Fish Oil and MTHFR, What Is The Link?

We’ve all heard about fish oils and omega3 fatty acids for so many incredible reasons. They are strongly anti-inflammatory and perform almost as well as non-steroidal anti-inflammatory tests for pain relief, without side effects. 

They have been most strongly studied for heart disease and show an almost unbelievable array of benefits. Fish oils reduce the risk of sudden death from cardiac arrhythmias, reduce all-cause mortality in patients with known cardiac disease, and help to treat high cholesterol (hyperlipidemia) and high blood pressure (hypertension.) All of this, without significant side effects or drug interactions

Studies have also shown that countries with higher intake of omega-3 fatty acids have lower rates of depression. Fish oils have also shown beneficial effects in both research and clinical practice for diabetes, Alzheimer’s disease, stroke, and autoimmune disease. 

What about Fish Oil and MTHFR?

Most studies aren’t MTHFR-specific.  But, fish oil has benefits for so many of the long-term consequences of unbalanced methylation in MTHFR, that it makes sense that there would be some link.  What reserach has found is some kind of synnergy between fish oil and B vitamins, in which the combination works better than either therapy alone.

Omega-three fatty acids and B vitamins for cognitive decline

A randomized placebo-controlled  trial of people with mild cognitive impairment found that treatment with B vitamins lowered homocysteine and slowed the rate of cognitive decline. Researchers went back and re-analyzed the data from this study to see if baseline levels of omega-three fatty acids interacted wtih the results in any way. The study involved mental testing over the course of two years.They found that for all outcome measures, higher concentrations of DHA significantly enhanced the effects of B vitamins, while the levels of EPA had less of an impact.

Not only that, when omega-3 fatty acid levels are low, B vitamin treatment has no effect on cognitive decline, but when omega threes are in the high-normal range, B vitamin treatment becomes effective. There is some synnergy happening here that needs further investigation to fully understand, but since omega-three fatty acids are good for so many things and truly haven’t shown negative consequences it makes sense to add them in as a no-risk measure for seniors with cognitive decline.

Omega-three fatty acids and homocysteine

The methylation process itself seems to be involved in the metabolism and distribution of these polyunsaturated fats through your body, which means that MTHFR and omega-3s are intimately linked. Also, it has been theorized that omega-three fatty acids actually have expression control on enzymes within the methylation cycle, so effectively MTHFR controls omega-threes, which control MTHFR. There is not a big enough body of research yet to draw firm conclutions, but the evidence is pointing in this direction.  For MTHFR folks, the most important thing to understand is that using fish oils and B vitamins together produces a great reduction in homocysteine levels than using either one alone. 


This research suggests that omega-3 fatty acids (referred to here as PUFA or polyunsaturated fatty acids) actually stimulates the action of the MTHFR enzyme, which activates folate to generate SAMe, the methyl donor. PUFA also stimulates the MAT enzyme which converts methionine to SAM, the CCT enzyme which is involved in the conversion of choline to phosphatidylcholine, and the CGL enzyme which is involved in the conversion of Homocysteine to Glutathione. 

Inflammation, heart disease, cognitive decline, and high homocysteine are all problems that happen more frequently in folks who have MTHFR with unbalanced methylation, and since fish oils effectively address these problems, it almost seems like a gimme.

Next week, we’ll talk about a few bits of research being done regarding fish oil and gene expression for MTHFR folks. The research is new, but it’s starting to get good.

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Lowering Homocysteine with MTHFR

As with everything to do with MTHFR, balancing your methylation and boosting your B vitamins, especially B2, folate or 5-LMTHF, and B12, is the first step. Balance your methylation! There are some other things you can look into as well.

MTHFR Isn’t The Only Cause of High Homocysteine

Of course, our focus is MTHFR, but high homocysteine has other causes as well and the sad truth is, you can have fleas and ticks on the same dog. That is one of my favorite Texas expressions. What I mean by that is that just because you have MTHFR, doesn’t mean you don’t have to also watch out for other causes of high homocysteine. It’s important to manage those too. Other Causes of high homocystein (or hyperhomocysteinemia) include:

  • Poor diet
  • Poor lifestyle
  • Smoking
  • Diabetes
  • Rheumatoid Arthritis
  • Thyroid imbalance
  • Chronic inflammatory diseases
  • Celiac disease
  • Crohn’s disease
  • Long-term use of corticosteroids
  • Prescription medications
    • methotrexate (because it lowers folate)
    • metformin (long term use because it interferes with B12 absorption)
    • hydrochlorothyazide
    • Fibrate type cholesterol-lowering medications
    • Levodopa
    • Anti-epileptic drugs (long-term use)
    • Possibly nicotinic acid or niacin, but research is very conflicted.

If you have one of these underlying conditions or are taking a medication known to elevate homocysteine, then working on that condition or talking with your physician about the medication can be a great place to start. Outside of that, let’s talk about useful steps.

The MTHFR Plan to Lower Homocysteine To Optimal

  1. Balance your methylation – I’ve said it already, but the first step is always boosting your methylation cycle because this is where we tend to stall out with MTHFR. This means following the To Health With That! Plan. Eliminate folic acid, add a methylation-friendly B complex, then add 5-LMTHF, or folinic acid, or whatever workaround you are using if you don’t tolerate folate. If you aren’t familiar with the plan you can start to walk through it here.
  2. Limit your protein intake – The more protein (and consequently methionine) you take in, the more homocysteine your body makes. There’s a full article about the methionine and homocysteine link here.
  3. Quit smoking – As though you needed one more reason why smoking is bad for your health. But yes, smoking raises your homocysteine levels.
  4. Take a look at your alcohol intake – alcohol blocks folate absorption, and so increased drinking can raise your homocysteine levels. This is probably mitigated by extra folate intake, but possibly not.
  5. Balance your coffee intake – As much as it pains me, too much coffee has consequences and high homocysteine is one of them.
  6. Zinc – zinc is a cofactor in some of the enzymes involved in the recycling of homocysteine to methionine, and so zinc deficiency can increase homocysteine levels while zinc supplementation can help to improve beneficial conversion.
  7. NAC – NAC, or N-acetyl cysteine, has been shown to lower homocysteine levels as well as folate supplementation in studies.
  8. Fish oils – in a magical synergy, fish oils + B vitamins work better together than they do apart.
  9. Make sure there aren’t other underlying causes – If you’re doing everything right and your homocysteine still isn’t where you want it to be, it matters to talk to your doctor about other underlying causes. If you’re living the perfect lifestyle, but you still have a low thyroid, then fixing your thyroid is probably the only thing to bring your levels back to balance.

Don’t forget that every little step you take towards getting healthy, counts. They all add together to contribute to your state of health, today. So every little step you take in the right direction, matters. Don’t get discouraged if things don’t move right away, just keep trying.

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MTHFR and Homocysteine By The Numbers

These past few weeks we’ve gone over some general information about MTHFR and homocysteine, the link between methionine and homocysteine, and the new information about MTHFR, homocysteine, and Covid-19. What we haven’t talked about is Homocysteine testing and parameters – what is normal, what isn’t, and what is considered normal but maybe shouldn’t be.

Testing Homocysteine

Homocysteine tests are simple blood tests that can be ordered by your doctor. It must be performed fasting for accurate results. Any protein you eat before your test can skew the numbers because methionine in your food may cause a temporary rise in homocysteine. The best way to ensure a blood test is fasting is to schedule your blood test early in the day before you have eaten anything. 8 – 12 hours of fasting (like you would get overnight) is best for the most accurate results.

“Normal” Levels

The current medical standard in the U.S. is a normal range from 5 – 15 umol/L (that is micro mols/Litre). Anything above 15 micro mols/L is considered high, or hyperhomocysteinemia. There is a growing body of evidence that the normal level should be adjusted:

  • A study published in the New England Journal of Medicine shows that carotid artery thickening and stenosis risk begins to increase for men by 9.2 umol/L (although the risk for women seems to remain stable until 11.4 umol/L). Both of these are significantly lower than the 15 umol/L that is considered normal.
    • Risk increases at 9.2 umol/L
  • A meta-analysis published in the Journal of the American Medical Association shows that a 3 umol/L decrease in homocysteine leads to an 11% lower risk of ischemic heart disease and a 19% lower risk of stroke.
  • A strong linear relationship exists between homocysteine levels and death in patients with coronary disease. The lowest risk group has homocysteine below 9 umol/L and the risk increases from there both within what is considered the normal level and outside of it.
    • Homocysteine <9 umol/L = 3.4% risk of death
    • Homocysteine 9 umol/L – 14.9 umol/L = 8.6% risk of death
    • Homocysteine >15 umol/L = 24.7% risk of death.
    • Risk increases at 9 umol/L
  • The study we discussed last week dealing with homocysteine levels as a predictive marker for worse outcomes with Covid-19 also showed an increased risk for pathological lung changes on CT at 8 umpl/L
    • Risk increases at 10.58 umol/L

If The “Normal” Levels aren’t Ideal, What Is?

All of the risks for negative health outcomes seems to be lowest around the 6 – 8 umol/L mark, so we’re going to call that “Optimal.” This is an estimation based on the research that we talked about above. Joe Pizzorno (a legend in the natural wellness community), estimates the ideal range to be 5.0 to 7.0. Ben Lynch, the epigenetic expert, estimates ideal to be between 6 to 9 umol/L.

If Homocysteine Is So Bad, Why Aren’t We Aiming for Zero?

Too much homocysteine is bad for sure, and with MTHFR and homocysteine that is the direction we usually trend, but remember that homocysteine is absolutely essential. If your homocysteine is too low (hypohomocysteinemia), then there are also health consequences. Without homocysteine you can’t make glutathione, which is one of your main defenses against oxidative stress. Without glutathione, things would go sideways pretty quickly.

Homocysteine is also the precursor for something called alpha-ketobutyrate, which is a vital ingredient in the process that makes cellular energy. Very few studies are done about low homocysteine levels (I mean VERY few. I can count them on two hands). By far the most interesting one shows a link between low homocysteine and peripheral neuropathy. It states that fully 41% of people with low homocysteine have peripheral neuropathy, which is hugely significant.

In my opinion, this implies that the lack of glutathione and consequent difficulty with free radicals is leading to higher levels of inflammation and nerve damage. Ben Lynch put forward a similar theory on his website here, and Joe Pizzorno, here.

I wouldn’t be surprised to see a link between low homocysteine and chronic fatigue, as well, although the research has never been done.

The bottom line is that we need homocysteine, but too much of it becomes a big problem. Aim for 6 – 8ish micro mols/L. Next week we’ll talk about ways to lower your homocysteine levels if they’re too high.

Has your homocysteine ever tested too low? I”d love to hear your comments here, or in Genetic Rockstars, our amazing MTHFR community.

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