The Folic Acid Story
methyl-B12, trimethylglycine (TMG), or SAMe may help restore normal ranges (11).
B12, SAMe, TMG
The end product of folate metabolism, 5-MTHF, is an essential precursor for neurotransmitter metabolism and the synthesis of dopamine, serotonin, and norepinephrine. It is also necessary for the production of SAMe, which participates in over 200 enzymatic reactions in the body.
Did the FDA’s attempt to reduce birth defects have unintended consequences? In the 1990’s, the US and UK mandated the enrichment of all grain products with folic acid in hopes of reducing the occurrence of neural tube defects.
In the decades since neural tube defects have indeed declined yet little long term research has been done to determine the effects excess folate might have on non-pregnant adults. The tolerable upper limit (TUL) for folate is set at 1,000 mcg/day for adults, but with the overconsumption of fortified grain products many may exceed this threshold.
Recent studies are now taking a closer look at potential health risks of folic acid fortification for adults. Folate is not only a concern for adults, but may have particular relevance for some people with Chronic Fatigue Syndrome (ME/CFS).
What Role Might folate play in ME/CFS? folate is a vital component of the single carbon pool that participates in basic cellular processes such as amino acid metabolism, synthesis of nucleotides (DNA, RNA, ATP), and methylation (including epigenetic methylation of DNA). Low levels of folate are implicated in increased risk of cardiovascular disease, stroke, dementia, depression, cancers, and birth defects. Similarly, high levels are also associated with carcinogenesis (1). Folate metabolism is a complex, multi-step process that occurs in every cell in the body. It requires three key enzymes: dihydrofolate reductase (DHF), methylenetetrahydrofolate reductase (MTHFR), and methionine synthase (MTR).
When you consume the synthetic form of folate – folic acid – in enriched foods or supplements, it must be converted to different forms utilizing these enzymes. If this conversion is inadequate, functional folic acid deficiencies can emerge that may dampen methylation, amino acid metabolism, etc. Despite the fact that this biochemistry has been known for decades, few studies have examined the exact mechanisms by which folic acid is taken up or metabolized in the body after consumption. Those studies which have examined folic acid metabolism have relied only on mouse models which have substantially different concentrations of the above enzymes than humans (2).
A recent study in patients with stable liver disease indicated, however, that synthetic folic acid from traditional supplements was inefficiently absorbed in the intestinal tract compared to the active 5-methyl-hydrofolate (5-MTHF) form (which was taken up twice as readily). The researchers concluded that food regulatory bodies should rethink their position on folic acid enrichment.
Interestingly, the FDA and European Food Standard Agency have already approved products containing 5-MTHF derivatives to replace folic acid (3).
A Key Metabolic Factor – More Biochemistry
B12, an essential co-factor in folic acid metabolism, is often low in ME/CFS The folate cycle feeds into other key biochemical cycles as well. The end product of folate metabolism, 5-MTHF, is an essential precursor for neurotransmitter metabolism and the synthesis of dopamine, serotonin, and norepinephrine. It is also necessary for the production of SAMe, which participates in over 200 enzymatic reactions in the body.
After 5-MTHF is produced, it is then recycled back into the cycle through the enzyme methionine synthase (MTR). This reaction requires adequate B12 as a cofactor. With B12 deficiency in near epidemic proportions in the elderly, vegetarians, chronic antacid users, SIBO, and people with ME/CFS or FM, it’s possible that folic acid can become trapped as 5-MTHF in what is called the “folate trap.” This “folate trap” prevents the recycling of 5-MTHF back to THF and slows methylation and many other downstream reactions.
Finally, there is a growing understanding of the link between hypothyroidism and proper folate cycle function. Many ME/CFS and FM patients have subclinical hypothyroidism that may be related to inadequate production of 5-MTHF. This methylated form of folate is essential for the conversion of tyrosine to thyroid hormone (1).
Who With ME/CFS or Fibromyalgia Should Be Concerned With This Study? It’s possible but not certain that people with ME/CFS and FM may already be behind the eight ball, so to speak, regarding folate metabolism. Dr. Amy Yasko and the late Rich VonKoynenberg proposed that genetic mutations (single nucleotide polymorphisms or SNPs) in enzymes involved in the folate methylation pathway may be common in the ME/CFS and/or FM populations. Of the three enzymes involved in folate metabolism, methylenetetrahydrofolate reductase (MTHFR) plays the largest role in the conversion and utilization of folates. A genetic defect in this key enzyme could dramatically affect the ability to convert, recycle, and utilize folates.
Genetic Aspects An Open Medicine Institute study is examining the effects of MTHFR mutations on folate metabolism in ME/CFS. Two common genetic variations, C677T and A1298C, have been identified in the MTHFR gene that codes for the MTHFR enzyme. The C677T type has been associated with increased incidence of cardiovascular disease and other health risks (4). This MTHFR SNP has been found to be prevalent in certain populations of people. Heterozygous MTHFR C677T, meaning one copy of the gene is mutated while the other is normal, is found in 42% of Hispanics, 35% of Caucasians, and 14% of African Americans. Homozygotes, where both copies of the gene are mutated, are less common in the general population with 10% preponderance (5).
Further research and stricter study design are certainly warranted. Another study measuring levels of homocysteine in the cerebrospinal fluid of CFS/FM patients found elevations suggestive of problems recycling folate back to methionine. However, it was unclear whether these findings were due to genetic SNPs in enzymes, folate deficiencies, or B12 deficiencies (8).
The Open Medicine Institute is currently engaged in a study to determine the extent of MTHFR mutations and the role they may play in aberrant folate metabolism in ME/CFS.
What Problems Might High Levels of Unmetabolized Folic Acid (UMFA) Pose?
If enzymatic road blocks from genetic mutations or inadequate enzyme cofactors inhibit synthetic folic acid metabolism, high concentrations of folic acid can spill over into the portal circulation. A natural killer connection, of all things, may be possible Elevated levels of unmetabolized folic acid (UMFA) have been implicated in increased overall mortality (9). Epidemiological studies have found a striking association between the incidence of colon cancers and folic acid food enrichment. In the US, rates of colorectal cancer began to increase in 1996 and reached a maximum in 1998. Rates have continued to exceed those present during folic acid pre-enrichment days by as much as 15,000 extra cases per year (2).
Worth mentioning is that these observational studies are inadequate to determine causation due to the inability to control for all possible confounders. Nonetheless, hindsight tells us that careful study of genetic and biochemical factors should have been more thoroughly investigated before implementing a potentially harmful change in food policy.
Some studies also speculate that excess folic acid may be related to decreased natural killer cell cytotoxicity (10). This could be due to the fact that excess naturally occurring folate (DHF) blocks normal function of the MTHFR enzyme providing another potential block in methylation and other downstream biochemical cycles.
More study is urgently needed to determine if synthetic folates hinder immune functioning.
Recommendations for People Who Are Concerned? CFS/FM patients and perhaps everyone should check their methylation status utilizing genetic testing such as 23andMe (see www.23andme.com for $99). Conventional laboratories like Quest or LabCorp also now have MTHFR studies that may be ordered by a healthcare provider. Specialty labs like SpectraCell or HealthDiagnostics specialize in more in-depth methylation studies. (The FDA now allows 23andme to only provide raw data. Several free online tools can, however, do that job. Yasko has an excellent tool plus there’s http://geneticgenie.org/and http://www.promethease.com)
Dietary and Supplementation Suggestions
If MTHFR SNPs are found, consider avoiding all forms of synthetic folate and folic acid—including those found in grain products. (Regardless, avoiding grains due to the high incidence of gluten sensitivity in CFS and FM patients is sometimes recommended.)
Some supplement changes may be in order
Foods high in naturally occurring folate (dihydrofolate, DHF)
spinach, turnip greens, beans, sunflower seeds, Brewer’s yeast, liver.
Foods often fortified with folic acid breakfast cereal, bread, flour, corn meal, pasta, rice. When choosing supplements, opt for a multi-vitamin or B-complex with active forms of folate such as folinic acid or 5-MTHF.
To assess if supplementation is sufficient to bypass methylation defects, routine homocysteine, folate, and B12 can be measured. Folate is most accurately measured as red blood cell folate. Serum B12 measurements are notoriously inaccurate, so methylmalonic acid (MMA) is the preferred test to perform. If MMA is depressed and homocysteine remains high, there may be an additional need for methyl donors to recycle folate through the cycle. Supplemental methyl-B12, trimethylglycine (TMG), or SAMe may help restore normal ranges (11).
Read more: The Folic Acid Controversy, MTHFR and Chronic Fatigue Syndrome http://www.cortjohnson.org/blog/2014/08/12/folic-acid-controversy-mthfr-chronic-fatigue-syndrome/
1 Kelly GS. Folates: Supplemental Forms and Therapeutic Applications. Alt Med Rev 1998. 3(3): p. 208-220. http://www.ncbi.nlm.nih.gov/pubmed/9630738 2 Smith AD, Kim YI, Refsum H. Is folic acid good for everyone? Am J Clin Nutr March 2008 vol. 87 no. 3 517-533. http://www.ncbi.nlm.nih.gov/pubmed/18326588 3 Patanwala I, et al. Folic acid handling by the human gut: implications for food fortification and supplementation. Am J Clin Nutr. 2014 Jun 18;100(2):593-599. [Epub ahead of print]. http://www.ncbi.nlm.nih.gov/pubmed/24944062 4 Klerk M, et al. MTHFR 677C⟶T Polymorphism and Risk of Coronary Heart Disease: A Meta-analysis. JAMA 2002;288:2023-31. http://www.ncbi.nlm.nih.gov/pubmed/12387655 5 Hughes LB et al. Racial or ethnic differences in allele frequencies of single-nucleotide polymorphisms in the methylenetetrahydrofolate reductase gene and their influence on response to methotrexate in rheumatoid arthritis. Ann Rhuem Dis 2006; 65: 1213-1218. http://www.ncbi.nlm.nih.gov/pubmed/16439441 6 Botto Lorenzo, Yang Quanhe. 5,10-Methylenetetrahydrofolate Reductase Gene Variants and Congenital Anomalies: A HuGE Review. Am. J. Epidemiol. 2000; 151(9): 862-877. http://www.ncbi.nlm.nih.gov/pubmed/10791559 7 Regland,B, Andersson M, Abrahamsson L, Bagby J, Dyrehag LE, Gottfries CG. (1997) Increased concentrations of homocysteine in the cerebrospinal fluid in patients with fibromyalgia and chronic fatigue syndrome. Scand J Rheumatol. 26(4):301-7. http://www.ncbi.nlm.nih.gov/pubmed/9310111 8 Harmon DL, McMaster D, McCluskey DR, Shields D, Whitehead AS. (1997) A common genetic variant affecting folate metabolism is not over-represented in chronic fatigue syndrome. Ann Clin Biochem. 34 (Pt 4):427-9. http://www.ncbi.nlm.nih.gov/pubmed/9247678 9 Neuhouser ML, et al. Mathematical modeling predicts the effect of folate deficiency and excess on cancer-related biomarkers. Cancer Epidemiol Biomarkers Prev. 2011 Sep;20(9):1912-7. Epub 2011 Jul 13. http://www.ncbi.nlm.nih.gov/pubmed/21752986 10 Troen AM, et al. Unmetabolized folic acid in plasma is associated with reduced natural killer cell cytotoxicity among postmenopausal women. J Nutr. 2006 Jan;136(1):189-94. http://www.ncbi.nlm.nih.gov/pubmed/16365081 11 Olthof Margreet, Trinette van Vliet, Esther Boelsma, Petra Verhoef. Low Dose Betaine Supplementation Leads to Immediate and Long Term Lowering of Plasma Homocysteine in Healthy Men and Women. J. Nutr. 2003 Dec. 1; 133(12): 4135-4138. http://www.ncbi.nlm.nih.gov/pubmed/14652361
methyl-B12, trimethylglycine (TMG), or SAMe may help restore normal ranges (11).
The end product of folate metabolism, 5-MTHF, is an essential precursor for neurotransmitter metabolism and the synthesis of dopamine, serotonin, and norepinephrine. It is also necessary for the production of SAMe, which participates in over 200 enzymatic reactions in the body.
Did the FDA’s attempt to reduce birth defects have unintended consequences? In the 1990’s, the US and UK mandated the enrichment of all grain products with folic acid in hopes of reducing the occurrence of neural tube defects.
In the decades since neural tube defects have indeed declined yet little long term research has been done to determine the effects excess folate might have on non-pregnant adults. The tolerable upper limit (TUL) for folate is set at 1,000 mcg/day for adults, but with the overconsumption of fortified grain products many may exceed this threshold.
Recent studies are now taking a closer look at potential health risks of folic acid fortification for adults. Folate is not only a concern for adults, but may have particular relevance for some people with Chronic Fatigue Syndrome (ME/CFS).
What Role Might folate play in ME/CFS? folate is a vital component of the single carbon pool that participates in basic cellular processes such as amino acid metabolism, synthesis of nucleotides (DNA, RNA, ATP), and methylation (including epigenetic methylation of DNA). Low levels of folate are implicated in increased risk of cardiovascular disease, stroke, dementia, depression, cancers, and birth defects. Similarly, high levels are also associated with carcinogenesis (1). Folate metabolism is a complex, multi-step process that occurs in every cell in the body. It requires three key enzymes: dihydrofolate reductase (DHF), methylenetetrahydrofolate reductase (MTHFR), and methionine synthase (MTR).
When you consume the synthetic form of folate – folic acid – in enriched foods or supplements, it must be converted to different forms utilizing these enzymes. If this conversion is inadequate, functional folic acid deficiencies can emerge that may dampen methylation, amino acid metabolism, etc. Despite the fact that this biochemistry has been known for decades, few studies have examined the exact mechanisms by which folic acid is taken up or metabolized in the body after consumption. Those studies which have examined folic acid metabolism have relied only on mouse models which have substantially different concentrations of the above enzymes than humans (2).
A recent study in patients with stable liver disease indicated, however, that synthetic folic acid from traditional supplements was inefficiently absorbed in the intestinal tract compared to the active 5-methyl-hydrofolate (5-MTHF) form (which was taken up twice as readily). The researchers concluded that food regulatory bodies should rethink their position on folic acid enrichment.
Interestingly, the FDA and European Food Standard Agency have already approved products containing 5-MTHF derivatives to replace folic acid (3).
A Key Metabolic Factor – More Biochemistry
B12, an essential co-factor in folic acid metabolism, is often low in ME/CFS The folate cycle feeds into other key biochemical cycles as well. The end product of folate metabolism, 5-MTHF, is an essential precursor for neurotransmitter metabolism and the synthesis of dopamine, serotonin, and norepinephrine. It is also necessary for the production of SAMe, which participates in over 200 enzymatic reactions in the body.
After 5-MTHF is produced, it is then recycled back into the cycle through the enzyme methionine synthase (MTR). This reaction requires adequate B12 as a cofactor. With B12 deficiency in near epidemic proportions in the elderly, vegetarians, chronic antacid users, SIBO, and people with ME/CFS or FM, it’s possible that folic acid can become trapped as 5-MTHF in what is called the “folate trap.” This “folate trap” prevents the recycling of 5-MTHF back to THF and slows methylation and many other downstream reactions.
Finally, there is a growing understanding of the link between hypothyroidism and proper folate cycle function. Many ME/CFS and FM patients have subclinical hypothyroidism that may be related to inadequate production of 5-MTHF. This methylated form of folate is essential for the conversion of tyrosine to thyroid hormone (1).
Who With ME/CFS or Fibromyalgia Should Be Concerned With This Study? It’s possible but not certain that people with ME/CFS and FM may already be behind the eight ball, so to speak, regarding folate metabolism. Dr. Amy Yasko and the late Rich VonKoynenberg proposed that genetic mutations (single nucleotide polymorphisms or SNPs) in enzymes involved in the folate methylation pathway may be common in the ME/CFS and/or FM populations. Of the three enzymes involved in folate metabolism, methylenetetrahydrofolate reductase (MTHFR) plays the largest role in the conversion and utilization of folates. A genetic defect in this key enzyme could dramatically affect the ability to convert, recycle, and utilize folates.
Genetic Aspects An Open Medicine Institute study is examining the effects of MTHFR mutations on folate metabolism in ME/CFS. Two common genetic variations, C677T and A1298C, have been identified in the MTHFR gene that codes for the MTHFR enzyme. The C677T type has been associated with increased incidence of cardiovascular disease and other health risks (4). This MTHFR SNP has been found to be prevalent in certain populations of people. Heterozygous MTHFR C677T, meaning one copy of the gene is mutated while the other is normal, is found in 42% of Hispanics, 35% of Caucasians, and 14% of African Americans. Homozygotes, where both copies of the gene are mutated, are less common in the general population with 10% preponderance (5).
Further research and stricter study design are certainly warranted. Another study measuring levels of homocysteine in the cerebrospinal fluid of CFS/FM patients found elevations suggestive of problems recycling folate back to methionine. However, it was unclear whether these findings were due to genetic SNPs in enzymes, folate deficiencies, or B12 deficiencies (8).
The Open Medicine Institute is currently engaged in a study to determine the extent of MTHFR mutations and the role they may play in aberrant folate metabolism in ME/CFS.
What Problems Might High Levels of Unmetabolized Folic Acid (UMFA) Pose?
If enzymatic road blocks from genetic mutations or inadequate enzyme cofactors inhibit synthetic folic acid metabolism, high concentrations of folic acid can spill over into the portal circulation. A natural killer connection, of all things, may be possible Elevated levels of unmetabolized folic acid (UMFA) have been implicated in increased overall mortality (9). Epidemiological studies have found a striking association between the incidence of colon cancers and folic acid food enrichment. In the US, rates of colorectal cancer began to increase in 1996 and reached a maximum in 1998. Rates have continued to exceed those present during folic acid pre-enrichment days by as much as 15,000 extra cases per year (2).
Worth mentioning is that these observational studies are inadequate to determine causation due to the inability to control for all possible confounders. Nonetheless, hindsight tells us that careful study of genetic and biochemical factors should have been more thoroughly investigated before implementing a potentially harmful change in food policy.
Some studies also speculate that excess folic acid may be related to decreased natural killer cell cytotoxicity (10). This could be due to the fact that excess naturally occurring folate (DHF) blocks normal function of the MTHFR enzyme providing another potential block in methylation and other downstream biochemical cycles.
More study is urgently needed to determine if synthetic folates hinder immune functioning.
Recommendations for People Who Are Concerned? CFS/FM patients and perhaps everyone should check their methylation status utilizing genetic testing such as 23andMe (see www.23andme.com for $99). Conventional laboratories like Quest or LabCorp also now have MTHFR studies that may be ordered by a healthcare provider. Specialty labs like SpectraCell or HealthDiagnostics specialize in more in-depth methylation studies. (The FDA now allows 23andme to only provide raw data. Several free online tools can, however, do that job. Yasko has an excellent tool plus there’s http://geneticgenie.org/and http://www.promethease.com)
Dietary and Supplementation Suggestions
If MTHFR SNPs are found, consider avoiding all forms of synthetic folate and folic acid—including those found in grain products. (Regardless, avoiding grains due to the high incidence of gluten sensitivity in CFS and FM patients is sometimes recommended.)
Some supplement changes may be in order
Foods high in naturally occurring folate (dihydrofolate, DHF)
spinach, turnip greens, beans, sunflower seeds, Brewer’s yeast, liver.
Foods often fortified with folic acid breakfast cereal, bread, flour, corn meal, pasta, rice. When choosing supplements, opt for a multi-vitamin or B-complex with active forms of folate such as folinic acid or 5-MTHF.
To assess if supplementation is sufficient to bypass methylation defects, routine homocysteine, folate, and B12 can be measured. Folate is most accurately measured as red blood cell folate. Serum B12 measurements are notoriously inaccurate, so methylmalonic acid (MMA) is the preferred test to perform. If MMA is depressed and homocysteine remains high, there may be an additional need for methyl donors to recycle folate through the cycle. Supplemental methyl-B12, trimethylglycine (TMG), or SAMe may help restore normal ranges (11).
Read more: The Folic Acid Controversy, MTHFR and Chronic Fatigue Syndrome http://www.cortjohnson.org/blog/2014/08/12/folic-acid-controversy-mthfr-chronic-fatigue-syndrome/
1 Kelly GS. Folates: Supplemental Forms and Therapeutic Applications. Alt Med Rev 1998. 3(3): p. 208-220. http://www.ncbi.nlm.nih.gov/pubmed/9630738 2 Smith AD, Kim YI, Refsum H. Is folic acid good for everyone? Am J Clin Nutr March 2008 vol. 87 no. 3 517-533. http://www.ncbi.nlm.nih.gov/pubmed/18326588 3 Patanwala I, et al. Folic acid handling by the human gut: implications for food fortification and supplementation. Am J Clin Nutr. 2014 Jun 18;100(2):593-599. [Epub ahead of print]. http://www.ncbi.nlm.nih.gov/pubmed/24944062 4 Klerk M, et al. MTHFR 677C⟶T Polymorphism and Risk of Coronary Heart Disease: A Meta-analysis. JAMA 2002;288:2023-31. http://www.ncbi.nlm.nih.gov/pubmed/12387655 5 Hughes LB et al. Racial or ethnic differences in allele frequencies of single-nucleotide polymorphisms in the methylenetetrahydrofolate reductase gene and their influence on response to methotrexate in rheumatoid arthritis. Ann Rhuem Dis 2006; 65: 1213-1218. http://www.ncbi.nlm.nih.gov/pubmed/16439441 6 Botto Lorenzo, Yang Quanhe. 5,10-Methylenetetrahydrofolate Reductase Gene Variants and Congenital Anomalies: A HuGE Review. Am. J. Epidemiol. 2000; 151(9): 862-877. http://www.ncbi.nlm.nih.gov/pubmed/10791559 7 Regland,B, Andersson M, Abrahamsson L, Bagby J, Dyrehag LE, Gottfries CG. (1997) Increased concentrations of homocysteine in the cerebrospinal fluid in patients with fibromyalgia and chronic fatigue syndrome. Scand J Rheumatol. 26(4):301-7. http://www.ncbi.nlm.nih.gov/pubmed/9310111 8 Harmon DL, McMaster D, McCluskey DR, Shields D, Whitehead AS. (1997) A common genetic variant affecting folate metabolism is not over-represented in chronic fatigue syndrome. Ann Clin Biochem. 34 (Pt 4):427-9. http://www.ncbi.nlm.nih.gov/pubmed/9247678 9 Neuhouser ML, et al. Mathematical modeling predicts the effect of folate deficiency and excess on cancer-related biomarkers. Cancer Epidemiol Biomarkers Prev. 2011 Sep;20(9):1912-7. Epub 2011 Jul 13. http://www.ncbi.nlm.nih.gov/pubmed/21752986 10 Troen AM, et al. Unmetabolized folic acid in plasma is associated with reduced natural killer cell cytotoxicity among postmenopausal women. J Nutr. 2006 Jan;136(1):189-94. http://www.ncbi.nlm.nih.gov/pubmed/16365081 11 Olthof Margreet, Trinette van Vliet, Esther Boelsma, Petra Verhoef. Low Dose Betaine Supplementation Leads to Immediate and Long Term Lowering of Plasma Homocysteine in Healthy Men and Women. J. Nutr. 2003 Dec. 1; 133(12): 4135-4138. http://www.ncbi.nlm.nih.gov/pubmed/14652361
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