Preprint Biological Insights from Genome-Wide Association Studies and Whole Genome Sequencing of [ME/CFS], 2026, Maccallini et al

Have there been any studies looking at me/cfs and glutamate?

Or with memantine?

I am in no way an expert but I believe glutamate has been implicated in autism and Alzheimer's which also have sensory sensitivities.

{Apologies if this is a bit simplistic for the experts!)
 
Dude said:
Topic Glutamate: I’m currently testing a medication that inhibits the release of neurotransmitters such as glutamate. It’s still far too early to say anything about its effectiveness, but two days ago I was able to watch half a football match on my phone. Before starting the medication, that had no longer been possible since becoming very severe 2 years ago.
The background for trying this was the study “Imbalance of Excitatory and Inhibitory Neurotransmitter Systems in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.”
If this experiment leads to a Bell score improvement, I’ll make a separate thread about it, especially since I know at least one other person who reportedly had success with it.
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I’ve always wondered if something like that would help with the “wired” feeling and sensory overexertion. Do keep us updated. I hope you continue to see improvement :)
 
Impressive work @paolo! I appreciate how much detail is provided in the methods section.

One thing that wasn't clear to me is how the connection was made from the cerebellar glutamatergic neuron finding in the Results section to interstitial white matter neurons in the Discussion section. Are these the same thing?

Edit: Okay, yes, sorry, the first reference about IWMNs says that this is basically what neurons in the white matter are called, and that's where this cell type was found.
 
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Huge fan of Maccalini; he's a model for what a careful and (very) bright independent pwme can achieve.

A great example of why we may hope some of the progress can come from outside the mainstream system. (which is, I think, part of the purpose of this forum - kicking things along, sorting good from bad, doing post publication reviews, filtering and combining existing data, sending feedback into the formal research system, etc).
 
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Topamax a med that reduces glutamate and increases gaba helped to improve my sensory tolerance a bit and i wasn't crashing as easily from small basic activities(like receiving bed bath). Really improved mental health and fight/flight response to minor stimuli and also helped migraine symptoms, also helped me get deep sleep. Still bedbound apart from bathroom though.
 
rvallee said:
It would be surprising if it wasn't, or at least involves it prominently, especially given how prominent brain fog is, and given how much problems in the brain have downstream effects on all systems.
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Adverse brain function can be downstream consequences of all sorts of other non-brain systems failing or being sub-par.

Problems with kidney or liver function, for example, can really mess with cognition and emotion.

I agree that whatever ME/CFS is must somehow affect brain function. But doesn't mean that the brain is a part of the primary pathology, just that it is affected somewhere in the causal chain.
 
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Rutin improves glutamate uptake and inhibits glutamate excitotoxicity in rat brain slices​


pubmed.ncbi.nlm.nih.gov

Rutin improves glutamate uptake and inhibits glutamate excitotoxicity in rat brain slices - PubMed

Rutin is an important flavonoid consumed in the daily diet. It is also known as vitamin P and has been extensively investigated due to its pharmacological properties. On the other hand, neuronal death induced by glutamate excitotoxicity is present in several diseases including neurodegenerative...
pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov

" We showed that rutin inhibited the cell death and loss of glutamine synthetase (GS) induced by glutamate that was associated with an increase in glutamate-aspartate transporter (GLAST) in brain organotypic cultures from post-natal Wistar rats. Additionally, it was observed that rutin increased the glutamate uptake in cerebral cortex slices from adult Wistar rats. We conclude that rutin is a neuroprotective agent that prevents glutamate excitotoxicity and thereof suggest that this effect involves the regulation of astrocytic metabolism."
 
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If ME/CFS is in fact partially driven by immune dysregulation wouldn't we see peripheral immune or neuroimmune susceptibility genes? Like we see in GWAS in MS for example.

I'm trying to make sense of these results now that we have this new analysis which also includes a second independent cohort and more or less confirms what DecodeME has found. Sorry I haven't been able to follow the DecodeME thread in closer detail. Did anyone propose any new mechanisms given the GWAS findings?
 
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From the paper:
Gene-set analysis identified multiple neuronal and synaptic gene sets, several of which were independently replicated, with glutamatergic synapses as the most specific replicated signal
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And:
Glutamatergic dysregulation may also explain the unusual prevalence of alcohol intolerance in ME/CFS [7], since alcohol inhibits NMDA receptor-mediated transmission
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I’m out of my depth here but as far as I understand kynurenine pathway metabolites interfere with glutamate. From memory, it has been suggested that the kynurenine pathway may be involved in ME/CFS but I can’t remember the details and I don’t have the capacity to look it up at the moment. I’m just wondering if this could join up any dots.

[Edit: formatting]
 
leokitten said:
If ME/CFS is in fact partially driven by immune dysregulation wouldn't we see peripheral immune or neuroimmune susceptibility genes? Like we see in GWAS in MS for example.
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Perhaps we do.

Autoimmune diseases tend to link to HLA-D (MHC Class II) loci. The known T cell dependent diseases - spondarthropathies - tend to link to HLA-B or C. More innate autoinflammatory diseases can link to obscure proteins involved in macrophage or neutrophil activation - the familial fevers.

ME/CFS has a link to BTN2A1, which is involved in innate immune recognition. It is one of the clearest peaks and now seems to be fairly well pinned down to this gene. It might be linked because of a 'non-immune' role in lipid regulation but its role in T cell recognition is much more clearly defined in the literature.
 
Robert 1973 said:
I’m just wondering if this could join up any dots.
Click to expand...

I am wary of suggestions that we can explain ME/CFS just be an imbalance of something like glutamate metabolism. A gene variant that changes glutamate regulation might make neural circuits that use glutamate more likely to flip into an abnormal signalling pattern but there has to be an account of what that flip involves. I think it is likely to be very specific and local within the brain.

And that makes me sceptical of any proposal to try to shift the metabolic balance back with supplements etc..
 
Jonathan Edwards said:
Perhaps we do.

Autoimmune diseases tend to link to HLA-D (MHC Class II) loci. The known T cell dependent diseases - spondarthropathies - tend to link to HLA-B or C. More innate autoinflammatory diseases can link to obscure proteins involved in macrophage or neutrophil activation - the familial fevers.

ME/CFS has a link to BTN2A1, which is involved in innate immune recognition. It is one of the clearest peaks and now seems to be fairly well pinned down to this gene. It might be linked because of a 'non-immune' role in lipid regulation but its role in T cell recognition is much more clearly defined in the literature.
Click to expand...

Ok yes sorry I missed mentioning of this gene, like you said it does have a very important role in modulating the immune system https://maayanlab.cloud/Harmonizome/gene/BTN2A1
 
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