MTHFR in Fatigue, Brain Fog, and Athletic Performance
Methylenetetrahydrofolate reductase (MTHFR) is a gene involved in folate metabolism and methylation, a set of reactions that support DNA synthesis, red blood cell production, neurotransmitter balance, and amino acid metabolism. In athletic and performance settings, MTHFR is often discussed as a primary driver of fatigue, poor recovery, or brain fog. When interpreted correctly and paired with functional labs, MTHFR testing can support a more personalized, targeted plan rather than trial and error supplementation. The two common variants, C677T and A1298C, can reduce enzyme activity to varying degrees. Many people carry one or both variants and remain completely healthy.
How MTHFR Can Influence Performance
If methylation capacity is limited, individuals may notice less resilient recovery during high training loads, poorer sleep quality, higher perceived fatigue, or slower improvement in body composition. This is not only true for athletes, but the general population as well. The pathway becomes clinically relevant when there is a measurable signal such as elevated homocysteine, low folate, low vitamin B12, or anemia patterns.
Homocysteine as a Biomarker
Homocysteine is an important biomarker in athletes. Homocysteine as a biomarker integrates methylation capacity with diet, B vitamin status, thyroid function, kidney function, and inflammation. When homocysteine is elevated, targeted methylation support is often helpful. The standard reference levels for homocysteine may underestimate symptoms in athletes, with many having symptoms at homocysteine levels that are half of the upper limit for the normal population.
Treating Elevated Homocysteine
A common first line treatment option for elevated homocysteine is methylated vitamin B12 (methylcobalamin). B12 is required for homocysteine recycling, and it is a frequent bottleneck in active adults. B12 is a required cofactor for homocysteine recycling and because subclinical B12 insufficiency is more common in athletes, treating with B12 can be helpful.
MTHFR variants mainly reduce the body’s ability to generate 5 MTHF (5 methyltetrahydrofolate), which is the folate form that supplies the methyl group needed to recycle homocysteine back to methionine. This recycling reaction (methionine synthase) requires vitamin B12 in its methylated cofactor form (methylcobalamin). So in an MTHFR context, B12 matters because if B12 is low or borderline, the pathway bottlenecks further and homocysteine is more likely to rise.
Where the form matters is simpler: cyanocobalamin has to be converted by the body into active coenzyme forms (including methylcobalamin) before it can function in methionine synthase. Methylcobalamin is already in the active form used in that step, so it is a reasonable first line choice when the goal is to support energy metabolism in individuals with MTHFR mutations. Methylfolate and riboflavin (B2) supplementation may also be useful in some individuals.
If homocysteine remains elevated despite correcting the basics, betaine (trimethylglycine) can be considered as an additional methyl donor strategy in selected patients. This is not a default supplement for everyone, but it can be helpful when the goal is specifically reducing homocysteine after addressing B12, folate, and riboflavin foundations.
When MTHFR Testing is Warranted
Genetic testing can be useful when a symptomatic individual has persistently elevated homocysteine without a clear nutritional explanation, a strong family history of premature vascular disease, recurrent pregnancy loss concerns in a partner context, or when a clinician is trying to make sense of an atypical pattern of labs across folate, B12, and homocysteine.
A common trap is building a large "methylation stack" without labs, then attributing any symptom change to MTHFR. For athletes, other drivers of fatigue and recovery are sleep, energy availability, iron status, training load management, and cardiometabolic health. Supplements should support those foundations, not replace them. It is also important to avoid chronically high dose B6, and to be careful with stacking multiple products that contain B vitamins.
Conclusion
MTHFR variants are common and are not, by themselves, a performance diagnosis. The most practical approach is to focus on functional consequences, especially homocysteine and B vitamin status, then treat what is treatable. When supplementation is appropriate, methylated B12 is a common first line option, often paired with folate and riboflavin support, with careful dosing and follow up testing.
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References
Froese D, et al (2019). Vitamin B12 , folate, and the methionine remethylation cycle-biochemistry, pathways, and regulation. J Inherit Metab Dis Jul;42(4):673-685.
Moll S, Varga EA (2015). Homocysteine and MTHFR Mutations. Circulation132(1):e6-e9.
McNulty H, et al (2006). Riboflavin lowers homocysteine in individuals homozygous for the MTHFR 677C→T polymorphism. Circulation 113(1):74-80.