Folate deficiency and why folic acid supplements may NOT work

November 14, 2018

Folate deficiency and why folic acid supplements may NOT work

Everyone has heard of folate, but what does it mean to be deficient in folate, and what can anyone do about it?

What are the possible symptoms of folate deficiency?

  • Low functioning Autism1,2,3
  • Depression4,5
  • Hypertension6
  • Cancer7,8,9,10,11
  • Muscle pain
  • InsomniaIrritable bowel syndrome
  • Fibromyalgia12
  • Chronic fatigue syndrome12
  • Memory loss
  • Headaches
  • Brain fog
  • ADD/ADHD13,14
  • Erectile dysfunction
  • Migraine15
  • Alzheimer’s disease
  • Parkinson’s disease

What causes folate deficiency?

  • Problems with absorption of folate – e.g. Crohn’s disease, coeliacs disease
  • Drinking too much alcohol
  • Eating overcooked food
  • Haemolytic anaemia
  • Some medications (e.g. Phenytoin, sulphasalazine, trimethoprim)
  • Poor diet
  • And most importantly, genetics

Some sources estimate that up to 50% of the Australian population have a gene that renders folic acid un-useable by the body. Folic acid is the artificial source by which the population at large acquires their folate requirements.

Folic acid, Folinic acid and 5-MTHF

Folic acid: Is a fully oxidised synthetic compound which is not formed naturally. It is commonly used in dietary supplementation and in food fortification.

Folinic acid (5-Formyl Tetrahydrofolate): Is formed when folic acid is reduced by the enzyme dihydrofolate reductase (DHFR). It is an active form of folate that is involved in nucleic acid biosynthesis

5-Methyltetrahydrofolate (5-MTHF): Is formed when folinic acid is reduced by methyl-tetrahydrofolate reductase (MTHFR). It is the active form of folate which is responsible for homocysteine metabolism, DNA methylation, and neurotransmitter synthesis.

What does this mean?

Folic acid is not actually used by the body. It must first be converted to folate (e.g., folinic acid) and then to 5-MTHF.

The process by which folic acid is metabolised to 5-MTHF is long and complex. This process occurs in the liver and intestines and requires several bodily enzymes. This can be a problem for folic acid supplementation for a few reasons.

Firstly, if the liver or intestines are not working optimally (for reasons such as taking certain medications or anatomical anomalies or fast intestinal transit time), this process cannot occur sufficiently enough to meet the body’s needs.

Secondly, the DHFR enzyme which initially converts folic acid to folate, is not as active in everybody. This means that some people are able to ‘activate’ folic acid quickly while others very slowly.  If the activation of folic acid happens slowly, it could potentially accumulate in the blood stream as well as not providing adequate conversion into a usable product. Furthermore, some drugs are designed to inhibit this enzyme, rendering folic acid supplementation near useless.

Thirdly, even if all the folic acid has been converted to the folate (folinic acid) form, it still requires activation by a final enzyme MTHFR. It is estimated that up to 50% of the population have a faulty gene that prevents MTHFR being made effectively by the body.

What is the solution?

For those individuals displaying any of the symptoms of low folate status mentioned above, a pathology test for folate along with an MTHFR gene test can be conducted.  If supplementation is required, then 5-MTHF should be looked at in preference to folic acid or folinic acid. Read more about our Nutrigenomic and neutraceutical services.

Contact our pharmacists for more information


  1. Ramaekers VT, Husler M, Opladen T, Heimann G, Blau N. Psychomotor retardation, spastic paraplegia, cerebellar ataxia and dyskinesia associated with low 5-methyltetrahydrofolate in cerebrospinal fluid: a novel neurometabolic condition responding to folinic acid substitution. Neuropediatrics. 2002 Dec;33(6):301-8
  2. Ramaekers VT, Blau N. Cerebral folate deficiency. Dev Med Child Neurol. 2004 Dec;46(12):843-51
  3. Ramaekers VT, Rothenberg SP, Sequeira JM, Opladen T, Blau N, Quadros EV, Selhub J. Autoantibodies to folate receptors in the cerebral folate deficiency syndrome. N Engl J Med.  2005 May 12;352(19):1985-95
  4. Coppen A, Bolander-Goualille C. Treatment of depression: time to consider folic acid and vitamin B12. J Psychopharmacol. 2005 jan:19(1):59-65
  5. Fava M, Mischoulon D. Folate in depression: efficacy, safety, differences in formulations, and clinical issues. J Clin Psychiatry. 2009; 70 Suppl 5:12-7
  6. Golbahar J, Mostafavi E.Association between low red blood cell 5-methyltetrahydrofolate and hyperhomocysteinaemia with hypertension : a cross-sectional study..High Blood Press Cardiovasc Prev. 2012 Dec;19(4):229-35
  7. Mason JB. Folate status: Effects on carcinogenesis. In: BaileyLB, ed. Folates in Health and Disease. New York Marcel Dekker, 1995; 361-378
  8. 8, Giovanucci E, RImm EB, Acherio A, et al. Alcohol low methionine low folate diets and risk of colon cancer in men. J Natl Cancer Inst 1995; 87: 265-273
  9. Glynn SA , Albanes D Pietinen P, et al. Colorectal cancer and folate status: a nested case-control study among male smokers. Cancer Epidemiol Biomarkers Prev 1996; 5: 487-494
  10. Sanjoaquin MA, Allen N, Couto E, et al. Folate intake and colorectal cancer risk: a meta-analytical approach. Int J cancer 2005; 113: 825-828
  11. Giovannucci E, Stampfer MJ, COlditz GA, et al. Multivitamin use, folate and colon cancer in women in the nurses’ health study. Ann Intern Med 1998; 129: 517-24
  12. Jacobson W, Saich T, Borysiewicz LK, Behan WM, Behan PO, Wreghitt TG. Serum folate and chronic fatigue syndrome. Neurology 1993 Dec: 43(12):2645-7
  13. Millichap JG, Yee MM. The diet factor in attention-deficit/hyperactivity disorder. Pediatrics 2012 Feb:129(2): 330-7
  14. Gokcen C, Kocak N, Pekgor A. Methylenetetrahydrofolate reductase gene polymorphisms in children with attention deficit hyperactivity disorder. Int J Med Sci 2011: 8(7):523-528
  15. Di Rosa G, Attina S, Spano M, Ingegneri G, Sgro DL Pustorino et al. Efficacy of folic acid in children with migraine, hyperhomocysteinemia and MTHFR polymorphisms. Headache 2007 Oct: 47(9): 1342-4

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