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Depression and Folate

Studies have shown that low folate levels are present in depressed individuals.1 Additionally, trials have shown that supplementing folate through diet or folic acid supplements can quicken recovery from a depressive episode and even enhance the effects of antidepressants.1

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Effect of Folate on Depression

Folate is a B-vitamin and, like all vitamins, cannot be synthesized by the body alone but must come from diet or supplements.2 Folate attained through diet (like leafy green vegetables, legumes, beans, liver, citrus fruits and yeast) is not as highly absorbed as the synthetic molecule of folate called folic acid. Regardless, once absorbed, many biochemical conversions are needed to convert folate to the metabolically active, tissue-usable form that aids in neurotransmitter shynthesis, DNA biosynthesis, regulation of gene expression, amino acid synthesis and metabolism, and meyelin synthesis and repair.2 Since depression has an effect in neurotransmitter synthesis, the participation of folate in this process is in part responsible for how these neurotransmitters effect one's depression.1 Additionally, folate is involved in single-carbon transfer methylation reactions connected with the synthesis of serotonin and other monoamine neurotransmitters.4

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Research Evidence on Folate

Studies dating back to the 1970s show the correlation between folate deficiencies and depression. One of the first examined serum floate status in 272 psychiatric in-patients and found that low folate was significantly correlated with depressed patients.3

A study conducted in 2003 on 2,682 participants found that those in a low-level dietary folate intake were 67% more likely to become depressed than those in a high-level dietary folate intake group and that the symptoms of depression were also elevated for those in the low-folate group.4

Specifically used in conjunction with pharmaceutical SSRI treatments for depression, higher baseline folate levels are associated with greater responses to these drugs thereby warranting supplementation of folic acid for those with low levels of folate.5,6

How to Use Folate

Dietary folate is found in leafy green vegetables, legumes, beans, liver, citrus fruits and yeast.2

Amounts of folic acid supplements can vary and must be discussed with a licensed medical professional. However, it is generally recommended that adults take between 400-600 micrograms of folic acid per day.7

Safety Issues

Folate at nutritional doses is extremely safe. The only serious potential problem is that folate supplementation can mask the early symptoms of vitamin B 12 deficiency (a special type of anemia), potentially allowing more irreversible symptoms of nerve damage to develop. For this reason, when taking more than 400 mcg daily, it is important to get your B 12 level checked. See the article on Vitamin B 12 for more information.

Very high dosages of folate, greater than 5 mg (5,000 mcg) daily, can cause digestive upset. The maximum recommended dosage of folate for pregnant or nursing women is 1,000 mcg daily (800 mcg if under 19 years old). 1 Media reports that use of folate by pregnant women may increase their risk of breast cancer are based on a single study of highly questionable validity. 2 At present, this is not considered a significant concern, but further research will follow.

As mentioned previously, the antiseizure drug phenytoin may interfere with folate absorption. However, folate may reduce the effectiveness of phenytoin. 3 4 5 6 7 If you are taking phenytoin, you should consult with a physician about the proper dosage of folate for you.

Also, as noted above, individuals who are taking the drug methotrexate for rheumatoid arthritis, juvenile rheumatoid arthritis, or psoriasis can safely take folate supplements at the same time. However, if you are taking methotrexate for any other purpose, do not take folate except on the advice of a physician.

Interactions You Should Know About

If you are taking

  • Aspirin and other anti-inflammatory medications , drugs that reduce stomach acid (such as antacids , H 2 blockers , and proton pump inhibitors ), bile acid sequestrants (such as cholestyramine and colestipol ), carbamazepine , estrogen-replacement therapy , nitrous oxide , oral contraceptives , oral hypoglycemic drugs , phenobarbital , primidone , sulfa antibiotics , triamterene , valproic acid or the antibiotic trimethoprim-sulfamethoxazole : You may need to take extra folate.
  • Phenytoin : You may need more folate. However, too much folate can interfere with this medication and cause seizures! Physician supervision is essential.
  • Drugs in the nitroglycerin family: Folate may help them remain effective
  • Pancreatin (a proteolytic enzyme ): It may be advisable to separate your dose of pancreatin from your dose of folate by at least 2 hours in order to avoid absorption problems.
  • Methotrexate for rheumatoid arthritis, juvenile rheumatoid arthritis, or psoriasis: Evidence suggests that folate supplements may reduce side-effects of the drug without decreasing its benefits. Nonetheless, physician supervision is highly recommended. Note: If you are taking methotrexate for other conditions, folate might decrease the drug's effectiveness.


  1. Dietary reference intakes for thiamin, riboflavin, niacin, vitamin B 6 , folate, vitamin B 12 , pantothenic acid, biotin, and choline. Available at: Accessed October 4, 2001.
  2. Charles D, Andy R Ness AR , Campbell D, et al. Taking folate in pregnancy and risk of maternal breast cancer BMJ. 2004;329:1375-1376.
  3. Butterworth CE Jr, Tamura T. Folic acid safety and toxicity: a brief review. Am J Clin Nutr. 50(2):353-8.
  4. Lewis DP, Van Dyke DC, Willhite LA, Stumbo PJ, Berg MJ. Phenytoin-folic acid interaction. Ann Pharmacother. 29(7-8):726-35.
  5. Berg MJ, Stumbo PJ, Chenard CA, Fincham RW, Schneider PJ, Schottelius DD. Folic acid improves phenytoin pharmacokinetics. J Am Diet Assoc. 95(3):352-6.
  6. Ono H, Sakamoto A, Eguchi T, Fujita N, Nomura S, Ueda H, Sakura N, Ueda K. Plasma total homocysteine concentrations in epileptic patients taking anticonvulsants. Metabolism. 46(8):959-62.
  7. Kishi T, Fujita N, Eguchi T, Ueda K. Mechanism for reduction of serum folate by antiepileptic drugs during prolonged therapy. J Neurol Sci. 145(1):109-12.
  8. Alemdaroglu NC, Dietz U, Wolffram S, Spahn-Langguth H, Langguth P. Influence of green and black tea on folic acid pharmacokinetics in healthy volunteers: potential risk of diminished folic acid bioavailability. Biopharm Drug Dispos. 29(6):335-48.

1 Morris, M.S., Fava, M., Jacques, P.F., Selhub, J. & Rosenberg, I.H. (2003). Depression and folate status in the US population. Psychotherapy and Psychosomatics, 72(2) 80-7. Retrieved June 1, 2010 from ProQuest Psychology Journals. (Document ID: 305028821).

2 Miller, A.L. (2008). The Methylation, Neurotransmitter, and Antioxidant Connectsion Between Folate and Depression. Alternative Medicine Review 13(3).

3 Carney, M.W. & Sheffield, B.F. (1978). Serum Folic Acid and B12 in 272 Psychiatric In-Patients. Psychology Medicine 8, 139-144.

4 Tolmunen, T., Voutilainen, S., Hintikka, J.. Rissanen, T., Tanskanen, A., Viinamaki, H., Kapalan, G.A. & Salonen, J.T. (2003). Dietary Folate and Depressive Symptoms are Associated in Middle-Aged Finnish Men. The Journal of Nutrition 133(10), 3233.

5 Alpert, M., Silvia, R.R. & Pouger, E.R. (2003). Prediction of Treatment REsponse in Geriatric Depression from Baseline Folate Level: Interaction with an SSRO or a Tricyclic Antidepressant. Journal of Clinical Psychopharmacol 23, 309-313.

6 Alpert, J.E., Mischoulon, D., & Rubenstein, G.E. (2002). Folinic Acid (Leucovorin) as an Adjunctive Treatment for SSRO-Refractory Depression. Annals of Clinical Psychiatry14, 33-38.


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