Citicoline

# Overview
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, and suggest that CDP-choline supplementation helps prevent memory impairment resulting from poor environmental conditions. 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.  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.
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.

# 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. Once these cross the bloodbrain barrier it is reformed into citicoline by the rate-limiting enzyme in phosphatidylcholine synthesis, CTP-phosphocholine cytidylyltransferase.

## Memory disorders
In the hippocampi of rats with induced Alzheimers Disease, citicoline counteracts neuronal degeneration and reduces the number of apoptotic cells present. Citicoline supplementation also improves memory retention.

## 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. It has been claimed that citicoline reduces rates of death and disability following an ischemic stroke.
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.
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.

## Vision
Citicoline improves visual function in patients with glaucoma, amblyopia, and non-arteritic ischaemic optic neuropathy.

## Satiety
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. 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.

# Mechanism of action

## 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. Citicolines effects may also be explained by the reduction of phospholipase A2 activity. 
Citicoline increases phosphatidylcholine synthesis. The mechanism for this may be:
- By converting 1, 2-diacylglycerol into phosphatidylcholine
- Stimulating the synthesis of SAMe, which aids in membrane stabilization and reduces levels of arachidonic acid. This is especially important after an ischemia, when arachidonic acid levels are elevated.

## 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. Supplementation with citicoline can increase the amount of choline available for acetylcholine synthesis and aid in rebuilding membrane phospholipid stores after depletion. 
Citicoline decreases phospholipase stimulation. This can lower levels of hydroxyl radicals produced after an ischemia and prevent cardiolipin from being catabolized by phospholipase A2. It can also work to restore cardiolipin levels in the inner mitochondrial membrane.

## Cell signalling
Citicoline enhances cellular communication by increasing the availability of neurotransmitters, including acetylcholine, norepinephrine, and dopamine.

## Blood flow
Citicoline increases glucose metabolism in the brain and cerebral blood flow.

## 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 bloodbrain barrier breakdown.

## 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 citicolines ability to decrease levels of glutamate in the brain.

# Pharmacokinetics
Citicoline is water-soluble, with more than 90% oral bioavailability. 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.

## 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.

# Synthesis

## 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
- The Kennedy pathway, which includes the transformation of choline to citicoline, by way of phosphorylcholine, to produce phosphatidylcholine when condensed with diacylglycerol.
- Phosphatidylcholine can also be produced by the methylation pathway, where phosphatidylethanolamine is sequentially methylated.