By Alexander G. Schauss, PhD, FACN
CDP Choline (cytidine-5′-diphosphocholine, or citicoline) is a unique form of the essential nutrient choline that helps regulate bioelectrical activities in the brain. Over the last thirty years, CDP Choline has been studied in numerous animal and human clinical trials for its potential to enhance brain and cognitive function in a variety of clinical situations including memory loss, dementia, stroke, and head trauma. CDP Choline has achieved promising results in older individuals with inefficient memory, cognitive deficits, and early-stage Alzheimer’s. Therefore, it is worthwhile to discuss the many facets of CDP Choline’s role in cognition.
Aging and Memory
Difficulties with attention, learning, and recall are considered typical for most people in middle age and older. Starting around age fifty, we tend to experience brain changes that directly affect memory and cognitive function. It is now known that as we age there are decreases in the number of synapses between neurons and in the number and functionality of receptors (where chemical messengers are received on neurons). It is also known that, with aging, the availability of certain brain neurotransmitters is diminished, and that proper functioning of the bundles of neuronal fibers that transmit messages (white matter pathways) is impaired. All of these age-associated brain changes hinder communication between neurons and ultimately decrease our ability to pay attention, learn, and remember.
However, even in the face of these brain changes, successful aging without disruptive cognitive decline is definitely possible. Even centenarians may not exhibit memory problems despite the fact that their brains might show the hallmark features of degenerative brain disease, or Alzheimer’s, on autopsy. Genetics, environment, and lifestyle all play roles in determining why some people in their nineties are nearly as sharp as they have always been while others begin to deteriorate in their fifties.
The Role of CDP Choline
Studies have shown that supplementation with CDP Choline may be one way to modify this disruptive process of age-related cognitive decline. Produced naturally inside the body, CDP Choline is a compound used to synthesize phospholipids, the essential building blocks of all biological membrane systems. Phosphatidylcholine, one of the primary phospholipids synthesized by CDP Choline, is an integral component of cellular membranes that adds strength and fluidity to cells. Phosphatidylcholine in brain cell membranes decreases with age. Studies indicate that CDP Choline supplementation may increase phosphatidylcholine synthesis and might reverse this age-related loss.1
CDP Choline (citicoline) is synthesized and marketed in the US as a dietary supplement, and as a drug in Japan. In Europe, citicoline is approved and sold as a drug. It is frequently prescribed for cognitive impairment in several European countries, as well as for stroke and head trauma recovery, and other neurological disorders.
In addition to its role in producing phosphatidylcholine, citicoline may also serve as a choline donor for the synthesis of acetylcholine, a neurotransmitter that plays an important role in both learning and memory. Animal studies have indicated that it may increase dopamine and enhance the amount of bioactive reduced glutathione levels as well. Glutathione is a potent antioxidant, especially in the brain, while dopamine, a neurotransmitter, is essential for the healthy functioning of the central nervous system; it has effects on emotion, perception and movement. When taken as a supplement (or drug), citicoline appears to help preserve the structure and function of neuron membranes and possibly decrease the progression of neuron cell damage that occurs, for example, after a stroke.
Several clinical studies demonstrate that citicoline can be used successfully in some patients with stroke, brain trauma, chronic cerebrovascular disorders, and vascular dementia, as well as for some elderly non-demented individuals with memory deficits.
CDP Choline and Cognition
Among the aging baby boom population, memory problems are some of the most feared age-related health issues. Experts continue to disagree on what, if any, relationship exists between age-related memory loss (which is not considered a disorder), and the two memory disorders, mild cognitive impairment and dementia. As it now stands, the official term for the normal memory problems associated with aging is “age-associated memory impairment.”
Further studies looking at the full benefits and efficacy of CDP Choline in improving memory loss in “healthy” older adults are still needed. The few studies that have looked specifically at this subset, however, have demonstrated improved memory performance among elderly adults taking CDP Choline.
Prevention of memory loss has become a growing area of research. Because of CDP Choline’s intermediary role in phosphatidylcholine synthesis, early researchers theorized that it could restore memory function by repairing age-related changes within the brain neuronal membrane. One of the earliest studies evaluating CDP Choline’s potential as a treatment for age-related memory loss was a double-blind, placebo-controlled, randomized trial involving 84 patients, mean age 72, with mild to moderate memory deficits but no other cognitive dysfunctions. Memory loss was assessed using the Mini Mental State Examination (MMSE). After being administered 1,000 mg CDP Choline daily for six weeks, subjects were assessed with the Randt Memory Test for changes in immediate recall, delayed recall, and global memory efficiency. Global memory efficiency improved, primarily due to the subjects’ significantly improved ability to learn new information.2
A randomized, placebo-controlled, double-blind trial using 95 healthy volunteers, ages 50-85, tested CDP Choline‘s effect on memory.3 Subjects were recruited from the clinical research center at MIT and were screened to have no dementia. The researchers noted that a few of the patients might have met the criteria for age-associated memory impairment (a decline in memory, especially in verbal memory, can be observed in normal elderly people as well as in elderly with mild cognitive impairments).
The study had two phases. In the first phase, all subjects took 1,000 mg citicoline or placebo per day for three months. A portion of the group with relatively poor memories was recruited for the second phase and given either a placebo or 2,000 mg citicoline per day for three months. After the first phase, improvement with citicoline occurred only in the people with poor memories, who showed gains in delayed recall and logical memory. At the end of the second phase, verbal memory clearly improved in the 2,000 mg group, suggesting that 2,000 mg daily may be a more effective dose for people with age-associated memory impairment. The researchers concluded that in subjects with relatively inefficient memory, citicoline facilitated memory acquisition and retention.
A third placebo-controlled clinical trial demonstrated that citicoline possesses memory-enhancing activity in free recall tests (but not in recognition tests) at doses ranging from 300-1,000 mg per day. Four weeks of citicoline supplementation significantly improved the ability of 24 elderly subjects with memory deficits to recall words and objects after viewing them for two seconds each. No significant improvement was observed, however, for recognition tasks in which patients had to recall previously viewed words and objects randomly mixed with non-viewed items.4
CDP Choline has gone through a number of clinical trials to assess its effectiveness in cognitive enhancement in subjects with dementia, including dementia of the Alzheimer’s type as well as vascular, or multi-infarct, dementia. For instance, a double-blind, placebo-controlled trial tested the efficacy of CDP Choline in improving symptoms in patients with mild to moderate Alzheimer’s-type dementia. Thirty patients were administered 1,000 mg CDP Choline daily for twelve weeks. Using four different scales, researchers determined there were changes between the CDP Choline and placebo groups, but the changes were not statistically significant. Results were better in patients with more mild mental deterioration.5 In 20 patients with Alzheimer’s, a double-blind study found that spatial-temporal orientation also significantly improved, while Mini Mental State Examination scores showed statistically significant increases only in a patient subgroup with early-onset Alzheimer’s.6
To determine the overall clinical efficacy of CDP Choline for the symptoms of cognitive, emotional, and behavioral impairment in older patients with dementia or mild cognitive impairment, a large meta-analysis in 2005 examined the data from 14 double-blind, placebo-controlled clinical studies. The results indicated a positive and consistent effect of CDP Choline on memory and behavior, at least in the short to medium turn, since none of the studies available were assessing long-term efficacy. The authors found the evidence to be especially strong for the efficacy of CDP Choline in patients with cognitive impairments related to cerebral vascular disorders, such as the complications of stroke.7
Strokes
Reduced blood flow to the brain, as occurs during a stroke, causes the degradation of phosphatidylcholine to free fatty acids (particularly the inflammation-inducing arachadonic acid) and free radicals. CDP Choline enhances the re-synthesis of phospholipids, primarily phosphatidylcholine, of cell membranes. It has shown promise for reducing stroke-related injury by stabilizing cell membranes long enough to prevent large-scale brain cell damage after stroke. A review published in 2005 identified thirteen stroke clinical trials of CDP Choline since 1980 in Europe, Japan, and the US.8 Both European and Japanese trials found that CDP Choline significantly improved neurological function and helped speed motor and cognitive recovery. A multicenter double-blind, placebo-controlled study was conducted to evaluate possible clinical benefits of CDP Choline in patients with acute cerebral infarction and disturbances of consciousness. Patients were allocated randomly to either CDP Choline (1,000 mg per day i.v. once daily for 14 days) or with placebo (physiological saline). One hundred thirty-three patients received CDP Choline treatment, and 139 received placebo. The group given CDP Choline showed significant improvements in level of consciousness compared with the placebo-treated group. CDP Choline was found to be entirely safe.9
Other studies evaluating the effects of CDP Choline after strokes have resulted in different outcomes. In a recent U.S. clinical trial involving nearly 400 patients in 33 centers nationwide, patients were first given citicoline or a placebo within a few hours of their stroke, then for six weeks afterward, with a six-week, post-treatment follow-up period.10 Results for the entire group as a whole showed no statistically significant difference in five areas-including full recovery and mortality rates, neurological and cognitive function-between patients with stroke who were given citicoline, and those who were given a placebo. However, it was found effective in the subgroup of the subjects with moderate to severe strokes. The same group of researchers then conducted an even larger trial using 2,000 mg citicoline for six weeks following a stroke. Again, they found that citicoline was ineffective in improving the outcome of acute stroke patients.11 The review authors concluded that further studies are essential before making any conclusions on using CDP Choline after strokes.
Conclusion
CDP Choline is a form of the essential nutrient choline and a precursor of phosphatidylcholine and acetylcholine. Oral CDP Choline supplementation has been found to promote phospholipid biosynthesis, increase cerebral blood flow, inhibit cytotoxic (cell-destroying) free fatty acids and formation of diacylglycerol (a precursor to triglyceride formation), and promote healthy brain bioelectrical activity. In clinical studies, it has improved verbal memory functioning in older individuals with relatively inefficient memories and has been very well tolerated. The latest meta-analysis found no noticeable side effects evidenced in the fourteen various studies evaluated.7
Alexander G. Schauss, PhD, FACN,
Dr. Schauss is the Director of Natural and Medicinal Products Research, in Puyallup, Washington. He has previously held the rank of an Adjunct Research Professor of Botanical Medicine and Clinical Professor of Natural Products Research at the National College of Naturopathic Medicine in Portland, Oregon, as well as Associate Professor of Research at the Southwest College of Naturopathic Medicine and Health Sciences in Tempe, Arizona. Dr. Schauss has been a member of the National Institutes of Health (NIH) Office of Alternative Medicine (OAM) Advisory Council (AMPAC); and a reviewer of botanical standards and information monographs for the U.S. Pharmacopoeia Convention (USP). In 1985, Dr. Schauss was appointed by the US government to represent the United States as a voting member to the World Health Organization (WHO) Study Group on Health Promotion. He is the author or a co-author of more than 140 papers or works that have appeared in various scientific journals as well as books covering such topics as his discovery that Acai (Euterpe oleracea) contains the richest amount of antioxidants found in any food, and the problem of intra-abdominal obesity (the potbelly) in men. Dr. Schauss’ many accomplishments over a span of three decades were formally recognized when he received the Linus Pauling Lecture Award for contributions in the medical sciences in 2005 from the American College for the Advancement of Medicine.
References
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- Agnoli A, Bruno G, Fioravanti M, et al. Therapeutic approach to senile memory impairment: a double-blind clinical trial with CDP choline. In: Wurtman RJ, Corkin S, Growden JH, eds. Alzheimer’s Disease: Proceedings of the Fifth Meeting of the International Study Group on the Pharmacology of Memory Disorders Associated with Aging. Boston: Birkhauser. 1989: 649-654.
- Spiers PA, Myers D, Hochanadel GS, Lieberman HR, Wurtman RJ. Citicoline improves verbal memory in aging. Arch Neurol. 1996; 53: 441-8.
- Alvarez XA, Laredo M, Corzo D, Fernandez-Novoa L, Mouzo R, Perea JE, Daniele D, Cacabelos R. Citicoline improves memory performance in elderly subjects. Meth Find Exp clin Pharmacol. 1997;19: 201-210.
- Alvarez XA, Mouzo R, Pichel V, Perez P, Laredo M, Fernandez-Novoa L, Corzo L, Zas R, Alcaraz M, Secades J J, Lozano R, Cacabelos R. 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: 633-44.
- Caamano J, Gomez MJ, Franco A, Cacabelos R. Effects of CDP-choline on cognition and cerebral hemodynamics in patients with Alzheimer’s disease. Methods Find Exp Clin Pharmacol. 1994;16: 211-8.
- Fioravanti M, Yanagi M. Cytidinediphosphocholine (CDP-choline) for cognitive and behavioural disturbances associated with chronic cerebral disorders in the elderly. 2005. Cochrane Database Syst Rev. CD000269.
- Adibhatla RM, Hatcher JF. Cytidine 5′-diphosphocholine (CDP-choline) in stroke and other CNS disorders. Neurochem Res. 2005 Jan;30(1):15-23.
- Tazaki Y, Sakai F, Otomo E, Kutsuzawa T, Kameyama M, Omae T, Fujishima M, Sakuma A. Treatment of acute cerebral infarction with a choline precursor in a multicenter double-blind placebo-controlled study. Stroke. 1988. 19: 211-6.
- Clark WM, Williams BJ, Selzer KA, Zweifler RM, Sabounjian LA, Gammans RE. A randomized efficacy trial of citicoline in patients with acute ischemic stroke. Stroke. 1999;30: 2592-7.
- Clark WM, Wechsler LR, Sabounjian LA, Schwiderski UE. A phase III randomized efficacy trial of 2000 mg citicoline in acute ischemic stroke patients. Neurology. 2001;57: 1595-1602.