The Ultimate Guide to CDP Choline - Lifetropics

CDP Choline (Citicoline), like Alpha GPC, is a popular Choline supplement - typically taken on a regular basis for its long-term brain development and memory benefits. In this ultimate guide, we're going to read studies, discover stacking ideas, and learn how much of it to take.

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Table of Contents:

1. Quick overview of CDP Choline (Citicoline)
2. What is CDP Choline
3. Studies on Brain Development
4. Studies on Memory and Learning
5. Studies on Motivation and Productivity
6. How to take CDP Choline (Step-by-Step)
7. Should you choose CDP Choline or Alpha GPC?
8. What stacks well with CDP Choline?

Quick overview of CDP Choline (Citicoline):

• Benefits: Memory
• Actions: Creates the learning neurotransmitter Acetylcholine and Builds and repairs neurons (brain-cells)
• Who is it good for? Iowa State University stated that 80% of people are "Choline deficient". For people under the recommended daily allowance, taking a Choline supplement can benefit their brain-connectivity. People taking Racetams should also take a Choline supplement.
• Quality of studies: Robust human and animal trials with positive results. Over 35,000 publications of Pubmed. The US government endorsed Choline as an "essential nutrient" in .
• Time to effect: Long-term beneficial effects on brain development and memory which might not be immediately noticed.
• Stacks with: Uridine Monophosphate and/or DHA (found in omega-3 capsules) for enhanced Acetylcholine release and brain-cell repair.
• Don't stack with: Other Choline supplements like Alpha GPC as extremely high levels of Acetylcholine can cause nausea.
• Recommended dose: 500mg CDP Choline per day. (More information on this below)

What is CDP Choline?

CDP Choline is a popular Choline supplement typically taken on a regular basis for its long-term brain development and memory benefits.

Once ingested, the CDP Choline metabolizes into the Choline B-Vitamin, which is integral to brain-cell connectivity.

Choline creates Phosphatidylcholine, which is used to create the wrappers of our brain-cell membranes. Choline also creates Acetylcholine, our brain's primary neurotransmitter. Neurotransmitters send information from brain-cell to brain-cell around our neural network.

"Choline is essential for neurodevelopment and brain function." (University of Oxford - 1)

Studies on Brain Development

CDP Choline contains Choline, which is a naturally occurring B-vitamin that provides the “raw materials” used in 2 nutrition-dependent brain-processes:

1. Choline is used in the creation of the Acetylcholine neurotransmitter, used for communication between neurons (brain cells). (University of North Carolina – 2)

2. Choline is used to build and repair the outer layer of neurons called their cell membranes.

3. Without regular Choline intake, these processes are slowed down. It is widely acknowledged that “Choline is essential for neurodevelopment and brain function.” (University of Oxford – 1)

4. CDP Choline also breaks down into Uridine in the blood-stream, which is a naturally occurring compound found in tomatoes and broccoli. Uridine has been studied to “amplify” Acetylcholine release and repair neurons (Massachusetts Institute of Technology – 3)

Studies on memory and learning

The Acetylcholine neurotransmitter produced by Choline plays a significant role in communicating information to the memory region of the brain (the hippocampus).

1. 1,371 healthy men and women saw improvements in verbal and visual memory. (Boston University School of Medicine – 4)

2. Improved immediate memory-recall among healthy men aged 18-39. (University of Milan – 5)

3. Higher concentrations of Choline are associated with greater executive function, global cognition, sensory motor speed and perceptual speed. (University of Oslo - 6)

4. A summary of 13 placebo-controlled clinical trials with 4,000 human volunteers found 3 months of Choline supplementation improved memory task performance by an average of 15.6%. (University of Perugia – 7)

Studies on Motivation & Productivity

Because Choline promotes overall brain connectivity and encourages the release of the motivation neurotransmitter dopamine, studies have also shown it to increase levels of focus.

1. Improved attention among healthy young women. (University of Utah

2. Improved mental energy by as much as 14%. (McClean Hospital & Harvard Medical School – 9)

3. Increases dopamine release, the motivation neurotransmitter. (Trabucchi M.)

4. Increases the sensitivity of the dopamine receptors. (University of Barcelona – 11

5. Brain scans showed that people with higher dopamine levels tend to be “go-getters” and work harder. People with lower dopamine levels tend to be “slackers”. (Vanderbilt University – 12)

CDP Choline also breaks down into Uridine, which has been studied to enhance focus and concentration by encouraging the release of the "motivation-to-work" neurotransmitter Dopamine.

6. Dietary uridine-5′-monophosphate supplementation increases potassium-evoked dopamine release and promotes neurite outgrowth in aged rats (Massachusetts Institute of Technology – 13)

7. Chronic uridine modulates the stimulant-induced release of dopamine (Rutgers University – 14)

8. “Uridine supplementation appears to enhance dopamine output from activated neurons without significantly affecting basal levels of dopamine.” (Massachusetts Institute of Technology – 15)

How to take CDP Choline (Step-by-Step)

For most people, taking 500mg of CDP Choline every day will provide them with the right amount of Choline for optimal brain-development and memory function.

The finer details and scientific reasoning behind this:

1. The Recommended daily Choline intake: The Linus Pauling Institute and the US institute of Medicine recommend that only a daily basis, men should get 550mg and women get 425mg of Choline

2. Calculate your current Choline intake: Roughly work out your daily Choline intake from your diet using these official guidelines. Most people get around 200mg - 300mg per day. PS: If you are way below 550mg/425mg – you’re in a position to make some great cognitive gains right here.

3. Understand how much Choline CDP Choline actually gives you: CDP Choline is 18.5% Choine by weight, which means that each 250mg CDP Choline tablet would give you 46 mg of Choline and 1 gram of CDP Choline powder would give you 185mg of Choline.

4. CDP Choline lasts in the body for 3 days: Taking CDP Choline requires a bit of forward thinking because it has a half-life of 3 days. If you took 250mg CDP Choline today, you would get 46mg of Choline. But if you continued to take once per day for a total of 3 days, your body would have an extra 138mg of Choline (46 x 3 = 138).

5. Take your CDP Choline: Take however much CDP Choline you need to get the recommended Choline intake after 3 days, and maintain that dose to keep it at that level. If you wanted an extra 300mg of Choline, you could take 500mg of CDP Choline per day. After 3 days, you would have an extra 276mg of Choline.

6. Find your optimal dosage: Some people have seen better results from exceeding the “official” recommended dose. According to Dr. Steven Zeisel, 10% of men would be better served by getting 850mg/day of Choline. All of our bodies break down Choline at different rates, so some people may need more.

7. Knowing your limit: If you produce too much Acetylcholine from too much Choline intake, you will get a headache or experience brain-fog. This won’t last long, but it’s a good indication of what your “limit” is.

Should you choose CDP Choline or Alpha GPC?

Alpha GPC is also a favourite for Choline supplementation. Essentially, it serves the same purpose as Alpha GPC, since it is also a Choline supplement. It’s best to choose either one or the other, because too much Acetylcholine can cause nausea and “brain fog”.

1. Alpha GPC contains more Choline versus CDP Choline: Alpha GPC is 40% Choline by weight, whereas CDP Choline is 18.5% Choline by weight. 250mg of Alpha GPC would provide 100mg of Choline. 250mg of CDP Cholline would provide 46mg of Choline. For strictly Choline supplementation, Alpha GPC tends to be the more popular choice.

2. Alpha GPC has a shorter half-life versus CDP Choline: Alpha GPC lasts 4-6 hours in the body, whereas CDP Choline lasts 60-70 hours (roughly 3 days). As a result, Choline accumulates in the system.

3. CDP Choline also breaks down into Uridine: This is the reason why Citicoline is only 18.5% Choline by weight. It’s essentially a 2-in-1 supplement. Uridine is a powerful nootropic on its own, with motivation and brain development benefits that synergise well with Choline. But…You could always just buy Uridine and stack it with Alpha GPC.

In the end, it’s usually down to personal preference and trying both to see which one works best for you. Alpha GPC and CDP Choline are both fantastic Choline supplements with numerous studies behind them.

Regardless of which one you decide to take on a regular basis, the research suggests that your brain-development, memory, and overall cognition will see great benefits.

A study which tested people with both Alpha GPC and CDP Choline found both to work well at improving cognition, but concluded that "Alpha-GPC possessed a statistical higher efficacy and an overall more satisfactory activity."

What stacks well with CDP Choline?

1. Uridine Monophosphate – Choline synergizes with Uridine to improve the production of neuron cell membranes and improve attention spans (Numico Research B.V - 17).

2. Caffeine – Caffeine "significantly" increases Acetylcholine production. It does this by improving our ability to absorb Choline. (Massachusetts Institute of Technology - 18)

3. DHA (found in Omega-3) – DHA works in synergy with Choline and Uridine to produce Phosphatidylcholine. MIT researchers found the trio of supplements to boost its production by by 45%. (Massachusetts Institute of Technology – 19)

References:

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).[4][5][6]

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In this pathway, choline kinase (CK) catalyzes choline into phosphocholine consuming an ATP molecule in the process[7][8] and has a micrmolar affinity in doing so (thus, much cellular choline is readily converted into phosphocholine[6]), and although this is not the only possible way to create phosphocholine (sphingomyelin degradation also confers phosphocholine[9]) it is the most prominent one and the first committed step of PC synthesis via the Kennedy cycle.[6]

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.[10][11][12] Usually in cellular cultures, there is an abundance of phosphocholine and a lack of CDP-choline.[6]

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).[13][14] There is also an enzyme called choline–ethanolamine phosphotransferase (CEPT) which has dual specificity for CDP-choline and CDP-ethanolamine[15][16] (and one specific for CDP-ethanolamine[17]), 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.[18][19]

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)

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[20][21][22] whereas in humans the two products are uridine and choline; supplemental CDP-choline (500-mg) in humans increases plasma uridine concentrations (101-136%) without detectable increases in cytidine.[18] This is accredited to rapid conversion of cytidine into uridine in humans.[22]

CDP-choline increases serum concentrations of free choline at doses as low as 500mg which tends to occur 2-3 hours after administration[18][3] and following ingestion of mg 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

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[23][24] colocalized with adrenergic receptors[25]) and is blocked by choline reuptake inhibitors.[26]

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[19][27]) has been noted to increase blood pressure and reduce heart rate when delivered either systemically[28][29] or intracerebrally;[30][31] the cardiac appears to be mediated via the cholinergic system[30][31] as well as the histaminergic system (as H1 receptor antagonists block the effects[29] whereas cholinergic antagonists do not[28]).

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.[32]

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

Choline itself has pain killing effects[36][37] which is abolished by either preventing choline uptake into the brain or by blocking nicotinic receptors (particularly the α7 subset)[38][39][40] which choline is an agonist of,[41] while muscarinic antagonists fail to abolish the effects[40][39] (despite the musarinic system being involved in pain[42]).

Activation of the nicotinic receptors is known to release opioid peptides (endogenous painkillers[43]) which has been demonstrated with nicotine[44][45] and appears to apply to choline.[46]

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.[39] This analgesic effect is dose-dependent[46] and is inhibited by naloxone (opioid inverse agonist) and CGP- (GABAB receptor antagonist),[46][40] 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).[46]

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[47] and is known to have a variety of actions including preservation of ATP synthase activity,[48] acetylcholinesterase,[48] and both cardiolipin and sphingomyelin[49] while preventing the release of fatty acids from damaged neurons[50] and promoting glutathione activity[51] while reducing apoptosis.[52] 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).[53]

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[54][55][56][57][53] in a manner that is synergistic with growth factors[58] and SIRT1 activators.[59] 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.[60]

In persons with Traumatic brain injury who (after admission to trauma centers) were placed on either placebo or mg 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.[61]

Due to choline being the substrate for production of acetylcholine, CDP-Choline is thought to increase acetylcholine synthesis secondary to its choline component[65] although uridine is also implicated (as uridine in isolation has been noted to increase acetylcholine concentrations in aged rats[66]).

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.[60]

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).[67][68] 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.[69]

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

CDP-Choline appears to have dopaminergic activity as assessed by its efficacy in animal models of Parkinson's disease,[75] which is likely related to the uridine component of CDP-choline, as the augmentation of potassium-evoked dopamine release seen with uridine[76] is also seen with CDP-Choline (250mg/kg oral intake causing a 59% increase in dopamine release),[77] 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%).[78] For studies assessing basal dopamine concentrations (concentrations of dopamine at rest without stimulation), there do not appear to be long term changes.[74][78][77]

A single injection of 900mg/kg has been reported to possess a suppressive effect, indicative of an antagonistic effect.[78] This is thought to be related to the increased dopamine release upon neuronal activation[77] as dopamine antagonists are known to increase dopamine synthesis[79] (agonists reduce synthesis[80]).

In studies where dopamine agonists are used, chronic injections (300mg/kg, but not 100mg/kg) are known to enhance apomorphine induced turning (42%).[78] This may be related to the dopamine transporter being upregulated by subchronic CDP-choline ingestion (cerebellum and frontal cortex)[74] which has been noted to occur in aged rats (11-18% with 100-500mg/kg CDP-Choline oral intake) over 7 months[69] 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.[69]

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+[81] and 6-hydroxydopamine[82] which may be related to its general anti-apoptotic effects.[52] 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[83] (as well as serotonergic[84]) 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[85] 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).[86] 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).[87]

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.[88]

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

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[93][94] and humans[95] associated cholinergic[96] and membrane[97][98] 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,[99] 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[89] and 10mg/kg has been found to improve performance in active avoidance tasks in aged rats.[100]

In elderly humans without dementia, supplemnetation of 500-1,000mg CDP-choline is associated with improvements in memory recall[32] and verbal memory (1,000mg effective only in those with poor scores at baseline, 2,000mg effective in all subjects)[101] but not object recognition.[32]

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.[102] 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