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Clinical data
SynonymsCytidine diphosphate choline
AHFS/Drugs.comInternational Drug Names
ATC code
CAS Number
PubChem CID
E number{{#property:P628}}
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Chemical and physical data
Molar mass489.332 g/mol
3D model (JSmol)
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]


Citicoline (INN), also known as cytidine diphosphate-choline (CDP-Choline) & cytidine 5'-diphosphocholine is a psychostimulant/nootropic. It is an intermediate in the generation of phosphatidylcholine from choline.

Studies suggest that CDP-choline supplements increase dopamine receptor densities,[1] and suggest that CDP-choline supplementation helps prevent memory impairment resulting from poor environmental conditions.[2] Preliminary research has found that citicoline supplements help improve focus and mental energy and may possibly be useful in the treatment of attention deficit disorder.[3][4] Citicoline has also been shown to elevate ACTH independently from CRH levels and to amplify the release of other HPA axis hormones such as LH, FSH, GH and TSH in response to hypothalamic releasing factors.[5] These effects on HPA hormone levels may be beneficial for some individuals but may have undesirable effects in those with medical conditions featuring ACTH or cortisol hypersecretion including, but not limited to, PCOS, type II diabetes and major depressive disorder.[6][7]

Medical uses

Citicoline is available as a supplement online and in stores. It is sold in over 70 countries under a variety of brand names: Ceraxon, Cognizin, NeurAxon, Somazina, Synapsine, etc. When taken as a supplement citicoline is hydrolyzed into choline and cytidine in the intestine.[8] Once these cross the blood–brain barrier it is reformed into citicoline by the rate-limiting enzyme in phosphatidylcholine synthesis, CTP-phosphocholine cytidylyltransferase.[9][10]

Memory disorders

In the hippocampi of rats with induced Alzheimer’s Disease, citicoline counteracts neuronal degeneration and reduces the number of apoptotic cells present. Citicoline supplementation also improves memory retention.[9]

Ischemic stroke

Citicoline is approved for treatment in cases of head trauma, stroke, and neurodegenerative disease in Japan and Europe. Citicoline improves the clinical outcome following an ischemic stroke, as evidenced by the reduction in size of lesions caused by ischemic strokes after supplementation.[11] It has been claimed that citicoline reduces rates of death and disability following an ischemic stroke.[12] However, the largest trial to date, a randomised, placebo-controlled, sequential trial in patients with moderate-to-severe acute ischaemic stroke in Europe, enrolling 2298 patients, found no benefit of administering citicoline on survival or recovery from stroke.[13]

It should be noted that Citicoline is the only substance that ever showed any significant neuroprotective effect at least in patients with less severe stroke events.[14]


Citicoline improves visual function in patients with glaucoma, amblyopia, and non-arteritic ischaemic optic neuropathy.[15][16]


Cocaine dependence is associated with depleted dopamine levels in the central nervous system. In cocaine-dependent individuals citicoline increases brain dopamine levels and reduces cravings.[17] In the general population citicoline increases brain responses to food stimuli, specifically in the amygdala, insula, and lateral orbitofrontal cortex, which correlate with decreased appetite.[18]

Mechanism of action

Enzymes involved in reactions are identified by numbers. See file description.

Neuroprotective effects

The neuroprotective effects exhibited by citicoline may be due to its preservation of cardiolipin and sphingomyelin, preservation of arachidonic acid content of phosphatidylcholine and phosphatidylethanolamine, partial restoration of phosphatidylcholine levels, and stimulation of glutathione synthesis and glutathione reductase activity. Citicoline’s effects may also be explained by the reduction of phospholipase A2 activity.[19] Citicoline increases phosphatidylcholine synthesis.[20][21][22] The mechanism for this may be:

Neuronal membrane

The brain prefers to use choline to synthesize acetylcholine. This limits the amount of choline available to synthesize phosphatidylcholine. When the availability of choline is low or the need for acetylcholine increases, phospholipids containing choline can be catabolized from neuronal membranes. These phospholipids include sphingomyelin and phosphatidylcholine.[19] Supplementation with citicoline can increase the amount of choline available for acetylcholine synthesis and aid in rebuilding membrane phospholipid stores after depletion.[24] Citicoline decreases phospholipase stimulation. This can lower levels of hydroxyl radicals produced after an ischemia and prevent cardiolipin from being catabolized by phospholipase A2.[25][26] It can also work to restore cardiolipin levels in the inner mitochondrial membrane.[25]

Cell signalling

Citicoline enhances cellular communication by increasing the availability of neurotransmitters, including acetylcholine, norepinephrine, and dopamine.[27]

Blood flow

Citicoline increases glucose metabolism in the brain and cerebral blood flow.[28]

Inflammation and stress

Citicoline reduces oxidative stress. It also prevents excessive inflammatory response in the brain by inhibiting the release of free fatty acids and decreasing blood–brain barrier breakdown.[21]

Glutamate transport

Citicoline lowers increased glutamate concentrations and raises decreased ATP concentrations induced by ischemia. Citicoline also increases glutamate uptake by increasing expression of EAAT2, a glutamate transporter, in vitro in rat astrocytes. It is suggested that the neuroprotective effects of citicoline after a stroke are due in part to citicoline’s ability to decrease levels of glutamate in the brain.[29]


Citicoline is water-soluble, with more than 90% oral bioavailability.[24] Plasma levels peak one hour after oral ingestion, and a majority of the citicoline is excreted as CO2 in respiration, and again 24 hours after ingestion, where the remaining citicoline is excreted through urine.[30]

Side effects

Citicoline has a very low toxicity profile in animals and humans. Clinically, doses of 2000 mg per day have been observed and approved. Minor transient adverse effects are rare and most commonly include stomach pain and diarrhea.[21]


In vivo

phosphatidylcholine is a major phospholipid in eukaryotic cell membranes. Close regulation of its biosynthesis, degradation, and distribution is essential to proper cell function. phosphatidylcholine is synthesized in vivo by two pathways

See also


  1. Giménez R, Raïch J, Aguilar J (November 1991). "Changes in brain striatum dopamine and acetylcholine receptors induced by chronic CDP-choline treatment of aging mice". British Journal of Pharmacology. 104 (3): 575–8. doi:10.1111/j.1476-5381.1991.tb12471.x. PMC 1908237. PMID 1839138.
  2. Teather LA, Wurtman RJ (2005). "Dietary CDP-choline supplementation prevents memory impairment caused by impoverished environmental conditions in rats". Learning & Memory. 12 (1): 39–43. doi:10.1101/lm.83905. PMC 548494. PMID 15647594.
  3. "Supplement naturally boosts ageing brain power". Sydney Morning Herald. 2008-02-25. Retrieved 2009-07-28.
  4. Silveri MM, Dikan J, Ross AJ; et al. (November 2008). "Citicoline enhances frontal lobe bioenergetics as measured by phosphorus magnetic resonance spectroscopy". NMR in Biomedicine. 21 (10): 1066–75. doi:10.1002/nbm.1281. PMID 18816480.
  5. Cavun S, Savci V (October 2004). "CDP-choline increases plasma ACTH and potentiates the stimulated release of GH, TSH and LH: the cholinergic involvement". Fundamental & Clinical Pharmacology. 18 (5): 513–23. doi:10.1111/j.1472-8206.2004.00272.x. PMID 15482372.
  6. Benson S, Arck PC, Tan S; et al. (June 2009). "Disturbed stress responses in women with polycystic ovary syndrome". Psychoneuroendocrinology. 34 (5): 727–35. doi:10.1016/j.psyneuen.2008.12.001. PMID 19150179.
  7. Florio P, Zatelli MC, Reis FM, degli Uberti EC, Petraglia F (2007). "Corticotropin releasing hormone: a diagnostic marker for behavioral and reproductive disorders?". Frontiers in Bioscience. 12: 551–60. doi:10.2741/2081. PMID 17127316.
  8. Wurtman, RJ; Regan, M; Ulus, I; Yu, L (Oct 1, 2000). "Effect of oral CDP-choline on plasma choline and uridine levels in humans". Biochemical pharmacology. 60 (7): 989–92. doi:10.1016/S0006-2952(00)00436-6. PMID 10974208.
  9. 9.0 9.1 Alvarez, XA; Sampedro, C; Lozano, R; Cacabelos, R (October 1999). "Citicoline protects hippocampal neurons against apoptosis induced by brain beta-amyloid deposits plus cerebral hypoperfusion in rats". Methods and findings in experimental and clinical pharmacology. 21 (8): 535–40. doi:10.1358/mf.1999.21.8.794835. PMID 10599052.
  10. Carlezon, WA; Pliakas, AM; Parow, AM; Detke, MJ; Cohen, BM; Renshaw, PF (Jun 1, 2002). "Antidepressant-like effects of cytidine in the forced swim test in rats". Biological Psychiatry. 51 (11): 882–9. doi:10.1016/s0006-3223(01)01344-0. PMID 12022961.
  11. Warach, S; Pettigrew, LC; Dashe, JF; Pullicino, P; Lefkowitz, DM; Sabounjian, L; Harnett, K; Schwiderski, U; Gammans, R (November 2000). "Effect of citicoline on ischemic lesions as measured by diffusion-weighted magnetic resonance imaging. Citicoline 010 Investigators". Annals of neurology. 48 (5): 713–22. doi:10.1002/1531-8249(200011)48:5<713::aid-ana4>;2-#. PMID 11079534.
  12. Saver, JL (Fall 2008). "Citicoline: update on a promising and widely available agent for neuroprotection and neurorepair". Reviews in neurological diseases. 5 (4): 167–77. PMID 19122569.
  13. Davalos (2012). Lancet. 380 (9839). Missing or empty |title= (help)
  14. Overgaard, K (2014). "The effects of citicoline on acute ischemic stroke: a review". Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association. 23(7): 1764–9. doi:10.1016/j.jstrokecerebrovasdis.2014.01.020. PMID 24739589.
  15. Parisi, V; Coppola, G; Centofanti, M; Oddone, F; Angrisani, AM; Ziccardi, L; Ricci, B; Quaranta, L; Manni, G (2008). "Evidence of the neuroprotective role of citicoline in glaucoma patients". Progress in brain research. 173: 541–54. doi:10.1016/S0079-6123(08)01137-0. PMID 18929133.
  16. Parisi, V.; Coppola, G.; Ziccardi, L.; Gallinaro, G.; Falsini, B. (1 May 2008). "Cytidine-5'-diphosphocholine (Citicoline): a pilot study in patients with non-arteritic ischaemic optic neuropathy". European Journal of Neurology. 15 (5): 465–474. doi:10.1111/j.1468-1331.2008.02099.x.
  17. Renshaw, PF; Daniels, S; Lundahl, LH; Rogers, V; Lukas, SE (February 1999). "Short-term treatment with citicoline (CDP-choline) attenuates some measures of craving in cocaine-dependent subjects: a preliminary report". Psychopharmacology. 142 (2): 132–8. doi:10.1007/s002130050871. PMID 10102764.
  18. Killgore, WD; Ross, AJ; Kamiya, T; Kawada, Y; Renshaw, PF; Yurgelun-Todd, DA (January 2010). "Citicoline affects appetite and cortico-limbic responses to images of high-calorie foods". The International Journal of Eating Disorders. 43 (1): 6–13. doi:10.1002/eat.20658. PMC 3378241. PMID 19260039.
  19. 19.0 19.1 Adibhatla, RM; Hatcher, JF; Dempsey, RJ (January 2002). "Citicoline: neuroprotective mechanisms in cerebral ischemia". Journal of Neurochemistry. 80 (1): 12–23. doi:10.1046/j.0022-3042.2001.00697.x. PMID 11796739.
  20. López-Coviella, I; Agut, J; Savci, V; Ortiz, JA; Wurtman, RJ (August 1995). "Evidence that 5'-cytidinediphosphocholine can affect brain phospholipid composition by increasing choline and cytidine plasma levels". Journal of Neurochemistry. 65 (2): 889–94. doi:10.1046/j.1471-4159.1995.65020889.x. PMID 7616250.
  21. 21.0 21.1 21.2 Conant, R; Schauss, AG (March 2004). "Therapeutic applications of citicoline for stroke and cognitive dysfunction in the elderly: a review of the literature". Alternative medicine review : a journal of clinical therapeutic. 9 (1): 17–31. PMID 15005642.
  22. Babb, SM; Wald, LL; Cohen, BM; Villafuerte, RA; Gruber, SA; Yurgelun-Todd, DA; Renshaw, PF (May 2002). "Chronic citicoline increases phosphodiesters in the brains of healthy older subjects: an in vivo phosphorus magnetic resonance spectroscopy study". Psychopharmacology. 161 (3): 248–54. doi:10.1007/s00213-002-1045-y. PMID 12021827.
  23. Rao, AM; Hatcher, JF; Dempsey, RJ (Dec 1, 1999). "CDP-choline: neuroprotection in transient forebrain ischemia of gerbils". Journal of neuroscience research. 58 (5): 697–705. doi:10.1002/(sici)1097-4547(19991201)58:5<697::aid-jnr11>;2-b. PMID 10561698.
  24. 24.0 24.1 D'Orlando, KJ (August 1995). "Citicoline (CDP-choline): mechanisms of action and effects in ischemic brain injury". Neurological research. 17 (4): 281–4. PMID 7477743. Unknown parameter |coauthors= ignored (help)
  25. 25.0 25.1 Rao, AM; Hatcher, JF; Dempsey, RJ (Mar 2, 2001). "Does CDP-choline modulate phospholipase activities after transient forebrain ischemia?". Brain Research. 893 (1–2): 268–72. doi:10.1016/S0006-8993(00)03280-7. PMID 11223016.
  26. Adibhatla, RM; Hatcher, JF (Aug 1, 2003). "Citicoline decreases phospholipase A2 stimulation and hydroxyl radical generation in transient cerebral ischemia". Journal of neuroscience research. 73 (3): 308–15. doi:10.1002/jnr.10672. PMID 12868064.
  27. Secades, JJ; Lorenzo, JL (September 2006). "Citicoline: pharmacological and clinical review, 2006 update". Methods and findings in experimental and clinical pharmacology. 28 Suppl B: 1–56. PMID 17171187.
  28. Watanabe, S; Kono, S; Nakashima, Y; Mitsunobu, K; Otsuki, S (1975). "Effects of various cerebral metabolic activators on glucose metabolism of brain". Folia psychiatrica et neurologica japonica. 29 (1): 67–76. PMID 1098982.
  29. Hurtado, Olivia. "Neuroprotection afforded by prior citicoline administration in experimental brain ischemia: effects on glutamate transport". Neurobiology of Disease. 18 (2): 336–345. doi:10.1016/j.nbd.2004.10.006. Unknown parameter |coauthors= ignored (help)
  30. Dinsdale, JR; Griffiths, GK; Rowlands, C; Castelló, J; Ortiz, JA; Maddock, J; Aylward, M (1983). "Pharmacokinetics of 14C CDP-choline". Arzneimittel-Forschung. 33 (7A): 1066–70. PMID 6412727.
  31. Fernández-Murray, JP; McMaster, CR (Nov 18, 2005). "Glycerophosphocholine catabolism as a new route for choline formation for phosphatidylcholine synthesis by the Kennedy pathway". The Journal of Biological Chemistry. 280 (46): 38290–6. doi:10.1074/jbc.M507700200. PMID 16172116.

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