Glutamate, similarities with underlying mechanisms? ME, PLMD/RLS

Polysomnography has shown that I have Periodic Limb Movement Disorder (PLMD). I also tick all boxes for RLS (and never been diagnosed with fibromyalgia). I can't describe how happy I was to see, written in black and white, numerically quantified, accompanied by "obviously [patient] has PLMD that needs to be investigated and treated".

I found myself going down rabbit holes wondering how this fits together with my ADHD, fatigue, ME/CFS, stress intolerance, anxiety, and medication response. I found the following interesting - I noticed recent studies talking about glutamate and sarcosine and long COVID. I know these are all seperate diseases (and there are many others where excess glutamate is implicated) but what does all of this mean in terms of predisposing/ precipitating/ perpetuating factors and possible treatments? Basically, I am no scientist so what might this all mean?


Some sources say that PLMD can't be diagnosed if RLS is present and others disagree, but the general consensus is that they are distinct disorders with overlapping features, and that PLMD may be associated with sympathetic hyperactivity*.


1. **Hormonal and Neurological Factors:**
- Abnormal hormone secretion, increased metabolic activation, elevated heart rate, and sympathetic nervous system activation during sleep are observed in RLS. ([Study Link](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4096207/))

2. **Nocturnal Cortisol Excretion:**
- Enhanced nocturnal cortisol excretion in RLS suggests nocturnal hypothalamic-pituitary-adrenal system overactivity. ([Study Link](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4096207/#B20))

3. **NREM Sleep Instability:**
- A significant increase in NREM sleep instability reported in RLS, indicating arousal-related transient events during sleep. ([Study Link](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4096207/#B3))

4. **Spinal Cord Excitability:**
- Abnormal spinal excitability implicated in RLS symptoms, affecting daytime muscle activation patterns during gait. ([Details](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4096207/#B37))

5. **Autonomic Involvement:**
- Disinhibition of autonomic spinal nuclei in RLS may enhance sympathetic activity, contributing to hyperarousal. ([Details](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4096207/#B34))

6. **Glutamate System:**
- Thalamic glutamate/glutamine increase in RLS supports the hypothesis of a hyperarousal state. ([Details](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4096207/#B34))

8. **Role of Adenosine:**
- Low levels of adenosine receptors contribute to high glutamate and dopamine, indicating a potential treatment avenue. ([Details](https://rlsfoundation.blogspot.com/2018/07/new-research-identifies-adenosine-role.html))

10. **Glutamate in Pain Signaling:**
- Glutamate plays a crucial role in peripherally-mediated pain signaling to the central nervous system (CNS). ([Details](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4693272/))

11. **Migraine and Glutamate:**
- Peripheral glutamate dysregulation may play a role in migraine pathogenesis. ([Details](https://journals.sagepub.com/doi/10.1177/03331024211017882))

12. **Glutamate Inhibitors:**
- Glutamate inhibitors or antagonist drugs can inhibit the action of neurotransmitter glutamate on neurons.

13. **Role of Vitamin B6:**
- Vitamin B6 deficiency associated with elevated serum glutamate in animal models.

14. **Central System Glutamate Dysregulation:**
- Linked to symptoms of anxiety, posttraumatic stress, OCD, mania, depression, and psychosis. ([Details](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4630664/#:~:text=In examining the effects of,of key ER stress pathways.))

15. **Mitochondrial Deficits and Glutamate Excitotoxicity:**
- Mitochondrial deficits contribute to excitotoxicity via increased extracellular glutamate levels. ([Details](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4630664/#:~:text=In examining the effects of,of key ER stress pathways.))

16. **Taurine's Protective Role:**
- Taurine acts to restore calcium homeostasis, inhibiting ER stress pathways. ([Details](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4630664/#:~:text=In examining the effects of,of key ER stress pathways.))

17. Association with POTS:
Higher prevalence of RLS in patients with Postural Orthostatic Tachycardia Syndrome (POTS), possibly due to shared inflammatory/autoimmune load and autonomic dysfunction.

18. Additional information:
The role of RLS in sympathetic hyperactivity, leading to increased risks of inflammatory mediators, lipolysis, glycolysis, endothelial damage, and atherosclerosis. (Details)

Excuse the unlabelled links, I used chat GPT to create bullet points from pasted text and hyperlinks and then to create a smaller list of only the ones referencing certain words.

*As they seem to overlap in terms of proposed mechanisms and medications that help or exacerbate, and as a lot of the literature covers both as if they are the same, I have considered information about both PLMD and RLS.