Citicoline (CDP Choline) Nootropic Research, Effects & Safety Overview

CDP-choline (Cytidine-5′-diphosphate choline, citicoline) is an endogenous organic molecule.

It is primarily known as an intermediate compound in the biosynthesis of the membrane phospholipid phosphatidylcholine (a process commonly referred to as the Kennedy cycle).

Thus, CDP-choline and its hydrolysis products (choline and cytidine, which is metabolized into uridine in humans) play an important role in synthesizing phospholipids to support membrane formation and repair.

Exogenous CDP-choline (citicoline) has been observed to exhibit cholinergic and neuroprotective actions.

Citicoline has been used to treat a variety of neurodegenerative disorders, particularly in relation to ischemic stroke, head trauma, age-related cognitive deterioration and Alzheimer’s Disease. [1]

Exogenous citicoline is hydrolyzed in the small intestine to form choline and cytidine, both of which are easily absorbed and dispersed throughout the organism.

Choline and cytidine can cross the blood brain barrier (BBB), where they are re-synthesized into CDP-choline.[2]

In humans, cytidine is metabolized into the amino acid uridine, which can also cross the BBB and help support the biosynthesis of phospholipids.

Product name: Citicoline, CDP-choline
Chemical Name: Cytidine-5′-diphosphate choline
Formula: C14H26N4O11P2
Molecular Weight: 488.33; Monosodium salt of CDP-Choline: 510.31

Citicoline

Cholinergic Supplement

Memory

Focus

Brain Health

How It Works:

• Supports memory, focus & mental clarity
• Increases levels of acetylcholine neurotransmitter
• Promotes brain cell health & communication

Dosage:

Between 250 - 2,000 mg per day

Safety:

Rated Likely Safe

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Chemical Structure

Citicoline (C14H26N4O11P2) is a polarized mononucleotide comprised of ribose, cytosine, pyrophosphate, and choline. [3]

Exogenous citicoline undergoes hydrolysis in the small intestine to form choline and cytidine. In humans the resulting cytidine is metabolized to uridine.

Choline is grouped with B vitamins and has a trimethylated nitrogenous base. Choline is involved in a number of metabolic pathways, including those responsible for phospholipid synthesis and acetylcholine synthesis. [4]

Cytidine is a common component of RNA and is converted in the cytoplasm to form cytidine triphosphate (CTP).

In the brain, choline is catalyzed by the enzyme choline kinase to form phosphorylcholine.

Phosphorylcholine combines with CTP to form citicoline, which combines with diacylglycerol (DAG) to form phosphatidlycholine (this biosynthetic pathway is known as the Kennedy Cycle).

Pharmacokinetics

Citicoline is a water soluble compound that is effectively absorbed by the body, both when taken orally and administered intravenously; Orally administered citicoline is almost completely absorbed.[5]

In humans, evidence suggests only one percent of orally consumed citicoline is excreted through feces.[6]

In general, citicoline is eliminated in the human body through Co2 respiration and urine excretion. [6]

As noted, citicoline is hydrolyzed in the small intestine to form choline and cytidine. Administration of citicoline has been observed to increase plasma choline levels. [7][8]

However, CDP-choline consumption has been illustrated to increase uridine levels in humans and not cytidine levels, suggesting the cytidine released through hydrolysis of citicoline is transformed into circulating uridine.[7]

Like cytidine, uridine can cross the BBB and is converted to uridine triphosphate (UTP).

UTP can be converted to cytidine triphosphate (CTP) by the enzyme CTP synthase. Uridine has also been observed to convert directly to CTP in PC-12 cells.[7]

In sum, the circulating substrates through which exogenous CDP-choline aids in phosopholipid synthesis in the brains of humans is uridine and choline, as opposed to cytidine and choline as found in rat models.[7]

Citicoline Mechanisms of Action

Citicoline’s role as a precursor to the biosynthesis of the phospholipid phosphatidylcholine has been illustrated in animal studies.

Exogenous citicoline has been illustrated to break down to choline and cystine, which has been observed to increase choline and uridin serum levels in humans.[7]

In the same study uridine was observed to be directly converted to CTP. Thus, citicoline is hypothesized to support neuronal membrane health by providing necessary components for phospholipid synthesis.

Exogenous citicoline is also thought to help protect neuronal membrane integrity by providing additional choline stores, which help prevent neural membrane degradation when endogenous levels of choline become too low.[4]

Citicoline has been investigated as a treatment for ischemic stroke. During ischemia, phosphatidylcholine is broken down into free fatty acids, which are then converted to free radicals.

Exogenous citicoline is thought to slow or prevent phosphatidylcholine breakdown brought on by ischemic episodes. [9]

Citicoline also serves as an intermediary in the production of the membrane phospholipid known as sphingomyelin. Citicoline has been observed to restore sphingomyelin to pre-stroke levels in patients who have experienced an ischemic stroke. [10]

Evidence of citicoline’s efficacy in treating Alzheimer’s Disease (AD) is limited and preliminary. Some evidence suggests that citicoline may also be able to counteract the deposit of a neurotoxic protein that plays a role in the development of AD.[4]

Citicoline for Stroke Recovery

Citicoline is mostly used to treat cerebrovascular disorders.[11] In Europe and Japan, citicoline is a prescription drug primarily used to treat stroke. [7]

Citicoline is observed to improve the recovery of patients who experience ischemic stroke.

Studies illustrate that stroke patients who receive 500-2000 mg of citicoline per day (orally) within 24 hours of acute ischemic stroke have a higher likelihood of making a full recovery in three months compared to the placebo group.[12]

Recovery rates varied in accordance with the quantity of citicoline administered.

The largest difference was between individuals how received 2000mg of citicoline versus the placebo: 27.9% of patients who received 2000mg of citicoline/day made a full recovery in three months, versus 20.2% in the placebo group. [12]

Treatment of Cognitive Impairment

Citicoline has been observed to improve verbal memory in people aged 50-85 who have illustrated age-related memory loss or cognitive impairment.[13]

Individuals characterized as having ‘inefficient memory’ were found to have improved verbal memory functioning with citicoline therapy. [13]

In another study it was observed that 1000md/day of citicoline over a four-week period improved memory recall in a group of elderly individuals as compared to the placebo group. [1]

A study published in 2000 examined the use of citicoline to treat cognitive impairment or memory loss due to traumatic brain injury.

Researchers observed taking 1000mg/day citicoline improved memory, learning and verbal ability. [14]

Alzheimer’s Disease (AD)

Research into the effect of citicoline on health outcome for individuals with AD is still in the preliminary stages.[15]

A review of studies focused on the cognitive and behavioural disturbances associated with chronic cerebral disorders noted that there is some evidence that the administration of CDP-choline has a positive effect on memory and behaviour over the short and medium term.[11]

A 1999 study specifically focused on individuals with Alzheimer’s Disease observed 1000mg/day citicoline improved cognitive performance, among other measures.[1]

Glaucoma

A slowed neural conduction in the visual pathways of the brain is thought to play a role in visual effects of open-angle glaucoma.

1000mg/day citicoline taken orally was observed to improve visual evoked potentials in some glaucoma patients.[16]

Safety and Side Effects

Citicoline consumption is associated with low toxicity in humans.[4]

However, some undesirable effects have been noted during periods of citicoline administration, including nausea, vomiting, diarrhrea, bradicardia, tachycardia and hypotension.[15]

The LD50 of intravenously delivered citicoline was observed to be 4,600mg/kg in mice and 4,150 mg/kg in rats.

The LD50 of orally ingested citicoline remains unknown because the highest available dosage did not cause any death in test animals.[17][4]

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