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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MTHFR and Homocysteine – The Basics

High homocysteine is often the first indication of an MTHFR issue, and it’s certainly the one that doctors take the most seriously. There is a good reason for this. Homocysteine is implicated in heart disease including heart attack and stroke, so it shouldn’t be taken lightly. 

What is Homocysteine?

Homocysteine is an amino acid that is made within your body as a part of methionine metabolism. Amino acids are the basic building blocks of protein, and we take in amino acids every time we eat protein-containing foods.

We need homocysteine in order to make ATP, our cellular energy, and also to make cysteine and ultimately glutathione, which is our master antioxidant. The problem comes when levels get too high, and this happens when your body is unable to recycle homocysteine back into methionine.

The primary recycling pathway relies on the MTHFR enzyme, as well as active folate and B12. There is a secondary pathway called the BHMT pathway that ramps up when homocysteine levels start to rise and this relies on other methylators like betaine, trimethylglycine (TMG), and choline. 

Why does Homocysteine Get High?

As usual, there are a number of reasons and many of them are related to MTHFR.

  • MTHFR compromise – your body recycles homocysteine into methionine in an MTHFR-dependent process. It requires the active form of folate for the process so if your MTHFR is running slowly or inefficiently then homocysteine levels can build up causing inflammation and damage.
  • Folate deficiency – Whether or not you have an MTHFR issue, if you don’t have folate then the recycling doesn’t happen either.
  • B2 or B12 deficiency – Like folate, these vitamins are necessary for methionine recycling, and not having enough of them can raise your homocysteine to an unhealthy level.
  • Too Much Protein intake – This is certainly a first-world problem and a bigger one recently with everyone doing fad diets from Keto to Atkins to Paleo. If you’re taking in higher levels of methionine than your body can easily process, then homocysteine is going to build up. Also, meats and dairy have some naturally occurring homocysteine in them. We’ll talk more about the methionine situation next week.
  • Other medical conditions – thyroid disease, rheumatoid arthritis, and diabetes are linked to higher homocysteine levels.
  • Medications that decrease folate absorption – proton pump inhibitors, birth control pills, antifolate agents, and some anticonvulsant medications interfere with folate absorption or metabolism.
  • High coffee intake – I am sorry to say, high coffee intake is also linked to elevated homocysteine.

What Does Homocysteine Do That’s So Bad?

So many things. Homocysteine is vital, of course, but in this situation, too much of a good thing becomes toxic.

  1. Inflammation – Inflammation is the most well-documented issue to do with homocysteine. It is specifically damaging to cell membranes and the lining of your blood vessels, which is part of why it is so linked to heart disease.
  2. Clotting – Clotting in the blood vessels can lead to heart attack, stroke, pulmonary embolism, and deep vein thrombosis, none of which are good. This is thought to be due to a combination of factors. One is that nitric oxide metabolism is compromised and so blood vessels aren’t able to dilate properly. The other is that thromboxane A2 (TXA2) activity is increased in both blood vessels and platelets, possibly because of a higher free radical burden. This promotes clotting.
  3. Neurological issues – High homocysteine levels are implicated in a number of neurological disorders including stroke and Alzheimer’s disease, but extending to disorders like epilepsy, Parkinson’s, multiple sclerosis, and ALS. The research is unclear in terms of whether homocysteine is actually a causative factor in its own right or just a marker of low B-vitamin status.
  4. Fractures –  Research shows that homocysteine significantly increases fracture risk and it appears to be independent of other risk factors, but it is unclear whether or not B vitamin supplementation decreases that risk.
  5. Microalbuminuria – Microalbuminuria is an abnormal protein in the urine and it indicates a high future risk of cardiovascular disease as well as kidney dysfunction. Every 5 umol/L increase in homocysteine levels is associated with an increased risk of developing microalbuminuria.
  6. Atherosclerosis – As a consequence of the increased inflammation in your arteries, your body is more likely to lay down arterial plaque to protect itself. This isn’t the direction you want to go. High blood pressure – possibly because of the issues with blood vessel dilation, blood pressure and homocysteine go hand in hand. High homocysteine increases the thickness of arterial walls, reduces the elasticity of arteries, and increases the production of stiffer collagen fibers in the vascular system. 
  7. Pregnancy complications – High homocysteine levels have been implicated in spontaneous abortion, placental abruption, and preeclampsia. 

Is There Anything Good About Homocysteine at All?

Homocysteine is certainly an issue for MTHFR folks, but it’s also incredibly helpful for us as a biomarker. Testing your homocysteine gives you an easy way to see if your methylation is becoming unbalanced at the moment. While it’s a small silver lining, it’s still a good one.

We’ll talk more about the role of methionine in this conversation as well as testing homocysteine and optimal levels in the next couple of weeks.

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