Quality Rating

About Folate:

Folate is involved in a variety of processes in the body including generating energy from food, helping support stable mood, and even plays a role in immunity.

Mood & Folate:

  • Building block for many “feel-good” neurotransmitters such as serotonin, dopamine and norepinephrine
  • Low folate causes poor response to antidepressant meds
  • The lower the folate, the more severe the depression.

Digestive & Folate

  • Gastrointestinal- Deficiency alters genes in a way that makes colon cells more likely to become cancerous
  • Folate also plays a key role in cellular immunity. Low folate status is linked to severity of allergic response

Neurological:

  • MTHFR gene raises methylated folate requirements and is linked to migraines
  • Sleep- Folate acts as a cofactor for several neurotransmitters such as serotonin and dopamine. Many regulate sleep patterns.

Cardiovascular & Folate:

  • Lowers blood pressure through improving endothelial function (ability of blood vessels to properly dilate
  • Folate also forms red blood cells in the bone marrow

Other Aspects to Folate:

  • Folate is involved in many methylation reactions in the body including neurotransmitter synthesis
  • Repair- Influences telomere length through its role in methylation. Folate is also required for DNA synthesis
  • Hormones- Deficiency reduces circulating testosterone; testosterone is also involved in folate metabolism

Deficiency Presentation:

  • Megaloblastic/microcytic anemia
  • Diarrhea and fatigue

Recommended Food sources: Green leafy vegetables, citrus fruits, lentils, beans, grains, spinach, black eyed peas, brussel sprouts

Recommendations for Supplemented Forms: See Clinical Notes on Folate for Details

  • Folate from food sources like leafy greens, beans and citrus
  • Avoid Folic Acid in Multivitamins since it can block absorption of other forms and accumulate
  • Look for 5-MTHF or methylated folate in multivitamins
  • Folinic Acid is another form that can be used (not to be confused with folic acid

 

 

Clinical Notes on Folate (For Health Care Providers)

Introduction to Folate

Folate is a water-soluble B vitamin, B9. Folate, formerly “folacin,” is the general term used to describe the many forms of B9: folic acid, dihydrofolate (DHF), tetrahydrofolate (THF), 5, 10-methylenetetrahydrofolate (5, 10-MTHF), and 5-methyltetrahydrofolate (5-MTHF). 

Folate functions: 

  • Coenzyme in single-carbon transfers in the synthesis of DNA and RNA and metabolism of amino acids
  • The conversion of homocysteine to methionine is folate dependent 
  • Methylation of deoxyuridylate to thymidylate in the formation of DNA is folate dependent – required for proper cell division. Impairment to this is what leads to megaloblastic anemia, a hallmark of folate deficiency.

Food folates, naturally occurring folate in foods, are in the tetrahydrofolate form. Food sources of folate include: 

  • Leafy greens, particularly boiled spinach
  • Citrus
  • Beans
  • Black eyed peas
  • Grains
  • Brussels sprouts

Folate Deficiency 

Folate deficiency is typically not seen in isolation but rather associated with other nutrient deficiencies. It’s strongly associated with alcoholism, poor diet quality, and malabsorptive disorders. The primary clinical sign of folate or B12 deficiency is megaloblastic anemia, characterized by abnormally large cells with incompletely developed nuclei. Symptoms include: 

  • Weakness 
  • Fatigue
  • Difficulty concentrating
  • Irritability
  • Headache
  • Heart palpitations
  • Shortness of breath 
  • Soreness in the mouth and shallow mouth ulcers
  • Changes in skin, hair, and nail pigmentation
  • GI symptoms
  • Elevated blood homocysteine concentrations
  • Inadequate maternal folate = low birth weight, preterm birth, growth retardation, and neural tube defects

People at risk: 

  • Those with alcohol use disorder
  • Women of childbearing age
  • Pregnant women
  • People with malabsorptive disorders: 20-6% of those with IBD have folate deficiency; lowered gastric acid secretion seen with gastritis and gastric surgery also reduce folate absorption 
  • People with MTHFR polymorphism 

Medication Interactions

  • Methotrexate (Rheumatrex®, Trexall®) is a folate antagonist. Folate supplements may reduce the drug’s anti-cancer effects, however they may also reduce the GI side effects of low-dose methotrexate used in autoimmune conditions. 
  • Antiepileptic drugs like phenytoin (Dilantin®), carbamazepine (Carbatrol®, Tegretol®, Equetro®, Epitol®), and valproate (Depacon®) can reduce serum folate levels. In turn, folate supplements can reduce serum levels of these drugs.
  • Sulfasalazine (Azulfidine®) is a folate antagonist, it inhibits intestinal absorption of folate.

Why We Prefer Folate rather than Folic Acid (FA)

Folic Acid vs 5-MTHF:

  • While it has a higher heat tolerance than folate, FA still must be converted to active folate
  • The conversion process makes the utilization slower than folate
  • Conversion: FA – DHF (dihydrofolate) – THF (tetrahydrofolate). THF is the only one that can enter the metabolic cycle.
  • Many people have low levels of the enzyme that converts folic acid to the “active form” which makes them more vulnerable to buildup of unmetabolized folic acid in the body
  • Excessive unmetabolized folic acid can have several health issues which makes folate a safer option
  • FA and 5-MTHF are similar in increasing folate, but folate is slightly better is some studies
  • Too much FA in the body can negatively impact natural killer cells which can impact the immune system, while 5-MTHF cannot lead to high FA levels
  • 5-MTHF is the preferred form for those with genetic polymorphisms

Potential Risks of Folic Acid:

  • Excessive intake increases cancer risk (Link
  • US, Canada and Chile introduced the folic acid supplementation program which has been associated with an increase in colon cancer (Link, Link)
  • Excessive cognitive decline has been found in older adults who supplement (Link)

Other Variations: Folinic Acid 

Folinic acid (5-formyltetrahydrofolate ([R, S]5-CHOFH4)) is a naturally occurring, reduced form of folic acid commonly known in clinical practice as leucovorin. Folinic acid is used in combination with other chemotherapy drugs to either enhance effectiveness, or as a “chemoprotectant.” It is also used as an antidote to folic acid antagonists like methotrexate. 

Administering folinic acid after weekly doses of methotrexate reduces: 

  • Hepatic damage
  • GI complications
  • Stomatitis (oral ulcers)

Mechanism

Folinic acid does not require dihydrofolate reductase for conversion into tetrahydrofolate. This is how folinic acid functions as an antidote by rescuing cells from the chemotherapeutic toxicities of folate antagonists such as methotrexate. 

The list of non-FDA approved indications of folinic acid are far more extensive and include the following:  

  • Similar to its use in colorectal cancer, folinic acid has also been shown to potentiate the effects of 5-FU ( 5-fluorouracil, a chemotherapy drug) in the treatment of breast carcinoma. 
  • Regimens including folinic acid and 5-FU also have non-FDA-approved indications for the treatment of unresectable/advanced gallbladder and biliary tree carcinoma, gastric cancer, squamous cell carcinoma of the head and neck, and resectable pancreatic cancer.
  • Combination chemotherapy regimens that include folinic acid have been effective in various non-Hodgkin lymphomas. Methotrexate and rescue folinic acid, in conjunction with other chemotherapy agents (i.e., doxorubicin, cyclophosphamide), have shown a complete response rate of 84% in the treatment of diffuse large cell lymphoma.

 

Research: