Should You Take Citicoline As A Nootropic?

Written by Andy Mobbs
featured image for article on citicoline, a seneca ingredient

Citicoline is gaining traction as a nootropic or natural focus enhancer. When taken as a supplement, citicoline has a number of benefits, including stimulating the production of phospholipids which are vital for energy production and brain health. But is there real science behind all the hype? Read on to find out if taking citicoline supplements is worth your money.

What is Citicoline?

Citicoline is probably most famous as a nootropic. It’s a mixture of choline and cytidine. When taken as a supplement, it’s quickly broken down into these 2 molecules in the gut. Choline and cytidine can then go through a number of biochemical changes in a cycle known as the ‘Kennedy Cycle’, and end up as a Phospholipid or as the neurotransmitter, Acetylcholine.

What does Citicoline do in the brain?

Although cytidine doesn’t easily pass the blood-brain barrier, it can be turned into uridine, which does cross into the brain and can easily be combined with choline in the brain to produce phosphatidylcholine (1).

kennedy pathway
The Kennedy Cycle

From here, the body can transform phosphatidylcholine into all the other main phospholipids that make up the membranes of all of our 20 trillion cells. The phospholipids also make up the membranes of all of our cell organelles. Cell organelles can be thought of as the organs of our cells and support their functioning, just like organs in our bodies. Cell organelles include structures like the Endoplasmic Reticulum, the Golgi apparatus, and the Mitochondria.

phosphatidylcholine
Phosphatidylcholine can be turned into the other major phospholipids that make up cell membranes, sphingomyelin, phosphatidylethanolamine and phosphatidylserine, as well as choline and acetylcholine.

Phosphatidylcholine and sphingomyelin make up the outer layer of the membranes, whereas phosphatidylserine and phosphatidylethanolamine make up the inner layer as shown in the image below. Cholesterol is also needed in all cell membranes to provide overall stability to the structure.

Diagram of a cell membrane showing all the main phospholipids
The diagram shows the basic structure of a cell membrane with phosphatidylcholine and sphingomyelin forming the outside layer and phosphatidylserine and phosphatidylethanolamine forming the inside layer, with both sides stabilized by cholesterol

The mitochondria are where energy is produced. Their ability to produce energy relies not just on them having a healthy outer membrane, but also a healthy inner membrane too. The inner membrane allows mitochondria to pump hydrogen ions through an enzyme called ATP synthase, which acts as a turbine. The whole process can be thought of a little like a hydroelectric dam.

The neurotransmitter acetylcholine is used throughout the peripheral and central nervous systems to transmit synapses or nerve impulses. Every time your brain sends a signal to a muscle to make it move, it uses acetylcholine to transmit the signal from the nerve to the muscle. Acetylcholine is also key in the brain to stimulate memory, focus, and learning.

What is Citicoline’s role in DNA, RNA, and antioxidant production?

Once broken down, citicoline can also be used for the production of RNA and DNA, as well as being converted into Betaine. Betaine is vital for the methylation cycle and gets transformed into s-adenosyl-methionine (SAMe), which transfers methyl groups all around the body. SAMe is also broken down into the amino acid cysteine, which contains the sulfur group that is vital for the production of glutathione, the body’s main antioxidant (2).

What’s The Science Behind Citicoline’s Effects?

Protecting your brain

When choline levels become low, the brain prioritizes acetylcholine production, and it does this by sacrificing the phospholipids in the brain. This means we can still move, which is the most vital thing for life, but if it goes on for too long this process can end up with neurons eventually dying. This is because the body uses choline in the phospholipids in cell membranes to produce acetylcholine. It’s actually a process that has been described as ‘autocannibalism’ (3).

However, citicoline can increase brain choline levels and stimulate acetylcholine synthesis, which can spare phospholipids and prevent the death of neurons (4-5).

Neuronal repair

When patients suffer strokes, an artery gets blocked and this stops the flow of blood to the brain; this is known as ischemia. If patients survive the initial stroke, unfortunately, the danger still hasn’t passed, because there can still be significant damage to the brain when the blood flow is restored. This is known as reperfusion injury.

There are a number of causes of reperfusion injury. For example, the mitochondrial membranes can be damaged, so when a full supply of blood is restored they can no longer produce energy efficiently. This means that too many free radicals are produced and can’t be properly controlled by the antioxidant defense system.

Also, there is the excess activity of a neurotransmitter called Glutamate that causes inflammation and increased immune response from specialized brain immune cells called Astrocytes, as well as an increase in Phospholipase 2 which is an enzyme that breaks down the phospholipids in cell membranes (6).

A study by Rao et al. published in the journal Stroke used a stroke model in gerbils. They found that citicoline was able to significantly increase brain phospholipid levels and reduce brain phospholipase activity. Citicoline was also specifically able to increase levels of Cardiolipin, a phospholipid critical to the inner membrane of mitochondria, that allows them to produce energy efficiently. Glutathione levels were increased as well (7).

Using Citicoline in human clinical trials (stroke patients)

A number of studies have tested these effects in patients suffering from strokes. For example, one study looked at 272 stroke patients who had suffered a moderate to severe stroke. The researchers gave half the patients 1000mg of citicoline a day and the other half a placebo and found that conscious awareness improved significantly in the citicoline group. After 2 weeks of the study, 54% of the patient’s given citicoline had seen an improvement, whereas only 29% in the placebo group had improved (8).

Another study was conducted by Citicoline Stroke Study Group on 259 stroke patients. The patients were split into 4 groups of 65 patients each and were treated with either 500mg, 1000mg, 2000mg of citicoline, or a placebo. All the patients received their citicoline or the placebo within 24 hours of suffering a stroke and their treatment was continued for 6 weeks. At the end of the 6 week period, the researchers found that the patients in the 500mg and 2000mg groups had twice the chance of recovering from their strokes as the patients that were given the placebo. They also found a higher level of dizziness in the 2000mg group so concluded that the best citicoline dosage from stroke patients was 500mg per day (9). The one caveat with this study is that there were was no difference between the 1000mg group and the placebo group, and the researchers couldn’t find a reason for this.

What are other examples of Citicoline benefits?

Benefit #1 – Cognitive Decline

A number of studies have shown that citicoline has the potential to improve the cognitive decline that seems almost inevitable as we age. For example, one study that used brain scans to judge results of a 6-week study in the USA found that the subjects who supplemented with citicoline had increased brain phospholipid levels and a 14% increase in brain ATP levels (10).

A further study on 95 subjects from 50-85 years old found that those who initially had poor functioning memories had improved memory on delayed recall memory tests. Delayed recall tests are often used to diagnose dementia. Subjects are given information to remember and then they take a break and after the break are asked to recall the information (11).

Benefit #2 – Dopamine Release

Citicoline was shown to stimulate tyrosine hydroxylase activity which leads to increased dopamine release most likely through stimulating acetylcholine synthesis. Dopamine is a neurotransmitter associated with attention and motivation (12).

Benefit #3 – Cognitive Function and ADHD

A 2015 study on healthy adolescent males used several different tests to judge cognitive function including the finger tap test which measures how quickly subjects can tap a button, and tests to measure attention, focus and impulsivity. Increased impulsivity is often associated with ADHD.

The researchers gave the participants either 250mg or 500mg of citicoline and then followed them for 28 days. At the end of the 28 day period they found that the subjects who had supplemented with citicoline scored significantly higher in the cognitive speed test (i.e finger tap), and the attention and focus tests. They also scored lower in the impulsivity test, indicating less impulsivity (13).

Benefit #4 – Neuronal Growth

Whilst the human studies with citicoline have so far focused on stroke patients, animal studies have looked at whether the breakdown components of citicoline, choline, cytidine, and uridine can promote growth of the neuronal dendrites and increase neuronal synapses. Dendrites are branch-like structures that grow from the ends of neurons that connect with other neurons through synapses.

Several studies have combined cytidine, uridine and choline with the omega 3 fatty acid DHA, and have found that together they increase brain synapses, dendritic spines, and membrane-rich phospholipids (14, 15, 16)

dendrite image

What’s the right Citicoline dosage? Any side effects?

There is currently no official Citicoline dosage. In the studies we quoted above, dosages varied from 250mg to 2000mg per day. Even at relatively higher doses, citicoline side effects seem to be a non-issue. Studies show it’s a non-toxic and well-tolerated compound (17).

Want to try this Citicoline, Uridine, and DHA stack?

If trying the combination of citicoline, DHA and Uridine sound interesting to you, we recommend trying our Seneca Nootropic which contains both uridine monophosphate (150mg per serving) and citicoline (250mg per serving) along with 16 other proven nootropics. Then combine Seneca with our Ultra Pure Omega 3, which contains 816mg of DHA per 3 capsules serving (along with 1224mg of EPA).

If you want to know more about nootropics, check out this article on “What Are Nootropics?”

References

(1) Mehmet Cansev, Uridine and cytidine in the brain: their transport and utilization, Brain Res Rev. 2006 Sep;52(2):389-97.

(2) Rao Muralikrishna Adibhatla, J. F. Hatcher and R. J. Dempsey, Citicoline: neuroprotective mechanisms in cerebral ischemia, Journal of Neurochemistry, 2002, 80, 12-23

(3) Klein J. Membrane breakdown in acute and chronic neurodegeneration: focus on choline-containing phospholipids. J. Neur.Tran. (2000) 107, 1027±1063.

(4) Kakihana M., Fukuda N., Suno M. and Nagaoka A. Effects of CDP-choline on neurologic defcits and cerebral glucose metabolism in a rat model of cerebral ischemia. (1988) Stroke 19, 217±222

(5) Adibhatla RM, Hatcher JF, Dempsey RJ. Citicoline: neuroprotective mechanisms in cerebral ischemia. J Neurochem 2002;80:12-23.

(6) Rao Muralikrishna Adibhatla,,J. F. Hatcher* and R. J. Dempsey, Citicoline: neuroprotective mechanisms in cerebral ischemia Rao Muralikrishna Adibhatla,J. F. Hatcher and R. J. Dempsey, Journal of Neurochemistry, 2002, 80, 12±23

(7) Rao Muralikrishna Adibhatla, J.F. Hatcher, and R.J. Dempsey, Effects of Citicoline on Phospholipid and Glutathione Levels in Transient Cerebral Ischemia, Stroke Vol. 32, No. 10.

(8) Tazaki Y, Sakai F, Otomo E, et al. Treatment of acute cerebral infarction with a choline precursor in a multicenter double-blind placebo-controlled study. Stroke 1988;19:211-216.

(9) Clark WM, Warach SJ, Pettigrew LC, et al. A randomized dose-response trial of citicoline in acute ischemic stroke patients. Citicoline Stroke Study Group. Neurology 1997;49:671-678.

(10) Silveri M.M, J Dikan, A J Ross, J E Jensen, T Kamiya, Y Kawada, P F Renshaw, D A Yurgelun-Todd, Citicoline enhances frontal lobe bioenergetics as measured by phosphorus magnetic resonance spectroscopy, NMR in Biomedicine 2008 Nov;21(10):1066-75.

(11) Paul A. Spiers, PhD; Diane Myers, MA; Gail S. Hochanadel, PhD; Harris R. Lieberman, PhD; Richard J. Wurtman, MD, Citicoline Improves Verbal Memory in Aging, Arch Neurol. 1996;53:441-448

(12) Agut J, Coviella IL, Wurtman RJ., Cytidine(5’)diphosphocholine enhances the ability of haloperidol to increase dopamine metabolites in the striatum of the rat and to diminish stereotyped behavior induced by apomorphine. Neuropharmacology 1984;23:1403-1406.

(13) Erin McGlade, Anna Monica Agoston, Jennifer DiMuzio, Miho Kizaki, Eri Nakazaki, Toshikazu Kamiya, and Deborah Yurgelun-Todd, The Effect of Citicoline Supplementation on Motor Speed and Attention in Adolescent Males, Journal of Attention Disorders 1–14

(14) Sarah Holguin, Joseph Martinez, Camille Chow, Richard Wurtman, The FASEB Journal, Dietary uridine enhances the improvement in learning and memory produced by administering DHA to gerbils, Volume22, Issue11, November 2008

(15) Toshimasa Sakamoto, Mehmet Cansev, Richard J Wurtman, Oral supplementation with docosahexaenoic acid and uridine-5′-monophosphate increases dendritic spine density in adult gerbil hippocampus, Brain Res. 2007 Nov 28;1182:50-9. doi: 10.1016/j.brainres.2007.08.089. Epub 2007 Sep 21.

(16) M. Canseva,b and R. J. Wurtmana, Chronic administration of docosahexaenoic acid or eicosapentaenoic acid, but not arachidonic acid, alone or in combination with uridine, increases brain phosphatide and synaptic protein levels in gerbils, Neuroscience. 2007 Aug 24; 148(2): 421–431.

(17) Grieb, Pawel. “Neuroprotective properties of citicoline: facts, doubts and unresolved issues.” CNS drugs vol. 28,3 (2014): 185-93. doi:10.1007/s40263-014-0144-8