Epidemiological findings that would help confirm the adverse effects of folic acid

Following on from the previous post describing the wide-ranging health risks that are associated with the greatly increased folic acid consumption in many countries, let us try to define a few possible findings from epidemiological research studies that could help to confirm the adverse effects of long term exposure to high amounts of folic acid.

Differences in folic acid exposure between the US and Europe

An important fact that can be used to make comparisons is that Europe has as of today not mandated folic acid fortification of grains, even though folic acid intake in Europe has increased in the form of individually fortified products (e.g. breakfast products) and increased amounts in multivitamins, and there may be differences between different areas of Europe (for example relatively more voluntary fortification and supplementation in the UK and Western Europe compared to other countries, especially Southern and Eastern Europe where fortification and supplement use is likely to be much lower). Nevertheless, on the whole much less folic acid has been present since 1997 in the average European diet compared to the average US diet, due to the aggressive grain fortification program in the US and likely greater use of supplements and additionally fortified foods. Since many epidemiological studies with large population groups are conducted in both the US and in Europe, comparisons can be made between the two regions looking for potential adverse effects of the much higher folic acid exposure in the US since 1997.

Findings that would confirm the adverse effects of excessive folic acid

The following study results would help to confirm that long-term intake of large amounts of folic acid in the average diet has adverse effects:

• The incidence of dementia caused by neurological effects of unrecognized vitamin B12 deficiency may be much greater in the US (largely misdiagnosed as Alzheimer's disease and other forms of dementia), increasing as time goes on, and contrasting with findings in Europe. There may also be a contrasting trend of lower average age of onset of dementia in the US and a higher than expected incidence of early-onset dementia, directly attributable to high folic acid intake, which if already measurable would be very concerning, and is likely to continue to get worse.
• Due to the potentially increased homocysteine level in large subsections of the US population (those with relatively low B12 levels) as a result of high folic acid intake, an increase in the rate of stroke and other cardiovascular disease may be expected in the whole population or certain groups, even in the face of increased statin therapy, with the rate increasing as time goes on. The incidence of certain early-onset cardiovascular diseases (such as certain forms of stroke) that used to be rare may be unexpectedly increased. Disease rate would start to increase in earnest some time after 1997. In contrast, European rates of stroke and other cardiovascular disease would fare much better than in the US, potentially declining rather than increasing.
• Studies on long-term vegetarian or vegan populations may show a significant difference between the US and Europe since 1997, with the US populations suffering from higher than expected incidence of cardiovascular and neurological disease. The poor quality of information regarding the need for vitamin B12 for this group is illustrated by the fact that ironically, and even in Europe, many vitamin supplements specifically targeted at this group (sometimes with supposed special emphasis on "B12") are highly unbalanced, containing high amounts of folic acid and still negligable amounts of B12 (for example, 200 to 600 micrograms of folic acid and 25 micrograms or less of vitamin B12), which for the reasons explained is highly likely to only have adverse effects on this population. Since vegetarians typically already consume a high amount of folate from fruit and vegetable sources, in addition to the high amounts of folic acid from fortified grains and other products, the addition of excessive amounts of folic acid and relatively little B12 in supplements targeted at these groups can only be seen as extremely illogical and downright harmful.
• Any significant increase in the incidence of diagnoses like idiopathic neuropathy, diabetic neuropathy, multiple sclerosis and other neurological disorders in the US after 1997 may actually be due to misdiagnosed vitamin B12 deficiency symptoms, and would contrast somewhat with trends found in Europe (where such trend may also exist due to higher, but less pronounced folic acid intake among a large subsection of the population). Large increases in sales figures of medications promoted to treat idiopathic and other less specific forms of neuropathy can be directly explained by a large increase in neuropathy symptoms due to undiagnosed vitamin B12 syndromes among the general population. Due to the effect of greater folic acid intake and the resulting larger increase in occurence of neuropathy symptoms, any such sales increases would be expected to be significantly higher in the US than in Europe.
• Certain diagnosed childhood developmental and neurological disorders that may actually due to vitamin B12 deficiency in selected groups of patients may be seeing increasing incidence in the US, and contrasting with findings in Europe. Indeed, some physicians in the US now treat children with autism with vitamin B12, although without much effort to prove any relationship with vitamin B12 deficiency which could provide a scientific basis that a subgroup of these patients benefit from treatment for vitamin B12 deficiency.
• Incidence of diagnosed vitamin B12 deficiency and treatment is probably very poorly documented in most countries, especially in the US, and often not recognized as a "proper" disorder even when people are treated with therapeutic amounts of vitamin B12 and respond. However, sales figures of major providers of the actual vitamin used in vitamin B12-specific supplements (such as cyanocobalamin, hydroxocobalamin and methylcobalamin) and of intramuscular injection kits in the US and other countries could be used determine to what extent actual medical treatment and self-treatment by individuals with vitamin B12 has increased, which, in the face of widespread denial by the medical establishment, can help establish that the incidence of vitamin B12 deficiency has increased.
• There is potential for differences in cancer rates and progressions due to the different amounts of exposure to folic acid in the US and Europe, or changes in the US and Canada alone after 1997. Indeed, several studies have noted increases in certain cancer rates in the US after 1997 although these have attributed to improved detection techniques by some. Recently, an unexpected significant increase in early-onset prostate cancer since the last decade has been noted in the US, and similar increases have been observed for other common cancer types. Since the increase in folic acid levels is one of the most significant metabolic changes that has occurred since that time frame, across the whole population, it would be prudent to carefully investigate a possible connection. That folic acid has a major effect on cell replication with significant implications for cancer is well established and can also also be deducted from the fact that the so-called anti-folate medications such as methotrexate, which reduce folate/folic acid levels inside the body, are the classic form of effective cancer chemotherapy, and are today also commonly used in lower doses to suppress the immune system for several auto-immune disorders including rheumatoid arthritis. In Europe, concerns over effects on cancer rates have been a major factor in the decision not to initiate large-scale folic acid fortification programs.
• Increases in incidence of asthma and other allergies have been noted, and some research has hypothesized a link with folic acid fortification. One recent study, while finding that increased maternal dietary vitamin B12 during pregnancy seemed to be protective against the child developing asthma by age 7, did not link folic acid fortification to the increase in asthma incidence.^[16] However, given the clear metabolic relationship between folic acid and vitamin B12, the protective effect of a higher vitamin B12 intake is precisely what would be expected if the increase in folic acid intake is implicated in the increase in asthma occurence.

Impact of regional folic acid intake on Mediterranean diet studies

Is it possible that the health benefits seen in last 15 years from the Mediterranean diet in people that actually live in the region (i.e. Southern Europe) may in some part be due to lower recent exposure to folic acid supplements and fortified products in that region, even when compared to Western/Northern Europe, and more so when compared to the US? This may inflate the level of benefit from the mediterranean diet in recent studies when compared to Western diets with fortified folic acid. If this is true, one would expect that following a Mediterranean diet in the US (which would almost unavoidably contain a large amount of folic acid through fortification of grains of food products sourced from the US) would have relatively disappointing health benefits

Potential link with the obesity epidemic

Increased folic acid intake (including increased intake and additional supplement use by pregnant and nursing women) may play a role in the continuing increase in obesity seen in the US and other countries, and could help to explain a greater increase in obesity rates seen in the countries such as the US as compared to many countries in Europe.

Some recent research studies^[5][17] have hinted that early exposure to high amounts of folic acid (during pregnancy and infancy) may have consequences for glucose metabolism later in life. One recent study^[17] provides evidence that exposure to a high amount of folic acid during pregnancy can lead to offspring that will be at risk of being overweight and insulin resistant in adulthood.

Additional references:

(16) Michelle Trivedi et. al., 'Intake of Dietary Methyl Donors in the First Trimester of Pregnancy Affects Asthma Risk in Children at Age 7', 2014 American Thoracic Society International Conference

(17) E. Keating, A. Correia-Branco, J. R. Araujo, M. Meireles, R. Fernandes, L. Guardao, J. T. Guimaraes, F. Martel, C. Calhau, 'Excess perigestational folic acid exposure induces metabolic dysfunction in post-natal life', Journal of Endocrinology, 2015; 224 (3): 245

Updated February 11, 2015.