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CDP-Choline and alpha GPC: What to Feed Your Head

By now it’s not exactly news that choline is good for your brain. It’s been known for a long while that choline is probably the most basic nutrient necessary for optimal cognitive function. That’s because choline is a precursor for acetylcholine, a key neurotransmitter (signaling molecule) without which we couldn’t move, think, remember, or sleep. The body also uses choline for synthesizing phosphatidylcholine (PC), a component of the fatty membrane of every cell, brain cells included. In addition to its role as a structural element in cell membranes, PC can act as a choline reservoir for synthesizing more acetylcholine when needed.1

Aging humans and animals tend to suffer from impaired short-term memory. This loss of working memory is largely the result of deficient functioning of the “cholinergic” neurons in a part of the brain known as the basal forebrain.2,3 (Cholinergic neurons are the brain cells involved in acetylcholine synthesis, signaling, and metabolism.) The age-related deficits in this part of the brain include decreased synthesis and release of acetylcholine, as well as decreases in the number of cholinergic brain cells and in the number and function of acetylcholine receptors on such cells.4

The same neurons that are vulnerable in aging are especially vulnerable in Alzheimer’s disease (AD). In AD the cholinergic cells of the basal forebrain shrivel and die in manner resembling normal aging but at an accelerated pace. This abnormal behavior is partly the result of defective cell membranes caused by decreased availability of choline and increased breakdown of phosphatidylcholine.1,5 When choline is in short supply and cholinergic cells are active, any available choline goes to make more acetylcholine at the expense of building membranes. Eventually enough choline is withdrawn from the membrane so that the amount of PC in a cell actually decreases, a process known as “autocannibalism”. 1 In other words, the cell takes itself apart in an attempt to maintain normal acetylcholine signaling.

You might reasonably conclude from this that all we need to do to slow down brain aging or Alzheimer’s disease is supply more choline to the brain, but you’d be only partly right. The problem is that choline transport into the brain is not especially efficient and tends to decline with age.6,7 Attempts have been made to treat dementia and cognitive impairment with choline supplements such as lecithin (dietary PC, typically derived from eggs or soy), but a review of all unconfounded, randomized trials comparing lecithin with placebo revealed no particular benefit.8 Alternatives to choline or lecithin are clearly needed in order to reverse age-related cognitive decline.

Fortunately, there are two choline-based supplements that can do the trick—CDP-choline (cytidine 5'-diphosphocholine) and alpha GPC (alpha glycerophosphorylcholine). Both are natural, water-soluble compounds that achieve similar results in very different ways. CDP-choline is an essential intermediate in the biosynthesis of phosphatidylcholine and the better studied of the two compounds. Cells make CDP-choline out of choline and some other precursors before further processing it into PC. (If you’re eager for the biochemical details, an enzyme catalyzes PC synthesis by transferring the phosphocholine part of CDP-choline to diacylglycerol. Diacylglycerols are glycerine molecules with two fatty acids attached.)

In contrast alpha GPC works at the opposite end of PC metabolism. Unlike CDP-choline, alpha GPC is a metabolic breakdown product of PC rather than a PC precursor. You might say that whereas CDP-choline is an “anabolic” product, alpha GPC is a “catabolic” one. When phosphatidylcholine is metabolized and stripped of its fatty acids, what’s left behind is alpha GPC—a glycerine molecule bound to phosphocholine. As such it’s a source of choline in the same form that a cell would obtain from scavenging its own membranes, and therefore a form of choline that neurons prefer to use for synthesizing acetylcholine during times of choline scarcity.

Despite the fact that CDP-choline and alpha GPC are chemically distinct from each other and operate at opposite ends of the metabolic spectrum, both of them do pretty much the same thing. For example, both alpha GPC and CDP-choline have been shown to improve performance on behavioral and psychological tests among patients with mild to moderate Alzheimer’s disease (9, 10). Both can also counteract the amnesia induced by scopolamine, a compound which blocks acetylcholine receptors,11,12 thus confirming the role of the cholinergic system in the cognitive enhancing effects of alpha GPC and CDP-choline. And both can promote cognitive recovery from a recent stroke.13,14

More generally, a review of all relevant, controlled clinical trials concluded that CDP-choline is beneficial for treating cognitive and behavioral deficits caused by chronic brain disease in the elderly.15 This is in striking contrast to a similar review cited earlier that found no benefit for treating cognitive decline with choline in the form of lecithin.8 The superiority of CDP-choline over lecithin as a choline source should be evident. Unfortunately, however, there’s no comparable large-scale overview of the effects of alpha GPC as a cognition enhancer because alpha GPC is a newer product than CDP-choline and fewer studies have been done with it. Nevertheless, as the following selected examples show, the effects of alpha GPC and CDP-choline are remarkably similar on the molecular and cellular levels and are therefore likely to be similar on the cognitive and behavioral levels as well:

  • When incubated with brain tissue from rats, CDP-choline stimulates the activity of acetylcholinesterase (AChE), an enzyme involved in choline metabolism.16 Similarly, high-dose oral alpha GPC restores decreased AChE activity to more youthful levels in the brains of aged rats.17
  • Chronic administration of high-dose oral CDP-choline also restores the numbers of acetylcholine receptors in rat brain which otherwise decrease with normal aging .8 High-dose oral alpha GPC does the same.19
  • Both CDP-choline18 and alpha GPC19 decrease the viscosity (stiffness) of cell membranes, an effect almost certainly due to increased phosphatidylcholine synthesis.

Another useful property shared by alpha GPC and CDP-choline is that oral administration of either one increases the release of the neurotransmitter dopamine in the brain20,21 It’s worth recalling that defective dopamine signaling is associated with Parkinson’s disease in much the same way that defective acetylcholine signaling is associated with Alzheimer’s disease. There is evidence of enhanced PC metabolism in Parkinson’s, perhaps as a result of brain cells trying to compensate for the neurodegenerative process.22.In this sense there may be an increased demand for CDP-choline or alpha GPC in Parkinson’s disease, where they may be needed to rebuild damaged cell membranes and to facilitate dopamine release as well.

L-DOPA is an amino acid precursor to dopamine that is widely used in treating Parkinson’s. Animal studies have shown that oral CDP-choline treatment enhances the effects of L-DOPA by increasing the release of dopamine newly synthesized from it.23 In human trials, a combination of CDP-choline with L-DOPA was able to improve neurological symptoms with a smaller effective dose of L-DOPA than patients had previously received without CDP-choline .24,25 This result is important because chronic use of L-DOPA eventually results in neurotoxicity and loss of clinical effectiveness. The hope is that by combining CDP-choline with smaller doses of L-DOPA, it may be possible to prolong the period during which L-DOPA remains effective. In view of the known ability of alpha GPC to enhance dopamine release as well,20 a similar therapeutic enhancement of L-DOPA activity is also likely to occur with alpha GPC, but there aren’t any clinical data available yet to confirm this suggestion.

Since chronic cocaine abuse is likewise associated with dopamine depletion and increased turnover of cell membranes, the choline-dopamine connection predicts that CDP-choline and alpha GPC should each be effective for treating cocaine addiction. This has indeed been verified for CDP-choline26 but not yet for alpha GPC. In addition, I will personally go out on a limb here and predict that CDP-choline, alpha GPC, or both should be helpful in treating attention deficit hyperactivity disorder (ADHD), either as an adjunct to stimulants like Ritalin or as stand-alone supplements. I base my conclusion on the known involvement of dopamine metabolism in ADHD27 as well as on the dopamine-releasing and cognitive enhancing effects of CDP-choline and alpha GPC discussed in previous paragraphs.

Finally, there at least one more important anti-aging property shared by CDP-choline and alpha GPC—they’re both growth hormone (GH) sensitizers.28,29 As you probably know, GH levels decline with age, resulting in age-related decreases in bone mass and in muscle mass and strength.30 You may not be aware, however, that GH decline is also associated with age-related cognitive impairment.31 The cholinergic system is an important part of the mechanism that regulates GH release stimulated by GHRH.32 Here GHRH (growth hormone-releasing hormone) is the hypothalamic hormone that triggers secretion of GH from the pituitary. Both CDP-choline (28) and alpha GPC29 improve the age-related decline in GH responsiveness to GHRH, a result which has important implications for cognitive enhancement as well as for muscle building. Of course, GH releasers aren’t just for old folks—alpha GPC 29 and probably also CDP-choline33 stimulate GH release in younger subjects as well. This suggests the use of either or both as nutrients for sports, exercise, and weight training.

At this point I think I’ve made my case—CDP-choline and alpha GPC are both effective choline supplements for enhancing mental and physical performance and counteracting age-related decline. The big question is, which supplement is better? That’s a tough one to answer because there are only two published studies I’m aware of that directly compare the activities of each compound. The first study reported that the use of 1 gram per day of alpha GPC produced higher cognitive test scores in subjects with vascular dementia than did 1 gram per day of CDP-choline.34 The second study reported that alpha GPC raised plasma choline levels substantially higher in normal subjects than CDP-choline did.35

On the face of it, the two studies comparing alpha GPC and CDP-choline would seem to indicate that alpha GPC is the more effective of the two compounds, but things aren’t quite that simple. For one thing, both studies compared the effects of alpha GPC and CDP-choline administered intramuscularly rather than orally. For another, an increase in plasma choline levels may not be especially meaningful as a measure of enhanced activity or bioavailability of alpha GPC, since the lower plasma choline associated with CDP-choline injection might simply reflect an increased tissue uptake.

To gain some insight into this issue, let’s take a look at what happens to CDP-choline and alpha GPC after they are ingested. Orally administered CDP-choline is broken down into its components in the intestine, absorbed individually as choline and cytidine, and subsequently put back together again in various tissues.36 Experiments with cultured brain cells reveal that soon after the cells are incubated with CDP-choline, newly synthesized PC can be detected .37 The same does not happen if the cells are incubated with choline itself, suggesting that either a specific mechanism for uptake of intact CDP-choline exists37 or else that brain cells can use choline efficiently for making PC only if cytidine is also present.38 Either way, CDP-choline gets into the brain and more phosphatidylcholine gets made.

As for alpha GPC, it’s believed that intestinal enzymes known as phosphodiesterases are responsible for cutting it into its components,39 but there’s no information I can find on what percentage of an administered dose of oral alpha GPC is likely to make it through the gut intact. My best guess, however, is that a fair amount does get through and in fact makes it into the brain. The reason for this is that in animal experiments only alpha GPC—and not choline nor any other breakdown product of alpha GPC—is able to reverse age-related decreases in brain acetylcholine receptors and membrane fluidity.19 As a result, if all of an orally administered dose of alpha GPC were to be broken down in the intestine, plasma choline levels would indeed be elevated but you still wouldn’t get the same beneficial effects that alpha GPC is known to provide. Therefore, some of the alpha GPC must make it to the brain intact, otherwise there’d be no difference between taking alpha GPC and choline…and clearly there is a difference.

So if you’re trying to decide between CDP-choline and alpha GPC as a cognitive enhancer, my advice is—choose either. They do pretty much the same thing and I’m not convinced that either one is superior to the other. Better yet, I suggest trying a combination of both for optimal effect, since they work from complementary ends of PC metabolism. A good place to start might be to try one 250 mg capsule per day of either alpha GPC or CDP-choline for several days until you can gauge the effect. If you’re happy with the results, stop there. If not and you’re looking for more intense cognitive stimulation, trying adding a single capsule per day of the other enhancer to your regimen, so that you’re taking a total of one apiece. You can gradually increase the dosage of either if desired, since both nutrients are reportedly well tolerated with few if any side effects.

And if you can stand taking caffeine, consider washing down your capsules of alpha GPC and CDP-choline with a strong cup of java. The caffeine acts as a nonspecific phosphodiesterase inhibitor40 and should therefore allow more of each nutrient to be absorbed intact.

References.

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[19] Muccioli G, Raso GM, Ghe C, Di Carlo R. Effect of L-alpha glycerylphosphorylcholine on muscarinic receptors and membrane microviscosity of aged rat brain. Prog Neuropsychopharmacol Biol Psychiatry. 1996;20(2):323-39.

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[24] Cubells JM, Hernando C. Clinical trial on the use of cytidine diphosphate choline in Parkinson's disease. Clin Ther. 1988;10(6):664-71.

[25] Eberhardt R, Birbamer G, Gerstenbrand F, Rainer E, Traegner H. Citicoline in the treatment of Parkinson's disease. Clin Ther. 1990;12(6):489-95.

[26] Renshaw PF, Daniels S, Lundahl LH, Rogers V, Lukas SE. Short-term treatment with citicoline (CDP-choline) attenuates some measures of craving in cocaine-dependent subjects: a preliminary report. Psychopharmacology (Berl). 1999;142(2):132-8

[27] Levy F. The dopamine theory of attention deficit hyperactivity disorder (ADHD). Aust N Z J Psychiatry. 1991;25(2):277-83.

[28] Ceda GP, Ceresini G, Denti L, Magnani D, Marchini L, et al. Effects of cytidine 5'-diphosphocholine administration on basal and growth hormone-releasing hormone-induced growth hormone secretion in elderly subjects. Acta Endocrinol (Copenh). 1991;124(5):516-20.

[29] Ceda GP, Ceresini G, Denti L, Marzani G, Piovani E, et al. alpha-Glycerylphosphorylcholine administration increases the GH responses to GHRH of young and elderly subjects. Horm Metab Res. 1992;24(3):119-21.

[30] Johannsson G, Svensson J, Bengtsson BA. Growth hormone and ageing. Growth Horm IGF Res. 2000;10 Suppl B:S25-30.

[31] van Dam PS, Aleman A, de Vries WR, Deijen JB, van der Veen EA, et al. Growth hormone, insulin-like growth factor I and cognitive function in adults. Growth Horm IGF Res. 2000;10 Suppl B:S69-73.

[32] Giusti M, Marini G, Sessarego P, Peluffo F, Valenti S, et al. Effect of cholinergic tone on growth hormone-releasing hormone-induced secretion of growth hormone in normal aging. Aging (Milano). 1992;4(3):231-7.

[33] Matsuoka T, Kawanaka M, Nagai K. Effect of cytidine diphosphate choline on growth hormone and prolactin secretion in man. Endocrinol Jpn. 1978;25(1):55-7.

[34] Di Perri R, Coppola G, Ambrosio LA, Grasso A, Puca FM, et al. A multicentre trial to evaluate the efficacy and tolerability of alpha-glycerylphosphorylcholine versus cytosine diphosphocholine in patients with vascular dementia. J Int Med Res. 1991;19(4):330-41.

[35] Gatti G, Barzaghi N, Acuto G, Abbiati G, Fossati T, et al. A comparative study of free plasma choline levels following intramuscular administration of L-alpha-glycerylphosphorylcholine and citicoline in normal volunteers. Int J Clin Pharmacol Ther Toxicol. 1992;30(9):331-5.

[36] Weiss GB. Metabolism and actions of CDP-choline as an endogenous compound and administered exogenously as citicoline. Life Sci. 1995;56(9):637-60.

[37] Vecchini A, Binaglia L, Floridi A, Palmerini CA, Procellati G. Uptake and utilization of CDP-choline in primary brain cell cultures from fetal brain. Neurochem Res. 1983;8(3):333-40.

[38] Babb SM, Appelmans KE, Renshaw PF, Wurtman RJ, Cohen BM. Differential effect of CDP-choline on brain cytosolic choline levels in younger and older subjects as measured by proton magnetic resonance spectroscopy. Psychopharmacology (Berl). 1996;127(2):88-94.

[39] Abbiati G, Fossati T, Lachmann G, Bergamaschi M, Castiglioni C. Absorption, tissue distribution and excretion of radiolabelled compounds in rats after administration of [14C]-L-alpha-glycerylphosphorylcholine. Eur J Drug Metab Pharmacokinet. 1993;18(2):173-80.

[40] van Staveren WC, Markerink-van Ittersum M, Steinbusch HW, de Vente J. The effects of phosphodiesterase inhibition on cyclic GMP and cyclic AMP accumulation in the hippocampus of the rat. Brain Res. 2001;888(2):275-286.


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