Folate (B9) & Health

What is Folate & What Does it Do?

Folate is another of our water-soluble B-complex vitamins.  When it occurs naturally in food, it is called folate, and when it is found as a supplement, it is called folic acid.  This vitamin is found abundantly in green leafy plants (folate - foliage) and is commonly added to refined grains.  Folate plays many very important roles in the development of our nervous system, in the regulation of our DNA, the creation of our blood cells, and so much more. 

Methylation: 

Folate plays its major role in our health through methylation, so before we dive into learning more about folate, we need to know what methylation is, what it does, and why it’s important. 

What is Methylation? 

Methylation is the act of transferring single carbon units from one molecule to another. (1)

What Does Methylation Do?

Methylation is the way mammalian bodies “turn genes on and off”.  When a carbon unit is attached to a segment of DNA, that area is blocked and cannot be copied.  When that carbon unit is removed, the area of DNA is accessible and can be copied, and that set of instructions can now be carried out. (2)

Why is Methylation Important?

Our bodies are capable of a lot of different things, but we don’t need to do all of them at once.  We only need to go through fetal development once.  We only produce hormones when we need them.  We don’t want all of our cells dividing all of the time, nor do we want them to all die and be recycled at the same time.  There is a time for everything, and methylation is a major tool our bodies use to regulate and maintain this order.  

Folate Deficiency: 

To better understand the implications of a breakdown in this methylation process, we can start by exploring the symptoms of folate deficiency, and then we can look to disease prevention.  Clinical folate deficiency results in megaloblastic anemia which presents with: 

• Fatigue

• Weakness

• Shortness of breath

Folate is a nutrient of concern as deficiency is most often due to low intake.  Other causes of deficiency include heavy or chronic alcohol use; smoking; malabsorption diseases like IBS; the use of medications that inhibit folate; during states of increased folate use like pregnancy or cancer; and with genetic issues affecting folate absorption, transport, or metabolism. (1)

MTHFR defects: 

For a significant portion (up to 50%!) of the population, a genetic polymorphism (small change) to the MTHFR gene results in a defect of folate metabolism that slows down methylation. (1)  This defect has been associated with a growing list of concerns including: 

• Miscarriage

• Cancer

• Cardiovascular disease

• Neural tube defects

• Low birth weight

• Autism

• ADHD

• Autoimmune diseases

This is a hot topic for research.  In fact, a simple search on PubMed for “MTHFR” produces a total of 597 meta-analyses and systematic reviews!  To put that into perspective, a similar search for our last nutrient, biotin, reveals only 19 meta-analyses and systematic reviews. 

If you are interested in learning more about MTHFR, I recommend you discuss your risks and the benefits of testing with your healthcare team.  This is a standard test that can be ordered from many different laboratories, and if indicated, may be covered by your medical insurance.  Each plan has its own definition of what they consider “medically necessary”, so be sure to check with your insurance and your providers to see if you have a qualifying condition.

Prevention of Disease: 

Folate shines when it comes to disease prevention.  When we understand folate’s role in methylation and the importance of methylation, this makes sense. 

Neural Tube Defects: 

Folate, in the synthetic form of folic acid, became a nutrient of household fame due to the efforts of the March of Dimes.  In an effort to end “birth defects,” the March of Dimes turned to the latest research and noted the connection between low folate intake and the increased risk of neural tube defects like spina bifida and anencephaly.  These conditions are life-threatening and until recently, occurred at much higher rates.  Due to the efforts of the March of Dimes and their educational programs, folic acid is now added to refined food products, and folic acid supplementation is encouraged for all women of child-bearing age.  This last point is particularly important as the major developments of the neural tube occur before many women even know they are pregnant and can make changes to support their pregnancies. 

Neurodevelopment: 

A 2021 systemic review and meta-analysis weighed in on the suspected influence of folate on autism, ADHD, and other neurodevelopmental disorders.  “...[P]renatal FA [folic acid] supplementation had a positive impact on offspring's neurodevelopmental outcomes, including improved intellectual development and reduced risk of autism traits, ADHD, behavioral, and language problems. We also found that FA over-supplementation was not associated with an improvement in offspring's brain development, and may have a negative impact on offspring's neurodevelopmental outcomes.” (3)

From this study of the studies we learn two important things: 

1. Folic acid plays a role in neurodevelopment.

2. Taking too much folic acid can pose problems for neurodevelopment.

Just as with most things, too much folic acid is too much, so watch out for supplements with excessive amounts of folic acid. 

Cancer: 

When we understand the connection between folate, methylation, and DNA regulation, we can see why folate would play a role in the development of cancer.  Cancer at its most basic definition is the unregulated growth of certain cells.  The type of cancer will depend on where it is found in the body and what types of cells are growing out of control.

Regardless of the direct cause of cancer, maintaining good control of DNA regulation through sufficient methylation will be protective to some degree.  While we continue to research the connection between cancer and folate, we currently see evidence for folate’s role in cancer prevention for the following cancer types:

• Colorectal cancer (1)

• Breast cancer (1)

• Wilms’ tumor (1)

• Neuroblastoma (1)

• Ganglioneuroblastoma (1)

• Ependymoma (1)

• Lung Cancer (4)

• Esophageal Cancer (5)

• Pancreatic Cancer (6)

• Bladder Cancer (7)

Heart Disease: 

Heart disease remains the top cause of death in the United States, followed closely by cancer.  Both conditions are difficult to treat once they develop and require heroic medical efforts and significant costs in time, money, and quality of life to do so.  Anything we can do to decrease the incidence of these two conditions is well worth it.  

“Folate-rich diets have been associated with decreased risk of CVD, including coronary artery disease, myocardial infarction (heart attack), and stroke.” (1)  What does a folate-rich diet look like?  It is one that includes at least 5 servings of fruits and vegetables daily.  If you identify as a picky eater, a good blender can be your best friend for creating tasty smoothies and blending vegetables into sauces.  Creativity in the kitchen can go a long way in disease prevention.

Treatment of Disease: 

When it comes to the treatment of diseases, folate plays a role here too.  But always remember, disease prevention works so much better than treatment!

Hypertension: 

Hypertension -- high blood pressure -- has many causes that can include the heart, blood vessels, kidneys, hormonal systems, and nervous system.  That being said, it is a tricky condition to manage, often requiring higher doses of medication and multiple different medications over time.  A 2021 study shows folic acid to be helpful in the treatment of high blood pressure reducing both systolic (top) and diastolic (bottom) measures. (8)  

Untreated high blood pressure puts a person at risk for damage to the tiny blood vessels in their eyes and kidneys; this increases the risk of vision loss and kidney failure respectively.  High blood pressure also increases the risk of congestive heart failure and hemorrhagic stroke.  This common symptom shouldn’t be overlooked or underestimated. 

Depression: 

Depression is another condition that is hard to manage and often involves multiple interventions.  In another 2021 study, adding folic acid or L-Methylfolate to a patient's SSRI or SNRI medication improved patient response to treatment, depression scale scores, and rates of disease remission and recovery. (9)  This is a great example of how nutrients and medications can be used together.  It shouldn’t have to be one or the other.

Metabolic Disorders: 

Folate supplementation is most effective as a treatment for diseases of folate absorption, metabolism, or transport including: 

• Hereditary folate malabsorption

• Cerebral folate deficiency syndrome

• Dihydrofolate reductase deficiency

Additionally, “for those with a known MTHFR defect, naturally occurring folate or the supplement L-methylfolate may be key for overall health and preventing or reducing the risks associated with this genetic polymorphism.” (10)  That’s a significant statement given that up to 50% of the population may have an MTHFR defect!

Toxicity: 

We do not see adverse effects from overconsuming naturally occurring folate in food; however, we do see harmful side effects from excessive folic acid supplementation.  The most frequently seen issue with high doses of folic acid is a masking of vitamin B12 deficiency.  Both folate deficiency and B12 deficiency cause megaloblastic anemia.  When high doses of folic acid are given, this anemia can resolve even if it was due to B12 deficiency.  This is a concern as chronic B12 deficiency can result in permanent nerve and brain damage resulting in chronic pain syndromes and dementia. (1)

We also see issues with unmetabolized folic acid found with high dose supplementation.  This can cause problems with blood formation and cognitive decline. (1)  We also saw above that excessive folic acid supplementation has been associated with neurodevelopmental problems in children.

Currently, the upper limit (UL) for folic acid consumption is set at 1,000 mcg daily for adults 19 and older and much lower for children. (1)

Where to Find Folate: 

Folate is easy to consume in abundance as long as you are eating fruits and vegetables.  There are other foods rich in folate as well.  Unfortunately, even with the addition of folic acid to refined foods, folate deficiency continues to be a problem in the U.S. and around the world. 

Foods particularly rich in folate: 

• Lentils

• Garbanzo beans

• Asparagus

• Brussels sprouts

• Spinach

• Enriched pasta

• Enriched rice

Applications:

Our takeaways this week are: 

1. Folate is a nutrient of concern in the United States, meaning not enough of us are getting enough.

2. Folate is important for methylation and therefore DNA regulation.

3. Folate deficiency results in megaloblastic anemia.

4. Adequate levels of folate are preventative against a wide variety of conditions.

5. Up to 50% of the population may have an inherited defect in one of their MTHFR genes and need additional folate or L-methylfolate to prevent a long list of associated conditions.

6. Too much folic acid can be harmful, so don’t overdo it. 

Daily Intake:

If 1,000 mcg is too much, how much is enough?  Currently, the RDA to prevent megaloblastic anemia is 400 mcg daily for adults and 600 mcg daily during pregnancy.  Those with a known MTHFR mutation may need additional folate from food or as the supplement L-Methylfolate, but care should be taken to keep intake from supplementation below 1,000 mcg daily. 

As someone with a known, and lab verified, double change defect of one MTHFR gene, I know that I have passed down one defective copy to each of my children (they got one copy from my egg and one from their father’s sperm).  Knowing this, as they grew I was able to ensure they got plenty of folate in their diets and supplement a bit of L-methylfolate when needed. 

Medication Interactions:

Daily folate intake needs may be higher when taking the following medications: 

• NSAIDs (Ibuprofen, aspirin) taken in high doses

• Phenytoin

• Phenobarbital

• Primidone

• Cholestyramine

• Colestipol

• Methotrexate

• Chemotherapeutic agents

• Trimethoprim

• Pyrimethamine

• Triamterene

• Sulfasalazine

• Estrogen

There we have it: an overview of folate.  Now, go eat some lentils and spinach! 

Next week: 

We will finish our exploration of the B-complex vitamins with vitamin B12.  This will be our final vitamin we study.  Our next topic will be the minerals essential for life. 

To our health!

References: 

1. Higdon, J, “Folate” Linus Pauling Institute, 2000; last update: 2014; accessed November 5, 2021; https://lpi.oregonstate.edu/mic/vitamins/folate

2. Moore LD, Le T, Fan G. DNA methylation and its basic function. Neuropsychopharmacology. 2013;38(1):23-38. doi:10.1038/npp.2012.112

3. Chen H, Qin L, Gao R, Jin X, Cheng K, Zhang S, Hu X, Xu W, Wang H. Neurodevelopmental effects of maternal folic acid supplementation: a systematic review and meta-analysis. Crit Rev Food Sci Nutr. 2021 Oct 21:1-17. Doi: 10.1080/10408398.2021.1993781. Epub ahead of print. PMID: 34672229.

4. Bae JM. Serum Folate Levels and Lung Cancer Risk: A Meta- Epidemiological Study of Population-based Case-Control Studies. Asian Pac J Cancer Prev. 2020 Jun 1;21(6):1829-1833. doi: 10.31557/APJCP.2020.21.6.1829. PMID: 32592384; PMCID: PMC7568864.

5. Zhao Y, Guo C, Hu H, Zheng L, Ma J, Jiang L, Zhao E, Li H. Folate intake, serum folate levels and esophageal cancer risk: an overall and dose-response meta-analysis. Oncotarget. 2017 Feb 7;8(6):10458-10469. doi: 10.18632/oncotarget.14432. PMID: 28060731; PMCID: PMC5354672.

6. Lin HL, An QZ, Wang QZ, Liu CX. Folate intake and pancreatic cancer risk: an overall and dose-response meta-analysis. Public Health. 2013 Jul;127(7):607-13. doi: 10.1016/j.puhe.2013.04.008. Epub 2013 Jun 14. PMID: 23769243.

7. He H, Shui B. Folate intake and risk of bladder cancer: a meta-analysis of epidemiological studies. Int J Food Sci Nutr. 2014 May;65(3):286-92. doi: 10.3109/09637486.2013.866641. Epub 2013 Dec 16. PMID: 24328495.

8. Asbaghi O, Salehpour S, Rezaei Kelishadi M, Bagheri R, Ashtary-Larky D, Nazarian B, Mombaini D, Ghanavati M, Clark CCT, Wong A, Naeini AA. Folic acid supplementation and blood pressure: a GRADE-assessed systematic review and dose-response meta-analysis of 41,633 participants. Crit Rev Food Sci Nutr. 2021 Sep 3:1-16. doi: 10.1080/10408398.2021.1968787. Epub ahead of print. PMID: 34478339.

9. Altaf R, Gonzalez I, Rubino K, Nemec EC 2nd. Folate as adjunct therapy to SSRI/SNRI for major depressive disorder: Systematic review & meta-analysis. Complement Ther Med. 2021 Sep;61:102770. doi: 10.1016/j.ctim.2021.102770. Epub 2021 Aug 24. PMID: 34450256.

10. Scaglione F, Panzavolta G. Folate, folic acid and 5-methyltetrahydrofolate are not the same thing. Xenobiotica. 2014 May;44(5):480-8. doi: 10.3109/00498254.2013.845705. Epub 2014 Feb 4. PMID: 24494987.