I finished recording a podcast on riboflavin over the weekend with Chris Masterjohn, which I’ll link to here when it is published.

UPDATE: Here is a link to the podcast.

UPDATE #2: I personally use Pure Therapro’s Methyl B Complete because it is the best and most affordable ($10 per month) MTHFR-addressing supplement I have come across. Full disclosure: the link goes through my affiliate account on Amazon, so I do receive a small portion of the profit from your purchase.

During my research for the podcast, I came across the fascinating discovery that people with the 677C→T (A222V) polymorphism for the methylenetetrahydrofolate reductase (MTHFR) enzyme may simply need some extra riboflavin to make the enzyme work like normal.

People who have a mutation in MTHFR have reduced enzyme activity that affects their ability to use folate in the methionine cycle. Specifically, they are unable to convert 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate (5-methyl THF), the primary circulatory form of folate utilized in homocysteine remethylation to methionine.

The 677C→T (A222V) variant has been particularly noteworthy since it has become recognized as the most common genetic cause of elevated homocysteine levels. ¹

Most people, myself included, simply circumvent the issue by supplementing with 5-methyl THF, thereby supplying what the body has difficulty making.

But another option may simply be to take some riboflavin to make the enzyme work properly again. The 677C→T MTHFR mutation causes the enzyme to have a reduced binding affinity for the riboflavin-containing molecule flavin adenine dinucleotide (FAD). ^2,3

Supplementing riboflavin can saturate the mutated enzyme with FAD, compensating for its reduced ability to bind to FAD.

As shown in the image below, people with the 677C→T MTHFR mutation have elevated homocysteine levels only when riboflavin status (measured by the EGRAC) is inadequate (>1.2). ⁴

We also have at least one intervention that I’m aware of showing that supplementing 1.6 mg of riboflavin per day for 12 weeks reduces homocysteine in MTHFR 677C→T carriers, although statistical significance is achieved only in the TT genotype.⁵ All the participants had an EGRAC > 1.3 at baseline (average of 1.44).

This effect, however, was driven entirely by people with the TT MTHFR genotype and poor riboflavin status at baseline (EGRAC > 1.4), with homocysteine declining by 40% (22 → 13.2 umol/L).⁵

Importantly, supplementation improved riboflavin status by only 8–12% among all the participants, meaning that average EGRAC levels declined to a minimum of about 1.27.⁵ It is possible that effects in both CT and TT genotypes would have been more pronounced with a greater dose of riboflavin and greater improvement in riboflavin status.

Summing up

If you have the MTHFR 677C→T mutation, then consider supplementing with 2–5 mg of riboflavin per day, which appears to have a consistent effect on riboflavin status that we can see in as little as two weeks.⁶ If you want to use higher doses, riboflavin absorption is pretty solid up to about 27 mg in a single bolus,⁷ with no known upper limit for toxicity.

Improving riboflavin status may make MTHFR work like it should, since the 677C→T mutation simply reduces its ability to bind with its riboflavin-dependent cofactor (FAD). It’s literally addressing the cause (making MTHFR work like normal) rather than the symptom (supplementing with 5-methyl THF because you make less of it).

References