Cerebral Synergy
Getting More Brain power from Nutrients

Citicoline (also known as cytidine-5'-diphosphocholine or CDP-choline) is a cholinergic donor and agonist that helps boost acetylcholine levels and helps stimulate their receptor activity. Acetylcholine is a fundamental neurochemical messenger that serves many purposes in the body and brain. It is instrumental as a biochemical mobilizer that helps enhance and preserve memory.

In studies with aged animals and humans, citicoline has been found to improve memory in recall tasks (word recall, immediate object recall, and delayed object recall),1 improve learned behavior (e.g., motor performance),2 and protect neural tissue.3 In its protective role, it acts to reduce the formation of lesions on nerve membranes by increasing the synthesis of phospholipids, the specialized fats that are vitally important to membrane function and thus to memory.4

In cell membranes, phospholipids provide elasticity, permeability, strength, and resistence to stress. Without sufficient phospholipids, such as phosphatidylcholine and phosphatidylserine, energy metabolism would be labored and, especially in the brain, would result in mental inertia and reduced memory function. Citicoline may increase the activity of the nutrient phosphatidylserine, and create synergy in the process.5

In a very recent study, citicoline significantly restored the levels of phosphatidylcholine, sphingomyelin, and cardiolipin in the brain.6 These compounds, especially cardiolipin, are critical not only for stabilizing the cell membrane but for maintaining proper heart function. When cardiolipin levels increase in the brain, they are also likely to increase in heart tissue.7

Citicoline also inhibited the release of the highly oxidative fatty acid arachidonic acid, too much of which can act as a source of potential toxins and can interfere with the treatment of stroke or other brain damage. Finding that citicoline does so is good news.

In a recent review article on the benefits of citicoline for the treatment of ischemic cerebrovascular disease (ischemia is a reduced blood supply, which can lead to inadequate oxygen), citicoline was found in most of the studies to reduce cerebral infarction (tissue death) and the neurological consequences of memory loss and dysfunction.8 As well, in the studies reviewed, citicoline was found to enhance the neuroprotective effects of conventional drugs used to treat cerebral infarction.

In their analysis of the literature, the authors of the review found six randomized, double-blind, placebo-controlled clinical trials in which the effect of citicoline on patients with acute ischemic cerebrovascular accidents had been evaluated. In every one of these studies, citicoline equaled the expectations of the hypothesis that citicoline would be effective. It offered an advantage over fibrinolytic agents such as heparin and streptokinase (anticoagulants that break down fibrin, the insoluble protein involved in blood clotting), because it has a broad therapeutic "window" of 24-48 hours following the infarction, compared to 3-6 hours for the fibrinolytics.

In further controlled trials with citicoline, carried out with patients in the aftermath of cerebrovascular stroke, different degrees of neurological improvement were found, leading the researchers to conclude that citicoline has high efficacy. In one study, conducted with 2817 patients with chronic cerebrovascular circulatory problems (age range 60-80 years), the most significant benefits were:9

  • Dizziness - disappearance in 48%, improvement in 25%
  • Cephalea (fluid-pressure headache) - disappearance in 46%, improvement in 27%
  • Insomnia - disappearance in 39%, improvement in 25%
  • Depression - disappearance in 37%, improvement in 24%
  • Memory deficit - disappearance in 21%, improvement in 45%

Fatigue and speech troubles were also found to be improved with citicoline. Side effects were mild and few and were observed in only 5% of the patients.

The problem of failing memory was examined in a randomized, double-blind, placebo-controlled, parallel-group study using 32 volunteers selected from a wide age range (50-85 years; 47 female, 48 male), to whom citicoline was given.10 The subjects were screened for dementia, memory disorders, and other neurological problems, and from this group, a subgroup of 32 individuals was selected for poor memory. They received either citicoline or placebo at 1000 mg/day for 3 months. Then the treatment and control groups switched regimens (a "crossover"): those who had been taking citicoline switched to placebo, and vice versa, thus eliminating the placebo effect (none of the subjects, of course, knew what they were taking at any time). At this point, however, the dose was increased to 2000 mg/day for 2 months.

When the subjects were given memory tests throughout the study, it was found that citicoline therapy improved delayed memory. During the final 2 months, the doubled dosage of citicoline (2000 mg/day) improved immediate memory as well as delayed memory. Citicoline therapy also improved verbal memory in these older individuals. This study epitomizes the value of citicoline in treating age-related cognitive decline, which may be the precursor of dementia and possibly of Alzheimer's disease.

2 + 2 = 5
Two of the principal memory-function nutrients, pregnenolone and choline, are established in their usage as cognitive enhancers. Over many decades of study, both have produced favorable results, without significant side effects.

As we have previously noted (see Brain Tonic Synergy - Apr. 2000), when these two compounds come together in your body, the result is likely to be synergistic, with a 2 + 2 = 5 effect. Allied in their effect on the hippocampus (the seat of emotions in the brain; emotions are rooted in memory*), both have been found to collude in the enhancement of spatial memory tasks and their effects on memory.

* Emotions are automatic mind-body response evaluations based on past value judgments (including default judgments). They do not guarantee truth, but only reflect the sum of what our mind-body "remembers" from the past events and experiences of living, and our interpretation of this information.

Pregnenolone, which is synthesized naturally in the brain but to which we also respond when it is taken as a supplement, helps increase memory retention and resurrect old memories, making it an antiamnesiac. Choline, as the nutrient precursor to the important memory messenger molecule acetylcholine (also synthesized in our bodies), helps support, create, and maintain personality by giving us access to our memory of the past.

When, in a study reported in Brain Research, a very small pregnenolone dose was increased several times, the release of acetylcholine by the brain's hippocampus lasted for 20 minutes, whereas a slightly larger amount induced a longer-term 80-minute release of acetylcholine that peaked around 300% over the baseline value.11

Acetylcholine is strongly associated with focus, attention, and mental clarity. Combined with research showing the independent association of pregnenolone with improved spatial memory performance, the fact that pregnenolone enhances cholinergic function (and thus increases the value of choline) - the two enhancers are more than additive - makes for a synergistic relationship.

Small amounts of pregnenolone have been found by researchers to enhance spatial memory performance11 - an ability necessary for using computers, among other things - whereas larger amounts did not. This is consistent with other reports suggesting that there is an optimal level of acetylcholine release. If the dose of the precursor produces more than this, memory is not enhanced.

This is precisely how other nootropics (memory-enhancing supplements) operate. Characteristically, benefits rise in proportion to the amount used - up to a point, at which they then finally drop off as even more is used. However, pregnenolone seems to disobey this pattern, with benefits rising again at higher levels.

We might add that, as with all memory enhancers, there is a great deal of variation in responses among individuals. The right amount for you might not be right for the next person. Taking this to mind, it is a good idea to start with a smaller serving of a nutritional supplement and work up. If, beyond a certain level, the function-enhancing effects seem to fade, cut back on the amount. Try increasing and decreasing it several times until you get it right.

The researchers conclude that cerebrosteroids (such as pregnenolone) may be of value for the enhancement of cholinergic transmission in certain age-related memory disorders. The possible synergy between pregnenolone and choline, as well as the citicoline and phosphatidylserine and other nutrients, should be investigated personally. In this case the nutrients should be acquired separately and taken in different amounts. You may be happy to learn that less may be more for your pocketbook as well as for your mind.


  1. Alvarez XA, Laredo M, Corzo D, Fernandez-Novoa L, Mouzo R, Perea JE, Daniele D, Cacabelos R. Citicoline improves memory performance in elderly subjects. Methods Find Exp Clin Pharmacol 1997 Apr;19(3):201-10.
  2. Fioravanti M, Yanagi M. Cytidinediphosphocholine (CDP choline) for cognitive and behavioural disturbances associated with chronic cerebral disorders in the elderly. Cochrane Database Syst Rev 2000;4:CD000269.
  3. Ayuso-Gutierrez JL, Saiz-Ruiz J. The value of cytidine-5-diphosphate-choline in the prevention of impairment of memory function after electric convulsive therapy. A double-blind study. Prog Neuropsychopharmacol Biol Psychiatry 1982;6(3):243-8.
  4. Abad-Santos F, Gallego-Sandin S, Novalbos J, Galvez-Mugica MA. The current state of citicholine in cerebral ischemia. Rev Neurol 2000 Apr 1-15;30(7):663-70.
  5. Lopez-Coviella I, Agut J, Savci V, Ortiz JA, Wurtman RJ. Evidence that 5'-cytidinediphosphocholine can affect brain phospholipid composition by increasing choline and cytidine plasma levels. J Neurochem 1995 Aug;65(2):889-94.
  6. Rao AM, Hatcher JF, Dempsey RJ. Lipid alterations in transient forebrain ischemia: possible new mechanisms of CDP-choline neuroprotection. Neurochem 2000 Dec;75(6):2528-35.
  7. McGee CD, Lieberman P, Greenwood CE. Dietary fatty acid composition induces comparable changes in cardiolipin fatty acid profile of heart and brain mitochondria. Lipids 1996 Jun;31(6):611-6.
  8. Abad-Santos F, Gallego-Sandin S, Novalbos J, Galvez-Mugica MA. [No title.] Rev Neurol 2000 Apr 1-15;30(7):663-70.
  9. Lozano Fernandez R. Efficacy and safety of oral CDP-choline. Drug surveillance study in 2817 cases. Arzneimittelforschung 1983;33(7A):1073-80.
  10. Spiers PA, Myers D, Hochanadel GS, Lieberman HR, Wurtman RJ. Citicoline improves verbal memory in aging. Arch Neurol 1996 May;53(5):441-8. Published erratum in Arch Neurol 1996 Oct;53(10):964.
  11. Darnaudery M, Koehl M, Piazza PV, Le Moal M, Mayo W. Pregnenolone sulfate increases hippocampal acetylcholine release and spatial recognition. Brain Res 2000 Jan 3;852(1):173-9.

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