FOLIC ACID, Trick or Treat

Effective   7(out of 10 for NTD)       Safety   3

Folic Acid is the synthetic form of Folate

First, there are at least 3 issues related to natural folate or synthetic folic acid levels.

• The protecton against NTD developing in the fetus when given to women before pregnancy is well established for folate and folic acid.
• Does folate or folic acid protect and prevent or increase cancer growth rate? both
• How does folate or folic acid (and vitamin B12) influence neurological condtions?  (nerve damage at too low or too high. especially if vitamin B12 low) 
• How does folate or folic acid impact heart disease throught homocysteine control? (reduces homocysteine levels)
• Does folate or folic acid negatively impact immune cell activity? (yes ar both low and excess amounts)

Here are some Facts

Folate is the natural form while Folic Acid is synthetic. Folic Acid is more stable and has much better absorption making it the preferred form for use in supplements and the food fortification program. But, like some synthetics, there are differences from the natural folate form that gain significance with explanation. 

• The synthetic Folic Acid form is not native to the body and does may not perform natural folate functions.
• The Liver has to process the synthetic form and turn it into the natural folate form for activity.
• This Liver process has limits and only can process about 200 mcg of the synthetic form at once, with about 600 mcg over the whole day.
• Consumption over this limit spills unmetabolized folic acid into the blood stream.
• Scientists do not yet know the long term consquences of this situation.
• But what is known is that unmetabolized folic acid in the blood stream suppresses the innate immune system by reducing the activity level of cells called Natural Killer Cells (NK). ref
• NK cells protect against tumor development. ref  
• Folates in the body are hijacked by cancer cells to aid tumor growth.
• Folates protect against DNA damage before cancer, but once cancer is present, folates can help cancers grow faster.

From ScienceDirect, "reduction of NK cell cytotoxicity due to high folic acid intakes may increase the susceptibility to cancer and viral infections especially in the elderly who are already at increased risk for these diseases"

• There is a class of anti-cancer drugs called anti-folates that is designed to stop this hijacking.
• Folic acid and vitamin B12 are involved together in congnitive activites.
• Low Folic acid and low B12 are often associated in dementia as well as megaloblastic anaemia.
• Caution is needed with high folic acid and low vitamin B12, as this anaemia condition can be hidden.

Folate is a valuable nutrient in the body, especially for young women before they become pregnant and during the first trimester to prevent NTD. The important application here is to protect DNA and make sure cells duplicate properly to form a healthy spinal column. Scientists decided to have food manufacturers add synthetic folic acid to wheat and rice flour products to help prevent NTD birth defects. And this worked to reduce this condition. ref ref (<this Canadian study mixes up mg for mcg in flour fortification) ref  But, there appears to be a point where too much folic acid, especially the supplemented synthetic form, creates adverse reactions for some subsets of people, often simply by working too efficiently, or in cases of mutations to the genes involved in folate metabolism. ref For optimum health it is important to stay within the beneficial window of certain amounts, neither too little or too much. Increasing natural food sources of folate is preferred. 

NOTE: It is entirely possible that only natural food sources of folate should be consumed. This leaves out the synthetic folic acid fortified foods that include refined white flour and white rice. If some of these fortified foods are consumed, limits to amount of natural folates as well might be prudent in some situations. This is rather a new development that Science has recently uncovered but hesitates to expose. ref That would mean admitting they missed this aspect in the folic acid food fortification program. ref<large PDF file, you will have to click and download the PDF file, may take some time, BUT easy to read info, especially for colon cancer section 19. (** see below)

The folic acid fortification process in flours and rices, breads and cereals is added at amounts between 115 mcg/100gm to 160 mcg/100 mg. A slice of bread has about 60 mcg. Two slices in a sandwich would add 120 mcg. It is not unusual to have 3-4 servings of grains, breads, pasta, and cereals, and get 240 to 400 mcg per day. Add in a multiple vitmain with 400 to 800 mcg and that is alot of folic acid.

Here is one positive study ref. And another negative study, ref difficult to figure out exact response. And a most excellent review of studies up to 2008.

 Please follow the recommendations established here, especially for women of child-bearing years (16+). Enough red flags are present to demand a limit (or elimination) on the synthetic form, folic acid. ref  ref    ref

Folic Acid on Cancer (stage opposite)

Folic acid most likely does not cause cancer. ref  What it does appear to do, it's job, is to work with DNA and cell division. ref  Since cancer cells grow and divide very rapidly, they appear to hijack folic acid and folates from the body for this faster tumor growth action. This would explain many known observations. ref  ref  ref  ref

PRECAUTION: Numerous studies have now been reviewed together and the results are perhaps slightly mis-leading. The average mortality and/or cancer rates from all the studies shows very little effect overall from folic acid consumption. Just a non significant 6% average increase. What very likely is happening is a dual effect at the same time as explained below.

This next reference pretty much sums it up. Both too low and too high can have adverse effects, while within certain healthy amount limits, normal cell DNA division is protected and cancer is prevented. After a cancer tumor develops, high levels of folic acid may act to promote a faster growth rate. Some types of Cancers have cells with greater numbers of folate receptor docking sites that normal cells. The effect of this is to increase the rate of cell division, simply a normal folate function. There are anti-cancer Drugs that have Anti-folate activity are given to slow cancer growth. ref   ref  ref

A prostate cancer connection is revealed in this study, although just a one person case report, it is pretty dramatic. Notice high B12 was also mentioned since it is often included with folic acid supplement. ref Not all research has found that B12 connection. ref  Prostate cancer is the one that consistently shows a greater adverse connection to higher folic acid amounts. Colon polyp activation may be a close second. Remember, Swedish research from before 2015 should mention that foods are not yet fortified with folic acid and intake levels would be less that in Countries already with folic acid food fortification.

UPDATE 2014:  Check the latest for certain conditions in women exhibiting increased HPV infections and folate concentrations here.

On colon cancer enigma: read this study abstract for possible explanation of benefits/risks. 

Below is another disturbing link for folic acid you should read NOW. It may only be an association, but deserving of further research. Folic acid supplement levels of pregnant women may have lasting effects later in offspring:

Am J Epidemiol. 2009 Dec 15;170(12):1486-93. Epub 2009 Oct 30.

Effect of supplemental folic acid in pregnancy on childhood asthma: a prospective birth cohort study.

Whitrow MJ, Moore VM, Rumbold AR, Davies MJ.

Abstract

This study aimed to investigate the effect of the timing, dose, and source of folate during pregnancy on childhood asthma by using data from an Australian prospective birth cohort study (n = 557) from 1998 to 2005. At 3.5 years and 5.5 years, 490 and 423 mothers and children participated in the study, respectively. Maternal folate intake from diet and supplements was assessed by food frequency questionnaire in early (<16 weeks) and late (30-34 weeks) pregnancy. The primary outcome was physician-diagnosed asthma, obtained by maternal-completed questionnaire. Asthma was reported in 11.6% of children at 3.5 years (n = 57) and in 11.8% of children at 5.5 years (n = 50). Folic acid taken in supplement form in late pregnancy was associated with an increased risk of childhood asthma at 3.5 years (relative risk (RR) = 1.26, 95% confidence interval (CI): 1.08, 1.43) and with persistent asthma (RR = 1.32, 95% CI: 1.03, 1.69). The effect sizes did not change with adjustment for potential confounders. The association was similar at 5.5 years but did not reach statistical significance (RR = 1.17, 95% CI: 0.96, 1.42) in univariable models. These findings on childhood asthma support previous observations that supplementation with folate in pregnancy leads to an allergic asthma phenotype in mice via epigenetic mechanisms and is associated with poorer respiratory outcomes in young children."  More on this connection. ref

SIDEBAR:  A recent report just surfaced that found Women taking Folic Acid just before and during the first 2 months of pregnancy have significantly less autism in their children. ref  This study is from Europe where folic acid is not fortified in foods.

Here is a report on Homocysteine levels in disease and the effects from folic acid consumption along with other B vitamins. Read the section "Is synthetic folate fortification always good for us?."

Folic Acid. Pregnancy, and Breast MIlk

Obviously dietary folate has important roles to play just before pregnancy to safeguard against NTD developing in fetus. Then, after first trimester, a lower level of folic acid might be needed to deal with other future conditions of the fetus. And last, during breast feeding, folic acid might need to be further reduced to prevent unmetabolized folic acid UMFA showing up in blood plama and the possibility of it getting into breast milk. ref  The full consequences of UMFA in breast milk is not fully researched yet. But, with the reduced immune functions, this could have some impact.

DIABETES, HOMOCYSTEINE, and FOLIC ACID

Then, along comes this report on the use of high dose of the three B vitamins thought to be of benefit by lowering homocysteine levels in diabetics. BUT, the results revealed an increase in adverse heart events and a decrease in kidney function. The folic acid amount used in this study was 2,500 mcg. The vitamin B6 at 25Mg and B12 at 1000 mcg should not have been a problem, so most of the adverse effect could be from the folic acid, lowered homocysteine levels, or the combination of the three B vitamins. Interesting! Other studies have not shown a negative result. But, the studies that show a slight positive from folic acid on cardiovascular events are for populations where they DO NOY have grain fortification with folic acid. ref 

Folic Acid Metabolite

What is CALCIUM L-5-METHYLTETRAHYDROFOLATE?  

Copy from Reference best sums up specs:    "New specifications prepared at the 65th JECFA (2005) and published in FNP 52 Add 13 (2005). At the 65th JECFA (2005) the Committee had no safety concerns for the use of the substance in dry crystalline or microencapsulated form as an alternative to folic acid used in dietary supplements, foods for special dietary uses and other foods.

L-5-Methyltetrahydrofolic acid, calcium salt L-Methyltetrahydrofolate, calcium salt L-Methylfolate, calcium L-5-MTHF-Ca

Calcium L-5-methyltetrahydrofolate (L-5-MTHF-Ca) is a synthetic derivative of folic acid, the predominant, naturally occurring form of folate. It is synthesized by reduction of folic acid to tetrahydrofolic acid followed by methylation and diastereoselective crystallization (in water) of L-5-MTHF as its calcium salt. The product contains variable amounts of water of crystallization."  end of copy

Studies show this folic acid metabolite form has more influence lowering Homocysteine levels than taking synthetic folic acid and hoping some of it converts into this natural form by the liver. ref Another study shows that after time, they may be pretty much the same. ref  This gives the metabolism trail of folic acid. While this L-5 form is closer to the natural body folate form, it is not without side effects. Check out this website. And monitor your reactions to see which response you exhibit. Even though adverse effects may be rare, it is wise to be aware.

Wrap UP

One point needs to be addressed. The effects of synthetic form of Folic acid and the natural form folate are to this day quite controversial. The natural folate form is really about 9 different compounds made up of many different elements. The synthetic folic acid form is missing some of these elements which might explain why it has to be converted into the body ready form by the liver. Both deficiency and excess Folic acid intake may exhibit adverse effects in some cases. There is discussion that after tumor development, excess folic acid might increase tumor growth rate as referenced above. This is in contrast to before tumor development, when the excess could be protective and prevent abnormal cell DNA development. Vitamin B12 levels and folic acid both need to be addressed together.  Check out this informative article from Science-Based Medicine.  ref   This is a real eye-opener. Notice that cancers other than just colon may be involved, i.e. breast (tissue density) & prostate. Better outcomes in some cancers were observed when folic acid was deficient (low levels).

In studies looking at supplementing folic acid on dementia, research in Countries without food fortification of folic acid yielded positive results showing less dementia. ref  In Countries with fortification, the results tend to generally be negative showing more dementia in those with extra supplemented folic acid, ref, especially if vitamin B12 is low. The folic acid influence was due to lowering homocysteine blood levels, an element that exhibits a negative effect on dementia.

Folic acid at 400-600 mcg is appropriate for young woman of child-bearing age to prevent NTDs until about 12 weeks into pregnancy, than back off slightly. Not all fortification reports for preventing NTDs were as favorable as has been reported, it depends upon how many servings of folic acid fortified foods are also consumed. >  ref  

OF INTEREST: Here is a report that says folic acid does not increase cancer rate, or at least not significantly. 7.7 % for folic group and 7.3 % for no folic group. ref

Here is a section from this report "In a linked statement, Cornelia M Ulrich, Director of the National Center for Tumor Diseases and German Cancer Research Center, and Joshua W Miller, from Rutgers University in the USA, noted that it is important to remember the dual relationship of folate and cancer. Although it may protect against cancer development, it can also result in the growth of existing cancer cells. This is especially significant, they said, for "those who consume excess folic acid from fortification and supplements combined. Notably, 1-4% of the US population, depending on age, sex, and ethnic origin, exceed the tolerable upper limit (1 mg/day) for total consumption of folic acid." 

Adults should severely limit Folic Acid supplements, PERIOD!  ref  

BUT YOU NEED SOME from either fortified foods which most people consume or from low dose supplements of natural form.

Seniors, if they are not consuming enough natural dietary folates, or consuming fortified foods, might consider taking about 200 mcg. with vitamin B12 to help control Homocysteine levels.

The natural form folate needs to be verified that it does not also have the described synthetic folic acid adverse effects. When articles mention there are no adverse effects from natural folic acid, they are really referring to the fact that you cannot get very much just from natural foods. This does not necessarily imply that natural folates would be safe if consumed in high amounts in supplements that use the natural folate format.

The Homocysteine issue, as well as the whole methylation pathway, and any relationship with heart disease needs to be completely resolved. So far, if it is high, that is not good, but lowering it by taking folic and B12 and B6 does not appear to consistently lower risks. This is a major disappointment for scientists who were sure it would. ref

OF INTEREST: The Methylation reaction is a major area for folic acid. It is this area that sometimes will be the deciding factor as to whether a supplement is going to exhibit a positive or an adverse influence on the body. Methylation is simple the process of adding or removing a methyl group from another element. Adding will start a reaction process while removing the methyl group wil stop a reaction, such as for enzymes. This process is vital in many critical areas of body function: DNA, energy production, neurotransmitters, liver processess, and many others by switching on or off gene expression.

MORE INFO:   Article is copied here to prevent loosing it's website link.

By Steven Reinberg
HealthDay Reporter

TUESDAY, Nov. 17 (HealthDay News) -- Although folic acid fortification of foods can prevent many birth defects, it may also increase the risk for developing cancer, Norwegian researchers report.

Since 1998, many countries have mandated folic acid (vitamin B9) fortification of foods to decrease the incidence of neural-tube defects in newborns. By October 2009, the flour produced in these countries, plus the flour that is fortified voluntarily, represented 30 percent of the world's wheat flour produced in large mills. In addition, some 40 percent of those living in the United States also take dietary supplements containing folic acid, the researchers noted.

However, "Folic acid fortification and supplementation may not necessarily be as safe as previously assumed," said lead researcher Dr. Marta Ebbing, from the Department of Heart Disease at Haukeland University Hospital in Bergen. "Public health and food safety authorities should take this into consideration."

In Norway, foods are not supplemented with folic acid, making it the ideal place to investigate whether or not the supplement increases the risk for cancer, Ebbing noted.

"The study shows that treatment with folic acid for approximately three-and-a-half years was associated with a 21 percent increased risk of cancer and an increased risk of death after six-and-a-half years of follow-up in a large population of patients with heart disease living in Norway, where there is no folic acid fortification of foods," she said.

The report is published in the Nov. 18 issue of the Journal of the American Medical Association.

For the study, Ebbing's team collected data on 6,837 patients with heart disease from two trials. These trials were designed to see if vitamin B could lower homocysteine, a protein associated with an increased risk of heart disease.

In the studies, patients were randomly assigned to receive folic acid plus vitamins B12 and B6, folic acid plus B12, or B6 alone, or a placebo. These trials ran from 1998 to 2005, and were followed through the end of 2007.

The researchers found that patients who received folic acid had a 21 percent increased risk for developing cancer. In addition, of the 341 patients who received folic acid and developed cancer, 136 died -- a 38 percent increased risk compared with patients who did not take folic acid and developed cancer.

The most common cancers associated with folic acid were colorectal, lung, prostate and blood cancer, the researchers noted.

In all, 16.1 percent of the patients who were given folic acid plus vitamin B12 died from any cause, compared with 13.8 percent of patients who received neither folic acid nor vitamin B12, the researchers said.

Bettina F. Drake, an assistant professor of surgery at the Alvin J. Siteman Cancer Center of the Washington University School of Medicine in St. Louis and co-author of an accompanying journal editorial, said that "while the results by Ebbing and colleagues provide some short-term data that is important in helping us understand the complexities in the association between folic acid and cancer risk, this report does not nullify the vast potential long-term benefits that folic acid fortification may have on population health." (preventing birth defects and possibly dementia work coupled with vitamin B12 at moderate levels in seniors.)

Drake noted that the dose of folic acid given to patients in the Norwegian studies was significantly higher (1,000 mcg) than what most people in the United States get. "U.S. fortification appears to have left the population well within safe limits," she said. (unless supplement contains 800 mcg or 400 and one eats 3-4 servings of fortified breads.  1 serving =140 mcg, 3-4 = 420 - 560)

The true effect of folic acid on cancer may take many years of follow-up to determine, Drake said.

Cancer prevention efforts do not start or end with folic acid, Drake added. "Cessation from cigarette smoking for all who currently smoke and prevention of smoking in our youth and adolescents remains the highest priority for cancer prevention," she noted.

"For those who do not smoke, eating a healthy diet and exercising to avoid weight gain or maintain weight loss will translate to lower risk of cancer, diabetes and other chronic conditions," she said. "These are population-wide changes that take time, and the benefits of such lifestylechanges can take years to realize. Sometimes study results do, too."  end of copy

SIDEBAR: Anti-folate drugs are given to slow down cancer growth rate. These drugs hinder the cell division promotion action of folates in the body. Why is this vital bit of information left out of the discussion in the above article? Again, folic acid may not cause cancer, but it sure looks like it speeds up it's growth rate once the cancer has developed. This information fits all the situations described above for both views.

At the proper levels, natural folate in food may be protective against cancer initiation as some early studies observed. The effects of synthetic folic acid may depend upon beginning body level, a benefit against cancers if body stores are low but adverse if body levels are already high, especially if tumors are present. Since Chile initiated fortification of flour in 2001, the colon cancer rate has doubled. This would not mean as much if a similar effect although much smaller also occurred when the United States and Canada introduced fortification. Then there is that 163% increase in prostate cancer rates discovered from the Aspirin and Folic acid study on colon cancer. ref ref ref  Far too many RED FLAGS.

ONE CANCER FOLIC ACID MECHANISM- Immune NK Cell Activity

HOW Folic acid might be involved with increasing cancer risk. Excess Unmetabolized synthetic folic acid spills out into the blood stream if ingested at higher levels than the liver can convert into the natural folate form (260 mcg per meal and about 600 mcg per day). This results in a 22% reduction of the natural killer cell activity, vital to the innate immune system. ref ref  These killer cells are involved in stopping cancer cells so they do not grow into sufficient numbers to build a tumor.   ref    This reference is very important to show how Mother Nature sometimes uses adverse events for beneficial outcomes.  Like the Cyr61 increase from taking NAC with resulting ROS (a free radical) production to prevent Prostate cancer cells from migrating.

**

One last Scientific Report out of Europe from the Reference above copied here due to importance of this complex Folic Acid issue:

The use of folic acid has the benefit of bioavailability, stability and price. However, it is not used without giving rise to some concern. The most prominent concern is that it prevents the timely diagnosis of vitamin B12 deficiency. This issue depends upon the fact that folic acid above a certain level appears in the circulation and enters cells in a way that is not under normal metabolic control. In addition, it directly stimulates DNA biosynthesis and cell division. When this happens in B12 deficiency it masks the emergence of the usual anaemia, allowing the other effect of B12 deficiency, namely neuropathy, to proceed undiagnosed to where it may be irreversible. A more recent concern is that a similar mechanism may be at play in cancer. Thus, while folate/folic acid may prevent the occurrence of new cancers, it may accelerate the growth of pre-existing cancers. These latter concerns are based largely on animal models. More recently observations of apparent increases in colon cancer post fortification in US/Canada have been published. Of greater concern is that recurring polyps in subjects on high dose folic acid were more numerous and had worse pathology than placebo treated peers. Both with respect to masking of anaemia and accelerated cancer growth, greater risk exists in the face of increasing levels of unmetabolised folic acid is in the circulation. Such folic acid does not arise at low intakes but the body’s ability to convert it to natural folate is easily saturated by moderate levels of intake.

Update on Saturday, December 10, 2022 at 8:47AM by Team RightWay

To add support to the above article on Folic Acid, copied next are results from a 5 year review study of research published in 2018. These results highlight the significance of proper vitamin usage, dosages, forms, and synergistic combinations for Folic Acid on cancer risk. 

Folate and Its Impact on Cancer Risk

Renee Pieroth 1, Stephanie Paver 2, Sharon Day 3, Carolyn Lammersfeld 4

Affiliations expand

• PMID: 30099693
 
• PMCID: PMC6132377
 
• DOI: 10.1007/s13668-018-0237-y

Abstract

Purpose of review: Research has evaluated the potential impact of folate on cancer risk with conflicting findings. Studies have demonstrated increased risk, no effect, and decreased risk. This review summarizes findings of mixed results between folate intake, serum levels, gene polymorphisms, and cancer risk based on meta-analyses from the past five years.

Recent finding: Low or deficient folate status is associated with increased risk of many cancers. Folic acid supplementation and higher serum levels are associated with increased risk of prostate cancer. Gene polymorphisms may impact risk in certain ethnic groups. Folate has been studied extensively due to its role in methylation and nucleotide synthesis. Further prospective studies are needed to clarify optimal levels for nutrient remediation and risk reduction in those at risk, as well as elucidate the association between high intake, high serum levels, and prostate cancer risk. 

THIS IS ANOTHER VERY VITAL PIECE OF THE SUPPLEMENT PUZZLE.