April 12, 2010


“New Views On Folic Acid”


Karlis Ullis, M.D. and Cristiana Paul, M.S. Nutrition








    Too little folate may cause the formation of cancer cells to develop and other problems like neural tube defects in a fetus. While too much folate can cause of pre-cancerous cells (from various causes) to multiply too fast and may exceed the immune system's capability to recognize and eradicate them. 

    After reviewing hundreds of papers on folic acid it has been decided by some of the more progressive supplement companies that synthetic folic acid is not an ideal choice for a nutritional supplement because it is an unnatural molecule that now can be replaced by naturally occurring folates. Therefore those vitamin companies that incorporate in their vitamin formulations the natural forms of folates such as Designs For Health, Thorne, Pure Encapsulation, and Prothera, and some others are doing the right thing.

    One's genetic history, genetic "make up" and exposure to a lifetime of the unnatural molecule folic acid could possibly increase a person's risk of some cancers.

    There is also the issue of who will suffer and who will benefit from the fortification of foods with the unnatural molecule folic acid. Those with most to gain are pregnant women. Those with most to lose may be those with certain cancer predispositions. In general it seems most logical to avoid ingesting any unnatural molecules - those not occurring normally in nature.

    About when mandatory fortification of foods with folic acid started in 1998, it has been estimated that an additional 15,000 per year of colon cancer have occurred per year (Joel Mason, M.D. Tufts University Study, 2007) whereas neural tube defects decreased by about 19 percent.

    It may be best to strive to achieve a mid range folate level. Best test is a red blood cell (RBC) methylfolate level.

    Do a plasma folate level if the RBC test is not available. The RBC level tells you average folate levels over about over 90 days. Unmetabolized folic acid levels are available in research centers.

     Choose to ingest only natural folates as found in natural foods and select vitamin supplements  and not the unnatural synthetic compound folic acid, which is found in the majority of vitamins and in fortified-foods. 




    Folate and folic acid derive their names from the Latin word folium, which means "leaf," since there is a fair amount of folates in green vegetables, although they are also found in significant quantities in some animal foods, especially liver, eggs etc.

    Folic acid is a synthetic oxidized molecule that does not occur in nature, but  can be utilized by the human body as a precursor to form natural folates that are biologically active. Folic acid and the natural folates are also known as Vitamin B9 and are water-soluble.

    Many vitamins, such as other B-Vitamins, Vitamin C, Vitamin K, Vitamin E or amino acids can also be produced as synthetic compounds in the laboratory and many of them are identical molecules to the ones that occur naturally in plants, animals or inorganic matter. The folic acid molecule does not occur in nature and it is very different than the natural forms of folates.

    Folic acid is not biologically active on its own but is converted to biologically active forms after it enters the body.  The liver and gut transform folic acid into the active forms such as: tetrahydrofolate, 5-methyl-tetrahydrofolate, folinic acid (5-formyl-tetrahydrofolate) and a few other natural folate forms. The capacity of the human liver to perform these conversions is rather slow. Oral ingestion of folic acid over about 200 micrograms leads to appearance of unmetabolized folic acid in the serum as well as  natural folate metabolites (5-methyltetrahydrofolate etc.)  The result is an accumulation of the unnatural molecule folic acid, which has a greater capacity to enter cells and stimulate cell growth, potentially 100 times more than natural folates, which can set the stage for cancer cell growth.

    Most have heard that women who are about to become pregnant or are pregnant or lactating have been advised to have a daily intake of 400 to 800 micrograms of folic acid in order to prevent neural tube defects in the fetus. The US Reference Daily Intake (Daily Value) for adults is 400 micrograms, (mcg). However, supplementation with 400 to 800 micrograms  of natural folates would be much better, however very few have heard about the availability of natural folates in vitamins.

     Pregnant or lactating women could achieve adequate folate vitamin status if they took in about  800 mcg of natural folates from a natural balanced diet high in fruits and vegetables and with an adequate amount of animal derived foods. Natural folates are found in leafy greens, spinach, lentils, romaine lettuce, liver, eggs, beans, orange juice, broccoli, and vegetable juices, Brewer's yeast etc.

    US public health policy (1998) instituted the cheap and readily available synthetic folic acid fortification of many common foods, such as refined flour products (pasta, cereal, breads, crackers, cakes, cookies and many pre-packaged foods), because the majority of the population consumes these in large enough quantities. One serving of ready-to-eat cereals can have up to 800 mcg of folic acid per standard serving.  The April, 2010 issue of Prevention Magazine article on folic acid states:" Is your breakfast giving you cancer? Research links too much folic acid - a staple in multivitamins, as well as cereal and bread - to colon, lung and prostate cancer." (article by Laura Beil).

    Some European countries such as Norway are not fortifying foods at all with folic acid. Last Summer New Zealand abruptly delayed its mandatory plans for fortification of bread products.

    Food fortification with folic acid has created a complicated scenario depending on what foods are consumed and the fact that some people may ingest significant amounts or maybe excess amounts of the unnatural molecule folic acid from their diet adding to what they may also be taking in from most vitamin formulations. The population that is at risk for excess folic acid intake over a lifetime are all men and those women who can not or will not get pregnant. The long-term consequences of excess consumption of the unnatural molecule folic acid and even natural folates are not yet well known.  The Institute of Medicine Food and Nutrition Board recommends the upper limit for folic acid is 1 mg, which includes a combination of synthetic and natural sources of folate. Marion Neuhauser of the Fred Hutchinson Cancer Center, in Seattle states: "Folic acid is important to take, but not to overdo it. A tailored approach works best as individuals have different needs." (from Emily Sohn, Los Angeles Times "How much folic acid you should get? Does it matter where you get it from?", March 11, 2009).

Folate Physiology and Risk of Cancer

    Vitamin B9 represents a family of compounds called natural folates, which convert to various folate types in the body.

    The plant and animal derived folates occur more than 90% as an equal mix of 5-MethylTetraHydroFolate (5-MTHF) and folinic acid.  Other minor occurring folate forms are tetrahydrofolate and 5,10-methenyl-tetrahydrofolate.Technically folic acid is considered a pro-vitamin because the body can convert it partially into natural folates. However, synthetic folic acid is a compound that does not occur in nature as such and this should be of concern.

    Natural folates and folic acid influences many important functions in human physiology such as:

1.    Act as a coenzyme necessary for the synthesis of thymine and also purine bases, which are needed for DNA synthesis.

2.    Participate in the process of DNA repair and DNA methylation, which dictates which genes are expressed.

3.    Support cell division whether it is beneficial for new fetal cells, tissue repair and renewal or detrimental when it may support pre-cancerous or cancerous cells to divide and multiply.

4.    Control homocysteine levels, a vascular and cell toxin.

5.    Influence NK (Natural Killer) cells of the immune system, which are in charge of fighting infections and malignant cells, 

6.    Support immune cell replication.7.    Support red blood cell replication.

    Important research findings about folic acid which are causing many scientists to raise concerns about folic acid.

1.    Laboratory studies have shown that that folic acid can stimulate cells to proliferate much more rapidly, potentially 100 times more so, than natural folates. 

2.    When the unnatural folic acid molecule is ingested in amounts greater than 200 micrograms at one time from folic acid fortified-food and/or vitamin supplements, the liver and gut cannot  convert all the unnatural folic acid molecules to the natural biologically active forms such as 5-Methyl TetraHydroFolate (5-MTHF). This allows for a significant amount of the unnatural molecule folic acid to accumulate. Consequentially an unnatural compound can enter many cells. One study estimated that as many as 80 percent of Americans have detectable levels of unmetabolized folic acid in their bloodstream. This can be hazardous due to its ability to promote excessive cell proliferation when it is not desirable such as in pre-malignant cells.

3. Unmetabolized folic acid is associated with a reduction of natural killer cytotoxicity, which reduces the immune systems to capacity to kill off malignant or pre-malignant cells.

4. The long-term consequences of having our cells exposed to the unnatural folic acid molecule in the bloodstream and in the gut are not completely known today, but this abnormal physiology should be of concern. Pre-cancerous cells normally occur in our bodies all the time but they are typically identified and killed-off by a competent immune system. When there is an excessive amount of the unnatural folic acid molecule around, pre-cancerous cells can multiply faster, and there is a greater chance they may escape our natural immune surveillance system and become malignant. 

    People who have cancer or are predisposed or are under treatment such as chemotherapy or have overcome cancer and wish to reduce their risk of cancer re-occurrence should be advised to avoid the unnatural folic acid molecule in fortified-foods and supplements.  The recommended minimum Daily Value by the FDA is 400 micrograms per day for adults. Many vitamins and most fortified foods contain that much or more per to  a standard  serving. In general it may be best to keep a daily intake from all sources at no more than about 400 to 500 micrograms.


    Natural foods have a much lower concentration of the folates than fortified-foods. Also, natural folates found in foods are much slower absorbed and much less efficiently than natural folate supplements or folic acid because they are conjugated with a variable number of glutamic acid molecules.

    You would have to eat a greater volume of natural folate containing foods than taking in a natural folate supplement to get an equivalent boost in folate status.



    A Norwegian study published in the Journal of the American Medical Association (JAMA, November 17, 2009), tracked over 6,800 people who received 800 micrograms of the unnatural folic acid molecule and Vitamin B12 after a heart attack. These people later were found to be 21 percent more likely to develop lung cancer and 38 percent greater chance of dying from it. Norway does not fortify its foods with folic acid as the U.S. does.

    Daily intake of the unnatural molecule folic acid may double the risk of prostate cancer (Figeiredo MW, et al., " Folic acid and the risk of prostate cancer-A randomized trial", Journal of National Cancer Institute, March 2009). Daily supplements of folic acid of more than one mg was associated with more than twice the risk of prostate cancer. The paper states "There is a complex role of synthetic folate in prostate carcinogenesis". Dietary natural - folate intake showed a trend toward reduced risk of prostate cancer.

    A Swedish study in 2004 showed that a high dietary natural folate intake may play a role in reducing ovarian cancer especially among those women who consumed alcohol more than 20 gm per week. (Larson, SE, et al., J Natl Cancer Institute, 2004).

    Another Swedish study just published by Susanna C. Larrsen, Ph.D. at the Karolinska Institute in Stockholm (Am J Clin Nutrition, April 2009) studied 35,000 Swedish women (ages 49 to 83) who took multivitamins. Those taking multivitamins were 19 percent more likely to develop breast cancer than the controls. One of the reasons for the increased breast cancer risk was folic acid, which may increase breast density and potentially stimulate development of cancer. Vitamin C, E and B6 did not increase risk. Calcium appeared to be protective.

    It makes sense that ingesting an adequate, but not excessive amount of natural folates may be able to reduce cancer occurrence because folate deficiency predisposes the body to the risk of DNA errors during cell replication. This is due to improper or irregular formation of new DNA in new cells. This is similar to the situation when copier toner runs low and then the copies do not look exactly like the original. They are faded and may contain errors. This is how DNA mutations may occur and dangerous pre-cancerous cells may be created. This especially may be a problem in those over age 60 or those with impaired immune system.

    If the unnatural folic acid molecule is so inferior to natural folates and may potentially cause problems, why is the unnatural folic acid molecule still used in food and other fortification and is found in most widely used supplements? The answer is simple, natural folates have not been available in a stable form until recently and their prices are much higher than folic acid (about more than 400 times more expensive). Very few supplement companies have decided to replace folic acid with natural folates in their formulations.


    Have a diet rich in leafy greens, spinach, beans, Brewer's yeast, chickpeas, lentils, eggs, liver and some fruit like oranges, melons, and others. Minimize the consumption of foods fortified with the unnatural molecule folic acid.  These foods are typically made with refined flours, such as white breads, pasta, bagels, cereals, cakes, cookies, crackers, and packaged-processed foods, even in many "nutritional" shakes and bars.


    These foods are also problematic due to their high carbohydrate load (glycemic load), and are absorbed in the bloodstream very fast, and can rapidly produce elevated blood glucose and insulin levels. Excessively elevated blood levels of glucose and insulin can be stimulants for cell proliferation and may increase the risk of cancer. Also there is increased risk of obesity, diabetes, elevated blood cholesterol, (triglycerides) and the metabolic syndrome, which support cancer cell proliferation in synergistic ways.

    Since most people do not have an adequate intake of vegetables and other nutritious foods, supplementing with  high quality multivitamins can support optimal health and performance but make sure your vitamins contain the natural form of folates such as 5-MTHF (5-MethylTetraHydroFolate) and/or folinic acid (or calcium folinate).


    People beyond childbearing years and those with "weakened" immune systems and history of precancerous lesions should be monitored to avoid excessively high levels of all folates. It is estimated that as many as half of adults over age 60 could have in their tissues some pre-cancerous cells such as in colon polyps or in the prostate gland.

    I recommend Designs For Health vitamin supplements since all their vitamin formulas contain natural folates and are designed based on scientific principles and for maximal clinical effectiveness. Other good vitamin companies are starting to do the same: Thorne, Pure Encapsulations, Douglas, Prothera, and others.



    A blood test is available that measures red blood cell (RBC) levels of methylfolate, which maybe a good indicator of about the last three months average folate/folic acid intake and absorption. The type of folate measured by this test is "methylfolate" (Quest, LabCorp Labs). Plasma  levels" are less reliable since it may only indicate recent folic acid/folate intake.

    Keep in mind that some people have trouble absorbing natural folates from greens and other natural folate foods and those may be the people that need natural folate supplementation the most. It is a good idea to test everybody because health is not optimal at both ends of the spectrum, too high or too low red blood cell folate status may be problematic. This test is imperative for women trying to conceive (who need higher folate levels) or any male or female with pre-cancerous colon, polyps, or other suspicious cells and  have strong family histories of cancer. They need to have lower folate levels.

Stay in the Safe Range

    Read labels of foods and vitamins to see how much folic acid you may be consumingBut do keep eating natural non-fortified folate containing foods.

    I generally recommend the RBC methylfolate levels to be in mid range for healthy young people. Those with pre-cancerous lesions like polyps or strong family history of cancers (who need to be to be at the lower end of normal).




    Obtain natural folate from non-fortified foods and or vitamins containing natural forms of folates such as 5-MTHF (5-Methyl-tetradydrofolate), folinic acid (5-formyl-tetrahydrofolate) (or calcium folinate), with the proprietary formulation NatureFolate (TM) as found in all Designs for Health supplements (which are available via my office).  I do believe  the time has come for all to examine  ALL their vitamins and foods and see if they contain the unnatural molecule folic acid. If so, and you have cancer concerns then change your folic acid supplements to NatureFolate(TM) blend. Also measure RBC methylfolate levels. Avoid the extremes of folate deficiency or folate excess status.

    If you have any questions regarding your folate /folic acid supplements or others and cancer risk let me know so we can review and measure your RBC folate and cancer risk profile.  Other relevant lab tests I may do to evaluate your cancer risk and overall health status may include:

1.    The urinary marker (8-OHDG), which is an indicator of DNA damage of various cells in the body.

2.     Lipid peroxides, marker for oxidative stress, which may induce DNA damage.

3.    The red blood cell AA/EPA (Arachidonic Acid/Omega-3 fatty acid) ratio which influences cell proliferation, immune response, inflammation, clotting, vasoconstriction etc.

4.     Homocysteine blood levels.  High homocysteine or too low are not optimal and is an indicator of methylation status, which influences many aspects of health including the risk for cardiovascular disease. It also affects the methylation of DNA which dictate how genes are expressed or silenced and may influence the risk of cancer

5.     Immune system status indicators such as  NK (Natural Killer) cell numbers and NK cell activity (as a marker for immune status), WBC (white blood cells) and others.

6.    HS-CRP (high sensitive C-Reactive protein), an inflammation and/or infection marker.

7.    Vit D levels. Vit D influences cell proliferation and DNA repair

8.    Insulin levels. High insulin levels stimulate cell proliferation and can lead to weight gain.

9.    HBA1C, marker of average 90 day glucose levels. High glucose levels can stimulate cell proliferation.

    The tests mentioned above are some important general markers of cancer risk and overall health. These markers, along with medical history-exam  and a genetic evaluation can help with designing a rational program and specific interventions for each  individual's long term well-being.


Karlis Ullis, M.D.
2701 Ocean Park Blvd., Suite 101
Santa Monica, CA 90405
Voice: 310-452-1990
FAX:  310-452-5134
E-mail: kullismd@gmail.com