14 replies to this topic

[Leo]

I'd like to boost my acetylcholine levels and I understand that I can do this by using CDP-Choline, Alpha GPC, Acetyl-L-carnitine, Centrophenoxine, L-Huperzine A, DMAE, etc

I'm confused because I don't know which one to order. Do all these supplements achieve the same outcome in the end? Which one do you guys recommend for boosting acetylcholine in the brain?

[Mr.Bananas]

They all do similar thing but in the end they dont work the same. The "best" choline precursor is cdp choline and alpha gpc, huperzine inhibits acethylcholinesterase.
So what do you need?
It depends on what you need it for.

[Rags847]

Leo,
2 great articles on CDP-Choline

http://www.delano.co...GPC-Sharpe.html
http://aor.ca/int/ma...rain_health.pdf

Other articles:
http://www.imminst.o...les-t19546.html

Rags


P.S. The Delano Report article, in case the link (above) ever becomes dead:


CDP-Choline and alpha-GPC

What to feed your head

by Ed Sharpe

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 ¹⁸. High-dose oral alpha GPC does the same ¹⁹.
• Both CDP-choline ¹⁸ and alpha GPC ¹⁹ 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 brain ^{20, 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-choline ²⁶ 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 ADHD ²⁷ 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 GPC ²⁹ 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-choline ³³ 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 exists ³⁷ 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 inhibitor ⁴⁰ and should therefore allow more of each nutrient to be absorbed intact.

References

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[5] Nitsch RM, Blusztajn JK, Pittas AG, Slack BE, Growdon JH, et al. Evidence for a membrane defect in Alzheimer disease brain. Proc Natl Acad Sci USA. 1992;89(5):1671-5. [Abstract] [PDF (951 KB)]

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[10] Alvarez XA, Mouzo R, Pichel V, Perez P, Laredo M, 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):633-44. [Abstract]

[11] Schettini G, Ventra C, Florio T, Grimaldi M, Meucci O, et al. Molecular mechanisms mediating the effects of L-alpha-glycerylphosphorylcholine, a new cognition-enhancing drug, on behavioral and biochemical parameters in young and aged rats. Pharmacol Biochem Behav. 1992;43(1):139-51. [Abstract]

[12] Petkov VD, Kehayov RA, Mosharrof AH, Petkov VV, Getova D, et al. Effects of cytidine diphosphate choline on rats with memory deficits. Arzneimittelforschung. 1993;43(8):822-8. [Abstract]

[13] Barbagallo Sangiorgi G, Barbagallo M, Giordano M, Meli M, Panzarasa R. alpha-Glycerophosphocholine in the mental recovery of cerebral ischemic attacks. An Italian multicenter clinical trial. Ann N Y Acad Sci. 1994;717:253-69. [Abstract]

[14] Clark WM, Warach SJ, Pettigrew LC, Gammans RE, Sabounjian LA. A randomized dose-response trial of citicoline in acute ischemic stroke patients. Citicoline Stroke Study Group. Neurology. 1997;49(3):671-8. [Abstract]

[15] Fioravanti M, Yanagi M. Cytidinediphosphocholine (CDP choline) for cognitive and behavioural disturbances associated with chronic cerebral disorders in the elderly. Cochrane Database Syst Rev. 2000;(4):CD000269. [Abstract]

[16] Plataras C, Tsakiris S, Angelogianni P. Effect of CDP-choline on brain acetylcholinesterase and Na(+),K(+)-ATPase in adult rats. Clin Biochem. 2000;33(5):351-7. [Abstract]

[17] Amenta F, Bronzetti E, Mancini M, Vega JA, Zaccheo D. Choline acetyltransferase and acetylcholinesterase in the hippocampus of aged rats: sensitivity to choline alphoscerate treatment. Mech Ageing Dev. 1994 May;74(1-2):47-58. [Abstract]

[18] Gimenez R, Raich J, Aguilar J. Changes in brain striatum dopamine and acetylcholine receptors induced by chronic CDP-choline treatment of aging mice. Br J Pharmacol. 1991;104(3):575-8. [Abstract]

[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. [Abstract]

[20] Trabucchi M, Govoni S, Battaini F. Changes in the interaction between CNS cholinergic and dopaminergic neurons induced by L-alpha-glycerylphosphorylcholine, a cholinomimetic drug. Farmaco [Sci]. 1986;41(4):325-34. [Abstract]

[21] Agut J, Ortiz JA, Wurtman RJ. Cytidine (5')diphosphocholine modulates dopamine K(+)-evoked release in striatum measured by microdialysis. Ann N Y Acad Sci. 2000;920:332-5. [Abstract]

[22] Ross BM, Mamalias N, Moszczynska A, Rajput AH, Kish SJ. Elevated activity of phospholipid biosynthetic enzymes in substantia nigra of patients with Parkinson's disease. Neuroscience. 2001;102(4):899-904. [Abstract]

[23] Saligaut C, Daoust M, Moore N, Boismare F. Circling behaviour in rats with unilateral lesions of the nigrostriatum induced by 6-hydroxydopamine: changes induced by oral administration of cytidine-5'-diphosphocholine. Neuropharmacology. 1987;26(9):1315-9. [Abstract]

[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. [Abstract]

[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. [Abstract]

[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 [Abstract]

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

[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. [Abstract]

[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. [Abstract]

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

[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. [Abstract]

[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. [Abstract]

[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. [Abstract]

[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. [Abstract]

[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. [Abstract]

[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. [Abstract]

[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. [Abstract]

[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. [Abstract]

[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. [Abstract]

[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. [Abstract]

Edited by Rags847, 16 June 2008 - 01:04 PM.

[hamishm00]

I'd like to boost my acetylcholine levels and I understand that I can do this by using CDP-Choline, Alpha GPC, Acetyl-L-carnitine, Centrophenoxine, L-Huperzine A, DMAE, etc

I'm confused because I don't know which one to order. Do all these supplements achieve the same outcome in the end? Which one do you guys recommend for boosting acetylcholine in the brain?

You can even take Lecithin and Vitamin b5 together. Will work fine.
(Read the post above for other views on this)

Edited by hamishm00, 16 June 2008 - 05:16 PM.

[Leo]

Thanks, Rags. Great articles!

Leo,
2 great articles on CDP-Choline

http://www.delano.co...GPC-Sharpe.html
http://aor.ca/int/ma...rain_health.pdf

Other articles:
http://www.imminst.o...les-t19546.html

Rags

[Leo]

So what do you need?
It depends on what you need it for.

I need it for a speech problem. I tried DMAE two weeks ago and on day 5 there was 90% reduction in my speech problem. This lasted for 3 days then the effect diminished and now I don't think DMAE is working anymore. It certainly wasn't a placebo effect. I tried many supplements in the past and none has worked the way DMAE did for those 3 days. I'm sure my speech problem has to do with my acetylcholine levels. I think I'll try CDP-Choline and L-Huperzine A.

[matix7]

So what do you need?
It depends on what you need it for.

I need it for a speech problem. I tried DMAE two weeks ago and on day 5 there was 90% reduction in my speech problem. This lasted for 3 days then the effect diminished and now I don't think DMAE is working anymore. It certainly wasn't a placebo effect. I tried many supplements in the past and none has worked the way DMAE did for those 3 days. I'm sure my speech problem has to do with my acetylcholine levels. I think I'll try CDP-Choline and L-Huperzine A.

i feel ya, same problem here.. interersting with that DMAE. i supplement with AGPC and it helps, the reason i came to the conclusion its choline is because whenver i have nicotine, like chewing tobacco, the problem is gone, albiet temporarily and of course not safely. The reason is because nicotine acts on acetylcholine so greatly, i can actually FEEL it. Id say get some a-gpc and some alcar and see how it goes. Good luck

[Rags847]

So what do you need?
It depends on what you need it for.

I need it for a speech problem. I tried DMAE two weeks ago and on day 5 there was 90% reduction in my speech problem. This lasted for 3 days then the effect diminished and now I don't think DMAE is working anymore. It certainly wasn't a placebo effect. I tried many supplements in the past and none has worked the way DMAE did for those 3 days. I'm sure my speech problem has to do with my acetylcholine levels. I think I'll try CDP-Choline and L-Huperzine A.

Here is an article on DMAE that strongly recommends NOT taking DMAE for acetylcholine boosting.

"There is very little evidence that this increase in choline levels leads to a consequent rise in acetylcholine, and given that DMAE competitively inhibits choline transport, there is theoretical basis for an anticholinergic effect."

http://www.bulknutri...gredients_id=46

By David Tolson
This supplement has been proposed for the following purposes or treating the following conditions. Also given is the current scientific support for use (on a scale of 0-10). Note that a low rating does not necessarily indicate that a supplement does not work, just that research is either unavailable or has not demonstrated a benefit.

ADD/ADHD - 7
Learning/memory - 3
Alzheimer's - 1
Tardive dyskinesia - 1

Side effects

Reported side effects associated with DMAE use include gastrointestinal disturbances, bad body odor, drowsiness, sedation, retardation, confusion, increased blood pressure, depression, and hypomania.

DMAE may cause a decrease in the levels of some choline metabolites. Choline supplementation may help to correct this.

DMAE should be avoided under all circumstances by pregnant women.

DMAE is a naturally occuring analogue of choline. It is mareketed primarily as a memory enhancing agent and anti-aging nutrient. This article will review the presently available research on DMAE and whether or not it supports these claims.

Centrophenoxine (CPH), an established nootropic and anti-aging nutrient, is DMAE bonded to p-chlorophenoxyacetic acid (PCPA). CPH is a potent OH radical scavenger and also prevents the buildup of the age-related pigment lipofuscin. According to some research, the properties of CPH can be primarily attributed to DMAE moiety, while the PCPA just allows for better penetration of the blood brain barrier [1-2]. If this were the case, DMAE would be pharmacologically very similar to CPH, but with a higher amount needed for the same effect. However, other research contradicts this idea. For example, an in vitro study found that DMAE did not reduce age pigment accumulation, but the combination of DMAE and PCPA did [3]. Another found that PCPA had superoxide radical scavenging properties, whereas DMAE did not, although high concentrations of the substances were used [4]. Other researchers also indicate that PCPA is responsible for some of the important actions of CPH [5].

Research has also been conducted to see if DMAE shares the anti-aging properties of CPH. Like CPH, DMAE is a potent and site specific OH radical scavenger. This is due to DMAE's ability to become phosphatidyl-DMAE and replace phosphatidylcholine in nerve membranes, thus offering local protection from free radicals [1]. An in vitro study found that adding DMAE to myocytes protected from cell damage from ischemia and metabolic inhibition [6], while a study in mice found that DMAE did not change survival rate, but did reduce lipofuscin content [7]. However, a study in Japanese quail found that administration of DMAE (18 mg/kg) starting late in life actually reduced life span by twenty weeks [8]. Therefore, it is necessary to emphasize caution when applying the effects of CPH to DMAE. It also brings up a larger issue, that of possible toxicity or side effects from DMAE.

Another reputed effect of DMAE supplementation is a rise in choline and acetylcholine levels and a corresponding increase in memory ability. This is based on the assumption that DMAE is a choline precursor [1] and also crosses the blood brain barrier more effectively than choline itself [9], giving it the ability to reach the brain and then increase brain choline levels. DMAE does consistently increase levels of free choline in the brain and body, but this is not because it is a converted to choline – it is because it competitively inhibits choline kinase and choline oxidase, preventing the metabolism of choline to phosphocholine and betaine [10-12]. As mentioned above, this results in the production of phosphatidyl-DMAE. However, this is not necessarily beneficial, since it replaces phosphatidylcholine, and thus may effectively blunt some of the biological actions of phosphatidylcholine [39].

There is very little evidence that this increase in choline levels leads to a consequent rise in acetylcholine, and given that DMAE competitively inhibits choline transport, there is theoretical basis for an anticholinergic effect [10-11, 13-15]. If anything, this renders DMAE supplementation the equivalent of choline supplementation, since that also increases brain choline levels but generally fails to increase acetylcholine [16]. In an in vitro study, DMAE reduced the synthesis of acetylcholine by inhibiting high affinity choline transport, and the same researchers found no effect of DMAE on acetylcholine levels in vivo in rats [17]. In another study in which a wide range of doses of DMAE was administered to mice, there was no increase in brain acetylcholine levels except an increase in the striatum at the highest dose which appeared to be unrelated to tissue DMAE content [18].

Studies on the effects of DMAE on learning and memory have also been discouraging. In mice, DMAE improved one-week retention in mice on a T-maze active avoidance task [19]. However, trials in the healthy elderly and in people with Alzheimer's and amnestic disorders have found no positive effect on memory or cognition [20-23]. One study did report better mood after treatment, but there was no control group [23].

DMAE has also been researched in the treatment of tardive dyskinesia (a type of movement disorder). Although initial results were promising, they failed to be replicated in double-blind, placebo-controlled trials [24-30]. In two of these studies, choline was effective whereas DMAE was not [24, 29]. In one trial, symptoms were worse in the DMAE-treated group, and it was suggested that DMAE had actually interfered with cholinergic function [25].

A final use proposed for DMAE is in the treatment of childhood hyperactivity. A placebo-controlled trial in 74 children found that DMAE at 500 mg daily was as effective as methylphenidate (Ritalin) [15]. The mechanism of action for this effect is not established.

Numerous side effects from DMAE treatment have been reported in the literature. These include gastrointestinal disturbances, bad body odor, drowsiness, sedation, retardation, confusion, increased blood pressure, depression, and hypomania; some of these are causes of frequent withdrawal [20, 31-33]. Airborne DMAE is associated with a variety of adverse events (some of which have been reported in humans exposed to high concentrations in a label printing plant), primarily visual disturbances (blurry, halo, and blue-grey vision, corneal opacity, and decrements in visual acuity and contrast sensitivity) and skin irritation [34-36]. However, it is doubtful that oral supplementation will lead to these effects. DMAE also has potential teratogenic effects due to the fact that it inhibits choline uptake [10]. In one study, rat pups fed a choline-deficient diet containing DMAE died within 36 hours of birth, supporting the notion that DMAE does not function as an effective choline precursor [37]. In another experimental study, the presence of choline or acetylcholine offset developmental toxicity due to DMAE [38].

In conclusion, the scientific literature does not support many of the claims made regarding DMAE, although older research does support a possible benefit in the treatment of hyperactivity. When taken in the right amounts, there are some possible benefits related to its antioxidant effects and benefits resulting from an anticholinergic effect can even be hypothesized. Also, there is not enough research to determine the effects when DMAE and choline are taken together. It is possible that the two would just blunt one another's effects. However, it is also possible that this would offer the best of both worlds, both the antioxidant effects of DMAE but also sufficient choline metabolites to protect against any potential negative effects. Further research is clearly needed, but until then, it is unwise to use DMAE without a protective choline supplement.

If you have any questions or comments regarding this article, please email dvdtlsn@bulknutrition.com.

References

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7. Mech Ageing Dev. 1988 Feb; 42(2): 129-38. Effect of lifetime administration of dimethylaminoethanol on longevity, aging changes, and cryptogenic neoplasms in C3H mice. Stenback F, Weisburger JH, Williams GM.

8. J Gerontol. 1977 Jan;32(1):38-45. Effects of dimethylaminoethanol upon life-span and behavior of aged Japanese quail. Cherkin A, Exkardt MJ.

9. Ann Neurol. 1978 Oct;4(4):302-6. Deanol acetamidobenzoate inhibits the blood-brain barrier transport of choline. Millington WR, McCall AL, Wurtman RJ.

10. FASEB J. 2002 Apr;16(6):619-21. Perturbations in choline metabolism cause neural tube defects in mouse embryos in vitro. Fisher MC, Zeisel SH, Mar MH, Sadler TW.

11. Teratology. 2001 Aug;64(2):114-22. Inhibitors of choline uptake and metabolism cause developmental abnormalities in neurulating mouse embryos. Fisher MC, Zeisel SH, Mar MH, Sadler TW.

12. J Neurochem. 1981 Aug;37(2):476-82. Deanol affects choline metabolism in peripheral tissues of mice. Haubrich DR, Gerber NH, Pflueger AB.

13. J Neurochem. 1990 May; 54(5): 1467-73. Choline uptake by cerebral capillary endothelial cells in culture. Estrada C, Bready J, Berliner J, Cancilla PA.

14. J Nucl Med. 1985 Dec; 26(12): 1424-8. Carbon-11 choline: synthesis, purification, and brain uptake inhibition by 2-dimethylaminoethanol. Rosen MA, Jones RM, Yano Y, Budinger TF.

15. Clin Pharmacol Ther. 1975 May;17(5):534-40. Deanol and methylphenidate in minimal brain dysfunction. Lewis JA, Young R.

16. Mech Ageing Dev. 2001 Nov;122(16):2025-40. Treatment of cognitive dysfunction associated with Alzheimer's disease with cholinergic precursors. Ineffective treatments or inappropriate approaches? Amenta F, Parnetti L, Gallai V, Wallin A.

17. J Pharmacol Exp Ther. 1979 Dec;211(3):472-9. Dimethylaminoethanol (deanol) metabolism in rat brain and its effect on acetylcholine synthesis. Jope RS, Jenden DJ.

18. J Pharmacol Exp Ther. 1977 Mar;200(3):545-59. Is 2-dimethylaminoethanol (deanol) indeed a precursor of brain acetylcholine? A gas chromatographic evaluation. Zahniser NR, Chou D, Hanin I.

19. Neurobiol Aging. 1983 Spring;4(1):37-43. Memory retention: potentiation of cholinergic drug combinations in mice. Flood JF, Smith GE, Cherkin A.

20. Am J Psychiatry. 1981 Jul;138(7):970-2. Double-blind trial of 2-dimethylaminoethanol in Alzheimer's disease. Fisman M, Mersky H, Helmes E.

21. Ateneo Parmense Acta Biomed. 1980;51(4):383-9. [The effect of Deanol on amnesic disorders. A preliminary trial (author's transl)] [Article in Italian] Caffarra P, Cattelani R, Mazzucchi A, Moretti G, Parma M.

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28. Neuropsychobiology. 1978;4(3):140-9. Deanol, lithium and placebo in the treatment of tardive dyskinesia. A double-blind crossover study. Jus A, Villeneuve A, Gautier J, Jus K, Villeneuve C, Pires P, Villeneuve R.

29. Arch Neurol. 1977 Dec;34(12):756-8. Deanol acetamidobenzoate treatment in choreiform movement disorders. Tarsy D, Bralower M.

30. Am J Psychiatry. 1977 Jul;134(7):769-74. Cholinergic influences in tardive dyskinesia. Tamminga CA, Smith RC, Ericksen SE, Chang S, Davis JM.

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32. Schizophr Res. 1999 Aug 23;39(1):1-16; discussion 17-8. The treatment of tardive dyskinesia--a systematic review and meta-analysis. Soares KV, McGrath JJ.

33. Psychopharmacology (Berl). 1979 Apr 11;62(2):187-91. Mood alterations during deanol therapy. Casey DE.

34. Occup Environ Med. 2003 Jan;60(1):69-75. Visual and ocular changes associated with exposure to two tertiary amines. Page EH, Cook CK, Hater MA, Mueller CA, Grote AA, Mortimer VD.

35. Vet Hum Toxicol. 1996 Dec; 38(6): 422-6. Acute toxicity and primary irritancy of alkylalkanolamines. Ballantyne B, Leung HW.

36. J Appl Toxicol. 1996 Nov-Dec; 16(6): 533-8. Developmental toxicity study in Fischer 344 rats by whole-body exposure to N,N-dimethylethanolamine vapor. Leung HW, Tyl RW, Ballantyne B, Klonne DR.

37. Pediatr Res. 1978 Sep;12(9):952-5. Effects of dietary choline and N,N-dimethylaminoethanol on lung phospholipid and surfactant of newborn rats. Katyal SL, Lombardi B.

38. Environ Health Perspect. 2003 Nov;111(14):1730-5. The sea urchin embryo as a model for mammalian developmental neurotoxicity: ontogenesis of the high-affinity choline transporter and its role in cholinergic trophic activity. Qiao D, Nikitina LA, Buznikov GA, Lauder JM, Seidler FJ, Slotkin TA.

39. Biochim Biophys Acta. 2004 Mar 22;1636(2-3):175-82. Dimethylethanolamine does not prevent liver failure in phosphatidylethanolamine N-methyltransferase-deficient mice fed a choline-deficient diet. Waite KA, Vance DE.

Edited by Rags847, 17 June 2008 - 04:11 AM.

[Rags847]

Wiki talks about DMAE possibly increasing the lifespan of certain animals and possibly decreasing the lifespan of others (quail, namely).

Interestingly, DMAE is used in many skin and anti-wrinkle products. Here is an article warning about its possible dangers to skin cells and the body.

http://www.eurekaler...l-acc041107.php

A great website, Eurekalert.

Public release date: 11-Apr-2007
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Contact: Jean-François Huppé
jean-francois.huppe@dap.ulaval.ca
418-656-7785
Université Laval
<h1 class="title">Anti-wrinkle compound causes pathological reaction in skin cells</h1> Quebec City, April 11, 2007 -- Researchers from Université Laval’s Faculty of Medicine have discovered that a compound commonly used in many antiwrinkle products causes a pathological reaction in skin cells. Guillaume Morissette, Lucie Germain, and François Marceau present their conclusions about the mode of action of this substance—called DMAE—in the latest edition of the British Journal of Dermatology.

DMAE (2-dimethylaminoethanol) is used in many antiwrinkle products dubbed "instant anti-aging face-lifts." This compound, as well as other chemically similar ones, are also found in cosmetics, creams, lipsticks, shampoos, soaps, and baby lotions, although the way they work is not yet understood.

In vitro tests conducted by Dr. Marceau’s team revealed that the application of DMAE induces a quick and spectacular swelling of skin cell vacuoles called fibroblasts, which act as reservoirs and interface between the inside and the outside of the cell.

In the hours following the application of DMAE, the researchers observed an important slowing down of cell division—sometimes coming to a complete stop, the inhibition of certain metabolic reactions, and the death of a significant percentage of fibroblasts. The mortality rate of fibroblasts, which varied according to DMAE concentration, was above 25% after 24 hours in the case of a concentration similar to the one resulting from normal use of an antiwrinkle cream. The thickening of the skin induced by the pathological swelling of the fibroblasts would explain the antiwrinkle effect of DMAE, according to the researchers.

"Even though DMAE is similar to medication, there is very little scientific documentation about its pharmacological and toxicological effects," explains Dr. Marceau, who stresses his goal is not to condemn the use of this compound. "We’re not saying DMAE is dangerous to people exposed to it, but our results indicate it’s time to begin serious research to determine whether or not it poses a health risk."

DMAE is not a unique case in the world of beauty products, continues the researcher. "Several compounds found in cosmetics are just as complex as medication—they are absorbed through the skin, flow through the bloodstream, are expelled by the kidneys, or stocked in cells or even in the liver. Yet, the laws regulating their use are far less restrictive than those regulating drugs," concludes Dr. Marceau.

###

Photographs of cells reacting to contact with DMAE available upon request

Information:
François Marceau
Faculty of Medicine
Université Laval
Phone: (418) 525-4444, ext. 46155
Francois.Marceau@crchul.ulaval.ca


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Edited by Rags847, 17 June 2008 - 04:28 AM.

[Leo]

Very interesting, especially these two quotes:

DMAE does consistently increase levels of free choline in the brain and body, but this is not because it is a converted to choline – it is because it competitively inhibits choline kinase and choline oxidase, preventing the metabolism of choline to phosphocholine and betaine. As mentioned above, this results in the production of phosphatidyl-DMAE. However, this is not necessarily beneficial, since it replaces phosphatidylcholine, and thus may effectively blunt some of the biological actions of phosphatidylcholine

There is very little evidence that this increase in choline levels leads to a consequent rise in acetylcholine, and given that DMAE competitively inhibits choline transport, there is theoretical basis for an anticholinergic effect

[hamishm00]

So what do you need?
It depends on what you need it for.

I need it for a speech problem. I tried DMAE two weeks ago and on day 5 there was 90% reduction in my speech problem. This lasted for 3 days then the effect diminished and now I don't think DMAE is working anymore. It certainly wasn't a placebo effect. I tried many supplements in the past and none has worked the way DMAE did for those 3 days. I'm sure my speech problem has to do with my acetylcholine levels. I think I'll try CDP-Choline and L-Huperzine A.

If DMAE works, I would definitely try centrophenoxine. Do some research on it, and you'll see why I'm thinking this may be successful for a longer term.

[Leo]

If DMAE works, I would definitely try centrophenoxine. Do some research on it, and you'll see why I'm thinking this may be successful for a longer term.

Makes sense. I guess I'll try Centrophenoxine and see if it helps.

[luv2increase]

I've been taking 500mg X 3 of centro daily, and it kicks ass. I believe it affects my well-being for the better, not to mention my memory as well. I've never tried DMAE and never will due to the negative propaganda about it. Centro for the win!

[mentatpsi]

DMAE has sucked for me quite a bit. I am going to have to say that there is some sort of anticholinergic effect, given the way it affected my thinking process. I did however notice a very peculiar effect coming off of it, mental imagery increases. Luv2increase, i am kind of wondering, given Centro's similar nature to DMAE, is there not some form of resemblance in effects? What have you noticed?

[Leo]

Same here. My dreams became more vivid when I tried DMAE.

I did however notice a very peculiar effect coming off of it, mental imagery increases.