Folic acid supplementation: facts or folly?

I thought it might be a good idea to carry on where I left off in my review of the vitamins with a look at vitamin B9 (folic acid). This vitamin has been in the news recently for its association to help treat autism (more aboout that below). I wager that we shall be able to bridge the way to a bit of truth about this leafy vitamin.We are most familiar with folic acid's ability to reduce the adverse effects of methotrexate therapy, even though daily dosing does not affect efficacy.1,2 It is also routinely recommended to help prevent birth defects like spina bifida. Don’t forget its ability, along with vitamin B6 and B12, to help reduce the metabolic baddie homocysteine. But this vitamin may also be helpful for reducing the risk of developing depression, cognitive decline and blood pressure. The recommended daily intake of folates set by Health Canada is 400mcg for adult males and 400mcg-600mcg for females.3 The upper limit is set at 1mg. The rates of folate deficiency are thought to be less than 1%4 due in part to the addition of folic acid to Canadian grain products since the late 1990s.5 This addition is not without concerns, however—increased folic acid intake might mask anemia caused by vitamin B12 deficiency and increase the risk of certain cancers like colorectal cancer.6 Luckily a vegetarian diet is associated with a lower risk of colorectal cancer.7 Is there a link between folic acid and depression? Well, kinda, but not really. Most of the data suggests that depression can be associated with low folic acid status.8 There are a few theories behind why this occurs. The first is that folic acid is necessary for the biosynthesis of neurotransmitters serotonin, epinephrine, and dopamine.9 Another possible reason is that low folic acid is associated with increased blood levels of… wait for it…homocysteine.10,13 Homocysteine is known to be an agonist of the NMDA receptor which leads to neurotoxic effects on dopaminergic neurons.11 In one study, folic acid (2mg), vitamin B12 (500mcg) and B6 (25mg) sustained antidepressant therapy efficacy over one year, but not within the first 12 weeks of therapy.12 Other reviews have found that folic acid supplementation can improve outcomes with SSRI/SNRI depression therapy.14 However other reviews have not shown favourable results.15,16 Folic acid should be used with caution in depression treated with lamotrigine as one trial found that folic acid nullified the effects of lamotrigine.17 What about folic acid and blood pressure, is it effective? Again, yes and no. One meta-analysis of 41,633 patients found that folic acid significantly reduced SBP and DBP.18 These findings were still significant if patients received less than 5mg daily for longer than 6 weeks. However another meta-analysis only found that vitamin E (out of 5 common vitamins) could significantly reduce DBP.19 Ditto for another longer term trial.20 But in young smokers, 5mg of folic acid over 4 weeks significantly reduced BP.21 This short trial also showed reduction in homocysteine levels, but probably guessed that. One possible mechanism of action was folic acids positive influence on nitric oxide production.22,23 Homocysteine increases oxidative stress that down-regulates NO production and folic acid can directly scavenge superoxide anions that are capable of destroying the enzyme endothelial nitric oxide synthase.22 This one was new to me—folic acid can help reduce one of the side effects of phenytoin. One side effect of phenytoin is gingival overgrowth, which can occur in as many as 65% of users.24 This is also a side effect for many other antiepileptic drugs, cyclosporine and calcium channel blockers.24,25 In one small study, a dose of only 0.5mg was needed to reverse this adverse effect in 67% of patients.26 This study was in children aged 6-15 years old. I could not find any trials with folic acid and other drugs known to cause gingival overgrowth. There is also evidence to suggest that folic acid (in addition to other B vitamins) can reduce the risk of cognitive decline and dementia. Again, kinda yes and kinda no. One large meta-analysis (95 studies and 46000 patients) found that B-vitamin supplementation can slow cognitive decline in aged populations.27 The earlier the intervention resulted in greater risk reduction. Also vitamins B12 and B6 were not associated with a reduced risk. One proposed mechanism of protection was the reduction of neurodegeneration via tau protein phosphorylation.28 And the culprit in this process, you guessed it, was homocysteine. This review looked at development of Parkinson’s disease progression, but the researchers mentioned that similar processes can be applied to Alzheimer’s disease. Another review confirms folic acid supplementation and the reduced risk of cognitive impairment and Alzheimer’s disease.29 However this protection might not be seen in areas with mandatory folic acid fortification.30 In this meta-analysis study, folic acid supplementation did improve cognitive function in older adults. However, this was not significant in regions where folic acid fortification was mandatory. As mentioned above Canada has a mandatory fortification of grain products. I mentioned folic acid as a potential treatment option for children with Autism Spectrum Disorder (ASD). As with all of my answers today, this one is also a Yes and No. A small percentage of individuals with ASD have cerebral folate deficiency, which is caused by folate receptor antibodies which lead to lower folic acid level in the brain.32 This is thought to be a genetic disorder,33 which leads to the theory that folinic acid (trade name Leucovorin) can help with ASD. One meta-analysis found that folinic acid supplementation can be helpful in improving ASD symptoms.34 This treatment is currently off label. Anecdotally parents have told me that the OTC folic acid metabolite 5-methyltetrahydrofolate (5-mthf) have shown mild improvements with supplementation. It is known that folinic acid/leucovorin is extensively metabolised to 5-mthf is the intestine.35 The American Academy of Pediatrics has an excellent FAQ about leucovorin use in ASD.36So what should you tell your patients about folic acid supplementation? Further folic acid supplementation should not be required for the majority of people due to that fortification of Canadian grains. However, while flour supplementation is mandatory, according to a House of Commons report with Celiac Canada, only 5% of gluten-free grains are fortified.31 Those who exclusively consume these gluten-free grains should consider supplementation with folic acid. Early supplementation with folic acid (along with B12 and B6) might be helpful in preventing cognitive decline. If your patient takes their folic acid on their methotrexate day, it is not a big of a concern. And, as always, homocysteine is bad. References: Cline A, Jorizzo JL. Does daily folic acid supplementation reduce methotrexate efficacy? Dermatol Online J. 2017 Nov 15;23(11):13030/qt4hf5v2vk. PMID: 29447631.Singh JA. Folic acid supplementation for rheumatoid arthritis patients on methotrexate: the good gets better. Cochrane Database Syst Rev. 2013 Jul 22;2013(7):ED000063. doi: 10.1002/14651858.ED000063. PMID: 24151647; PMCID: PMC10846356.Health Canada (2025, September 23), Dietary reference intakes tables: Reference values for vitamins. Colapinto CK, O'Connor DL, Tremblay MS. Folate status of the population in the Canadian Health Measures Survey. CMAJ. 2011 Feb 8;183(2):E100-6. doi: 10.1503/cmaj.100568. Epub 2010 Dec 13. Erratum in: CMAJ. 2011 Sep 20;183(13):1519. PMID: 21149516; PMCID: PMC3033951.Government of Canada. Regulations amending the food and drug regulations (1066). Canada Gazette 1998;132.Crider KS, Bailey LB, Berry RJ. Folic acid food fortification-its history, effect, concerns, and future directions. Nutrients. 2011 Mar;3(3):370-84. doi: 10.3390/nu3030370. Epub 2011 Mar 15. PMID: 22254102; PMCID: PMC3257747.Orlich MJ, Singh PN, Sabaté J, Fan J, Sveen L, Bennett H, Knutsen SF, Beeson WL, Jaceldo-Siegl K, Butler TL, Herring RP, Fraser GE. Vegetarian dietary patterns and the risk of colorectal cancers. JAMA Intern Med. 2015 May;175(5):767-76. doi: 10.1001/jamainternmed.2015.59. PMID: 25751512; PMCID: PMC4420687.Reynolds EH. Folic acid, ageing, depression, and dementia. BMJ. 2002 Jun 22;324(7352):1512-5. doi: 10.1136/bmj.324.7352.1512. PMID: 12077044; PMCID: PMC1123448.Miller AL. The methylation, neurotransmitter, and antioxidant connections between folate and depression. Altern Med Rev. 2008 Sep;13(3):216-26. PMID: 18950248.Liwinski T, Lang UE. Folate and Its Significance in Depressive Disorders and Suicidality: A Comprehensive Narrative Review. Nutrients. 2023 Sep 4;15(17):3859. doi: 10.3390/nu15173859. PMID: 37686891; PMCID: PMC10490031.Bhatia P, Singh N. Homocysteine excess: delineating the possible mechanism of neurotoxicity and depression. Fundam Clin Pharmacol. 2015 Dec;29(6):522-8. doi: 10.1111/fcp.12145. Epub 2015 Sep 17. PMID: 26376956.Almeida OP, Ford AH, Hirani V, et al. B vitamins to enhance treatment response to antidepressants in middle-aged and older adults: results from the B-VITAGE randomised, double-blind, placebo-controlled trial. British Journal of Psychiatry. 2014;205(6):450-457. doi:10.1192/bjp.bp.114.145177Srinivasan K, Salazar LJ, Heylen E, Ekstrand ML. Elevated homocysteine and depression outcomes in patients with comorbid medical conditions in rural primary care. Int J Noncommun Dis. 2022 Apr-Jun;7(2):95-97. Epub 2022 Jul 22. PMID: 36483766; PMCID: PMC9728592.Altaf R, Gonzalez I, Rubino K, Nemec EC 2nd. Folate as adjunct therapy to SSRI/SNRI for major depressive disorder: Systematic review & meta-analysis. Complement Ther Med. 2021 Sep;61:102770. doi: 10.1016/j.ctim.2021.102770. Epub 2021 Aug 24. PMID: 34450256.Almeida OP, Ford AH, Flicker L. Systematic review and meta-analysis of randomized placebo-controlled trials of folate and vitamin B12 for depression. Int Psychogeriatr. 2015 May;27(5):727-37. doi: 10.1017/S1041610215000046. 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J Pharm Health Care Sci. 2017 Jul 19;3:19. doi: 10.1186/s40780-017-0088-5. PMID: 28729910; PMCID: PMC5518137.Arya R, Gulati S, Kabra M, Sahu JK, Kalra V. Folic acid supplementation prevents phenytoin-induced gingival overgrowth in children. Neurology. 2011 Apr 12;76(15):1338-43. doi: 10.1212/WNL.0b013e3182152844. PMID: 21482950; PMCID: PMC3090066.Wang Z, Zhu W, Xing Y, Jia J, Tang Y. B vitamins and prevention of cognitive decline and incident dementia: a systematic review and meta-analysis. Nutr Rev. 2022 Mar 10;80(4):931-949. doi: 10.1093/nutrit/nuab057. PMID: 34432056.Poulidou V, Liampas I, Arnaoutoglou M, Dardiotis E, Siokas V. The Imbalance of Homocysteine, Vitamin B12 and Folic Acid in Parkinson Plus Syndromes: A Review beyond Parkinson Disease. Biomolecules. 2024 Sep 26;14(10):1213. doi: 10.3390/biom14101213. PMID: 39456145; PMCID: PMC11506381.Puga AM, Ruperto M, Samaniego-Vaesken ML, Montero-Bravo A, Partearroyo T, Varela-Moreiras G. Effects of Supplementation with Folic Acid and Its Combinations with Other Nutrients on Cognitive Impairment and Alzheimer's Disease: A Narrative Review. Nutrients. 2021 Aug 26;13(9):2966. doi: 10.3390/nu13092966. PMID: 34578844; PMCID: PMC8470370.Zhang L, Chen X, Chen Y, Yan J, Huang G, Li W. A Comparative Study Evaluating the Effectiveness of Folate-Based B Vitamin Intervention on Cognitive Function of Older Adults under Mandatory Folic Acid Fortification Policy: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Nutrients. 2024 Jul 10;16(14):2199. doi: 10.3390/nu16142199. PMID: 39064642; PMCID: PMC11279592.Written Submission for the Pre-Budget Consultations in Advance of the Upcoming Federal Budget