First try at Active Protocol and have questions.

[CCC]

1. So your son was taking 100-200 mg FMN per day? I am guessing this was in multiple 25 mg doses throughout the day.

Correct.

2. Did you notice any difference between the sublingual and oral tablet? Which was more effective?

Initially the sublingual FMN was the only effective option, but he switched to the oral B2 after a few months. I was happy to make the switch for the sake of my son's teeth. He'd try the oral B2 every now and again, and after a few months on the sublingual FMN, the cheaper oral B2 suddenly felt like it did the same thing.

3. What brands are recommended?

We used this one for the sublingual: https://au.iherb.com/pr/source-naturals-coenzymated-b-2-sublingual-60-tablets/1036

For the oral, we use any tablet that has just B2. In Australia, that gives us only two brands to choose from: one brand at one local health food shop, and one brand on iherb. They're 100mg tablets, so my son splits the pills into quarters.

A note about B2 and folinic in this house
Taking the B2 with folinic acid gives the best results here. They seem to work together. Many people here can't tolerate folinic, but my son feels like it does something the methylfolate can't quite manage on its own. As I've said before, he still takes a 5mg does of methylfolate just before going to bed.

 

[JasonUT]

I started February 16 with the active methylation protocol. I had been trying hydroxo-B12 for about 4 months with very little improvement. I took the hydroxo-B12 route due to the my many COMT SNP variants.

So this is the start of week 6 and it continues to be a mixed bag of symptoms. Some good, bad, and strange. But I can say with confidence that things are definitely changing.

The Good:
1. Energy continues to improve.
2. Sleep continues to improve. I feel like I am starting to get a restorative type of sleep.
3. BP still continues to be better. From 100/65 to 115/65
4. Averaging about 98.6F. Body temperature is 98.6+ in the late afternoon.
5. I haven't had chills in several weeks. I actually am getting warm and find myself sweating when I start using this new increased energy.
6. Overall, I am feeling more relaxed, but I have these brief "episodes" that feel different and strange.

The Bad:
1. Aches and pains in muscles and joints.
2. Flu-like body aches
3. Sore throat
4. Abdominal Aches and Pains

The Strange:
1. I have these strange "episodes" where I suddenly feel sleepy. It's not fatigue. It's actual sleepiness, lay down take a nap sleepiness. It happens suddenly and randomly.
2. I also have these strange emotional "episodes" that remind me of the "windows" and "waves" that happen during benzo or SSRI withdrawal. They happen a few times per day and last between a few minutes and 1 hour.

I added FMN sublingual at breakfast and lunch in week 5.

Overall, it is difficult for me to say if the methylation protocol is working or if I am on the correct path. I must remind myself that this may be a 12+ month marathon.

 

[CCC]

With the FMN sublingual - are you yet excreting the excess?

 

[JasonUT]

With the FMN sublingual - are you yet excreting the excess?

@CCC

I don't think so.

 

[JasonUT]

OAT and L-Carnitine Analysis: This post will focus on markers which relate to L-Carnitine in my 5/26/2015 OAT.

3-Methylglutatic is High at 0.40 (Range is 0.02 to 0.38) - "Small elevations may be due to impairment of mitochondrial funcion... Supplement with CoQ10, NAD, L-Carnitine and acetyl-L-Carnitine, riboflavin, nicotinamide, biotin, and vitamin E"

Suberic Acid is High at 4.3 (Range is < 1.9) - "...is consitent with overnight fasting or increased fat in the diet. Regardless of cause, supplementation with L-Carnitine or acetyl-L-carnitine may be beneficial." Suberic acid appears to be a product of oleic acid [Source]. Oleic acid is also known as Omega-9 and commonly found in food oils [Source].

Here is an old post from Rich VK with regards to L-Carnitine and Omega Fatty Acids:

I just want to note that several studies have shown that carnitine is low in ME/CFS. I think the reason is that methylation is required to make carnitine in the body. One of the main roles of carnitine is to usher fatty acids into the mitochondria of cells to be burned as fuel. In the urine organic acids test results that many people have posted or sent to me, I usually find that the fatty acids markers are showing buildup of omega oxidation of fatty acids, which occurs when there is a carnitine deficiency. Under these conditions, it makes sense that your muscles would respond to carnitine supplementation, since it raises the supply of fuel to their mitochondria. When the methylation cycle partial block has been lifted, the cells should be able to make enough carnitine for themselves.

 

[pamojja]

My questions:

2. Active Protocol seems to suggest 50 mg Zinc per day. Should this be offset by copper to maintain a certain ratio? My current intake of Zinc/Copper is 31mg/3.5mg. By the way, I have some random prostate pain.

Though I actually never had negative side-effect from supplements (other than many here seem to have), the one exception is zinc above 60 mg/d, which gives my headaches after some time. Therefore started some copper to balance. However, already 2mg per day already after some time drove copper levels too high (serum, whole blood and hair tissue) and zinc down again, despite continuing supplementation.

The reason might be that I already got 4.2 mg/d of copper, but only about 13 mg of zinc from diet (measured and calculated dietary nutrient intake for quite some time to get an idea for it's weaknesses). The ideal ratio I read somewhere is zinc : copper = 10 : 1. Thereby found out that holds true for myself, but only after factoring in the dietary intake additional to supplemental.

 

[JasonUT]

Notes to self with regards to K+ deficiency symptoms. The following appear to be my symptoms, but more trial and error needs to occur before any clear conclusions can be drawn.

In order of symptom onset:
1. Tightness in arches of feet and thighs
2. Abdomnal Pain
3. Low appetite and nausea
4. Light headed and dizzy
5. Abnormal heart rhythms
6. Lowered body temperature and chills
7. Emotional changes, instability

Hard stools may be a latent indicator of the previous day's low K+ level. Also, potassium gluconate seems to have a hint of sweetness when I need it.

 

[JasonUT]

OAT and Krebs Cycle Analysis Post 2: The post will focus on my layman's analysis of my OAT in relation to a possible Krebs Cycle dysfunction.

Looking at my OAT in greater detail I noticed that my 2-oxoglutaric is low in the 2SD range and Aconitic is slightly elevated, but still in the 1SD range. Looking at the Krebs cycle it appears that cis-Aconitate goes to D-Isocitrate and then to a-ketoglutarate (aka 2-oxoglutaric).

Water and NAD+ appear to be the only two inputs into these steps in the process. So NAD (aka B2) pops up again.

Is this even more evidence that I am deficient in B2 and FMN supplementation will help?

It appears I made a mistake in this post. NAD is not Vitamin B2 vitamin. It appears NAD is related to Vitamin B3. Therefore, when looking at my OAT from 5/26/2015: Aconitic Acid is elevated and 2-Oxoglutaric (aka alpha-Ketoglutaric acid) is low. NAD+ is used in the reaction.

Precursors to NAD+ are [Source]:

• Nicotinamide Riboside (NR)
• Tryptophan (L-Trp)
• Nicotinic Acid (NA, Vitamin B3)
• Nicotinamide (NAM, also called no flush Niacin)
• Nicotinamide Mononucleotide (NMN)

I don't know if this is important for me yet. As of today, I am supplementing with:
500 mg Tryptophan at bedtime
25 mg Nicotinic Acid at Lunch
100mg Nicotinamide at Lunch
10mg Niacin at Breakfast
15 mg Niacinamide at Breakfast

 

[JasonUT]

So this is the end of week 7 and it continues to be a mixed bag of symptoms. Some good, bad, and strange. But I can say with confidence that things continue to change.

Good:
1. I feel more relaxed.
2. Moderate Sleep improvement. Feel more rested in the morning.
3. More energy
4. Improved cognitive function

Bad:
1. Aches and pains have increased a lot
2. Abdominal Aches and Pains
3. Low Appetite and Nausea

Strange:
1. The emotional "windows and waves" pattern seems to be diminishing a bit, but is still present
2. I have started waking up again at 4-5 AM feeling achy and nauseous.

Conclusions: I added sublingual B2 at breakfast and lunch on 3/20 and it continues to be a success. I think yesterday I saw a hint of B2 saturation in urine. I tried LCF at 62.5 mg at breakfast. It gives me more energy within a few hours, but it seems like it might be starting "refeeding syndrome." I have stopped for now while I research "refeeding syndrome."

 

[JasonUT]

Refeeding Syndrome and Me: This post will focus on my layman's understanding of "refeeding syndrome" and how it may apply to me. I don't think I am breaking new ground with this post. Just trying to tie some of this together.

Hypothesis: I am borrowing a hypothesis that have been brought up by many. Feeding the cells the correct form of nutrients it needs causes a starved and damaged cell to start healing and working. This could lead to "refeeding syndrome" at a functional cellular level.

What is Thiamine?
"Vitamin B1, also called thiamine or thiamin, is one of 8 B vitamins. All B vitamins help the body convert food (carbohydrates) into fuel (glucose), which the body uses to produce energy." [Source]

Research Notes:
1. NICE guidelines lists Thiamine, Phosphorous, Magnesium, Potassium as critical nutrients to monitor for "refeeding syndrome." Multi-vitamin, B-complex, and Thiamine are the the critical first nutrients. Thiamine should be given at initial loading dose of 200-300 mg daily for 2 weeks. Monitor electrolytes. [Source]

2. I decided to dive into Thiamine deficiency in greater detail. "Early symptoms are nonspecific: fatigue, irritability, poor memory, sleep disturbances, precordial pain, anorexia, and abdominal discomfort." [Source] "Muscle weakness, fatigue, muscle cramps, and stiffness... loss of appetite, nausea, digestive discomfort, constipation, weight loss, and incorrect production of hydrochloric acid... tingling, numbness, irritability, poor memory retention, and depression." [Source]

3. Thiamine deficiency can lead to a BeriBeri which translated means "weak, weak" or "I cannot, I cannot". Symptoms of Wet BeriBeri are "shortness of breath during physical activity, waking up short of breath, rapid heart rate, and swollen lower legs." Dry BeriBeri symptoms are "decreased muscle function, particularly in the lower legs, tingling or loss of feeling in the feet and hands, pain, mental confusion, difficulty speaking, vomiting, involuntary eye movement, paralysis."
[Source]

4. Thiamine deficiency can lead to Vasodilation. [Source] Vasodilation causes decrease in blood pressure and increase in cardiac output. [Need to add source] Vasodilation can cause nose bleeds. [Source]

5. Thiamine deficiency can cause hypoglycemia, because thiamine is critical in converting carbohydrates to glucose. [Need to add source]

6. Thiamine deficiency can cause high Oxolates [Source]

7. Thiamine is needed in 4 reactions: alpha-Ketoglutarate, Branch Chain Amino Acid Dehydrogenase, Pyruvate Dehydrogense, and Transketolase. The first 3 are part of the Krebs Cycle. [Source]

8. Thiamine Deficiency can cause low body temperature [Source]

So what does this mean for me?
Most of the non-specific symptoms above describe me very well. Fatigue, irritability, poor memory, sleep disturbances, abdominal discomfort, rapid heart rate, decreased muscle function, tingling in feet and hands, pain, mental confusion, low blood pressure, reactive hypoglycemia, high oxalates per OAT, low body temperature. Muscle weakness, muscle cramps, stiffness, loss of appetite, nausea, digestive discomfort, weight loss, tingling, numbness, irritability, poor memory retention, and depression... Low blood pressure, elevated oxalates.

Do I have something more concrete? Not really. However, there are two things buried in all these Sources which have peaked my interest.

"What happens if you do not give the thiamine first before starting an intravenous glucose infusion? As stated above, many of these cells and biochemical pathways may be upregulated in times of stress or with nutritional deficiencies. Therefore, if they are given the precursors for ATP production (such as glucose), then these cells will begin to rapidly utilize them. The problem comes in the inability of the previously described enzymes of glycolysis and the TCA cycle to move the reactions forward so that the precursor (i.e., glucose) can be utilized to generate the amount of ATP that it can normally produce. As a result, intermediate products within the pathways begin to accumulate and the system will eventually back up. So, not only is ATP failing to be adequately generated, but pyruvate is accumulating as a result of continued glycolysis. The inability of pyruvate to enter the TCA cycle causes the cell to convert the pyruvate to lactate (or lactic acid) in order to be able to maintain glycolysis.3,7 The reason the cell converts pyruvate to lactate is to regenerate the NAD+ required for the process of glycolysis to continue and to generate a net balance of at least 2 ATP.3 Therefore, as you feed the cell more glucose without giving the needed thiamine to allow for the forward movement of cellular reactions for complete ATP generation, you only increase the amount of lactic acid produced. This development of acidosis, the inability of the pentose phosphate pathway to protect the cell from reactive oxygen species that damage cellular structures and the mounting stress on the cell overall, results in either cell death or activation of apoptosis. " [Source]

Cell death and apoptosis sounds bad. I think I should be trying to heal my cells, not kill them. Now re-read the above quote, but think about refeeding syndrome. To me they sound them same.

Then I found this second thing buried deep in an article.

"Lack of thiamin is one of the reasons why lactic acid can build up in muscle tissues and consequently contribute to muscle pain and even fibromyalgia. A case report in the British Medical Journal found that muscle pain and fatigue problems were markedly improved when fibromyalgia patients were given high doses of thiamin or vitamin B1. The higher doses of thiamin were able to by-pass problems with transport defects and enzymatic abnormalities that interfered mitochodria function. This supported energy production without the by-product of lactic acid build-up in the tissues leading to fatigue and pain." [Source]

Can I tie the obscure details above to actual data?
Besides the symptom presentation, I have a low Pyruvic Acid level, but elevated Lactic Acid Level per OAT. Also, all of my OAT oxalates are elevated. Is this enough data?

So what do I do?
This seems to be the conundrum.
1. How do I experiment with thiamine correctly without causing a cascade of other issues?
2. The NICE guidelines detail 200-300 mg daily oral dosage for 2 weeks. Should I start there?
3. Which form should I use?
4. What if this is a functional issue in absorbing or converting Thiamine?

Couple more random thoughts:
1. B-Complex IM shot contained 50 mg B1. This IM consistently decreased symptoms for about 24 hours.
2. Could my 4-5 AM wake-up feeling sick be a cortisol spike due to hypoglycemia? Could this tie back to Thiamine deficiency?
3. This article suggests a waxing and waning of symptoms as thiamine crosses the 6% threshold window. Could this be one cause of PEM?

 

[JasonUT]

Oxalates and Me: I am reluctant to tackle this topic, because it seems like such a minefield. So far now, I am going to just post some theory that is bouncing around in my head. Hopefully, I can go back and be more thorough and site sources. Also, hopefully, my pending OAT, Methylation Pathways Panel Test, and SpectraCell Nutrient Panel will help bring some of this theory together.

Theory on Oxalates and Me:
1. "Oxalate and its acid form oxalic acid are organic acids that are primarily from three sources: the diet, from fungus such as Aspergillus and Penicillium and possibly Candida (1-9), and also from human metabolism" [Source]

2. Thiamine deficiency can cause high Oxolates [Source]. This seems to be part of the "human metabolism" component.

3. I have tried a very hardcore anti-fungal protocol consisting of diet changes and prescription anti-fungals, but my oxalate levels continued to increase over the next 5 months per OAT data. The Doctor seemed completely perplexed. Therefore, my assumption is that the oxalates where not of fungal origin.

4. Calcium Citrate and Magnesium Citrate did not seem to provide much relief and I believe these are used to bind oxalates in the digestive track. Does this further support the idea that the elevated oxalates where not from fungal overgrowth in the GI or food?

5. Low oxalate diet seemed to provide some symptom relief, but it was minor.

6. Therefore, I have to go back to the 3rd source of oxalates - Human Metabolism.

7. I have already mentioned that I have elevated Lactic acid and low Pyruvic Acid per old 5/26/2015 OAT. This suggests dysfunction in Pyruvate dehydrogenase enzyme step of the Krebs Cycle. This step is needed to form Acetyl CoA and then ATP via carbohydrates. Think functionally forced low carb diet possibly due to thiamine B1 deficiency. [This step 7 needs validation. I may be overreaching].

8. According to my 5/26/2015 OAT, there seems to be some slight dysfunction in the cis-Aconitate to alpha-ketoglutarate steps. My Aconitic Acid was slightly elevated, but my alpha-ketoglutarate (aka 2-oxoglutric) was low.

9. I think I can tie theory step 7 to theory step 8 together via this post. The post seems to suggest the salvage pathway created when there is dysfunction in low carb, high fat energy production. The salvage pathway short-cuts back to Malate and Succinate and by passes alpha-ketoglutarate. Per my 5/26/2015 OAT, both malic acid and succinic acid are both elevated, and alpha-ketoglutarate (aka 2-oxoglutric) is low. Does this mean that my body is using this salvage pathway?

10. Based on the above, it seems like I may need to address Human Metabolic source of high oxalates. It may be that thiamine is my answer, but I have also read that B6 somehow helps. If this is true, then oxalate dumping my be my next big hurdle.

Again this is all my theory. I don't have concrete science or sources to back this up. Hopefully, my pending OAT, Methylation Pathways Panel Test, and SpectraCell Nutrient Panel will steer my in the correct direction.

 

[JasonUT]

OAT March 2017 Analysis:
Seems to be some interesting shifts in my OAT results. Some expected, some unexpected.

The Good:
1. My Krebs cycle metabolites look somewhat improved.
2. Pyruvic Acid and Lactic Acid appear to be back in balance. Therefore, I must assume the B1 in my multi and B-Right dosage was enough to get that working again.
3. Alpha-Ketoglutarate step seems to be working again. Maybe this means my cells have stopped using the salvage pathway.
4. My Methylmalonic Acid is perfect. So does this mean that my current 3mg AdoB12 and 2mg mB12 daily is the correct dose?

The Bad:
1. Oxalates are still elevated, but not as bad as before. Does this debunk my previous post #31 theory?
2. There still seems to be a partial block in the Succinate to Fumarate step. FMN B2, L-Carnitine, Coq-10? Reference post #16 above.
3. B6 and B2 are both showing deficiencies
4. Uracil is showing elevated which somehow ties back to methyl donors and methylfolate. The lab analysis suggests increasing mFolate dosage, but I am already at 12 mg per day. This deficiency was completely unexpected. I felt for sure I was taking enough mFolate. I actually thought I was taking too much mFolate. I am very curious to see what my Methylation Pathways Panel shows, because I think it measures 7 forms of folate: Tetrahydrofolate (THE), 5-methyl-THF, 10-forrnyl-THF, 5-formyl-THF, Folic Acid, Folinic Acid, Folic Acid (RBC).

I think this is where I need help from the community on this forum...

Am I mFolate deficient or have I caused the "methyltrap" issue by not having enough mB12? I have read and read this concept of "methyltrap" and just can't grasp it no matter how many times I read it.

I found a couple articles on Uracil and Folate:
Folate deficiency causes uracil misincorporation into human DNA and chromosome breakage: Implications for cancer and neuronal damage - NCBI
Increased uracil misincorporation in lymphocytes from folate-deficient rats - BJC

Additional thoughts from OAT results:
1. Uracil Acid is elevated, but I am currently supplementing with 12 mg of L-methylfolate. How is this possible? Methylation pathway panel measures 7 forms of folate.

2. OAT shows low 5-HIAA (Serotonin Metabolite) - Is this a measurement of Serotonin level or MAO enzyme performance? For my OAT, does this truly indicate low Serotonin or a limitation in MAO enzyme causing an increase in circulating serotonin and decrease of 5-HIAA? This seems ambiguous to me.

3. Tryptophan to 5-HTP to Serotonin conversion requires Mg, Ca, B6, B9, Fe, Zinc, and Vit C. OAT shows deficiency in B6 and possibly B9. Need to review SpectraCell to determine Mg, Ca, Fe status. Zinc was okay on CPL Lab and Vit C was okay per OAT.

4. HVA (dopamine metabolite) was slightly elevated and VMA (norepinephrine/epinephrine metabolite) was slightly low. Cu, Vit C, SAMe, and Mg are the nutrients. My Cu and Vit C status are fine. Need Mg from SpectraCell and SAMe from methylation pathways panel.

 

[JasonUT]

SpectraCell Lab Results and me: I got my lab results and the results seem very consistent with my OAT results. We are starting to see a pattern which is hopefully reassuring and provides some treatment direction.

Deficient: Vitamin B1, Vitamin B3, and Fructose Sensitivity

Borderline: Vitamin B6, Folate, Serine, Glutamine, Oliec Acid, Glutathione, Spectrox, Immunidex

My Analysis

Vitamin B1 Deficiency: This doesn't come as a surprise I already theorized about this in post #30 above. I must be dancing with the 6% threshold [Source].

Vitamin B3 Deficiency: This isn't surprising either as I already theorized about this in post #28 above. It appears that B3 is needed to convert Glutamate to Glutamine and 2-oxoglutarate [Source]. My Glutamine per Spectracell and my 2-oxoglutarate per OAT are both low. Perhaps it's because of B3 deficiency.

Fructose Sensitivity: This was a complete surprise. This source and this source provides details. SpectraCell's info.

Vitamin B6 Borderline: This isn't surprising either. All of my OAT's have shown borderline deficiency. B6 info and SpectraCell B6 info. It appears that Vitamin B6 is needed to convert Glutamate to GABA [Source]. Maybe I have trouble calming down due to insufficient GABA via B6 shortage. It's interesting how the same source ties GABA back to the Krebs Cycle via the succinate step in the Krebs Cycle and then that feeds back to form Glutamate. Post #16 details my dysfunction in the Krebs Cycle. Therefore, it appears I have two partial blocks in this nice circle at B6 and Krebs.

Folate Borderline: OAT shows deficiency and I am posting in the methylation section of PR. However, this seems to shed some light on Folate deficiency vs. Methyl Trapping. I guess I am leaning toward deficiency now. My B12 levels were extremely good in my SpectraCell results; therefore, my current 2mg mB12 and 3mg AdoB12 dosage seems to be correct.

Glutamine Borderline: I am not sure how to fix this. Glutamine supplementation seems to have an excitatory response for me. It appears that Glutamine is a precursor to Glutathione Redox reaction. See figure 3 in the following link. Maybe it's helping to start-up methylation which is why it feels excitatory? Or maybe it is being converted to Glutamate, but then getting stuck at Glutamate? I may need to figure out how to titrate Glutamine.

It seems like there is this nice cycle that converts Glutamine <-> Glutamate <-> GABA [Source]. Glutamate should convert into Glutamine via glutamine synthetase enzyme [Source]. This conversion requires ATP and Ammonia and B3 [Source]. I assume this conversion is slow due to shortage of ATP and B3.

So it looks like Glutamate is stuck, because it needs either B3 (Glutamate synthase)
or B6 (Glutamate Decarboxylase) to convert.

Serine: This is a non-essential amino acid; however, I am deficient. Serine needs Folate, B6, and B3 for synthesis. Also, serine is needed to synthesis tryptophan into serotonin. Serine has also been shown to be low in CFS and Fibromyalgia patients. [Source1, Source2]. Will fixing Folate, B6, and B3 levels drive a cascade of healing via serine improvement?

Oleic Acid Borderline: This is fascinating to me. I referenced Oleic Acid in post #25 above. Also, this study links high blackheads to high oleic acid (or low linoleic acid) concentration in natural skin oil [Source]. I have always had severe issues with blackheads. Is there a connection here? SpectraCell's info on Oleic Acid.

Glutathione Borderline: Not a big surprise. After all I am in the methylation section of PR. Hopefully, the Methylation Pathways Panel will shed some light on where the block is. Link to panel interpretation by Rich VK.

Spectrox: Seems like a SpectraCell proprietary measurement of overall antioxidant status. Low Glutathione is driving this value down.

Immunidex Borderline: "The Immunidex is an indication of the patient's T-Lymphoproliferative response to mitogen stimulation relative to the response of a control population. An average or weakened immune response may improve with correction of the nutritional deficiencies determined by the micronutrient testing." - SpectraCell

Supplementation Levels on 3/28/2017 SpectraCell Blood draw:
B1 - Breakfast Multi 20mg + Lunch B-Right 25mg = 45mg
B3 - Breakfast Multi 25mg + Lunch B-Right 125mg = 150mg
mFolate - Breakfast Multi 0.4mg+5mg + Lunch B-Right 0.4mg+1 mg + Dinner 1mg + Bedtime 5mg = 12.8mg
B6 - Breakfast Multi 25mg + Lunch B-Right 35mg = 60mg

SpectraCell Recommendations:
B1 - 50 mg daily
B3 - 100 mg daily

Here is a link to my total protocol. I started noting revision history on 3/5/2017.

Side Notes:
1. Vitamin B5 (Pantothenic Acid) is one of the only B-vitamins high in my SpectraCell results. It appears that Pantothenic Acid is synthesized to Coezyme-A. CoA is used in several steps in the Krebs Cycle. [Source] Does this mean my B5 is getting backed-up and not converting to CoA? Why would this happen?

 

[JasonUT]

Appointment with nutritionist seemed to go well. We are waiting on Methylation Pathway Panel. He thinks raising Glutathione is key to getting me healthy. The struggle is how to do it. He also agreed that it is plausible that I could be stuck in perpetual refeeding syndrome due to low B-Vitamin status.

He liked my current total B-vitamin dosing based on my specific SpectraCell and OAT results:
B1 - 245 mg
B2 - 100 mg
B3 - 150 mg
B5 - 50 mg
B6 - 60 mg
B9 - 15.6 mg
aB12 - 3 mg
mB12 - 2.2 mg

He recommended two changes:
1. Increase Zinc to copper ratio closer to 15:1 by increasing daily zinc dosage. He also wants me to continue using the Zinc-L-Carnosine form, because of it's benefits to the GI lining. He has seen good results with Nature's Lining, Doctor's Best, and Source Naturals brands which come in 8 mg dosing per pill. Therefore, I need to get to about 52.5 mg of total zinc since I am currently taking 3.5 mg of copper. Multi contains 15 mg of Zinc; therefore, 4 pills of Zinc-L-Carnosine will get me to 47 mg per day. Ratio = 13.4 to 1. I should not exceed 15 to 1 ratio, because it could lead to Zinc toxicity.

2. Experiment with NAC to help lift Glutathione. He said start low and work up. Final dosage may be between 500 mg to 3000 mg per day. Kind of vague, but he did acknowledge that adverse side effects or detox might happen if/when glutathione level starts to improve. I am a bit apprehensive based on other people's experience on this forum. I may wait for my Methylation Pathway Panel results before venturing down this path.

N-Acetyl Cysteine (NAC), specifically cysteine, is a precursor to glutathione [Source]. Cysteine is converted to glutathione with Glutamate + 2 ATP + Glycine [Source]. Interestingly my SpectraCell cysteine level is very good. Does this mean my deficiency is in Glutamate, Glycine, or ATP? This is getting very complicated.

These articles have some info Zinc, Copper, NAC, and Glutathione.
Article 1
Article 2
Article 3

Open Items to review:
1. NAC
2. CoQ10
3. Acetyl-L-Carnitine
4. Revisit L-Carnitine Fumarate
5. Magnesium orotate
6. Lithium orotate

 

[JasonUT]

Methylation and Me: I found a very simple diagram from SpectraCell that lists all the variables in Methylation here.

Comparing diagram to my SpectraCell and OAT results. I'm deficient in 6 of the 13 items.
Vitamin B2: I'm deficient
Vitamin B3: I'm very deficient
Vitamin B6: I'm deficient
Vitamin B12: Very good status
Folate: I'm deficient
Choline: Very good status
Serine: I'm deficient
Glutathione: I'm deficient
Vitamin C: Good Status
Copper: Very good status
Magnesium: Very good status
Selenium: Good Status
Zinc: Very good status

 

[JasonUT]

Thiamine (B1) Repletion and Me: In this post I will provide my layman's research on Thiamine Deficiency, ways to replete, and how it applies to me. I discussed Thiamine in a previous post #30 with relation to refeeding syndrome, but did not get into great details on how to replete if found deficient. Also, Thiamine deficiency applies to many more medical conditions than just refeeding syndrome. Linus Pauling provides a good diagram in Figure 1 showing how Thiamine Pyrophosphate (TPP) is used in metabolic pathways.

Thiamine Deficiency Symptoms: Loss of Appetite, Anorexia, Constipation, Nausea, Irritability, Mental Depression, Peripheral Neuropathy, Fatigue, Headache, Abdominal Discomfort, Poor memory, sleep disturbance, Bilateral, symmetrical lower extremities paresthesias, burning pain, Muscle cramps (typically start in the calves and feet), Decreased vibratory position sensation, Absent knee and ankle jerk, Muscle atrophy,Tachycardia, Chest pain, Wide pulse pressure [Source1, Source2, Source3]

Severe Thiamine Deficiency Symptoms: Mental Confusion, Loss of Fine Motor Control, Loss of Eye Coordination, Weakness, Swelling, tingling, or burning sensation in the hands and feet, Foot drop [Source1, Source2, Source3]

I underlined the symptoms that I have.

Medical Conditions Associated with Thiamine Deficiency: Wet Beriberi, Dry Beriberi, Gastrointestinal Beriberi, Wernicke Encephalopathy, Korsakoff syndrome [Source3a, Source3b]

Repletion Issues: B1, B2, B3, and B6 are B-vitamins needed for digestion. B1 is also needed for the brain, heart, and muscle function [Source4]. However, oral B1 may be useless when trying to replete and is rate limited to 4.5 mg oral [Source5, Source6]. It's a Catch22 due to poor digestion caused by low B1. Also, B1 deficiency can cause anorexia leading to avoidance of eating and repleting [Source].

Ways to Replete Thiamine:
1. Oral: There is an active transport and passive transport. The active transport appears to be rate limited to 4.5 mg and the passive transport needs larger pharmacologic doses [Source7]. My guess is that the firbomyalgia treatment using high dose Thiamine was forcing passive transport to increase Thiamine levels. The clinical trials used oral therapeutic doses between 600 and 1800 mg [Source6].
2. Sublingual: There are a number of OTC options available and maybe required if there is a transport limiting factor. I don't know how this can be tested other than trial and error.
3. Transdermal: Creams and oils seems to be popular amoungst this PR community.
4. IV, IM, Subconscious Injection: This seems to be the preferred method when facilities, oversight, and doctors can prescribe and monitor the progress [Source5].

Testing: SpectraCell Micro Nutrient, Genova NutraEval, Erythrocyte Transketolase. The two nutrient panels have their advantages, because they will test for much more than just B1. Some insurance companies may cover Nutrient Panel tests.

Differential Diagnosis: It seems differential diagnosis is nearly impossible because all the symptoms seem very non-specific. The exception might be if there is a history of poor eating, massive weightless, alcoholism, alcoholism withdrawal, or other drug withdrawal. For me, I have wide pulse pressure which seems rather unique to Thiamine deficiency and might be something I can track during repletion. Standard pulse pressure width should be 30-40 mmHg [Source]. Mine is typically 50 with 115/65. However, I don't think elimination of wide pulse pressure means I am cured. A follow-up test will likely be needed to confirm.

A Step Back in History: I am here researching methylation and B-Vitamins, because for a time I was taking B-Complex IM's. These B-complex IM's noticeably reduced my symptoms for about 24 hours. The IM"s were compounded and expensive so it wasn't feasible for me to take them more than once or twice a week. I started diving into the recipe for these B-Complex IM's and noticed that they had a very high dosage of B12 and mFolate. Perhaps I should have spent more time looking at all the ingredients.

The B-Complex IM recipe is as follows:
B1 - 50 mg - I'm Deficient
B2 - 5 mg
B3 - 50 mg - I'm Deficient
B5 - 5 mg
B6 as P5P - 5 mg - I'm Deficient
mFolate - 5000 mcg - I'm Deficient
mB12 - 6250 mcg
hB12 - 6250 mcg
Biotin - 0 mcg
Methionine - 12.5 mg
Inostitol - 25 mg
Choline - 50 mg

 

[JasonUT]

Quick Update:
Doc and nutritionist are nervous that gut absorption and transport issues may be root cause of nutrient deficiencies. Therefore, I switched from Jarrow Oral B-Right B-Complex at lunch to Source Naturals Sublingual B-Complex, 1 lozenge at breakfast and 1 lozenge at lunch. I may increase this to 1 lozenge at breakfast, lunch, and dinner. The only downside to the Source Naturals Sublingual B-Complex is the 200 mcg of Folic Acid per lozenge. There seems to be many alternatives, but they are more pricey or don't contain all active vitamin forms.
Supplement Health Store - Coenzymated B Formula
Super Smart - Coenzymated B Formula
Pure Encapsulations - B-Complex Liquid

Also, there appears to be an IV Vitamin Clinic in town that can create custom IV's to meet my needs. Unfortunately, this may not be covered by insurance. Doc thinks that an IV series might be enough to "jump start" my body. We are waiting on Methylation Pathways Panel before doc prescribes a custom IV cocktail.

Good:
1. I feel more relaxed.
2. Continued sleep improvement.
3. More energy
4. Improved cognitive function

Bad:
1. Abdominal Aches and Pains has been diagnosed as Pelvic Floor Dysfunction. Prescribed physical therapy. Doc says that this could be contributing to IBS and IC symptoms.
2. Low Appetite

Strange:
1. The emotional and fatigue "windows and waves" pattern continues to diminish, but is still present
2. I am still waking up around 4-5 AM with symptoms, but this also seems to be diminishing a bit.

I take the symptoms with a grain of salt, because PEM can always sneak up on me.

 

[Jesse2233]

Quick Update:
Doc and nutritionist are nervous that gut absorption and transport issues may be root cause of nutrient deficiencies. Therefore, I switched from Jarrow B-Complex at lunch to Source Naturals Sublingual B-Complex, 1 lozenge at breakfast and 1 lozenge at lunch.

Also, there appears to be an IV Vitamin Clinic in town that can create custom IV's to meet my needs. Unfortunately, it appears this may not be covered by insurance. Doc thinks that a series might be enough to "jump start" my body. We are waiting on Methylation Pathways Panel before doc prescribes a custom cocktail.

Thanks for sharing all this, have you seen any symptomatic improvement thus far?

 

[JasonUT]

Thanks for sharing all this, have you seen any symptomatic improvement thus far?

Yes, I think I am seeing symptomatic improvement. Maybe too early to see if it sticks. It feels like 2 steps forward and 1 step back.

There seems to be many puzzle pieces and we are trying to put it all back together. I still don't know if we have discovered all the pieces yet. My nutritionist says that the nutrient repletion journey is a 4-6 month process once we have all the pieces. We will probably retest nutrients in another 3-5 months to see if we hit the target and also reevaluate symptom presentation. The pessimistic side of me is planning for a phase 2, phase 3, etc nutrient repletion journey. Hopefully, each phase will incrementally improve symptoms.

 

[JasonUT]

Methylation Pathways Panel Results from 3/28/2017 Blood Draw: I'll complete a follow-up post with my Layman's interpretation.

Derivates:
S-adenosyl-methionine (RBC) - 227 (221 - 256)
S-adenosyl-homocysteine (RBC) - 48.3 (38.0 - 49.0)
Folic Acid Derivates:
5-CH3-THF - 8.9 (8.4 - 72.6)
10-Formyl-THF - 2.7 (1.5 - 8.2)
5-Formyl-THF - 1.20 (1.20 - 11.70)
THF - 0.79 (0.60 - 6.80)
Folic Acid - 10.6 (8.9 - 24.6)
Folinic Acid (WB) - 7.8 (9.0 - 35.5)
Active folate (RBC) - 330 (400 - 1500)

Nucleoside:
Adenosine - 21.5 (16.8 - 21.4)

Amino Acids in Plasma:
Cystathionine - 0.09 (0.00 - 2.00)
Homocysteine - 1.83 (0.00 - 2.00)
Cysteine - 6.22 (15.00 - 60.00)
Taurine - 55 (60 - 240)
Methionine - 21.40 (14.30 - 28.70)
Glutathione (oxidized) - 0.48 (0.16 - 0.50)
Glutathione (reduced) - 2.7 (3.8 - 5.5)