CDP-choline (Cytidine Diphosphocholine or Citicholine) is a molecule which confers choline to the body and is able to convert into uridine, therefore conferring benefits associated with both molecules to a degree and being claimed to support acetylcholine and phospholipid metabolism.
Structurally, CDP-choline (Cytidine Diphosphocholine) is a Cytidine molecule bound to a choline molecule via two phosphate groups (pyrophosphate); as cytidine is also a term used to refer to cytosine bound to ribose CDP-choline is sometimes said to be cytosine, ribose, pyrophosphate, and choline.
CDP-choline is said to be water soluble.
In this pathway, choline kinase (CK) catalyzes choline into phosphocholine consuming an ATP molecule in the process and has a micrmolar affinity in doing so (thus, much cellular choline is readily converted into phosphocholine), and although this is not the only possible way to create phosphocholine (sphingomyelin degradation also confers phosphocholine) it is the most prominent one and the first committed step of PC synthesis via the Kennedy cycle.
Elsewhere, Phosphocholine cytidylyltransferase (CCT) converts cytidine triphosphate (CTP) into CDP-choline plus pyrophosphate (using the previously created phosphocholine as the source of choline). This enzyme is the slowest in the Kennedy cycle and rate-limiting, thus its activity determines overall PC synthesis. Usually in cellular cultures, there is an abundance of phosphocholine and a lack of CDP-choline.
Finally, Choline phosphotransferase (CPT, not to be confused with carnitine palmitoyltransferase which shares the CPT acronym) transfers the phosphocholine from CDP-choline to diacylglycerol (DAG). There is also an enzyme called choline–ethanolamine phosphotransferase (CEPT) which has dual specificity for CDP-choline and CDP-ethanolamine (and one specific for CDP-ethanolamine), the donation of phosphocholine towards DAG is what finally creates phospholipids such as phosphatidylcholine (the other enzymes that use CDP-ethanolamine instead create phosphatidylethanolamine).
The role of CDP-Choline is thought to be due to provision of cytidine (which increases uridine) and choline, thus providing substrate for the reaction. Although in the above reaction CDP-Choline is formed after the rate-limiting step, oral CDP-Choline is dissociated completely and is a prodrug for cytidine and choline rather than conferring bodily CDP-Choline.
The Kennedy cycle uses CDP-choline as an intermediate in phospholipid synthesis, which is important for the functioning of all cells but is usually most important for neurons. The rate-limiting step is the one that produces CDP-choline, but this is mostly irrelevant to supplementation since CDP-choline ingestion does not raise plasma CDP-choline levels (instead, it raises plasma cytidine and choline)
Studies assessing absorption of CDP-Choline note that it is near absolute, ranging from 97.55-100%.
There are some interspecies differences in the metabolism of CDP-Choline. While it is consistently degraded completely, in rats the two products created are cytidine and choline found in systemic circulation and the brain whereas in humans the two products are uridine and choline; supplemental CDP-choline (500-2000mg) in humans increases plasma uridine concentrations (101-136%) without detectable increases in cytidine. This is accredited to rapid conversion of cytidine into uridine in humans.
CDP-choline increases serum concentrations of free choline at doses as low as 500mg which tends to occur 2-3 hours after administration and following ingestion of 1000mg CDP-choline it has been noted to reach a Cmax of 2.085+/-0.189 at a Tmax of 3.292+/-0.689 hours,
In humans, CDP-choline acts as a prodrug for both choline and uridine
The half-life of elimination for the choline spike seen with supplemental CDP-choline (1000mg) appears to be fairly delayed, at 66.348+/-8.445 hours.
In vitro, CDP-Choline appears to potentiate acetylcholine-induced relaxation in the internal (reducing the EC50 from 120ng/mL to 23ng/mL with 1mg/mL CDP-choline), but not external, vascular carotid bed (the internal bed has rich cholinergic innervation colocalized with adrenergic receptors) and is blocked by choline reuptake inhibitors.
Possibly vessel relaxing properties associated with cholinergic signalling, which suggest that CDP-Choline may have relaxing properties on blood vessels. The concentrations seems quite high though, and CDP-Choline (used in the in vitro experiment) is not per se found in the blood
In instances of shock (haemorrhagic shock), injections of CDP-choline to rats (which rapidly produces cytidine monophosphate and phosphocholine) has been noted to increase blood pressure and reduce heart rate when delivered either systemically or intracerebrally; the cardiac appears to be mediated via the cholinergic system as well as the histaminergic system (as H1 receptor antagonists block the effects whereas cholinergic antagonists do not).
In hypotensive (low blood pressure) rats, injections of CDP-Choline appear to increase blood pressure and normalized heart rate. This is a dual effect mediated via both the histaminergic and cholinergic systems
In otherwise healthy elderly adults, one study assessing memory formation with 500-1,000mg CDP-Choline found modest but significant reductions in systolic blood pressure.
Limited oral supplementation studies in humans, but appears to have blood pressure reducing properties when there is not a hypotensive crisis
One study in older individuals given 500mg CDP-choline daily for 6 weeks has noted an increase in both phosphocreatine (7%) and beta-nucleotide phosphate concentrations (14% overall, mostly ATP), whereas 2,000mg was ineffective.
In a study in otherwise healthy persons administered 500mg or 2,000mg CDP-choline for six weeks, it was found that the higher dose was able to stimulate activity in the amygdala, insula, and lateral orbitofrontal cortex (in response to food intake) which was thought to underlie appetite suppressing effects noted with supplementation (on a scale of 1-10, reduced from 6.8 down to 5.92; as 1 is the lowest ranking this is a 27% decline) although weight did not appear affected.
May have minor appetite reducing properties in humans at higher doses (2,000mg daily), although the reason for this is currently unknown
In otherwise healthy women aged 40-60 given CDP-choline at 250-500mg for 28 days and then subject to a Continuous Performance Test II (CPT-II) it was noted that supplementation of both doses was able to reduce omission and comission errors, indicative of improved attentional focus and inhibition. The two groups were for the most part equally effective, although 250mg may have been slightly more potent.
At least one study has reported an improvement in attention with 250-500mg (250mg outperforming 500mg) with supplemental CDP-Choline
Choline itself has pain killing effects which is abolished by either preventing choline uptake into the brain or by blocking nicotinic receptors (particularly the α7 subset) which choline is an agonist of, while muscarinic antagonists fail to abolish the effects (despite the musarinic system being involved in pain).
Secondary to increasing choline in the brain, CDP-choline appears to also have pain killing effects via the nicotinic acetylcholine receptors; cytidine infusions do not have such a pain killing effect. This analgesic effect is dose-dependent and is inhibited by naloxone (opioid inverse agonist) and CGP-35348 (GABAB receptor antagonist), which confirms actions through the nicotinic receptor onto opioid release, but implicates GABAB receptors in the process (serotonin and adrenergic signalling, which is also induced by nicotinic activation, does not appear to be involved with the observed analgesic effect).
Choline itself appears to have pain-killing properties when it reaches the brain, as activation of choline receptors causes a release of opioid painkillers. CDP-Choline injections have been shown to have painkilling properties due to the choline content, but no orally supplemented studies currently exist (instead studies using 1-5µmol injections)
It has been noted that CDP-Choline acts as a membranes stabilizer after strokes and is known to have a variety of actions including preservation of ATP synthase activity, acetylcholinesterase, and both cardiolipin and sphingomyelin while preventing the release of fatty acids from damaged neurons and promoting glutathione activity while reducing apoptosis. These events are thought to be downstream of preserving membrane plasticity during experimental stroke with 500mg/kg CDP-Choline (rats) as assessed by higher levels of biomarkers (VEGF, Synaptophysin, LRP).
When looking at rat studies, infusions of CDP-Choline taken at the onset of experimental stroke are able to confer protective effects as assessed by reducing infarct size in a manner that is synergistic with growth factors and SIRT1 activators. Rats given experimental brain injury also experience a preservation of memory (usually impaired following brain injury) with intravenous CDP-Choline at the onset of injury.
In persons with Traumatic brain injury who (after admission to trauma centers) were placed on either placebo or 2000mg CDP-choline for 90 days, there did not appear to be any significant differences in cognitive or functional parameters when measured at the end of supplementations or after 90 days of supplement cessation.
It has been noted that supplementation of CDP-Choline is associated with improved recovery after stroke with an OR of 1.33 (95% CI 1.10–1.62) which has been noted elsewhere in another meta-analysis.
That being said, a subsequent trial using CDP-Choline (1000mg twice daily for three days followed by 500mg twice daily for six weeks) in persons with ischaemic stroke has been noted to have no significant effect relative to placebo, resulting in the trial's premature cessation.
Due to choline being the substrate for production of acetylcholine, CDP-Choline is thought to increase acetylcholine synthesis secondary to its choline component although uridine is also implicated (as uridine in isolation has been noted to increase acetylcholine concentrations in aged rats).
Injections of CDP-Choline (100mg/kg) have been confirmed to increase extracellular acetylcholine in the brain (hippocampus and neocortex) in free moving rats following traumatic brain injury.
Supplementation of CDP-Choline, via both of the components (choline and uridine), can increase acetylcholine release in living models
In the striatum and cortex the protein content of the vesicular acetylcholine transporter appears to be increased with supplemental CDP-Choline (325mg/kg), which also appears to apply to Alpha-GPC when controlled for choline content (although alpha-GPC affected more brain regions overall). This has been noted in a living system, where aged rats given 100-500mg/kg CDP-Choline daily for 7 months experienced a 6-17% increase in muscarinic acetylcholine receptor concentration (whereas control experienced a decline) although affinity of the receptor was not modified.
May increase choline transporters in the brain following oral ingestion of higher dosages, both choline itself and the uridine component are implicated in the observed changes
Choline (infusions) are known to increase serum concentrations of adrenaline and noradrenaline which appears to extend to CDP-choline, as choline itself acts upon nicotinic acetylcholine receptors to stimulate release of catecholamines. While it does not have efficacy under normal conditions in the hypothalamus, it may attenuate the reduction of noradrenaline seen with hypoxia at large oral doses (1,000mg/kg in rats).
Ingestion of 325mg/kg CDP-choline for seven days in rats does not modify concentrations of the norephedrine transporter nor the general vesicular monoamine transporter (VMAT2).
Ingestion of 325mg/kg CDP-choline for seven days does not modify concentrations of the serotonin transporter in the rat brain.
CDP-Choline appears to have dopaminergic activity as assessed by its efficacy in animal models of Parkinson's disease, which is likely related to the uridine component of CDP-choline, as the augmentation of potassium-evoked dopamine release seen with uridine is also seen with CDP-Choline (250mg/kg oral intake causing a 59% increase in dopamine release), with one study noting that CDP-Choline injections (300mg/kg) per se caused a minor acute spike in dopamine (23-29% that was normalized within 3 hours) that was lesser than L-DOPA (74%). For studies assessing basal dopamine concentrations (concentrations of dopamine at rest without stimulation), there do not appear to be long term changes.
A single injection of 900mg/kg has been reported to possess a suppressive effect, indicative of an antagonistic effect. This is thought to be related to the increased dopamine release upon neuronal activation as dopamine antagonists are known to increase dopamine synthesis (agonists reduce synthesis).
In studies where dopamine agonists are used, chronic injections (300mg/kg, but not 100mg/kg) are known to enhance apomorphine induced turning (42%). This may be related to the dopamine transporter being upregulated by subchronic CDP-choline ingestion (cerebellum and frontal cortex) which has been noted to occur in aged rats (11-18% with 100-500mg/kg CDP-Choline oral intake) over 7 months or the aforementioned enhancement of dopamine release from stimulation. The enhancement of dopamine receptor concentrations seems to be related to the uridine component as it has been noted to be associated with improvements in membrane rheology.
CDP-Choline does not appear to influence dopamine concentrations per se, but it does appear to augment dopaminergic signalling by both increasing levels of the dopamine transporter and by increasing the amount of dopamine released from a stimulated neuron. This augmentation seems to apply to dopamine agonists as well as dopamine itself
CDP-choline has noted a preservation of dopaminergic neurons in the face of the parkinson's research toxins MPP+ and 6-hydroxydopamine which may be related to its general anti-apoptotic effects. Although more reflective of the neuroprotective effects of the uridine component, preserving dopaminergic neurons can prevent a reduction in dopamine seen with toxins or other damages.
The neuroprotective effects of CDP-Choline, when applied to neurons that secrete dopamine, suggest that CDP-Choline can attenuate declines in dopamine secretion seen with neurological damage
The dopaminergic interactions of CDP-Choline seem to be more related to the uridine component than it is related to the choline component
It is generally believed that the mesolimbic and mesocortical dopaminergic systems (as well as serotonergic) play roles in addiction, and currently form the basis of pharmacological therapy. CDP-choline is thought to benefit cocaine addiction secondary to its cytidine component and dopamine metabolism.
Supplementation of 500mg CDP-choline twice daily for two weeks in persons previously addicted to cocaine reported more control over usage, less of a desire for cocaine-induced euphoria, and less overall cravings or desire for cocaine as assessed by self-report survey and in persons with bipolar disorder who also have cocaine habits supplementation of CDP-choline was found to reduce the amount of persons with cocaine positive urine at the end of the 12 week trial (despite not influencing bipolar symptomology). Conversely, in cocaine dependent populations not actively seeking treatment given 500mg twice daily, CDP-choline has failed to outperform placebo in reducing cocaine usage or cravings (although alcohol usage appeared to be reduced).
In persons with previous cocaine abuse (but not meeting DMS-IV criteria for dependence), supplementation of the same 500mg twice daily dose for four days prior to a cocaine challenge did not significantly alter cardiovascular parameters nor the cognitive alterations induced by cocaine self-administration.
CDP-Choline may have putative anti-addictive properties when taken at 500mg twice daily, but does not appear to be overly potent. The one study it has failed to have any actions was in the study where participants were not directed to try and reduce cocaine intake nor were they treatment seeking
In young and otherwise healthy rats, CDP-Choline has failed to improve spatial memory formation (500mg/kg for 8 weeks) as assessed by water maze but elsewhere at 10-500mg/kg has been found to improve active and passive avoidance tasks following 10 days of administration, the latter study having a comparable potency to Piracetam and meclofenoxate (Centrophenoxine). This potency comparable to piracetam (100-500mg/kg) has been noted elsewhere with CDP-Choline in mice (25-500mg/kg) and the two appear to be synergistic towards acute memory formation in otherwise healthy rodents.
In otherwise healthy and youthful rodents, CDP-Choline appears to have some potential as a nootropic compound and memory enhancer but is not 100% reliable. When it does enhance memory formation, it does so at a potency comparable to Piracetam
The aging process is known to cause a reduction of spatial memory formation in rats and humans associated cholinergic and membrane dysfunction in the hippocampus relative to youthful controls. Due to CDP-Choline being involved in both membrane and acetylcholine metabolism, it has been investigated for cognitive decline (as since uridine is also effective in this regard, it is thought that both molecules confer benefit).
Supplementation of 500mg/kg of CDP-choline to rats for 8 weeks was able to reverse the spatial memory deficits seen in aged rats and 10mg/kg has been found to improve performance in active avoidance tasks in aged rats.
In elderly humans without dementia, supplemnetation of 500-1,000mg CDP-choline is associated with improvements in memory recall and verbal memory (1,000mg effective only in those with poor scores at baseline, 2,000mg effective in all subjects) but not object recognition.
CDP-Choline appears to be effective in promoting memory formation and recall in elderly subjects in the dosage range of 500-2,000mg, and appears to have dose-dependent benefits within this range
In studies that assess memory following some form of injury, CDP-choline (100-1,000mg/kg) for seven days appeared to have neuroprotective effects in a rat model of cerebrovascular dementia as assessed by improved performance in a maze test and less hippocampal cell death. This was seen significantly at the highest dose (1,000mg/kg).
Secondary to the neuroprotective effects, there may be memory preserving effects in situations of cognitive damage. This requires a fairly high dosage, however
Both insulin and glucagon appear to be increased following infusions of CDP-choline or choline itself, which appears to be related to increasing acetylcholine concentrations in the pancreas secondary to activating the nicotinic acetylcholine receptors.
Choline can increase concentrations of both pancreatic hormones, practical relevance of this information not known
Seven days injections of CDP-choline to rabbits (50mg/kg) has been reported to increase retinal concentrations of dopamine (with a trend to increase adrenaline and no significant changes in noradrenaline).
Intramuscular injections of 1,000mg CDP-choline daily in persons with glaucoma over a period of 60 days was able to increase Visual evoked potential (VEP) and pattern-electroretinogram (PERG) parameters. After 180 days washout, although the benefits were attenuated they were still significantly better than placebo and this has been replicated elsewhere where 1000mg injections were similarly protective as 1600mg oral intake of CDP-choline.
When assessing intraocular pressure, regardless of whether participants are selected based on having an intraocular pressure of less than 18mmHg or greater than 21mmHg supplementation of CDP-choline does not appear to have an effect.
May be able to promote neural conductance along vision pathways, but does not appear to influence intraocular pressure
Intravenous CDP-choline is able to augment clonidine-stimulated growth hormone release, which is blocked by preventing neural choline uptake.
The stimulation of TSH appears to be augmented with intravenous infusion of CDP-choline in rats, which is prevented by blocking the actions of choline.
LHRH-stimulated luteinizing hormone release appears to be augmented with intravenous administration of CDP-choline to rats, which is abolished by preventing choline uptake into the brain.
CDP-Choline has been noted to induce release of ACTH from the adrenal glands secondary to acting upon nicotinic acetylcholine receptors.
CDP-Choline ingestion (500, 2000, and 4000mg) is able to cause increases in serum choline in humans following oral ingestion by 23, 32, and 43% when measured 2-3 hours after oral ingestion, and elevations persisted for up to 10 hours.
Uridine is a nucleotide base that is also a common dietary supplement.
Uridine and Cytidine are sometimes seen as interchangeable, as although cytidine can directly convert into cytidine triphosphate (CTP) for entry into the Kennedy cycle uridine can also convert into CTP (vicariously through forming uridine triphosphate).
Oral supplementation of CDP-Choline is able to increase plasma uridine concentrations, with 500mg (101% higher than baseline) being less effective than 2000mg (136%) yet 4000mg being no more effective (134%) when measured at 90 minutes post ingestion and lasting for 6 hours.
In rats given 0.2-2g/kg intravenous CDP-choline prior to an experimental stroke, it has been found that infusion was able to induce levels of the SIRT1 protein which mediated the neuroprotective effects seen with CDP-Choline. Coadministration of resveratrol (2.5mg/kg) was found to be synergistic in protection.