Is the Fatigue in ME an Eicosanoid Phenomena?

This is not one of my planned blogs, just something I thought I should report. I have been interested in eicosanoid impact on CFS and ME since 1993, based on the work of Dr. Andriya Martinovic. Eicosanoids are generally very short acting and short range hormones. They are used by a cell to communicate with itself, but also nearby cells.

I am experimenting with a new shotgun protocol. A simplified description is its a combination of methylation, antioxidant and one specific anti-inflammatory, with some minimal mineral support.

In particular:

Methylation: Methyl B12 and methyl folate.
Antioxidants: C, E, Q10, NAC, lipoic acid, resveratrol, grapeseed.
Antiinflammatory: Resveratrol.
Minerals: Magnesium, selenium.

I am still playing with doses, so have no idea what a proper dose is. I have selenium in there because it enhances tolerance to LPS which is something for another (planned) blog next year. I also wonder if molybdenum should be on the list.

Over the last two decades on various protocols I have completely restored my energy a number of times. In the most spectacular partial remission, on my first shotgun protocol leading up to my going to the 1999 Sydney CFS conference, I went from being too exhausted to want to walk across the room to walking five hours per day, every day, on the Sydney beachfront (Manly?). This in a matter of weeks. What is the issue though is that never, I mean absolutely never, has any of my protocols touched my deep down intractable fatigue.

Until today.

I am now having brief episodes of zero fatigue. This does not mean I have energy, I just have no fatigue. I can however feel that I have not had enough sleep, this is a different issue.

A huge downside of resveratrol is that it can wipe out my capacity to sleep if I take too much. No matter how tired I get, sleep is impossible. This is an eicosanoid phenomena I think, probably PGD2 (prostaglandin D2, an arachidonic acid derived eicosanoid) deficiency. On the other hand too much PGD2 can cause hypersomnia. This can be induced by antioxidants, excessive NO or excessive inflammation. The primary source of PGD2 affecting sleep is from the brain, though almost every tissue in the body makes it especially mast cells. PGD2, as well as other eicosanoids, appear to affect vasoregulation.

With respect to mast cells I think most of us do not have a mast cell problem. I do however think we have an eicosanoid regulation problem, and one of the sources of that could be mast cells. However I cannot rule out the existence of subgroups with mast cells disorders.

So the resveratrol, though a herbal antioxidant, makes tolerance of other antioxidants (and probably methylation) much greater, at least for me. However the reverse is also true. The antioxidant pentet makes resveratrol more tolerable.

With respect to methylation I find that the symptoms people are ascribing to low potassium disappear on resveratrol. This implies that these symptoms are eicosanoid induced, though this is not certain. So taking potassium may be a method of altering these symptoms in a drug-like not a deficiency-like way. However I am also aware that about half of us have low intracellular potassium, so there may be subgroups. This is because both potassium and eicosanoids are very important in maintaining blood vessel tone I think.

My respiratory hyper-responsiveness also seems to disappear on resveratrol. If I get an attack while on resveratrol I guess I will have disproved that, but it hasn't happened yet. It has happened when I forgot to take resveratrol and just took antioxidants.

To be clear though I am ignoring something here, at least for now. The source of resveratrol I am using also contains grape seed extract. I think thats a good antioxidant but I am not aware its anti-eicosanoid, though it can have an impact on nitric oxide (a biphasic impact depending on dose). It also might be important that my resveratrol is grape seed sourced.

My new Zombie Science blog is almost done.

Bye, Alex


One more mention ginger having a backlash as far as controlling the cytokines made from arachodonic acid. So...does that also apply to omega-3? Speciifically the strategy of taking so much o-3 that you use up the enzymes to digest o-6 and thus prevent those cytokines?

I am taking resveratrol first as an experiment, and second because it might stop me from dying. I have occasional severe breathing issues. The hospital docs can see I have a problem but are clueless. Resveratrol kills this problem for the most part, though it can surface in a mild form. Resveratrol is under intense big pharma scrutiny as it looks like it might be more powerfull than the current anti-asthma meds, but with mostly good side effects instead of bad.

Resveratrol alters the Ca++/cAMP axis. It looks like this axis is skewed in us, and resveratrol skews it the other way.

My selection of B vitamins is based in part on my own individual problems. I have supplemented with all of them, including all at once, and currently I am not taking any. What I have not done is try all the varieties of these vitamins.

If I have a reason to try other specific vitamins I will. The primary aim of my shotgun protocol in this thread is to boost antioxidant status, with a secondary goal of lowering homocysteine. Most of the other B vitamins do not help with that. I think that I need to take better account of adensyl cobalamin though. Its something I need to look into.

Melatonin is indeed an important antioxidant. THAT is its most important function. Too many of us take it to try to improve sleep though, which is not what it does. It helps trigger sleep if you can respond to it properly.

DHEA is a restricted streroid here. Supply is illegal, and good luck getting a doc to prescribe it, and if they do you pay 5-10x what is paid in the US. DHEA might be an important factor in treating us for another reason. IIRC it simulates mitochondrial replication.

At the moment this protocol is on hold for me anyway, as I cannot get vitamins delivered.

I will deal with eicosanoids in the next post.
There are many ways to modulate eicosanoid synthesis. I have tried nearly all of them.

You can play with substrate. How much you eat has an effect. People who try to balance their omega-3 and -6 do this. Unfortunately this effect is not entirely stable.

You can play with the enzymes. They have cofactors like magnesium and zinc (iirc), are very vulnerable to alcohol and salicylates, and more moderate doses of salicyltes can be used to slow but not block their action. Its one reason I like spicy food.

The primary regulator of the desaturases is glutathione, so glutatione oriented protocols can have a big impact.

You can provide mass affect modification with enzymes too. Omega-9 fats, monounsaturated fats, also interact with these enzymes, though poorly. This slows their activity.

You can reduce inflammation, and so reduce the release of arachidonic acid with is used to synthesize most (not all) eicosanoids.

You can take EPA, one of the two long chain omega-3 fats. This slows eicosanoid synthesis. EPA also provides competitive inhibition. One thing that most are not aware of is that EPA is usually proinflammatory, not antiinflammatory. The issue though is that taking it you lower omega-6 eicosanoid sythesis, and omega-3 eicosanoids are generally less inflammatory than omega-3 eicosanoids. So there is a relative improvement in inflammation.

One implication of this though is that taking too many omega-3s if you have a high inflammatory process might increase inflammation. I have yet to see any evidence of this however.

Finally here is one that most don't know about. Very low fat diets, especially how in omega-6, can stabilize the desaturase enzyme activity. Their activity is increased. However this runs risk of essential fatty acid deficiency.

Next: balance.
Balancing eicosanoids

I think we have big issues regulating these pathways. Generally speaking, low glutathione and high oxidative stress will limit the desaturase activity. Hence we are eicosanoid deficient.

High NO and inflammation, with lower cortisol, will drive arachidonic metabolism, though the thing that does this most powerfully is alcohol, and there is good evidence that this is how alcohol poisoning kills, not what most textbooks say. So any increased NO, ONOO or other inflammation can drive eicosanoid synthesis.

So we have drivers to make too much eicosanoids, and too little. If you starve the eicosanoids you get deficiency states. If you feed them you get inflammatory states. Catch-22. We need to fix the processes driving these factors, not the eicosanoids.

However taking omega-3s will not drive it much or at all, and will alleviate many eicosanoid deficiency symptoms.
On omega-3 and backlash, I think its possible but unlikely. Ginger messes about with the enzymes, omega-3 is about substrate. I have never observed an omega-3 backlash in myself. Its possible I suppose, but I wouldn't worry about it much as its probably very unlikely.
Thanks for the info - I would never have guessed resveratrol helps with breathing. Do you mean like asthma? I am starting to get wheezing with my allergies and asthma is a new fear for me. It's pretty scarey when you look at all the many deficiencies that can cause d6d to fail. Taking 9g of O-3 to use up the o-6 enzymes is more than my gut can handle...or maybe I just need to find a higher quality o-3.

I take ginger tea for sore throat and can say that if I do not have a sore throat I could never stand that much ginger. It is not like plain tea that you could drink all day. I almost want to say it's dehydrating or something.
I have unidentified breathing issues, like asthma but my capacity to breath starts and stops suddenly, some kind of reactive spasm. Resveratrol blocks that. Pharma is looking into asthma ... resveratrol is better than their entire suite of drugs in many respects, but they want to modify it for patent and to limit side effects.
Low quality O-3 will cause gastrointestinal upset if you take too much. Pharmaceutical grade is the key. At a minimum you need 60% purity, though 90% pharmaceutical grade is better. The regular fish oil is 30% and has had inadequate purification in my view.
Your deep knowledge of science is appreciated! I knew Resveratrol does affect sleep for some but didn´t know the exact mechanism.
does taking high doses of fish oil increase pgd2 (by way of increasing eicasanoid, which turns into pgd2, i believe)? thx
No, it might in fact lower PGD2. The number at the end tells you the pathway. Fish oil derived eicosanoids end in a 3. Borage and evening primrose oil supply the 1s and 2s, via two different pathways. However I think using either is problematic. They can help with symptoms but also drive symptoms for reasons

I found in the long term that only resveratrol offered a reliable response. I still take it. However I think that a grape sourced (not knotweed) version would more more tolerated.

In my case I don't respond to resveratrol till I take 600mg in one dose. Its like there is a minimum amount for effect. However that response lasts up to four days, though sometimes only three. More than 600mg does nothing extra either.

FIsh oil actually inhibits the process where we make more PGD2. I am not in favour of it for that reason, though it has many other good properties including anti-inflammatory effects. (Actually as I discussed elsewhere I think its pro-inflammatory, but very mildly so, and inhibits the series 2 pathway which is much more inflammatory in general.)

So finding a balance with fish oil is tricky. I think there will be people who benefit for a time, and others who do not. There is no easy way to predict how we will respond without trying it.

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