Supplements

Citicoline: A Potential Aid for Mild Cognitive Impairment

by Ari Magill, MD

Citicoline, naturally produced by the body as CDP-choline (cytidine-5′-diphosphate choline), serves as a precursor for phospholipids and acetylcholine, an important brain chemical messenger that plays a key role in memory consolidation. Phospholipids are the building blocks of the plasma cell membrane, the barrier that defines the border of the cell and allows cells to regulate what goes in or out.

Given its important structural and signaling roles, citicoline has been studied for its therapeutic potential following stroke and in improving activity in the aging brain and in brain-disease states, such as dementia, or cognitive impairment due to vascular disease, Alzheimer’s disease, and Parkinson’s disease.1 Overall, the results are positive, although published studies have been small.

The Takeaway:

Citicoline may help mild cognitive impairment because of its important structural and signaling roles.

Animal Studies

Petkov et al examined the impact of citicoline on the learning and memory performance of rodents.2 Memory tests included avoidance training using punishment reinforcement as well as food reward reinforcement and water maze training. It was compared to other agents believed to enhance memory, including piracetam and meclofenoxate.

Citicoline was administered both by mouth and via injection into the abdomen at a dose of 10 mg to 500 mg per kg of body weight. The investigators started training the animals one hour after the substances were given. Repeat testing was performed at 3 hours, 24 hours, 7 days, or 10 days after training with positive results. Dosage route did not impact the beneficial effect, which was roughly equivalent to that of piracetam and meclofenoxate.

Bruhwyler et al studied citicoline on learning and memory retrieval in dogs by testing the ability of ordinary dogs to learn a detailed reward-based schedule.3 It not only promoted learning and memory formation but also improved the memory retrieval process.

Possible Mechanisms of Action

Alvararez et al examined how the substance facilitates learning and memory.4 They induced neuronal injury to experimental rats by inserting beta amyloid protein into their right hippocampus,a the memory center of the brain, and by occluding one of their carotid arteries, which are the large arteries in the neck that supply blood to most of the front portion of the brain.

Abdominal injection of citicoline reduced the number of hippocampal neuronsb going through apoptosis, the process of programmed cell death that cells carry out when placed in stressed conditions for the benefit of overall organism survival. It also improved scores in a dose-dependent way in an avoidance learning task following experimentally induced neuronal injury.

Human Studies

Spiers et al investigated the effects of citicoline on verbal memory performance, using a story passage recall test, in older volunteers, 47 women and 48 men between the ages of 50 and 85, who were screened for dementia, memory disorders, and other neurological conditions.5 Subjects were given either 1 g per day of citicoline or placebo for three months, and found it only enhanced verbal memory in a subset of subjects who performed worse on the recall test.

Then, using a crossover design, the investigators studied the participants who performed less well. They were randomly assigned to the treatment or placebo arm and given 2 g per day of the substance or placebo for 60 days. Subjects were then switched to the other study arm and received the alternate management for another 60 days. Citicoline at the 2 g per day dosage facilitated verbal recall, both immediate and delayed.

Alvarez et al examined the effects of citicoline on memory skills in non-demented elderly subjects with cognitive problems using different dosages: 1 g per day, 500 mg per day, and 300 mg per day,c compared to placebo, for four weeks.6 Verbal and both delayed and immediate object recall were better in the citicoline groups. All dosages of citicoline resulted in similar benefit, suggesting that a 300 mg dose can be just as effective as a 1 g dose.

Citicoline and Alzheimer's Disease

Citicoline has also been investigated as a therapeutic agent for treatment of patients with established Alzheimer’s disease (AD). Caamaño et al evaluated the impact of 1 g per day on cognition in 20 AD patients between the ages of 57 and 78, as measured by the mini-mental state examination (MMSE), a common bedside screening test to assess cognition.7 They also tracked cerebrovascular blood flow using an ultrasound that images the direction and speed of blood flow.

After a month, they found significantly higher MMSE scores for the subset of patients with early-onset AD (EOAD) and MMSE orientation had significantly improved for both groups. Blood flow to each middle cerebral artery, the major branch of the carotid within the skull that supplies blood to most of the front and sides of the brain, was also significantly enhanced.

Alvarez et al examined citicoline in AD patients not only with a cognitive screening test, the ADAS,d and cerebral blood flow assessment but also by evaluating the electrical activity of the brain using an electroencephalogram (EEG).8 Thirty patients with mild-to- moderate stages of AD who were positive for the APOE4 allelee were enrolled. Investigators found improved ADAS scores. Benefit was greater in those with mild, compared to moderate, AD. It also promoted better blood flow and enhanced electrical activity within the brain.

Conclusion

Overall, citicoline has some evidence of benefit in combatting cognitive decline. Side effects are rare; the most common are gastrointestinal and may include diarrhea and stomach pain.9 Amazon sells a bottle of 60 300-mg capsules of CDP choline for about $20.

Notes

a Two important areas within the hippocampus were evaluated—the CA1 area (CA = cornu ammonis, which stands for “ram’s horn,” the general shape of the area) and the dentate gyrus (dentate being a reference to its tooth-shaped appearance).

b Neurons are the defining cells of the nervous system.

c Nimodipine (a blood pressure medicine that falls under the category of calcium channel blocker) was added to the 300 mg dose.

d Alzheimer’s Disease Assessment Scale

e The APOE4 allele is a genetic isoform that increases the risk of developing AD more than any other known genetic determinant. APOE4 stands for apolipoprotein E4. Apolipoproteins are a class of proteins that shuttle cholesterol and other fats in the circulation. The exact role of APOE in Alzheimer’s disease pathology has not been clearly elucidated.

References

  1. Gareri P, et al. The role of citicoline in cognitive impairment: pharmacological characteristics, possible advantages, and doubts for an old drug with new perspectives. Clin Interv Aging. 2015;10:1421.-1429. doi: 10.2147/CIA.S87886.
  2. Petkov VD, et al. Effect of CDP-choline on learning and memory processes in rodents. Methods Find Exp Clin Pharmacol. 1992;14(8):593-605.
  3. Bruhwyler J, et al. Facilitatory effects of chronically administered citicoline on learning and memory processes in the dog. Prog Neuro-psychopharmacol Biol Psychiatry. 1998;22(1):115-128. doi: 10.1016/s0278-5846(97)00183-8.
  4. Alvarez XA, et al. Citicoline protects hippocampal neurons against apoptosis induced by brain beta-amyloid deposits plus cerebral hypoperfusion in rats. Methods Find Exp Clin Pharmacol. 1999;21(8): 535-540. doi: 10.1358/mf.1999.21.8.794835.
  5. Spiers PA, et al. Citicoline improves verbal memory in aging. Arch Neurol. 1996;53(5):441-448. doi: 10.1001/archneur.1996.00550050071026.
  6. Alvarez XA, et al. Citicoline improves memory performance in elderly subjects. Methods Find Exp Clin Pharmacol. 1997;19(3):201-210.
  7. Caamano J, et al. Effects of CDP-choline on cognition and cerebral hemodynamics in patients with Alzheimer’s disease. Methods Find Exp Clin Pharmacol. 1994;16(3):211-218.
  8. Alvarez XA, et al. Double-blind placebo-controlled study with citicoline in APOE genotyped Alzheimer’s disease patients. Effects on cognitive performance, brain bioelectrical activity and cerebral perfusion. Methods Find Exp Clin Pharmacol. 1999;21(9):633.
  9. Conant R and Schauss AG. Therapeutic applications of citicoline for stroke and cognitive dysfunction in the elderly: a review of the literature. Altern Med Rev. 2004;9(1):17-31.

About the Author

Dr. Ari Magill is a holistic neurologist and medical consultant based in Mesa, AZ. He received medical school training at University of Texas Southwestern in Dallas and residency training at the University of Arizona in Tucson. He is passionate about finding innovative treatments for cognitive impairment, emphasizing lifestyle change and natural supplements.