Citicoline is a brain nutrient that supports mental energy, focus, attention, and overall cognitive health.
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Citicoline and CDP-choline have the same molecular structure. CDP-choline refers to the endogenous form that is present in every cell of the human body. Citicoline refers to the form that is taken exogenously. Citicoline is available in 2 forms: (1) citicoline sodium which is a prescription medication used to treat neurological disorders in numerous countries and (2) citicoline free-base which is a dietary supplement in the United States.
The biomolecule Citicoline (CDP-choline or cytidine-5 ́-diphosphocholine) is an essential precursor for the neurotransmitter acetylcholine in the central nervous system and also for the synthesis of membrane phospholipids. Phospholipids create the structural integrity of all cell membranes and are essential to cellular growth and repair. In the brain, phospholipids are also essential for the synaptic function of communication among all brain cells. The primary phospholipid in the brain—phosphatidylcholine—makes up 30% of the gray matter.
Despite the importance of CDP-choline in phospholipid synthesis, however, the brain preferentially uses CDP-choline for production of acetylcholine. If availability of CDP-choline is low, phospholipids are stolen from neuronal membranes for acetylcholine production andphospholipid synthesis slows down, compromising membrane integrity and function. Thus it is important to maintain adequate levels of citicoline.
A human study conducted at Harvard Medical School evaluated brain changes after citicoline supplementation in healthy older adults. The researchers detected brain MRI changes indicating increased phosphatidylcholine synthesis after 6 weeks of supplementation with 500 mg of citicoline per day.
Supplementation with citicoline is thought to improve cognitive dysfunction and neurological recovery in various conditions including traumatic brain injuries, stroke, vascular dementia, Parkinson’s disease, and aging. However, the research to support citicoline benefits remains lacking and definitive recommendations for supplementing with citicoline cannot be made.
That being said, citicoline is well documented to be safe and there is growing evidence of its benefits for improving cognition and improving nerve function and possibly in addiction recovery.
Pharmacology and mechanism of action
Citicoline is manufactured in the body from choline. However, the National Health and Nutrition Examination Survey (NHANES) revealed that only 8% of US adults consume the recommended amount of choline on a daily basis. Low dietary choline intake may be related to deficit performance on neuropsychological tests. In one study of a population of non-demented individuals, high dietary choline intake was related to better cognitive performance but the effects persisted only in association with continued high intake. Research findings show that early higher choline intake at midlife may be neuroprotective. Further study is necessary to determine whether an adequate dietary intake of choline is related to improved cognitive function throughout the life span and to determine the role it plays regarding the preservation of brain health.
Even if dietary choline consumption is sufficient, there are additional benefits to consuming sources of CDP-choline (citicoline) itself. CDP-choline is required for the rate-limiting step of phospholipid synthesis, making choline insufficient to support cell membrane integrity on its own. While citicoline is synthesized from choline which is found in foods like liver, meat, beans, eggs, and cruciferous vegetables (broccoli, cauliflower), only liver, brain, and organ meats provide ap
preciable amounts of CDP-choline (citicoline).
Both choline and citicoline support phospholipid metabolism, acetylcholine production, and cell signaling. But citicoline is also a source of cytidine. It is the cytidine component that gives supplementing with citicoline an advantage over choline. The cytidine component of citicoline converts to uridine before crossing the blood-brain barrier. The uridine component is required for the rate-limiting step of phosphatidylcholine production and that uridine also promotes neuronal growth. Uridine is the molecule responsible for increasing brain levels of norepinephrine and dopamine, improving mitochondrial function, and boosting energy production in the brain.
Supplementation with citicoline offers a way to boost endogenous levels of CDP-choline in a way that cannot be achieved by other means. The oral bioavailability of citicoline exceeds 90%, its metabolites cross the blood- brain barrier, and citicoline is resynthesized in the brain after oral consumption.
In healthy adults citicoline has been shown that oral dose of citicoline is rapidly absorbed with greater than 90-percent bioavailability. Citicoline is metabolized by hydrolysis into choline and cytidine in the gut wall and these two products (choline and cytidine) are distributed throughout the body and utilized in various biosynthetic pathways. They also cross the blood-brain barrier to re-synthesize into citicoline in the brain.
Dosing of Citicoline
It is estimated that the daily dietary allowance of choline is 550 mg/day for men and 425 mg/day for women.
Oral, intravenous and intramuscular doses for citicoline typically range from 500-2,000 mg/daily. Most clinical trials evaluating citicoline —particularly those involving healthy adults and teens—have utilized dosages of 250 mg or 500 mg per day. Both of these dosages have produced beneficial effects.
Dosages as high as 2,000 mg per day have shown benefit in patients with addictive disorders, and dosages of 2,000-4,000 mg per day for 6-12 weeks produced more significant improvements than lower dosages in patients recovering from a stroke. Researchers who conducted the Italian VITA and IDEALE studies, propose that citicoline administration of at least 6 months is required to observe its greatest neuroprotective effects.
The safety profile and tolerance of citicoline is excellent and no serious adverse events have been reported in clinical trials of citicoline at dosages ranging from 250 mg to 4,000 mg per day. Side effects are mild (never severe) and rare, mainly consisting of gastrointestinal discomfort, irritability, uneasiness and restlessness. Citicoline has also undergone several toxicological studies and has been proven safe.
Therapeutic Targets of Citicholine
Citicoline affects acetylcholine, dopamine, and glutamate neurotransmitter systems; serves as an intermediate in phospholipid metabolism; and enhances the integrity of nerve membranes. Interest has grown in citicoline as a treatment for addiction since it may have beneficial effects on craving, withdrawal symptoms, and cognitive functioning, as well as the ability to attenuate the neurotoxic effects of drugs of abuse.
One mechanism proposed for citicoline’s benefit for addiction is that it increases dopamine levels in the corpus striatum by enhancing tyrosine hydroxylase activity and inhibiting dopamine reuptake. This indicates citicoline’s potential enhancement of the condition of Reward Deficiency Syndrome, the underlying basis of addiction associated with depletion of dopamine in the reward centers of the brain.
Most addiction research has evaluated citicoline for cocaine and methamphetamine use although it is suggested that citicoline may also hold promise for other addictions including alcohol, cannabis dependence and binge eating. Although not well studied in opioid addiction, the benefit of citicoline is also suggested. Citicoline appears to decrease craving and is associated with a reduction in cocaine use, especially in patients with both bipolar disorder and cocaine addiction.
Learning and Memory
Experimental studies in both animals and humans have suggested that citicoline has ability to promote learning ability and memory. In a double blind, crossover trial, it was showed that citicoline improved the ability to recall words and objects.
A double-blind, placebo-controlled trial published in 2012 evaluated the effects of citicoline on attention in 60 healthy women (aged 40 to 60 years) who supplemented with 500 mg of citicoline, 250 mg of citicoline, or placebo for 28 days. Upon testing at the completion of the study, participants taking either the 250 or 500 mg dose of citicoline demonstrated significantly fewer commission errors (doing something wrong) than those taking placebo. The authors also concluded that both dosages of citicoline were equally effective at improving attentional performance in healthy adult women.
A double-blind, placebo-controlled trial, published in the Journal of the American Medical Association, demonstrated that citicoline supplementation improved verbal memory in healthy older adults who had “relatively inefficient memories.” The study initially compared 1,000 mg of citicoline per day with placebo in 95 healthy adults (aged 50 to 85 years) without memory problems, dementia, or other neurological disorders. The initial study found that citicoline improved delayed recall memory, but only in those who had relatively inefficient memories. That subgroup of 32 participants was then trialed with a dose of 2,000 mg of citicoline per day compared to placebo. In this subset of adults with relatively inefficient memories, citicoline improved immediate and delayed logical memory.
The causes of memory impairment in the elderly may also include decreased neurotransmitter formation, inadequate circulation (stroke and vascular dementia), Parkinson’s disease or Alzheimer’s disease.
A well-publicized European clinical trial involving 2,298 patients (the ICTUS trial), published in the Lancet in 2012, showed that citicoline did not affect global outcomes following stroke. However, patients received citicoline or placebo for a total of only 6 weeks post-stroke and some authors have argued that the duration of the trial was too short to detect positive results.
In contrast to the ICTUS trial, another study published in 2012, the VITA study, did show a benefit of citicoline in post-stroke patients. The VITA study evaluated 197 patients with moderate-to-severe neuro- logical deficits resulting from stroke. In this study, an intravenous 2 gram dose of citicoline for 5-10 days was effective at improving functional independence, reducing the burden of care, and improving temporal orientation, attention, and executive functions for up to 2 months.
A meta-analysis of 12 clinical trials published in 2017 concluded that citicoline significantly improves functional outcomes after stroke or traumatic brain injury (TBI).
Citicoline has neuroprotective and neuronal membrane-stabilizing effects and because of these properties it is expected that citicoline may be beneficial for individuals with Parkinson’s disease. In addition, citicoline has an ability to increase dopamine synthesis so may allow for the reduction of levodopa dosage. In the results from one study it was shown that citicoline improved speech, gait, posture, tremor, agility, and slowness of movements in Parkinson’s disease.
Citicoline supplementation has been found to improve blood flow to the brain in elderly individuals with senile dementia and improve mental function in patients with Alzheimer’s disease (particularly in early-onset Alzheimer’s patients). This benefit may also be due citicoline’s cholinergic effects and influence on cytokine production. It is also proposed that citicoline reduces excessive histamine that has been implicated in the cause of dementia associated with Alzheimer’s disease.
Traumatic brain injury
Citicoline’s neuroprotective benefits have been shown to be an effective with traumatic brain injury, improving motor, cognitive, and mental symptoms. Citicoline has also been shown to reduce post-concussion symptoms including improvements in recognition memory, and decreased incidence of headaches, dizziness, and tinnitus.
A report published in 2010 showed that citicoline may reduce appetite in healthy adults. Using functional MRIs to detect activation of certain areas of the brain in response to food stimuli, it was shown that 2,000 mg per day of citicoline altered brain activity and decreased appetite in healthy adults. This is preliminary and further research may show that citicoline could play a role in appetite control or eating disorders.
Several potential neuroprotective mechanisms of citicoline have been described including reinforcement of the intracellular glutathione antioxidative system, stabilization of cell membranes, restoration of Na+/K+- ATPase activity and prevention of glutamate mediated neurotoxicity. However, the mechanisms below account for some of the most significant proposed mechanisms for citicoline’s benefits.
Citicoline is the precursor to acetylcholine, a neurotransmitter, and also the precursor to sphingomyelin and phosphatidylcholine—structural components of cell membranes. The neurotransmitter acetylcholine is also intimately connected with nerve networks associated with memory. Cognitive impairments that precede the onset of Alzheimer’s disease have been related to alterations in brain neurotransmission systems, mainly acetylcholine deficits. The causes of the nerve structural changes, which lead to cognitive deterioration and are associated with this disease, are unknown. It has been proposed that citicoline may reverse these age-dependent changes in brain cells.
Mitochondrial Function and Brain Energy
The brain consumes approximately 20% of the entire body’s energy when at rest, which places a high demand on cellular mitochondria, the energy producers in all cells. Citicoline improves mitochondrial function via numerous mechanisms.
First, citicoline maintains healthy levels of the phospholipid cardiolipin in mitochondrial membranes which is essential for mitochondrial electron transport but thought to decline with age. Second, citicoline helps to restore mitochondrial ATPase activity which facilitates energy production. Third, citicoline decreases oxidative stress.
A 2008 study at Harvard Medical School demonstrated that 6 weeks of supplementation with 500 mg citicoline per day produced a 14% increase in ATP in the frontal lobe of the brain and the area of the brain most activated by citicoline was the anterior cingulate cortex (ACC), which is involved in cognitive functions like focus and attention.
When oxidized, choline forms the methyl donor betaine for the conversion of homocysteine to methionine. High homocysteine concentrations have been shown to be related to both cognitive impairment and an increased risk of Alzheimer’s disease.
Animal studies suggest that citicoline may increase density of the dopamine D2 receptors and acetylcholine receptors in areas of the brain associated with Reward Deficiency Syndrome (RDS) and addiction. This collection of proposed mechanisms for the actions of citocoline suggest potential benefits for the management of addiction and other manifestations of RDS.
Therapeutic nutrients often work in synergy with other nutrients in which the benefits of multiple nuitrients are superior to the sum of the individual nutrient benefits. Because citicoline offers neuroprotection via numerous mechanisms, one should consider the use of additional nutrients to complement citicoline and support neurotransmission, combat oxidative stress and/or support mitochondrial function. While most studies have evaluated citicoline as an isolated therapy, researchers in 2013 demonstrated that citicoline works synergistically with resveratrol, a NRF2 activator and antioxidant. Other supplements that offer potential synergy with citicoline include palmitoylethanolamide (PEA), honokiol, Acetyl-L-carnitine (ALC), Alpha-Lipoic Acid, Bacopa, curcumin and other NRF2 activators, and other supplements supportive of mitochondrial function.
Because citicoline has been shown to be quite safe and lacking significant side effects, there has been a growing interest for neuroprotection and neuronal repair with citicoline. Results of many studies seems to show benefits of citicoline on several cognitive functions however there is a need for further studies to confirm citicolins effectiveness for neuroprotection and nerve repair.
Citicoline – Overviews
- Citicoline Affects Appetite and Cortico-Limbic Responses to Images of High Calorie Foods – 2010
- Neuroprotective properties of citicoline – facts, doubts and unresolved issues – 2014
- An overview of clinical and therapeutic implications of citicoline – 2014
- Cognizin Citicoline—The Ultimate Brain Nutrient | Brain Health | Articles | Magazine
- Citicoline – The Unique Benefits 2018
- Enhancing Cognition with Citicoline – 2018
Citicoline – Addiction
- Citicoline in Addictive Disorders – A Review of the Literature – 2014
- Citicoline Treatment Improves Measures of Impulsivity and Task Performance in Chronic Marijuana Smokers – 2015
- Cholinergic modulation of mesolimbic dopamine function and reward. – 2011
- The role of acetylcholine in cocaine addiction – 2008
- A randomized, double-blind, placebo-controlled trial of citicoline for bipolar and unipolar depression and methamphetamine dependence. – PubMed – NCBI
- Neurochemical alterations in methamphetamine-dependent patients treated with cytidine-5′-diphosphate choline – 2010
- Short-term treatment with citicoline (CDP-choline) attenuates some measures of craving in cocaine-dependent subjects: a preliminary report. – PubMed – NCBI
- Effects of daily treatment with citicoline – A double-blind, placebo-controlled study in cocaine-dependent volunteers – 2011
- Effects of short-term citicoline treatment on acute cocaine intoxication and cardiovascular effects. – PubMed – NCBI
- Changes in brain striatum dopamine and acetylcholine receptors induced by chronic CDP-choline treatment of aging mice. – 1991
Citicoline – Dietary
- Citicoline – A Food That May Improve Memory -2015
- The relation of dietary choline to cognitive performance and white-matter hyperintensity – 2011
- Nutritional Cognitive Neuroscience – Innovations for Healthy Brain Aging – 2016
Citicoline – Memory
- Citicoline – A Food That May Improve Memory -2015
- Improvements in Concentration, Working Memory, and Sustained Attention Following Consumption of a Natural Citicoline-Caffeine Beverage – 2014
- Citicoline Improves Memory Performance in Elderly Subjects
- Citicoline Improves Verbal Memory in Aging
Citicoline – Cognitive Dysfunction & Traumatic Brain Injury
- Citicoline (Cognizin) in the treatment of cognitive impairment – 2006
- The role of citicoline in cognitive impairment – pharmacological characteristics, possible advantages, and doubts for an old drug with new perspectives – 2015
- Therapeutic Applications of Citicoline for Stroke and Cognitive Dysfunction in the Elderly – A Review of the Literature – 2004
- Neuroprotective Properties of Citicoline – Facts, Doubts and Unresolved Issues – 2014
- The Effects of Citicoline on Acute Ischemic Stroke – A Review – 2014
- CITICOLINE EFFICIENCY ON COGNITIVE FUNCTION – A SYSTEMATIC REVIEW – 2015
- Long-term citicoline (cytidine diphosphate choline) use in patients with vascular dementia: neuroimaging and neuropsychological outcomes. – PubMed – NCBI
- Is aura around citicoline fading? A systemic review – 2017
- Citicoline for traumatic brain injury – a systematic review & meta-analysis – 2017
- Nanoparticle-based therapeutics for brain injury – 2018
- Citicoline in severe traumatic brain injury: indications for improved outcome : A retrospective matched pair analysis from 14 Austrian trauma centers. – PubMed – NCBI – 2018
- Effect of citicoline on functional and cognitive status among patients with traumatic brain injury: Citicoline Brain Injury Treatment Trial (COBRIT). – PubMed – NCBI – 2012
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entional and complementary and alternative medical (CAM) treatments, he may encourage or provide advice about the use of supplements. However, the specifics of choice of supplement, dosing and duration of treatment should be individualized through discussion with Dr. Ehlenberger. The following information and reference articles are presented to provide the reader with some of the latest research to facilitate evidence-based, informed decisions regarding the use of conventional as well as CAM treatments.
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