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.
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.
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.
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).
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.
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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.
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