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


You may have looked into this but thought i would mention it anyway.
The amino acid taurine which doesnt become apart of the protein supply but instead polices our cell membranes, keeps potassium and magnesium inside the cells and keeps excess sodium out, so works like a natural diuretic. This mechanism can also possibly reduce your need to supplement with potassium which can have its issues if one over supplements with it. Taurine also has some brain calming effects and is used in seizure disorders. it can also reduce the excitotoxic effects of msg and aspartame.

I mainly mention this as it may be helpful for you in maintaining intracellular potassium levels.

My Zombie Science blog is done and I am now working on the sequel. I would like to post both together before Christmas, but if not I will post the Zombie Science blog alone. It discusses the impact of zombie science under the influence of churnalism and dogmatic verificationism. It leads into a discussion of the concept of balance of power.
Resveratrol appears to block a substance called PDE4, which might also make it an immune modulator.

However based on my reaction its affect on reducing sleep appears to be prolonged, which means that sleep might continue to be compromised for some time after ceasing resveratrol.

However there is some indication that some of the negative effects of lack of sleep will be alleviated with this approach, due to decreasing PDE4 activity, and this should improve memory.

It isn't simple.
Darn, via PDE4 I can now tie PGD2 to low HDL and to exaggerated LPS response. This is getting interesting. It is also linked to rheumatoid arthritis and abnormal adrenal response. Exploring the nature of those links is one of my goals for the next month or so. It can even drive a TH2 response perhaps ... still looking at this. It may even lower excessive folate usage, though this is still very unsure.

In case people are wondering, PDE4 is phosphodiesterase-4.

Other side effects of PDE4 inhibition include nausea or vomiting, but my sleep issues arrive at much lower doses than appear necessary for nausea or vomiting - I have not experienced either.
Resveratrol WARNING. Resveratrol appears to have high affinity for PDE4 and some for other phosphodiesterases. Its not specific. What we know about it on the good side is fantastic stuff. Here is the bad side.

This is altering intracellular messenging. It will have very broad consequences. So the continuous use of this at high doses will bring high risk.

Responsible use of resveratrol, I currently think, would be lower doses used intermittently, or higher doses used very briefly. Continuous use at higher doses will disrupt intracellular machinery with unknown but potentially serious consequences.

I will continue to use it, but pulse dose it at lower doses.
This may now explain muscle wastage in ME patients, eiabetes insipidis, cardiac and vascular irregularities and a lot of other things. I am still investigating. A recent finding of high purine excretion in fibromyalgia fits this model too.
To throw a wrench in this line of thinking, yesterday I discovered that alkaline phosphatase, a substance I will be talking about in a later blog, has phosphodiesterase catalytic activity. This may profoundly alter my opinions when I have looked into this some more.

According to this study, Distinct Cerebrospinal Fluid Proteomes Differentiate Post-Treatment Lyme Disease from Chronic Fatigue Syndrome, Prostaglandin D2 synthase 21kDa was abnormal in 113 CFS patients and 124 post Lyme, but only 79 controls.

However phosphodiesterases were often elevated, though in smaller numbers. A PDE2 precursor was raised in 189 CFS, 175 post Lyme, and only 57 controls. A second isoform is abnormal in 182 CFS, 170 post Lyme and 54 controls. This indicates that the chemistry I am tracking is probably relevant to post Lyme patients as well. However PDE proteins should be made in the brain in my hypothesis, and hence only a small amount will make it to the spinal fluid. So the question is whether or not the spinal fluid accurately reflects PDE in the brain. It might, but I am not sure.

Given that there were on the order of 2700 patients in each group, these are not huge numbers. However this might indicate a subset is involved.

Given that I think it can be raised or lowered or in transition, I think this might be important. I have been focussed on PDE4, but it looks like the abnormality might be in PDE2.
I sympathise over the lack of sleep - that is horrible. Is it the kind where you feel quite relaxed and convinced that you are about to drop off, but nothing happens? This was a type I first noticed in 2010. It may be coincidence, but it appeared to be alleviated when I started taking a bone-mineral supplement which also contains a few other things. This page shows you the product and its ingredients:

I've been taking it ever since. I actually started taking it as I was seeing evidence of bone mineral deficiency in the form of generalised tooth pain and a wrist fracture from a minor fall - the only fracture I have ever had in 59 years. It seems to have helped there too.

I do sometimes still get that weird kind of insomnia, usually when I appear to have been passing a lot of minerals in urine following over-exertion.

Another thing that may help is melatonin - the vital 'off switch' without which sleep doesn't happen.

Sorry I don't have time to read about all your research, but good luck with it.
Actually melatonin is not that important for sleep, its impact is way overblown. Melatonin is one of at least fifteen factors that influence sleep timing, and its an important antioxidant especially for the brain. Its also a factor that only works to assist sleep in two brief time windows during the day. Many of us simply do not respond to melatonin. I don't. In my case I tried to find an altered time window for response by taking it at different times. That didn't work either.

What actually switches off the brain is PGD2, so far as I am aware. Melatonin is simply one of at least fifteen factors that regulate the timing of PGD2 synthesis and release.

So when excessively insomniac on resveratrol I can rest, I can be relaxed, but my brain doesn't sleep.
I am so glad people like you Alex are forging ahead, I dearly miss having that zeal but after 25yrs I wish someone would hook me to an IV and cure me. I have trouble swallowing all the pills.
Hi @PNR2008, I had no zeal just seven years ago. I was burnt out after finishing my biochem degree, moving house, and going almost broke. This is a marathon, not a sprint, and with enough time recovering we can often catch our breath. If not ... in part I do what I do because so many are simply too sick to do anything. I have talked with quite a few very sick patients ... though anyone able to chat online is not the sickest of us.
I am happy you are here on PR. Just to tell you what happened to me today. I have a thinning membrane in my right eye that probably will detach in the future, the dr thought it was ready to blow 4yrs ago but here I am. My sister had two detached retinas and my brother one so I'm at risk. Anyway I'm concerned but know what to look for when it will happen so not obsessive about it. The thing is this, after two hrs of tests now at home I can barely walk and it was all brain stuff. One test my brain zoned out for a few seconds just to regroup. It's the tests that are killing me, eye tests, tilt table, MRI, spect and BEAM scans even spread out I'm losing it. DON"T TOUCH ME YOU CREEPS. Sorry had to vent a little, still glad for your input.
Ginger and rosemary are supposed to help with eicosanoids. I don't know the details and it seems there are good and bad eicosanoids (?) New Chapter is selling an extract of ginger and rosemary:
(actually, it's mostly ginger)
Be very very careful with ginger. It may help at first, but I predict a big crash if you use it too much. Lots of things help a bit with eicosanoids, but most of those fail at some point.
Why could ginger cause a crash? There were two periods where I was drinking ginger tea and lost some weight and each time I experienced a relapse afterwards. I thought maybe ginger played a part, but I wasn't sure why or if it was just a coincidence (since there were several other factors involved). It seems like for every good thing about a supplement I learn there's also a certain contraindication.
I am not sure why ginger causes a crash, but I have an idea - this is hypothetical though. Ginger suppresses excessive utilization of arachidonic acid, which blocks series 2 eicosanoid hormones, which is a good thing. However this means arachidonic acid levels rise ... and rise ... and rise. This then overwhelms the ginger and the benefits go away. However if you then stop taking the ginger, the increased arachidonic acid leads to increased eicosanoid synthesis. This magnifies symptoms, and induces a crash. Most supplements and herbs are tinkering with peripheral mechanisms of ME, they do not seem to be correcting the underlying cause ... and thats part of why they have problems. Until we really understand the cause its going to be hard to get treatment right, which is why we are all searching.
Ginger makes me overstimulated. I'm not sure if that has anything to do with triggering a crash or not.

And do you disagree with Rich about some of the symptoms from methylation due to excitotoxicity? He thought it was from a drop in glutathione in the astrocytes which then causes a glutamate buildup:

It seems that eicosanoids are involved with astrocytes or microglia which also leads to glutamate. Also quinolic acid (QUIN) or inflammatory cytokines.
There are so many pathways involved in excitotoxicity that I am mostly taking a wait and see what the research turns up attitude. Sure there are lots of possibilities, but which one do *I* have? Or most of us? We need both more science and more testing.
Hi Alex,

Very interesting! Were you using any particular form of resveratrol when you noticed this? It seems to come in two forms, the high purity 98% pharma grade or a lower 50% purity in typical supplements. Also was there any particular dosage you found necessary?

Hi Unim, I was using 98% resveratrol. Dosage seems to be variable. I am currently taking 600mg about once or twice a week. I don't need to take it every day. However I have higher body weight than most ME patients, so 300mg would be a more equivalent dose for many. There are signs that resveratrol sometimes fails to control my breathing issues, but only occasionally, and not very severely.
Heaps, my genetic makeup is a taurine-generator and I am drowning in taurine and I can tell you that w/o DHEA I am still EXTREMELY sensitive to msg (it could kill me).

Alex, your protocol disturbs me because you are picking and choosing B vitamins when they are synergistic and should be taken together at least in a low dose. I am wondering why you are attacking only phosphidoesterases [sic!] and skipping basics like supplying B2 and B3 for the Krebs cycle? And I am wondering if you are taking the active form of CoQ10 (ubiquinol).

I never got on the reservatrol bandwagon because I take sooooo many supplements and that one was merely touted to the rafters for longevity (when I am more interested in making the time I've got have quality). I have tried it several times with no discernible results, but maybe I'll give it a try again.

I started taking melatonin at 6mg)since Life Extension said it is the MOST IMPORTANT ANTIOXIDANT TO THE BRAIN NEXT TO DOPAMINE! (I lead my life by the principle that antioxidants are numero uno in importance in a supplementation strategy).

If I fail to take 400-600mg magnesium citrate/day I cannot sleep. I think this is actually a good thing because with low magnesium you die of heart trouble so I'd rather be notified by wakefulness and be forced to take care of it every day than let the problem build up. How much mg do you take? what form?
Alex, one of your comments indicates u r taking reservatrol for EXCITOTOXICITY? I just want to say that DHEA cures excitotoxicity for me. I have found studies that say estrogen protects against excitotoxocity. I cannot say if that is what does the job because DHEA makes other hormones. But I started taking DHEA for panic and high blood pressure and I am absolutely positive that neither bioidentical estrogen nor progesterone took care of THAT. So DHEA all of itself was proven to raise NO and maybe is the real factor in protecting against excitotoxicity. idk

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