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Latest research about glutamate involvement

Posted: Thu May 09, 2013 10:36 am
by ViewsAskew
As I sit here at almost 5 AM, relatively wide awake and forcing myself to consider going to sleep, I was thinking about the latest research. Both Ericka and Beth, if I remember correctly, posted versions of the new research.

The short of it is that people with WED/RLS have a lot of extra glutamate compared to people without WED. The hypothesis is that it may be directly involved with the being awake part, the insomnia even when symptoms are controlled, the ability to get by on a few hours sleep over and over again.

Random thoughts....

We seem to lose that ability to stay awake during the day after a time. When the disease progresses, when we've done it too many times? Or maybe it comes and goes? Not sure, but I don't think I do it as well as I used to.

Gapapentin (and Lyrica and Horizant, I'd guess) increases GABA which I think in return reduces glutamate. Maybe this is why I sleep like a LOG when I take it. To me, it's like the best sleeping pill imaginable. Except I want to sleep 12 to 16 hours! But, it doesn't ever control sensations and urge to move. OK, maybe a bit, but not nearly enough to actually sleep. Yet it does for others. I wonder how that will turn out? Different variant of the disease, maybe? There are other drugs that are known to reduce it, riluzole and memantine, for example. They have been used in a few OCD patients to reduce glutamate. Lamictal is supposed to reduce it,too - another drug that helps some of us - could be why?

I was wishing, tonight, that I had a bit of one of these drugs to take - hours ago! I'm finally tired enough to go to sleep - just wish it would have happened 5 to 7 hours earlier.

I was also thinking that I'm very glad we have researchers such as Dr Allen. He has done some of the most important research about this condition. I hope he has many more years to do so.

And that excess glutamate is linked to depression. Could be an explanation as to why we're more likely to be depressed than people without WED. It is also linked to OCD and several other conditions/disorders/diseases, from stroke to Alzheimer's. The good news is that because it's associated with other things, people are already researching how to lower it. It's fascinating that it's linked to so many disparate diseases - wonder how that works. It doesn't make us more likely to have those things - having them sometimes causes excess glutamate - wonder why?

I was also thinking of natural ways to decrease glutamate. Theanine comes up as one option. So does N-acetylcysteine. Could be why some people get help from the amino acid therapy. Glutamate is in a lot of food - MSG is about 70% glutamate - but I'm not sure reducing it in diet would do enough. It certainly could be a starting point, but there are many other things with glutamate in them, from meat to dairy to nuts and seeds.

Interestingly, foods high in glutamate include wheat - some people suggest they improve on a wheat free diet. Aspartate is also on the list of things to avoid as it converts to glutamate - that's Asparagus, another thing that causes problems for some of us.

It will be interesting to see how this research helps us over time.

Re: Latest research about glutamate involvement

Posted: Thu May 09, 2013 3:14 pm
by peanut1
Thanks for the information. I also saw the study on the newsletter and was wondering what natural thing would reduce it.

Re: Latest research about glutamate involvement

Posted: Thu May 09, 2013 4:06 pm
by Polar Bear
Thank you for explaining this information in a people friendly way, making is easy to understand.

Re: Latest research about glutamate involvement

Posted: Thu May 09, 2013 10:39 pm
by Chipmunk
Yes, I agree with everything you've said there. As I was reading about this new study I thought of how different treatments work for different people, and I wondered if glutamate was the culprit for some people but not all, or maybe that everyone with WED has problems with glutamate but that for some it's not the only thing, making their disease worse than others.

Glutamate involvement makes SO much sense for me. I have never in my life been able to nap - once I'm up, I'm up - and my mom used to always comment on how awake I would be even after I missed sleep. Gabapentin worked wonderfully for me in terms of sleep, unfortunately it acted as a diuretic at night so I was up 3x per night using the bathroom...uh, not really helping! Then I switched to Lamictal, which is also an anti-seizure med, and it works well enough for me to get some decent sleep, although my legs still start buzzing at about 6 p.m. each night.

I also take amino acids each day and it makes a big difference in my sleep if I miss them. I didn't know they reduced glutamate levels, interesting.

Re: Latest research about glutamate involvement

Posted: Thu May 09, 2013 11:16 pm
by Chipmunk
I was curious as to how Vit. D interacted with glutamate because several of us have said that treating low Vit. D made a noticable difference in our WED. I found this study which details how Vit D reduces the negative effects of glutamate - so interesting! I think I am going to email this to Dr. Allen.

Here's a snippet:
The results of the present study indicated that 1α,25-(OH)2 D3, a biologically active metabolite of vitamin D,
protected dopaminergic and non-dopaminergic neurons against glutamate- and ROS-induced neurotoxicity. The
neuroprotective effect of 1α,25-(OH)2 D3 was inhibited by the protein synthesis inhibitor, cycloheximide. Furthermore,
1α,25-(OH)2 D3 prevented the neurotoxic effects of ROS donors and inhibited the H2 O2-induced increase in intracellular
ROS. These results suggested that 1α,25-(OH)2 D3 protects both dopaminergic and non-dopaminergic neurons by
promoting de novo synthesis of functional molecules that inhibit the increase in ROS levels.

Source: Neuropharmacology
Volume 40, Issue 6, May 2001, Pages 761–771
Protective effects of 1α,25-(OH)2D3 against the neurotoxicity of glutamate and reactive oxygen species in mesencephalic culture
M Ibia, H Sawadab, M Nakanishia, T Kumea, H Katsukia, S Kanekoc, S Shimohamab, A Akaikea, ,
a Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan
b Department of Neurology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan
c Department of Neuropharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan

Re: Latest research about glutamate involvement

Posted: Fri May 10, 2013 2:35 am
by jul2873
This article explains how adenosine counteracts glutamate, and makes us sleepy: ... =218392537

Here is a quote from the article:

The research team showed that under normal "awake" conditions these arousal centers release an excitatory chemical called glutamate. Glutamate is a neurotransmitter, a chemical that carries messages between brain cells. In the arousal centers it keeps the cells firing, so they interact and respond effectively to everyday stimuli. Through the course of the day however, these same neurons release a second neurotransmitter called adenosine. Adenosine is a natural sleep chemical that counteracts the effects of glutamate and quiets the cells down, essentially making them, and us, sleepy.

D-ribose is mostly adenosine, which is why I think it helps with sleeping. At any rate, perhaps another piece of the puzzle.

Re: Latest research about glutamate involvement

Posted: Fri May 10, 2013 10:30 pm
by Chipmunk
I sent an email to Dr. Allen last night with a pdf of the article attached and he wrote me back already! He said:
thanks for the information

bit D interacts with Dopamine etc as well as the effects of increased glutamate so it might be that bit D deficiency exacerbates RLS.

So get your Vitamin D levels tested! :wink:

Re: Latest research about glutamate involvement

Posted: Mon May 13, 2013 1:41 am
by badnights
My understanding is that glutamate has two broad functions in cells: (1) in neurons, it's a neurotransmitter (leaving the neuron through a channel into the synapse, where it is taken up by receptors on other neurons and thereby sends a message), and (2) in all cells, not just neurons, glutamate is as an ingredient in the manufacture of GABA.

Drugs like gabapentin encarbil / Horizant and pregabalin/Lyrica reduce the amount of glutamate released into synapses. These drugs help RLS/WED, and are also more effective at helping sleep in WED than DAs. That's one of the reasons the researchers decided to study glutamate levels in WED brains.

Another observation is that NMDA-receptor antagonists (eg. methadone, ketamine) help RLS/WED. NMDA receptors are one of the two main glutaminergic receptors in neurons (they receive glutamate). Antagonising them means blocking them and thereby preventing them from receiving glutamate, thereby blocking the effect of the glutamate (so to speak).

I am too tired to follow that line of thought...

Glutamate dysfuntion is implicated in schiozophrenia too, (as is the dopaminergic system - interesting!). So - OCD, depression, schizophrenia,.. It's complicated and no one pretends to have it even close to figured out.

I don't think it follows or is even likely to be a good approach, to reduce glutamate intake in order to reduce brain levels of glutamate. It reminds me of the old advice not to eat cholesterol in order to avoid high blood cholesterol, when actually your body manufactures cholesterol from certain types of fat in the absence of other types of fat, whole grains, etc (and from some of the ingested cholesterol, so the advice was partly right but largely missed the point). More recently I've been impressed with the same concept in WED: ingesting huge amounts of iron does not automatically raise iron levels in the brain.

So I was surprised that stopping glutamate ingestion was the first thing my GP thought of when I told her about the study. I don't eat food with MSG anyway, if I can help it, but I am not convinced it would do me any good to stop intake of glutamate, because I think the problem is more likely to be a dysregulation within the brain and would happen no matter how much I ingested... within reason .. but I have to confess I really haven't a clue. Same with taking adenosine to counteract the glutamate; in a healthy brain, adenosine builds up over time until it reaches a level at which it counteracts the glutamate - I think - so it's not a simle matter of ingesting it, but ensuring it arrives in sufficient quantity at the brain at the right time. When is the best time to ingest it to ensure that happens, and given that it's normally manufactured in our neurons, will something that enters our stomach make it to our brains unchanged?

Another wierd thing is the amino-acid supplement I sometimes take (that I turned chipmunk on to) contains glutamine (a precusor of glutamate), and seems to promote sleep. Mabye the glutamine is outweighed by the other stuff in the pills.

The wheat question nags at me, and if only someone in a position of authority would tell me to go wheat-free, or at least gluten-free, I would try it... not sure why I think this way...

Thanks so much for the vitaminD/glutamate neurotoxicity reference. Wow. You (?) posted an earlier one about vitamin D, but I can't find it. I also have two abstracts on vitamin D and WED/RLS:

Gen Hosp Psychiatry. 2010 Mar-Apr;32(2):228.e1-3. doi: 10.1016/j.genhosppsych.2009.03.003. Epub 2009 Apr 15.
Restless legs syndrome with carbamazepine-induced osteomalacia: causal or casual association.
Prakash S, Bhanvadia RJ, Shah ND.
Department of Neurology, Medical College, SSG Hospital, Baroda, Gujarat 390001, India.

Restless legs syndrome (RLS) is a sensorimotor sleep-related disorder which can be idiopathic or secondary. Secondary RLS is associated with a variety of conditions. Here we report a 16-year-old girl with RLS secondary to vitamin D deficiency (VDD) caused by chronic administration of carbamazepine. We also speculate on the possible mechanisms for the development of RLS in patient with VDD.

Sleep Med. 2012 Aug;13(7):953-7. doi: 10.1016/j.sleep.2012.04.009. Epub 2012 Jun 15.
Serum 25-hydroxyvitamin D levels in restless legs syndrome patients.
Balaban H, Yıldız ÖK, Çil G, Şentürk İA, Erselcan T, Bolayır E, Topaktaş S.
Department of Neurology, Cumhuriyet University, Faculty of Medicine, TR-58140 Sivas, Turkey.

Restless legs syndrome is characterised by discomfort during rest and an urge to move the limbs that is accompanied by abnormal sensations. Studies on disease pathophysiology have focused on dopaminergic dysfunction. Vitamin D may play an important role in dopamine function, but the role of vitamin D in restless legs syndrome has not been examined. We compared the serum vitamin D levels of RLS patients and matched controls and explored the correlation of plasma vitamin D levels with disease severity.
We measured serum 25-hydroxyvitamin D levels in 36 patients with restless legs syndrome and compared them to 38 healthy control subjects.
The mean serum 25-hydroxyvitamin D levels were 7.31±4.63 ng/mL in female patients with restless legs syndrome and 12.31±5.27 ng/mL in female control subjects (p=0.001). We found a significant inverse correlation between vitamin D levels and disease severity in females (p=0.01, r=-0.47).
The mean serum vitamin D levels were lower in female patients with restless legs syndrome. Low vitamin D levels may cause dopaminergic dysfunction in restless legs syndrome patients. Further studies are required to confirm these results.

Re: Latest research about glutamate involvement

Posted: Mon May 13, 2013 1:43 am
by badnights
Ah, sorry, that second abstract is the one I was thinking of, it was already posted, by corrie not chipmunk
sorry :)

new research - hight glutamate levels

Posted: Tue Jul 23, 2013 7:21 pm
by moonlight
Did anyone read the other day about problems with high levels of Glutamate as well as low Dopamine as a possibility for the cause rls, looks like there going to go down a different route to treat rls, i dont think they mean now tho i think there looking into it.


they say its to do with the fact we dont sleep much cos of the high levels

Re: Latest research about glutamate involvement

Posted: Wed Jul 24, 2013 5:52 am
by ViewsAskew
Moonlight, I merged your post with this one - that is about the topic.

Re: Latest research about glutamate involvement

Posted: Sat Jul 27, 2013 9:03 pm
by moonlight
no probs

Re: Latest research about glutamate involvement

Posted: Sat Jul 27, 2013 11:53 pm
by veldon7
Where are you guys reading this article about the glutamate?

Re: Latest research about glutamate involvement

Posted: Sun Jul 28, 2013 3:13 am
by ViewsAskew
We almost always put research articles in the pinned sticky post about research.


Re: Latest research about glutamate involvement

Posted: Sun Jul 28, 2013 11:03 am
by veldon7