Citicoline, also known as cytidine diphosphate-choline or cytidine 5'-diphosphocholine is an intermediate in the generation of phosphatidylcholine from choline, a common biochemical process in cell membranes. Citicoline is naturally occurring in the cells of human and animal tissue, in particular the organs. Studies suggest that CDP-choline supplements increase dopamine receptor densities. Intracerebroventricular administration of 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 PCOS, type II diabetes and major depressive disorder.
Citicoline is available as a supplement online and in stores. It is sold in over 70 countries under a variety of brand names: Cebroton, Ceraxon, Cidilin, Citifar, Cognizin, Difosfocin, Hipercol, NeurAxon, Nicholin, Sinkron, Somazina, Synapsine, Startonyl, Trausan, Xerenoos, etc. When taken as a supplement citicoline is hydrolyzed into choline and cytidine in the intestine. Once these cross the blood–brain barrier it is reformed into citicoline by the rate-limiting enzyme in phosphatidylcholine synthesis, CTP-phosphocholine cytidylyltransferase.
Research
Memory and cognition
A 2015 review of published clinical trials of citicoline noted that while some studies have demonstrated positive effects of the compound on cognition, other studies have failed to confirm these results and additional clinical trials would be needed to confirm any potential benefits of citicoline.
Despite some suggestions that citicoline may reduce the rates of death and disability following an ischemic stroke, the largest citicoline clinical 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. A meta-analysis of seven trials reported no statistically significant benefit for long-term survival or recovery.
Vision
The effect of citicoline on visual function has been studied in patients with glaucoma.
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. Citicoline's 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 preferentially uses 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.
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.
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
