Vitamin B12 (Cobalamin)
Vitamin B12, also known as cobalamin, is an essential (meaning adequate amounts must be obtained from the diet) B-vitamin found primarily in animal foods such as dairy and meat. It serves as a coenzyme in several key processes in the body, including methylation and conversions between amino acids, the building blocks of protein1. Vitamin B12 deficiency results in various disorders, including neurodegeneration.
Studies suggesting a role of vitamin B12 in the neurodegenerative process relevant to MS have focused on homocysteine. Homocysteine is an amino acid made in the body from the essential amino acid methionine. An enzyme reconverts homocysteine back to methionine, requiring vitamin B12 and fellow B-vitamin folate as cofactors. When there is inadequate B12, homocysteine levels in the blood can get too high, a condition known as hyperhomocysteinemia or simply homocysteinemia3. Homocysteinemia is most commonly associated with cardiovascular disorders such as strokes and heart attacks, but is increasingly noted to be present in MS patients4-6, often with findings of lower blood vitamin B12 levels compared to healthy individuals6,7. Homocysteinemia can trigger inadequate genetic protection of myelin basic protein, a major component of CNS myelin, thereby destabilizing myelin structures8. It may also lead to CNS inflammation9 and interfere with immune cell responses10. Vitamin B12 itself is an important cofactor in myelin formation, and a deficiency has been associated with demyelination and nerve fiber degeneration 11,12.
Interestingly, a genetic study found that predisposition to homocysteinemia or to vitamin B12 deficiency was inversely associated with MS risk – meaning it would be expected to have the opposite effect13. This may suggest non-genetic mechanisms at work in the relationship.
It was shown that remyelination frequently ensues following the destruction of myelin in the CNS of patients with MS14. Thus, recurrent myelin repair in MS may increase the demand for vitamin B1215,16. It has been observed that patients with chronic progressive MS have significantly more demyelinating lesions than those with RRMS as seen in brain MRIs17,18. Therefore, the demand for vitamin B12 may be higher in patients with chronic progressive MS than in those with RRMS17.
In an open (uncontrolled) clinical study, six patients with progressive MS (5 PPMS, 1 SPMS) already receiving DMTs were given a metabolically active form of vitamin B12 (methylcobalamin) at a dose of 60 mg/day, 25,000 times higher than the daily recommended amount for adults of 2.4 mcg/day. After six months of treatment, improvements were seen in both visual and brainstem auditory evoked potentials17 – which are related to the location of demyelinating lesions as determined by magnetic resonance imaging (MRI) scans19 – though not in motor disability. Interestingly, MS patients showed significantly lower values of serum unsaturated vitamin B12 binding capacities than did the healthy controls (p<0.05), suggesting a possible mechanism for a lack of function despite adequate levels17.
In an open study with RRMS patients suffering from permanent visual disability following acute optic neuritis, participants received oral high-doses of three B-vitamins including B12 (300 mg of vitamin B1 or thiamine, 450 mg of vitamin B6 or pyridoxine, and 1,500 mcg of vitamin B12), as add-on treatment to DMTs. After 90 days of treatment, a statistically significant improvement was observed in the key measurements of ability to perceive light and distinguish details of objects at a given distance20. Vitamins B1 and B6 were selected for their reported synergistic neurologic effects with B1221-24.
The recommended intake of vitamin B12 for adults is 2.4 mcg, 2.6 mcg in pregnancy and 2.8 mcg while breastfeeding. The general safe upper limit is considered to be 2000 mcg/day25. However, research suggests that monitoring of the mother’s blood levels is key to safety, as too much vitamin B12 has been linked to autism in offspring26.
While some vitamin B12 can be produced in the human large intestine by bacteria, this amount is too small in the vast majority of people. Because the vitamin is found almost exclusively in animal foods such as beef and seafood, most vegans need to obtain it from fortified foods such as nutritional yeast or nutritional supplements27.
References
1.MacFarlane AJ, Greene-Finestone LS, Shi Y. Vitamin B-12 and homocysteine status in a folate-replete population: results from the Canadian Health Measures Survey. Am J Clin Nutr. Oct 2011;94(4):1079-87. doi:10.3945/ajcn.111.020230
2.Allen LH. How common is vitamin B-12 deficiency? Am J Clin Nutr. Feb 2009;89(2):693S-6S. doi:10.3945/ajcn.2008.26947A
3.Dardiotis E, Arseniou S, Sokratous M, et al. Vitamin B12, folate, and homocysteine levels and multiple sclerosis: A meta-analysis. Mult Scler Relat Disord. Oct 2017;17:190-197. doi:10.1016/j.msard.2017.08.004
4.Li X, Yuan J, Han J, Hu W. Serum levels of Homocysteine, Vitamin B12 and Folate in Patients with Multiple Sclerosis: an Updated Meta-Analysis. Int J Med Sci. 2020;17(6):751-761. doi:10.7150/ijms.42058
5.Mititelu RR, Albu CV, Bacanoiu MV, et al. Homocysteine as a Predictor Tool in Multiple Sclerosis. Discoveries (Craiova). Jul-Sep 2021;9(3):e135. doi:10.15190/d.2021.14
6.Zhu Y, He ZY, Liu HN. Meta-analysis of the relationship between homocysteine, vitamin B(1)(2), folate, and multiple sclerosis. J Clin Neurosci. Jul 2011;18(7):933-8. doi:10.1016/j.jocn.2010.12.022
7.Reynolds EH, Linnell JC, Faludy JE. Multiple sclerosis associated with vitamin B12 deficiency. Arch Neurol. Aug 1991;48(8):808-11. doi:10.1001/archneur.1991.00530200044017
8.Kim JK, Mastronardi FG, Wood DD, Lubman DM, Zand R, Moscarello MA. Multiple sclerosis: an important role for post-translational modifications of myelin basic protein in pathogenesis. Mol Cell Proteomics. Jul 2003;2(7):453-62. doi:10.1074/mcp.M200050-MCP200
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10.Fu YF, Zhu YN, Ni J, et al. A reversible S-adenosyl-L-homocysteine hydrolase inhibitor ameliorates experimental autoimmune encephalomyelitis by inhibiting T cell activation. J Pharmacol Exp Ther. Nov 2006;319(2):799-808. doi:10.1124/jpet.106.107185
11.Miller A, Korem M, Almog R, Galboiz Y. Vitamin B12, demyelination, remyelination and repair in multiple sclerosis. J Neurol Sci. Jun 15 2005;233(1-2):93-7. doi:10.1016/j.jns.2005.03.009
12.Najafi MR, Shaygannajad V, Mirpourian M, Gholamrezaei A. Vitamin B(12) Deficiency and Multiple Sclerosis; Is there Any Association? Int J Prev Med. Apr 2012;3(4):286-9.
13.Peng H, Wu X, Lin J, Guan W. Genetically predicted circulating homocysteine, vitamin B12, and folate levels and risk of multiple sclerosis: evidence from a two-sample Mendelian randomization analysis. Mult Scler Relat Disord. Nov 2021;56:103255. doi:10.1016/j.msard.2021.103255
14.Prineas JW, Barnard RO, Kwon EE, Sharer LR, Cho ES. Multiple sclerosis: remyelination of nascent lesions. Ann Neurol. Feb 1993;33(2):137-51. doi:10.1002/ana.410330203
15.Reynolds EH. Multiple sclerosis and vitamin B12 metabolism. J Neurol Neurosurg Psychiatry. May 1992;55(5):339-40. doi:10.1136/jnnp.55.5.339
16.Reynolds EH, Bottiglieri T, Laundy M, Crellin RF, Kirker SG. Vitamin B12 metabolism in multiple sclerosis. Arch Neurol. Jun 1992;49(6):649-52. doi:10.1001/archneur.1992.00530300089014
17.Kira J, Tobimatsu S, Goto I. Vitamin B12 metabolism and massive-dose methyl vitamin B12 therapy in Japanese patients with multiple sclerosis. Intern Med. Feb 1994;33(2):82-6. doi:10.2169/internalmedicine.33.82
18.Koopmans RA, Li DK, Grochowski E, Cutler PJ, Paty DW. Benign versus chronic progressive multiple sclerosis: magnetic resonance imaging features. Ann Neurol. Jan 1989;25(1):74-81. doi:10.1002/ana.410250112
19.Hendler T, Squires NK, Moore JK, Coyle PK. Auditory evoked potentials in multiple sclerosis: correlation with magnetic resonance imaging. J Basic Clin Physiol Pharmacol. 1996;7(3):245-78. doi:10.1515/jbcpp.1996.7.3.245
20.Mallone F, Lucchino L, Franzone F, Marenco M, Carlesimo SC, Moramarco A. High-dose vitamin B supplementation for persistent visual deficit in multiple sclerosis: a pilot study. Drug Discov Ther. 2020;14(3):122-128. doi:10.5582/ddt.2020.03031
21.Bonke D, Nickel B. Improvement of fine motoric movement control by elevated dosages of vitamin B1, B6, and B12 in target shooting. Int J Vitam Nutr Res Suppl. 1989;30:198-204.
22.Hakim M, Kurniani, N., Pinzon, R., Tugasworo, D., Basuki,, M. H, H., Pambudi, P., Fithrie, A., Wuysang, A. Management of peripheral europathy symptoms with a fixed dose combination of high-dose vitamin B1, B6 and B12: A 12-week prospective non-interventional study in Indonesia. Asian J Med Sci. 2018;9
23.Leuschner J. Antinociceptive properties of thiamine, pyridoxine and cyanocobalamin following repeated oral administration to mice. Arzneimittelforschung. Feb 1992;42(2):114-5.
24.Wang ZB, Gan Q, Rupert RL, Zeng YM, Song XJ. Thiamine, pyridoxine, cyanocobalamin and their combination inhibit thermal, but not mechanical hyperalgesia in rats with primary sensory neuron injury. Pain. Mar 2005;114(1-2):266-77. doi:10.1016/j.pain.2004.12.027
25.Safe upper intake levels for vitamins and minerals (Ministry of Family and Consumer Affairs) (2006).
26.Raghavan R, Fallin, M.D., Wang, X. Maternal plasma folate, vitamin B12 levels and multivitamin supplementation during pregnancy and risk of Autism Spectrum Disorder in the Boston Birth Cohort. FASEB J. 2016;30(S1)
27.Supplements OoD. Vitamin B12: Fact Sheet for Health Professionals. Accessed 18 Feb 2022. https://ods.od.nih.gov/factsheets/VitaminB12-HealthProfessional/