Does viral selection pressure on the GABAergic system mediate the etiopathogenesis of ME?

nerd

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Please beware, this theory is highly speculative. However, considering the good risk-benefit ratio from associated solutions, I'd like to discuss it.

One of the many unresolved questions of ME is the role of viral pathology and how it might mediate the ME etiopathogenesis. One of my existing theories is that an overgrown latent/abortive cell reservoir just increases the threshold of reactivation susceptibility so far that these viruses basically remain stuck in their early reactivation phases. This makes them difficult to quantify via IgM antibody and PCR testing.

How exactly this mechanism might work in detail, I haven't elaborated so far. In this post, I'd like to introduce one theory of how this mechanism might play out. The theory is based on the core assumption that one or more viruses have managed to infect the brain or CNS and form a latent/abortive cell reservoir in these regions.

Due to my current work on histone deacetylases (HDACs) and their adverse and therapeutic potential, I identified GABA as a potent HDAC inhibitor (more on this another time) [3, 4]. Given the findings of GABA brain tissue concentrations, I make a reasonable estimate that there is normally a sufficient GABA concentration in most brain regions and cell types for virus reactivations to be triggered (i.e. at high nM to low μM concentrations) [1, 2, 3]. This makes the brain very susceptible to infections if a virus manages to invade it since HDAC inhibition is a cross-cutting viral reactivation trigger.

One prevalent theory of the innate immune system is that it has been shaped via selection pressure from pathogens [7, 8, 9]. What if the selection pressure doesn't only affect the species on an evolutionary/host-macroscopic but also on a microscopic level, and pushes them to minor adaptations within their lifetimes?

Imagine viruses that aren't necessarily lethal (anymore) and hence trigger selection pressure on a cellular level. The immune system will be maternally and paternally inherited to different degrees, thereby coevolve parallel to the genetic sexual reproduction, one might say forming an evolutionary lineage on its own [5, 6, 7]. Generation by generation, viruses and the immune system might be inherited to the offspring and the selection pressure would continue on a cellular level, naturally forcing cells to adapt their gene expressions and gene functions to the parentally endemic pathogens.

The cellular adaptation is not proven and speculative since the subject is still in work in progress, e.g. in the context of the original antigenic sin. But how could it work mechanistically? Pathogens adapt to the species in which they are endemic, thereby integrating their genes in one way or another. This can lead to a cycle of species and pathogen evolution.

The first mechanism I can imagine is this kind of antigen-driven selection pressure, whereby antigens might affect the intracellular innate immune response and gene/enzyme expressions. This would happen on an intracellular level. On a macrocellular level, the cellular selection could be driven by the susceptibility of cells to be damaged by viral infections or by surrounding infected cells and the subsequent destruction of these cells. Lifecycle after lifecycle, the cells would adapt to the existing viral reservoirs.

Let's assume that this cell adaptation theory is applicable to the brain and its immune system. The reproductive cycle in the brain would be driven by GABA-regulated HDAC inhibition. This makes HDAC a target, but also GABA. GABA receptor function is regulated by HDAC3, after all [3]. What if there is a selection pressure that downregulates GABAergic mediators in order to protect the brain from viral reactivations and their toxicity?

This leads to hyperactivity, sleeplessness, unrest, cognitive over-exhaustion, oversensitivity, the incapability to properly rest, and thereby also the whole energy metabolism and excess of oxidative stress by sympathetic overactivation. The excess of oxidative/nitrosative stress subsequently blocks the citric acid cycle (CAC) and causes an oversupply of glutamate, thereby enhancing and enforcing the condition via a secondary pathway, creating a "GABA trap" situation.

The trap would be self-fueling in that the sympathetic overactivation triggers oxidative stressors that can reactivate viruses (e.g. via the CAC blockage). This might trigger PEM. During PEM, more GABA would be released. The GABA triggers reactivations. Also of note is that the oxidative stressors would affect the whole metabolism while the GABA affects the brain predominantly.

How can this translate into solutions? Besides the HDACi antiviral protocol that it is still work in progress and a topic for another time, GABA agonists and positive allosteric modulators could replace the role of GABA. These agonists would need to lack the property that makes GABA an HDAC inhibitor, namely its zinc ionophority and the small size that allows it to fit into the zinc finger binding sites of HDACs. Unfortunately, Taurine seems to be an HDAC inhibitor as well (with mild or moderate effect). At least, this is likely based on the docking simulations. So I'm still looking for more candidates that meet the criteria.

A matching GABA agonist/modulator could be taken in the evening to alleviate sympathetic overactivation without downregulating HDACs, thereby avoiding additional reactivation triggering but alleviating the metabolic consequences that indirectly lead to viral reactivations. At least one side of the GABA trap could be functionally handled this way. It would not remove the viral reservoirs immediately but it might provide a baseline for the immune system to get hold of the virus in the brain, which mediates the other side of the trap.

This theory doesn't exclude alternative theories that can create similar trap situations. For example, viral miRNA and viral proteins could also create reactivation cycles. They can also affect the sympathetic overactivation and indirectly maintain a GABA/HDAC trap. This would be an alternative explanation to the cellular adaptation, though the GABA agonist/modulator therapy would still be applicable. I think GABAergic activation without HDAC inhibition is as important as Melatonin for getting refreshing rest and not exhausting half-sleep, as it is often the case.

  1. BBB: Permeable Conjugate of Exogenic GABA (2017) [10.1021/acsomega.7b00425]
  2. Gamma-aminobutyric acid concentration in brain tissue at two stages of Alzheimer's disease (1988) [10.1093/brain/111.4.785]
  3. As a Histone Deacetylase Inhibitor, γ -Aminobutyric Acid Upregulates GluR2 Expression: An In Vitro and In Vivo Study (2019) [10.1002/mnfr.201900001]
  4. Study of GABA in Healthy Volunteers: Pharmacokinetics and Pharmacodynamics (2015) [10.3389/fphar.2015.00260]
  5. Review: Fetal antigens – Identity, origins, and influences on the maternal immune system (2011) [10.1016/j.placenta.2010.12.014]
  6. Exposure to non-inherited maternal antigens by breastfeeding affects antibody responsiveness (2019) [10.3324/haematol.2018.199406]
  7. Adaptive Evolution as a Predictor of Species-Specific Innate Immune Response (2015) [10.1093/molbev/msv051]
  8. Genomic Signatures of Selective Pressures and Introgression from Archaic Hominins at Human Innate Immunity Genes (2016) [10.1016/j.ajhg.2015.11.014]
  9. Pathogen-Driven Selection in the Human Genome (2013) [10.1155/2013/204240]
 
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SlamDancin

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I’m a super responder to all benzos and am currently trying Allopregnanolone. It’s definitely nothing like a benzo but I think I’ve been getting more refreshing sleep since starting it. It’s not nearly as anxiolytic unfortunately
 

Hip

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@nerd , you might consider dividing your text into paragraphs of about 3 or 4 lines, as lots of ME/CFS patients struggle to read longer paragraphs (especially when the subject matter is itself complex). I am one of these patients that struggles with long paragraphs, and would like to read your hypothesis.
 

Wishful

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My eyes kind of glazed over too, but that's mostly due to unfamiliarity with all the biochemistry terms. :xeyes:

Can you think of any ways to test your hypothesis?
 

nerd

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@nerd , you might consider dividing your text into paragraphs of about 3 or 4 lines, as lots of ME/CFS patients struggle to read longer paragraphs (especially when the subject matter is itself complex). I am one of these patients that struggles with long paragraphs, and would like to read your hypothesis.
Sorry, @Hip, I tend to forget that my screen width is over the average. Your input would be very much appreciated.

Can you think of any ways to test your hypothesis?
There are a couple of assumptions that could be verified.

First, a study could look at early viral proteins and RNA in order to confirm that the viruses don't reactivate by chance but are stuck in this phase most of the time and most dominantly associated with PEM. This is still work in progress. But, for all intents and purposes, the emerging evidence points into the direction that viral pathology at least correlates with the condition, even if it might just be the immune dysfunction or another pathogen that opens the door, so to speak.

The evolutionary aspect is difficult to prove, just as the original antigenic sin (in a complete manner, not just selective).

Most importantly, the trap itself and its etiology could be verified in observational studies, beginning with healthy participants, children ideally, and looking at their viral markers, HDAC function, and GABA function. There is already some evidence showing the HDAC dysregulation, but not how it evolves and how it is maintained. We can make the assumption that the HDAC dysregulation affects the GABAergic system, though, just as I explained, based on the mechanistic understanding of GABA receptor regulation.

It is also possible to look at some samples of ME patients, ideally from the brain or CNS, and use antibodies against HDACs, GABA, receptors, viral proteins, etc. to rule/figure out what dysregulates the HDACs and SIRTs ex vivo.
 
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SlamDancin

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@nerd Its available and affordable from https://idealabs.ecwid.com/

It’s a trustworthy source. I haven’t noticed side effects other than maybe some slight sedation. I need to try some different ROAs, I’ve only tried it orally and it’s metabolized quickly and extensively through that route. Going to try topically next. It’s very very subtle all things considered and especially compared to benzos.
 

katabasis

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@nerd Its available and affordable from https://idealabs.ecwid.com/

It’s a trustworthy source. I haven’t noticed side effects other than maybe some slight sedation. I need to try some different ROAs, I’ve only tried it orally and it’s metabolized quickly and extensively through that route. Going to try topically next. It’s very very subtle all things considered and especially compared to benzos.
If you like allopregnanolone, you might also be interested in etifoxine. Its main MoAs seem to be related to GABA and neurosteroid synthesis. I would imagine that it has some similarities to allopregnanolone, and it probably has better bioavailability/duration. As far as I know it's pretty safe, with few side effects - it's a prescription drug in some countries so there are studies out there if you'd like to confirm this for yourself. While it's not prescribed in the USA (if that's where you're located), it's not illegal here either, so it's pretty easy to buy from an online pharmacy.
 
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SlamDancin

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If you like allopregnanolone, you might also be interested in etifoxine. Its main MoAs seem to be related to GABA and neurosteroid synthesis. I would imagine it has some similarities to allopregnanolone, and probably as better bioavailability/duration. As far as I know it's pretty safe, with few side effects - it's a prescription drug in some countries so there are studies out there if you'd like to confirm this for yourself. While it's not prescribed in the USA (if that's where you're located), it's not illegal here either, so it's pretty easy to buy from an online pharmacy.
I’ve tried Russian brand name Etifoxine (Stresam) but unfortunately never noticed any effects whatsoever.

I just tried the Allopreg through topical ROA (navel application) and I think I feel it much stronger. I will continue to report
 

nerd

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I’ve tried Russian brand name Etifoxine (Stresam)
I have concerns if the Russian brands that are sold in gray markets are real or counterfeit. I have more trust in Indian generics than Russian ones, simply because there's not much of a financial incentive in India to fake drugs unless they aren't available on the generic market at all. The margin for that is just too small.

I just tried the Allopreg through topical ROA (navel application) and I think I feel it much stronger. I will continue to report
I can try and run some pharmacokinetic calculations to see if transdermal application can achieve sufficient concentrations and how much would have to be applied. What recipe do you use for the dermal application? Do you include any additives that enhance the transdermal availability (10.3390/molecules161210507)?
 

nerd

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I tried to model the transdermal administration, but the inaccuracy of the available plasma protein binding + sustained release from the skin made the result as inaccurate as the plasma protein binding is inaccurate on a logarithmic scale, which can be multiple orders of magnitudes, having only the lower boundary of 99%.

Fortunately, there is already one in vivo study on transdermal administration:
Allopregnanolone Preclinical Acute Pharmacokinetic and Pharmacodynamic Studies to Predict Tolerability and Efficacy for Alzheimer’s Disease (2015) [10.1371/journal.pone.0128313]

The limitation of the study is the timeframe of 24h. The topical availability might be longer, leading to a build-up in the brain if taken regularly. This means that the peak concentration in the brain for regular administration might happen days or weeks after the first topical application, which could be multitudes of the concentration that was measured within the first 24h. The fact that, after 24h, they still had one order of magnitude of the lower limit in the brain tissue from transdermal, while it was far lower at this point of time after IV, makes me believe that the plasma levels might not reflect the transport medium accurately.

Probably, this is due to the high plasma protein binding that adds such a bias so that it becomes unclear for low plasma concentrations how much there really is in circulation. Comparing it to the IV, I suspect that the topical availability lasts for 24h at least, and it's unclear how much time it will take for at least 90% to be absorbed or degraded. Based on my modeling, it might be 2-3 days. This means that the effects of the drug can potentiate on the first days of administration if the same dose is taken on these days as has shown to be effective on the first day alone.
 

SlamDancin

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@nerd I swear I could feel the effects almost immediately from topical application and it felt stronger than my days prior trying it orally. From a lower dose as well. Navel application has been shown I believe to be almost as efficacious as IV administration due to thin skin and being located just above a major hub of the lymphatic system.

thank you so much for your research
 

nerd

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This study explains a potential link to depression and a potential link to the cholinergic pathophysiology of ME, which might be caused by G protein-coupled receptor antibodies. It also gives a possible explanation for the mental numbness that occurs with ME but also with depression and other psychiatric conditions.

Ventral tegmental area GABAergic inhibition of cholinergic interneurons in the ventral nucleus accumbens shell promotes reward reinforcement (2021) [10.1038/s41593-021-00898-2]

The long-range GABAergic input from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) is relatively understudied, and therefore its role in reward processing has remained unknown. In the present study, we show, in both male and female mice, that long-range GABAergic projections from the VTA to the ventral NAc shell, but not to the dorsal NAc shell or NAc core, are engaged in reward and reinforcement behavior. We show that this GABAergic projection exclusively synapses on to cholinergic interneurons (CINs) in the ventral NAc shell, thereby serving a specialized function in modulating reinforced reward behavior through the inhibition of ventral NAc shell CINs. These findings highlight the diversity in the structural and functional topography of VTA GABAergic projections, and their neuromodulatory interactions across the dorsoventral gradient of the NAc shell. They also further our understanding of neuronal circuits that are directly implicated in neuropsychiatric conditions such as depression and addiction.
 

hapl808

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Is there anything else besides taurine that looks promising in this case as a GABA agonist? Or is there anything that could be taken with taurine for better action?
 

nerd

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Is there anything else besides taurine that looks promising in this case as a GABA agonist? Or is there anything that could be taken with taurine for better action?
Oral GABA itself, of course, but it doesn't directly cross the BBB in large quantities. The question is if you need large quantities. But regardless, GABA is also a stronger HDAC inhibitor and it's questionable if this is desired without antivirals/antibiotics and a dysfunctional immune system.

Via HDAC, GABA concentrations might also be affected because receptor to agonist ratio (i.e. the availability of agonists at receptors) also influence the GABA activity, and the receptor expression is regulated via HDACs. This way dysregulated histone acetylation might also cause the GABAergic dysregulation in consequence.

GABA positive allosteric modulators might actually work better than agonists, but not necessarily in every scenario. One such scenario I'm thinking of is based on my recent experiences with antihistamines.

Maybe you share this experience. I've had this issue for a long time, even when my ME was still mild, that sometimes, I completely shut down within minutes. My brain is barely able to process anything motivationally, it's like I'm somnolent but without losing perception and memory. I perceive my environment but I can't think straight, how to intentionally do anything. It's like I don't know of any reason to move and can't create a thought of how to do anything. But it's nothing like sleepiness that melatonin triggers.

Sometimes I notice it and try to intervene by taking supplements, not that it helps. If I don't react quickly enough, it's too late and I'm stuck in this half-sleep. I wonder if this is similar to the effects of these knock out drugs creeps mix women into their drinks.

The first thought for this would be that the GABA system is overactivated, but then again, why is it different from the effects of sleeping drugs, which are GABA agonists? Another theory, after having read the previous paper, is something cholinergic. Maybe insufficient choline availability? But I doubt that it's a simple immunological answer because (auto-)immunity in the brain works completely different. But I could imagine that a dysregulation of the fatty acid pathways could cause it because fat tissue plays a major part in the brain's immune regulation.

Nevertheless, I noticed that the sleepiness effects from antihistamines might actually manifest similarly, just in a milder form. Antihistamines cause delirium depending on how much of it can cross the BBB because the combined histaminergic-GABAergic activity maintains cognition and motivational thinking.

Histamine and Delirium: Current Opinion (2019) [10.3389/fphar.2019.00299]

Delirium is a very common, but refractory clinical state, notably present in intensive care and in the growing aging community. It is characterized by fluctuating disturbances in a number of key behavioral features, namely cognition, mood, attention, arousal, and self-awareness. Histamine is arguably the most pleotropic neurotransmitter in the human brain, and this review provides a rationale, and proposes that this neuroactive amine plays a role in modulating the characteristic features of delirium. While centrally permeable H1 and H2 histamine receptor antagonists have pro-delirium potential, we propose that centrally permeable H3 histamine receptor antagonists may provide an exciting new strategy to combat delirium. The Histamine H4 receptor may also have an indirect inflammatory neuroglial role which requires further exploration.
In an indirect manner, chronic antihistamine use also increases the susceptibility for seizures after withdrawal, pointing out the significance of histamine for glutamatergic activity, especially when there's an oversupply of glutamate.

Chronic H1-Antihistamine Treatment Increases Seizure Susceptibility After Withdrawal by Impairing Glutamine Synthetase (2012) [10.1111/j.1755-5949.2012.00356.x]

Conclusion
Chronic H1-antihistamine treatment produces long-lasting increase in seizure susceptibility in nonepileptic rodents after drug withdrawal and its mechanism involves impairment of GS through blocking the action of histamine.
This falls back to MCAS, but also suggests that there may not only be an acute activation manifestation of it, but also chronically elevated availability of histamine in the brain, and this disproportionate to the GABA availability. Histamine would explain the hyperexcitability as long as GABA is still available in a sufficient manner, but once GABA depletes, the nervous system crashes.

If it doesn't deplete completely, the metabolism is overwhelmed by the nerve system activity. There might be trouble sleeping. But a severe deficiency would trigger the other phase of the GABAergic activity because now, histamine-GABAergic activity is also reduced too much. This doesn't make sleeping easier, rather the opposite, but it blocks cognition.

So where does this rabbit hole lead? If mast cells in the gut can be dysfunctional, as many experience it, is it possible that the same mast cell dysfunction applies to the brain while the GIT-focused therapies only try to fix the mast cells in the GIT? Might the brain mast cells be responsible for this GABAergic, potentially histaminergic dysregulation? If pathogens in the GIT are responsible for MCAS in the GIT, is this finding transferable to the brain? Unfortunately, research on MCAS is limited. I tried to link it to HDACs in a previous post. But it's more an explanation for the pathophysiology and not so much for the etiology. Latent viral reservoirs might maintain MCAS nonetheless.

What does it mean for treatment? Taking Ketotifen would resolve the mast cell issue if sufficient quantities reached the brain tissue, but at the same time, it would cause the delirium it's supposed to prevent. However, it's possible that the brain manages to adapt to the reduced histamine in the brain. Still, not the best option when we consider the intentionally limited BBB permeability of antihistamines. Lager amounts might circumvent this, but the withdrawal would actually make things far worse. This is a no-brainer to me. Unfortunately, I don't know of any other mast cell stabilizers that are systemically available.

Still assuming that GABA depletion is the issue, GABA modulation wouldn't really fix the issue either because it doesn't prevent the depletion but rather increases the activity of the receptor.

Agonists themselves, e.g. in the form of low-dosed sleeping pills or anxiolytics, will have to be checked for their susceptibility to cause adaptation/addiction, and if this still applies if preexisting deficiency is compensated. Drugs such as diazepam dock to different subunits and different rules might apply for these subunits in the context of histamine. This also needs to be checked.

HDAC inhibitors might help against MCAS and also reduce the receptor interaction, thereby decelerating a potential depletion of GABA, but this only works if the other effects from the reduced receptor (subunit) expression can be adapted to. A very speculative option this is, and one that also raises the question of pathogen reactivation again. But it's definitely worth looking into further. Maybe I can eliminate the unresolved questions by more literature research and by doing more simulations.

For now, I've already identified CBD as a neuroactive HDAC inhibitor and oral GABA as the non-neuroactive one (at least directly, due to the limited BBB permeability). It's possible that large doses of oral GABA might still become available in the brain though. Large doses (ca. 2g) would also be necessary for IC50s at class I HDACs.

Moreover, I'll also look into the GABAergic potential of CBD. It's possible that CBD is also agonistic or modulatory at GABA receptors if it shares certain structural features with GABA itself.

If viral pathology is responsible for the MCAS, the right antiviral treatment that is active in the brain might also work. If the viral pathology is latent or abortive, it would have to be combined with HDAC inhibitors or other apoptosis-inducing drugs.

If the mast cells contain fragmented mitochondria due to HHV, and this is responsible for their instability, we can only hope that Dr. Prusty finds a drug that antagonizes the viral proteins. Virustatics would only work in this case when HHV also manifests in cell activity and not just the mitochondrial dormant state. This is a real nut to crack.

One more point. I'll also need to check if histaminergic-GABAergic activity affect cholinergic neurons downwards. It would close the circle if a histamine-induced neuroexcitotoxicity at cholinergic neurons was responsible for the G protein-coupled receptor autoimmunity. It comes down to the question if there's a feedback from brain lymphocytes to the remaining lymphatic system. In this case, first innate immunity would attack peripheral GPCRs, and this would lead to the low but elevated levels of antibodies.
 
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hapl808

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I experimented slightly with CBD and found a rebound effect. That's one of the reasons I'm careful with experimenting - as you mention, any of these things could make it worse if they're discontinued or if they upregulate or downregulate a receptor or whatever.

I almost never take diazepam (few times a year) but it does seem to help my general brain fog type symptoms - or more accurately, turns down my system so it doesn't seem to lead to the same level of brain fog. I've also tried to focus on diets with low levels of free glutamates and such which are moderately helpful but not fixing the issue.

The gut involvement is always fascinating to me. Any time I trigger a crash, I get horrible acid reflux and other gut related symptoms. Low histamine levels, Robillard's fast tract diet, probiotics, and so on help a lot with my digestion, but something like sexual activity (back when I was moderate) would trigger all the gut symptoms easily.

I'm not sure if it's the GABA-glutamate balance or dopamine or what makes my mental exertion PEM crashes so bad. When I was moderate, in retrospect I would still get them but I recovered quickly and they were mild. Now they're multi-day crashes.

Thanks - always enjoy reading your thoughts and theories. I'm tempted to try oral GABA as I wonder if my BBB is compromised anyways so it might cross over more easily, but again the concerns of rebound or withdrawal. Same concern with gabapentin, and doesn't seem like anyone here reported taking gabapentin and having huge improvements except maybe with neuropathic pain, etc.
 

nerd

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Same concern with gabapentin, and doesn't seem like anyone here reported taking gabapentin and having huge improvements except maybe with neuropathic pain, etc.
It's not a GABA agonist, but it upregulates GABA synthesis. The primary MoA is directed against neuropathic pain by reducing glutamatergic activity at NMDA receptors. It's unclear how much gabapentin is necessary for sufficient regulation of the glutamate decarboxylase to GABA.

The α2δ-1-NMDA Receptor Complex Is Critically Involved in Neuropathic Pain Development and Gabapentin Therapeutic Actions (2018) [10.1016/j.celrep.2018.02.021]

α2δ-1, commonly known as a voltage-activated Ca2+ channel subunit, is a binding site of gabapentinoids used to treat neuropathic pain and epilepsy. However, it is unclear how α2δ-1 contributes to neuropathic pain and gabapentinoid actions. Here, we show that Cacna2d1 overexpression potentiates presynaptic and postsynaptic NMDAR activity of spinal dorsal horn neurons to cause pain hypersensitivity. Conversely, Cacna2d1 knockdown or ablation normalizes synaptic NMDAR activity increased by nerve injury. α2δ-1 forms a heteromeric complex with NMDARs in rodent and human spinal cords. The α2δ-1-NMDAR interaction predominantly occurs through the C terminus of α2δ-1 and promotes surface trafficking and synaptic targeting of NMDARs. Gabapentin or an α2δ-1 C terminus-interfering peptide normalizes NMDAR synaptic targeting and activity increased by nerve injury. Thus, α2δ-1 is an NMDAR-interacting protein that increases NMDAR synaptic delivery in neuropathic pain. Gabapentinoids reduce neuropathic pain by inhibiting forward trafficking of α2δ-1-NMDAR complexes.
I experimented slightly with CBD and found a rebound effect.
I noticed that I sometimes get infection symptoms when taking it longer. Since I don't have any other medications for this purpose, I use it when I have anxiety, restlessness, or pain (topically and orally).

Before I developed moderate ME, unknowingly what caused my mild symptoms at the time, I regularly used CBD. I had to gradually increase the dose for the same effect. I think there's some adaptation and this would also lead to a rebound effect under special circumstances such as ME pathophysiology.

I'm tempted to try oral GABA as I wonder if my BBB is compromised anyways so it might cross over more easily, but again the concerns of rebound or withdrawal.
If you start with low-doses. Withdrawal effects can be avoided by slowly leveling it off. But honestly, I don't think that the BBB can be damaged enough for large quantities to pass. The difference might be small.

And there's still the issue of viral reactivations it can cause. However, the same could be said about ketogenic diet and I'm still doing fine, except for the period when I took Valtrex and it affected my kidney/liver biomarkers, presumably triggered by hyperalbuminemia. I had this keto rash though and I'm not sure if this might actually be some kind of zoster virus reactivation. Some researchers think this type of rash is bacterial but antibiotics didn't help and acetone bacteria might just be a correlation because the inflammated skin provides the best breeding ground.

What I also forgot to consider prior: Drugs that bind to the diazepam subunits don't prevent GABA from being docked. Some PAMs actually upregulate docking, which might be the opposite of useful in the context of the histamine theory. I think it has to be a "real" agonist of GABA that docks to the same subunit. The best way might still be the upregulation of glutamate decarboxylase. Gabapentin does the job. Diazepam would be a solution for short-term effects from glutamatergic overactivity at non-NMDA receptors because it doesn't have the potential to reduce GABA availability further. How a change in GABA receptor (subunit) expression from HDACs affects this ecosystem of activation and the recycling of GABA, I'm not sure.
 

nerd

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FWIW @nerd Gabapentin, especially at higher doses, has consistently been one of the only meds that helps acutely
Interesting. Against which of your acute symptoms does it help? How does your acute CFS/ME manifest?

One MoA I missed, because its potential is lower than the NMDA one is the same subunit inhibition at Voltage-gated calcium channels. But there are many drugs for the inhibition of VGCCs.