Is taking BH4 a problem for COMT++ ?

[Hip]

@ppodhajski
Interesting study. I wonder if it applies to the general population (of rats) as well.

Flaxseed oil helps reduce my generalized anxiety disorder symptoms, along with other supplements, such as N-acetyl-glucosamine, which is the best anti-anxiety supplement I have found (info on this thread).


I did not find riboflavin-5′-phosphate (R5P), at a dose of 36.5 mg daily, had any noticeable effects on me, at least over the period of a few weeks that I took it (tried this on a few occasions).

I did not notice much when taking pyridoxal-5-phosphate (P5P) 50 mg either, which I tried out on many occasions, often in conjunction with the simplified methylation protocol supplements (which never seem to help me much either).


And in the last two weeks, I switched from taking my regular vitamin B complex, which I have taken daily for years, to Thorne B complex #12, which contains the active forms of the B vitamins, and in the last two weeks my fatigue / brain fog symptoms have got worse, and my depression symptoms have returned. It could be a coincidence of course.

 

[ppodhajski]

@ppodhajski
Interesting study. I wonder if it applies to the general population (of rats) as well.

Biologically I do not see why not.

Flaxseed oil helps reduce my generalized anxiety disorder symptoms, along with other supplements, such as N-acetyl-glucosamine, which is the best anti-anxiety supplement I have found (info on this thread).

What do you think the mechanism is for N-acetyl-glucosamine?
I can see it lowering glutamate by inhibiting the pathway:
http://www.ultimateglucosamine.com/consumers/images/clipart_f39.gif

I did not find riboflavin-5′-phosphate (R5P), at a dose of 36.5 mg daily, had any noticeable effects on me, at least over the period of a few weeks that I took it (tried this on a few occasions).

Have you tried it alone, with no other supplements? I found this to be extremely important. You take a lot of products of these pathways and that could interfere with the action. Also, sublingual.

Also, I am not convinced that R5P is the same as FMN, I need to look into that more. It might be as well that swallowing it is much less effective than sublingual. This is true for methylcobalamin.

I take 25 MG of flavin mononuecliotide.
http://www.iherb.com/Source-Naturals-Coenzymated-B-2-Sublingual-60-Tablets/1036

I did not notice much when taking pyridoxal-5-phosphate (P5P) 50 mg either, which I tried out on many occasions, often in conjunction with the simplified methylation protocol supplements (which never seem to help me much either).
And in the last two weeks, I switched from taking my regular vitamin B complex, which I have taken daily for years, to Thorne B complex #12, which contains the active forms of the B vitamins, and in the last two weeks my fatigue / brain fog symptoms have got worse, and my depression symptoms have returned.

Yeah, so all these multivitamins and methylation protocols, when I look at them I see why people get worse sometimes. If you take folate or methylB12 and you have no issues with the folate cycle you will create too much BH4 and then create too many catecholamines making you feel worse.

I am going to go through these ingredients one by one someday and show you the concern i have over taking multis like this.

One Capsule Contains:
Thiamin (as Thiamin HCl) 40 mg.
Riboflavin (25 mg as Riboflavin and 3.6 mg as Riboflavin 5'-Phosphate Sodium) 28.6 mg.
Niacin (as Niacinamide) 80 mg.
Vitamin B6 (20 mg as Pyridoxine HCl and 3.4 mg as Pyridoxal 5'-Phosphate) 23.4 mg.
Folate (200 mcg as Calcium Folinate and 200 mcg as L-5-Methyltetrahydrofolate from L-5-Methyltetrahydrofolic Acid, Glucosamine Salt) 400 mcg.
Vitamin B12 (300 mcg as Adenosylcobalamin and 300 mcg as Methylcobalamin) 600 mcg.
Biotin 80 mcg.
Pantothenic Acid (as Calcium Pantothenate) 45 mg.
Choline Citrate 40 mg.

 

[ebethc]

Missed this. A low amine diet is very important in all this as well since MAO breaks down biogenic amines as well. Eating more amines will deplete you of riboflavi, inhibiting your MAO enzyme even further. This is why people on MAO inhibitors are instructed not to eat certain cheeses high in tyramines.

/

Is Tyramine just ONE amine? ie, are there many/multiple amines and Tyramine is just one to avoid?

The Chloramine thing is annoying... I'm sensitive to ammonia.

thanks

 

[ebethc]

\

Basically, by speeding up MAO we remove O2 from the cell and create H2O2. Removing O2 from the cell lowers the chances of creating superoxides forming in the cell. (Superoxides are created when and electron is added to O2) Hydrogen peroxide is not as bad as superoxides.

Since SOD turns superoxides into hydrogen peroxides and SOD SNP will keep even more superoxides around. And then bad GPX SNPs will have a hard time getting rid of the hydrogen peroxide.

View attachment 10836

And that is what I see in many of these diseases; MAO, COMT, SOD, CAT, and GPX SNPs.

So, Superoxide = Bad.... BUT S.O.D = good? S.O.D is an antioxidant, like Glutathione, correct?

I have a bad SOD3, and 2 semi-bad SOD2's:

+/- SOD2 - rs2758331
+/- SOD2 - rs4880
+/+ SOD3 - rs2855262

 

[ebethc]

Here's a comment from another thread:

@ahmo @ppodhajski

I take SAMe and for awhile it helps... my mind feels "brighter" and my joints feel better... THEN is poops out... Do you think if I take active B2 along w the SAMe, I will avoid the poop out?? My theory (based on this string) is that the SAMe does what it's supposed to do until the catecholamines are not broken down, then it "poops out"... If I take the active B2, then the catecholamines will be broken down.

does that theory make sense? chemistry was my worst class... I really have no chemistry common sense... thanks.

 

[ebethc]

The only SNPs that are worth supplementing are the antioxidant SNPs. And other SNPs you supplement are to reduce the oxidation. So for me, COMT is treated with magnesium and MAOA MAOB with FMN. This lowers oxidation. Next I treat my CBS, GAD1, SUOX, SOD1, SOD2 and GPX . Result? Complete recovery.

@ppodhajski how do you treat CBS, BHMT2/8, GAD1, SOD2/3? i.e., What are the the corresponding co-factors that you recommend?

thanks.

 

[ppodhajski]

Is Tyramine just ONE amine? ie, are there many/multiple amines and Tyramine is just one to avoid?

The Chloramine thing is annoying... I'm sensitive to ammonia.

thanks

Chloramine is not ammonia and there will be no ammonia in the water. The chloramine mixes with ammonia to make chloramine. It is chemically different from ammonia.

 

[ppodhajski]

So, Superoxide = Bad.... BUT S.O.D = good? S.O.D is an antioxidant, like Glutathione, correct?

I have a bad SOD3, and 2 semi-bad SOD2's:

+/- SOD2 - rs2758331
+/- SOD2 - rs4880
+/+ SOD3 - rs2855262

SOD2 is in the mitochondria. The RED in the image below are the oxidative stressors.

 

[ppodhajski]

@ahmo @ppodhajski

I take SAMe and for awhile it helps... my mind feels "brighter" and my joints feel better... THEN is poops out... Do you think if I take active B2 along w the SAMe, I will avoid the poop out?? My theory (based on this string) is that the SAMe does what it's supposed to do until the catecholamines are not broken down, then it "poops out"... If I take the active B2, then the catecholamines will be broken down.

does that theory make sense? chemistry was my worst class... I really have no chemistry common sense... thanks.

I hear this time and again from people taking "products" of pathways instead of taking cofactors that help the enzyme make the product.

I do not take product for the reason you experienced. They work until the do not. The reason why it stops working is an inhibitory feedback mechanism.

Feedback inhibition of methylene-tetrahydrofolate reductase in rat liver by S-adenosylmethionine
http://www.sciencedirect.com/science/article/pii/0005274467901404
It has nothing to do with catecholamines.

 

[ppodhajski]

@ppodhajski how do you treat CBS, BHMT2/8, GAD1, SOD2/3? i.e., What are the the corresponding co-factors that you recommend?

thanks.

There are a lot more/different genes to look at treating. But if you ant to investigate cofactors for these genes loo at
http://www.uniprot.org/

For example:
http://www.uniprot.org/uniprot/P35520

 

[ahmo]

Do you think if I take active B2 along w the SAMe

Sorry, I don't take SAMe and don't know the answer. Just wanted to give you another B2 choice.

 

[ebethc]

I hear this time and again from people taking "products" of pathways instead of taking cofactors that help the enzyme make the product.

I do not take product for the reason you experienced. They work until the do not. The reason why it stops working is an inhibitory feedback mechanism.

Feedback inhibition of methylene-tetrahydrofolate reductase in rat liver by S-adenosylmethionine
http://www.sciencedirect.com/science/article/pii/0005274467901404
It has nothing to do with catecholamines.

What you're saying makes sense in concept, but the problem is that I don't know the difference between a co-factor or a product until someone tells me.

How do I find the co-factor to stimulate the pathway that produces SAMe (and what is that pathway called?? is it related to BHMT?)

 

[Valentijn]

I have a bad SOD3, and 2 semi-bad SOD2's:

+/- SOD2 - rs2758331
+/- SOD2 - rs4880
+/+ SOD3 - rs2855262

It sounds like SOD2 SNPs are only having an impact if homozygous. So those two really shouldn't be a problem.

I also don't see anything implicating rs2855262 causing problems, unless it's part of a haplogroup. Which usually mean that it doesn't do anything, but was a false-positive result due to failing to correct for increased odds when looking at multiple combinations. Is +/+ TT or CC? All versions are so common that the study is giving a different minor allele than the dbSNP data.

 

[ebethc]

It sounds like SOD2 SNPs are only having an impact if homozygous. So those two really shouldn't be a problem.

I also don't see anything implicating rs2855262 causing problems, unless it's part of a haplogroup. Which usually mean that it doesn't do anything, but was a false-positive result due to failing to correct for increased odds when looking at multiple combinations. Is +/+ TT or CC? All versions are so common that the study is giving a different minor allele than the dbSNP data.

thanks. I think if I can get the antioxidant activity up & more robust (glutathione & SOD) I will be a lot better off in regard to immunity & keeping healthy and strong..

2nd - if I can figure out the acetylcholine pathway, I'll be better off in regard to brain fog..I have a lot of Alzheimer's genes, so I'm worried about it for that reason, too... I've experimented w TMG / DMG / SAMe and I know i"m on to something w that pathway, but I can't quite get it right... Maybe those are all products of that pathway and I need the right co-factor(s)..

thanks

 

[brenda]

What would high citrate in urine mean please? Thanks.

 

[Hip]

Biologically I do not see why not.

Well the study is not on humans, and it is on diabetes rather than generalized anxiety disorder or ME/CFS.

In the study they had four groups of rats, and one of the groups was non-diabetic rats given flaxseed oil. So that would be the group to check. However they do not mention the results from this group in the study abstract, so you would have to get the full paper to find out.

In any case, this study does not really explain the anti-anxiety effects I noticed with flaxseed oil, as the studies finding that neurotransmitters were raised are not very specific.

What do you think the mechanism is for N-acetyl-glucosamine?

My guess is that NAG works by reducing brain inflammation. A lot of new research is now focusing on brain inflammation underpinning mental conditions such as depression, schizophrenia, etc. Autopsies on ME/CFS patients have shown enterovirus infections of the brain, which might explain why there is chronic immune activation (ie, inflammation) of the immune system in the brain (chronic microglial activation). Activated microglia release lots of glutamate, which is associated with generalized anxiety disorder.

By inhibiting brain inflammation, you are getting closer to the root of the (hypothesized) problem of too much glutamate causing generalized anxiety disorder. If you take benzodiazepines, you may just be counteracting the effect of high glutamate by activating the GABA receptors (the NMDA and GABA receptors are two sides of a neuronal excitation seesaw).

But by reducing brain inflammation, you are targeting the actual production of glutamate, which gets more to the root of the problem. This post has some info on this inflammation-driven anxiety idea. Of course the real route of the problem may be the infection in the brain, but this may not be so easy to eradicate. So instead you can target the inflammation this infection causes.

I can see it lowering glutamate by inhibiting the pathway:
http://www.ultimateglucosamine.com/consumers/images/clipart_f39.gif

Could you please explain how.

Also, I am not convinced that R5P is the same as FMN

I believe flavin mono nucleotide is just a chemical synonym for riboflavin-5′-phosphate.

Have you tried it alone, with no other supplements? I found this to be extremely important. You take a lot of products of these pathways and that could interfere with the action.

Seems a bit unlikely, unless perhaps you are taking certain supplements that have been hypothesized to inhibit methylation, like say sulfur-containing supplements when you have a significant CBS mutation.

Also, sublingual.

I have not tried sublingual, I will give it a go.

 

[ahmo]

@ebethc Just a comment re antioxidants. I've been implementing Martin Pall's suggestions, and it's been very helpful. In addition to astaxnthine and resveratrol, I've been drinking Lots of green tea, eating carrots. Martin Pall's website has been unavailable for many weeks now, but the vid linked in my signature lists many antioxidants in the last 20 minutes, a slide presentation. At the top of his list, though I don't know that it's in order of significance, is Mfolate. Also B12 and Acetyl Carnitine, all components of Freddd's Deadlock Quartet.

 

[ebethc]

You need to start doing some inquiry on your own as well instead of waiting for people to tell you.

You need to stop giving "action items".... You have no idea where I am in this process, or what I've done.

 

[Hip]

Inflammation and oxidation is a two way street in the body. Reducing inflammation is only half the battle which is why I think you are still suffering. Inflammation can cause oxidation and oxidation can cause inflammation. Do you see how a vicious circle could develop if you got infected by an enterovirus and you had a lot of oxidative stress already from bad genes, or you had the inability to get rid of oxidative stress?

I have tried many, but I have not found antioxidants that are useful personally, except acetyl-L-carnitine 1000 mg which I find helps reduce the feeling of inflammation I have in my head (though it does not do much more than that for me, so even this antioxidant is not very useful).

You see that double arrow before fructose 6 phosphate? When you take glucosamine the glucose you eat gets shunted into glycolsis because it sees it already has enough glucosamine and thinks it has enough energy. So instead it stores the glucose in the liver.
http://cardiovascres.oxfordjournals.org/content/73/2/288

Since they know this happens we can be safe to assume that you are also producing less glutamate from glutamine.

Because you store more glucose in the liver, somehow this leads to producing less glutamate in the brain? I do not see the connection.

Also, if you are concerned about glutamate why not look into your GAD1 and GABRA genes?

Good suggestion, thanks. I managed to find this study which found "variations in the GAD1 gene may contribute to individual differences in N and impact susceptibility across a range of anxiety disorders and major depression".

In the abstract they don't provide any further info though.

But anxiety, it is my strong belief, is caused by high catecholamines and glutamate plays a smaller role because glutamate releases catecholamines.

I am trying to work backwards from empirical evidence: I tested hundreds of supplements, and found that the 29 supplements listed on my thread all had good anti-anxiety effects. Provided I take several of these supplements together, I am able to eliminate my horrendous severe generalized anxiety disorder, which is quite a thing, since normally you would have to use something like benzodiazepines or SSRIs.

Many other ME/CFS patients with significant GAD also found these same supplements worked very well for them (according to the feedback I received on the thread). However, many others said they found no benefit. This could be because GAD may have more than one etiology.

So these supplements definitely work for many people, but the question is why.

Can you explain what you think sulfur has to do with methylation?

According to Yasko, a significant CBS mutation can throw a spanner in the works of the methylation process if this CBS mutation is not addressed. Addressing it includes reducing ammonia and sulfur in the diet. See:

The CBS enzyme is located right between homocysteine and the rest of the transsulfuration pathway, where it acts as a gatekeeper. With this upregulation, the “gate” is always open, sending all of the nutritional support used in this program down a road that does not lead to glutathinone but instead depletes the rest of the cycle. Instead of being directed to produce glutathione, which helps the body to detoxify, our supports head out the open CBS “gate” into the transsulfuration pathway, and may end up as harmful byproducts, such as excess ammonia and sulfites.

Addressing CBS entails the following:

• Detoxifying ammonia
• Lowering excessive taurine levels
• Limiting foods and nutrients that contribute to ammonia or sulfites
• Supplying the body with nutrients depleted by this process

Source: Chapter 6: Step Two, Part One | Dr. Amy Yasko

And if you take the sublingual please let us know what else you are taking with it.

Daily meds (which I have taken for years) are:

N-acetyl-glucosamine 750 mg
Turmeric 1000 mg
Flaxseed oil 15 ml
Vinpocetine 10 mg
Selenium (selenomethionine) 400 mcg
Amisulpride 12.5 mg
Vitamin B complex
Biotin 5 mg
Inulin 2 heaped tsp
Phosphatidylserine 400 mg
Acetyl-L-carnitine 1000 mg
Choline bitartrate 500 mg

 

[Oci]

A low amine diet is very important in all this as well since MAO breaks down biogenic amines as well. Eating more amines will deplete you of riboflavi, inhibiting your MAO enzyme even further. This is why people on MAO inhibitors are instructed not to eat certain cheeses high in tyramines.

The first thing I did was go on a low amine diet and things changed rapidly. Since amines are not really measured in foods this is not an exact science. But it is more about reducing amines not totally eliminating them.....
...Another huge source of amines could be your tap water. It took me years to figure this out because my skin would change from bad to great when I visited different cities. Turns our some cites treat their water with amines: Chloramines. It is a combination of chlorine and ammonia. I have had four other people with MAO snps and are sensitive to chloramines.

For more about how this is effecting people see:
http://www.chloramine.org/

Very interesting and thanks for the lists. I am very careful about not eating leftovers after second day as I feel the amines can contribute to migraines. I will look at the lists more closely. Actually, touch wood, migraines are getting more and more infrequent.

I live in Toronto and there are Chloramines in te drinking water. I have a whole house filter for chlorine and also 3 cartridge filters on the kitchen sink....one being for fluoride.

Will filters take out the amine part of the chloramine or will it be left after the chlorine is filtered out?

If I take more Riboflavin will I be able to better handle amines?

Many thanks, Oci