Turmeric/Curcumin poll

[gbells]

I don't have a way to interpret the dose. I probably take only 300 mg 3x/day. I'm not sure how many molars dose that would be. According to that study the effect is is at 50 M. If I stopped taking curcumin the negatives of the NF-kB inflammation far outweigh the energy cost and I don't regain enough energy for it to really matter. The positives outweigh the negatives. Also, if the mitochondrial chain is broken and leading to free radical generation then inhibiting it would be a good thing overall because it would lower the number of free radicals produced.

 

[keenly]

Curcumin can be a great antiinflammatory but will be a disaster for some people with ME/CFS because of its negative effect on ATP production.

It's what's known as an "uncoupler" because it inhibits the mitochondrial enzyme ATP synthase (Complex V) and prevents that enzyme from making use of the driving force provided by the electron transport chain.(Complexes I, III & IV).[1]

I tried it a number of times over several years always with the result: I would feel better the first day from the antiinflammatory effect but then the next day would begin suffering from increased fatigue/ exhaustion which would not resolve.

This effect of curcumin is for me very consistent with the latest study by Paul Fisher showing that Complex V is impaired in lymphoblasts from ME/CFS patients. (See this thread: https://forums.phoenixrising.me/thr...lized-lymphocytes-from-me-cfs-patients.77577/)

[1] Uncoupling of oxidative phosphorylation by curcumin: implication of its cellular mechanism of action.
https://www.ncbi.nlm.nih.gov/pubmed/19715674/

Any pan killers that are not uncouplers?

 

[Wishful]

Please list the symptoms.

Mainly mental lethargy, and general malaise (for lack of a better term). At more severe levels, I feel muscle aches, but those seem to be neurological misperception rather than physically caused. I haven't noticed that my insomnia correlates with general ME severity.

I can't think of any definite physical symptoms from my ME; they all seem to be neurological. My rosacea does seem to be worse when my ME symptoms are worse, but I think the correlation is between immune system activation and both of those, rather than ME->rosacea.

 

[Wishful]

Curcumin can be a great antiinflammatory but will be a disaster for some people with ME/CFS because of its negative effect on ATP production.

Does this effect also apply to other peroxynitrite scavengers such as cinnamon and rosemary? If not, it seems more likely that some other mechanism is at work. Peroxynitrite does play some important roles in the body, such as deactivating IDO, which is what I think it's doing in my case (scavenging ONOO- means more nasty neurotoxic kynurenines).

 

[gbells]

I haven't researched cinnamon or rosemary and I don't know if any research exists about them. I've never noticed any effect eating them. I would assume they don't have any effect on NF-kB. I also don't know what their safety is if you take them frequently or if they can penetrate the blood brain barrier. Cinnamon is supposed to have effects on blood sugar so I would be leary of that. I wouldn't use either.

I have researched and use curcumin personally so I'm familiar with how much to use and what its effect is.

 

[Wishful]

I'm certainly not taking these herbs/spices regularly. I wondered why turmeric made my symptoms worse, and one of the effects it has is peroxynitrite scavenging. To test that hypothesis I tried some other scavengers. They produced what seemed to be exactly the same effects. I didn't test them further, because I really don't like feeling worse for a day, and I always have some worry that the worsening might somehow 'stick'.

It is a bit surprising how we can share so many aspects of this disease (immune activation triggers, PEM) yet have such different responses in other ways. One drug/compound works well for one, but has the opposite effect for someone else. Some of use have treatments that work really well, but don't work for anyone else.

I still think a good approach to figuring out ME is to get a bunch of PWME who have reliable responses to various factors and do comprehensive before/after testing, and identify what changes they have in common. It's like trying to spot comets: staring at static sky photos (or test results of PWME) won't let you pick out what is a comet, but if you look for changes between two times, the movement is easy to spot.

 

[JES]

Curcumin is a strange supplement. I remember the first time I tried it, I felt some sort of relief, but over a week or so I started getting strange symptoms, where it felt like my brain was more on fire than usual. I didn't get the effect with some other anti-inflammatories like flaxseed oil or NAG, which have been discussed a lot in the long anti-anxiety thread. On the other hand, fish oil in high dose also increases my anxiety, which it shouldn't if it was dampening inflammation.

It could be that my reaction was due to the MAO inhibitor properties of curcumin (source), or as @Wishful mentioned, the peroxynitrite scavenging. It wouldn't be the first time I react in the opposite fashion to a supplement that would be considered beneficial by all reasoning.

The last time I tried curcumin a couple of years ago (I think it was one of the high potency ones that was supposed to have higher bioavailability) I could barely tolerate it at all, so my tolerance to it had actually got worse over time, which doesn't make sense if this disease was simply about inhibiting NF-κB mediated inflammation.

 

[nandixon]

Does this effect also apply to other peroxynitrite scavengers such as cinnamon and rosemary?

Yes, most of the many naturally occurring polyphenolic compounds, including also quercetin and resveratrol in addition to curcumin and the two you mentioned (i.e., rosemary = rosmarinic acid, and cinnamon = derivatives of cinnamic acid) are inherently capable of scavenging peroxynitrite (which is more likely to be a benefit) and in addition are likely to inhibit ATP synthase (which is more likely to be a detriment where energy impairment already exists).

 

[Wishful]

Resveratol is another ONOO- scavenger that affects me the same way turmeric, cinnamon and rosemary do.

the two you mentioned (i.e., rosemary = rosmarinic acid, and cinnamon = derivatives of cinnamic acid) are inherently capable of scavenging peroxynitrite (which is more likely to be a benefit)

Peroxynitrite is harmful in the wrong place, but it's also critical for normal function in the right place (and the right amount, of course). You can't just look at one function (inhibiting the electron transport chain, for example) and say that reducing ONOO- is good for you. Reducing its beneficial effects can be bad for you. So, whether it makes you feel better or worse is a matter of individual cases. For me, ONOO- scavengers seem to make me feel much worse. I haven't thought of any way yet to figure out why they are having the effect they do on me.

@JES if you want to test whether curcumin's effect on you is due to peroxynitrite scavenging, try a spoonfull of cinnamon, rosemary, or some other strong ONOO- scavenger. If your symptoms get worse in the same way, that's the likely cause. At least I think it's unlikely that those particular spices/herbs all have in common some other biological effect and that other similar spices/herbs that aren't strong ONOO- scavengers don't.

 

[nandixon]

For me, ONOO- scavengers seem to make me feel much worse. I haven't thought of any way yet to figure out why they are having the effect they do on me.

At least I think it's unlikely that those particular spices/herbs all have in common some other biological effect and that other similar spices/herbs that aren't strong ONOO- scavengers don't.

You might have missed the most important part of what I wrote so here it is bolded:

Yes, most of the many naturally occurring polyphenolic compounds…..are inherently capable of scavenging peroxynitrite ….and in addition are likely to inhibit ATP synthase...

To give you a visual, below are just some of the polyphenols that by 2010 had been found to inhibit ATP synthase (Complex V). And curcumin and numerous other polyphenols which have also been found to inhibit ATP synthase aren't even shown. ***All of these polyphenols also scavenge peroxynitrite because that is inherent in the polyphenol structure.***

Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4734657/


It seems to me that you're trying to fit a square peg in a round hole because:

1. You're trying to take a known positive attribute of polyphenols (i.e., peroxynitrite scavenging) and ascribe to it a negative outcome, rather than using their known, much more potentially negative attribute (especially in regard to ME/CFS), which is inhibition of ATP synthesis.*

(*Note that in other diseases like cancer, inhibition of ATP synthase may be a benefit.)

2. Your own bloodwork that you've noted elsewhere is inconsistent with your hypothesis (although you would argue that it's not reflective of what's happening in your brain).

I can't say that your idea is impossible, it's just that the alternative appears much more likely to me.

Edited to add: I mentioned it in my first post in this thread but again, having a negative reaction to polyphenols like curcumin, quercetin, etc., appears very consistent with the latest study by Paul Fisher showing that ATP synthase is impaired in lymphoblasts from ME/CFS patients, and that study had excellent p-values. (See this thread: https://forums.phoenixrising.me/thr...lized-lymphocytes-from-me-cfs-patients.77577/)

 

[Wishful]

I found several lists of herbs/spices tested for ONOO- scavenging effectiveness, and tested the strongest ones readily available to me. I didn't find (wasn't looking for) a list of effectiveness as ATP synthase inhibitors, so I don't know whether these herbs and spices are also similarly effective as inhibitors, and the other herbs and spices which also contain polyphenols but don't make my symptoms worse are known to be ineffective inhibitors.

By the scientific method, I'm making an observation: these herbs/spices make my symptoms worse, and their effectiveness as ONOO- scavengers correlates strongly with my symptom severity. I can't rate those herbs/spices for other functions, so I don't know how well they correlate with the observations. Also, my ME severity correlates with TRP levels in my brain and IDO levels (raised during t-cell activation via IFN-g), and a logical result of ONOO- scavenging would be increased IDO lifetime and thus more kynurenines. I haven't found a serious counterargument to that hypothesis. The existence of an alternative hypothesis, involving ATP synthase, without observational evidence supporting it (ie. the effectiveness of ATP synthase inhibitors correlating with how they make me feel) doesn't disprove my hypothesis.

Yes, blood tests seems pretty meaningless for my ME, since my symptoms all seem to reside within my BBB, and the factors that affect the severity correlate with ability to cross the BBB.

I haven't found a strong ONOO- scavenger that crosses the BBB easily that doesn't trigger worse symptoms, although I haven't done an exhaustive search. A quick check didn't find a convenient list of herbs/spices that strongly inhibit ATP synthase in the brain. If you come across a suitable substance that would test my hypothesis, or the ATP synthase one, please let me know.

 

[nandixon]

Also, my ME severity correlates with TRP levels in my brain and IDO levels (raised during t-cell activation via IFN-g), and a logical result of ONOO- scavenging would be increased IDO lifetime and thus more kynurenines. I haven't found a serious counterargument to that hypothesis. The existence of an alternative hypothesis, involving ATP synthase, without observational evidence supporting it (ie. the effectiveness of ATP synthase inhibitors correlating with how they make me feel) doesn't disprove my hypothesis.

I haven't found a strong ONOO- scavenger that crosses the BBB easily that doesn't trigger worse symptoms, although I haven't done an exhaustive search. A quick check didn't find a convenient list of herbs/spices that strongly inhibit ATP synthase in the brain. If you come across a suitable substance that would test my hypothesis, or the ATP synthase one, please let me know.

You have to understand that the very same polyphenolic portion of a molecule, i.e., a phenyl ring with multiple hydroxyl groups attached, that enables it to scavenge peroxynitrite is the very same part of the molecule that also binds to ATP synthase and inhibits it.[1]

So it is quite likely that any peroxynitrite scavenger you have used that crosses the blood brain barrier (BBB) that is a polyphenol will also inhibit ATP synthase. For example, curcumin, resveratrol and quercetin all cross the BBB. They all scavenge peroxynitrite. And they all inhibit ATP synthase.

A good test for you might be ginger. Fresh ginger contains compounds called gingerols which are potent peroxynitrite scavengers and which are able to cross the blood brain barrier. But they are monophenols and so do not significantly inhibit ATP synthase.

If fresh ginger (or a ginger extract of gingerols) makes your symptoms worse then it may be that your hypothesis about peroxynitrite scavengers causing increased kynurenines and being harmful for yourself is correct.

For me, most polyphenols make my fatigue/energy impairment worse but even a large quantity of fresh ginger has no effect.

[1] See, e.g., https://www.pnas.org/content/104/34/13632

 

[Wishful]

I'll have to get some fresh ginger next time I'm in town. I used it years ago with no problems. Small amounts of powdered ginger aren't a problem, but I can't remember whether I had problems with larger amounts.

 

[Wishful]

I tried some powdered ginger. Cooking seems to deactivate it, and the drying process converts some gingerol to other chemicals too, so I didn't notice much effect when I used it in pancakes. Then I took a heaping tsp of the powder on its own. An hour an a half later I was feeling much worse; beyond my normal daily variation in severity. I'm still feeling much worse 24 hrs later. I did buy some fresh ginger root, and I'll try that in a few days (have to stabilize again first), since a single test isn't scientifically valid. However, so far it's pointing to peroxynitrite scavenging.

Thanks for the useful scientific test. Wish I could share the feeling of it with you. Oh well, it'll pass.

 

[Wishful]

Aaaaagh! I tried some fresh ginger yesterday. When I woke up, I felt groggy, but no serious aches, so I thought 'Maybe I don't react to ginger', though I wondered how much fresh ginger it took to equal a tsp of powdered ginger. As the morning has progressed, I've felt progressively worse. Very groggy, like I'd taken a big dose of Benadryl , or maybe melatonin. I would go for a walk, but I fear I'd fall over, or walk into a tree (the woods are full of 'em). I keep having to backspace over my spelling errors.

I really should repeat this experiment to verify that it is the ginger, but I really, really don't want to repeat this experience. I really, really don't want to have to eat raw ginger either.

 

[Sarah94]

@Avena @Irabu @LongMacc @edawg81
Since you answered 'yes' to this poll, I clearly have something in common with you. Please, can you tell me whether you've found anything else that improves your cognitive function / mental energy as well?

 

[Avena]

@Sarah94 B12 - make sure to try different kinds to find the right type and/or brand for you before you settle.

 

[Sarah94]

@Sarah94 B12 - make sure to try different kinds to find the right type and/or brand for you before you settle.

Me too, I already take that.

Well, I guess that's two similarities we have.

Anything else that helps you?

 

[edawg81]

@Avena @Irabu @LongMacc @edawg81
Since you answered 'yes' to this poll, I clearly have something in common with you. Please, can you tell me whether you've found anything else that improves your cognitive function / mental energy as well?

Benzos, nsaids, post-migraines and sleep deprevation.
none of which i really recommend on a regular basis.

NAC may have helped but it made me too jittery.

 

[Avena]

@Sarah94

Me too, I already take that.

Well, I guess that's two similarities we have.

Anything else that helps you?

One that is quite essential for my cognitive function is Equazen Eye Q (Europe only product, I think?). I think Vitamin D and a combination product with different kinds of vitamin B also contributes.