Scientific Support

The scientific literature supports the involvement of iodide, selenium, and molybdenum as essential to activation of vitamin B2.  Vitamin B2 in the active form of flavin adenine dinucleotide (FAD) is the co-enzymatic form that allows MTHFR to function, hence is involved in methylation.  Here are several papers that explain the interconnected dynamic of iodide, selenium, molybdenum, vitamin B2, and folate in vitamin B12 activation.

 

[This paper explains how both iodine and selenium are involved in thyroid hormone production.]

Schomburg, L. and Köhrle, J. (2008), On the importance of selenium and iodine metabolism for thyroid hormone biosynthesis and human health. Mol. Nutr. Food Res., 52: 1235-1246. https://doi.org/10.1002/mnfr.200700465

 

"It had been shown that thyroxine regulates the conversion of riboflavin to riboflavin mononucleotide and flavin adenine dinucleotide (FAD) in laboratory animals. In the hypothyroid rat, the flavin adenine dinucleotide level of the liver decreases to levels observed in riboflavin deficiency. We have shown that in six hypothyroid human adults, the activity of erythrocyte glutathione reductase, an accessible FAD-containing enzyme, is decreased to levels observed during riboflavin deficiency. Thyroxine therapy resulted in normal levels of this enzyme while the subjects were on a controlled dietary regimen. This demonstrates that thyroid hormone regulates the enzymatic conversion of riboflavin to its active coenzyme forms in the human adult."

Cimino JA, Jhangiani S, Schwartz E, Cooperman JM. Riboflavin metabolism in the hypothyroid human adult. Proc Soc Exp Biol Med. 1987 Feb;184(2):151-3. doi: 10.3181/00379727-184-42459. PMID: 3809170.

"In the entire studied population, the concentration of vitamin B2 was significantly negatively correlated with TSH level (R =  − 0.254; p < 0.005). In the control group, there was a positive correlation between vitamin B2 concentration and fT4 level (R = 0.378; p < 0.005). Moreover, in the [Hashimoto's] group, there was a negative correlation between vitamin B2 concentration and TSH level (R =  − 0.250; p < 0.005) and positive with age (R = 0.262; p < 0.005)." [This is saying that people with reduced thyroid output were shown to have lower vitamin B2 status.]

Mikulska-Sauermann, A.A., Karaźniewicz-Łada, M., Filipowicz, D. et al. Measurement of Serum Vitamins B2 and B6 in Patients with Hashimoto’s Thyroiditis by LC–MS/MS Method. Chromatographia 87, 433–443 (2024). https://doi.org/10.1007/s10337-024-04319-x

 

"Activation of riboflavin into its physiologically important coenzymes requires an initial phosphorylation by flavokinase (ATP:riboflavin 5-phosphotransferase) to form FMN and a subsequent pyrophosphorylation with AMP catalyzed by FAD synthetase (ATP:FMN adenylyl transferase). Both flavin biosynthetic enzymes are up-regulated by thyroid hormones in most mammalian cells."

"Primary deficiencies and diminished intestinal transport are not the only causes of riboflavin deficiency. Endocrine abnormalities (aldosterone and thyroid hormone insufficiency), specific drugs (tricyclic antidepressants and tetracyclic antibiotics), and ethanol abuse may interfere significantly with riboflavin utilization."

Pinto JT, Zempleni J. Riboflavin. Adv Nutr. 2016 Sep 15;7(5):973-5. doi: 10.3945/an.116.012716. PMID: 27633112; PMCID: PMC5015041.

[This study concludes that human FAD synthase (FADS) converts flavin mononucleotide into FAD, and its activity is influenced by the presence of molybdenum. The enzyme contains a molybdopterin-binding domain that is critical for its function.  Proper activation of vitamin B2 to its FAD form is dependent upon sufficient molybdenum status.]

Giancaspero TA, Galluccio M, Miccolis A, Leone P, Eberini I, Iametti S, Indiveri C, Barile M. Human FAD synthase is a bi-functional enzyme with a FAD hydrolase activity in the molybdopterin binding domain. Biochem Biophys Res Commun. 2015 Sep 25;465(3):443-9. doi: 10.1016/j.bbrc.2015.08.035. Epub 2015 Aug 12. PMID: 26277395.

 

figure 2
[This paper explains the possible link between dysfunctional MTHFR and psychiatric diseases.  Whether there is a strong link or not, the biochemical pathway diagram above depicts FAD as a coenzyme involved in MTHFR activity, meaning it is dependent upon FAD availability.]
Wan, L., Li, Y., Zhang, Z. et al. Methylenetetrahydrofolate reductase and psychiatric diseases. Transl Psychiatry 8, 242 (2018). https://doi.org/10.1038/s41398-018-0276-6
      "The vitamins folic acid and B-12 serve as coenzymes in one-carbon metabolism...Vitamin B-12 acts as a cofactor for methionine synthase (MS), which catalyzes the remethylation of homocysteine to methionine. The methyl group is donated by [methyl-folate], which is derived by the irreversible reduction of methylene-THF to methyl-THF by methylene-THF reductase. If MS is inactivated by a lack of vitamin B-12, the result is a functional folate deficiency (ie, a lack of the nonmethylated folates needed for serine-glycine interconversion and the synthesis of purines and pyrimidines) as folate becomes increasingly “trapped” as methyl-THF."
      Selhub J, Morris MS, Jacques PF, Rosenberg IH. Folate-vitamin B-12 interaction in relation to cognitive impairment, anemia, and biochemical indicators of vitamin B-12 deficiency. Am J Clin Nutr. 2009 Feb;89(2):702S-6S. doi: 10.3945/ajcn.2008.26947C. Epub 2009 Jan 13. Erratum in: Am J Clin Nutr. 2009 Jun;89(6):1951. PMID: 19141696; PMCID: PMC2647758.
      "Biochemical and clinical symptoms common to both folate and vitamin B12 deficiency are due to the induction of a functional folate deficiency, which in tum is induced by [vitamin B12] deprivation."  [This review also highlights the direct correlation of thyroid hormone on MTHFR acitivity.]
      Shane B, Stokstad EL. Vitamin B12-folate interrelationships. Annu Rev Nutr. 1985;5:115-41. doi: 10.1146/annurev.nu.05.070185.000555. PMID: 3927946.