Yes i've had PEM before I started taking this dose. I usually ramp up my doses of everything for the winters here anyway, this time I just decided to take much more cos the 15mg dose of it was at least able to to keep the SAD away.
I started in Nov I would say. I nvr believed that methylation was the issue but at these higher doses it virtually eliminated all the chronic fatigue. I take mb12 at a half the amount of whatever mfolate I take and I take p5p too. So i really focus on B6,9,12 all in their active forms. I make sure I take the mfolate freely but I notice that it works out to 90-120mg for me. If you drink a cup of coffee you get about 100mg of methyl groups straight away from caffeine - a methylxanthine. No guarantee that it goes where it is supposed to.
The reason I ask is because this could be helping in 3 ways 1. methylation, which I doubt. 2. purine synthesis to increase ATP and NAD pool, but without extra niacin or niacinamide, it probably isn't making so much difference in the NAD pool, and in our experience, you have to take the other ingredients for purine synthesis for it to keep working or you run low on either glutamine, glycine (probably not glycine if you are taking extra B6) or aspartate, or 3. You are using the folate pathway to produce ATP. There is a danger in using this pathway, but it takes time to do damage so if this is the case with you it might not have had time to change your symptoms, or you may not even get symptoms from it, OR you might not get new symptoms for years. This is all according to my hypothesis, of course, I don't have proof. Take a look at this, maybe you have already seen this because I have posted it before.
There are a couple of pathways in the folate cycle that can produce ATP. If you use the SHMT patheway it produces glycine, but might use up B6. This pathway produces 1 NADPH.
If you use this pathway for a while the glycine will be building up and you will start using the glycine decarboxylase pathway (which is only in the mitochondria), but that will increase ammonia, and getting rid of the ammonia takes several ATP. This pathway makes 1 NADPH, too.
If you use the little pathway shown in the enlarged box, you use up 1 NADPH for each ATP produced. You can use this pathway both in the mitochondial matrix and the cytosol, as far as I know. This will drain both the NADPH made by the Pentose Phosphate Pathway, and the NNT enzyme and the other enzymes in the matrix which produce NADPH.
Since NADPH is required to recycle glutathione, oxidative stress will increase, and this will gradually increase the amount of damage to the electron transport chain enzymes, leading to increased dependence on the folate pathway for energy.
Eventually you may start experiencing symptoms that relate to low NADPH, specifically symptoms caused by nonfunctioning catalase, because catalase depends on NADPH to stay in a functional form.
This is especially relevant to you because you experience SAD. NADPH is needed for recycling BH4, and BH4 is needed for synthesis of serotonin and dopamine and the other catecholamines. The folate pathway is one of the main ways that BH4 is recycled, as you can see in the illustration, so taking a lot of it helps.
BUT after a while the amount of NADPH being drained through the folate pathway of ATP production becomes high enough to interfere with the dopamine beta-hydroxlyase enzyme which changes dopamine to norepinephrine, and in some people low noripinephrine causes depression, at least I think that is the case with my son D.
After a bout with the Epstien Barr Virus, my son D had extreme fatigue (all the time and without PEM) for well over a year before we started giving him high dose methylfolate. The large dose of folate made his fatigue go away in a few hours, but after 4-6 weeks on high folate he started having symptoms of depression which eventually became very severe. I have spent the last two years working on figuring out why this happened and what I have written above is my conclusion about how it happened.
If you can tolerate it, you might be able to take the NAD recipe to avoid needing so much folate. I am in the process of trying to figure out if this solution also increases damage to the ETC or not.
At this time I think the low norepinephrine is one of the factors that leads to the damage in diseases like Alzheimer's, which probably takes years before symptoms are noticed, so if I am correct, and I don't have proof that I am.