Help me to sort this out: Histamines, PPIs and gastric acid

[Frunobulax]

Hi,

I'm trying to sort this out but I'm not sure I understand it correctly. And my brain hurts

In the last Nightwalkers publication there is an article that H3 receptor antagonists may be helpful for reducing RLS symptoms.
Now, I have wondered for quite some time if my proton-pump inhibitor therapy (meds to block production of stomach acid - 40 mg pantoprazole a day, since I suffer from diaphragmatic hernia) has something to do with my restless legs, since my RLS began shortly after I started the PPIs. (Although I have a lot of relatives with RLS not taking PPIs.) Earlier on I assumed that the mechanism may be that the reduced stomach acid would cause some problems in the uptake of some nutritients, and possibly with some increase in some bacterial levels (even though I know I have no helicobacter bacteria, I checked this about a year ago). Wikipedia reads "Gastric acid is important for breakdown of food and release of micronutrients, and some studies have shown possibilities for interference with absorption of iron, calcium, magnesium, and Vitamin B12. With regard to iron and vitamin B12 the data are weak and several confounding factors have been identified" (https://en.wikipedia.org/wiki/Proton-pump_inhibitor). And we all know the connection between RLS, iron and vitamin B12.

In any case there was an interaction between the PPIs and my RLS medication (oxycodone) due to both being metabolized by the same enzyme CYP3A4 (I posted something about that here). Now, I underwent fundoplication surgery 3 weeks ago, and I'm suffering from some presumed side effects of tapering the PPIs. I started to read more about it and found another possible connection between RLS and PPIs: Histamine levels. (Having read the Nightwalkers article I felt a "click" when I read about histamines and PPIs.) What's the connection? I'm not sure. This is highly theoretical. Most likely I'm wrong. I'll still make a fool out of myself and present it. Here we go.

PPI therapy increases the histamine levels, the histamine activates the H3 receptors and this in turn reduces the production of dopamine and GABA.

OK, why should this be true?

Histamine has a role in sleep-wake regulation. "Histamine is released as a neurotransmitter. The cell bodies of histamine neurons are found in the posterior hypothalamus, in the tuberomammillary nuclei. From here, these neurons project throughout the brain, including to the cortex, through the medial forebrain bundle. Histamine neurons increase wakefulness and prevent sleep." (https://en.wikipedia.org/wiki/Histamine)

Continued from Wikipedia:
There are 4 receptors:

• The H1 receptor has a function on the CNS, affecting sleep-wake cycle, body temperature, nociception, endocrine homeostasis, appetite, mood, learning, and memory.
• The H2 receptor: Primarily involved in vasodilation. Also stimulate gastric acid secretion.
• The H3 receptor: Decreased neurotransmitter release: histamine, acetylcholine, norepinephrine, serotonin
• The H4 receptor: Plays a role in mast cell chemotaxis.

As for the H3 receptors: "Histamine H3 receptors are expressed in the central nervous system and to a lesser extent the peripheral nervous system, where they act as autoreceptors in presynaptic histaminergic neurons, and also control histamine turnover by feedback inhibition of histamine synthesis and release. The H3 receptor has also been shown to presynaptically inhibit the release of a number of other neurotransmitters (i.e. it acts as an inhibitory heteroreceptor) including, but probably not limited to dopamine, GABA, acetylcholine, noradrenaline, histamine and serotonin. [...] The H3 receptor is coupled to the Gi G-protein, so it leads to inhibition of the formation of cAMP. Also, the β and γ subunits interact with N-type voltage gated calcium channels, to reduce action potential mediated influx of calcium and hence reduce neurotransmitter release. H3 receptors function as presynaptic autoreceptors on histamine-containing neurons." (Wikipedia, https://en.wikipedia.org/wiki/Histamine_H3_receptor).

So in english, the H3 receptor is a histamine level regulator: Its function is to make sure that the higher the histamine levels, the lower the histamine production. Right. Blocking the H3 receptor will increase the release of other neurotransmitters like dopamine and GABA. (Hey, I did ask what's the connection between GABA and RLS. We know that GABA helps, but why?)
So, high histamine levels may prevent sleep and and reduce the amount of GABA and dopamine produced.

What puzzles me: It is known that antihistamines like Benadryl (Diphenhydramine) are known to exacerbate RLS symptoms. Hmm. "Diphenhydramine is an inverse agonist of the histamine H1 receptor." (https://en.wikipedia.org/wiki/Diphenhydramine). So, Diphenhydramine will decrease the effect of the H1 receptor - it makes us drowsy. Why are RLS symptoms exacerbated by this? "Diphenhydramine has also been shown to inhibit the reuptake of serotonin." Now, that sounds familiar. Maybe the RLS interactions comes from the SSRI action and not from the histamine H1 action?

OK, what's the connection to PPIs?

"PPI therapy leads to diminished acid secretion, diminished antral D-cell release of somatostatin, consequent increased G-cell release of gastrin and hypergastrinemia. This causes oxyntic cell hyperplasia, increased parietal cell mass, glandular dilatations and stimulation of enterochromaffin-like (ECL) cells to release chromogranin and histamine, raising their concentrations in serum.
[...]
PPIs inhibit acid secretion, leading antral G cells to release gastrin, causing hypergastrinemia. Gastrin, in turn, binds to gastric mucosal ECL cells, causing them to release chromogranin, histamine and other substances. The acid-secretory effects of gastrin are inhibited by PPI[...]. In most patients, PPI-induced elevations in serum gastrin are moderate (50–400 pg/ml) and normalize when the drug is stopped. " (http://www.medscape.com/viewarticle/730747_6).
The thing that puzzled me at first is that PPIs increase the histamine level, while histamines should activate the H2 receptors and produce gastric acid. however, "Proton pump inhibitors act by irreversibly blocking the hydrogen/potassium adenosine triphosphatase enzyme system (the H+/K+ ATPase, or, more commonly, the gastric proton pump) of the gastric parietal cells.[3] The proton pump is the terminal stage in gastric acid secretion, being directly responsible for secreting H+ ions into the gastric lumen, making it an ideal target for inhibiting acid secretion." (https://en.wikipedia.org/wiki/Proton-pu ... _of_action). Basically gastric acid is a result of a chain of biochemical reactions. The H2 stimulation is early in the chain, while the PPIs block a later stage in that chain. OK.

So, there you have it.
PPIs increase histamine production.
Histamine levels induce wakefulness and activate the H3 receptor.
The H3 receptor is responsible for a reduced production of dopamine and GABA.

Sounds sensible? Please chime in. Or make sure to crush my argument if I'm wrong.

Regards, Thomas

[badnights]

Forgive my rambling reply. I have not researched this as much as I should, but I am interested in the histamine angle particularly, and also in the whole issue of gastric acid and PPIs... though I am not taking any (as yet).

This is how my thoughts went: Anti-histamines are bad for us. So I thought that histamines ought to be good for us, and anything that interfered with their action, such as histamine receptor antagonists, would be bad for us. Clearly it’s more complicated than that. Histamines in general are activator neurotransmitters - they increase wakefulness and prevent sleep, supposedly – so why would the opposite of that (the effect of anti-histamines) be bad? And the new possibility for a medication mentioned in Nightwalkers is a histamine receptor antagonist, just the thing I thought would be bad for us. So I needed clarification. I looked, but not hard enough, so I'm still confused.

A review: A receptor antagonist, upon binding to a receptor, "blocks or dampens agonist-mediated responses rather than provoking a biological response itself." An agonist binds to a receptor and activates it to produce a biological response. Whereas an agonist causes an action, an antagonist blocks the action and an inverse agonist causes an action opposite to that of the agonist.

There are 4 types of histamine receptor, and undoubtedly a range of histamine molecule types. Anti-histamines (or at least Benadryl) are inverse agonists of the H1 histamine receptors: they will do the opposite of whatever histamine does when bound to H1. “The H1 receptor has a function on the CNS, affecting sleep-wake cycle, body temperature, nociception, endocrine homeostasis, appetite, mood, learning, and memory.” Which of these things is ‘opposited’ by Benadryl? And even that is an over-simplification, because in detail, there are different H1 agonists that do different things, eg. a specific H1 receptor agonist called histamine dihydrochloride "exhibits inflammatory, vasodilatory and bronchoconstrictory activity, stimulates gastric acid secretion, and acts as a neurotransmitter in vivo". So will the inverse agonist of it (eg. Benadryl) have anti-inflammatory, vasoconstrictive, and bronchodilatory activity, reduce gastric acid, & not act as a neurotransmitter??? I’m not sure why any of that would be bad for WED (except that vasoconstriction ?might? affect oxygen delivery to the limbs, which has been implicated in WED via muscle hypoxia). So I’m still confused about how anti-histamines wreak their havoc in us.

You say “So, Diphenhydramine (Benadryl) will decrease the effect of the H1 receptor - it makes us drowsy. “ You’re assuming the H1 receptor when bound to an agonist will increase wakefulness. Histamines in general increase wakefulness, but I don’t see where it says that specifically about any of the 4 receptors. Argh.
_________
As for the potential new drug talked about in Nightwalkers, the H3 receptor antagonist: H3 when activated by histamine will DECREASE further histamine release. Stopping it from doing that (by an H3 receptor antagonist) increases histamine which supposedly keeps us awake. Why would that be a good thing? OK, H3 DECREASES DOPAMINE release, so the H3 receptor antagonist would permit dopamine release, which should make us feel better, if nothing else is interfering. H3 activation inhibits cAMP formation so the antagonist would permit cAMP formation . cAMP is essential to cellular metabolism, so that would be a good thing. But is it al good enough to balance out the increased histamine?

You say “Blocking the H3 receptor will increase the release of other neurotransmitters like dopamine and GABA. “ Yes, but blocking H3 also increases the release of histamine (it breaks the feedback loop). Might that not counteract the benefit of having more dopamine and GABA?

You say “So, high histamine levels may prevent sleep and reduce the amount of GABA and dopamine produced.” Are you suggesting that we may have abnormally high histamine levels for some reason, and those high levels will activate the feedback loop that is supposed to lower histamine production (and dopamine and GABA), but the abnormally high histamine levels persist because something else is broken (eg. maybe because we’re taking PPIs), so the only noticeable effect will be the prolonged suppression of dopamine and GABA release, which might cause WED…? is that what you’re thinking?
___________

“"Diphenhydramine has also been shown to inhibit the reuptake of serotonin." Now, that sounds familiar. Maybe the RLS interactions comes from the SSRI action and not from the histamine H1 action?” Possibility. But serotonin has not yet been implicated in WED.

[Frunobulax]

Forgive my rambling reply.

I strongly prefer rambling replies over silence

This is how my thoughts went: Anti-histamines are bad for us. So I thought that histamines ought to be good for us, and anything that interfered with their action, such as histamine receptor antagonists, would be bad for us. Clearly it’s more complicated than that. Histamines in general are activator neurotransmitters - they increase wakefulness and prevent sleep, supposedly – so why would the opposite of that (the effect of anti-histamines) be bad?
[...]
There are 4 types of histamine receptor, and undoubtedly a range of histamine molecule types. Anti-histamines (or at least Benadryl) are inverse agonists of the H1 histamine receptors: they will do the opposite of whatever histamine does when bound to H1. “The H1 receptor has a function on the CNS, affecting sleep-wake cycle, body temperature, nociception, endocrine homeostasis, appetite, mood, learning, and memory.” Which of these things is ‘opposited’ by Benadryl? And even that is an over-simplification, because in detail, there are different H1 agonists that do different things, eg. a specific H1 receptor agonist called histamine dihydrochloride "exhibits inflammatory, vasodilatory and bronchoconstrictory activity, stimulates gastric acid secretion, and acts as a neurotransmitter in vivo". So will the inverse agonist of it (eg. Benadryl) have anti-inflammatory, vasoconstrictive, and bronchodilatory activity, reduce gastric acid, & not act as a neurotransmitter??? I’m not sure why any of that would be bad for WED (except that vasoconstriction ?might? affect oxygen delivery to the limbs, which has been implicated in WED via muscle hypoxia). So I’m still confused about how anti-histamines wreak their havoc in us.

Some meds that make us drowsy are known to cause RLS, especially many antidepressants. I guess there are several actions that may make us drowsy, GABA helps with RLS (mostly), other meds make it worse.
I'm not a doctor, but I think this is kinda like fighting fire. Sometimes it's a good idea to use water, but in some cases water will make the fire worse.
You've got to know what causes WED to counter it successfully. A problem in the dopamine production may be that the body lacks an ingredient (like Ferritin, SAMe or whatever), or it could be that the production is blocked by invoking something else like the H3 histamine receptor.

You say “So, Diphenhydramine (Benadryl) will decrease the effect of the H1 receptor - it makes us drowsy. “ You’re assuming the H1 receptor when bound to an agonist will increase wakefulness. Histamines in general increase wakefulness, but I don’t see where it says that specifically about any of the 4 receptors. Argh.

"Its effects on central H1 receptors cause drowsiness.[34]" (https://en.wikipedia.org/wiki/Diphenhydramine).

As for the potential new drug talked about in Nightwalkers, the H3 receptor antagonist: H3 when activated by histamine will DECREASE further histamine release. Stopping it from doing that (by an H3 receptor antagonist) increases histamine which supposedly keeps us awake. Why would that be a good thing? OK, H3 DECREASES DOPAMINE release, so the H3 receptor antagonist would permit dopamine release, which should make us feel better, if nothing else is interfering. H3 activation inhibits cAMP formation so the antagonist would permit cAMP formation . cAMP is essential to cellular metabolism, so that would be a good thing. But is it al good enough to balance out the increased histamine?

You say “Blocking the H3 receptor will increase the release of other neurotransmitters like dopamine and GABA. “ Yes, but blocking H3 also increases the release of histamine (it breaks the feedback loop). Might that not counteract the benefit of having more dopamine and GABA?

Well, that's why my brain hurt after writing this article We need somebody good with neurochemistry to figure that out. My assumption is that histamine levels shouldn't be too high or too low. Or it could be that the H1 action of Diphenhydramine is not responsible at all, because there is a different chain of cause and effect.

BTW, I stumbled over cAMP several times, but never really figured out if there may be a connection to RLS.

You say “So, high histamine levels may prevent sleep and reduce the amount of GABA and dopamine produced.” Are you suggesting that we may have abnormally high histamine levels for some reason, and those high levels will activate the feedback loop that is supposed to lower histamine production (and dopamine and GABA), but the abnormally high histamine levels persist because something else is broken (eg. maybe because we’re taking PPIs), so the only noticeable effect will be the prolonged suppression of dopamine and GABA release, which might cause WED…? is that what you’re thinking?

I am thinking that I don't understand enough of this
Look at http://bb.rls.org/viewtopic.php?f=5&t=9015&p=76840&hilit=allergies#p76840, which I wrote some time ago. There are some parallels between RLS and allergies.

“"Diphenhydramine has also been shown to inhibit the reuptake of serotonin." Now, that sounds familiar. Maybe the RLS interactions comes from the SSRI action and not from the histamine H1 action?” Possibility. But serotonin has not yet been implicated in WED.

Right. But I always wondered why this was never considered. I'm tired and my memory refuses to comply, but I remember reading about several other meds causing high serotonin levels that are known to cause RLS. Where's the connection? After all, serotonin levels rise precisely when our WED is at its worst, with a circadian rhythm.

In fact, if we can't figure it out then we should ask a researcher. (I actually mailed to Dr. Lai, but he didn't respond.)

Regards, Thomas

[ViewsAskew]

I have often wished we could get a few physicians to join us in these discussions. Everyone bringing a different perspective.

[badnights]

Really, that's what we need, a researcher/physician on this board who takes an interest in all this arm-waving we do. I know - from my own experience - that I can easily miss some key piece of information and go off in the totally wrong direction as a result. It comes from only scratching the surface of the body of knowledge. And lately, I have not had the energy to devote to it - - - I save my energy for geological research to keep from getting fired from my job

[Frunobulax]

I have often wished we could get a few physicians to join us in these discussions. Everyone bringing a different perspective.

Well, I sent a few questions to two researchers in Germany (Trenkwalder and Oertel). They both answered basically that they were over their heads in research and have no time to answer questions like that.
Very frustrating. You know, who else should we ask? 99,9% of us have neurologists that are not active researchers.

.f

[ViewsAskew]

I agree - it's really hard. We are curious and want to ask questions that just might help the researchers. I once read that many discoveries come from people who don't understand something well. They are too ignorant to believe something cannot work and do not know the current accepted beliefs about the field/topic. So, they think something can work that a veteran might dismiss. But, by pushing it, they find a way or discover the hole in the knowledge or realize something that was accepted as correct is actually incorrect.

How fascinating it would be to have that happen here. Even if people were wrong, we'd learn more about why.

[figflower]

Hi all. Frunoblax, I am amazed that the PPI's seemingly triggered your RLS. I shouldn't be amazed. Like I've said on here before just about any medication, supplement, sugar substitute is guilty until we all say otherwise. I too have a hiatal hernia and struggle with the acid entering the esophagus. One Tagamet will give me RLS for about six hours. Same is true with Benedryl. Same is true with splenda and aspartame. Not saccharin that I've noticed. Like you, I have read that histamine will inhibit the release of dopamine. I have allergies but have not made a connection between exposure to say pet dander and the onset of an attack but next time I will pay closer attention. I'll add my two cents in here as to what I think is going on and I am probably repeating myself. I think we all (no exceptions) have pathetic dopamine receptors and low levels of brain iron which cause those receptors to be pathetic. And maybe a lot of us when we're young and medication free only rarely get attacks. But as we age the receptors get more pathetic. I read that everyone's receptors age but ours are bad to begin with. So you went your whole life without really having RLS and then you started the PPIs and it pushed you over the cliff. For others it can be SSRIs, or diabetes, thyroid issues, bad gut, or a back injury. From what I understand, dopamine is released from the dopamine receptors and bounces its way down our spines (called the central nervous system) to the peripheral nervous system (legs and arms) and quiets them. And maybe, generally speaking, we have just enough dopamine flowing down our spines to stave off the RLS. But one bump in the road, either upstream or downstream, and we have full blown RLS. I read a study that indicated that 100% of people with traumatic spinal cord injuries had RLS. Makes sense, no? The dopamine/neurotransmitter cant make it to the peripheral nervous system when the spine is severed. What amazes me, and I'm going to get in trouble here, are people who say "how can there be a connection between the thyroid and RLS when my thyroid is fine." Don't they get it??? It's like having a permanently broken arm and someone says tennis triggers pain in my broken arm and then another person with a broken arm says how can their be a connection between tennis and a broken arm when I've never played tennis in my life. I just want to scream "hey we all have broken arms, anything and everything can trigger pain."

I think we all have broken receptors and we have to try to avoid each and everything that might be making them worse. So far I have heard people say that statins, HRT, metformin, calcium channel blockers, beta blockers, melatonin and even magnesium has made their RLS worse (and a big meal seems to trigger mine as well). One man in Costa Rica never even heard of RLS until he had the worst case of stomach flu and nearly died. After the flu began to subside he developed the RLS and basically said that he wished he had died. He went on to state that coconut water cured him, but for all we know time may have done the trick for him. Anyways, for all we know, these very things that trigger our RLS might also be the best treatment for it too. I read an old article that basically said that even though magnesium is necessary for the production of dopamine (which we allegedly have plenty of) it does tend to inhibit the release of dopamine from our receptors. So it's a dopamine antagonist, right, if we are to believe that old article? Maybe a dopamine antagonist by day is better than a dopamine agonist by night??? If an agonist down-regulates our receptors then shouldn't antagonists up-regulate them? After a few weeks or months of up-regulating with magnesium then maybe you'll achieve some relief. Just a theory as to why so many people get relief from magnesium. But if you're taking a substance that down-regulates your receptors at the same time then you're going to come to the conclusion that magnesium doesn't work.

Ever wonder why we get relief when we stand and walk? Drove me crazy. Eventually I came upon enough articles that discussed what happens when we rise from a supine position. These were not RLS articles. Anyways, the articles stated that dopamine is released in a nano second to balance us as we stand and to coordinate movement as we walk. I believe the dopamine is released from a part of the brain called the meso-cortex. As we know, Parkinson's patients are low on dopamine (unlike us) and maybe that's why their gait is so bad. I've noticed that when I have RLS, even mild RLS, leaning on a wall will not relieve it completely. Now that was a scary sensation, to have RLS while basically standing. I guess the brain doesn't sense imbalance while leaning and doesn't release dopamine.

Do we really need researchers? Who better than us? And I think our receptors will take and take and take and then one day the barrel is full and will take no more and we have all out RLS. Then we run for agonists and opiates and get relief but just adds more water to the barrel in the long run and it becomes a vicious circle. We have to start reducing the water in the barrel, somehow, someway, or maybe make a bigger barrel or more barrels. Supposedly under-eating or intermittent fasting will cause our D2 receptors to grow bigger and stronger but probably needs to be kept up for a lifetime. And maybe that's why RLS is higher among those who are obese. Iron also supposedly makes our receptors bigger and stronger but it probably has to reach the brain. Exercise too helps the receptors. Lastly, uridine monophosphate is supposed to make our receptors bigger and stronger. Gave me horrible RLS at night, probably like that guy who took a huge amount of magnesium one night and had out of control RLS all night. He repeated a second and third time with the same reaction. I repeated a second and third time with the uridine and still triggered RLS. By day it does not trigger RLS.

In the meantime, everyone has to have an emergency med which is only taken during emergencies. This does not apply to people who have RLS 24/7/365. It's for people with intermittent attacks or mild attacks or RLS of recent onset due to things like PPIs. My emergency med is iron bis-glycinate. For another it's a litre of tonic water, for another it's a teaspoon of cream of tartar in a glass of water. Some people have sworn by Niacin. It relieved the RLS while I was flushing and for a short time thereafter but came back with a vengeance. Niacin is supposed to cause the cells in your bodies to release stored histamine in a big way. Hence the flushing, burning, I'm ready to call 9/11 feeling. No RLS while this is happening but so short lived for me!!! Same is true for cream of tartar, so short lived but definitely helped for a few hours. Large amounts of potassium is supposed to cause a pop of dopamine. So it's a dopamine agonist, like quinine. And like I said before should only be a emergency med.

Keep searching for answers everyone, they're out there, I guarantee it, kind of.

[Rustsmith]

I am not going to pretend that I understand enough neurochemistry to be able to provide a substantive contribution to this discussion. However, it would appear to me from what I do know that for everything to function, there has to be a balance between the dopamine, glutamate and histamine neurotransmitters. Add to this the opiate receptors and the cannabinoid receptors along with the roles of magnesium and iron to in the creation of all of these and you end up with a system where if one gets out of balance, the others are also affected.

In addition to severe RLS/WED, I also have very severe allergies to virtually everything in the air. My RLS started when I was about 30, but the allergies have been with me since I was about 4. As a result, I have been on just about every allergy med introduced to the market since the 50's. Everyone talks about how benedryl triggers their RLS. For me it does nothing (for my allergies or my RLS) and I believe that this is because my body's allergy system simply soaks up the bendryl so that it only a very tiny about ever makes it across the blood/brain barrier.

So although antihistamines (first or second generation) do not trigger my RLS, I have notices that my RLS is worse in the spring and fall when the pollen seasons are in full swing. I asked my doctor (who is also a researcher) about a correlation and he indicated that there wasn't one and assumed it was due to an increased use of antihistamines. When I told him that I take the same antihistamine dose 365 days a year, he sort of shrugged his shoulders and told me that I needed to limit my use of the antihistamines for my RLS. So I currently limit my use zyrtec to the spring and fall months.

Finally, I have seen that higher histamine levels in the blood (from allergy attacks) do not translate into histamine levels in the brain because the histamines cannot cross the blood brain barrier. I am not sure that I completely buy into that based upon my experience, but then again, that is miles beyond my understanding of that level of the chemistry involved.

[figflower]

Hmmm, Ive read just the opposite. That histamine blocks the release of dopamine. At any rate, Niacin, at least the kind that causes flushing (and should never ever be taken on an empty stomach), is supposed to cause our bodies to "dump" histamine. Maybe over the long run, Niacin might help? The human body is so amazing. Pollen will cause the "release of histamine" and we'll get allergy symptoms, runny nose water eyes. But Niacin, that I know of, will not cause the symptoms of allergy. Instead you will feel like you're on fire for about 20 minutes. Anyways, some people swear by Niacin for RLS.

[badnights]

Figflower, re.all the people you use as examples - such as, lots of people swear by niacin, or some people find that full bowels brings it on, etc etc : where do you talk to these people? how do you know them, who are they?

[figflower]

You name it, these sure fire cures are everywhere, all over the internet, just like the bar of soap one. Mustard, black strap molasses, cream of tartar, apple cider vinegar, Tylenol, magnesium oil, Epsom salts, aspirin, banana, gingko biloba, baking soda, tonic water. I read it and then take the so called "sure fire cure" and google it with dopamine or dopamine receptors to see if these substances have any affect on them. Here's one on Niacin but I've read others. And like I said, I experimented on myself with Niacin:

http://boingboing.net/2010/05/17/restle ... yndro.html

Here's the one on magnesium where it makes it sound like magnesium actually inhibits the release of dopamine. But note that it was injected intra-cerebral. The guy who had trouble with magnesium is on the Patients.co.rls website. His name his Graham. Funny, now that I think about it, I think he actually used magnesium bisglycinate. Not that long ago I read that magnesium bisglycinate may actually cross the BBB. I was looking to see if iron bisglycinate crosses the BBB but only found the one on magnesium. The point being, maybe he (Graham that is) had such a rough time because he took the magnesium bisglycinate at night and a large dose. If it truly did cross his BBB and if it truly does inhibit the release of dopamine then it makes sense. Here's the article:

http://www.ncbi.nlm.nih.gov/pubmed/11044573

[figflower]

Here's the "guy" that took magnesium:

Some people say Mg should be taken in the morning. Of course I.m not suggesting you change if its working.


I took a bigger dose of Magnesium (800mg I think) at night and it I had two really bad RLS nights. At the moment I am not taking any medication - just sticking to the diet - and I have had about 10 nights with no symptoms up to a few days ago when it returned after meal at a snazzy restuarant. Maybe there was garlic or something in the sauce? The symptoms were present and woke me but I was back asleep in half an hour. I am taking iron,.and fish oil in the mornings. I have dropped all my magnesium and I want to see if the RLS returns. After a week of no symptoms I will hit the old magnesium again and see what happens. I dread doing it in case it ruins a weeks sleep but its worth trying.


Glad to hear that things are working for you

Cheers

[badnights]

Thanks! You're just doing an incredible amount of legwork, then. I envy you your brainpower. I haven't been able to keep a straight thought in my head longer than a split second for most of the last eight years. Keep those links coming.

[figflower]

This is an interesting article on magnesium as well. Claims that it increases synaptic densities. Not sure if dopamine receptors fall into that category but if it does then it explains a lot. If magnesium really is a "dopamine antagonist" as the 2000 article above claims then like I said, maybe magnesium, in the long run, will up-regulate the receptors and that is why it works so well for so many:

http://blog.lifeextension.com/2012/01/b ... onate.html