Does anyone have any ideas, or papers which might shed light on the mechanism behind Magnesium being beneficial as a supplement?
What is the mechanism of Magnesium, and how or why does it help?
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In high doses, magnesium acts as a potent NMDA receptor inhibitor. Dr Cheney has speculated that the overstimulated "wired" state of ME/CFS may be due to too much extracellular glutamate in the brain. This is a reasonable idea, since brain inflammation and microglial activation produce high amounts of glutamate.
So taking high doses of magnesium (via magnesium sulfate injections or via magnesium cream applied transdermally from head to toe) acts as an NMDA receptor blocker, and may thereby help calm the "wired" state.
Another possible reason why magnesium may benefit ME/CFS is because there is a deficiency of intracellular magnesium in the red blood cells in ME/CFS. Ref: 1
And if you look at the studies on mitochondrial dysfunction in ME/CFS by Myhill, Booth and McLaren-Howard, you will see that many ME/CFS patients' cells are low in what these authors refer to as the ATP Ratio.
In the cell, in order for ATP to be able to liberate its energy, it must first form a complex with the magnesium present in the cell (this complex is called Mg-ATP). Any ATP molecule that is not bonded onto magnesium in such a complex cannot liberate the energy its carries.
The ATP Ratio of a cell is the fraction of ATP molecules in the cell that are complexed with magnesium, and the higher this ratio, the more of the ATP molecules in the cell are available to supply energy. ME/CFS patients are often found to have a low ATP Ratio, which may reflect low levels of magnesium in the cell (see row B, column 2 of fig 2 of the Myhill study to see the ATP Ratios of ME/CFS patients).
Thus magnesium supplementation may help raise the ATP Ratio, thereby making more energy available in the cell.
So taking high doses of magnesium (via magnesium sulfate injections or via magnesium cream applied transdermally from head to toe) acts as an NMDA receptor blocker, and may thereby help calm the "wired" state.
Another possible reason why magnesium may benefit ME/CFS is because there is a deficiency of intracellular magnesium in the red blood cells in ME/CFS. Ref: 1
And if you look at the studies on mitochondrial dysfunction in ME/CFS by Myhill, Booth and McLaren-Howard, you will see that many ME/CFS patients' cells are low in what these authors refer to as the ATP Ratio.
In the cell, in order for ATP to be able to liberate its energy, it must first form a complex with the magnesium present in the cell (this complex is called Mg-ATP). Any ATP molecule that is not bonded onto magnesium in such a complex cannot liberate the energy its carries.
The ATP Ratio of a cell is the fraction of ATP molecules in the cell that are complexed with magnesium, and the higher this ratio, the more of the ATP molecules in the cell are available to supply energy. ME/CFS patients are often found to have a low ATP Ratio, which may reflect low levels of magnesium in the cell (see row B, column 2 of fig 2 of the Myhill study to see the ATP Ratios of ME/CFS patients).
Thus magnesium supplementation may help raise the ATP Ratio, thereby making more energy available in the cell.
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All I know is that it helps with muscle cramps!
If I take it daily I get far fewer problems with cramp...
If I take it daily I get far fewer problems with cramp...
Thanks @Hip. The Lancet paper is interesting (I'm suprised that they publish credible science related to CFS to be honest, I've not come across any published by them yet). Do you know if they looked in other cell lines other than Red Blood Cells? That paper is fairly old now, 1991, I wonder what else happened in regards to that finding?
There is also the possibility that patients have a disturbed mineral metabolism which may be difficult to detect with standard testing.
http://clinmedjournals.org/articles...cal-nephrology-and-renal-care-jcnrc-2-008.pdf
Magnesium deficiency is also difficult to detect. Low blood magnesium is not an indicator magnesium deficiency. So patients that respond to magnesium may simply have a magnesium deficiency.
57% of the US population does not meet the US RDA for dietary intake of magnesium. Presumably us patients are at even greater risk due to general poor health.
https://en.wikipedia.org/wiki/Magnesium_deficiency_(medicine)
http://clinmedjournals.org/articles...cal-nephrology-and-renal-care-jcnrc-2-008.pdf
Magnesium deficiency is also difficult to detect. Low blood magnesium is not an indicator magnesium deficiency. So patients that respond to magnesium may simply have a magnesium deficiency.
57% of the US population does not meet the US RDA for dietary intake of magnesium. Presumably us patients are at even greater risk due to general poor health.
https://en.wikipedia.org/wiki/Magnesium_deficiency_(medicine)
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I have to warn people that this is not a simple high/low magnesium question, and definitely not "more is better". I've been trying to understand problems with ion channels and electrolytes for some time. Rarely, I come across something as clear-cut as happened with Gingergrrl. She was given IV saline with up to 4 grams of magnesium salts. (I don't know how much got into her before she was rushed to emergency.) The result was flash pulmonary edema, a medical emergency. Conventional medical wisdom was simply that they had tried to run the infusion too fast -- end of discussion.
Magnesium ions act as competitive antagonists of calcium ions, so this pointed to a problem with calcium channels. When I later found out she had had a severe reaction to a calcium blocker I felt sure the problem was with calcium channels. Because of sudden onset, I was convinced this was an autoimmune problem. She tested positive for antibodies to N-type calcium channels on the Mayo PAVAL paraneoplastic panel.
Like the account above, she also had problems with glutamate demonstrated by antibodies to GAD65. This knocks out an important enzyme which is needed to convert glutamic acid to GABA. The result is a shift from GABA to glutamates, and from parasympathetic to sympathetic activation. It should have been no surprise to anyone that she was constantly "wired", but this was considered a psychological problem. Here's how serious this interaction can be.
The most serious problem this reveals is a medical profession depending on "diagnostic tripwires" where a single measurable quantity goes past some threshold. Every such metabolic process involves feedback, so it is quite likely there will be compensation for changes in levels until they reach pathological levels where they destroy pancreatic cells (GAD65 antibodies causing type 1 diabetes), prevent chest muscles from supporting breathing (N-type calcium channel antibodies), or interfere with the functioning of the heart.
At this point we haven't even touched on NMDA receptors, which also control ion channels, and can cause really bizarre symptoms of autoimmune encephalitis. All these things must interact for natural function of nervous systems, and the important factors are not levels, but ratios of rates under different conditions. Does anyone measure rates?
I know a patient who has normal levels of electrolytes without any special activity, but has severe reactions to changes in potassium levels triggered by carbohydrate intake or exercise which can cause paralysis lasting up to 3 days. Potassium uptake during metabolism or exercise is well documented. Potassium moves from the blood to cells or muscle fibers. At this time I don't have a single reliable reference for the way all these things are related. I can only suggest doing a Google Scholar search for potassium uptake and transport, omitting references to plants. These are not trivial metabolic processes.
You will find many references to energy production, neurons, glial cells, muscle fibers, glutamate, GABA, NMDA, ion channels, intestinal flora, etc. At this point the absurdity of thinking about each problem in isolation should be apparent. This is not a problem for nature, but it is a problem for many medical professionals.
Likewise, questions about calcium and magnesium are tied closely together. What is more, calcium channels must be active every time a vesicle in a cell fuses with the cell membrane to release chemicals stored inside. A special case of this takes place when neurons release neurotransmitters in response to changes in voltage. This is fundamental to the operation of all nervous systems.
The big question has to be how we arrived at this point in 2016 without addressing these problems earlier. As always, I must say that I am not a medical doctor, so I have not been indoctrinated with reasons why this evidence should be ignored.
Magnesium ions act as competitive antagonists of calcium ions, so this pointed to a problem with calcium channels. When I later found out she had had a severe reaction to a calcium blocker I felt sure the problem was with calcium channels. Because of sudden onset, I was convinced this was an autoimmune problem. She tested positive for antibodies to N-type calcium channels on the Mayo PAVAL paraneoplastic panel.
Like the account above, she also had problems with glutamate demonstrated by antibodies to GAD65. This knocks out an important enzyme which is needed to convert glutamic acid to GABA. The result is a shift from GABA to glutamates, and from parasympathetic to sympathetic activation. It should have been no surprise to anyone that she was constantly "wired", but this was considered a psychological problem. Here's how serious this interaction can be.
The most serious problem this reveals is a medical profession depending on "diagnostic tripwires" where a single measurable quantity goes past some threshold. Every such metabolic process involves feedback, so it is quite likely there will be compensation for changes in levels until they reach pathological levels where they destroy pancreatic cells (GAD65 antibodies causing type 1 diabetes), prevent chest muscles from supporting breathing (N-type calcium channel antibodies), or interfere with the functioning of the heart.
At this point we haven't even touched on NMDA receptors, which also control ion channels, and can cause really bizarre symptoms of autoimmune encephalitis. All these things must interact for natural function of nervous systems, and the important factors are not levels, but ratios of rates under different conditions. Does anyone measure rates?
I know a patient who has normal levels of electrolytes without any special activity, but has severe reactions to changes in potassium levels triggered by carbohydrate intake or exercise which can cause paralysis lasting up to 3 days. Potassium uptake during metabolism or exercise is well documented. Potassium moves from the blood to cells or muscle fibers. At this time I don't have a single reliable reference for the way all these things are related. I can only suggest doing a Google Scholar search for potassium uptake and transport, omitting references to plants. These are not trivial metabolic processes.
You will find many references to energy production, neurons, glial cells, muscle fibers, glutamate, GABA, NMDA, ion channels, intestinal flora, etc. At this point the absurdity of thinking about each problem in isolation should be apparent. This is not a problem for nature, but it is a problem for many medical professionals.
Likewise, questions about calcium and magnesium are tied closely together. What is more, calcium channels must be active every time a vesicle in a cell fuses with the cell membrane to release chemicals stored inside. A special case of this takes place when neurons release neurotransmitters in response to changes in voltage. This is fundamental to the operation of all nervous systems.
The big question has to be how we arrived at this point in 2016 without addressing these problems earlier. As always, I must say that I am not a medical doctor, so I have not been indoctrinated with reasons why this evidence should be ignored.
Magnesium is a cofactor in many cellular reactions in the body. In addition to the ones mentioned, magnesium is a co-factor in the methylation cycle, which regulates over 40 major reactions in the body.
The adrenals regulate electrolytes levels in the body. If you have adrenal fatigue (highly likely if you have this disease), you will be losing electrolytes like crazy and need to replace them. That helps you feel better.
A disturbed mineral metabolism is caused by mercury. I don't know if there is anything else which causes this.
Mercury also causes adrenal fatigue.
The adrenals regulate electrolytes levels in the body. If you have adrenal fatigue (highly likely if you have this disease), you will be losing electrolytes like crazy and need to replace them. That helps you feel better.
A disturbed mineral metabolism is caused by mercury. I don't know if there is anything else which causes this.
Mercury also causes adrenal fatigue.
I do. I use topical sulfate and chloride (both saturated solutions) all over the body followed by body lotion (I think the latter helps with uptake of the former) every day. Also take some bisglycinate orally.
It makes a significant difference to muscle pain, twitches, cramps and seems to have a calming effect on my overactive sympathetic nervous system.
On the interrelatedness issues which @ancientdaze raises, I believe this heavy use of magnesium eventually depleted/interfered with calcium availability and I had to start supplementing with calcium citrate despite adequate sources of calcium in my diet.
I don't know that this is the case but base my conclusion on my positive response to the calcium supplements. The only sign of possible compromised calcium status was a high 1,25 diOH vit D to 25 OH vit D ratio. I had had this for some time but it was not until I read the excellent review which @ancientdaze has linked that I understood the significance.
As soon as I started supplementing calcium this normalised.
I also benefit from potassium supplementation even with a high dietary intake.
It makes a significant difference to muscle pain, twitches, cramps and seems to have a calming effect on my overactive sympathetic nervous system.
On the interrelatedness issues which @ancientdaze raises, I believe this heavy use of magnesium eventually depleted/interfered with calcium availability and I had to start supplementing with calcium citrate despite adequate sources of calcium in my diet.
I don't know that this is the case but base my conclusion on my positive response to the calcium supplements. The only sign of possible compromised calcium status was a high 1,25 diOH vit D to 25 OH vit D ratio. I had had this for some time but it was not until I read the excellent review which @ancientdaze has linked that I understood the significance.
As soon as I started supplementing calcium this normalised.
I also benefit from potassium supplementation even with a high dietary intake.
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I had direct experience of high transdermal doses of magnesium depleting calcium: at one stage I was using transdermal magnesium sulfate on my skin from head to toe two or three times a day, because I found it was helping with the severe anxiety I had at the time (mostly likely via its NMDA blocking effects).
I'd been on this very high dose regimen for several weeks, when suddenly I developed an inexplicable adoration for the taste of milk, a drink that I am not normally that fond of. I began drinking milk by the liter each day, just because it suddenly tasted so damn good. I am sure you guess why. Answer and full story in this post.
I'd been on this very high dose regimen for several weeks, when suddenly I developed an inexplicable adoration for the taste of milk, a drink that I am not normally that fond of. I began drinking milk by the liter each day, just because it suddenly tasted so damn good. I am sure you guess why. Answer and full story in this post.
I have a problem with glutamate excitotoxcity. I'm not scientific and could not follow some of the links provided but from my understanding high glutamate levels allow ca ions into glutamate receptors sites like NMDA and activate enzymes which destroys the cells releasing more glutamate starting a chain reaction. Appearantly magnesium molecules are bigger and serve to block these channels.
I can appreciate the need for calcium supplements but am wary of doing this. Is there any reassurance that doing this will not cause glutamate storms?
I can appreciate the need for calcium supplements but am wary of doing this. Is there any reassurance that doing this will not cause glutamate storms?
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@Jimbo39
First, there are some common problems leading to glutamate exitotoxicity. Have you been tested for antibodies to GAD65? This targets an enzyme which converts glutamic acid to GABA and shifts autonomic activity toward sympathetic activation and away from parasympathetic activity. Doctors may worry about this causing type 1 diabetes, but rarely make the connection with any form of dysautonomia.
The explanation you have for the effect of magnesium ions needs some changes. Magnesium ions are smaller than calcium ions, and zip right through some ion channels. They do not function like calcium after they get inside the cell. Magnesium blocks calcium activity via "competitive antagonism." Effects are strongly non-linear. This can lead to paradoxical reactions which are the opposite of what you expect.
There are lots of other possibilities than NMDA receptors. Glutamate receptors are found throughout the autonomic system, and even in places you don't connect with neurological problems. You might also have problems with calcium receptors on neuromuscular junctions or mast cells. If so, that is a whole new subject to investigate.
It may take a long trawl through your medical history, and evidence of adverse responses to drugs, to isolate the cause of your problems with glutamate.
Whatever you do with supplements remember that this is experimental. Start at a low dose with no effect and slowly titrate up to see what happens. Never assume "more is better".
First, there are some common problems leading to glutamate exitotoxicity. Have you been tested for antibodies to GAD65? This targets an enzyme which converts glutamic acid to GABA and shifts autonomic activity toward sympathetic activation and away from parasympathetic activity. Doctors may worry about this causing type 1 diabetes, but rarely make the connection with any form of dysautonomia.
The explanation you have for the effect of magnesium ions needs some changes. Magnesium ions are smaller than calcium ions, and zip right through some ion channels. They do not function like calcium after they get inside the cell. Magnesium blocks calcium activity via "competitive antagonism." Effects are strongly non-linear. This can lead to paradoxical reactions which are the opposite of what you expect.
There are lots of other possibilities than NMDA receptors. Glutamate receptors are found throughout the autonomic system, and even in places you don't connect with neurological problems. You might also have problems with calcium receptors on neuromuscular junctions or mast cells. If so, that is a whole new subject to investigate.
It may take a long trawl through your medical history, and evidence of adverse responses to drugs, to isolate the cause of your problems with glutamate.
Whatever you do with supplements remember that this is experimental. Start at a low dose with no effect and slowly titrate up to see what happens. Never assume "more is better".
No, I haven't. How do I get tested for this?
So are they in completion with each other to activate our deactivate certain processes? @alicec called it a yin/yang relationship.
Are you saying too much magnesium without calcium is bad?
I think my forced cold turkey from Vicodin and taper/withdrawal from Valium may be the cause of this.
Sorry everybody for going on a tangent.
So are they in completion with each other to activate our deactivate certain processes? @alicec called it a yin/yang relationship.
Are you saying too much magnesium without calcium is bad?
I think my forced cold turkey from Vicodin and taper/withdrawal from Valium may be the cause of this.
Sorry everybody for going on a tangent.
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This is a standard clinical test for common autoantibodies which any doctor can order. Here's the Mayo Clinic page on interpretation. Other companies also sell test panels which include this. It shows up in many conditions other than diabetes.
Assuming some typographic correction, yes they are sometimes in competition. When magnesium ions are going through calcium channels it is likely calcium ions are not. If they were completely equivalent that would not matter, but magnesium will not participate in all the same chemical reactions as calcium.
We had a case turn up here where an IV containing magnesium caused flash pulmonary edema, a medical emergency. That is extreme, but it is definitely an example of bad.
That would complicate lots of things, the next question would be what conditions required those drugs in the first place. This takes us into new territory. This often takes place when doctors treat symptoms without a clue to underlying problems, except their feeling "patient is crazy, and I want him/her to go away".
Don't worry about wasting our time, we hear all kinds of wild things. If you bring up something that we have heard before, I'm sure there are other people out there who have never heard of them either. This forum has been a continuing education.
Assuming some typographic correction, yes they are sometimes in competition. When magnesium ions are going through calcium channels it is likely calcium ions are not. If they were completely equivalent that would not matter, but magnesium will not participate in all the same chemical reactions as calcium.
We had a case turn up here where an IV containing magnesium caused flash pulmonary edema, a medical emergency. That is extreme, but it is definitely an example of bad.
That would complicate lots of things, the next question would be what conditions required those drugs in the first place. This takes us into new territory. This often takes place when doctors treat symptoms without a clue to underlying problems, except their feeling "patient is crazy, and I want him/her to go away".
Don't worry about wasting our time, we hear all kinds of wild things. If you bring up something that we have heard before, I'm sure there are other people out there who have never heard of them either. This forum has been a continuing education.
I'm going off on a tangent again but I think I'm a classic example of "modern" medicine treating symptoms rather than the cause: Vicodin and gabapentin for nerve pain; Valium for stress; trazadone for insomnia; Paxil for depression. I'm so polydrugged it's hard to tell if supplements are working for me or not. It's going take me 2-4 years to get off this s***.
Stupid question- where is this thread? I can't seem to find it in the Symptoms or General Treatment forum.
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It is in the General Treatment forum about seven down from the top. I diagnose some cognitive impairment, which is not too surprising.
Your other medications violate some rules of thumb I have. No telling what the combination is doing. In general, except for emergencies where you need a complete washout (as this might be), I recommend one change at a time, just so you can tell what is causing what.
Another rule of thumb, based on painful experience, is that I have never met a doctor who really understood what more than 3 interacting drugs were doing. Several have failed the step from two to three.
If you are being treated for conditions that really are unrelated, then more drugs may be managed, but what you seem to be telling us is that they have wandered off any known treatment path, and you are now in strange territory corresponding to what golfers call "the rough". You need to get back to the fairway where it is at least possible to tell if you are getting closer to some goal, not farther away.
I've known patients who needed to be hospitalized for a kind of detox for this to happen. There are situations where you can't expect to "tough it out" alone. Just make sure those in charge understand that the problem is unwinding an overly complex treatment situation, not administering larger doses or more dangerous drugs in a search for a "bigger hammer". This is where the maxim Primum Non Nocere (first, do no harm) needs to be remembered.
Your other medications violate some rules of thumb I have. No telling what the combination is doing. In general, except for emergencies where you need a complete washout (as this might be), I recommend one change at a time, just so you can tell what is causing what.
Another rule of thumb, based on painful experience, is that I have never met a doctor who really understood what more than 3 interacting drugs were doing. Several have failed the step from two to three.
If you are being treated for conditions that really are unrelated, then more drugs may be managed, but what you seem to be telling us is that they have wandered off any known treatment path, and you are now in strange territory corresponding to what golfers call "the rough". You need to get back to the fairway where it is at least possible to tell if you are getting closer to some goal, not farther away.
I've known patients who needed to be hospitalized for a kind of detox for this to happen. There are situations where you can't expect to "tough it out" alone. Just make sure those in charge understand that the problem is unwinding an overly complex treatment situation, not administering larger doses or more dangerous drugs in a search for a "bigger hammer". This is where the maxim Primum Non Nocere (first, do no harm) needs to be remembered.
Yes, I don't think there was any treatment plan. My psychiatrist and general doc "threw" meds at whatever symptom I had not bothering to look into the underlying cause. To tell you the truth, I've lost all faith in the medical establishment. I don't know where you live but here in the US our system is run by the insurance companies heavily influenced by the pharmacology industry. So their answer is to throw drugs at the problem. The insurance companies do not recognize adrenal fatigue hence doctors cannot treat it if they want to be reimbursed. How crazy is that?
Now I've really hijacked this thread. I apologize.
Now I've really hijacked this thread. I apologize.