Choline

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Citicoline

An essential nutrient required for a myriad of functions, choline should be part of a well-rounded diet. Studies indicate that only about 10% of Americans consume enough dietary choline.^[39]

Additionally, endurance athletes, and people who regularly consume alcohol, are at risk of choline deficiency. Now is an important time to admit that you're probably among the looming majority of choline neglectors.

Benefits

Brain

Choline is classified as an essential nutrient. While it can be synthesized within the body, we only produce insufficient amounts -- and doing so compromises the structural integrity of our cells. Phosphatidylcholine helps to compose the lipid membrane of cells, and when enough free choline isn't available, your body breaks this structure down to obtain the compound.

This is an interesting and vicious example of biological self-immolation -- a process that favors short-term performance at the behest of compromised long-term health. Supplementing choline into your diet may circumnavigate this issue. In other words, you can have your cake and eat it too. Below are a few benefits:

Improved global cognitive function

Choline is a precursor to the neurotransmitter acetylcholine, which is implicated in memory, intelligence, and mood. Animal studies suggest that high choline intake protects the brain's ability to form and recall memories despite the progression of age. In particular, "choline-supplemented older mice performed as well as young three-month-old mice."^[31] The supplemented mice were also observed to have increased communication within the hippocampus.
Heart health and depression

Dietary choline is an essential source of methyl groups for many biological processes. For example, one metabolite of choline is trimethylglycine, or betaine (an ingredient in many pre-workout formulations), which participates in the production of SAM-e. Deficits of SAM-e are implicated in Alzheimer's disease, diabetes, heart disease, depression, and more.^[27,28,29]
Anti-inflammatory

Higher dietary intake of choline is associated with lower inflammatory markers, and reduced symptoms of allergic rhinitis.^[30]

Body

Acetylcholine is the most abundant neurotransmitter in the entire body, responsible for muscle contractions. "Consumption of supplemental choline can also increase the release of acetylcholine from nerve endings, including those that cause skeletal muscle to contract," according to a study published in Pharmalogical Reviews.^[35]

Intense exercise

Unsurprisingly, intensive exercise results in a significant reduction in plasma choline levels, particularly prolonged and strenuous activity. After two hours of exercise, participants lost about 40% to 50% of free choline.

The good news is that ingesting choline pre-exercise can not only prevent this loss, but raise it above baseline for up to two hours post-exercise (2g of free choline was used in this study).^[36]

In one study, individual performance was enhanced after choline supplementation compared to when the same individuals consumed a placebo.^[37]

Choline sources

Many different choline formulations are available. There is a huge price disparity between certain supplements. Some are very cheap and others comparatively expensive. Naturally, you would want potency to increase along with price -- which the expensive ones certainly do -- but the real advantage of CDP-choline (expensive) over something like choline citrate (cheap) is its fanciness.

Choline Molecule

All choline precursors follow the same protocol: choline bound with some other chemical. For the cheap supplements, the choline is bound to another relatively inactive compound, so you're essentially getting just choline. But the expensive acetylcholine precursors consist of choline bound with other biologically active compounds that enhance absorption or produce other reactions that work to multiply choline's effects. Below is a list of the most common formulations. Each has its own particular benefits and detractions.

Choline bitartrate and choline citrate

These two are thrown together because they are so similar in the most important respects. Simple choline salts are cheap as dirt, but have questionable potency. Users have complained of stomach aches because of the amount consumed for desired effects, but you get what you pay for.

You may ask why these compounds are not very potent. Technically free choline, due to its polarity, would not be able to cross the blood-brain barrier. While we have a choline transport system, it's sadly inefficient and seems to decline with age.

CDP-choline

Hands down, this is the best choline source available. Multitudes of animal research and fair amounts of human research attest to the efficacy of CDP-choline, or citicoline.

Human studies have shown neuro-protective and neuro-regenerative effects

and a proven efficacy for improving the following conditions:

Alzheimer's disease
Parkinson's disease
Age-related memory and learning deficits
Stroke
Drug addiction
Glaucoma-induced ocular damage
Traumatic brain injury
Schizophrenia

CDP-choline is more expensive than bitartrate and citrate, but generally cheaper than alpha-GPC.

Alpha-GPC

A natural choline compound already swimming around your brain and derived from soy lecithin, this is probably the most bioavailable choline source, but also the most expensive. You should expect similar effects as you would with citicoline. One study found alpha-GPC more effective than citicoline for vascular dementia^[15], with another showing higher plasma choline levels after alpha administration over CDP.

As you can see, alpha-GPC and CDP-choline are the two rock stars of acetylcholine precursors. Some studies suggest GPC is better, but there is just so much more research attesting to the efficacy of CDP-choline.

Other enhancers

Choline metabolism

You may notice by now that you need an acetyl to go with that lonely choline for magic to happen. That is absolutely true, and a great addition to a basic choline stack is ALCAR, or acetylcarnitine.

ALCAR

Acetyl L-carnitine is great stuff -- no argument. It's naturally produced in your body during strenuous exercise, and supplementation has dramatic effects, irrespective of its role in energy production.

By donating the acetyl group, ALCAR enhances acetylcholine production.
Both ALCAR and L-carnitine stimulate muscle production.
It stimulates nerve growth factor release.
Improves neuronal membrane fluidity (more communication).
Acetylcholine receptor agonist.
Increases the utilization of glucose, ketone bodies, and lipid substrates in the brain.
Improves choline uptake (thus acetylcholine synthesis).^[21]

Aside from the pro-cognitive effects, ALCAR may have overall lifespan enhancing effects. Simply put, our mitochondria (powerhouse of cells) have to put up with decades of abuse, and they produce toxic reactive oxygen species (ROS), or free radicals. A damaged mitochondrion is leaky and our current understanding of the aging process points many fingers toward this compromised structure. "Acetyl-L-carnitine, a high-energy mitochondrial substrate, appears to reverse many age-associated deficits in cellular function."^[16]

DMAE

This compound is frequently cited as a choline precursor, but it probably has little if anything to do with acetylcholine production.^[25] Rather, DMAE seems to bind with phospholipids that compose cellular membranes. Where phosphatidylcholine would be, phosphatidyl-dimethylaminoethanol now takes its place, increasing membrane permeability and antioxidant capacity.^[26]

Centrophenoxine

Also known as meclofenoxate, this is basically supercharged DMAE (specifically an ester of DMAE). Though limited evidence suggests mental stimulation and memory improvement, it has beneficial phospholipid properties with little direct effects on choline or acetylcholine.

Racetams

Bacon and eggs

If you are taking any of the racetam derivatives, then you probably know that the cholinergic system is involved with their effects. Many people believe this means your brain on piracetam, for example, will consume more choline than otherwise. Two studies, conducted on rats, assert that piracetam and oxiracetam reduces hippocampal acetylcholine levels.^[32,33] Regardless, other animal studies suggest a synergistic effect with racetams and a choline source.^[34] For many, choline and piracetam is like bacon and eggs -- it just feels right for them to keep each other company.

Consider Noopept

Although it's not technically a "racetam", Noopept is structurally very similar, and yields a piracetam-like effect, but many think it's even better.

It stacks incredibly well with choline -- you can read more on the Noopept blog post linked just above.

Choline intake

According to the Institute of Medicine, the adequate intake (AI) of choline is 425mg/day for women and 550mg/day for men. As a reference, any of the choline salts (bitartrate, citrate) are about 41% free choline. So something over 1000mg should satisfy your minimum daily requirements.

Remember that choline is present in many foods, most prominently in beef, beef liver, and eggs.

Hands down, CDP choline (citicoline) is the best choline source available.

It's difficult to determine what the optimal dose would be for cognitive function. The cholinergic system is tricky, and everyone is different. With that said, the most common dose for all choline precursors falls somewhere between 250mg to 2000mg.

None of these statements constitute medical advice. These supplements are not regulated or approved by the FDA. You should consult a medical doctor before embarking on self-treatment.

Side effects

The side effects of choline supplementation seem few, mild, and transient. As mentioned above, people occasionally complain of stomach discomfort. If you happen to have the rare genetic disorder, trimethylaminuria, consuming too much choline will make your body exude the odor of overripe fish.

References

Alvarez, XA; Methods and Findings in Experimental and Clinical Pharmacology; "Double-blind placebo-controlled study with citicoline in APOE genotyped Alzheimer's disease patients. Effects on cognitive performance, brain bioelectrical activity and cerebral perfusion;" 1999
Secades, JJ; Methods and Findings in Experimental and Clinical Pharmacology; "CDP-choline: pharmacological and clinical review;" 1995
Marti Masso, JF; Clinical Therapeutics; "Citicoline in the treatment of Parkinson's disease;" 1991
Cubells, JM; Clinical Therapeutics; "Clinical trial on the use of cytidine diphosphate choline in Parkinson's disease;" 1988
Babb, SM, et. al.; Psychopharmacology; "Chronic citicoline increases phosphodiesters in the brains of healthy older subjects: an in vivo phosphorus magnetic resonance spectroscopy study;" 2002
Antoni D?valos, MD, et. al.; American Heart Association; "Oral Citicoline in Acute Ischemic Stroke An Individual Patient Data Pooling Analysis of Clinical Trials;" 2002
Lukas, SE, et. al; Psychopharmacology; "Effects of short-term citicoline treatment on acute cocaine intoxication and cardiovascular effects;" 2001
Renshaw, PF, et. al.; Psychopharmacology; "Decreased activity of brain phospholipid metabolic enzymes in human users of cocaine and methamphetamine;" 1999
Renshaw, PF, et. al.; Psychopharmacology; "Short-term treatment with citicoline (CDP-choline) attenuates some measures of craving in cocaine-dependent subjects: a preliminary report;" 1999
Parisi, V, et. al.; Progress in Brain Research; "Evidence of the neuroprotective role of citicoline in glaucoma atients;" 2008
Secades, JJ, et. al.; Methods and Findings in Experimental and Clinical Pharmacology; "CDP-choline: pharmacological and clinical review;" 1995
Zafonte, R.; Journal of Neurotrauma; "The citicoline brain injury treatment (COBRIT) trial: Design and methods;" 2009
Deutsch, SI, et. al.; Clinical Neuropharmacology; "First administration of cytidine diphosphocholine and galantamine in schizophrenia: A sustained alpha7 nicotinic agonist strategy;" 2008
De Jesus Moreno Moreno, M; Clinical Therapeutics; "Cognitive improvement in mild to moderate Alzheimer's dementia after treatment with the acetylcholine precursor choline alfoscerate: A multicenter, double-blind, randomized, placebo-controlled trial;" 2003
Di Perri, R, et. al; Journal of International Medical Research; "A multicentre trial to evaluate the efficacy and tolerability of alpha-glycerylphosphorylcholine versus cytosine diphosphocholine in patients with vascular dementia." 1991
Shigenaga, MK, et. al.; PNAS; "Oxidative damage and mitochondrial decay in aging;" 1994
Na?ecz, KA, et. al.; Molecular Aspects of Medicine; "Carnitine: transport and physiological functions in the brain;" 2004
Gibson, GE, et. al.; Biochemical Pharmacology; "Studies on the metabolic pathway of the acetyl group for acetylcholine synthesis;" 1980
Aureli, T, et. al.; Brain Research; Aging brain: Effect of acetyl-L-carnitine treatment on rat brain energy and phospholipid metabolism. A study by 31P and 1H NMR spectroscopy;" 1990
Angelucci, L, et. al; Journal of Neuroscience Research; "Nerve growth factor binding in aged rat central nervous system: Effect of acetyl-L-carnitine;" 1988
Plovesan, P, et. al.; Brain Research; "Acetyl-L-carnitine treatment increases choline acetyltransferase activity and NGF levels in the CNS of adult rats following total fimbria-fornix transection;" 1994
Precursors of acetyl groups in acetylcholine in the brain in vivo. https://pubmed.ncbi.nlm.nih.gov/?term=Biochim+Biophys+Acta.+1970+Jun%3B208(3)%3A538-40.
Acetyl-L-carnitine as a precursor of acetylcholine. https://pubmed.ncbi.nlm.nih.gov/?term=Neurochem+Res.+1990+Jun%3B15(6)%3A597-601.
Acetyl-L-carnitine and Alzheimer's disease: pharmacological considerations beyond the cholinergic sphere. https://pubmed.ncbi.nlm.nih.gov/8239306
Is 2-dimethylaminoethanol (deanol) indeed a precursor of brain acetylcholine? A gas chromatographic evaluation. https://pubmed.ncbi.nlm.nih.gov/850128
On the role of intracellular physicochemistry in quantitative gene expression during aging and the effect of centrophenoxine. A review https://www.sciencedirect.com/science/article/pii/0167494389900423
Brain S-adenosylmethionine levels are severely decreased in Alzheimer's disease. https://pubmed.ncbi.nlm.nih.gov/8752143
Oral S-adenosylmethionine in depression: a randomized, double-blind, placebo-controlled trial. https://pubmed.ncbi.nlm.nih.gov/2183633
Choline and betaine in health and disease. https://pubmed.ncbi.nlm.nih.gov/20446114
Comparison of the efficacy of inhaled budesonide and oral choline in patients with allergic rhinitis. https://pubmed.ncbi.nlm.nih.gov/15806211
Zeisel, Steven; Annual Review of Nutrition; "Choline: critical role during fetal development and dietary requirements in adults;"
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2441939/; 2006
Piracetam diminishes hippocampal acetylcholine levels in rats. https://pubmed.ncbi.nlm.nih.gov/?term=Life+Sci.+1981+Mar+9%3B28(10)%3A1091-3
Effect of oxiracetam and piracetam on central cholinergic mechanisms and active-avoidance acquisition. https://pubmed.ncbi.nlm.nih.gov/3594455
Profound effects of combining choline and piracetam on memory enhancement and cholinergic function in aged rats. https://pubmed.ncbi.nlm.nih.gov/7301036
Wurtman, RJ; Pharmacological Reviews; "Precursor control of neurotransmitter synthesis;" 1980 https://pubmed.ncbi.nlm.nih.gov/6115400
Spector SA, Jackman MR, Sabounjian LA, Sakas C, Landers DM, Willis VVT. Effect of choline supplementation on fatigue in trained cyclists. Med Sci Sports Exerc 1995;27(5):669-73.
Conlay LA, Wurtman RJ, Blusztajn JK, Covielia IJ, Maher TJ, Evoniuk GE; NEJM, "Decreased plasma choline concentrations in marathon runners;" 1986.
The differential effects of meclofenoxate on memory loss in the elderly. https://pubmed.ncbi.nlm.nih.gov/329662
Choline: an essential nutrient for public health.https://pubmed.ncbi.nlm.nih.gov/19906248

By Mike

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