High Norepinephrine Can Be Used To Diagnose Fibromyalgia

[haidut]

Fibromyalgia is one of the "mysterious" spectrum disorders, which baffles doctors. There is no structural abnormality in muscle tissue and as a result many patients are treated as if the condition is a psychiatric one. It is known to be greatly exacerbated by stress, which is a convenient excuse to lump it as a symptom of depression or another mental disorder. The typical treatment is with SSRI drugs and more recently drugs like Lyrica. However, neither of these options helps much and in fact SSRI have been shown to worsen the condition. A few studies showed anti-serotonin drugs to be therapeutic, suggesting fibromyalgia is a metabolic/stress driven condition.
https://raypeatforum.com/community/threads/anti-serotonin-drugs-may-treat-fibromyalgia.12521/

Some of the other mediators of chronic stress are cortisol, and epinephrine/norepinephrine. While there are no recent studies on the role of cortisol in fibromyalgia, this recent study found a causative role for norepinephrine. In fact, it found that norepinephrine levels beyond a certain point can be used as a reliable diagnostic fibromyalgia biomarker. This findings is not surprising, considering epinephrine/norepinephrine elevate lactate and deplete magnesium, both of which can quickly bring about symptoms of "fibromyalgia" even in people not diagnosed with it.
I know a few users on the forum found out they have high epinephrine/norepinephrine. I wonder if they also have "fibromyalgia" symptoms...
@Regina

SAGE Journals: Your gateway to world-class journal research
Neurotransmitters May Have Important Role in Fibromyalgia, Study Says

"...Further analysis revealed that higher norepinephrine blood levels were associated with worse physical health status of the patients, as determined by the physical component summary of the SF-12 survey. Also, the levels of this particular neurotransmitter were found to have diagnostic potential. Researchers found that 90 percent of individuals with norepinephrine blood levels above 694.69 pg/ml (picogram/milliliter) may be diagnosed with fibromyalgia. Supported by these results, the team believes that norepinephrine “may be an accurate predictor” of fibromyalgia that is associated with worse physical health status, which “may greatly help in the diagnosis and treatment of this syndrome.”"

 

[MrSmart]

Interesting. Although I reckon NE serum levels reflect sympathetic rather than central nervous system levels. These are symptoms of sympathomemtic drugs as well, and indeed a marker of chronic stress response, or inability to metabolize NE and D. It's also largely genetic on the COMT gene, I forgot the name, but quite common.

 

[Kartoffel]

@haidut I think it is not completely accurate to say they found a causative role. From quickly looking at the paper, it looks like it is only a correlation, and I am not sure whether the increased norepinephrine might not be a protective attempt of correction by the body. Consuming sugar rather than starch raises norepinephrine levels. Peat has spoken very "favorably" about norepinephrine as an important integrator of energy metabolism. Below are two responses I got from him regarding norepinephrine.

Btw, here is the sci-hub link to the full-text: Sci-Hub | Catecholamine and Indolamine Pathway: A Case–Control Study in Fibromyalgia | 10.1177/1099800418787672

"We also found that high norepinephrine levels were related to worse physical health status in patients with FM. These data together suggest that the dysregulation of norepinephrine may be involved in the physiopathology of FM. These results provide insight into thephysiopathologic mechanisms of FM that may ultimately helpin the diagnosis, management, and treatment of patients with FM" (Rus et al. 2018: 8).​

"It increases oxygen consumption and carbon dioxide production, with many protective effects. Noradrenalin is a central part of brain functioning, and integrates energy metabolism throughout the body, releasing glucose from stored glycogen; it isn't a stress hormone. Sugar protects against increased cortisol/cortisone. The cultists say it's addictive and causes stress, but that's their problem." (RP)​

"Hypothyroidism makes cells insensitive, and to keep functioning, the body has to increase the signals to activate them. Some hypothyroid people get very tense, alert, and sometimes even hypermetabolic, while others become sluggish, dull, and cold. Noradrenalin is largely responsible for the better kind of adaptive response. Serotonin dominance tends toward hibernation as a way to get through stress. Evidence from lizards and hibernating squirrels shows that polyunsaturated fats are responsible for that kind of adaptive avoidance. When thyroid functions, and the available energy fuels (sugars and saturated fats) are optimal, cells are very sensitive to all appropriate signals, and so the nerve signals, and other hormones, can decrease to very low levels. Both glucose and fructose help to keep the brain's T3 level up." (RP)
​

Here is the noradrenaline daily pattern of people that have been on a high-sucrose diet for 14 days (Raben et al. 1997)

​

 

[haidut]

@haidut I think it is not completely accurate to say they found a causative role. From quickly looking at the paper, it looks like it is only a correlation, and I am not sure whether the increased norepinephrine might not be a protective attempt of correction by the body. Consuming sugar rather than starch raises norepinephrine levels. Peat has spoken very "favorably" about norepinephrine as an important integrator of energy metabolism. Below are two responses I got from him regarding norepinephrine.

Btw, here is the sci-hub link to the full-text: Sci-Hub | Catecholamine and Indolamine Pathway: A Case–Control Study in Fibromyalgia | 10.1177/1099800418787672

"We also found that high norepinephrine levels were related to worse physical health status in patients with FM. These data together suggest that the dysregulation of norepinephrine may be involved in the physiopathology of FM. These results provide insight into thephysiopathologic mechanisms of FM that may ultimately helpin the diagnosis, management, and treatment of patients with FM" (Rus et al. 2018: 8).​

"It increases oxygen consumption and carbon dioxide production, with many protective effects. Noradrenalin is a central part of brain functioning, and integrates energy metabolism throughout the body, releasing glucose from stored glycogen; it isn't a stress hormone. Sugar protects against increased cortisol/cortisone. The cultists say it's addictive and causes stress, but that's their problem." (RP)​

"Hypothyroidism makes cells insensitive, and to keep functioning, the body has to increase the signals to activate them. Some hypothyroid people get very tense, alert, and sometimes even hypermetabolic, while others become sluggish, dull, and cold. Noradrenalin is largely responsible for the better kind of adaptive response. Serotonin dominance tends toward hibernation as a way to get through stress. Evidence from lizards and hibernating squirrels shows that polyunsaturated fats are responsible for that kind of adaptive avoidance. When thyroid functions, and the available energy fuels (sugars and saturated fats) are optimal, cells are very sensitive to all appropriate signals, and so the nerve signals, and other hormones, can decrease to very low levels. Both glucose and fructose help to keep the brain's T3 level up." (RP)
​

Here is the noradrenaline daily pattern of people that have been on a high-sucrose diet for 14 days (Raben et al. 1997)

View attachment 9979

​

Those are good points. I guess it would depend if adrenaline and cortisol were also elevated. If they were, then I guess we can say the norepinephrine release was a part of stress-cascade. So, while it may be protective in this situation it may be a biomarker of bad things happening. Btw, Peat's quotes do not necessarily absolve noradrenaline. They make it sounds more like a less suboptimal adaptation to hypothyrodism. I wonder if noradrenaline drops with improving thyroid function. Maybe you can ask him about it?

 

[Kartoffel]

Those are good points. I guess it would depend if adrenaline and cortisol were also elevated. If they were, then I guess we can say the norepinephrine release was a part of stress-cascade. So, while it may be protective in this situation it may be a biomarker of bad things happening. Btw, Peat's quotes do not necessarily absolve noradrenaline. They make it sounds more like a less suboptimal adaptation to hypothyrodism. I wonder if noradrenaline drops with improving thyroid function. Maybe you can ask him about it?

I think increased noradrenaline might just be like increased cholesterol, it's not really bad by itself but a sign of something not working properly. Chronically elevated noradrenaline certainly doesn't seem to indicate good health, but it might represent "making the best out of the situation". I can ask him about thyroid function and noradrenaline levels, but I think the answer is already included in the above quote. I think what he says is that hypothyroidism makes cell less responsive to signals by hormones and neurotransmitters. Thus, the body has to increase the output of these signals to keep communication running. Once proper thyroid function is restored, the cells become more sensitive, and weaker signals (fewer neurotransmitters and hormones) are required. I think Peat's big theory is that hormones in general are mainly an adaptation to a less than optimal state, and wouldn't be required at all (or in tiny amounts), if metabolic energy and CO2 were abundant.

When thyroid functions, and the available energy fuels (sugars and saturated fats) are optimal, cells are very sensitive to all appropriate signals, and so the nerve signals, and other hormones, can decrease to very low levels.​

 

[Kartoffel]

There is also quite a bit of in vivo and in vitro evidence indicating that noradrenaline increases deiodinase activity in various cell types and therefore can help them to maintain adequate thyroid function.

Am J Physiol. 1989 Jan;256(1 Pt 1):E74-9.
Effect of thyroid status on catecholamine stimulation of thyroxine 5'-deiodinase in brown adipocytes.
Mills I1, Raasmaja A, Moolten N, Lemack G, Silva JE, Larsen PR.
Author information
Abstract
We examined type II 5'-iodothyronine deiodinase activation by adrenergic agonists in dispersed brown adipocytes from euthyroid and hypothyroid rats. In euthyroid cells, basal deiodinase activity was 30-100 fmol I-.h-1.10(6) cells-1 and increased four- to fivefold during exposure to norepinephrine, an effect that was enhanced by alprenolol. In cells from hypothyroid rats, norepinephrine caused a three- to fourfold greater deiodinase stimulation than occurred in euthyroid cells but alprenolol inhibited the response. In euthyroid cells, phenylephrine caused greater stimulation than did norepinephrine, but this was inhibited by alprenolol. Isoproterenol and 8-bromoadenosine 3',5'-cyclic monophosphate (8-BrcAMP) inhibited the phenylephrine response but were modestly stimulatory alone. Although both alpha 1- and beta-adrenergic agonists increased deiodinase activity modestly in hypothyroid cells, in combination they caused a marked synergistic stimulation. This synergism was induced by 8-BrcAMP and forskolin, as well as by isoproterenol. The stimulation of deiodinase in both cell types was due to an increase in Vmax without an alteration in the Km and required mRNA synthesis. The markedly greater deiodinase response of the hypothyroid brown adipocyte to catecholamines may serve to enhance the impaired thermogenic response of this tissue to cold exposure.

 

[haidut]

I think Peat's big theory is that hormones in general are mainly an adaptation to a less than optimal state

Yes, I have seen a few of his quotes on this. In one interview he said that if CO2 is sufficiently high then one get by with no hormones at all, except progesterone. I wonder what is the special role of progesterone that cannot be replaced by better thyroid function...

 

[Kartoffel]

Yes, I have seen a few of his quotes on this. In one interview he said that if CO2 is sufficiently high then one get by with no hormones at all, except progesterone. I wonder what is the special role of progesterone that cannot be replaced by better thyroid function...

Maybe it's just the body's favorite hormone because it is the most general, most protective, and can perform (to a lesser degree) all the functions of the other steroids (except estrogen and testosterone). At least that is what Ray says. I can't actually say whether that is true - I know that it can perform the functions of cortisol at the very least.

 

[Regina]

Fibromyalgia is one of the "mysterious" spectrum disorders, which baffles doctors. There is no structural abnormality in muscle tissue and as a result many patients are treated as if the condition is a psychiatric one. It is known to be greatly exacerbated by stress, which is a convenient excuse to lump it as a symptom of depression or another mental disorder. The typical treatment is with SSRI drugs and more recently drugs like Lyrica. However, neither of these options helps much and in fact SSRI have been shown to worsen the condition. A few studies showed anti-serotonin drugs to be therapeutic, suggesting fibromyalgia is a metabolic/stress driven condition.
https://raypeatforum.com/community/threads/anti-serotonin-drugs-may-treat-fibromyalgia.12521/

Some of the other mediators of chronic stress are cortisol, and epinephrine/norepinephrine. While there are no recent studies on the role of cortisol in fibromyalgia, this recent study found a causative role for norepinephrine. In fact, it found that norepinephrine levels beyond a certain point can be used as a reliable diagnostic fibromyalgia biomarker. This findings is not surprising, considering epinephrine/norepinephrine elevate lactate and deplete magnesium, both of which can quickly bring about symptoms of "fibromyalgia" even in people not diagnosed with it.
I know a few users on the forum found out they have high epinephrine/norepinephrine. I wonder if they also have "fibromyalgia" symptoms...
@Regina

SAGE Journals: Your gateway to world-class journal research
Neurotransmitters May Have Important Role in Fibromyalgia, Study Says

"...Further analysis revealed that higher norepinephrine blood levels were associated with worse physical health status of the patients, as determined by the physical component summary of the SF-12 survey. Also, the levels of this particular neurotransmitter were found to have diagnostic potential. Researchers found that 90 percent of individuals with norepinephrine blood levels above 694.69 pg/ml (picogram/milliliter) may be diagnosed with fibromyalgia. Supported by these results, the team believes that norepinephrine “may be an accurate predictor” of fibromyalgia that is associated with worse physical health status, which “may greatly help in the diagnosis and treatment of this syndrome.”"

Thx haidut. I am following and trying to connect the dots. I do have some symptoms of fibromyalgia that seem to "randomly" percolate in one way or another. Currently and perplexingly in my fingers. Interesting that high NE depletes magnesium--further elucidating stress effect on MR (I think). There is also the "SIBO" effect on RA, which I am not discounting in the overall metabolic dysregulation or areas out of coherency. Thx

 

[Kartoffel]

By the way, @haidut what is the reference for "noradrenaline depletes magnesium?" Sorry if this was already posted somewhere...

 

[Regina]

Those are good points. I guess it would depend if adrenaline and cortisol were also elevated. If they were, then I guess we can say the norepinephrine release was a part of stress-cascade. So, while it may be protective in this situation it may be a biomarker of bad things happening. Btw, Peat's quotes do not necessarily absolve noradrenaline. They make it sounds more like a less suboptimal adaptation to hypothyrodism. I wonder if noradrenaline drops with improving thyroid function. Maybe you can ask him about it?

That is certainly how I feel since improving thyroid function. I would say I have never been prone to serotonin dominance. And that my high NE (and hypermetabolic, alert, skinny, tense) in the past was compensatory adaption to long standing hypothyroid condition. And yes, NE has dropped (I'm fat and easy-going ).

 

[haidut]

By the way, @haidut what is the reference for "noradrenaline depletes magnesium?" Sorry if this was already posted somewhere...

I have seen a few references mentioned in books and it is a common mentioning in biochemistry books that catecholamines, glucocorticoids and especially mineralocorticoids deplete magnesium. One of them is in "The Magnesium Miracle", top of page 14. See attached screenshot.

Here is one study that mentions several others.
https://www.annalsthoracicsurgery.org/article/0003-4975(94)91657-8/pdf
"...Numerous reports have documented myocyte depletion of magnesium by catecholamines, ischemia and reperfusion, and extracellular magnesium by potassiumlosing diuretics [5-7]."

And here is a specific study, but with adrenaline.
Effect of intravenous epinephrine on serum magnesium and free intracellular red blood cell magnesium concentrations measured by nuclear magnetic re... - PubMed - NCBI
"...Endogenous catecholamine release during stress or acute illness may therefore contribute to the hypomagnesemia seen in acutely ill patients. Our data also suggest that hypomagnesemia seen under conditions of acute stress may not always imply depleted tissue Mg stores."

If I find something specifically on norepinephrine I will post it here, but if its effects were unique among the catecholamines it would have been mentioned.

 

[Kartoffel]

I have seen a few references mentioned in books and it is a common mentioning in biochemistry books that catecholamines, glucocorticoids and especially mineralocorticoids deplete magnesium. One of them is in "The Magnesium Miracle", top of page 14. See attached screenshot.

View attachment 9986

Here is one study that mentions several others.
https://www.annalsthoracicsurgery.org/article/0003-4975(94)91657-8/pdf
"...Numerous reports have documented myocyte depletion of magnesium by catecholamines, ischemia and reperfusion, and extracellular magnesium by potassiumlosing diuretics [5-7]."

And here is a specific study, but with adrenaline.
Effect of intravenous epinephrine on serum magnesium and free intracellular red blood cell magnesium concentrations measured by nuclear magnetic re... - PubMed - NCBI
"...Endogenous catecholamine release during stress or acute illness may therefore contribute to the hypomagnesemia seen in acutely ill patients. Our data also suggest that hypomagnesemia seen under conditions of acute stress may not always imply depleted tissue Mg stores."

If I find something specifically on norepinephrine I will post it here, but if its effects were unique among the catecholamines it would have been mentioned.

Thanks, I just suspect that it is unjustly named with the others here, and that correlation might not equal causation. It's action on thyroid activity might actually have some magnesium-sparing effect, but I haven't looked into that.

 

[lampofred]

What are some actionable ways to reduce norepinephrine besides just the vague "reduce stress" and "have good thyroid function"? I know the dopamine to -> norepinephrine conversion is copper dependent, so one way is to make sure you are high in zinc and low in copper, but is there anything else? I suspect moving to a high altitude will also reduce the conversion, but that's not actionable...

 

[Frankdee20]

I developed this condition many years ago after experiencing a negative reaction to 5htp, then 7 years later, after a negative reaction to SSRI. I’m fine today, but only after carrying around magnesium deficiency for years.

 

[haidut]

What are some actionable ways to reduce norepinephrine besides just the vague "reduce stress" and "have good thyroid function"? I know the dopamine to -> norepinephrine conversion is copper dependent, so one way is to make sure you are high in zinc and low in copper, but is there anything else? I suspect moving to a high altitude will also reduce the conversion, but that's not actionable...

I think iron status is also important in keeping (nor)epinephrine from rising too high. Both high and low iron are known to increase catecholamine secretion. Low iron usually results in higher copper levels since the two can fill in for each other (partially), and as you mentioned higher copper can induce dopamine breakdown into the *phrines. Salt, taurine, and pro-GABA substances like GABA itself, progesterone, magnesium, etc are also good at keeping the *phrines low. Magnesium infusions are well-known to quickly drop elevated adrenergic tone and is commonly used in hospitals in so-called "adrenergic storms". So, I guess a salty meal with some magnesium would be the easiest/safest way.

 

[lampofred]

I think iron status is also important in keeping (nor)epinephrine from rising too high. Both high and low iron are known to increase catecholamine secretion. Low iron usually results in higher copper levels since the two can fill in for each other (partially), and as you mentioned higher copper can induce dopamine breakdown into the *phrines. Salt, taurine, and pro-GABA substances like GABA itself, progesterone, magnesium, etc are also good at keeping the *phrines low. Magnesium infusions are well-known to quickly drop elevated adrenergic tone and is commonly used in hospitals in so-called "adrenergic storms". So, I guess a salty meal with some magnesium would be the easiest/safest way.

Thanks for the info about the iron. And Peat says salt + magnesium retention depends on thyroid status and not intake, so I guess at the end of the day, it does go back to thyroid.

 

[lampofred]

I developed this condition many years ago after experiencing a negative reaction to 5htp, then 7 years later, after a negative reaction to SSRI. I’m fine today, but only after carrying around magnesium deficiency for years.

So it's related to excess serotonin? And how did you manage to fix it?

 

[Frankdee20]

So it's related to excess serotonin? And how did you manage to fix it?

It was so scary, all of a sudden one day, a switch in my nervous system was activated. Wasn’t a good one either, it was intense anxiety too. Only time, and lots of calming implementation for brain chemistry