Vitamin B12 Deficiency



Vitamin B12 Deficiency and psychoses


Vitamin B12 deficiency is associated with a number of psychoses including dementia, depression, Alzheimer's disease, Obsessive Compulsive Disorder, Schizophrenia, and anxiety, General Anxiety Disorder and panic attacks. The association, though is controversial and for this reason we have provided a wide range of references on the topic at the end of the page. In addition, it should be noted that by the time vitamin B12 deficiency is measurable in serum, levels of vitamin B12 in the brain have already been low for some considerable period of time. Further, the ability to modify some serum markers of vitamin B12 deficiency does not necessarily mean that such modifications have occurred in the brain. In addition, it is known that even in healthy individuals levels of vitamin B12 in the brain decrease with age.


Vitamin B12 Deficiency, depression and treatment with SSRIs


Depression affects around one-in-four people in the US at some time during their life, and approximately 350 people world wide. The major antidepressant therapies include SSRIs, SNRIs and tricylci antidepressants, which are used in the treatment of Major Depressive Disorder, Obsessive-Compulsive Disorder, Generalized Anxiety Disorder, and Panic Disorder. The antidepressant market is significant at around $13.4 billion in 2018, and appears to be focused on treatment of symptoms, rather than on disease modification. In many instances persons with depression are not tested properly for B12 deficiency or folate deficiency and we have found no studies looking at functional deficiency in vitamin B2. Rather the majority of patients are simply placed on one of the many different anti-depressant drugs including SSRIs. If the health professionals in question actually checked they would find that in many instances, those who are B12 deficient are actually already making way too much serotonin, and some are making 10-100 to even 600 times the amount of serotonin that a normal, vitamin B12 sufficient person is making. Obviously the prescription of an SSRI or SNRI in these circumstances should be contra-indicated. It is though quite typical in treatment resistant depression. Typical drugs would include Sertraline (Zoloft, Lustral), Citalopram (Celexa, Cipramil), Escitalopram (Lexapro, Cipralex), Paroxetine (Paxil, Seroxat), Fluoxetine (Paxil, Seroxat), Fluvoxamine (Luvox, Faverin). SNRIs include Desvenlafaxine (Pristiq), Duloxetine (Cymbalts), Levomilnacipran (Fetzima), Milnacipran (Ixel, Savella), Venlafaxine (Effexor).


Functional vItamin B12 deficiency should be suspected in nearly every situation in which SSRIs, or SNRIs are prescribed. Surprisingly measurement of functional B12 deficiency is seldom, if ever, done, with few practitioners understanding the concepts of paradoxical B12 deficiency, nor what happens in receptor down-regulation due to over-administration of SSRIs or SNRIs. Given the huge number of side effects that taking such drugs can potentially elicit many practitioners will treat the potential side effects of the drugs before they even administer the first dose of the drug. An intractable web of Polypharmacy can often result.


Vitamin B12 Deficiency and down-regulation of serotonin receptors


The possibility that over-production of serotonin, with resultant down-regulation of serotonin receptors does not seem to have been considered as the reason for depression in those treated with SSRIs, or those who are deemed to have treatment resistant depression. There are studies though that have shown that there may be down-regulation of serotonin receptors as a result of treatment with anti-depressants (1,2). There is data that suggests that there are alterations in one-carbon metabolism (methylation) in conditions such as schizophrenia, in which SSRIs and other antipsychotics are used (3), and there is also evidence of elevated homocysteine in such patients (3,4,5), lower folate concentrations (6,7,8), which would also affect vitamin B12 cycling, once again suggesting a role for vitamin B12 deficiency in these conditions. Several studies have also shown a benefit of B group vitamin supplementation in treatment with antidepressants (9) and also vitamin B12 supplementation alone (10). Further, co-treatment with folic acid and fluoxetine was found to reduce both homocysteine and serotonin levels in depressed subjects (11), whilst adjunctive treatment with high dose 5MTHF was beneficial in SSRI treatment of major depressive disorder (12). There are also numerous studies showing decreased vitamin B12 levels in people with depression (13-41). Supporting the hypothesis that vitamin B12 deficiency is involved in depression, several studies have also shown lower levels of the methylation product, CoQ10 in depression (42-45), and an improvement of symptoms following addition of CoQ10 (46,47). Several studies have also suggested a role for low selenium and low levels of functional vitamin B2, both of which would lead to vitamin B12 deficiency. Thus, both glutathione peroxidase and glutathione reductase are reduced in depressive disorders (48)


What none of the studies have addressed is what is going on in vitamin B12 deficiency, in low folate, elevated homocysteine, and increased effectiveness of treatment with high dose 5MTHF, elevated serotonin, and the use of SSRIs, and why they are linked and why this causes depression or other psychoses. The most obvious answer is the reduced rate of methylation that occurs in B12/folate deficiency and elevated homocysteine. More specifically the relationship between lack of methylation and elevated serotonin.


Serotonin is a precursor molecule in the synthesis of melatonin. For the synthesis, tryptophan is initially taken into the cell and then converted to serotonin. Serotonin is then acetylated to form N-acetylserotonin, which is then methylated to form melatonin via the enzyme N-acetylserontonin-O-methyl transferase. In B12 deficiency, however, the rate of methylation is restricted due to lower production of the methylating agent S-adenosylmethionine. Potentially this would mean that in vitamin B12 deficiency, large amounts of the precursor, serotonin, would accumulate within cells and either be degraded to 5-hydroxyindole acetic acid (5HIAA), or the excess tryptophan, imported into the cells would be degraded to Quinolinic Acid or Kynurenic acid, or the excess serotonin would be excreted from the cells. Increased uptake and usage of tryptophan could explain the decreased levels of tryptophan seen in the serum of those with major depressive disorder (49) as well as the increased levels of Quinolinic acid (42,50,51). Further, lack of production of melatonin would also account for the sleep disturbance common in depression (52).


Studies on over 400 persons with various degrees of vitamin B12 deficiency have shown a correlation between decreasing functional vitamin B12, as measured by increasing MMA levels and increasing levels of Quinolinic Acid.


Vitamin B12 treatment of Depression


Treatment of depression with vitamin B12 appears to be hampered by the basic lack of understanding of the biochemistry of vitamin B12 cycling and the lack of understanding of the limited uptake of vitamin B12 into the brain, particularly after oral administration. The later point is discussed elsewhere, but basically the amount of vitamin B12 that reaches the brain after oral administration is less than 0.01% of the orally administered dose. The dose that reaches the brain, even after injection is less then 0.1 % of the injected dose at 24 and 48 hours (53,54,55). In this regard, vitamin B12 delivery to the brain is very different to delivery of any other B group vitamin. Whilst the limited access of vitamin B12 to the brain has been known for over 50 years, for some reason it is largely forgotten in nearly all studies on vitamin B12 supplementation for the treatment of basically a "brain" malady, depression. Thus, there are a litany of oral vitamin B12 supplementation studies, which have, not surprisingly, shown little effect of supplementation on reducing depressive symptoms (56-65,33). Further, to date the majority of such studies have used cyanocoblamin or hydroxocobalamin, neither of which are effective in persons who are functionally deficient in vitamin B2 (9,56,58).


Further to this, whilst the essential role of folate in vitamin B12 cycling is well known, the necessity for functional vitamin B2 (as FMN and FAD) for maintenance of vitamin B12 activity, and the co-dependence on sufficient Iodine, Selenium and Molybdenum for activation of vitamin B2 to form FMN and FAD, has been completely ignored, despite their (FMN and FAD) critical involvement of the activity of MTHFR and MTRR (66).


In order to achieve effective treatment of vitamin B12 deficiency related depression, it would be necessary to ensure that the subject to be treated was obtaining sufficient Iodine (150-300 ug/day), Selenium (as selenite - 55-200 ug/day), Molybdenum (100-300 ug/day), vitamin B2 (>2 mg/day) and folate (400 ug/day). Supplementation with vitamin B12 would require either injection, preferably of Adenosyl/Methyl  B12, or transdermal administration of vitamin B12 using Transdermoil technology.


Despite the caveats listed above, vitamin B12 supplementation has had a mild additive effect on treatment responsiveness to SSRIs in at least one study, but certainly not all (10).


Other activities of Serotonin potentially suppressed in vitamin B12 deficiency


Serotonin in the brain also has been shown to regulate anxiety, and aggressive behavior, via the 5HT1A receptor (a specific serotonin receptor) as well as having activity in coping, cognitive flexibility, and creative thinking, via the 5HT2A receptor (a second type of serotonin receptor). Many people with vitamin B12 deficiency have also been shown to have issues with anxiety, aggressive behaviour, an inability to cope, or are unable to "think outside the box" or have reduced creativity.



References on Vitamin B12 and Psychoses


1.    Stahl S. 5HT1A receptors and pharmacotherapy. Is serotonin receptor down-regulation lined to the mechanism of action of antidepressant drugs Psychopahm. Bull 1994 30, 39-43 PMID 7972628

2.    Stahl etal. Downregulation of serotonin receptor subtypes by nortriptyline and adinzolam in major depressive disorder: Neuroendocrine and platelet markers. Clin. Neuropharmacol. 1993 15 supl. 3:S19-31

3.    Misiak etal. Effects of second-generation antipsychotics on selected markers of one-carbon metabolism and metabolic syndrome components in first-episode schizophrenia patients. Eur. J Clin Pharmacol 2014 70: 1433-41

4.    Mischoulon etal, Prevalence of MTHFR  C677T and MS A2756G polymorphisms in major depressive disorder, and their impact on response to fluoxetine treatment. CNS Spectr. 2012 17: 76-86

5.    Kang etal. Predictive value of homocysteine for depression after acute coronary syndrome. Oncotarget 2016 7:69032-69040.

6.    Papakostas etal. Serum folate, vitamin B12, and homocysteine in major depressive disorder, Part 1: predictors of clinical response in fluoxetine-resistant depression. J Clin Psychiatry 2004a 65: 1090-5

7.    Papakostas etal. Serum folate, vitamin B12, and homocysteine in major depressive disorder, Part 2: predictors of relapse during the continuation phase of pharmacotherapy. J Clin Psychiatry 2004b 65: 1096-8

8.    Papakostas etal. The relationship between serum folate, vitamin B12, and homocysteine levels in major depressive disorder and the timing of improvement with fluoxetine. Int J. Neurophychophamacol. 2005 8: 523-8.

9.    Almeida etal 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. B J Psychiatry 2014 205: 450-7

10.    Syed etal. Vitamin B12 supplementation in treating major depressive disorder: a randomized controlled trial. Open Neurol J. 2013 7: 44-8

11.    Resler etal. Effect of folic acid combined with fluoxetine in patients with major depression on plasma homocysteine and vitamin B12, and serotonin levels in lymphocytes. Neuroimmunomodulation 2008 15:145-152

12.    Papakostas etal. Effect of adjunctive L-methylfolate 15 mg among inadequate responders to SSRIs in depressed patients who were stratified by biomarker levels and genotype: results from a randomized clinical trial. J Clin Psychiatry 2014 75: 855-63

13.    Robinson DJ, O'Luanaigh C, Tehee E, O'Connell H, Hamilton F, Chin AV, Coen R, Molloy AM, Scott J, Cunningham CJ, Lawlor BA. Associations between holotranscobalamin, vitamin B12, homocysteine and depressive symptoms in community-dwelling elders. Int J Geriatr Psychiatry. 2011 Mar;26(3):307-13. doi: 10.1002/gps.2530 - Lower levels of holotranscobalamin and vitamin B12 were associated with higher levels of depressive symptoms but. Homocysteine was not associated with depressive symptoms

14.    Kate N, Grover S, Agarwal M. Does B12 deficiency lead to lack of treatment response to conventional antidepressants? Psychiatry (Edgmont). 2010 Nov;7(11):42-4

15.    Weber GA, Sloan P, Davies D. Nutritionally induced peripheral neuropathies. Clin Podiatr Med Surg. 1990 Jan;7(1):107-28. Review

16.    Bodnar LM, Wisner KL. Nutrition and depression: implications for improving mental health among childbearing-aged women. Biol Psychiatry. 2005 Nov 1;58(9):679-85. Epub 2005 Jul 25. Review

17.    Bar-Shai M, Gott D, Marmor S. Acute psychotic depression as a sole manifestation of vitamin B12 deficiency. Psychosomatics. 2011 Jul-Aug;52(4):384-6. Epub 2011 Apr 15

18.    Almeida OP, Flicker L, Yeap BB, Alfonso H, McCaul K, Hankey GJ. Aspirin decreases the risk of depression in older men with high plasma homocysteine. Transl Psychiatry. 2012 Aug 14;2:e151. doi: 10.1038/tp.2012.79.

19.    Kalita J, Agarwal R, Chandra S, Misra UK. A study of neurobehavioral, clinical psychometric, and P3 changes in vitamin B12 deficiency neurological syndrome. Nutr Neurosci. 2012 Jul 9. [Epub ahead of print]

20.    Moorthy D, Peter I, Scott TM, Parnell LD, Lai CQ, Crott JW, Ordovás JM, Selhub J, Griffith J, Rosenberg IH, Tucker KL, Troen AM. Status of Vitamins B-12 and B-6 but Not of Folate, Homocysteine, and the Methylenetetrahydrofolate Reductase C677T Polymorphism Are Associated with Impaired Cognition and Depression in Adults. J Nutr. 2012 Aug;142(8):1554-60. Epub 2012 Jun 27.

21.    van de Rest O, van Hooijdonk LW, Doets E, Schiepers OJ, Eilander A, de Groot LC. B Vitamins and n-3 Fatty Acids for Brain Development and Function: Review of Human Studies. Ann Nutr Metab. 2012;60(4):272-92. Epub 2012 Jun 1.

22.    Bochyńska A, Lipczyńska-Łojkowska W, Gugała-Iwaniuk M, Lechowicz W, Restel M, Graban A, Lipska B, Ryglewicz D. The effect of vitamin B supplementation on homocysteine metabolism and clinical state of patients with chronic epilepsy treated with carbamazepine and valproic acid. Seizure. 2012 May;21(4):276-81. Epub 2012 Feb 22.

23.    Davison KM, Kaplan BJ. Nutrient intakes are correlated with overall psychiatric functioning in adults with mood disorders. Can J Psychiatry. 2012 Feb;57(2):85-92.

24.    Davison KM, Kaplan BJ. Vitamin and mineral intakes in adults with mood disorders: comparisons to nutrition standards and associations with sociodemographic and clinical variables. J Am Coll Nutr. 2011 Dec;30(6):547-58.

25.    Huijts M, Duits A, Staals J, van Oostenbrugge RJ. Association of vitamin B12 deficiency with fatigue and depression after lacunar stroke. PLoS One. 2012;7(1):e30519. Epub 2012 Jan 20.

26.    Ezzaher A, Mouhamed DH, Mechri A, Omezzine A, Neffati F, Douki W, Bouslama A, Gaha L, Najjar MF. Hyperhomocysteinemia in Tunisian bipolar I patients. Psychiatry Clin Neurosci. 2011 Dec;65(7):664-71. doi: 10.1111/j.1440-1819.2011.02284.x.

27.    Walker JG, Batterham PJ, Mackinnon AJ, Jorm AF, Hickie I, Fenech M, Kljakovic M, Crisp D, Christensen H. Oral folic acid and vitamin B-12 supplementation to prevent cognitive decline in community-dwelling older adults with depressive symptoms--the Beyond Ageing Project: a randomized controlled trial. Am J Clin Nutr. 2012 Jan;95(1):194-203. Epub 2011 Dec 14

28.    Dogan M, Ariyuca S, Peker E, Akbayram S, Dogan ŞZ, Ozdemir O, Cesur Y. Psychotic disorder, hypertension and seizures associated with vitamin B12 deficiency: a case report. Hum Exp Toxicol. 2012 Apr;31(4):410-3. Epub 2011 Oct 25.

29.    Bar-Shai M, Gott D, Marmor S. Acute psychotic depression as a sole manifestation of vitamin B12 deficiency. Psychosomatics. 2011 Jul-Aug;52(4):384-6. Epub 2011 Apr 15.

30.    Ladika DJ, Gurevitz SL. Identifying the most common causes of reversible dementias: a review. JAAPA. 2011 Mar;24(3):28-31, 57. Review

31.    Murakami K, Miyake Y, Sasaki S, Tanaka K, Arakawa M. Dietary folate, riboflavin, vitamin B-6, and vitamin B-12 and depressive symptoms in early adolescence: the Ryukyus Child Health Study. Psychosom Med. 2010 Oct;72(8):763-8. Epub 2010 Aug 17.

32.    Robinson DJ, O'Luanaigh C, Tehee E, O'Connell H, Hamilton F, Chin AV, Coen R, Molloy AM, Scott J, Cunningham CJ, Lawlor BA. Associations between holotranscobalamin, vitamin B12, homocysteine and depressive symptoms in community-dwelling elders. Int J Geriatr Psychiatry. 2011 Mar;26(3):307-13. doi: 10.1002/gps.2530

33.    Almeida OP, Marsh K, Alfonso H, Flicker L, Davis TM, Hankey GJ. B-vitamins reduce the long-term risk of depression after stroke: The VITATOPS-DEP trial. Ann Neurol. 2010 Oct;68(4):503-10.

34.    Beydoun MA, Shroff MR, Beydoun HA, Zonderman AB. Serum folate, vitamin B-12, and homocysteine and their association with depressive symptoms among U.S. adults. Psychosom Med. 2010 Nov;72(9):862-73. Epub 2010 Sep 14

35.    Skarupski KA, Tangney C, Li H, Ouyang B, Evans DA, Morris MC. Longitudinal association of vitamin B-6, folate, and vitamin B-12 with depressive symptoms among older adults over time. Am J Clin Nutr. 2010 Aug;92(2):330-5. Epub 2010 Jun 2.

36.    Williamson C. Dietary factors and depression in older people. Br J Community Nurs. 2009 Oct;14(10):422, 424-6

37.    Stanger O, Fowler B, Piertzik K, Huemer M, Haschke-Becher E, Semmler A, Lorenzl S, Linnebank M. Homocysteine, folate and vitamin B12 in neuropsychiatric diseases: review and treatment recommendations. Expert Rev Neurother. 2009 Sep;9(9):1393-412. Review

38.    Güzelcan Y, van Loon P. Vitamin B12 status in patients of Turkish and Dutch descent with depression: a comparative cross-sectional study. Ann Gen Psychiatry. 2009 Aug 13;8:18

39.    Sánchez-Villegas A, Doreste J, Schlatter J, Pla J, Bes-Rastrollo M, Martínez-González MA. Association between folate, vitamin B(6) and vitamin B(12) intake and depression in the SUN cohort study. J Hum Nutr Diet. 2009 Apr;22(2):122-33. Epub 2009 Jan 16

40.    Triantafyllou N, Evangelopoulos ME, Kimiskidis VK, Kararizou E, Boufidou F, Fountoulakis KN, Siamouli M, Nikolaou C, Sfagos C, Vlaikidis N, Vassilopoulos D. Increased plasma homocysteine levels in patients with multiple sclerosis and depression. Ann Gen Psychiatry. 2008 Sep 9;7:17.

41.    Folstein M, Liu T, Peter I, Buell J, Arsenault L, Scott T, Qiu WW.The homocysteine hypothesis of depression. Am J Psychiatry. 2007 Jun;164(6):861-7.

42.    Wigner etal. The molecular aspects of oxidative and nitrosative stress and the tryptophan catabolites pathway (TRTCATs) as potential causes of depression. Psychiatry Res 2018 262: 566-574

43.    Forester etal. Coenzyme Q10 effects on creatine kinase activity and mood in geriatric bipolar depression. J Geriatr Psychiatry Neurol 2012 25:43-50

44.    Saoobar,  etal. Coenzyme Q10 as a treatment for fatigue and depression in multiple sclerosis patients... Nutr Neurosci. 2016 19: 138-43

45.    Morris etal. Coenzyme Q10 depletion in medical and neuropsychiatric disorders: potential repercussions and therapeutic implications. Mol Neurobiol 2013 48: 883-903

46.    Mehrpooya etal. Evaluating the effect of Coenzyme Q10 augmentation on treatment of bipolar depression: A double-blind controlled clinical trial. J. Clin Psychopharmacol 2018 38: 460-466

47.    Forester etal. Antidepressant effects of open label treatment with coenzymeQ10 in geriatric bipolar depression. J Clin Psychopharmacol 2015 35:338-40

48.    Wigner etal. Oxidative and nitrosative stress as well as the tryptophan catabolites pathway in depressive disorders. Psychiat. Danubina 2017 29: 394-400

49.    Doolan etal Altered tryptophan catabolite concentrations in major depressive disorder and associated changes in hippocampal subfield volumes. Psychoneuroendocrinology 2018 95: 8-17.

50.    Ogyu etal. Kynurenine pathway in depression: A systematic review and meta-analysis. Neruosci Biobehav. Rev. 2018 90:16-25

51.    Kanchanatawan etal. In schizophrenia, depression, anxiety , and physiosomatic symptoms are strongly related to psychotic symptoms .... Neurotox Res 2018 33: 641-644

52.    Cho etal. Sleep disturbance and kynurenine metabolism in depression. J Psychosom Res 2017 99 : 1-7

53.    Kuda-Wedegedara etal 89Zr Cobalamin PET Tracer: synthesis, cellular uptake, and use for tumor imaging. ACS Omega 2017 2:6314-6320

54.    Collins etal Biodistribution of radiolabeled adenosylcobalamin in patients diagnosed with various malignancies Mayo Clin Proc 2000 75: 568-80

55.    Collins and Hogenkamp Transcobalamin II receptor imaging via radiolabeled diethylene-triaminepentataacetate cobalamin analogs. J. Nucl Med. 1997 38; 717-23

56.    de Koning etal, Effects of two-year vitamin B12 and folic acid supplementation on depressive symptoms and quality of life in older adults with elevated homocysteine concentrations:.... Nutrients 2016 23 piiE748

57.    Almeida etal Systematic review and meta-analysis of randomized placebo-controlled trials of folate and vitamin B12 for depression. Int Psychogeriatr. 2015 27: 727-37

58.    Okerede etal. Effect of long-term supplementation with folic acid and B vitamins on risk of depression in older women. Br J Psychiatry 2015 206: 324-31

59.    Christensen etal No clear potentiation of antidepressant medication effects by folic acid + vitamin B21 in a large community sample. J Affect Disorder 2011 130:37-45

60.    Walker etal. Mental health literacy, folic acid and vitamin B12, and physical activity for the prevention of depression in older adults: randomised control trial Br J Psychiatry 2010 197: 45-54

61.    Ford etal. Vitamins B12, B6 and folic acid for onset of depressive symptoms in older men: results from a 2 year placebo-controlled randomized trial. J Clin Psychiatry 2008 69: 1203-9.

62.    van Dyck etal Cognitive and psychiatric effects of vitamin B12 replacement in dementia with low serum B12 levels: a nursing home study. Int Psychogeriatr 2009 21: 138-47.

63.    Mikkelsen, etal The effect of vitamin B in depression. Curr Med Chem 2016 23:4317-4337

64.    Mikkelsen, etal The effects of vitamin B on the immune/cytokine network and their involvement in depression. Mturitas 2017 96:58-71

65.    Almeida etal B vitamins to enhance treatment response to antidepressants in middle-aged and older adults:.. BJ Psych 2014 205:450-457

66.    Hiraoka and Kagawa 2017 Genetic polymorphisms and folate status. Congenit Anom (Kyoto) 2017 57: 142-149






Copyright © 2018 All Rights Reserved. 
The statements on this site compose a compendium of generally recognized signs of vitamin B12 deficiency, and problems that can then ensue They also are formulated from a summary of relevant scientific publications. In addition they may contain some forward looking statements of a general nature.
Reproduction in whole or in part in any form or medium without express written permission is prohibited