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Moody Methylation

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The success of antidepressant drug therapy is not high, with studies suggesting 19%-60% of patients are unresponsive to the treatment.[1,2] It is essential that we continue the search for more effective mood disorder management. Integrative approaches may complement pharmaceuticals, or, offer an alternative in cases where negative side effects or contraindications are noted.

Antidepressant drugs function to prevent the re-uptake or degradation of our “feel good” neurotransmitters: serotonin, dopamine and noradrenalin. But what if an individual is depleted of these chemicals due to nutritional insufficiencies? Is this an underlying factor that must be addressed before optimal outcomes can be achieved? If so, how do we determine this, and how do we correct it?

Methylation support appears to be one very important piece of the mood puzzle. Methylation is required to manufacture neurotransmitters, and it’s no surprise then that hyperhomocysteinaemia, a complication of under-methylation, has been noted in both depression[3] and bi-polar depression.[4] Additionally, deficiencies in folate[5] and vitamin B12,[6] two key methylation nutrients, positively correlate with depression risk. Furthermore, it has been suggested that accumulation of homocysteine leads to excito-toxic reactions and may enhance depression,[6] whilst high levels also interfere with GABA binding at its receptor[7] contributing to anxiety.

Evidently, B vitamin supplementation to reduce homocysteine has demonstrated to reduce depression scores and improve cognitive function.[8] This seems to support the hypothesis that such nutrients are key drivers in mood disorder management.

Supplying the methylation nutrients will assist not only in a reduction in the damaging chemical homocysteine, but will also improve beneficial neurotransmitter availability and therefore, offer a potential reduction in the symptoms of mood disorders.

When looking to provide the most suitable supplement for your patient, folinic acid (5-formyl THF) may be a superior choice in some instances where methylation support with folate is required. Synthetic folic acid requires numerous steps to be converted to 5-MTHF. 

Folinic acid is a form of folate which naturally occurs within the food chain and is believed to be more biologically active. Folinic acid by-passes the deconjugation and reduction steps (involving dihydrofolate reductase (DHFR)) required for folic acid to be activated.[9] Folinic acid may be the more desirable supplement for patients with malabsorption issues (e.g. inflammatory bowel disease), on specific medications or individuals with single nucleotide polymorphisms (SNPs) on the genes encoding for the DHFR enzyme.

Magnesium,[2] zinc [1] and omega-3 fatty acids from fish oil [10] have demonstrated benefits for enhancing patient response to antidepressant therapy, thus repletion of these nutrients, as an adjunct to methylation support, are also valid considerations. Further integrative measures worthy for incorporation into a mood management protocol include physical activity,[11] mindful meditation, anxiolytic herbs and, most importantly, appropriate counseling.


  1. Ranjbar E, Kasaei MS, Mohammad-Shirazi M, et al. Effects of zinc supplementation in patients with major depression: a randomized clinical trial. Iran J Psychiatry 2013;8(2):73-79. [Full Text
  2. Eby GA 3rd, Eby KL. Magnesium for treatment-resistant depression: a review and hypothesis. Med Hypotheses 2010;74(4):649-660. [Abstract
  3. Nabi H, Bochud M, Glaus J, et al. Association of serum homocysteine with major depressive disorder: results from a large population-based study. Psychoneuroendocrinology 2013;38(10):2309-2318. [Abstract
  4. Permoda-Osip A, Dorszewska J, Skibinska M, et al. Hyperhomocysteinemia in bipolar depression: clinical and biochemical correlates. Neuropsychobiology 2013;68(4):193-196. [Abstract
  5. Miller AL. The methylation, neurotransmitter, and antioxidant connections between folate and depression. Altern Med Rev 2008;13(3):216-226. [Full Text
  6. Seppälä J, Koponen H, Kautiainen H, et al. Association between vitamin b12 levels and melancholic depressive symptoms: a Finnish population-based study. BMC Psychiatry 2013;13(1):145. [Full Text
  7. Bhargava S, Tyagi SC. Nutriepigenetic regulation by folate-homocysteine-methionine axis: a review. Mol Cell Biochem [ePub] 2013 Nov 10. [Abstract
  8. Loria-Kohen V, Gómez-Candela C, Palma-Milla S, et al. A pilot study of folic acid supplementation for improving homocysteine levels, cognitive and depressive status in eating disorders. Nutr Hosp 2013;28(3):807-815. [Full Text
  9. Kelly GS. Folates: supplemental forms and therapeutic applications. Altern Med Rev 1998;3(3):208-220. [Full Text
  10. Gertsik L, Poland RE, Bresee C, et al. Omega-3 fatty acid augmentation of citalopram treatment for patients with major depressive disorder. J Clin Psychopharmacol 2012;32(1):61-64. [Full Text
  11. Gill A, Womack R, Safranek S. Clinical Inquiries: Does exercise alleviate symptoms of depression? J Fam Pract 2010;59(9):530-531. [Abstract
  12. Davis SR, Stacpoole PW, Williamson J, et al. Tracer-derived total and folate-dependent homocysteine remethylation and synthesis rates in humans indicate that serine is the main one-carbon donor. Am J Physiol Endocrinol Metab 2004;286(2):E272-279. [Full Text
  13. Bottiglieri T. Folate, vitamin B12, and S-adenosylmethionine. Psychiatr Clin North Am 2013;36(1):1-13. [Abstract
  14. Carpenter DJ. St. John's wort and S-adenosyl methionine as "natural" alternatives to conventional antidepressants in the era of the suicidality boxed warning: what is the evidence for clinically relevant benefit? Altern Med Rev 2011;16(1):17-39. [Full Text]


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Belinda Reynolds
Belinda is a dietitian and Senior Educator at one of Australia's leading nutraceutical companies. She graduated with an Honours Degree in Nutrition and Dietetics, and has been involved in the complementary medicine industry for over 15 years. Her key interests are immune modulation, the human microbiome and the impact they have on overall health.