Info Cart -

Folate, Folinic Acid, Methylfolate for Brain Health

Summary: Folate is a form of vitamin B9 essential for many bodily processes. Problems with low folate can lead to all manner of brain problems such as autism, seizures, troubles with gait and coordination. In adolescents, it can appear as treatment-resistant psychosis and schizophrenia. In older adolescents and adults, it can appear as treatment-resistant depression. The challenge is that even giving usual folate supplements may be insufficient. The good news is that giving other forms of folate, such as methylfolate or folinic acid may be helpful.
Add to Info Cart
PDF
Image credit: Freepik

Summary

Folate is a form of vitamin B9 essential for many bodily processes.

Problems with low folate can lead to all manner of brain problems such as autism, seizures, troubles with gait and coordination. In adolescents, it can appear as treatment-resistant psychosis and schizophrenia. In older adolescents and adults, it can appear as treatment-resistant depression.

The challenge is that even giving usual folate supplements may be insufficient. The good news is that giving other forms of folate, such as methylfolate or folinic acid may be helpful.

What Is Folate Used For?

Folate is a form of vitamin B9 essential for many bodily processes:

  • Making RNA and DNA
  • Cell growth
  • Making red blood cells and protein metabolism
  • In the brain, folate is vital for
    • Constructing myelin
    • Making chemical messengers (neurotransmitters such as serotonin, dopamine and noradrenaline) that transmit signals in the brain.
  • In a woman who is pregnant
    • In early pregnancy, folate is important so that the baby can have normal brain and spine growth. Low folate dramatically increases the risk of congenital defects in the baby, whereas taking folate supplements reduces the risk of congenital defects of the brain and spine.

What are the Signs and Symptoms of Low Folate?

Signs of Low Folate (i.e. folate deficiency)

Classic signs of low folate include the following;

  • General weakness and fatigue;
  • Cardiovascular: Irregular heartbeat; shortness of breath;
  • Megaloblastic anemia, a condition where the lack of folate results in fewer red blood cells, and they appear larger (‘megaloblastic’) than normal;
  • Skin/hair: Hair loss; pale skin; mouth sores.
  • Congenital disabilities (aka birth defects): When a pregnant woman has low folate during their pregnancy, this is very serious as it puts a baby at a higher risk of neural tube defects which affects the spine, spinal cord and brain, and can be fatal for the baby.

Signs of Low Folate in the Brain (i.e. cerebral folate deficiency, aka CFD)

In addition to the classic signs of low folate above, there are also specific signs and symptoms when people have low folate in the brain (aka cerebral folate deficiency). Symptoms can vary depending on what age the person develops low brain folate (Ramaekers, 2016.)

In young children, low folate may show up as

  • Infant-onset cerebral folate deficiency (CFD) syndrome
    • This is a syndrome where a child has normal development in the first year, but at about two years of age, they have regression of mental and motor skills.
  • Infant/childhood autism (with or without neurologic problems)
    • When people have low folate in the brain (cerebral folate deficiency), about 44% have ASD (Rossignol, 2021).
    • People with ASD have FRAAS (FRA auto-antibody syndrome) much more frequently than other people -- when people have ASD, their chance of having FRAA is 19X more likely than typically developing children without an ASD sibling (Rossignol, 2021).
  • Neurologic problems such as
    • Seizure disorders.
    • Spastic-ataxic syndrome (i.e. problems with balance and coordination).

In adolescents, low folate may show up as

  • Schizophrenia or treatment-resistant psychosis. Research suggests that at least some cases of psychosis may be due to problems with low folate in the brain.

In adults, low folate may show up as

  • Treatment-resistant major depression.
    • In particular, depression that has not responded to antidepressant medication (such as SSRIs) may suggest folate deficiency.
    • When people have low folate, they have a) lower levels of tetrahydrobiopterin (BH4) which leads to lower levels of serotonin and dopamine, as well as b) higher levels of homocysteine, which is linked to conditions such as depression, Alzheimer's and heart disease.

    How Does Folate Get Into Our Body?

    The process starts when we eat folate…

    Folate

    Folate is found in many foods such as dark green leafy vegetables, eggs, beans and citrus fruits.

    X Problems can happen here when people do not get enough folate in their diet for example:

    • Some people are extremely selective or picky eaters.
    • Pregnant people have higher than usual need for folate.
    • Some people have troubles absorbing folate due to digestive disorders, celiac disorder, due to excessive alcohol use, etc.

    OR

    Folic acid

    Folic acid is a synthetic form of folate often placed into supplements and fortified foods.

    Folinic acid

    After ingesting folate or folic acid, an enzyme (methylenetetrahydrofolate reductase aka MTHFR), converts folate or folic acid into folinic acid.

    X Some people have problems with their MTHFR gene so the MTHFR enzyme doesn’t work.

    Pharmacogenomic testing for the MTHFR gene can show if this is the case.

    5-Methyltetrahydrofolate (5-MTHF)

    Folinic acid is then converted into the active form of 5-methyltetrahydrofolate (5-MTHF) aka l-methylfolate, or simply methylfolate.

    Transported into the brain

    Cerebral folate receptor alpha (FRα) transports 5-methyltetrahydrofolate (5-MTHF) into the brain.

    X A problem at this step is that some people have folate receptor alpha autoantibodies (FRAAS), which keeps 5-MTHF from getting into the brain.

    Drinking cow’s milk appears to trigger FRAAS in certain people.

    Most cerebral folate deficiency (CFD) syndromes appear to be due to folate receptor alpha (FRα) autoimmunity with low MTHF in the cerebrospinal fluid (CSF), which leads to low brain folate. Other causes such as FRα gene abnormalities and mitochondrial gene defects are rare.

    Summary of the Folate Pathway

    Folate or folic acid

    Converted by MTHFR enzyme

    Folinic acid (leucovorin)

    L-Methylfolate, aka 5-methyl-tetra-hydrofolate (5-MTHF)

    What is the Daily Recommended Amount of Folate?

    People should get the following amounts of folate every day (according to the National Instiutes of Health)

    Age

    Recommended amount of dietary folate equivalents (DFE)

    1-3 years

    150 mcg DFE

    4-8 years

    200 mcg DFE

    9-13 years

    300 mcg DFE

    14-18 years

    400 mcg DFE

    19+ years

    400 mcg DFE

    Females aged 19+ years planning a pregnancy

    600 mcg DFE

    * DFE is dietary folate equivalents. For more information, visit https://ods.od.nih.gov/factsheets/Folate-HealthProfessional/

    Investigations.

    The classic folate test measures how much folate is in the blood.

    Pharmacogenetic testing can see if a person has trouble with methylenetetrahydrofolate reductase (MTHFR), the enzyme responsible for converting folic acid to methylfolate.

    Not all pharmacogenomic testing includes this test, so one must check with the company beforehand.

    Treating Low Folate with General Symptoms

    Are there symptoms of folate deficiency in general?

    Start by making sure that you eat enough foods with folate:

    • Vegetarian
      • Dark green leafy vegetables (turnip greens, beets and beet greens, spinach, romaine lettuce, asparagus, Brussels sprouts, broccoli)
      • Beans (e.g. lentils)
      • Peanuts
      • Sunflower seeds
      • Fresh fruits and citrus fruits (e.g. oranges, lemons, grapefruit, lime)
      • Whole grains
      • Eggs
    • Non-vegetarian
      • Liver

    Are there still problems with low folate despite increasing folate in your diet and having folate supplements?

    Some people are not helped by eating more folate because they may have other issues with folate, such as problems with metabolising folate to a useful form or transporting it into their brain.

      Treating Low Folate with Cerebral Folate Deficiency Syndromes such as Depression, Psychosis, or Autism Spectrum Disorder (ASD)

      Are there Symptoms of Depression?

      L-Methylfolate (aka 5-MTHF)

      Many studies suggest that L-methylfolate supplements may be helpful for those with depression, particularly treatment-resistant depression (Bender, 2017). Why are some people low in folate despite taking enough folate in their diet? It may be that they have trouble converting folic acid to L-methylfolate. Hence the advantage of simply giving L-methylfolate (rather than folic acid).

      Dosage

      • Studies on depression usually used 7.5-15 mg daily.
      • Some child psychiatrists report success with using 2-3 mg daily.

      Are there symptoms of autism spectrum disorder (ASD) and psychosis?

      Folinic acid (Leucovorin)

      • In order to reduce the FRα autoantibody titer in those positive for the antibody, some authors recommend (Raemakers, 2016)
        • Corticosteroids
        • Milk-free diet, as milk appears to trigger the FRAAS autoimmune antibody.

      How to Find L-Methylfolate in Canada?

      L-methylfolate (5-MTHF) is not a prescription prescription medication. However, it is available at many pharmacies, health food stores and online retailers.

      Examples for informational purposes are shown here. Note that the presence or lack of presence of a brand does not imply endorsement or non-endorsement.

      Are you looking for L-methylfolate 7.5-15 mg daily for treatment-resistant depression in an adolescent / adult? (i.e. aged 12+)

      FolateMaxx L-methylfolate 15 mg capsules

      https://www.amazon.com/FolateMaxx-L-Methylfolate-Capsules-Professional-Quality/dp/B07P9KQMXW/

      $60 CDN for 90 capsules = $0.67 per capsule (15 mg capsule)

      Our Daily Vites L-methylfolate 15 mg capsules

      https://www.amazon.ca/Our-Daily-Vites-L-Methylfolate-Cofactors/dp/B083WQQSK8/

      $60 CDN for 60 capsules = $1 per capsule (15 mg capsule)

      Our Daily Vites L-methylfolate 7.5 mg + B Complex ($70 CDN / 60 capsules)

      $1.17 per capsule (7.5 mg capsule)

      https://www.amazon.ca/Our-Daily-Vites-L-Methylfolate-Cofactors/dp/B083WHKD21/

      Looking for L-methylfolate 1-3 mg daily, such as for treatment resistant depression in a child (i.e. up to age 12)?

      Intelligent Labs L-5 MTHF 1 mg

      $25 for 120 capsules

      = $0.21 per 1 capsule (1 mg)

      = $0.42 per 2 capsules (2 mg)

      = $0.63 per 3 capsules (3 mg)

      https://www.amazon.ca/Intelligent-Labs-L-5-methyltetrahydrofolate-Supplement-Quatrefolic/dp/B075C7M9HJ/

      NOW Methylfolate 1000 mcg (= 1 mg)

      $21 for 90 tablets

      = $0.23 per 1 tablet (1 mg)

      = $0.46 per 2 tablets (2 mg)

      = $0.66 per 3 tablets (3 mg)

      https://www.amazon.ca/Now-Methyl-Folate-1000mcg-Tablets/dp/B07HPS1ZHP/

      Natural Factors BioCoenzymated methylfolate + B12

      https://kardish.com/products/natural-factors-biocoenymated-methylfolate-b12

      $20 for 60 tablets

      = $0.33 per 1 capsule (1 mg)

      = $0.66 per 2 capsules (2 mg)

      = $0.99 per 3 capsules

      Douglas Laboratories Methylfolate L-5-MTHF 1,000 mcg (= 1 mg)

      https://www.amazon.ca/Douglas-Laboratories-Metafolin-Formation-Deficiency/dp/B088P8RCLJ/

      $30 for 60 tablets

      = $0.50 / 1 tablet (1 mg)

      = $1.00 / 2 tablets (2 mg)

      = $1.50 / 3 tablets (3 mg)

      * Price data from Amazon.ca retrieved June 30, 2022.

      References

      Bender A, Hagan K, Kingston N: The association of folate and depression: A meta-analysis. J. Psychiatr Res 95 (2017): 9-18. https://doi.org/10.1016/j.jpsychires.2017.07.019

      National Institute of Health (NIH), published Mar 29, 2021. Retrieved May 27, 2022 from https://ods.od.nih.gov/factsheets/Folate-HealthProfessional/

      Ramaekers VT, Sequeira JM, Blau N, Quadros EV. A milk-free diet downregulates folate receptor autoimmunity in cerebral folate deficiency syndrome. Dev Med Child Neurol. 2008 May;50(5):346-52. doi: 10.1111/j.1469-8749.2008.02053.x. Epub 2008 Mar 19. PMID: 18355335; PMCID: PMC2715943.

      Ramaekers VT, Sequeira JM, Quadros EV. The basis for folinic acid treatment in neuro-psychiatric disorders. Biochimie. 2016 Jul;126:79-90. doi: 10.1016/j.biochi.2016.04.005. Epub 2016 Apr 8. PMID: 27068282.

      https://pubmed.ncbi.nlm.nih.gov/27068282/

      Shelton RC, Sloan Manning J, Barrentine LW, Tipa EV. Assessing Effects of L-methylfolate in Depression Management: Results of a Real-World Patient Experience Trial. Prim Care Companion CNS Disord. 2013;15(4):PCC.13m01520. doi: 10.4088/PCC.13m01520. Epub 2013 Aug 29. PMID: 24392264; PMCID: PMC3869616.

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3869616/

      Authors

      Written by the health professionals at CHEO and the Department of Psychiatry, at uOttawa.

      Disclaimer

      Information in this pamphlet is offered ‘as is' and is meant only to provide general information that supplements but do not replace your health provider's information. Always contact a qualified health professional for further information in your specific situation or circumstance.

      Creative Commons License

      You are free to copy and distribute this material in its entirety as long as 1) this material is not used in any way that suggests we endorse you or your use of the material, 2) this material is not used for commercial purposes (non-commercial), 3) this material is not altered in any way (no derivative works). View full license at http://creativecommons.org/licenses/

      Date Posted: May 28, 2022
      Date of Last Revision: Jul 5, 2022

      Was the information on this page helpful?