Methylfolate and Methyl B12 Play a Profound Role in Health

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Surprising new research demonstrates that diabetic neuropathy, an extremely painful condition, may respond to supplementation with the active forms of three b vitamins: methyl B12, methylfolate, and the active form of vitamin B6 (pyridoxal-5′-phosphate). In a 2011 study in the Review of Neurological Diseases, researchers reported that eleven diabetic patients with diabetic neuropathy were placed on these three supplements, and tested by means of punch biopsy before treatment and after six months of treatment. An astounding 73% of patients showed actual improvement in tissue on biopsy, and 82% reported reduced frequency and intensity of pain and numbness.(1)

Major depression responded to methyfolate in combination with antidepressants in a 2011 study. Ninety-five adults were treated with antidepressants alone, while 147 were treated with both methylfolate and antidepressants. The combination therapy worked faster and helped significantly more patients. Forty percent of those on the combination therapy experienced major improvements, compared to only 16.3 percent on antidepressants alone. Time for improvement averaged 177 days in the combination group, and 231 days in the monotherapy group.(2)

Methylfolate alone may sometimes be useful in clinical depression. A 2009 report and review from Harvard Medical school notes that folate is needed for the synthesis of norepinephrine, serotonin and dopamine. Methyfolate “indicated efficacy as an adjunctive therapy or monotherapy in reducing depressive symptoms in patients with normal and low folate levels, improving cognitive function and reducing depressive symptoms in elderly patients with dementia and folate deficiency, and reducing depressive and somatic symptoms in patients with depression and alcoholism.”(3)

Another 2011 study finds that methyl B12 rescues neurons from homocysteine-mediated cell death. Excess homocysteine is known to be toxic to neurons and can initiate cell death. MethylB12 was able to reduce levels of an enzyme, caspase, involved in cell death. The researchers concluded that methyl B12 might be useful in treatment of late stage ALS, since homocysteine levels have been found to be increased in animal models of the disease.(4)

Autism also responds to treatment with methycobalamin. A 2009 open-label study treated forty autistic children with methylcobalamin twice a week and folinic acid, a form of folate, twice a day for three months. The researchers report that there were “significant increases in cysteine, cysteinylglycine and glutathione…the oxidised disulfide form of glutathione was decreased…targeted nutritional intervention with methylcobalamin and folinic acid may be of clinical benefit in some children who have autism.”(5)


  1. Jacobs AM, Cheng D. Management of diabetic small-fiber neuropathy with combination L-methylfolate, methylcobalamin, and pyridoxal 5′-phosphate. Rev Neurol Dis. 2011;8(1-2):39-47. PMID: 21769070
  2. Ginsberg LD, Oubre AY, Daoud YA. L-methylfolate Plus SSRI or SNRI from Treatment Initiation Compared to SSRI or SNRI Monotherapy in a Major Depressive Episode. Innov Clin Neurosci. 2011 Jan;8(1):19-28. PMID: 21311704
  3. Fava M, Mischoulon D. Folate in depression: efficacy, safety, differences in formulations, and clinical issues. J Clin Psychiatry. 2009;70 Suppl 5:12-7 PMID: 19909688
  4. Hemendinger RA, Armstrong EJ 3rd, Brooks BR. Methyl Vitamin B12 but not methylfolate rescues a motor neuron-like cell line from homocysteine-mediated cell death. Toxicol Appl Pharmacol. 2011 Mar 15;251(3):217-25. PMID: 21237187
  5. James SJ, Melnyk S, Fuchs G, Reid T, Jernigan S, Pavliv O, Hubanks A, Gaylor DW. Efficacy of methylcobalamin and folinic acid treatment on glutathione redox status in children with autism. Am J Clin Nutr. 2009 Jan;89(1):425-30. PMID: 19056591
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