undergo a detailed procedure of safety assess-
ment conducted by the European Food Safety Authority (EFSA)
located in Parma (Italy). There is nothing strange in such a pro-
cedure, since food has to be truly safe.
Can food supplements be effective in correcting disorders and
slowing down memory loss? About 10 years ago McDaniel et
al. [16] summarized scientific data on this subject, taking into
account mainly the results of randomized trials. The items dis-
cussed included both xenobiotics to human body: piracetam,
vinpocetine and Gingko extract (which are not food supple
-
ments in UE), and substances naturally occurring in the hu-
man body: acetyl-L-carnitine, antioxidants (especially vitamin
E) and precursors of phospholipid synthesis in cells, namely
phosphatidylserine, phosphatidylcholine and citicoline. The au-
thors concluded that pre-clinical (animal) data allow us to ex
-
pect that some of the discussed substances may be effective,
and results of some clinical trials also indicate positive effect.
However, no definite conclusion can be reached.
For the last ten years little has changed in this respect. This
is well illustrated by a recent article in a popular medical on-
line bulletin of the Harvard University. A part of its title is: “Are
any supplements helpful at all?” – and a part of its summa-
ry says: “There is no good evidence that dietary supplements
help improve memory.”
Citicoline as a Drug: Historical Outline
Citicoline is an international non-proprietary name (INN) of
a substance whose chemical name is cytidinediphosphocho
-
line (CDP-choline). In the 1950s, Eugene P. Kennedy and his
69
Grieb P.
Citicoline and memory
© Med Sci Rev, 2015; 2: 67-72
associates from Harvard University found that this substance
is a natural precursor of biosynthesis of phospholipids that
comprise cellular membranes [18]. It started to be used as a
medicine in Japan at the beginning of the 1970s. First medical
publications in English were on the use of CDP-choline in the
treatment of Parkinson’s disease [19] and – what may sound
surprising today – acute pancreatic [20]. Soon after nootropic
properties of CDP-choline were discovered, including stimula-
tion glucose metabolism [21] and increasing concentrations
of neurotransmitters noradrenaline, dopamine and serotonin
[22]. These observations allowed citicoline to be registered in
some European countries (e.g. in Italy, Spain and France) as
a psychostimulant and nootropic (ATC N 06 B). It belongs to
the subgroup of “other drugs”, occupying position N 06 BX
06 next to the above-mentioned piracetam and vinpocetine.
A few years later an exciting perspective of using CDP-choline
as a neuroprotective agent appeared. Lloyd A. Horrocks and
associates from the Ohio State University in Columbus (USA)
found that it inhibits breakdown of membrane phospholip
-
ids induced by cerebral ischaemia [23]. This invention was
patented [24]. In Japan and in some European countries (e.g.
Italy, Spain, France), and also in numerous countries in Asia
and South America, citicoline for injection was registered as a
prescription drug. The substance became quite popular espe-
cially in the 1980s, when a series of interesting studies were
conducted and their results were published in 23 papers in
the book 7A of volume 33 of a renowned international journal
Arzneimittel-Forschung (currently Drug Research). Noticeably,
studies in both animals and human volunteers or patients re-
vealed minimal toxicity of the medicine. Also, pharmacokinet-
ic studies showed that citicoline is fully metabolized to natural
body components – which should not be surprising, since it is
the natural constituent of cells. Results of clinical trials (most-
ly small) resulted in establishing the following indications for
its use: Parkinson’s disease, acute strokes and brain injuries,
rehabilitation following strokes and brain injuries, lapses of
memory and dementia [25]. However, in the other countries
of the European Union and in the USA, citicoline has not be
-
come a registered drug.
A promising global career of citicoline as “the neuroprotective
drug of confirmed efficacy” came to the end due to a series of
multicentre, randomized, placebo-controlled and double-blind
trials, results of which did not confirm its neuroprotective effi-
cacy. The “black series” started with two American trials con-
cerning strokes; the first one involved 349 patients and the sec-
ond 899 patients [26, 27]. The last unsuccessful clinical trials
include COBRIT conducted in the USA on 1,213 patients with
brain injuries [28] and ICTUS conducted in Germany, Spain and
Portugal involving 2,298 patients with ischemic strokes [29].
Reasons for the failure of these trials are uncertain, but criti
-
cal analysis of pre-clinical experiments revealed that actually
little is known about the mechanism of neuroprotective activi-
ty of this substance, and some interpretations which had been
taken for granted are certainly not acceptable [30].
Citicoline as a Food
The above-mentioned unsuccessful clinical trials concerning
ischemic stroke conducted at the end of 1990s in the USA used
citicoline supplied by a Japanese pharmaceutical and biotech-
nological company Kyowa Hakko Kirin (abbreviated to: Kyowa).
When it became clear that citicoline efficacy in strokes and
brain injuries would not be confirmed, the company changed
its attitude and decided to focus on low toxicity and low tol
-
erance of this substance. At the end of May 2009, the branch
of Kyowa in the USA announced [31], that based on prop-
er legislation, it notified suitable authorities that a citicoline
preparation, Cognizin, met the requirements of so called GRAS
(“Generally Recognized as Safe”) substance, i.e. is a substance
safe enough to be added to food. Kyowa informed that it was
going to offer citicoline on the American market as a compo-
nent of foods and drinks. In August of the same year, a toxi-
cological study on rats showing no adverse effects of citico-
line doses up to 1 g/kg bw per day for the period of 90 days
has been published [32].
At the end of March 2012, Kyowa submitted an application
to the Food Safety Authority of Ireland (FSAI) for market-
ing authorization of citicoline as a food supplement being a
source of cytidine and choline, which could be added to vari
-
ous food products and drinks. The maximum doses proposed
in the application were 250 mg/serving in food products and
500 mg daily dose in dietary supplements. In June 2012, FSAI
issued opinion that the application did not raise any doubts
[33]. Although citicoline has to be treated as novel food in the
European Union for procedural reasons, the substance itself
and its components (cytidine, choline, phosphate) occur nat
-
urally in the body and are consumed in various food products,
and their metabolic changes are well known. The same opin-
ion was expressed by the EFSA panel on dietetic products, nu
-
trition and allergies, which one year later, on behalf of the all
European Union Member States, issued further positive opin-
ion on the safety of citicoline as a new food [34]. On the basis
of the above opinions and the positive outcome of voting that
took place in EFSA on 1 July 2014, “Commission Implementing
Decision authorizing the placing on the market of citicoline as
a novel food ingredient under Regulation (EC) No 258/97 of the
European Parliament and of the Council” was taken and pub-
lished in the Official Journal of the European Union. The an-
nex to the decision includes analytical specification that must
be achieved by citicoline (free base) as a new food approved
for use in the European Union.
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Citicoline and memory
© Med Sci Rev, 2015; 2: 67-72
Effects of Citicoline on Memory
Two types of studies concerning effects of citicoline on human
memory have been performed. The first included patients with
memory disorders of various intensity (but excluding demen-
tias). Most of these studies, in which citicoline was administered
at different doses and with different routes of administration
but for a short period of time (no longer than 3 months) to pa
-
tients with subjective memory disorders, or mild or moderate
vascular cognitive impairment, were conducted prior to 2005;
their results are summarized in the meta-analysis [35]. Nine of
these studies, in which the total number of 491 patients received
citicoline and 435 placebo, assessed the effect of treatment on
memory with the use of various methods, revealed statistical
-
ly significant positive effect of the treatment. Positive effects
of citicoline administration starting 7 weeks after brain stroke
were also observed in a recent study involving 437 patients [36].
The second type includes a few studies performed with healthy
volunteers. Although the number of participants was small, the
outcomes are interesting and clearly positive. Two publications
described metabolic effects of citicoline revealed by phospho
-
rus magnetic resonance spectroscopy (
31
P-MRS). This meth-
od enables noninvasive assessment on a selected area (voxel)
of several cellular metabolites containing phosphorus, namely
phosphomonoesters and phosphodiesters (phospholipid metab-
olites), inorganic phosphate, phosphocreatine and nucleoside tri-
phosphates (mainly ATP). In the first study [37] 17 volunteers
aged about 70 received 500 mg of citicoline daily in capsules
for 6 or 12 weeks. Comparison of results obtained prior to and
following supplementation revealed increase in phosphodies
-
ters in the voxel located in corpus callosum by 7.6% on average.
Moreover, the authors observed a positive correlation between
the change in results of California Verbal Learning Test (a popu-
lar neuropsychological test used to assess verbal memory) and
the change in the level of brain phosphodiesters. In the second
study [38]
31
P-MRS was used to show effects of citicoline on the
level of metabolites containing phosphorus in the frontal cortex
and the occipito-parietal cortex. The study group contained 16
healthy subjects of middle age (47.3±5.4 years), who received
citicoline at the dose of 500 mg or 2 g daily for 6 weeks. In the
frontal lobes, there was increase in the phosphocreatine level by
7%, nucleoside triphosphates by 14% and the phosphocreatine/
inorganic phosphate ratio by 32%. There were also changes in
the level of phospholipid metabolites. Importantly, no changes
were observed in the occipito-parietal lobes. In the interpreta
-
tion of these results the authors pointed out that metabolic ef-
fect of citicoline occurred in the region of the cerebral cortex re-
sponsible for cognitive functions such as attention and memory.
Citicoline supplementation may, therefore, reduce age-related
cognitive and memory disorders by increasing energetic reserves
and metabolites necessary to synthesize and maintain cell mem-
branes in cortical areas of key importance to memory function.
Three other publications described the effect of citicoline (tak-
en alone or in combination with caffeine) on cognitive functions
in healthy subjects. A randomized, double-blind, placebo-con-
trolled study including 60 women aged 40–60 years [39] using a
Continuous Performance Test (CPT) revealed positive effects of cit-
icoline received at the dose of 250 or 500 mg daily for 4 weeks.
CPT is a neuropsychological test assessing the ability to react to
significant stimuli and ignore insignificant stimuli. It is also used
to assess attention. Attention is obviously quite closely related
to working memory [40]. Two other randomized, placebo-con
-
trolled studies referred to short-term effects of citicoline in sub-
jects aged 20–40 years. EEG revealed increased electric activity of
the brain after receiving a drink containing 250 mg of citicoline,
alone[41] or combined with caffeine [42]. The other study using
neuropsychological tests revealed a significant improvement in at-
tention and working memory after taking citicoline with caffeine.
Conclusions
Since the first use of citicoline in medicine at the beginning of
the 1970s, the views on its safety and efficacy have undergone
vast changes. In countries where it was registered as a drug,
for many years it was administered only as injections and used
only in hospital treatment or sold by prescription. Later it was
also administered orally – and since it is surprisingly nontox-
ic and causes no adverse events, it became a para-pharma-
ceutical product in many countries. Finally, it received GRAS
status in the USA and became a novel food in the European
Community. This created a new situation of unrestricted legal
distribution of citicoline, not only in the form of food supple-
ments but also in various drinks and food products.
In agreement with definition of a food supplement, citicoline
intake should benefit health thanks to its nutritional or phys-
iologic effects. The scientific data discussed above allow iden-
tification of three target groups that may particularly benefit
from citicoline supplementation. The first includes subjects with
mild-to-moderate age-related memory disorders; the second –
convalescents after brain strokes and injuries, and the third –
healthy subjects of any age facing requirements of enhanced
memory capabilities (for example preparing for exams), or in-
creased concentration of attention (for example during night
duties at work or long car drive). Other clinical data indicate
that citicoline may retard progression of open angle glaucoma
[43], and may be useful in treatment of addictions [44]. These
issues, however, are beyond the scope of the present opinion.
Statement regarding conflict of interest
There is no conflict of interest at the date of the manuscript
submission.
71
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© Med Sci Rev, 2015; 2: 67-72
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