Here's a short article from Johns Hopkins followed by a long conversation discussing it.
MR X -
I tried some N-acetyl cysteine at one time to try to lower my glutamate. No change to my RLS.
Besides continuing the biochemistry we really also want to know about who gets RLS. Is it genes, genes plus environment, those who have led a particular lifestyle (too fat, too thin; little exercise, athletes; teetotallers, regulars at the pub; calorie restricted diets, carbohydrate restricted diets, fat restricted diets, protein restricted diets, vegetarians, heavy meat eaters, vitamin poor diets, mineral poor diets; anxiety limited; stress limited; sleep limited; academic, skilled, unskilled). What drugs sufferers have taken. What other medical conditions they have suffered from. What is the frequency of occurrence in different parts of the country, different parts of the continent, different parts of the world and what is different about these different places?
Why? Dead men don't lie. The autopsies showed that our dopamine transport system/receptors are puny...almost as puny as our brain iron levels. I'm avoiding ALL of the no no substances, I'm taking iron bis-glycinate or potassium during an attack, I'm going to give under-eating a shot, and I'm waiting for all of you out there in the RLS world to start figuring out ways to up-regulate our receptors.
MR X -
Yours is a slightly special case, of course, in that it responds to iron supplementation. Eating, and possibly more so eating carbohydrates, like orgasm, increases dopamine production, and increases iron transport, so maybe you'd need to be careful how you go on about that. But if our receptors can work properly in the morning, there must be a reason they don't later in the day and during the night. Do we just become understimulated as the day goes on?
There is a known correlation between the incidence of RLS and latitude. There are far fewer cases as you move towards the equator. The occurrrence is only 0.2-0.7% in Africa compared to 3.2% to over 18% in Europe, and it's much lower in Turkey and Greece than in France and England where it's lower than in the Scandinavian countries.
There have been numerous correlations made between the rise in use of antidepressants in the Scandinavian countries and RLS. I think we with RLS are pre-disposed to it, and certain people from certain families and certain countries have a higher incidence of that pre-disposition, but then it takes an environmental trigger. I bet RLS is almost non-existent among the aborigines of the Amazon but give them anti-histamines and anti-depressants, especially to the older members, and RLS will rear its ugly head.
Also, I believe that iron levels have a circadian rhythm. Serum iron levels drop off in the evening and begin to rise again after 3am. As we age so do our bodies (duh) including our dopamine receptors. Everyone's receptors age, however, I believe that we with RLS feel it more acutely. So yes, there are numerous factors to consider, but I think we have covered alot of them. DONT take antidepressants, we see how well that worked out for the Scandanavian countries. Since all RLS brains are anemic, allegedly, then if we can get some iron to our brains (not just our bodies) at the right time it should help an awful lot of people.
MR X -
Penn State's Hershey Medical Center (and others?) state:
– The cells forming the Blood Brain Barrier are a reservoir for iron not a simple conduit.
– The reservoir allows for fluctuations in serum iron status not to effect immediate brain iron needs. Serum iron circadian rhythms for example.
– In RLS the reservoir is empty.
The question, it seems, is whether or to what extent it's to do with signaling processes involving the likes of iron regulatory protein 1 (IRP1) and hepcidin.
JANE DOE –
Wow, our brain reservoir of iron is empty!!! Thank you for sharing that information. My puny brain needs time to process that protein signaling thing. I do understand about hepcidin, the iron gatekeeper as I like to call it. Hepcidin is released from the liver in the face of infection or even cancer. The hepcidin which is a hormone is able to regulate, or flat out stop, iron from getting into our bloodstream, either via our stores or the food in our stomachs. Every living thing loves and needs iron so by making our blood devoid of it, the infection has a hard time surviving. Quite an amazing defense mechanism. But in the meantime we get RLS... maybe. The vast majority of the world can develop a horrible infection have hepcidin coming out of their ears yet never develop RLS. So I guess the question is for those of us who are predisposed to RLS and can't handle any drop in serum iron, is it possible that our bodies always think it's under attack and we always have too much hepcidin floating around.
JANE DOE -
Speaking of demographics, it seems that studies of people with end stage renal failure are upwards of 50% in terms of RLS. It's almost like there's a point of no return. If we're so sick, and there's so much hepcidin in our bodies and so little iron, then just about anyone can fall prey to RLS. BUT in India, one small study of patients with end stage renal disease showed that RLS was still in the single digits among them. Is it all that tumeric? So yes, studying demographics is very worthwhile but we know so much about the nuts and bolts of RLS that I say let us all figure out a way to fill that reservoir, be it by lowering the hepcidin in our bodies, lowering glutamate etc.
The International Restless Leg Foundation had a symposium in October 2015 and summaries of that meeting are now on the internet. It's long and somewhat difficult to understand but most, if not all, of the buzz is still around iron. There's talk about those genes they discovered and one of them they believe has something to do with iron management but what's interesting is 75% of RLS patients have that gene but so does 65% of the control population that has no symptoms of RLS. They suspect there are more genes out there that they will find someday. Lastly they debate the protocol and first line treatments for RLS. DAs versus opiates versus Gaba. Even the excess glutamate they believe is not a cause of RLS but a by-product of iron insufficiency - if I read the article correctly.
What are you taking to control your RLS?
MR. X -
I take 2 mg ropinirole mid-afternoon and another 2 mg maybe an hour before bed to control my RLS. Gabapentin doesn't work nor any supplement I've tried.
JANE DOE –
Is your RLS well-controlled with the Ropinirole? Some people say that iron or iron infusions delay augmentation even though alone it does not get rid of their RLS symptoms.
I truly believe that people who do not get any relief from iron are taking the wrong kind or at the wrong time. I believe that iron is to RLS what insulin is to type I diabetics. Taken in the right amount at the right time, insulin should do a good job of controlling blood sugar levels. Not a cure but the best treatment we have so far for diabetes. Pancreas transplant is a cure. Brain transplant anyone?
MR. X –
Yes, ropinirole is controlling my RLS well and has for a few years now. I still worry about the next step if my RLS augments though.
I might have to ask my doc what he thinks about all this and iron infusions. I've always feared that overdosing on iron can damage the liver.
JANE DOE -
That's key to all things in life, not to over do, but especially heavy metals, which iron is. Menstruating women probably have to worry less but men and older women have to be more mindful. I look at it this way, my son's Flintstone's vitamins have 18mg of iron and I take 25 mg but I bet I'm absorbing more because the kind I take is so bio-available. It's so broken down I don't know that my body can even stop it from entering when it feels it has enough iron. Anyways, I think 45mg of iron (that actually gets absorbed) is the upper limit on a daily basis. I think that ferrous sulfate pills are 65mg but studies have shown that a ridiculously low amount of it gets absorbed. Even pharmacists will tell you that. Anyways, if you're worried then you can take it under a doctor's supervision. I go annually for bloodwork and my iron levels stay around 100. I want it lower. The lower the better. Supposedly less iron = less chance of heart attack. I know the RLS experts will tell you over 50 but I think they got it all wrong. Including Johns Hopkins where they will infuse you to up over 200. Plus they found that unlike the rest of the world, RLS patients' stores will drop. They think that drop is why the RLS returns. I think like you or the article that you provided at least, that it's because the BBB reservoir is depleted and our dopamine receptors (that gorged themselves on infused iron) are beginning to once again wither on the vine like flowers from lack of water.
Essentially what I'm saying is that if I need iron to sleep, even on a long term basis, I'm not worried about the 25 mg capsules of it. On the other hand, I'm a firm believer that with heavy metals, less is more . Hello potassium...shouldn't take too much of that either.
MR. X -
Yesterday, I took 4 x 18mg of iron as ferrous bisglycinate chelate at about 11:30 a.m. (so, on an essentially empty stomach) and the same again at about 6:30 p.m. (again on an essentially empty stomach) and ate over 400g of lamb's liver at lunchtime (around 1:30 p.m.). I did not take my first ropinirole until 6 p.m. (rather than 3:30 p.m.) and had virtually no trace of RLS at that time, nor all evening.
Now, I may have been going through a rough patch with my RLS lately, and it may be that it's now swinging the other way, but it has been that 3:30 p.m. was the latest I wanted to leave taking my first ropinirole – if I'd left it until 6 p.m. I probably wouldn't have known what to with my legs, and indeed my upper torso, (and hence myself) until after 8 p.m.
I don't know how long I will keep this iron intake up for, probably no longer than 10 days if it doesn't stop my RLS without the ropinirole.
JANE DOE -
Robert, how did you determine what amount to take? Like I said, I take only one pill which is 25 mg. Did your doctor tell you to take the amount? Well, I'm VERY happy for you. You are a brave soul indeed.
Maybe you and I can come up with a regimen of iron, potassium, and undereating that will help most of the RLS world. Then we'll be awarded a nobel peace prize and all this ridiculous suffering won't be in vain.
MR X -
I think 144 mg a day is near the lower end of the suggested amount for oral administration (before trying IV). If I ask my doc, he will probably just ask me if it's something I want to try. If I do get positive results from taking the iron, I'll probably check with him if it's something I should continue and if so within what limits and whether I shouldn't have blood tests.
I found this 2001 report on experiments on rats and pigs stating:
" ... [ferrous bisglycinate chelate] has been demonstrated to have a No Observable Adverse Effect Level (NOAEL) of at least 500 mg per kg rat body weight."
"Toxicology and safety of Ferrochel and other iron amino acid chelates", Robert B. Jeppsen, Albion Laboratories Inc. Clearfield, Utah U.S.A.
If you read that report you will understand that I would not be trying it with any other source of iron other than ferrous bisglycinate chelate.
JANE DOE -
You are simply the best!!! I feel alot better now too about taking the bis-glycinate. Well if you're like me it will work every time without need for increasing dose, although I started from a point of no prescription drugs. Thinking back on it, when I increased my dose of melatonin I had to double dose of iron. That didn't last too long. Shortly thereafter I found that melatonin was triggering attacks. Will you keep us posted? Xx
MR X -
Yes, of course, I'll keep you posted. It wasn't an hour ago that I took my ropinirole and I've no RLS symptoms at the moment.
[I still take 5mg melatonin time release each night. The only thing it does is give me a deeper sleep; I don't think it affects my RLS.]
JANE DOE -
I'm glad that stuff works for you. I was on 1.5 mg and had restless body, when I went to 3mg I had to take two iron pills just to keep from jumping out of the second floor window. We're all so different...and then not really...if you know what I mean . The iron isn't just an RLS reliever but sometimes I take it when I can't fall asleep. I consider iron to be a sleeping pill as well. I have taken it and then found myself on the living room floor four hours later. An hour after I take it I have to be in bed because I just drop.
Why do you take the ropinirole if you have no symptoms? Is it more like blood pressure medication where you have to keep it in your system or a pain killer like aspirin?
MR X -
Well, yesterday I took the iron as I described the day before yesterday, but I left taking the ropinirole until just after 7 p.m. (rather than the 6 p.m. of the previous night described above). I had just begun to feel a few RLS-like twinges in my leg. And that's about the most I felt throughout evening. If I hadn't taken the ropinirole then though, I think my RLS would still have become strongly prevalent. Still 6 p.m. and 7 p.m. onset is a lot better than 3:30 p.m., but there again I may just be on a rebound swing.
Iron is needed by so many processes, I'm fairly sure some of them have to do with sleep.
I would not expect my iron levels to recover in just a day or two, if they are indeed low, even on the supplementation I'm taking, so I'm expecting to need to take ropinirole for a while yet even if the iron therapy works.
The question in my mind at the moment is whether mitochondrial iron hogging, if that is indeed the problem, is a/the disease or just a facet of, a need for, our individual make-up and lifestyle.
JANE DOE -
Yes, the under, under lying cause of RLS is still very much a mystery. Is it just genes or our gut microbiome or out of control hepcidin levels or iron hogging? But we know how it presents - low brain iron resulting in very shoddy dopamine receptors but plenty of dopamine kicking around just waiting to be transported down our central nervous system by those pathetic receptors.
Like I said on here before, probably for a good portion of our lives there's just enough iron going to our brains (even at night when everyone's serum iron level drops) and there's just enough dopamine coming out of those receptors such that we don't even know we have RLS. Then something happens. Like the aging process which includes the aging of those already pathetic receptors. Or a spinal injury so that now that drip of dopamine which is traveling down our CNS, bouncing from spinal neuron to spinal neuron has to contend with a road block so to speak. Or we become obese which allegedly is also a drag on our already pathetic receptors. Or we start to take statins, anti-histamines, antacids, a near endless list of substances that interfere with the release of dopamine. Magnesium allegedly intereferes with the release of dopamine!!!
Of course, the report of increased dopamine levels was in 1985 (Montplaisir et al) and I do not find any later ones supporting it. Others suggest near normal dopamine levels. And "normal" levels might well be expected if dopamine receptors are fewer but dopamine production is lower.
Another rat experiment showed "The loss of iron in the striatum due to dietary ID was significantly correlated with the decrease in D(2) receptor density ...".† Since the amount of dopamine in the synapse is closely controlled, the lack of availability of dopamine will, I understand (perhaps falsely), signal the creation of fewer receptors. However it goes on to say that it was more pronounced in males than females. Women are more likely to suffer with RLS than men in the human population, so there's some tying up to do there, I feel.
In all, I seem to be seeing that the problem is indeed with iron, whether it's the amount available or the control of it I don't see fully answered yet.
Indeed the levels of many nutrients fall with age. Iron, though, it is reported, tends to build up in the brain with age. Not in everyone? We can't access it? It's because we can't access it that it builds up?
[It's now well gone 8:00 p.m., I've not taken any ropinirole today so far, and I've only very, very minimal, scarcely any, RLS symptoms. I went out walking today, some miles, so I in fact took five ferrous bisglycinate chelate capsules (18 mg elemental iron) both this morning and earlier this evening.]
JANE DOE -
OMG, unbelievable! 8pm and no drugs and little to no symptoms. What about Melatonin? Can't even type that word without shuddering. For me it's the devil incarnate. Are you still going to take it?
Is it time for a revolution yet? Should we take our anecdotal evidence on the road and let the RLS world know that this is something that MIGHT work for others as well? You realize that you are one of the lucky ones. Your symptoms were controlled with drugs. There are some that are one step away, night after night, of going off the RLS cliff.
MR. X. -
I still took melatonin last night. Don't know about stopping that – I barely got 5 hours sleep last night.
Of course, it is known that those IV iron treatments relieve RLS symptoms in about 70% of cases. I wonder about the position of biglycinate oral treatment though. Biglycinate capsules don't seem to appear on the NHS drug price list (not under biglycinate, ferrous or iron), so I don't know about getting them on prescription on the NHS in the UK. I have seen high dose capsules for the medical treatment of anaemia exist though. If the medical profession agrees with the rat and pig results for the non-toxicity of the bisglycinate, maybe they should let on a little more.
JANE DOE -
Five hours really isn't enough, at least not for me. This is what I would do (but you're not me and that's important to remember) I would save the iron for at night, for sleep. By day I would gut it out and I would experiment with some form of bio-available potassium or even a tonic water that has quinine in it if you're desperate during the day. So I would take some (not a ton) of iron before bed and then if I wake up too early I would take a little more iron. Well that's me.
MR. X -
RLS was not the problem with my sleep. 5 hours was all I got with the help of 7.5 mg of zopiclone. 5 hours is about the minimum I can cope with; on a very good night I might get 7 hours.
[Moving towards ten o'clock, now, and I've some mild RLS symptoms. If they persist I'll have to take ropinirole – in any case I will take some before bed, because I want to be sure I'm not kicking about in bed for two hours or more!]
JANE DOE –
Ahh, I'm a bit of an insomniac myself. Like I said, regardless of RLS, iron is the best sleeping pill I have found to date, and that includes the prescription ones. It might not affect you that way, but it does me. I hit the bed about 45 minutes after taking the iron otherwise I fall asleep where ever I happen to be.
MR. X -
Got down to 1 x 2 mg ropinirole a night with only mild symptoms in the evening. On Thursday though I took quite large doses of di-calium phosphate and magnesium citrate, and Thursday evening my RLS symptoms were thoroughly moderate. Now trying to minimize calcium intake since it both increases mitochondial activity and decreases iron absorption.
However, I've now found this:
"We believe that iron deficiency, at some point in the earlier life of the patient, sets into motion well-defined changes in cellular iron homeostasis, which leads to paradoxical redistribution in cellular iron, possibly as a way to protect the cells from complete starvation and cell death. Once iron is returned to the body, the process should reverse itself and cells should return to a “normal” iron balance. However, the initially altered mitochondrial iron homeostasis may not return to a normal balance and instead persist in a "new" homeostatic state at least in the brain, which, over time, leads to the development of RLS. This proposed dynamic readjustment of mitochondrial iron homeostasis, following a low-iron insult, is similar to the HIF-dependent, cellular protective mechanisms that occur with repeated hypoxia."
"Altered Brain iron homeostasis and dopaminergic function in Restless Legs Syndrome (Willis–Ekbom Disease)", Earley et al, 2014
[Go to the RLS-UK website, "More" menu > "For Professionals", then click "Resources" on the page you are taken to.]
Very interesting paper – only wish I could understand it all!
JANE DOE -
Hi there. I've been hoping u continue to be well. Taking calcium or magnesium with iron is tantamount to violating one of the Ten Commandments. Iron is a jealous substance. It will tolerate no others before or after it. Plus magnesium in my humble opinion is a dopamine ANTAGONIST. So not something u want to take at night either.