Tawinn

Genetic variants in SLC19A1 (G80A), MTHFD1 (G1958A), MTHFR (A1298C, C677T) cause a reduction in methylfolate production,, and low B2,B3,B6,B9,B12,zinc can also worsen methylfolate production. These reductions in methylfolate production impairs methylation via the folate-dependent methylation pathway. Symptoms can include depression, fatigue, brain fog, muscle/joint pains.

Your compound heterozygous MTHFR reduces methylfolate production by ~53%. Without the compensatory choline/TMG listed below you will be in a state of undermethylation.

Optimal homocysteine is 7-9.

Impaired methylation can cause the COMT enzyme to perform poorly, which can cause symptoms including rumination, chronic anxiety, OCD tendencies, high estrogen. These effects can be amplified when one has slow COMT (V158M of 'AA' or 'Met/Met')).

Impaired methylation can also cause the HNMT enzyme to perform poorly at breaking down histamine, which can make one more prone to histamine/tyramine intolerances, and high estrogen increases that likelihood.

See the COMT and MAO-A sections of this post for more about COMT and histamine intolerance.

The body tries to compensate for the methylation impairment in the folate-dependent methylation pathway by placing a greater demand on the choline-dependent methylation pathway. This increases the amount of choline + TMG needed to support this extra demand. A homozygous PEMT (5465G>A) will also increase this demand.

Here is a general protocol:

• 550-600mg of choline, preferably from food

  • 550mg is the baseline adult Adequate Intake

  • Choline sources include such foods as meat, eggs, liver, lecithin, nuts, some legumes, and vegetables such as crucifers.

• 750mg of trimethylglycine (TMG aka betaine)

  • I.e., one 750mg capsule

  • Choline is converted to TMG for methylation use, so TMG reduces need for even more choline.

• 400-800mcg of folate, preferably from food

  • Folinic acid or methylfolate can also be used, as needed and as tolerated.

  • Target serum folate levels are 15+ ng/mL (34+ nmol/L).

• 2.4-10mcg B12, preferably from food

  • Past history of B12 deficiency, malabsorption issues, etc., may suggest that supplemental B12, in the form of hydroxocobalamin, adenosylcobalamin, or methylcobalamin may be prudent.

  • Target serum B12 levels are 500-950 pg/mL (~370-700 pmol/L).

• (Optional) 3-15g of creatine monohydrate or creatine HCL

  • The body uses ~40% of methylation output, SAM, just to produce creatine. So supplementing creatine can free up a lot of SAM for other uses.

• Low vitamin A, iron, and/or glycine can cause the built-in methyl buffer system to not work properly, which can make overmethylation (rising anxiety, irritability, insomnia, etc.) from methylation-related supplements much more likely.

  • Beta carotene is not vitamin A and some people genetically have poor conversion of beta carotene to real vitamin A (retinol).

A food app like Cronometer is helpful for tracking nutrients in your diet.

RBC folate is a good measure of longer-term folate status. So it indirectly shows whether or not there is enough folate for methylation use. Folate or B12 deficiency will impair methylation, so repleting folate will help methylation. Folinic acid is generally more well-tolerated than methylfolate.

Could be due to high histamine. It is an important excitatory neurotransmitter, and at night the body can try to rid itself of excess histamine with "histamine dumping". Due to its excitatory nature, this causing waking in the middle of the night.

When methylation is impaired, intracellular histamine breakdown is reduced, resulting in higher histamine levels; so its easier to overflow your "histamine bucket" when symptoms start appearing. Search for "insomnia" on r/HistamineIntolerance and see if those stories match your experience.

See the MAO-A section of this post for more on histamine intolerance.

As for methylation, please upload your data to the Choline Calculator to check a few more genes related to methylation. Reply here with the results.

I'm not well-versed on benfotiamine reactions, but a quick search turned up a similar report, which was in a mold exposure subreddit, which is interesting given your high mycotoxin levels.

Although in the comments of that post someone mentions that B1 is a histamine liberator (I don't know if that's true or not), I wonder if it has more to do with the sulfur pathway, as both molybdenum and B1 are needed for the conversion of sulfite to sulfate. Sometimes sulfur symptoms look a lot like histamine symptoms, but your symptoms seem more aligned to sulfur intolerance than histamine intolerance. Further, benfotiamine itself is a source of sulfur.

So one speculation is that supplying the benfotiamine form caused excess sulfur load, and if there is inadequate molybdenum then that cannot be processed to sulfate, resulting in symptoms.

Elliot Overton, who's really focused on B1 and its use, has an article on paradoxical reactions to TTFD where he describes using selenium and B2 to avoid glutathione depletion. My guess is that the larger doses typical of benfotiamine are supplying more sulfur than the typical much smaller doses of HCL or TTFD form. So, adding molybdenum, selenium, B2 may facilitate switching to low-dose TTFD instead of benfotiamine with less side effects. Just a speculation.

I don't know what might be causing the high B12. A FUT2 variant typically causes ~20% excess level on average, so if you had that variant then your "actual" level might be ~1600pg/mL. Still high, but the folate deficiency could then account for the high level due to under-use of B12 in the methylation cycle.

What type of insomnia - difficulty falling asleep or middle of the night waking?