Imbalanced Brain Neurochemicals in long COVID and ME/CFS: A Preliminary Study using MRI

[SWAlexander]

Abstract​

Purpose​

Long COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) patients experience multiple complex symptoms, potentially linked to imbalances in brain neurochemicals. This study aims to measure brain neurochemical levels in long COVID and ME/CFS patients as well as healthy controls to investigate associations with severity measures.

Methods​

Magnetic resonance spectroscopy (MRS) data was acquired with a 3T Prisma MRI scanner. We measured absolute levels of brain neurochemicals in the posterior cingulate cortex in long COVID (n=17), ME/CFS (n=17), and healthy controls (n=10) using Osprey software. The statistical analyses were performed using SPSS version 29. Age and sex were included as nuisance covariates.

Results​

Glutamate levels were significantly higher in long COVID (p=0.02) and ME/CFS (p=0.017) than in healthy controls. No significant difference was found between the two patient cohorts. Additionally, N-acetyl-aspartate levels were significantly higher in long COVID patients (p=0.012). Importantly, brain neurochemical levels were associated with self-reported severity measures in long COVID and ME/CFS.

Conclusion​

Our study identified significantly elevated Glutamate and N-acetyl-aspartate levels in long COVID and ME/CFS patients compared with healthy controls. No significant differences in brain neurochemicals were observed between the two patient cohorts, suggesting a potential overlap in their underlying pathology. These findings suggest that imbalanced neurochemicals contribute to the complex symptoms experienced by long COVID and ME/CFS patients.
https://www.sciencedirect.com/science/article/pii/S000293432400216X

 

[linusbert]

another marker found for diagnostics,
but whats the reason for the chemical imbalance?

 

[SlamDancin]

Could this be a clue as to why benzodiazepines seem to increase capacity/functionality acutely?

This is anecdotal of course but it seems to at least be true for other patients as well.

“Thus, in vivo low concentrations of benzodiazepines may reduce synaptic glutamate concentrations by increased uptake, providing an additional mechanism to modulate neuronal excitability.”

https://pubmed.ncbi.nlm.nih.gov/10582598/

 

[SWAlexander]

whats the reason for the chemical imbalance

Good question.

 

[SWAlexander]

benzodiazepines

I would look toward sodium cotransporters such as the sodium/D-glucose cotransporter SGLT1, stably transfected in CHO cells.

Sodium cotransporters, including the sodium/D-glucose cotransporter SGLT1, play vital roles in cellular functions by using the sodium gradient across the cell membrane to drive the transport of other substances into the cell. While SGLT1 is primarily recognized for its role in glucose absorption in the intestines and kidneys, understanding its involvement in the context of extracellular glutamate in glial cells requires a bit of indirect connection through cellular energy metabolism and the support of neuronal and glial functions.

 

[SlamDancin]

@SWAlexander I’m not so sure about that. A quick read into currently available SGLT inhibitors seems to show an increase in glutamate through, in part, inhibiting Glutamate dehydrogenase.

The anticonvulsant Lamotrigine on the other hand can block Glutamate release in certain contexts.

 

[SWAlexander]

Just in. Mitochondria again.

Powering Brain Repair: Mitochondria Key to Neurogenesis​

Summary: Researchers made a groundbreaking discovery about the maturation process of adult-born neurons in the brain, highlighting the critical role of mitochondrial fusion in these cells. Their study shows that as neurons develop, their mitochondria undergo dynamic changes that are crucial for the neurons’ ability to form and refine connections, supporting synaptic plasticity in the adult hippocampus.

This insight, which correlates altered neurogenesis with neurological disorders, opens new avenues for understanding and potentially treating conditions like Alzheimer’s and Parkinson’s by targeting mitochondrial dynamics to enhance brain repair and cognitive functions.
https://neurosciencenews.com/mitochondira-neurogenesis-neuropplasticity-25869/

and this:
Enhanced mitochondrial fusion during a critical period of synaptic plasticity in adult-born neurons
https://www.cell.com/neuron/fulltext/S0896-6273(24)00167-3

 

[SlamDancin]

“In total, 75 healthy participants were investigated in a double blind, placebo-controlled, randomized, parallel-group study and underwent two scanning sessions (acute/post 24 h.). Acute ketamine administration was associated with higher perfusion in interior frontal gyrus (IFG) and dorsolateral prefrontal cortex (DLPFC), but no other investigated brain region. Inhibition of glutamate release by pretreatment with lamotrigine abolished ketamine's effect on perfusion. At the delayed time point, pretreatment with lamotrigine was associated with lower perfusion in IFG.”

https://pubmed.ncbi.nlm.nih.gov/37231079/

Perhaps the increased glutamate relates to the lower CBF seen in pwME

 

[SWAlexander]

increased glutamate relates to the lower CBF

According to my reading, yes, increased levels of glutamate can be related to lower cerebral blood flow (CBF).
Excessive glutamate release or impaired uptake can lead to neurotoxicity, a condition known as excitotoxicity, which can harm neural tissue and lead to cell death.

Not finished reading yet. Is very complex. Will write a summary tomorrow.

 

[SlamDancin]

@SWAlexander Indeed it is complex but it would appear to my dumb ass that Glutamate actually increases perfusion and so maybe the reason it’s elevated is some compensatory mechanism to existing low CBF in pwME

 

[SWAlexander]

compensatory mechanism to existing low CBF in pwME

The more I read about it: Here is the summary of some of my search, although I believe not complete yet.

Elevated glutamate levels can potentially lead to lower CBF:

1. Excitotoxicity and Neuronal Damage: High levels of glutamate can overactivate glutamate receptors, leading to an excessive influx of calcium ions into neurons. This can trigger a cascade of events leading to cell damage, inflammation, and death (neuronal death). As neurons are damaged, there can be a disruption in the normal function of the brain, including the mechanisms that regulate CBF.
2. Vasodilation and Vasoconstriction: Glutamate has been shown to affect the blood vessels in the brain directly. Its effect on cerebral blood vessels can vary under different conditions, potentially causing either vasodilation or vasoconstriction. While glutamate-induced vasodilation could theoretically increase CBF, in the context of excitotoxicity and the resulting cellular stress and inflammation, the overall effect might lead to impaired vasodilation or enhanced vasoconstriction, thus reducing CBF.
3. Inflammatory Response: The neuronal damage caused by high glutamate levels can trigger an inflammatory response, which can further affect cerebral blood vessels and potentially reduce CBF. Inflammation can lead to changes in the blood-brain barrier, affect the smooth muscle cells of the vessels, and ultimately influence blood flow.
4. Energy Metabolism: Elevated glutamate and the subsequent cellular stress can disrupt the energy metabolism in neurons and astrocytes. This disruption can affect the production of vasodilators such as nitric oxide, which play a critical role in regulating CBF. Reduced availability of these vasodilators can lead to decreased CBF.

To manage conditions associated with excitotoxicity often aim to regulate glutamate levels, protect neurons from glutamate-induced damage, and ensure adequate CBF to affected regions of the brain.
Still looking for the exact relationship between glutamate levels and CBF in specific contexts (e.g., ischemic stroke, traumatic brain injury, or neurodegenerative diseases). Waiting for Danielle Beckman paper.

 

[alcasa]

another marker found for diagnostics,
but whats the reason for the chemical imbalance?

My opinion is that for a lot of people with CFS there's been a loss in ATPasa Na/K+ for regulate the ion pump necessary to recycle glutamate, use it as energy and keep the pump up: so you are in a situation in which you have to much glutamate in synapses, too litle ATP to actually recycle it (glutamate pay its own price of ATP, if it is not reuptaken, the pump can't keep it up) and any kind of prolonged exertion leads heighten the problem

This mechanism explains PERFECTLY fenomena as Post Exertional Malaise. I will sometime in the future make a long post on it, I'm too unwell at the moment to further explain. But I think this could be all the disease for lot of people

 

[linusbert]

This mechanism explains PERFECTLY fenomena as Post Exertional Malaise.

for this i have also a theory, i think in normal energy demands where ATP and ADP can re cycled everything is okish. but on strenuous exercise ADP gets reduced to AMP , which is discarded. the body needs 48+ hours for de-novo synthesis. so there is a effective loss of ATP molecules which cannot be recycled which the body needs to completely replete.
thats bad, because cycling between ADP and ATP is cheap, but resynthesize it is expensive and sluggish.

 

[alcasa]

for this i have also a theory, i think in normal energy demands where ATP and ADP can re cycled everything is okish. but on strenuous exercise ADP gets reduced to AMP , which is discarded. the body needs 48+ hours for de-novo synthesis. so there is a effective loss of ATP molecules which cannot be recycled which the body needs to completely replete.
thats bad, because cycling between ADP and ATP is cheap, but resynthesize it is expensive and sluggish.

Please don't interpret anything I'm about to say as a personal attack. The mere fact that you are participating in this forum is sufficient for me to sympathize with you, but:

I believe that the theory in question is flawed. It was proposed by Myhill, whose work I once followed, but I now perceive it as defective. I adhered to her keto diet for two years and experienced dreadful results.

1st, fatty acids generate significantly less ATP than glucose. Likewise, ketones do not produce more ATP than glucose. The explanation is lengthy, and I am too unwell to elaborate now, but despite there being more carbons in each fatty acid, they burn more slowly with less oxygen use per unit of time, resulting in a lower ATP yield (JT Brosnan, 1999). Ketones also produce less CO2 and less heat, thus the process's efficiency is reduced, also yielding less ATP (A. Prince et al., 2013). From my perspective, keto diets are not a solution for any metabolic issue (again, I did keto for two years, so I'm not discussing nuances).

2nd, the notion that AMP leakage causes post-exertional malaise because the rate of D-Ribose generation is limited is easily debunked: simply take 15 grams (of D-Ribose) a day. It is a sugar, and I don't believe there is any risk of harm at even high dosages (though, take this with a pinch of salt as I haven't researched it thoroughly). Take those very high doses. Is your CFS resolved? That’s why I doubt that it's not the issue. I also have no idea where Myhill got the idea that ATP replenishment from AMP takes two days. It's seems like a wacky argument.

3rd, CFS appears to be a nervous system disease for most people (NOT ALL). This might be why there are still no definitive markers or mechanisms identified—it's arguably the least understood and most complex system in the human body. How would you reconcile the INFAMOUS TIRED BUT WIRED state with the AMP theory? I assure you, the glutamate + GLT-1 theory can explain this without stretching the argument at all.

 

[bob800]

I think this kind of analysis (measuring neurotransmitters in the brain, glutamate buildup, etc) is on the right track. However, the situation with glutamate seems very complex.

Goldstein Background

If you read the Goldstein books, you'll notice that he becomes increasingly focused on glutamate / NMDA receptors in the final volume (Tuning the Brain). He makes it very clear that all his learnings point toward glutamate/NMDA being the crux of CFS. Yet, he admits that a significant minority of his patients get worse with NMDA antagonists and improve with (indirect) NMDA agonists, such as acetylcholinesterase inhibitors or nitroglycerin. What is going on here?

One of his hypotheses for this discrepancy is that NMDA antagonists make more glutamate available at the AMPA receptors as a result of its displacement from the NMDA receptors. If this is the problem for a particular patient (having an adverse reaction to ketamine for example), he suggests administrating topiramate to block AMPA receptors as well.

However, I have some skepticism about all of this.

Examples

Too many CFS patients have tried NMDA antagonists (like memantine or ketamine) with no effect on CFS or even worsening symptoms. And I have not heard any rave reviews about topiramate either.

Instead, should we reduce glutamate secretion (and/or increase reuptake)? Drugs that do this:

• Riluzole - seems not many have tried it. One of the few search results I got was a mention from @SlamDancin coincidentally, seemed like a pretty negative review
• Lamotrigine - (as @SlamDancin mentioned above). Goldstein liked this drug a lot, but it seems many have tried this without much core CFS improvement.
• Chlorzoxazone - Goldstein says this inhibits presynaptic glutamate secretion. I've never heard of it before

Doesn't seem like there is a magic bullet in this list.

Yet another approach would be selective antagonism of particular NMDA subunits, e.g.:

• Ifenprodil / Isoxsuprine / Nyldrin (GluN2B antagonists), Goldstein liked these. I haven't heard of anyone trying them. Only Ifenprodil is available, from Japan only. If anyone has tried it, please speak up
• Antagonists of the glycine co-binding site of the NMDA receptor, like guaifenesin. Many have tried this with no improvement

My Conclusion

Overall, it seems that most members of this forum (including myself) generally do not respond to these anti-glutamatergic drugs. Sometimes I wonder if Goldstein's success with them was because he did not screen his patient population with a strict definition of CFS. Many of them were roped into that bucket because they had generalized "somatic" complaints like IBS, chronic pain, etc, which do seem more responsive to NMDA antagonists than true CFS.

 

[junkcrap50]

the glutamate + GLT-1 theory can explain this without stretching the argument at all.

Are you referring to Kat Boniface's theory? https://x.com/tessfalor/status/1777435098247250347

 

[alcasa]

I think this kind of analysis (measuring neurotransmitters in the brain, glutamate buildup, etc) is on the right track. However, the situation with glutamate seems very complex.

Goldstein Background

If you read the Goldstein books, you'll notice that he becomes increasingly focused on glutamate / NMDA receptors in the final volume (Tuning the Brain). He makes it very clear that all his learnings point toward glutamate/NMDA being the crux of CFS. Yet, he admits that a significant minority of his patients get worse with NMDA antagonists and improve with (indirect) NMDA agonists, such as acetylcholinesterase inhibitors or nitroglycerin. What is going on here?

One of his hypotheses for this discrepancy is that NMDA antagonists make more glutamate available at the AMPA receptors as a result of its displacement from the NMDA receptors. If this is the problem for a particular patient (having an adverse reaction to ketamine for example), he suggests administrating topiramate to block AMPA receptors as well.

However, I have some skepticism about all of this.

Examples

Too many CFS patients have tried NMDA antagonists (like memantine or ketamine) with no effect on CFS or even worsening symptoms. And I have not heard any rave reviews about topiramate either.

Instead, should we reduce glutamate secretion (and/or increase reuptake)? Drugs that do this:

• Riluzole - seems not many have tried it. One of the few search results I got was a mention from @SlamDancin coincidentally, seemed like a pretty negative review
• Lamotrigine - (as @SlamDancin mentioned above). Goldstein liked this drug a lot, but it seems many have tried this without much core CFS improvement.
• Chlorzoxazone - Goldstein says this inhibits presynaptic glutamate secretion. I've never heard of it before

Doesn't seem like there is a magic bullet in this list.

Yet another approach would be selective antagonism of particular NMDA subunits, e.g.:

• Ifenprodil / Isoxsuprine / Nyldrin (GluN2B antagonists), Goldstein liked these. I haven't heard of anyone trying them. Only Ifenprodil is available, from Japan only. If anyone has tried it, please speak up
• Antagonists of the glycine co-binding site of the NMDA receptor, like guaifenesin. Many have tried this with no improvement

My Conclusion

Overall, it seems that most members of this forum (including myself) generally do not respond to these anti-glutamatergic drugs. Sometimes I wonder if Goldstein's success with them was because he did not screen his patient population with a strict definition of CFS. Many of them were roped into that bucket because they had generalized "somatic" complaints like IBS, chronic pain, etc, which do seem more responsive to NMDA antagonists than true CFS.

Goldstein's publication of his book in 2004 marked a time when the significance of glutamate in medical science was not fully understood. Subsequent research has provided clearer insights into its mechanisms.

I appreciate that you have addressed the concerns I raised, as I had similar questions a year ago when I first considered glutamate as a key factor in Chronic Fatigue Syndrome. While I am in the process of writing a book to provide a comprehensive response, I can offer a brief reply here:

1. It is surprising that Riluzole has not been effective, as it directly targets key issues related to glutamate. However, it's uncertain whether it effectively upregulates GLT-1/GLAS, or if GLT-1 can sustain such upregulation. The downregulation of GLT-1 may result from chronic excessive excitation, ATP depletion—also linked to glutamate oxidation—and reversible damage to glial cells. My skepticism towards anecdotal online endorsements, such as those praising the ketogenic diet, has grown following personal experiences that contradicted such claims.
2. Regarding other drugs, my theory suggests they are unlikely to be effective. NMDA antagonism may worsen conditions at least in the short term, with uncertain long-term effects. Any significant improvement from NMDA agonism would be unexpected. The crux of the issue is that none of these drugs address the vital aspects of glutamate's reuptake and metabolism by glial cells and potentially neurons, which are crucial for sustaining the Na+/K+ ATPase. If this ATPase fails, NMDA receptors become severely downregulated, preventing glutamate uptake and leading to a failure of the metabolic support needed for glutamate without its oxidation.

This mechanism is relatively straightforward compared to other theories proposed for Chronic Fatigue Syndrome and is a continuation of the pioneering work by Goldstein and Marco, along with other researchers in this field.

Are you referring to Kat Boniface's theory? https://x.com/tessfalor/status/1777435098247250347

Yes, I must also say, if there are still people willing to battle over ownership of a theory (as your message seems to go in that direction) concerning this disease. She was the first to publicly address this issue, so all credit goes to her. I just wat to recover and move on with my life.

Thought, I've to say I reached the same conclusions independently; I discovered her through a Twitter search for 'GLT-1' where she was the only one making any logical sense. If 2 persons (actually glt-1 has been metioned in this forum lot of times, so various people) separated by 10.000 kilometers reach to the same conclusion without information exchange between them... I think they are probably onto something. She educated me greatly on the subject initially since I knew very little. While I have since pursued my own path—partly because she doesn’t respond as much as I might need—I'm primarily focused on regaining my life as soon as possible. Regardless of how the theories pan out, she deserves all the recognition. I merely want to contribute and further develop these ideas as best as I can, without any intention of taking undue credit. I've not read any elaborated theory on glt-1, I'm 23 years old and I can't wait a year till they publish whatever they are publishing

Also, if we are goint to give merit to someone. Then MARCO AND GOLDSTEIN... should be the ones... Marco's work + my symptoms when the disease started were what led me to think about glutamate reuptake, and then searched glt-1 on twitter and found Kat's work...

 

[junkcrap50]

Yes, I must also say, if there are still people willing to battle over ownership of a theory (as your message seems to go in that direction) concerning this disease. She was the first to publicly address this issue, so all credit goes to her. I just wat to recover and move on with my life.

Thought, I've to say I reached the same conclusions independently; I discovered her through a Twitter search for 'GLT-1' where she was the only one making any logical sense. If 2 persons (actually glt-1 has been metioned in this forum lot of times, so various people) separated by 10.000 kilometers reach to the same conclusion without information exchange between them... I think they are probably onto something. She educated me greatly on the subject initially since I knew very little. While I have since pursued my own path—partly because she doesn’t respond as much as I might need—I'm primarily focused on regaining my life as soon as possible. Regardless of how the theories pan out, she deserves all the recognition. I merely want to contribute and further develop these ideas as best as I can, without any intention of taking undue credit. I've not read any elaborated theory on glt-1, I'm 23 years old and I can't wait a year till they publish whatever they are publishing

Ah, well I'm not trying to battle who gets credit. The first I heard about it was from her / on twitter. Maybe I've come across it on PR but it never clicked for me. But it's good multiple people are contributing and coming to similar conclusions. If it was up to me, I would assign credit to whoever can put out a written out, full theory/proposal since then it'd be all in one place & useful for reference - or even a longer, better video presentation than her's. I've asked her to, but her CFS + school makes it hard for her, so she's pretty slow (the vid presentation was from last year).

Also, if we are goint to give merit to someone. Then MARCO AND GOLDSTEIN... should be the ones... Marco's work + my symptoms when the disease started were what led me to think about glutamate reuptake, and then searched glt-1 on twitter and found Kat's work...

Yes, Goldstein deserves significant credit. I've always thought his protocols would be the most helpful, but no doctor will really do it. I appologize for my ignorance, but who is Marco? This individual I presume: https://www.healthrising.org/authors/marco/ ?

I have some pure potassium clavulanate - without any antibiotics - coming slowly from China to test/try. I can share my source if you're interested.

 

[linusbert]

@alcasa just to be clear, i do not know who milhill is and i am no proponent of a ketogenic idea either nor did i mention either. guess you answered somebody else.

d-ribose isnt the only thing required for de novo synthesis, its complicated and any part in the process can be broken or cofactors missing, even on mitochondrial level. just throwing one thing in from the process might not cut it.
there are enough people who benefit from d-ribose supplementation a lot, and also a lot of people who dont. i do not. i actually get worsening of diabetes from d-ribose.

your assumptions that fatty acid metabolism generating less atp than from glucose's is not correct. well at least as its working fully. but fatty acid metabolism is more complicated and has more chance to fail. glucose is easier. but fat more optimal if it works.
thats comparison how much each pathway yields in atp: (generated by gpt4o , might be prone to error but on short oversight correlates with what i have read before)

ATP Yield from Glucose Metabolism​

1. Glycolysis:
   • 1 Glucose molecule → 2 Pyruvate molecules
   • Net gain: 2 ATP (produces 4 ATP, consumes 2 ATP)
   • 2 NADH (equivalent to 5 ATP when converted in the electron transport chain)
2. Pyruvate Decarboxylation:
   • 2 Pyruvate → 2 Acetyl-CoA
   • Produces 2 NADH (equivalent to 5 ATP)
3. Citric Acid Cycle (Krebs Cycle):
   • 2 Acetyl-CoA → 4 CO2 + 6 NADH + 2 FADH2 + 2 GTP (or ATP)
   • Net gain: 2 ATP
   • 6 NADH (equivalent to 15 ATP)
   • 2 FADH2 (equivalent to 3 ATP)
4. Total ATP from One Molecule of Glucose:
   • Glycolysis: 2 ATP + 5 ATP (from 2 NADH) = 7 ATP
   • Pyruvate Decarboxylation: 5 ATP (from 2 NADH)
   • Citric Acid Cycle: 2 ATP + 15 ATP (from 6 NADH) + 3 ATP (from 2 FADH2) = 20 ATP
   • Total ATP yield from one glucose molecule: 7 + 5 + 20 = 32 ATP

ATP Yield from Fatty Acid Metabolism​

Let's take palmitic acid (a common fatty acid, C16H32O2) as an example:

1. Beta-Oxidation:
   • Palmitic acid (16-carbon) undergoes 7 cycles of beta-oxidation.
   • Each cycle produces:
     • 1 FADH2 (equivalent to 1.5 ATP)
     • 1 NADH (equivalent to 2.5 ATP)
     • 1 Acetyl-CoA (8 Acetyl-CoA molecules from one palmitic acid)
   • Total from beta-oxidation: 7 FADH2 + 7 NADH = 7 * 1.5 + 7 * 2.5 = 10.5 + 17.5 = 28 ATP
2. Citric Acid Cycle:
   • Each Acetyl-CoA enters the citric acid cycle, producing:
     • 3 NADH (equivalent to 7.5 ATP)
     • 1 FADH2 (equivalent to 1.5 ATP)
     • 1 GTP (equivalent to 1 ATP)
   • Total per Acetyl-CoA: 10 ATP
   • Total from 8 Acetyl-CoA: 8 * 10 = 80 ATP
3. Total ATP from One Molecule of Palmitic Acid:
   • Beta-Oxidation: 28 ATP
   • Citric Acid Cycle: 80 ATP
   • Total ATP yield from one palmitic acid molecule: 28 + 80 = 108 ATP

Summary​

• Glucose: 32 ATP per molecule
• Palmitic Acid (a 16-carbon fatty acid): 108 ATP per molecule

 

[alcasa]

@alcasa just to be clear, i do not know who milhill is and i am no proponent of a ketogenic idea either nor did i mention either. guess you answered somebody else.

d-ribose isnt the only thing required for de novo synthesis, its complicated and any part in the process can be broken or cofactors missing, even on mitochondrial level. just throwing one thing in from the process might not cut it.
there are enough people who benefit from d-ribose supplementation a lot, and also a lot of people who dont. i do not. i actually get worsening of diabetes from d-ribose.

your assumptions that fatty acid metabolism generating less atp than from glucose's is not correct. well at least as its working fully. but fatty acid metabolism is more complicated and has more chance to fail. glucose is easier. but fat more optimal if it works.
thats comparison how much each pathway yields in atp: (generated by gpt4o , might be prone to error but on short oversight correlates with what i have read before)

The answer to this is embedded in both articles I quoted. The proper response will be addressed in the book I am planning to publish, which I may distribute freely on this forum (don't want to make profit). The reasoning, which I too once believed, is far too simplistic. It is perpetuated by all the pseudoscientific keto advocates on the internet. All the famous influencers who were once advocates of the keto carnivore diet are now following a Peatarian diets, except for Bart Kay and Shawn Baker... something worth pondering. I followed it strictly for 18 months, and it turned out to be an extremely poor decision, filled with a lot of pseudoscientific nonsense. Also, I don't blame myself because the doctors didn't know any better, and initially, I did feel better.

You are oversimplifying the issue. Key points to consider:

1. You're comparing the oxidation of a 6-carbon molecule (glucose) with a 16-carbon molecule (palmitic acid). Do you think they burn at the same rate?
2. You are comparing a molecule that forms a hexagon, with the maximum distance between carbons being 0.5 nm, to a molecule that is a straight line of carbons, with a maximum distance from the first to the last of 2.3 nm.
3. MOST IMPORTANTLY: You are comparing a molecule with a carbon to oxygen ratio of 8:1 to a molecule with a 1:1 ratio.

This is crucial because oxygen is the limiting factor in energy metabolism in a healthy cell. Glucose provides much of the oxygen it needs for its own oxidation, whereas fatty acids require more input. This results in a higher ATP yield per oxygen molecule due to greater efficiency in the process.

As oxygen is the limiting factor, even with the same amount of oxygen, glucose results in a higher ATP yield. On an average day with 32 mol of O2 used, you get 72.3 moles of ATP from fatty acids and 82.5 from glucose.

MOREOVER:

1. There’s an additional effect known as the Bohr Effect: increased CO2 helps the cell increase its own oxygen supply. This means that glucose oxidation, which increases CO2 compared to fatty acid oxidation, is able to take up more oxygen from the surroundings, yielding even more ATP.

When considering the central nervous system, the results are clear: beta-hydroxybutyrate alone is NOT capable of maintaining excitatory transmission and requires glucose simultaneously.

Please don't take offense at my responses... I once believed what you believe now.