CDP-choline

CDP-choline (citicholine) is a nootropic compound that converts to both Choline and cytidine upon ingestion, the latter of which converts into Uridine in the body. It appears to confer cognitive-promoting properties as a prodrug for these two compounds.

This page features 108 unique references to scientific papers.

Summary

All Essential Benefits/Effects/Facts & Information

CDP-choline is a Nootropic compound that is essentially a prodrug for both Choline and Uridine, conferring both of those molecules to the body following oral ingestion of CDP-Choline. Specifically, the CDP-choline dissociates into choline and cytidine, with the cytidine then converting into uridine. CDP-choline is one of the three choline-containing phospholipids that can be orally supplemented (the other two being Alpha-GPC and Phosphatidylcholine).

This supplement is catered towards preventing or treating memory impairments associated with aging due to the fact that both of the molecules it confers are neuroprotective and potentially enhance learning. While it appears to be more effective than phosphatidylcholine (PC) at this role, in part due to also increasing PC synthesis in the brain, its potency is somewhat comparable to that of Alpha-GPC.

CDP-choline has some other potential uses in relation to cognition. It is commonly used as a memory enhancer in youth, but despite some rodent studies suggesting that this is possible with oral CDP-choline, there are no human studies in youth at this point in time. One study has noted an increase in attention with low dose CDP-choline (which needs to be replicated), and CDP-choline may have roles as an anti-addictive compound against both cocaine and (preliminary evidence suggests) food as well.

for updates

Confused about supplements?

Free 5 day supplement course

Things To Know

Also Known As

Citicholine, Cytidine Diphosphocholine

Do Not Confuse With

Choline (CDP-choline contains some choline, but is not exclusively choline), Uridine (similar in function to CDP-choline)

Is a Form Of

Goes Well With

  • Potentially synergistic with the same things as Uridine

  • Acetylcholinesterase inhibitors (for increasing acetylcholine content)

Caution Notice

Examine.com Medical Disclaimer

How to Take

Recommended dosage, active amounts, other details

Standard dosing of CDP-choline is to take 500-2,000 mg in two divided doses (of 250-1,000 mg) usually separated by 8-12 hours, although a single daily dose is also sometimes used. A single dose of 4,000 mg does not appear to affect the blood any differently than 2,000 mg, and so it is not necessary to take such a high dose.

There are some properties, such as attention-promotion or improving bioenergetics, that seem to respond exclusively or more strongly to the lower dosage range. Other properties like appetite are the opposite, and thus the ideal dosage depends somewhat on the goal.

Confused about supplements?

Free 5 day supplement course

Human Effect Matrix

The Human Effect Matrix looks at human studies (it excludes animal and in vitro studies) to tell you what effects cdp-choline has on your body, and how strong these effects are.

Grade Level of Evidence
Robust research conducted with repeated double-blind clinical trials
Multiple studies where at least two are double-blind and placebo controlled
Single double-blind study or multiple cohort studies
Uncontrolled or observational studies only
Level of Evidence
? The amount of high quality evidence. The more evidence, the more we can trust the results.
Outcome Magnitude of effect
? The direction and size of the supplement's impact on each outcome. Some supplements can have an increasing effect, others have a decreasing effect, and others have no effect.
Consistency of research results
? Scientific research does not always agree. HIGH or VERY HIGH means that most of the scientific research agrees.
Notes
Cocaine Addiction Minor High See all 3 studies
CDP-Choline appears to be weakly anti-addictive against cocaine addiction, although the one study undertaken in persons with no intention to minimize cocaine usage can back negative.
Attention Minor Very High See study
There appear to be attention promoting effects of CDP-Choline, with the one study in adult women noting that 250-500mg was effective but 250mg was more effective.
Blood Pressure Minor Very High See study
One study in older adults noted, as a side-effect, that systolic blood pressure was slightly reduced
Cognitive Decline Minor Very High See study
The rate of memory decline seen in older persons during the aging process appears to be attenuated with supplementation of CDP-Choline
Memory Minor Very High See 2 studies
Appears to promote cognition in otherwise healthy older adults. Although animal studies suggest this may apply to youthful subjects as well, no human currently exists for youth
Symptoms of Bipolar Disorder - Very High See study
The lone study in persons with bipolar disorder was one investigating addiction, and when measuring symptoms of bipolar disorder they failed to find any influence of supplementation on symptoms.
Appetite Minor Very High See study
There appear to be minor appetite suppressing effects at higher doses of oral CDP-choline ingestion (2,000mg daily), although on a 1-10 point Likert scale the reduction measured at 27% (6.8 to 5.92; 1 being the lowest possible ranking)
Visual Acuity Minor Very High See study
In persons with glaucoma, CDP-Choline ingestion appears to be somewhat protective of vision and has been noted to cause improvements in visual acuity
Intraocular Pressure - Very High See study
Despite the improvements seen in visual acuity and eye health with supplementation of CDP-Choline, intraocular pressure does not appear to be affected.
Weight - Very High See study
No significant effects of CDP-Choline on weight, despite the small appetite reducing effect

Studies Excluded from Consideration

  • Used intramuscular injections[1]


Disagree? Join the CDP-choline Discussion

Scientific Research

Table of Contents:

  1. 1 Sources and Structure
    1. 1.1 Sources
    2. 1.2 Structure and Properties
    3. 1.3 Biological Significance
  2. 2 Pharmacology
    1. 2.1 Absorption
    2. 2.2 Metabolism
    3. 2.3 Excretion
  3. 3 Cardiovascular Health
    1. 3.1 Blood Pressure
  4. 4 Neurology
    1. 4.1 Bioenergetics
    2. 4.2 Appetite
    3. 4.3 Attention
    4. 4.4 Pain and Analgesia
    5. 4.5 Neuroprotection and Injury
    6. 4.6 Stroke
    7. 4.7 Cholinergic Neurotransmission
    8. 4.8 Noradrenergic Interactions
    9. 4.9 Serotonergic Interactions
    10. 4.10 Dopaminergic Interactions
    11. 4.11 Addiction
    12. 4.12 Memory and Cognition
  5. 5 Interactions with Glucose Metabolism
    1. 5.1 Pancreatic Hormones
  6. 6 Interactions with Organ Systems
    1. 6.1 Eyes
  7. 7 Interactions with Hormones
    1. 7.1 Growth Hormone
    2. 7.2 Thyroid Hormones
    3. 7.3 Luteinizing Hormone
    4. 7.4 Corticosteroids
  8. 8 Nutrient-Nutrient Interactions
    1. 8.1 Choline
    2. 8.2 Uridine
    3. 8.3 Resveratrol

Don't Miss an Update!

Your e-mail is safe with us. We don’t share personal data.


1Sources and Structure

1.1. Sources

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.[2]

1.2. Structure and Properties

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.[3]

CDP-choline is said to be water soluble.[4]

1.3. Biological Significance

CDP-choline is a cofactor in Phosphatidylcholine (PC) synthesis via the Kennedy cycle (also known as the CDP-choline pathway, phosphatidylethanolamine also made via this pathway).[5][6][7]

In this pathway, choline kinase (CK) catalyzes Choline into phosphocholine consuming an ATP molecule in the process[8][9] and has a micrmolar affinity in doing so (thus, much cellular choline is readily converted into phosphocholine[7]), and although this is not the only possible way to create phosphocholine (sphingomyelin degradation also confers phosphocholine[10]) it is the most prominent one and the first committed step of PC synthesis via the Kennedy cycle.[7]

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.[11][12][13] Usually in cellular cultures, there is an abundance of phosphocholine and a lack of CDP-choline.[7]

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).[14][15] There is also an enzyme called choline–ethanolamine phosphotransferase (CEPT) which has dual specificity for CDP-choline and CDP-ethanolamine[16][17] (and one specific for CDP-ethanolamine[18]), 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.[19][20]

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)


2Pharmacology

2.1. Absorption

Studies assessing absorption of CDP-Choline note that it is near absolute, ranging from 97.55-100%.[4]

2.2. Metabolism

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[21][22][23] 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.[19] This is accredited to rapid conversion of cytidine into uridine in humans.[23]

CDP-choline increases serum concentrations of free choline at doses as low as 500mg which tends to occur 2-3 hours after administration[19][4] 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

2.3. Excretion

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.[4]


3Cardiovascular Health

3.1. Blood Pressure

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[24][25] colocalized with adrenergic receptors[26]) and is blocked by choline reuptake inhibitors.[27]

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[20][28]) has been noted to increase blood pressure and reduce heart rate when delivered either systemically[29][30] or intracerebrally;[31][32] the cardiac appears to be mediated via the cholinergic system[31][32] as well as the histaminergic system (as H1 receptor antagonists block the effects[30] whereas cholinergic antagonists do not[29]).

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.[33]

Limited oral supplementation studies in humans, but appears to have blood pressure reducing properties when there is not a hypotensive crisis


4Neurology

4.1. Bioenergetics

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.[34]

4.2. Appetite

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.[35]

May have minor appetite reducing properties in humans at higher doses (2,000mg daily), although the reason for this is currently unknown

4.3. Attention

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.[36] The two groups were for the most part equally effective, although 250mg may have been slightly more potent.[36]

At least one study has reported an improvement in attention with 250-500mg (250mg outperforming 500mg) with supplemental CDP-Choline

4.4. Pain and Analgesia

Choline itself has pain killing effects[37][38] which is abolished by either preventing choline uptake into the brain or by blocking nicotinic receptors (particularly the α7 subset)[39][40][41] which choline is an agonist of,[42] while muscarinic antagonists fail to abolish the effects[41][40] (despite the musarinic system being involved in pain[43]).

Activation of the nicotinic receptors is known to release opioid peptides (endogenous painkillers[44]) which has been demonstrated with Nicotine[45][46] and appears to apply to choline.[47]

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.[40] This analgesic effect is dose-dependent[47] and is inhibited by naloxone (opioid inverse agonist) and CGP-35348 (GABAB receptor antagonist),[47][41] 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).[47]

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)

4.5. Neuroprotection and Injury

It has been noted that CDP-Choline acts as a membranes stabilizer after strokes[48] and is known to have a variety of actions including preservation of ATP synthase activity,[49] acetylcholinesterase,[49] and both cardiolipin and sphingomyelin[50] while preventing the release of fatty acids from damaged neurons[51] and promoting glutathione activity[52] while reducing apoptosis.[53] 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).[54]

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[55][56][57][58][54] in a manner that is synergistic with growth factors[59] and SIRT1 activators.[60] 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.[61]

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.[62]

4.6. Stroke

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)[63] which has been noted elsewhere in another meta-analysis.[64]

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.[65]

4.7. Cholinergic Neurotransmission

Due to Choline being the substrate for production of acetylcholine, CDP-Choline is thought to increase acetylcholine synthesis secondary to its choline component[66] although Uridine is also implicated (as uridine in isolation has been noted to increase acetylcholine concentrations in aged rats[67]).

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.[61]

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).[68][69] 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.[70]

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

4.8. Noradrenergic Interactions

Choline (infusions) are known to increase serum concentrations of adrenaline and noradrenaline[71] which appears to extend to CDP-choline,[72] as choline itself acts upon nicotinic acetylcholine receptors to stimulate release of catecholamines.[71][72][73] 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).[74]

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).[75]

4.9. Serotonergic Interactions

Ingestion of 325mg/kg CDP-choline for seven days does not modify concentrations of the serotonin transporter in the rat brain.[75]

4.10. Dopaminergic Interactions

CDP-Choline appears to have dopaminergic activity as assessed by its efficacy in animal models of Parkinson's disease,[76] which is likely related to the Uridine component of CDP-choline, as the augmentation of potassium-evoked dopamine release seen with uridine[77] is also seen with CDP-Choline (250mg/kg oral intake causing a 59% increase in dopamine release),[78] 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%).[79] For studies assessing basal dopamine concentrations (concentrations of dopamine at rest without stimulation), there do not appear to be long term changes.[75][79][78]

A single injection of 900mg/kg has been reported to possess a suppressive effect, indicative of an antagonistic effect.[79] This is thought to be related to the increased dopamine release upon neuronal activation[78] as dopamine antagonists are known to increase dopamine synthesis[80] (agonists reduce synthesis[81]).

In studies where dopamine agonists are used, chronic injections (300mg/kg, but not 100mg/kg) are known to enhance apomorphine induced turning (42%).[79] This may be related to the dopamine transporter being upregulated by subchronic CDP-choline ingestion (cerebellum and frontal cortex)[75] which has been noted to occur in aged rats (11-18% with 100-500mg/kg CDP-Choline oral intake) over 7 months[70] 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.[70]

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+[82] and 6-hydroxydopamine[83] which may be related to its general anti-apoptotic effects.[53] 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

4.11. Addiction

It is generally believed that the mesolimbic and mesocortical dopaminergic systems[84] (as well as serotonergic[85]) 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[86] 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).[87] 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).[88]

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.[89]

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

4.12. Memory and Cognition

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[90] but elsewhere at 10-500mg/kg has been found to improve active and passive avoidance tasks following 10 days of administration,[91] 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)[92][93] and the two appear to be synergistic towards acute memory formation in otherwise healthy rodents.[92]

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[94][95] and humans[96] associated cholinergic[97] and membrane[98][99] 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,[100] 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[90] and 10mg/kg has been found to improve performance in active avoidance tasks in aged rats.[101]

In elderly humans without dementia, supplemnetation of 500-1,000mg CDP-choline is associated with improvements in memory recall[33] and verbal memory (1,000mg effective only in those with poor scores at baseline, 2,000mg effective in all subjects)[102] but not object recognition.[33]

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.[103] 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


5Interactions with Glucose Metabolism

5.1. Pancreatic Hormones

Both insulin[104] and glucagon[105] 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.[104]

Choline can increase concentrations of both pancreatic hormones, practical relevance of this information not known


6Interactions with Organ Systems

6.1. Eyes

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).[106]

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.[1] After 180 days washout, although the benefits were attenuated they were still significantly better than placebo[1] and this has been replicated elsewhere where 1000mg injections were similarly protective as 1600mg oral intake of CDP-choline.[107]

When assessing intraocular pressure, regardless of whether participants are selected based on having an intraocular pressure of less than 18mmHg[107] or greater than 21mmHg[1] 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


7Interactions with Hormones

7.1. Growth Hormone

Intravenous CDP-choline is able to augment clonidine-stimulated growth hormone release, which is blocked by preventing neural choline uptake.[108]

7.2. Thyroid Hormones

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.[108]

7.3. Luteinizing Hormone

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.[108]

7.4. Corticosteroids

CDP-Choline has been noted to induce release of ACTH from the adrenal glands secondary to acting upon nicotinic acetylcholine receptors.[108]


8Nutrient-Nutrient Interactions

8.1. Choline

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.[19]

8.2. Uridine

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).[23]

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.[19]

8.3. Resveratrol

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.[60]

Scientific Support & Reference Citations

References

  1. [No authors listed Citicoline. Monograph . Altern Med Rev. (2008)
  2. Bracken BK, et al Eight weeks of citicoline treatment does not perturb sleep/wake cycles in cocaine-dependent adults . Pharmacol Biochem Behav. (2011)
  3. Sarkar AK, et al A rapid LC-ESI-MS/MS method for the quantitation of choline, an active metabolite of citicoline: Application to in vivo pharmacokinetic and bioequivalence study in Indian healthy male volunteers . J Pharm Biomed Anal. (2012)
  4. Gibellini F, Smith TK The Kennedy pathway--De novo synthesis of phosphatidylethanolamine and phosphatidylcholine . IUBMB Life. (2010)
  5. Vance JE, Vance DE Phospholipid biosynthesis in mammalian cells . Biochem Cell Biol. (2004)
  6. Fagone P, Jackowski S Phosphatidylcholine and the CDP-choline cycle . Biochim Biophys Acta. (2013)
  7. Aoyama C, Liao H, Ishidate K Structure and function of choline kinase isoforms in mammalian cells . Prog Lipid Res. (2004)
  8. Wu G, Vance DE Choline kinase and its function . Biochem Cell Biol. (2010)
  9. Jansen SM, et al Biosynthesis of phosphatidylcholine from a phosphocholine precursor pool derived from the late endosomal/lysosomal degradation of sphingomyelin . J Biol Chem. (2001)
  10. Jackowski S, Fagone P CTP: Phosphocholine cytidylyltransferase: paving the way from gene to membrane . J Biol Chem. (2005)
  11. Cornell RB, Northwood IC Regulation of CTP:phosphocholine cytidylyltransferase by amphitropism and relocalization . Trends Biochem Sci. (2000)
  12. Kent C Regulatory enzymes of phosphatidylcholine biosynthesis: a personal perspective . Biochim Biophys Acta. (2005)
  13. Cornell RB Cholinephosphotransferase from mammalian sources . Methods Enzymol. (1992)
  14. The enzymatic formation of lecithin from cytidine diphosphate choline and D-1,2-diglyceride
  15. Henneberry AL, Wistow G, McMaster CR Cloning, genomic organization, and characterization of a human cholinephosphotransferase . J Biol Chem. (2000)
  16. Henneberry AL, McMaster CR Cloning and expression of a human choline/ethanolaminephosphotransferase: synthesis of phosphatidylcholine and phosphatidylethanolamine . Biochem J. (1999)
  17. Horibata Y, Hirabayashi Y Identification and characterization of human ethanolaminephosphotransferase1 . J Lipid Res. (2007)
  18. Wurtman RJ, et al Effect of oral CDP-choline on plasma choline and uridine levels in humans . Biochem Pharmacol. (2000)
  19. Lopez G-Coviella I, et al Metabolism of cytidine (5?)-diphosphocholine (cdp-choline) following oral and intravenous administration to the human and the rat . Neurochem Int. (1987)
  20. Galletti P, et al Biochemical rationale for the use of CDPcholine in traumatic brain injury: pharmacokinetics of the orally administered drug . J Neurol Sci. (1991)
  21. Weiss GB Metabolism and actions of CDP-choline as an endogenous compound and administered exogenously as citicoline . Life Sci. (1995)
  22. Cansev M Uridine and cytidine in the brain: their transport and utilization . Brain Res Rev. (2006)
  23. Vásquez JV, Pinardi G Vasomotor responses in the isolated perfused external and internal carotid vascular beds of the rat . Gen Pharmacol. (1992)
  24. Edvinsson L, et al Cholinergic mechanisms in pial vessels. Histochemistry, electron microscopy and pharmacology . Z Zellforsch Mikrosk Anat. (1972)
  25. Iwayama T, Furness JB, Burnstock G Dual adrenergic and cholinergic innervation of the cerebral arteries of the rat. An ultrastructural study . Circ Res. (1970)
  26. Pinardi G, et al Effects of CDP-choline on acetylcholine-induced relaxation of the perfused carotid vascular beds of the rat . Gen Pharmacol. (1994)
  27. López-Coviella I, et al Evidence that 5'-cytidinediphosphocholine can affect brain phospholipid composition by increasing choline and cytidine plasma levels . J Neurochem. (1995)
  28. Cansev M, et al Cardiovascular effects of CDP-choline and its metabolites: involvement of peripheral autonomic nervous system . Eur J Pharmacol. (2007)
  29. Jochem J, et al Involvement of the histaminergic system in cytidine 5'-diphosphocholine-induced reversal of critical haemorrhagic hypotension in rats . J Physiol Pharmacol. (2010)
  30. Savci V, et al Intravenously injected CDP-choline increases blood pressure and reverses hypotension in haemorrhagic shock: effect is mediated by central cholinergic activation . Eur J Pharmacol. (2003)
  31. Savci V, et al Cardiovascular effects of intracerebroventricularly injected CDP-choline in normotensive and hypotensive animals: the involvement of cholinergic system . Naunyn Schmiedebergs Arch Pharmacol. (2002)
  32. Alvarez XA, et al Citicoline improves memory performance in elderly subjects . Methods Find Exp Clin Pharmacol. (1997)
  33. Silveri MM, et al Citicoline enhances frontal lobe bioenergetics as measured by phosphorus magnetic resonance spectroscopy . NMR Biomed. (2008)
  34. Killgore WD, et al Citicoline affects appetite and cortico-limbic responses to images of high-calorie foods . Int J Eat Disord. (2010)
  35. Improved Attentional Performance Following Citicoline Administration in Healthy Adult Women
  36. Rowley TJ, et al Antinociceptive and anti-inflammatory effects of choline in a mouse model of postoperative pain . Br J Anaesth. (2010)
  37. Yaksh TL, Dirksen R, Harty GJ Antinociceptive effects of intrathecally injected cholinomimetic drugs in the rat and cat . Eur J Pharmacol. (1985)
  38. Gurun MS, et al The effect of peripherally administered CDP-choline in an acute inflammatory pain model: the role of alpha7 nicotinic acetylcholine receptor . Anesth Analg. (2009)
  39. Hamurtekin E, Gurun MS The antinociceptive effects of centrally administered CDP-choline on acute pain models in rats: the involvement of cholinergic system . Brain Res. (2006)
  40. Bagdas D, et al The antihyperalgesic effect of cytidine-5'-diphosphate-choline in neuropathic and inflammatory pain models . Behav Pharmacol. (2011)
  41. Alkondon M, et al Choline is a selective agonist of alpha7 nicotinic acetylcholine receptors in the rat brain neurons . Eur J Neurosci. (1997)
  42. Bartolini A, et al Role of muscarinic receptor subtypes in central antinociception . Br J Pharmacol. (1992)
  43. Houdi AA, et al Nicotine-induced alteration in Tyr-Gly-Gly and Met-enkephalin in discrete brain nuclei reflects altered enkephalin neuron activity . Peptides. (1991)
  44. Zarrindast MR, Pazouki M, Nassiri-Rad S Involvement of cholinergic and opioid receptor mechanisms in nicotine-induced antinociception . Pharmacol Toxicol. (1997)
  45. Zarrindast MR, Nami AB, Farzin D Nicotine potentiates morphine antinociception: a possible cholinergic mechanism . Eur Neuropsychopharmacol. (1996)
  46. Hamurtekin E, Bagdas D, Gurun MS Possible involvement of supraspinal opioid and GABA receptors in CDP-choline-induced antinociception in acute pain models in rats . Neurosci Lett. (2007)
  47. Adibhatla RM, Hatcher JF, Dempsey RJ Citicoline: neuroprotective mechanisms in cerebral ischemia . J Neurochem. (2002)
  48. Plataras C, Tsakiris S, Angelogianni P Effect of CDP-choline on brain acetylcholinesterase and Na(+), K(+)-ATPase in adult rats . Clin Biochem. (2000)
  49. Rao AM, Hatcher JF, Dempsey RJ Lipid alterations in transient forebrain ischemia: possible new mechanisms of CDP-choline neuroprotection . J Neurochem. (2000)
  50. Dorman RV, Dabrowiecki Z, Horrocks LA Effects of CDPcholine and CDPethanolamine on the alterations in rat brain lipid metabolism induced by global ischemia . J Neurochem. (1983)
  51. Adibhatla RM, Hatcher JF, Dempsey RJ Effects of citicoline on phospholipid and glutathione levels in transient cerebral ischemia . Stroke. (2001)
  52. Krupinski J, et al CDP-choline reduces pro-caspase and cleaved caspase-3 expression, nuclear DNA fragmentation, and specific PARP-cleaved products of caspase activation following middle cerebral artery occlusion in the rat . Neuropharmacology. (2002)
  53. Gutiérrez-Fernández M, et al CDP-choline treatment induces brain plasticity markers expression in experimental animal stroke . Neurochem Int. (2012)
  54. Sahin S, et al Effects of citicoline used alone and in combination with mild hypothermia on apoptosis induced by focal cerebral ischemia in rats . J Clin Neurosci. (2010)
  55. Andersen M, et al Effects of citicoline combined with thrombolytic therapy in a rat embolic stroke model . Stroke. (1999)
  56. Alonso de Leciñana M, et al Effect of combined therapy with thrombolysis and citicoline in a rat model of embolic stroke . J Neurol Sci. (2006)
  57. Schäbitz WR, et al The effects of prolonged treatment with citicoline in temporary experimental focal ischemia . J Neurol Sci. (1996)
  58. Schäbitz WR, et al Synergistic effects of a combination of low-dose basic fibroblast growth factor and citicoline after temporary experimental focal ischemia . Stroke. (1999)
  59. Hurtado O, et al Citicoline (CDP-choline) increases Sirtuin1 expression concomitant to neuroprotection in experimental stroke . J Neurochem. (2013)
  60. Dixon CE, Ma X, Marion DW Effects of CDP-choline treatment on neurobehavioral deficits after TBI and on hippocampal and neocortical acetylcholine release . J Neurotrauma. (1997)
  61. Zafonte RD, et al Effect of citicoline on functional and cognitive status among patients with traumatic brain injury: Citicoline Brain Injury Treatment Trial (COBRIT) . JAMA. (2012)
  62. Dávalos A, et al Oral citicoline in acute ischemic stroke: an individual patient data pooling analysis of clinical trials . Stroke. (2002)
  63. Saver JL Citicoline: update on a promising and widely available agent for neuroprotection and neurorepair . Rev Neurol Dis. (2008)
  64. Dávalos A, et al Citicoline in the treatment of acute ischaemic stroke: an international, randomised, multicentre, placebo-controlled study (ICTUS trial) . Lancet. (2012)
  65. Amenta F, Tayebati SK Pathways of acetylcholine synthesis, transport and release as targets for treatment of adult-onset cognitive dysfunction . Curr Med Chem. (2008)
  66. Wang L, Albrecht MA, Wurtman RJ Dietary supplementation with uridine-5'-monophosphate (UMP), a membrane phosphatide precursor, increases acetylcholine level and release in striatum of aged rat . Brain Res. (2007)
  67. Tayebati SK, et al Effect of choline-containing phospholipids on brain cholinergic transporters in the rat . J Neurol Sci. (2011)
  68. Tomassoni D, et al Effects of cholinergic enhancing drugs on cholinergic transporters in the brain and peripheral blood lymphocytes of spontaneously hypertensive rats . Curr Alzheimer Res. (2012)
  69. Giménez R, Raïch J, Aguilar J Changes in brain striatum dopamine and acetylcholine receptors induced by chronic CDP-choline treatment of aging mice . Br J Pharmacol. (1991)
  70. Ilcol YO, et al Intraperitoneal administration of choline increases serum glucose in rat: involvement of the sympathoadrenal system . Horm Metab Res. (2002)
  71. Ilcol YO, et al Intraperitoneal administration of CDP-choline and its cholinergic and pyrimidinergic metabolites induce hyperglycemia in rats: involvement of the sympathoadrenal system . Arch Physiol Biochem. (2007)
  72. Cansev M, et al Peripheral administration of CDP-choline, phosphocholine or choline increases plasma adrenaline and noradrenaline concentrations . Auton Autacoid Pharmacol. (2008)
  73. Saligaut C, et al Effects of hypoxia and cytidine (5') diphosphocholine on the concentrations of dopamine, norepinephrine and metabolites in rat hypothalamus and striatum . Arch Int Pharmacodyn Ther. (1987)
  74. Tayebati SK, et al Modulation of monoaminergic transporters by choline-containing phospholipids in rat brain . CNS Neurol Disord Drug Targets. (2013)
  75. Mechanism of action of CDP-choline in parkinsonism
  76. Wang L, et al Dietary uridine-5'-monophosphate supplementation increases potassium-evoked dopamine release and promotes neurite outgrowth in aged rats . J Mol Neurosci. (2005)
  77. Agut J, Ortiz JA, Wurtman RJ Cytidine (5')diphosphocholine modulates dopamine K(+)-evoked release in striatum measured by microdialysis . Ann N Y Acad Sci. (2000)
  78. Shibuya M, et al Effects of CDP-choline on striatal dopamine level and behavior in rats . Jpn J Pharmacol. (1981)
  79. Dusseau JW, Hutchins PM Stimulation of arteriolar number by salbutamol in spontaneously hypertensive rats . Am J Physiol. (1979)
  80. Effects of apomorphine on the in vivo release of dopamine and its metabolites, studied by brain dialysis
  81. Radad K, et al CDP-choline reduces dopaminergic cell loss induced by MPP(+) and glutamate in primary mesencephalic cell culture . Int J Neurosci. (2007)
  82. Barrachina M, et al Neuroprotective effect of citicoline in 6-hydroxydopamine-lesioned rats and in 6-hydroxydopamine-treated SH-SY5Y human neuroblastoma cells . J Neurol Sci. (2003)
  83. Pulvirenti L, Koob GF Dopamine receptor agonists, partial agonists and psychostimulant addiction . Trends Pharmacol Sci. (1994)
  84. Walsh SL, et al Fluoxetine alters the effects of intravenous cocaine in humans . J Clin Psychopharmacol. (1994)
  85. Renshaw PF, et al Short-term treatment with citicoline (CDP-choline) attenuates some measures of craving in cocaine-dependent subjects: a preliminary report . Psychopharmacology (Berl). (1999)
  86. Brown ES, Gorman AR, Hynan LS A randomized, placebo-controlled trial of citicoline add-on therapy in outpatients with bipolar disorder and cocaine dependence . J Clin Psychopharmacol. (2007)
  87. Licata SC, et al Effects of daily treatment with citicoline: a double-blind, placebo-controlled study in cocaine-dependent volunteers . J Addict Med. (2011)
  88. Lukas SE, et al Effects of short-term citicoline treatment on acute cocaine intoxication and cardiovascular effects . Psychopharmacology (Berl). (2001)
  89. Teather LA, Wurtman RJ Dietary cytidine (5')-diphosphocholine supplementation protects against development of memory deficits in aging rats . Prog Neuropsychopharmacol Biol Psychiatry. (2003)
  90. Petkov VD, et al Effect of CDP-choline on learning and memory processes in rodents . Methods Find Exp Clin Pharmacol. (1992)
  91. Mosharrof AH, Petkov VD Effects of citicholine and of the combination citicholine + piracetam on the memory (experiments on mice) . Acta Physiol Pharmacol Bulg. (1990)
  92. Petkov VD, Mosharrof AH, Petkov VV Comparative studies on the effects of the nootropic drugs adafenoxate, meclofenoxate and piracetam, and of citicholine on scopolamine-impaired memory, exploratory behavior and physical capabilities (experiments on rats and mice) . Acta Physiol Pharmacol Bulg. (1988)
  93. Gallagher M, Pelleymounter MA Spatial learning deficits in old rats: a model for memory decline in the aged . Neurobiol Aging. (1988)
  94. Rapp PR, Rosenberg RA, Gallagher M An evaluation of spatial information processing in aged rats . Behav Neurosci. (1987)
  95. Albert M Neuropsychological and neurophysiological changes in healthy adult humans across the age range . Neurobiol Aging. (1993)
  96. Rylett RJ, et al Acetylcholine synthesis and release following continuous intracerebral administration of NGF in adult and aged Fischer-344 rats . J Neurosci. (1993)
  97. Ando S, et al Turnover of synaptic membranes: age-related changes and modulation by dietary restriction . J Neurosci Res. (2002)
  98. Salvador GA, López FM, Giusto NM Age-related changes in central nervous system phosphatidylserine decarboxylase activity . J Neurosci Res. (2002)
  99. Teather LA, Wurtman RJ Chronic administration of UMP ameliorates the impairment of hippocampal-dependent memory in impoverished rats . J Nutr. (2006)
  100. Mosharrof AH, Petkov VD, Petkov VV Effects of meclofenoxate and citicholine on learning and memory in aged rats . Acta Physiol Pharmacol Bulg. (1987)
  101. Spiers PA, et al Citicoline improves verbal memory in aging . Arch Neurol. (1996)
  102. Takasaki K, et al Neuroprotective effects of citidine-5-diphosphocholine on impaired spatial memory in a rat model of cerebrovascular dementia . J Pharmacol Sci. (2011)
  103. Ilcol YO, et al Choline increases serum insulin in rat when injected intraperitoneally and augments basal and stimulated aceylcholine release from the rat minced pancreas in vitro . Eur J Biochem. (2003)
  104. Cansev M, et al Choline, CDP-choline or phosphocholine increases plasma glucagon in rats: involvement of the peripheral autonomic nervous system . Eur J Pharmacol. (2008)
  105. Rejdak R, et al Citicoline treatment increases retinal dopamine content in rabbits . Ophthalmic Res. (2002)
  106. Parisi V, et al Cytidine-5'-diphosphocholine (citicoline) improves retinal and cortical responses in patients with glaucoma . Ophthalmology. (1999)
  107. Parisi V, et al Evidence of the neuroprotective role of citicoline in glaucoma patients . Prog Brain Res. (2008)
  108. Cavun S, Savci V CDP-choline increases plasma ACTH and potentiates the stimulated release of GH, TSH and LH: the cholinergic involvement . Fundam Clin Pharmacol. (2004)