Skip to main content
PMC home page
Journal of Neurology, Neurosurgery, and Psychiatry logoLink to Journal of Neurology, Neurosurgery, and Psychiatry
. 2002 May;72(5):567–571. doi: 10.1136/jnnp.72.5.567

Benefits and risks of folic acid to the nervous system

E Reynolds 1
PMCID: PMC1737896  PMID: 11971038

Abstract

During three decades of neurological practice I have witnessed a remarkable change in attitudes to the benefits and risks of folic acid therapy in nervous system disorders. In the 1960s all that was known and taught was that folic acid was harmful to the nervous system, especially in precipitating or exacerbating the neurological complications of vitamin B12 deficiency. So deeply held was this view that the possibility of neuropsychological benefits from this vitamin was initially viewed with considerable scepticism.1

Full Text

The Full Text of this article is available as a PDF (88.0 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Berg M. J., Fincham R. W., Ebert B. E., Schottelius D. D. Phenytoin pharmacokinetics: before and after folic acid administration. Epilepsia. 1992 Jul-Aug;33(4):712–720. doi: 10.1111/j.1528-1157.1992.tb02352.x. [DOI] [PubMed] [Google Scholar]
  2. Botez M. I., Fontaine F., Botez T., Bachevalier J. Folate-responsive neurological and mental disorders: report of 16 cases. Neuropsychological correlates of computerized transaxial tomography and radionuclide cisternography in folic acid deficiencies. Eur Neurol. 1977;16(1-6):230–246. doi: 10.1159/000114904. [DOI] [PubMed] [Google Scholar]
  3. Bottiglieri T., Godfrey P., Flynn T., Carney M. W., Toone B. K., Reynolds E. H. Cerebrospinal fluid S-adenosylmethionine in depression and dementia: effects of treatment with parenteral and oral S-adenosylmethionine. J Neurol Neurosurg Psychiatry. 1990 Dec;53(12):1096–1098. doi: 10.1136/jnnp.53.12.1096. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bottiglieri T., Laundy M., Crellin R., Toone B. K., Carney M. W., Reynolds E. H. Homocysteine, folate, methylation, and monoamine metabolism in depression. J Neurol Neurosurg Psychiatry. 2000 Aug;69(2):228–232. doi: 10.1136/jnnp.69.2.228. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bottiglieri T., Reynolds E. H., Laundy M. Folate in CSF and age. J Neurol Neurosurg Psychiatry. 2000 Oct;69(4):562–562. doi: 10.1136/jnnp.69.4.562a. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Carney M. W., Chary T. K., Bottiglieri T., Reynolds E. H. The switch mechanism and the bipolar/unipolar dichotomy. Br J Psychiatry. 1989 Jan;154:48–51. doi: 10.1192/bjp.154.1.48. [DOI] [PubMed] [Google Scholar]
  7. Clarke R., Smith A. D., Jobst K. A., Refsum H., Sutton L., Ueland P. M. Folate, vitamin B12, and serum total homocysteine levels in confirmed Alzheimer disease. Arch Neurol. 1998 Nov;55(11):1449–1455. doi: 10.1001/archneur.55.11.1449. [DOI] [PubMed] [Google Scholar]
  8. Clifford D. B., Ferrendelli J. A. Neurophysiologic effects of folate compounds in hippocampus, in vitro. Brain Res. 1983 May 5;266(2):209–216. doi: 10.1016/0006-8993(83)90651-0. [DOI] [PubMed] [Google Scholar]
  9. Coppen A., Bailey J. Enhancement of the antidepressant action of fluoxetine by folic acid: a randomised, placebo controlled trial. J Affect Disord. 2000 Nov;60(2):121–130. doi: 10.1016/s0165-0327(00)00153-1. [DOI] [PubMed] [Google Scholar]
  10. Coppen A., Chaudhry S., Swade C. Folic acid enhances lithium prophylaxis. J Affect Disord. 1986 Jan-Feb;10(1):9–13. doi: 10.1016/0165-0327(86)90043-1. [DOI] [PubMed] [Google Scholar]
  11. Davies J., Watkins J. C. Facilitatory and direct excitatory effects of folate and folinate on single neurones of cat cerebral cortex. Biochem Pharmacol. 1973 Jul 1;22(13):1667–1668. doi: 10.1016/0006-2952(73)90034-8. [DOI] [PubMed] [Google Scholar]
  12. Diaz-Arrastia R. Hyperhomocysteinemia: a new risk factor for Alzheimer disease? Arch Neurol. 1998 Nov;55(11):1407–1408. doi: 10.1001/archneur.55.11.1407. [DOI] [PubMed] [Google Scholar]
  13. Dickinson C. J. Does folic acid harm people with vitamin B12 deficiency? QJM. 1995 May;88(5):357–364. [PubMed] [Google Scholar]
  14. Godfrey P. S., Toone B. K., Carney M. W., Flynn T. G., Bottiglieri T., Laundy M., Chanarin I., Reynolds E. H. Enhancement of recovery from psychiatric illness by methylfolate. Lancet. 1990 Aug 18;336(8712):392–395. doi: 10.1016/0140-6736(90)91942-4. [DOI] [PubMed] [Google Scholar]
  15. Goodwin J. S., Goodwin J. M., Garry P. J. Association between nutritional status and cognitive functioning in a healthy elderly population. JAMA. 1983 Jun 3;249(21):2917–2921. [PubMed] [Google Scholar]
  16. Hassing L., Wahlin A., Winblad B., Bäckman L. Further evidence on the effects of vitamin B12 and folate levels on episodic memory functioning: a population-based study of healthy very old adults. Biol Psychiatry. 1999 Jun 1;45(11):1472–1480. doi: 10.1016/s0006-3223(98)00234-0. [DOI] [PubMed] [Google Scholar]
  17. Hill R. G., Miller A. A. Antagonism by folic acid of presynaptic inhibition in the rat cuneate nucleus. Br J Pharmacol. 1974 Mar;50(3):425–427. doi: 10.1111/j.1476-5381.1974.tb09619.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Hommes O. R., Obbens E. A. The epileptogenic action of Na-folate in the rat. J Neurol Sci. 1972 Jul;16(3):271–281. doi: 10.1016/0022-510x(72)90192-x. [DOI] [PubMed] [Google Scholar]
  19. Hommes O. R., Obbens E. A., Wijffels C. C. Epileptogenic activity of sodium-folate and the blood-brain barrier in the rat. J Neurol Sci. 1973 May;19(1):63–71. doi: 10.1016/0022-510x(73)90057-9. [DOI] [PubMed] [Google Scholar]
  20. Hunter R., Barnes J., Oakeley H. F., Matthews D. M. Toxicity of folic acid given in pharmacological doses to healthy volunteers. Lancet. 1970 Jan 10;1(7637):61–63. doi: 10.1016/s0140-6736(70)91845-3. [DOI] [PubMed] [Google Scholar]
  21. Laborit H., Baron C., Laborit G., Laurent J. Recherches concernant le mécanisme d'action convulsivante de l'acide folique (pteroyl-glutamate) et du folinate de calcium (N5 formyl-tetrahydrofolinate de Ca) injectés par voie intraventriculaire chez le lapin I. - Action de l'acide amino-4 methyl-10 folique (methotrexate) Agressologie. 1974;15(1):45–52. [PubMed] [Google Scholar]
  22. Morrison L. D., Smith D. D., Kish S. J. Brain S-adenosylmethionine levels are severely decreased in Alzheimer's disease. J Neurochem. 1996 Sep;67(3):1328–1331. doi: 10.1046/j.1471-4159.1996.67031328.x. [DOI] [PubMed] [Google Scholar]
  23. Oakley G. P., Jr Let's increase folic acid fortification and include vitamin B-12. Am J Clin Nutr. 1997 Jun;65(6):1889–1890. doi: 10.1093/ajcn/65.6.1889. [DOI] [PubMed] [Google Scholar]
  24. Ogier de Baulny H., Gérard M., Saudubray J. M., Zittoun J. Remethylation defects: guidelines for clinical diagnosis and treatment. Eur J Pediatr. 1998 Apr;157 (Suppl 2):S77–S83. doi: 10.1007/pl00014307. [DOI] [PubMed] [Google Scholar]
  25. Otis L. C., Madison D. V., Nicoll R. A. Folic acid has a disinhibitory action in the rat hippocampal slice preparation. Brain Res. 1985 Nov 4;346(2):281–286. doi: 10.1016/0006-8993(85)90861-3. [DOI] [PubMed] [Google Scholar]
  26. Passeri M., Cucinotta D., Abate G., Senin U., Ventura A., Stramba Badiale M., Diana R., La Greca P., Le Grazie C. Oral 5'-methyltetrahydrofolic acid in senile organic mental disorders with depression: results of a double-blind multicenter study. Aging (Milano) 1993 Feb;5(1):63–71. doi: 10.1007/BF03324128. [DOI] [PubMed] [Google Scholar]
  27. Reynolds E. H., Carney M. W., Toone B. K. Methylation and mood. Lancet. 1984 Jul 28;2(8396):196–198. doi: 10.1016/s0140-6736(84)90482-3. [DOI] [PubMed] [Google Scholar]
  28. Reynolds E. H. Effects of folic acid on the mental state and fit-frequency of drug-treated epileptic patients. Lancet. 1967 May 20;1(7499):1086–1088. doi: 10.1016/s0140-6736(67)92654-2. [DOI] [PubMed] [Google Scholar]
  29. Reynolds E. H. Interictal psychiatric disorders. Neurochemical aspects. Adv Neurol. 1991;55:47–58. [PubMed] [Google Scholar]
  30. Reynolds E. H. Mental effects of anticonvulsants, and folic acid metabolism. Brain. 1968 Jun;91(2):197–214. doi: 10.1093/brain/91.2.197. [DOI] [PubMed] [Google Scholar]
  31. Reynolds E. H. Neurological aspects of folate and vitamin B12 metabolism. Clin Haematol. 1976 Oct;5(3):661–696. [PubMed] [Google Scholar]
  32. Reynolds E. H., Rothfeld P., Pincus J. H. Neurological disease associated with folate deficiency. Br Med J. 1973 May 19;2(5863):398–400. doi: 10.1136/bmj.2.5863.398. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. SCHWARTZ S. O., KAPLAN S. R., ARMSTRONG B. E. The long-term evaluation of folic acid in the treatment of pernicious anemia. J Lab Clin Med. 1950 Jun;35(6):894–898. [PubMed] [Google Scholar]
  34. Savage D. G., Lindenbaum J. Neurological complications of acquired cobalamin deficiency: clinical aspects. Baillieres Clin Haematol. 1995 Sep;8(3):657–678. doi: 10.1016/s0950-3536(05)80225-2. [DOI] [PubMed] [Google Scholar]
  35. Scott J. M., Dinn J. J., Wilson P., Weir D. G. Pathogenesis of subacute combined degeneration: a result of methyl group deficiency. Lancet. 1981 Aug 15;2(8242):334–337. doi: 10.1016/s0140-6736(81)90649-8. [DOI] [PubMed] [Google Scholar]
  36. Shorvon S. D., Carney M. W., Chanarin I., Reynolds E. H. The neuropsychiatry of megaloblastic anaemia. Br Med J. 1980 Oct 18;281(6247):1036–1038. doi: 10.1136/bmj.281.6247.1036. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Sneath P., Chanarin I., Hodkinson H. M., McPherson C. K., Reynolds E. H. Folate status in a geriatric population and its relation to dementia. Age Ageing. 1973 Aug;2(3):177–182. doi: 10.1093/ageing/2.3.177. [DOI] [PubMed] [Google Scholar]
  38. Snowdon D. A., Tully C. L., Smith C. D., Riley K. P., Markesbery W. R. Serum folate and the severity of atrophy of the neocortex in Alzheimer disease: findings from the Nun study. Am J Clin Nutr. 2000 Apr;71(4):993–998. doi: 10.1093/ajcn/71.4.993. [DOI] [PubMed] [Google Scholar]
  39. Van Rijn C. M., Van der Velden T. J., Rodrigues de Miranda J. F., Feenstra M. G., Hommes O. R. The influence of folic acid on the picrotoxin-sensitive site of the GABAa-receptor complex. Epilepsy Res. 1988 May-Jun;2(3):215–218. doi: 10.1016/0920-1211(88)90058-7. [DOI] [PubMed] [Google Scholar]
  40. WILL J. J., MUELLER J. F., BRODINE C., KIELY C. E., FRIEDMAN B., HAWKINS V. R., DUTRA J., VILTER R. W. Folic acid and vitamin B12 in pernicious anemia; studies on patients treated with these substances over a ten year period. J Lab Clin Med. 1959 Jan;53(1):22–38. [PubMed] [Google Scholar]
  41. Wang H. X., Wahlin A., Basun H., Fastbom J., Winblad B., Fratiglioni L. Vitamin B(12) and folate in relation to the development of Alzheimer's disease. Neurology. 2001 May 8;56(9):1188–1194. doi: 10.1212/wnl.56.9.1188. [DOI] [PubMed] [Google Scholar]
  42. van der Westhuyzen J., Fernandes-Costa F., Metz J. Cobalamin inactivation by nitrous oxide produces severe neurological impairment in fruit bats : protection by methionine and aggravation by folates. Life Sci. 1982 Nov 1;31(18):2001–2010. doi: 10.1016/0024-3205(82)90039-x. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Neurology, Neurosurgery, and Psychiatry are provided here courtesy of BMJ Publishing Group

RESOURCES