Supplements

What I’m taking right now:

Hydroxocobalamin ca.500-1000µg (capsule)
Vitamin B2/ riboflavin 10mg

 

I take all vitamins as written above unactivated and low-dose.
Many vitamins are light-sensitive, like riboflavin and calcium pantothenate, so I would not leave supplement jars open and supplements lying around.

My light-sensitivity symptoms have improved significantly in the last few weeks on vitamin B2, B3, B12. I am still homebound with cognitive symptoms, low energy levels, and am sensitive to stress and exertion.

Why I think these supplements might be helpful?
Vitamin B2 is a cofactor for the MTHFR enzyme and helps recycle glutathione, vitamin B3 supports glutathione synthesis and recycling and can lower adrenaline levels. Hydroxocobalamin/B12 can be used to produce both methyl- and adenosylB12. It supports methylation but does it at a, for me, more tolerable pace than methylB12. I don’t get any overmethylation or potassium deficiency symptoms from it.

Problematic effects of supplements

 

I think might raise adrenaline levels by producing more SAMe and lower glutathione synthesis by increasing conversion of homocysteine to methionine. This might be problematic if adrenaline is high and glutathione is very low. Niacin can lower methylation by reducing thyroid hormones and might increase histamine symptoms.

 

 

Vitamins & Minerals: Functions, Personal Experience

 

Vitamin B1/ Thiamine

Daily requirement: ca. 2mg

Activation of vitamin B1 to thiamine diphosphate requires magnesium. Thiamine is a cofactor in the pyruvate dehydrogenase complex and therefore important for the breakdown of carbohydrates. Thiamine is also needed in the citric acid cycle in the ketoglutarate-dehydrogenase. Additionally, vitamin B1 is a cofactor in the pentose phosphate pathway, which produces ribose. Ribose is used for the synthesis of AMP, the precursor of ATP, or for niacin-synthesis and -activation.

Thiamine deficiency can increase lactate levels, by reducing pyruvate dehydrogenase function and increasing conversion of pyruvate to lactate. Thiamine deficiency might also inhibit AMPK (1).

 

My personal experience with vitamin B1 is that it helped raise energy levels, but possibly at the same time raised SAMe requirement and made me feel less calm/ more hyped up and stressed.

  1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3995829/

 

Vitamin B2/Riboflavin

Daily requirement: ca. 2mg

The active forms of riboflavin are FAD and FMN. The activation depends on thyroid hormones ().

FAD is a cofactor in the MTHFR enzyme and supports function in mutated variants, especially in homozygous mutations. At the same time FAD might increase breakdown of serotonin as a MAO cofactor and conversion of choline to betaine. At times I have experienced anxiety after taking riboflavin which might be caused by reduced serotonin or acetylcholine.

Riboflavin also improves function is some MTRR mutations with cobalamin. (More information in ‘theories-> Cofactors in Gene Mutations’)

Some other functions:

FAD is a cofactor in the fatty acid oxidation, pyruvate dehydrogenase and transfers its electrons into the oxidative phosphorylation as FADH2. FAD aids detox by helping regenerate glutathione by the glutathione reductase. FAD-dependent MAO (monoamineoxidase) is important in histamine intolerance by breaking down amines and also breaks down the neruotransmitters serotonin, norepinephrine, epinephrine.

Vitamin B2 is one of the supplements I had the biggest benefit from. It reduced my fatigue-after-meals and high histamine symptoms significantly.

https://www.ncbi.nlm.nih.gov/pubmed/3809170

 

Vitamin B3/ Niacin

Daily requirement: 13-16 mg

Active cofactors of niacin are NAD+/NADH and NADP+/NADPH.

NAD+ and NADP+ can take up and transfer electrons. NADH from the citric acid cycle is needed in the oxidative phosphorylation to produce ATP. NADPH is required for the biosynthesis of fatty acids or cholesterol and for enzymes like the glutathione reductase, MTHFR and Methionine Synthase Reductase (converts cob(II)alamin to methylcobalamin).

The body can synthesize niacin from the amino acid tryptophane but it is unclear wether you still need niacin-intake from foods (or supplements) to not develop niacin deficiency. Pellagra, the niacin-deficiency disease, is associated with photosensitive skin reactions (2).

NAD+ is required to synthesize inositol which might make it important for calcium-signaling via inositol triphosphate receptor. Niacin can reduce thyroid hormones (3) and is given against symptoms of overmethylation, when having taken too many supplements that increase methylation.

  1. http://www.umm.edu/health/medical/altmed/condition/photodermatitis
  2. https://www.ncbi.nlm.nih.gov/pubmed/7776715

 

Vitamin B5/ Pantothenic Acid

Daily requirement: ca. 10mg

Vitamin B5 needs to be activated to coenzyme A (CoA-SH), to be a cofactor in the body. This requires cysteine and FMN (vitamin B2 coenzyme). Coenzyme A is relevant in all energy processes that produce or use acetyl-CoA, because acetyl-CoA contains CoA-SH. This makes vitamin B5 a cofactor in the fatty acid oxidation, pyruvate dehydrogenase and the citric acid cycle.

Vitamin B5  deficiency might cause elevated unbound copper levels in the blood (4). Pantothenic acid is also often supplemented to support adrenal function. The cholesterolbiosynthesis is fueled by acetyl-CoA and produces cortisol, which could be one way how vitamin B5 affects the adrenal glands.

  1. https://core.ac.uk/download/pdf/82086362.pdf

https://de.wikibooks.org/wiki/Biochemie_und_Pathobiochemie:_Druckversion#Pantothenat-Stoffwechsel

 

Vitamin B6/ Pyridoxine

Daily requirement: ca. 2mg

Vitamin B6’s activated form pyridoxal 5-phosphate is needed in methlyation, glucose breakdown, amino acid metabolism, cysteine conversion from homocysteine etc.

Vitamin B6 helps produce dopamine and serotonin and is a cofactor in glutamate to GABA conversion. In the choline metabolism the enzyme that converts phosphatidylserine to phosphatidylethanolamine is B6-dependent. Phosphatidylethanolamine then gets methylated to phosphatidylcholine.

A key enzyme in the pentose phosphate pathway, which produces NADPH, needs vitamin B6 (5).

Even though vitamin B6 is required in so many important pathways, I think I had some very bad reactions from vitamin B6. While taking several vitamins, fatigue after meals receeded but at some point I developed photosensitivity, with increased stress and symptoms immediately after too much light exposure as well as a slight discomfort and burning of the skin. Vitamin B6 can cause photosensitive skin reactions (6).
Also, I felt the B6 increased stress-levels at times. Even though it is required for choline- and serotonin-synthesis that might have not compensated the increase in dopamine and following noradrenaline and adrenaline production.

  1. https://www.ncbi.nlm.nih.gov/pubmed/8698911
  2. “Liver glucose-6-phosphate dehydrogenase, and adipose tissue and liver malic enzyme were significantly lowered in deficient rats..”
    https://www.ncbi.nlm.nih.gov/pubmed/139463

 

Vitamin B12/ Cobalamin

Daily requirement: ca. 5µg

Hydroxocobalamin needs to be activated to methylcobalamin and adenosylcobalamin, only they are active cofactors in the metabolism (more on the cobalamin metabolism in ‘Info‘).

Cobalamin supports MTRR function in enzyme mutations.

I have very good experience with taking cobalamin as the unactivated form hydroxocobalamin and sublingual. Since hydroxycobalamin can be activated to both adenosylcobalamin and methylcobalamin you don’t have the problem of taking one form and depleting the other. Also as unactivated form, I have the experience that hydroxycobalamin tends to start methylation slower and deplete other cofactors less.

It might be important to take supplements in sublingual form, so absorption is not too low because of the intrinsic factor. I guess hydroxocobalamin injections should work too, although I don’t have any personal experience with that.
Vitamin C may interfere with vitamin B12 (7,8). Some sublingual B12 tablets contain a vitamin C form as additive. I would be aware that the vitamin C may interact to reduce the effect of B12 when taking these tablets.

Some functions of vitamin B12:

Adenosylcobalamin supports the energy metabolism by helping degrade uneven-numbered fatty acids to Succinyl-CoA (->Citric Acid Cycle). Methylcobalamin regenerates homocysteine with folate to methionine/SAMe. Thereby it supports carnitine-, alpha lipoic acid-, Q10-synthesis in the energy metabolism and histamine breakdown. Methylcobalamin also influences neurotransmitter metabolism.

 

  1. http://www.umm.edu/health/medical/altmed/condition/photodermatitis
    ‘Vitamin C may interfere with vitamin B12, so take doses at least 2 hours apart’
  2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4179674/

 

Folate

Daily requirement: ca. 160µg

There are several folate forms. 5-MTHF (5-methyltetrahydrofolate) is needed to regenerate homocysteine to methionine in the methylation cycle.

10-Formyl-THF is a cofactor in the purine synthesis where the body produces AMP and GMP the precursors of ATP and GTP.

I am a bit unsure about taking folate. I had folate deficiency at one point, but profited more from supplementing vitamin B2 than methylfolate. Also, I have the feeling that methylfolate sometimes increases a feeling of general weakness. Folate has some functions, like stabilizing the binding og MTHFR to the FAD-cofactor (->Theories: Cofactors in mutated enzymes) or being a cofactor in the purine synthesis, which could be important. So at the moment, I’m not ruling it out completly but also not taking methylfolate often.

 

Vitamin C/ Ascorbate

Daily requirement: ca. 75-200mg

Vitamin C supports the immune system. I don’t really know why, except that it is an important antioxidant, but where I come from it’s normal to have vitamin C at home and take some when you have a cold or the flew.

Ascorbate aids the energy metabolism as a cofactor in synthesizing carnitine and has the ability to regenerate vitamin E and Q10. The oxidized form of vitamin C is dehydroascorbate (DHA) which can be recycled by glutathione or alpha lipoic acid. Also ascorbate supports iron absorption and conversion of Fe3+ to Fe2+, making it more active/reactive.

Vitamin C deficiency has been associated with reduced levels of Vitamin D receptors in animal trials (9), so vitamin C might increase the effect of vitamin D in the body. In neurotransmitter metabolism ascorbate converts dopamine to norepinephrine and can recycle tetrahydrobiopterin (BH4), which might increase serotonin and dopamine synthesis.

In my experience vitamin C aided detox and energy levels, but didn’t always have a calming effect and needed other calming supplements to compensate it.

I have read about people taking mega doses of far more than several grams of vitamin C which I would be careful with. You can get overdose symptoms from too much vitamin C. Also, if dehydroascorbate can’t be recycled it gets broken down to oxalate (10) and high oxalate levels in the body increase the risk of kidney stones.

  1. https://www.ncbi.nlm.nih.gov/pubmed/2830915
  2. https://www.researchgate.net/figure/6580036_fig5_Figure-4-Spontaneous-breakdown-of-dehydroascorbate-oxidation-product-of-ascorbate-in

 

Vitamin D

Daily requirement: ca. 5-15µg/ 200-600IU (international unit)

The body can produce vitamin D in the cholesterinbiosynthesis. Vitamin D synthesis also requires UV-B light. Vitamin D is a fat-soluble vitamin and resorption depends on the bile acids. It is found in plant foods (mushrooms) as vitamin D2 and in animal products (fish, cheese, dairy products,..) as D3.

Supplementation can increase glutathione synthesis (glutamate cysteine ligase) and glutathione regeneration (glutathione reductase) (11).

Vitamin D deficiency in rats reduced glucose-6-phosphate dehydrogenase activity by 60%, a pace-setting enzyme in the pentose phosphate pathway that produces NADPH from NADP (12).

  1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4063448/
  2. https://www.ncbi.nlm.nih.gov/pubmed/2596609

https://ods.od.nih.gov/factsheets/VitaminD-HealthProfessional/

 

Choline

Choline and acetyl-CoA form acetylcholine. Choline can be converted to betaine and then methylate homocysteine to methionine in the middle-pathway of the methylation cycle. The body produces choline from the phospholipid phosphatidylcholine. The conversion of phosphatidylcholine to choline is increased by uv-light and calcium (->Info: Choline Metabolism).

Acetylcholine is the main transmitter in the parasympathetic nervous system. The parasympathetic nervous system is almost exclusively cholinergic/ activated by acetylcholine (13).

There are two receptor types that are activated by choline: nicotinic acetylcholine receptors and muscarinic acetylcholine receptors.

Nicotinic acetylcholine receptors (also activated by nicotine) cause calcium and sodium entry into the cell. There are five muscarinic acetylcholine receptor subtypes, three of which stimulate phospholipase C, causing calcium release. The M3-subtype is found in the smooth musculatur of the digestive system and receptor activation leads to contraction of these muscles (14) and supports digestion.

I think sufficient acetylcholine levels are very important in ME/CFS, but my experience with supplementing choline is a bit mixed. While choline hydrogentartrate had a calming effect and also enabled me to do some things I couldn’t have otherwhise, it sometimes induced a feeling of hypoglykemia and weakness. I didn’t actually have any low blood sugar though. Phosphatidylcholine seemed a bit better in that regard, but I think I developed calcium deficiency from it at times.

Here is a list of choline forms found in common foods.

There is no established RDA /recommended daily allowance for choline. The ‘Adequate Intake’ is set at 425mg/day for adult females and 550mg/day for adult males and the average daily intake of choline from foods and drinks is 402 mg in men and 278 mg in women (15).

  1. https://en.wikipedia.org/wiki/Cholinergic
  2. https://de.wikipedia.org/wiki/Parasympathikus
  3. https://ods.od.nih.gov/factsheets/Choline-HealthProfessional/

 

 Copper

Daily requirement: 1-1,5 mg

Copper is a cofactor in the oxidative phosphorylation and methylation (16). It helps regenerate methylcobalamin from cob(I)alamin. Copper also supports dopamine synthesis from tryptamine and conversion to noradrenaline.

Copper binding

Ceruloplasmin is the main copper-binding protein. Its synthesis depends on adrenal and liver function. Copper can also bind to glutathione. In ME/CFS, many people have low glutathione and adrenal dysfunction. This might make copper binding a problem, often leading to bad copper bioavailability or copper toxicity.

Therefore I think it is unlikely to develop sole copper deficiency in ME/CFS and that rather the body’s binding capacity is impacted. If you then take copper, it might bind to glutathione and further worsen antioxidant function. Therefore you might want to carefully think about supplementing copper and rather try to improve the adrenals and glutathione if you feel you have a bad copper metabolism.

 

16. List of copper-dependent enzmes:
https://en.wikipedia.org/wiki/Copper_deficiency#Pathophysiology

 

Magnesium

Daily requirement: ca. 350mg

Magnesium supports glucose breakdown and glucose synthesis. It also activates the pyruvate dehydrogenase complex directly, with calcium. Magnesium is needed for activation of vitamin B1.

In methylation the conversion of methionine to S-adenosylmethionine requires magnesium. Magnesium also supports glutathione synthesis.

 

Zinc

Daily requirement: 15mg

Zinc, like magnesium, is a cofactor in glucose breakdown/ glycolysis and gluconeogenesis. Several methylation enzymes are also zinc dependent. Additionally, zinc is important for the immune system and for copper balance.

Copper and zinc seem to have a bit of an adverse relationship. Copper toxicity can be associated with zinc deficiency. High zinc-doses can deplete copper and at the same time zinc deficiency can cause copper deficiency (17).

Zinc deficiency might impact vitamin D and calcium metabolism. Zinc  deficency reduces the protein expression of vitamin D receptor (VDR) and calcium binding protein in rats (18), which would impact calcium signaling.

17. “Persons who consume diets high in zinc and low in protein are at risk of copper deficiency. ”
https://www.ncbi.nlm.nih.gov/pubmed/6280488

18. https://www.pubfacts.com/detail/16623997/Effect-of-zinc-deficiency-on-the-protein-expression-of-vitamin-D-receptor-and-calcium-binding-protei

 

 

Food Fortifications

Folic Acid

In parts of the United States some foods (mainly grain products) are being fortified with folic acid. Folic acid is the synthetic folate form, it is not found naturally in foods. Folic acid is converted to natural folates that are needed in the metabolism by the enzyme dihydrofolate reductase (DHFR). DHFR requires NADPH as a cofactor (19). NADPH is also a cofactor in enzymes like the glutathione reductase, the methionine synthase reductase (synthesis of methylB12), or the MTHFR enzyme and increased requirement of NADPH by taking folic acid might decrease the availability for these enzymes.
I would avoid folic acid in fotrified foods as far as possible.

Cyanocobalamin

A few foods like soy products or almond milk are sometimes fortified with cyanocobalamin. Cyanocobalamin is  a synthetic form of vitamin B12 that does not occur naturally in foods. To be converted to natural cobalamin forms that the body can use it needs glutathione. The cyanide that is released is toxic and needs to be detoxed by glutathione. Cyanide poisoning usually only happens with very high amounts of cyanide that are not found in cobalamin supplements, but cyanide needs to be detoxed in small amounts nonetheless. Especially in people with chronic illness the capability to detox is often bad and could worsen by taking cyanocobalamin. So I don’t take cyanocobalamin supplements and also avoid fortified foods.

19. http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/enzymes/GetPage.pl?ec_number=1.5.1.3

 

Reference for daily requirements:

https://jumk.de/bmi/vitamintabelle.php

https://jumk.de/bmi/mineralstofftabelle.php

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