High Dose Thiamine [Article on EonNutrition]

[godlovesatrier]

This article on EonNutrition discusses the use of High Dose Thiamine on enzyme processes in the body (Recently mentioned In Cort's HR article. Even if a deficiency isn't present high dose Thiamine appears to exert influence over several enzyme processes. It also discusses KGDH which was mentioned in the study posted on PR here last week.

Date: Nov 2020

https://www.eonutrition.co.uk/post/mega-dose-thiamine-beyond-addressing-deficiency

Author: Elliot Overton

The below quotes are abstracted from the main article:

Overview: " I have since come to the conclusion that one does not need to be deficient (in the nutritional sense) to benefit from this type of therapy, because high-dose thiamine is not simply working by correcting nutritional deficiency. Rather, thiamine is functioning as a metabolic stimulant to restore oxidative energy metabolism in cells that has been inhibited by factors unrelated to nutritional status. "

A key enzyme involved in mitochondrial energy metabolism called alpha ketoglutarate dehydrogenase (KGDH). Several nutrients serve as cofactors for this enzyme complex, with thiamine taking center stage. KGDH is a rate-limiting step in in the TCA cycle, meaning that when this enzyme slows down, every other downstream step also slows down. Whilst a deficiency of any of the necessary cofactors will reduce the activity of this enzyme, it is also exquisitely sensitive to oxidative stress.

By saturating the cell, you can bypass the low affinity and restore enzyme function back to its normal state. Extremely high doses are often required to achieve this effect and this therapy must be maintained lifelong.

Examples of nutrient-responsive genetic conditions include:

• Thiamine-responsive maple syrup urine disease: A genetic defect in the branched chain ketoacid dehydrogenase enzyme results in remarkably low affinity for its coenzyme TPP. Continued high doses are necessary restore the function of this enzyme complex.
• Thiamine responsive Leigh’s disease: Inherited mutation in the gene encoding Pyruvate Dehydrogenase, with a decreased affinity for its TPP cofactor. Treated with pharmacological doses of thiamine to stimulate defective enzyme activity
• B12-responsive Methylmalonic acidaemia: Genetic defect encoding the methylmalonyl-CoA mutase enzyme, causing low affinity for adenosylcobalamin cofactor and a pathological accumulation of methylmalonic acid. This condition can be treated with megadoses of B12.
• Biotin-responsive holocarboxylase synthetase deficiency: Genetic mutation renders biotin-responsive carboxylase enzymes much less able to bind with biotin cofactor due to markedly decreased affinity. Supraphysiologic doses can restore normal enzyme function
• B6-responsive homocysteinuria: A rare defect in the cystathionine-B-synthase enzyme reduces affinity for its coenzyme pyridoxal-5-phosphate. This leads to the toxic buildup of homocysteine. Mega-doses of vitamin B6 can return enzyme activity back to normal.

It is worth noting at this point that these genuine genetic defects are extremely rare and are not applicable to the large majority of people. However, similar principles can also be applied when an enzyme has been inactivated by other factors.

However, administering massive doses of thiamine to the rats before TBI was able to completely protect the KGDH enzyme. The thiamine-treated group maintaining normal activity of KGDH, mitochondrial respiration, and ATP despite being exposed to the injury.

Furthermore, the restoration/protection of KGDH might have also conferred some degree of cytoprotection by combating inflammation, which was demonstrated by reduced inflammatory gene expression at 3 days post-TBI.

Human evidence

The late Italian neurological A. Constantini published several case studies on the use of mega doses of thiamine for different conditions and saw impressive results.

In one of the case reports on fibromyalgia, two patients saw an abrupt and immediate improvement only when they reached 1,800mg per day. At lower doses, improvements were negligible.

Constantini hit the nail on the head with one quote from another paper:

“ We may suppose that symptoms decrease when the energetic metabolism and other thiamine-dependent processes return to physiologic levels. Our aim was not to correct a systemic deficit of thiamine, but rather to increase the activity of enzymes involved in cell production energy in selective brain regions; ​

Thiamine and benfotiamine supplements

exhibit “anti-stress” properties in the brain, protecting against stress induced suppression of hippocampal neurogenesis. These effects stem from anti-oxidant, rather than coenzyme roles.

Here are a list of some of the non-coenzyme targets of high dose Benfotiamine:

 

[nerd]

1,800mg per day

If only 1800mg help, there has to be a more direct way to achieve the same effect.

Here is a piece I wrote some time ago in the context of the potential neuroexcitotoxicity of Ivermectin.

Thiamine is an essential cofactor of α-ketoglutarate dehydrogenase, which catalyzes α-ketoglutarate to Succinyl-CoA, and pyruvate dehydrogenase, which breaks down pyruvate to Acetyl-CoA, which ensures that glucose metabolites are integrated into the citric acid cycle (CAC). This ensures that α-ketoglutarate is readily available after glycolysis and glutamate utilization (10.1007/s13312-019-1592-5). This utilization depends on the metabolic phase and cognitive enablement. Without thiamine, the CAC will be blocked and channeled into the GABA pathway due to the accumulation of α-ketoglutarate. This causes a short excitatory phase and a subsequent long inhibitory phase with potential excitotoxicity since the CAC can not balance but only replenish glutamate levels then (10.1111/nyas.13919). The blocked CAC will additionally reduce ATP availability.

There is a third thiamin-dependant enzyme, i.e. transketolase, in the pentose-phosphate pathway (PPP). If transketolase is impaired due to thiamine deficiency, the recycling of cytosolic glutathione levels via the 6-phosphogluconate dehydrogenase can not contribute to ER function and protein secretion via VCP (10.1016/j.chembiol.2019.05.006). Additionally, Glucose-6-phosphate could not sufficiently be recycled from 6-phosphogluconate, which makes glycolysis the only Glucose-6-phosphate source. Thereby, glutathione recycling and the lipid metabolism become dependant on glycolysis.

Also, this glycolysis-channeled utilization of the PPP without transketolase recycling will lead to a buildup of ribose-5-phosphate, erythrose-4-phosphate, and xylulose-5-phosphate, which can be catalyzed to ribose-5-phosphate as well via isomerase and epimerase (10.5653/cerm.2012.39.2.58). The buildup of erythrose-4-phosphate only serves pathogens that encode the shikimate pathway and can utilize this metabolite as an energy source. The buildup of ribose-5-phosphate can be compensated by the human metabolism by channeling it into the purine and pyrimidine pathways.

To summarize the effects of TD on the PPP, it causes mitochondrial dysfunction, disrupted protein synthesis, makes glutathione recycling and lipid metabolism dependant on glycolysis activation, thereby impairs the endogenous response to oxidative stress, and it might also provide energy to certain pathogens. This affects myelin sheaths in particular and thereby opens a door for neuropathy (10.1172/JCI106727). Via glycolysis and the CAC, TD causes a neurotransmitter imbalance with potential excitotoxicity and reduces ATP availability. Long-term TD also reduces glutamate and GABA levels and makes glutamate replenishment dependant on glutamine.

So it's not just the citric acid cycle. There are three Thiamine-dependant enzymes that originate from energy utilization pathways (i.e. normally glycolysis). Which of the three is really the problem or is it just the general hyperactivation of glycolysis and the mitochondrial dysfunction in CFS/ME patients that causes the problems?

Credits: 10.1016/B978-0-12-815245-4.00027-2

 

[pamojja]

If only 1800mg help, there has to be a more direct way to achieve the same effect.

Considering the low side-effect profile of 1800mg thiamine and easy availabilty, what could be more straight-forward?

I've experimented with 1350mg of thiamine since about half a year, along with 250mg of benfotiamine I already took (and some seem to think 5-times as effective). Nothing spectacular to report yet, though I already had remission from PEMs 3 years ago.

Only was worried this year when I run out of LDN (before always bought on vacations in India) its most direct effect in me - reduction of excessive sleeping need >10 your - would deminish. Didn't happen.

 

[nerd]

Considering the low side-effect profile of 1800mg thiamine and easy availabilty, what could be more straight-forward?

I gave it another thought. If very large doses of thiamine help, then it's most likely the depletion of a precursor of a thiamine-dependant enzyme. This precursor has to have multiple catalytic pathways and the other pathways except for the one of the thiamin-dependant enzyme have to be prevented to avoid overall depletion of the whole cycle in that this enzyme participates. This would be consistent with the following theories:

1. An overdemand of alpha-ketoglutarate prevents sufficient dehydrogenase. The thiamin-induced increased enzymatic activity would force it to stay in the CAC. The side effect would be a depletion of glutamate and GABA pathways.
2. NAD+ dysbalance prevents sufficient pyruvate to be properly oxidized. Hence, pyruvate accumulates and the CAC isn't properly refueled, gradually depletes consequentially. The thiamine-induced increased enzymatic activity would prioritize NAD+ utilization for pyruvate oxidation. The side effect would be a decreased NAD+ availability for other metabolic pathways, such as the methylation cycle.
3. The NADP to NAD+ ratio is too high due to heterogeneous Niacin deficiency (IDO trap). The increased thiamine-induced Transketolase activity can force Ribulose-5-phosphate to recycle through the PPP and not stay in the Ribose-5-phosphate state to participate in the PRPP. Hence, the NAD+ to NADP ratio increases. The side effect would be a reduced NADP cycle buffer, which has many crosscutting functions in the metabolism. But this can be compensated by taking D-Ribose.
4. There is insufficient ATP available. The increased thiamine-induced Transketolase activity can force Ribulose-5-phosphate to stay in the PPP and not be metabolized to Ribose-5-phosphate. Hence, GMP synthase activity is reduced and thereby less ATP is consumed for glutamate synthesis. The side effect would be a reduced NADP cycle buffer, which has many crosscutting functions in the metabolism. Moreover, glutamate would have to be provided by other sources, e.g. from the CAC, which is impossible at the same time due to increased KGDH activity. I think this is the least likely case because the overall potential of total ATP alteration by GMP synthase is low.

 

[godlovesatrier]

In my own experience I hit 1200mg today and that was the first dose where I noticed a big difference. I could feel my muscle cells literally being energised (almost akin to a good meditation session) so maybe this was simply extra oxygen getting driven into the mitochondrial cells. It was a really nice feeling. Whereas 800mg a day just made me feel very spaced out like I was floating/in a daze. I therefore found this writeup about the mode of action and studies really interesting.

 

[nerd]

@godlovesatrier I have a suspicion of what happens when you experience side effects of after a certain period or when hitting a different dosage target. May I ask how exactly the neurological side effects manifest and how the headache feels? Do you feel tired or excited at the time?

 

[godlovesatrier]

Yes so I should update my original post really. This must be day 14 or something. I've titrated down to 600mg a day while I try to figure things out. Amazingly I am still almost entirely PEM buffered. Sadly I have been getting exceptionally tired (falling asleep more or less) from 5pm and then either just conking out at 8pm or 9. Normally I go to bed at 10pm every single night and have been doing this for about 3 years. So to not be able to get to 10pm is for me not routine. I find melatonin keeps me asleep most nights, unless I'm immune stimulated in which case I wake up about 6am starving and/or wide awake.

As for the neurological side effects from thiamine. The first 5 or 6 days as I titrated up I felt spaced out, I am having difficult explaining it any better than that sadly. I just felt drugged/dazed. Not sedated though, not that sort of dazed. More like my brain is doing a lot more active operations than normal.

After I hit the higher dose and tested my PEM limits, I eventually only crashed from a high level of exertion. I then started to feel spaced out again, but also began to suffer with headaches that felt like sharp electric shocks that would just tear down one side of my head (mid brain). This came on in the evening.

Symptoms changed a bit 4 days ago to become muscular pain (pulled muscle pain and stiffness throughout my back and into my shoulders neck and shoulderblades). Not sure if this was a product of aerobic respiration or tiredness from the body being pushed beyond what it can normally do. Suffice to say I didn't have any headaches on those days I just fell asleep about 8 or 9pm on multiple occasions. Every day the tiredness got worse.

Until yesterday I took some aco b12 (transdermal oil) and almost all my symptoms vanished. Took quite a few things to get to sleep last night, woke up thismorning feeling pretty hungover to be honest (but that might be the nytol+B12 over stimulation).

I should say I've got a few things in the mix each day, probiotic, thiamine, a little zinc, a little selenium // 500mg glycine and 3000mg omega 3 before bed.

I also took some potassium today just in case my potassium was going low. However Mary and Fred's posts point out that refeeding syndrome can't possibly be happening 5-9 days after starting something. Refeeding syndrome occurs within 3-4 days of starting something. Even so the b12 appeared to be needed, which it isn't normally (I take it once a week/month).

I have felt a little wired but tired yes, but not as bad as some other things have made me feel. However this is probably because I have lowered the dose. I reckon if I had stayed at 1200mg a day, I would have been very giddy, but very very tired.

 

[sb4]

@godlovesatrier You might want to look up what people have written on paradoxical increases in symptoms with high dose thiamine. Think maybe Dr Lonsdale has writ on it as well as others. Its something to do with certain symptoms increasing before they get better. Cant remember if the advice was to power through or to use cofactors.

I didn't read too much about it as I never had that problem. My problem was noticing good effects that vanished after 2 / 3 days.

 

[godlovesatrier]

Yeah 2 to 3 days could definitely be refeeding syndrome according to Fred. Thank you! I wasn't aware of him. I'll get to reading

 

[godlovesatrier]

@sb4

This backs up what I was saying about thaimine calming me down (only when I first take it) and seperately causing me to no longer get woken up at night by the slightest noise or sound. This fight or flight response seems a constant in ME patients. I've been able to sleep with my partner all week and haven't woken up due to this particular issue. Which is really interesting:

https://www.vitality101.com/nutrition-guide

 

[godlovesatrier]

@sb4 Found it

Thanks so much for making me aware of this. Hopefully it will help.

 

[sb4]

@godlovesatrier Are you in the same boat as me now where thiamine has no effect even with mega doses? I know I asked this early but couldn't find my answer in this thread.

 

[godlovesatrier]

Yep. No effect anymore. Based on my experiments in b12 land maybe thiamine levels get too high and the body looses equilibrium. Might not be a cofactor issue.

I think several other people also all had the same effect. Felt great for a few days...symptom free. Then everything came right back.