[Sweden] Opinion piece: B12/B9 – possible treatment for mental fatigue


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An opinion piece in Läkartidningen (Swedish website for doctors), written by professor emeritus Björn Regland: "Vitamin B12/B9 -- possible treatment for mental fatigue"

Vitamin B12/B9 – möjlig behandling vid mental trötthet

Google translate said:
As early as 1973, a placebo-controlled study showed that patients with unexplained fatigue were significantly better when 5 mg of hydroxocobalamin (vitamin B12) were injected intramuscularly twice a week [1]. Today, they would probably be diagnosed with myalgic encephalomyelitis (ME), but there were no defined criteria. A similar controlled study at ME has not yet been possible, since hired pharmacological expertise has not been able to find any currently approved placebo preparation which is red-colored and gives red-colored urine.

Vitamin B12, in association with folic acid (Vitamin B9), is fundamental in maintaining methylation capacity in various elementary cell processes. As an indirect sign of vitamin B12 / B9 insufficiency at ME, hypomethylation has been detected in the majority of some immune cells [2], as well as in DNA of genes associated with immune cell regulation [3]. There is a particular chemical signature in blood plasma that suggests that ME is a hypomethabolic syndrome and should be counteracted by intervention with "B9, B12, glycine, serine and B6" [4]. Interestingly, the three B vitamins, like glycine and serine, are related to the turnover of homocysteine.

ME is not rarely associated with the intense muscle soreness called fibromyalgia (FM). In 1997, spinal fluids were examined in the study of patients who met criteria for both FM and ME, then called chronic fatigue syndrome [5]. Homocysteine in spinal fluid was higher in all patients than in the control range, a clear indication that the central nervous system was exposed to vitamin B12 / B9 deficiency. The level in spinal fluid coincided with the degree of fatigue. Since then, vitamin B12 / B9 has been used as treatment in Mölndal at Sweden's first specialist clinic for patients with ME / FM. For optimal efficacy, high and frequent injections are required [6]. The publication is freely available on the internet and also highlights that high doses of vitamin B12 / B9 itself are completely without serious side effects. However, there is an interaction risk that needs to be addressed with: Vitamins B12 and B9 are potent methyl stimulants, which means that they interact with many pharmacists that need to be desmethylated by the CYP 3A4 or 2D6 liver enzymes to achieve the pharmacological efficacy. This interaction is more common in patients with FM who often need relief from strong analgesics such as opioids (tramadol, codeine) and duloxetine. SSRIs are also metabolised by desmethylation. If the patient is addicted to such drugs, one has to compromise with a lower vitamin B12 / B9 dose and unfortunately have a lesser effect [6].

Using frequent high dose B12 injections has in recent years met the most closely organized resistance from general practitioners. Many healthcare centers are still rejecting prescription because they do not believe in either the treatment or the patient. On the other hand, we have the Patient Safety Act, Chapter 6, Section 1, which basically states that prescribing of medicines should be done according to science and proven experience, and when there is no treatment with scientifically assured effect, care must focus on symptom relief, conducted in agreement between patient and doctors, using treatment and medicines that can not be harmful.

I think the combination of vitamins B12 and B9 is a treatment that does not hurt and often gives a very good symptom relief. In the right dose, the response is quite immediate, and those who appreciate the treatment quickly learn to inject themselves subcutaneously. Research provides support for the metabolic disturbances being located where vitamin B12 / B9 is central, and there is some scientific reason why treatment is effective and without placebo effect in unexplained severe fatigue. ME / FM is a large patient group, and the disease causes major suffering with significant disability. It is of utmost importance that more studies be done to address scientifically substantiated treatment of this public health problem, but one can ask whether it is not reasonable to accept treatment at the time based on the proven experience that exists.

Potential conflicts of interests or relationships: Björn Regland was employed as a senior physician at Gottfrieskliniken in Mölndal 1997-2007 (subsequently a senior physician at the neuropsychiatric clinic at Sahlgrenska University Hospital until retirement) and has been involved in clinical research at Gottfrieskliniken as an unpaid lecturer and retired physician in recent years. This has so far resulted in the publication of [6].
ETA references:

  1. Ellis FR, Nasser S. A pilot study of vitamin B12 in the treatment of tiredness. Br J Nutr. 1973;30(2):277-83.
  2. Brenu EW, Staines DR, Marshall-Gradisnik SM. Methylation profile of CD4+ T cells in chronic fatigue syndrome/myalgic encephalomyelitis. J Clin Cell Immunol. 2014;5:228.
  3. De Vega WC, Vernon SD, McGowan PO. DNA methylation modifications associated with chronic fatigue syndrome. PLoS One. 2014;9(8):e104757.
  4. Naviaux RK, Naviaux JC, Li K, et al. Metabolic features of chronic fatigue syndrome. Proc Natl Acad Sci U S A. 2016;113(37):E5472-80.
  5. Regland B, Andersson M, Abrahamsson L, et al. Increased concentrations of homocysteine in the cerebrospinal fluid in patients with fibromyalgia and chronic fatigue syndrome. Scand J Rheumatol. 1997;26(4):301-7.
  6. Regland B, Forsmark S, Halaouate L, et al. Response to vitamin B12 and folic acid in myalgic encephalomyelitis and fibromyalgia. PLoS One. 2015;10(4):e0124648.
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I have the biggest benefits from sublingual hydroxocobalamin, I don't have that good reactions to other b12 forms. It makes me feel that sufficient hydroxocobalamin intake is important. Don't know if it would make a difference to get injections.
And I can also agree that it's a helpful combination taking b12 and methylfolate. I don't have good reactions to taking b6 or amino acids though.
This text does confirm that methylation and homocysteine are important issues to look at.