Scientists have no shortage of ways to measure a person&#;s cardiovascular disease risk. You are likely very familiar with low-density lipoprotein cholesterol (LDL-C), blood pressure, or markers of inflammation like c-reactive protein, just to name a few. In recent years you may have also heard of another potential risk factor for cardiovascular disease: trimethylamine-N-oxide (TMAO).

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TMAO can form after eating foods that contain choline, an important nutrient for brain health found in egg yolk, fish, poultry, and red meat. It can be measured in the blood but is actually produced in the gut. TMAO has been linked with atherosclerosis in animal studies, while observational studies in humans have shown that those with higher blood levels of TMAO have higher cardiovascular disease risk.1  The foods you eat may impact the amount of TMAO precursors and potentially the gut microbial composition, which in turn, could impact the development of TMAO.2  A lingering question has been to what extent is TMAO impacted by diet &#;  is TMAO just an indicator or are underlying disruptions in metabolism leading to the relationship with atherosclerosis?3,4

Ten years ago, researchers at The Cleveland Clinic published one of the first studies proposing a link between TMAO, dietary choline, and cardiovascular disease risk,5 but have just published a new study that offers some important new information about choline from eggs, one of the best food sources of choline available. The new study published in The American Journal of Medicine explored the difference between consuming eggs, a whole food source of choline, and taking supplemental choline on TMAO production, and concluded &#;&#; it may be more prudent to recommend natural sources of choline, like eggs, over supplements.&#;6

In this study of healthy adults, TMAO concentrations increased from baseline to end-of-study in the participants who consumed a choline bitartrate supplement alone or in combination with whole eggs or egg whites; however, there was no change in TMAO concentrations in the participants who consumed eggs alone or for those who took supplement of phosphatidylcholine, a form of choline found in eggs.

The results of this new study from Cleveland Clinic align with other studies in healthy, young adults that have indicated higher intake of choline from eggs (2-3 eggs/day) has no impact on blood levels of TMAO.7-9  Additionally, a recent study in postmenopausal women who were overweight found that consuming two eggs per day for four weeks did not impact TMAO concentration.10  Overall, &#;Most recent dietary interventions do not support significant increases in TMAO in healthy individuals or in those with a chronic condition.&#;3

This new study is important for eggs, as it demonstrates that food sources of choline may be viewed differently than dietary supplements. &#;These findings imply that the form of choline ingested may differentially influence gut-microbiota dependent TMAO generation.&#;6  Although the supplement data need to be replicated, these new data strongly support previous work showing eggs as a food source of choline can be an important part of heart-healthy diets.

You&#;ve likely heard of the benefits of choline and that it is an important nutrient for brain health throughout the lifespan. Here are some ways choline plays an essential role in overall health:

• During pregnancy, choline helps the baby&#;s brain and spinal cord develop properly and supports brain health throughout life.
• Infants and young children need choline for continued brain development and health.
• Choline is part of a neurotransmitter called acetylcholine, which is important for muscle control, memory and mood.11

• Choline is also important for the support of membranes that surround your cells, the transportation of fats throughout the body and for liver health.
• New research is exploring how choline throughout life may have lasting effects on cognition and prevention of cognitive decline.12

In fact, the - Dietary Guidelines for Americans recommends eggs as a notable source of choline to support brain health and development during pregnancy. Most Americans, about 90%, don&#;t consume enough choline. Fortunately, eggs are an excellent source. Just one large egg provides the daily choline needs for babies and toddlers, and two large eggs provide more than half of the daily choline needs for pregnant moms.

References

1. Blesso, C.N. and M.L. Fernandez, Dietary Cholesterol, Serum Lipids, and Heart Disease: Are Eggs Working for or Against You? Nutrients, . 10(4).
2. Yang, J.J., et al., Circulating trimethylamine N-oxide in association with diet and cardiometabolic biomarkers: an international pooled analysis. Am J Clin Nutr, .
3. Thomas, M.S. and M.L. Fernandez, Trimethylamine N-Oxide (TMAO), Diet and Cardiovascular Disease. Curr Atheroscler Rep, . 23(4): p. 12.
4. Jia, J., et al., Assessment of Causal Direction Between Gut Microbiota-Dependent Metabolites and Cardiometabolic Health: A Bidirectional Mendelian Randomization Analysis. Diabetes, . 68(9): p. -.
5. Wang, Z., et al., Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature, . 472(): p. 57-63.
6. Wilcox, J., et al., Dietary Choline Supplements, but Not Eggs, Raise Fasting TMAO Levels in Participants with Normal Renal Function: A Randomized Clinical Trial. Am J Med, .
7. Lemos, B.S., et al., Effects of Egg Consumption and Choline Supplementation on Plasma Choline and Trimethylamine-N-Oxide in a Young Population. J Am Coll Nutr, : p. 1-8.
8. DiMarco, D.M., et al., Intake of up to 3 Eggs/Day Increases HDL Cholesterol and Plasma Choline While Plasma Trimethylamine-N-oxide is Unchanged in a Healthy Population. Lipids, . 52(3): p. 255-263.
9. Missimer, A., et al., Compared to an Oatmeal Breakfast, Two Eggs/Day Increased Plasma Carotenoids and Choline without Increasing Trimethyl Amine N-Oxide Concentrations. J Am Coll Nutr, . 37(2): p. 140-148.
10. Zhu, C., et al., Whole egg consumption increases plasma choline and betaine without affecting TMAO levels or gut microbiome in overweight postmenopausal women. Nutr Res, . 78: p. 36-41.
11. Wallace TC. A comprehensive review of eggs, choline, and lutein on cognition across the life-span. J Am Coll Nutr , 37(4), 269-285.
12. Caudill MA, et al. Maternal choline supplementation during the third trimester of pregnancy improves infant information processing speed: a randomized, double-blind, controlled feeding study. FASEB J. ;32:-.

Citicoline Warning

park_bear

&#;

7 months ago

&#;

16 Replies

Citicoline and choline contain the trimethylamine structure which can be detached by gut bacteria into standalone trimethylamine. Trimethylamine is toxic. Excessive intake of choline results in a dramatic increase in the risk of cardiovascular disease. My writing on this subject here: tinyurl.com/2p8jjuf8

How about citicoline? According to this paper: ncbi.nlm.nih.gov/pmc/articl...

"It is hypothesized that, compared to choline moiety in other dietary sources such as phosphatidylcholine, choline in citicoline is less prone to conversion to trimethylamine (TMA) " [Emphasis added] This is merely an hypothesis which has not been validated by laboratory testing.

On the other hand I've experienced a bit of numbness in my toes when I have ingested things that are detrimental to my circulation. After taking 1,000 mg of citicoline for about a week I began again experiencing that numbness, so I will be stopping this particular experiment.

I have also added the foregoing warning to my post Laurie Mischley on Using High DHA Fish Oil and Citicoline to Reduce Levodopa-Induced Dyskinesia, located here: healthunlocked.com/cure-par...

Update - If you are already taking citicoline, have no adverse indications, and have reason to believe it is doing you some good, my advice is to get your TMAO blood level checked before too long. Based on that result you can back off if your level is high.

If you are taking a lot of levodopa, wish to reduce your dosage, and would like to try citicoline for that purpose, my advice is to monitor your TMAO levels.

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park_bear

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MBAnderson7 months ago

Ain't nothing sacred. (Every "Related Post" to the right extolls to virtues of Citicoline.)

garygjs7 months ago

Worth noting these things but it seems appropriate to consider the entirety of the evidence.

Citicoline has been used for decades - both as an approved drug and a supplement - and safety issues have not been raised. Indeed, its excellent side-effect profile is perhaps the standout feature of the literature.

It has been widely used in the elderly and those already vascularly compromised, and yet cardiac issues have not been flagged.

There are cardiac red flags in the choline literature - in animal and human studies. Not so with citicoline.

park_bear

in reply to

garygjs7 months ago

Is there any study that actually measured TMAO levels as a result of citicoline supplementation? It is very frustrating to find a recent study like this: sciencedirect.com/science/a...

Citicoline and Memory Function in Healthy Older Adults: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial

Where they were aware of the TMAO issue, but neglected to actually make any measurements. This is a standard blood test at Labcorp and Quest.

I have added to my posts the suggestion that people using citicoline monitor their TMAO levels as an alternative to abandoning it.

garygjs

in reply to

park_bear7 months ago

Not that I've seen. Which is a shame, I agree.

Looks like TMAO principally causes a problem through its tendency to damage blood vessels..principally the endothelium. Most everything I've seen indicates that citcoline is vasculo-protective.

We don't know if citicoline pushes TMAO levels up. We do know that cold water fish tends to contain both TMA and TMAO, that consumption of eg salmon can result in higher TMAO...but that ultimately these things tend to be cardio-protective.

Things are rarely simple.

For more information, please visit Citicoline Tmao.

Squarepusher

in reply to

garygjs7 months ago

Agree. Nothing elevates TMAO levels like fish, but the many of the longest lived people in the world eat fish regularly

Squarepusher

in reply to

garygjs7 months ago

Looks like garlic consumption ameliorates the effect of TMAO in the gut

nature.com/articles/s-...

park_bear

in reply to

Squarepusher7 months ago

Good find. They obtained this result with allicin from raw garlic. The implication being that cooked garlic may not be as effective.

JackBruce months ago

Very helpful indeed. And I was just about to try Citicoline for the very first time.

Rufous27 months ago

I agree with garygjs that we should be careful about vilifying cholinergic substances, including (maybe especially) citicoline. Choline is an essential nutrient that's vital for brain function and deficiency predisposes one to cognitive decline. And there is new evidence of cholinergic degeneration in PD; ncbi.nlm.nih.gov/pmc/articl....

"There is increasing interest in the clinical effects of cholinergic basal forebrain and tegmental pedunculopontine complex (PPN) projection degeneration in Parkinson&#;s disease (PD). Recent evidence supports an expanded role beyond cognitive impairment, including effects on olfaction, mood, REM sleep behavior disorder, and motor functions."

Those trying a low sulphur diet in an attempt to discourage desulfovibrio need to be careful. They could be dramatically lowering their choline levels, since the two are found in many of the same foods. Perhaps get one of those apps that analyzes one's food intake for nutrients? Sulphur is also important in the production of glutathione, arguably the body's most important antioxidant.

Citicoline appears not to elevate TMAO very much, and I really doubt Dr. Mischley would recommend it if it had substantial cardiovascular effects. 

park_bear

in reply to

Rufous27 months ago

Agree that choline is necessary in appropriate amounts. Of course Dr Mischley would not recommend something known to be detrimental, but our knowledge in this matter is incomplete.

The amount by which citicoline elevates TMA is unknown, unless you have actual data that speaks to this issue. Cardiovascular effects take a long time to manifest. Increased risk may not be obvious without a study tracking the matter. In this case risk is known to be the result of high levels of TMA. TMAO is a marker for TMA. I advise people taking citicoline, especially at a thousand milligrams per day, to have their TMAO levels checked. You can call this advice whatever you like but I call it good sense.

BeedieBird7 months ago

How about reducing the citicoline instead of dropping it altogther to see if your numbness improves? I have neuropathy in my feet but only on 300 mg of citicoline, which I started about 4 weeks ago. Huge improvements for me in stiffness, levodopa efficiency, reduced levodopa and no more dyskinesia. No additional numbness in my feet as a result of starting citicoline. I am on gabapentin, 300 mg a day for the neuropathy.

Rufous27 months ago

Park Bear, you said..."Cardiovascular effects take a long time to manifest."  That's why I don't think TMAO is to blame for your numbness. Atherosclerosis wouldn't develop or worsen that quickly. And vasoconstriction isn't a likely cause either, as citicoline is known for improving circulation. Have you considered the possibility that nerves in your feet might be responding to improved micro-circulation?

Anyway, those who want to try citicoline could start with small doses, as BeedieBird suggests. And they could consider supplementing with things that inhibit TMAO, like Vit. D, fish oil, berberine and 3,3-Dimethyl-1-butanol. The latter is found in olive oil, balsamic vinegar, grapeseeds and red wine, and may contribute to the Mediterranean diet's heart healthy reputation. Fish oil's ability to inhibit TMAO production might explain why fish is heart healthy, even though it contains high levels of TMA.

Those who want to be super cautious can do as you suggest and test their TMAO levels, no doctor's orders required. walkinlab.com/products/view...

park_bear

in reply to

Rufous27 months ago

There's more to it and I'm not going to get into all the details except to say that it has been medically diagnosed as a circulatory problem and I believe that diagnosis is correct.

Rufous27 months ago

Got it. Hope that gets better for you.

tiredpuppy7 months ago

Studies I've seen in the past used 500 mg per day. Taking too much of anything may cause unwanted side effects.

Ashti6 months ago

Thank you for this.

Here is a summary of TMAO related to diet, and includes links to more the short videos related to TMAO and diet at the bottom. This info is gathered and evaluated from the peer-reviewed nutrition research:

nutritionfacts.org/topics/t...

It is not specific to citicoline supplementation, but it is pointing to a vegan diet limiting your ability to produce TMAO, which sounds like a possible strategy to avoid the potential TMAO problem.

From the link: &#;TMAO, short for trimethylamine oxide, was identified when the blood of patients who had experienced a heart attack or stroke was compared to the blood of those who hadn&#;t. The more TMAO people had in their blood, the more likely they were to go on to suffer a heart attack, stroke, or otherwise die prematurely. Where does TMAO come from? Just as short-chain fatty acids are produced by good bacteria in our gut when we eat fiber, TMAO originates from bad bacteria in our gut when we eat lots of choline (concentrated in eggs, but also lecithin supplements) or carnitine (concentrated in meat, but also some energy drinks).

If you eat eggs or meat, you get a bump in TMAO levels within hours, unless you recently took antibiotics that wipe out your gut flora. In that case, it can be weeks before your bad bacteria grow back. Alternately, you can prevent the growth of these bad bacteria by not feeding them in the first place. Feed a vegan a steak, and they make virtually no TMAO, presumably because they hadn&#;t been fostering the growth of steak-eating bacteria.

The egg and beef industries funded a joint study that showed TMAO levels were lowest after eating the non-egg and non-beef control food: fruit. Even relatively choline-rich plant foods don&#;t seem to cause a problem. For example, two ounces of pistachios every day actually seemed to cause a reduction in levels.

TMAO may help explain why those who eat more plant-based diets are more protected from heart disease. &#;

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