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16 Nov, 13 tweets, 4 min read
Normally in undermethylation we see decreased levels of serotonin and dopamine activity at their receptors, since higher levels of DNA methylation can inhibit the reuptake of these neurotransmitters

This "mimics" the effects of SSRIs and DRIs to some extent

However this can also be paired with more adrenaline and noradrenaline through a separate mechanism, where methyl groups are required to metabolize adrenaline

Because of this when methyl groups are depleted we see lower levels of metanephrine, an adrenaline metabolite
One of the main causes of niacin toxicity is the depletion of methyl groups, since niacin forms methyl-nicotinamide in the liver

This is paired with more adrenaline/noradrenaline, less betaine (a methyl donor in the liver), and high levels of homocysteine…
I talk a lot about the mental impacts of these methylation imbalances, but they can also contribute to metabolic issues ranging from heart disease to insulin resistance

This is a good overview of the pathways involved… Image
As the article mentioned above describes, there's often an under-appreciated role of methyl depleting compounds in these pathologies

For example, niacin raising homocysteine may increase the risk of heart disease, even though niacin simultaneously lowers LDL and raises HDL
This seems to explain the neutral results found in niacin clinical trials for heart disease treatment, it was originally considered very promising but in the end it doesn't seems to raise or lower risk much at all…
This may just be because individual differences in methylation status, homocysteine level, and lipids

For some perhaps niacin does lower heart disease risk, while in undermethylation perhaps it raises it, so on average the effect appears neutral
Undermethylation likely also explains the counter-intuitive ability of niacin to induce insulin resistance….

This again seems to tie back to the pathway chart above and its ability to regulate gene expression
To a lesser extent, folic acid can also act as a methyl-depleting agent since it has to be converted into methylfolate

I was curious to see if it would induce similar effects as niacin, but it turns out folic acid lowers homocysteine via the MTRR pathway…
This is just because folate acting as a cofactor for this pathway has a bigger impact on homocysteine than the small amount of methyl depletion that occurs

To get the best of both worlds I'd still prefer methylfolate in cases of methylation issues or elevated homocysteine
Folic acid also seems to improve insulin resistance, which also comes down to the positive impacts on methylation outweighing any negative impacts, at least in most individuals
(again, methylfolate is still optimal)
I think the moral of the story is that if you're going to take high doses of niacin for any reason, especially long term, you'd better make sure your methylation status is in order beforehand
If you take it I'd monitor homocysteine periodically and supplement with betaine and/or get extra dietary choline, since betaine will be depleted

And if you have symptoms/bloodwork of undermethylation, I'd avoid higher doses of niacin completely until you get things balanced out

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More from @ck_eternity_

16 Nov
Niacin deficieny causes tryptophan to be funneled away from serotonin production into endogenous niacin production

Some of the intermediates in the conversion are neurotoxic, especially quinolinic acid which imitates excess glutamate Image
This is often implicated in schizophrenia pathology

These intermediates are created due to lack of niacin stemming from dietary deficiency or higher demand to drive essential reactions like NAD+ creations
Reducing the formation of quinolinic and kynurenic acids is also one of the mechanisms through which niacin supplementation significantly improves some cases of schizophrenia

This seems to be especially useful in cases of overmethylation
Read 4 tweets
26 Oct
If we look at the structure of cytochrome C oxidase, the rate limiting protein in energy production in mitochondria, it becomes obvious why light is so important

The heme and copper cores act as chromophores absorbing light and using it to excite electron transfer
If we compare the structure of chlorophyll (left) with hemoglobin (right) there is a distinct similarity

Both contain similar structures that harness light to drive redox reactions, this works via the photoelectric effect where the energy of light is transferred into electrons
Cytochrome C oxidase is the last protein in the electron transport chain, which operates by using a current of electrons to drive ATP production

It's absorption peaks in the 630-670nm range, red light, which is the part of the spectrum that penetrates the farthest into the body
Read 6 tweets
25 Oct
It's important to note that with ideal digestion you only absorb something like 60% of the B12 RDI per servings

So for resolving deficiency, sublingual B12 may be necessary, and for maintenance 2-3 meals containing B12 are necessary to prevent deficiency
With bowel inflammation disorders like IBS, B12 absorption is even more impaired

It's also usually necessary to include a combination of oral methylfolate with sublingual B12 to avoid the methyl trap, especially with high doses
For sublingual B12 either the activated methylcobalamin or a combination of the methylated form with adenosylcobalamin works best

Methyl-B12 drives methylation, while adenosyl-B12 is used primarily in mitochondria
Read 4 tweets
15 Oct
Parvalbumin may be another reason for the added benefits from eating whole seafood rather than fish oil

It is produced endogenously, and plays a role in photoreceptor activity, neurogenesis, muscle contraction, memory formation, stress response, and neuroprotection
It does seem to be at least somewhat orally absorbed since it is one of the mediators of fish allergy (but not shellfish)

As long as you're not allergic to seafood however it may still be absorbed but instead may be redistributed into various tissues
Most parvalbumin is likely broken down into amino acids during digestion, similar to what occurs when you take a collagen supplement, but the benefit may be more in providing higher amounts of the same amino acids used specifically for parvalbumin synthesis
Read 5 tweets
11 Oct
When megadoses of vitamin D supplements are taken orally, the body may actually shunt conversion away from the active form of vitamin D (1,25D), instead increasing production of its analogs in the epi-25D pathway
These analogs are significantly less calcemic, so this shunt may be used to minimize increases in serum calcium seen with excess vitamin D

Unfortunately this pathway has not been studied in humans, but we see this consistently in studies in rodents with supplemental vitamin D
Infants also demonstrate a higher ratio of epi-25D to 1,25D and 25D (aka D3), perhaps to preserve calcium in the skeletal system as much as possible during early development
Read 8 tweets
11 Oct
Bowel flush from high doses of magnesium is caused by excess of it reaching the large intestine/colon

Magnesium is hydroscopic, so it draws water more than other minerals, and past the small intestine there is almost no ability to absorb it so it pulls water into the bowel
The flush reaction is directly proportionate to the unabsorbed magnesium fraction

This also plays a role in why forms that are less soluble in water like magnesium hydroxide, citrate, or oxide, are the most laxative as they are the least well-absorbed
The solution to minimize flush is to opt for more soluble forms like magnesium chloride, and to space out intake as much as possible throughout the day

I like to fill a liter jar with water and add 1-2tsp mag chloride to gradually drink, start small (~0.5 tsp) and taper up
Read 4 tweets

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