Lactic acid, lactate in ME/CFS

[Mark Vink]

I was asked to comment here because in 2015 I published research on myself in which I used lactate testing to show that the main energy production process in my cells, the aerobic one, is severely impeded.

In the article I answer many of the questions that are raised in this thread and I show the relevance and importance of lactate testing in severe ME.

The article can be read and downloaded here for free:

https://www.researchgate.net/public...gic_EncephalomyelitisChronic_Fatigue_Syndrome

A recent article by Mughal et al. shows that if muscle tissue from healthy people is exposed to serum from ME/CFS patients, that their aerobic energy production also starts to malfunction thereby confirming my finding.

 

[forestglip]

Since high lactate in the brain in ME/CFS seems to be a finding that keeps coming up, I'll link those papers here. Titles link to threads for papers where we have a thread.

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Ventricular cerebrospinal fluid lactate is increased in chronic fatigue syndrome compared with generalized anxiety disorder: an in vivo 3.0 T 1H MRS imaging study (Shungu et al, 2009, NMR in Biomedicine)

Mean lateral ventricular lactate concentrations measured by 1H MRSI in CFS were increased by 297% compared with those in GAD (P < 0.001) and by 348% compared with those in healthy volunteers (P < 0.001), even after controlling for ventricular volume, which did not differ significantly between the groups. Regression analysis revealed that diagnosis accounted for 43% of the variance in ventricular lactate.

Increased ventricular lactate in chronic fatigue syndrome measured by 1H MRS imaging at 3.0 T. II: comparison with major depressive disorder (Shungu et al, 2010, NMR in Biomedicine)

we sought to assess the specificity of this observation for CFS by comparing ventricular lactate levels in a new cohort of 17 CFS subjects with those in 19 healthy volunteers and in 21 subjects with major depressive disorder (MDD) [...] Ventricular CSF lactate was significantly elevated in CFS compared to healthy volunteers [...] Ventricular lactate measures in MDD did not differ from those in either CFS or healthy volunteers. We found a significant correlation between ventricular CSF lactate and severity of mental fatigue that was specific to the CFS group.

Increased ventricular lactate in chronic fatigue syndrome. III. Relationships to cortical glutathione and clinical symptoms implicate oxidative stress in disorder pathophysiology (Shungu et al, 2012, NMR in Biomedicine)

Fifteen patients with CFS, 15 with MDD and 13 HVs were studied using the following modalities: (i) (1)H MRSI to measure CSF lactate [...] We found elevated ventricular lactate and decreased GSH in patients with CFS and MDD relative to HVs. [...]

In exploratory correlation analyses, we found that levels of ventricular lactate and cortical GSH were inversely correlated, and significantly associated with several key indices of physical health and disability.

Prefrontal lactate predicts exercise-induced cognitive dysfunction in Gulf War Illness (Baraniuk et al, 2013, American Journal of Translational Research)

We performed single voxel 1H MRS to evaluate brain metabolic differences in the left anterior cingulate cortex and the changes associated with exercise.

Results: Eight GWI subjects increased their 2-back scores after exercise (labelled increasers) and seven GWI subjects decreased their 2-back scores after exercise (labelled decreasers). [...]

Decreasers had significantly elevated prefrontal lactate levels compared to Increasers prior to completion of the exercise stress tests.

Multimodal and Simultaneous Assessments of Brain and Spinal Fluid Abnormalities in Chronic Fatigue Syndrome and the Effects of Psychiatric Comorbidity (Shungu et al, 2017, Journal of the Neurological Sciences)

proton magnetic resonance spectroscopy (1H MRS) was performed to measure ventricular lactate [...]

lower GSH and CBF and higher ventricular lactate and rates of spinal fluid abnormalities in CFS patients compared to healthy controls.

Elevations of ventricular lactate levels occur in both chronic fatigue syndrome and fibromyalgia (Shungu et al, 2017, Fatigue: Biomedicine, Health & Behavior)

Ventricular lactate was assessed in vivo with proton magnetic resonance spectroscopic imaging (1H MRSI) [...] Mean CSF lactate levels in CFS, FM and CFS + FM did not differ among the three groups, but were all significantly higher than the mean values for control subjects.

Evidence of widespread metabolite abnormalities in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Assessment with whole-brain Magnetic Resonance Spectroscopy. (Younger et al, 2019, Brain Imaging and Behavior)

Fifteen women with ME/CFS and 15 age- and gender-matched healthy controls completed [...] whole-brain echo-planar spectroscopic imaging (EPSI). [...] Choline (CHO), myo-inositol (MI), lactate (LAC), and N-acetylaspartate (NAA) were quantified in 47 regions, expressed as ratios over creatine (CR). [...]

We found increased LAC in ME/CFS patients in the bilateral insula, bilateral parietal cortex, left hippocampus, left middle cingulate gyrus, left precuneus, right thalamus, right rolandic operculum, left temporal cortex, right calcarine sulcus, right fusiform gyrus, right lingual gyrus, and cerebellum. [...] we note that three out of the five regions with elevated brain temperature in individuals with ME/CFS also contained elevated lactate: the right insula, right thalamus, and cerebellum.

Brain and muscle chemistry in ME/CFS and long COVID: a 7T magnetic resonance spectroscopy study, 2025, Godlewska et al

24 patients with ME/CFS, 25 patients with long COVID and 24 healthy controls (HC) underwent brain (pregenual and dorsal anterior cingulate cortex, respectively, pgACC and dACC) and calf muscle MRS scanning at 7 Tesla, followed by a computerised cognitive assessment. Compared to HC, ME/CFS patients had elevated levels of lactate in both pgACC and dACC, while long COVID patients had lowered levels of total choline in dACC. By contrast, skeletal muscle metabolites at rest did not significantly differ between the groups.

Neurometabolite alterations in Gulf War Illness: a whole-brain magnetic resonance spectroscopy study, 2025, Jones, Younger et al

In this human observational study, 20 veterans with GWI and 20 healthy Gulf War veterans (HV) underwent whole-brain magnetic resonance spectroscopy to non-invasively measure several metabolites associated with neuroinflammation. Veterans also completed an arterial spin labeling scan to assess cerebral perfusion.

Compared to HV, veterans with GWI demonstrated widespread decreases in brain choline, N-acetylaspartate, and creatine, and regional elevations in lactate and brain temperature.

581. A Window Into Mitochondrial Dysfunction in Myalgic Encephalitis/Chronic Fatigue Syndrome (ME/CFS): Increased Lactate Production During Brain Stimulation With a Flashing Checkerboard Using 7T Functional MRS (2026, Godlewska et al, Abstract)

20 CFS/ME patients and 20 HC were included; in-dependent samples t-test showed that while the groups did not differ in terms of baseline lactate levels (t=0.034,p=0.973), the ME/CFS patients had a significantly higher increase in lactate during stimulation compared to the baseline rest period, expressed as a % change of the rest value (t=2.847, p=0.007; mean (SD): ME/CFS 22.20 % (12.74), HC 10.55 % (13.14)). A change in comparator, NAA, did not differ between groups (t=0.85, p=0.932).

Edit: Re-ordered by year.

 

[ScoutB]

Thanks for sharing that @forestglip, I was wondering how that most recent paper fit.

I was curious if we had any results from cerebrospinal fluid and found a few papers but they are each a bit odd in different ways...

1. The NIH deep phenotyping study. From the table forestglip posted in #812 of that thread, looks like lactate was not significantly different, but trended towards being *lower* in the ME/CFS cases. On the other hand, this point about the NIH data seems relevant:

One note is that I have some concerns that there might have been some sort of issue with the CSF metabolomics part of the deep phenotyping study, as nearly all of the 435 metabolites (88%) were lower in ME/CFS. I posted about it on PubPeer.

2. This Insights into the pathogenesis of ME/CFS through metabolomic profiling of cerebrospinal fluid study which, from what I can tell, may have never been fully published? Instead of a paper the link goes to this metabolomics workbench site where it seems like you can just look at all the data. Based on my foggy clicking around and looking at graphs I think their data might also be a null result on lactic acid/lactate question.

3. Cerebrospinal fluid metabolomics, lipidomics and serine pathway dysfunction in [ME/CFS]. The S4ME naming scheme did this paper a favour because they misspelled 'syndroome' in their published title. (Other surprising things: entire paper is just by one guy, and seems to be one of multiple very similar papers published by him.) It might just be all the lactate in my brain (joking!!) but I'm finding the paper impenetrable right now and I'm not actually sure what they are claiming on lactate. They don't call it out specifically at least. They have a supplementary data table of 'significantly different' molecules but I'm not sure how to read it or what the situation is with multiple test corrections.

4. There may well be more, presumably even weirder papers on this topic, but I am out of juice for now.

 

[forestglip]

Nice detective work @ScoutB. One thing is that I think CSF represents a different compartment from what is being measured with MR spectroscopy.

I don't know much about the specifics. I asked a researcher a while ago about this, who said MRS is primarily measuring intracellular lactate, while CSF measurements are primarily extracellular. Maybe someone can confirm.

One study tested lactate using both methods, but it was only high when using MRS, as mentioned below.

Other ME/CFS studies are generally neuroimaging using 1H MR spectroscopy, measuring intraventricular CSF, but I don't think they did that in Walitt et al. The legend for the most significant metabolites heat map above is —

i Heatmap of statistically significant (false discovery rate adjusted p-value < 0.05) differentially expressed metabolites in the indicated groups on x axis and the metabolites labeled on y axis. Red: upregulated; Blue: downregulated. Supervised clustering of metabolites measured from the cerebrospinal fluid samples

So they are indicating that lactate was downregulated in ME/CFS CSF samples, which is counter to other studies I've seen but those have used MRS.

Eg in Multimodal and simultaneous assessments of brain and spinal fluid abnormalities in chronic fatigue syndrome and the effects of psychiatric comorbidity (2017, Journal of the Neurological Sciences) —

When permitted by the subject, lumbar puncture was then performed with fluid sent to the laboratory for white cell count, protein and lactate concentrations.

There were no significant differences in peripherally obtained spinal fluid lactate levels among groups, and spinal fluid lactate did not correlate with ventricular lactate levels (r = 0.21, p = 0.17).

Pooled CFS patients, but not the CFS-P or CFS-NP separately, had significantly higher ventricular lactate and significantly lower occipital lobe glutathione than healthy controls

Peripherally obtained spinal fluid lactate was a variable that discriminated between the brain-affected group and the patients with b2 of the 4 brain-related outcomes [15.94 (±2.34 SEM) vs. 13.48 (±1.46), respectively; t = 3.22, p = 0.004]; lactate levels in the brain-affected group were also significantly higher than in healthy controls [15.94 (±2.34) vs. 13.05 (±4.27), respectively; t = 2.14, p = 0.043;

It would have been ideal if Walitt et al had done ventricular CSF MRS — they had the patients in the MRI scanner doing functional MRI. Perhaps ventricular lactate is high but direct lumbar cistern CSF sampling is normal or (genuinely?) low in ME/CFS.

Do we have older papers with direct measurements of CSF lactate?

 

[forestglip]

I asked a researcher a while ago about this, who said MRS is primarily measuring intracellular lactate, while CSF measurements are primarily extracellular.

I think the intracellular/extracellular point above may be wrong. Most of the MRS studies are on ventricular spaces. Doesn't the fluid in the ventricles contain very few cells? It's more or less the same fluid as CSF in a spinal tap, right?

Edit: added quote

 

[Jonathan Edwards]

Doesn't the fluid in the ventricles contain very few cells? It's more or less the same fluid as CSF in a spinal tap, right?

It is pure CSF, the same.
But... it is conceivable that lactate reflects not metaboolic changes but CSF flux/stasis changes. The CSF is made in the ventricles and ends up in the spinal tap. Ventricular CSF might have more lactate if brain uses it up as a substrate, or less, if brain produces it and it leaks out at the perimeter. I rather doubt CSF flow is an issue but it could be. Moreover, posture could affect CSF stasis.

 

[forestglip]

Is it possible the MRS isn't very precise and gets some of the cells lining the ventricles, and that's where lactate is high? Other studies seem to show high lactate in non-ventricle regions, such as anterior cingulate cortex in Godlewska 2025

Increased ventricular lactate in chronic fatigue syndrome. III. Relationships to cortical glutathione and clinical symptoms implicate oxidative stress in disorder pathophysiology (Shungu et al, 2012, NMR in Biomedicine)

Looking at this ventricle paper, Shungu 2012, the caption for figure 1 includes this:

(B) Sample 1H spectrum from a voxel (see box in A) in the lateral ventricle of a patient with chronic fatigue syndrome (CFS) showing a clear lactate doublet peak at 1.33 ppm; also shown are contaminating resonances for N-acetylaspartate (NAA), total creatine (tCr) and total choline (tCho) from surrounding brain tissue as a result of partial volume averaging.

Edit: Cited wrong study previously.

 

[Jonathan Edwards]

Is it possible the MRS isn't very precise and gets some of the cells lining the ventricles, and that's where lactate is high? Other studies seem to show high lactate in non-ventricle regions, such as anterior cingulate cortex in Godlewska 2025

But anterior cingulate isn't all round the ventricles - i.e. it doesn't really add up.

I would hope that studies made sure they did not include brain tissue itself, but that quote is a bit worrying. I don't know enough about the methodology to be sure.

 

[forestglip]

But anterior cingulate isn't all round the ventricles - i.e. it doesn't really add up.

Well, I was thinking cells throughout the brain could have high lactate. Not localized necessarily. Maybe all neurons or all of a certain glial cell.

 

[Jonathan Edwards]

Well, I was thinking cells throughout the brain could have high lactate.

I presume someone would have reported it if so.

 

[Nightsong]

Just to add that in the most recent one of these studies, the poster presentation (link), the task was a visual stimulus, as opposed to some of the other studies that have assessed lactate at baseline or post-exercise:



It would be useful, I think, to have a lactate MRS study with an additional physically inactive comparator group, and to examine the effects of both light physical & cognitive exertion.

 

[ScoutB]

One study tested lactate using both methods, but it was only high when using MRS, as mentioned below.

Ah interesting, that is really handy to have.

it is conceivable that lactate reflects not metaboolic changes but CSF flux/stasis changes. The CSF is made in the ventricles and ends up in the spinal tap. Ventricular CSF might have more lactate if brain uses it up as a substrate, or less, if brain produces it and it leaks out at the perimeter.

Am I understanding you correctly: the suggestion is maybe the brain is both making more lactate and also using all that lactate before the CSF reaches the spinal tap?

I had forgotten that in the brain we now think of lactate as being a fuel source rather than a waste product.

Actually, looking into that, this quote from wiki might be answering our question:

Although glucose is usually assumed to be the main energy source for living tissues, there is evidence that lactate, in preference to glucose, is preferentially metabolized by neurons in the brains of several mammalian species that include mice, rats, and humans. According to the lactate-shuttle hypothesis, glial cells are responsible for transforming glucose into lactate, and for providing lactate to the neurons. Because of this local metabolic activity of glial cells, the extracellular fluid immediately surrounding neurons strongly differs in composition from the blood or cerebrospinal fluid, being much richer with lactate, as was found in microdialysis studies.

(I guess we still need to figure out if that would explain the ventricles having more lactate too.)

I also found this study: Lactate supply overtakes glucose when neural computational and cognitive loads scale up. From skimming, it sounds like they gave rats cognitive tests (an easier one and a harder one) and found that if they injected the rats with oxamate (which, I gather, blocks lactate production), the rats could still do the easy task but did more poorly on the harder task. They argue this shows that while the brain uses both glucose and lactate as a fuel source, lactate is needed for more advanced/energy-intensive cognitive tasks.

So if the findings of these studies pan out -- sounds like ME/CFS neurons might be requiring (or at least receiving) more lactate than healthy controls need for equivalent cognitive tasks? (as in that poster Nightsong just posted). Seems pretty compelling to me.

 

[Jonathan Edwards]

So lactate might be a good thing, produced to help neurons do hard cognitive tasks?

It all seems rather complicated and I have a nasty suspicion that people doing studies on lactate, wherever, in ME/CFS work on the simplistic assumption:

lactate = bad = metabolic failure = ME/CFS = bingo.

 

[Turtle]

Could the brain prefer lactate as fuel, when oxygen is low?

 

[ScoutB]

It all seems rather complicated and I have a nasty suspicion that people doing studies on lactate, wherever, in ME/CFS work on the simplistic assumption:

lactate = bad = metabolic failure = ME/CFS = bingo.

Yes, and if it holds up that lactate is disappearing (i.e. being used up?), leaving levels normal in CSF, then maybe that's a point in favour of it being something the neurons are successfully using, rather than the side effect of a lack of oxygen?

I wonder if there's some other metabolite we would expect to be raised in the cerebrospinal fluid if the lactate is indeed being used as an energy source.

Could the brain prefer lactate as fuel, when oxygen is low?

Yea I'm curious too why the brain would prefer lactate. Biology folks correct me if I'm wrong, but I believe the deal with lactate is that it is a useful fuel when you have oxygen, and a 'waste product' when you don't? (Probably waste product is unfair, but what I mean is: the no-oxygen ways of getting energy *produce* lactate rather than use it, I think?)

 

[SNT Gatchaman]

Prefrontal lactate predicts exercise-induced cognitive dysfunction in Gulf War Illness (Baraniuk et al, 2013, American Journal of Translational Research)

Also referenced by @forestglip here, there are relevant passages relating to the above questions about brain lactate use in this paper —

Glucose has traditionally been considered the principal energy source for the brain. However, recent findings in brain energetics suggest that lactate is an alternative fuel under conditions of high neural demand for energy metabolism during cognition and memory acquisition. Cerebral lactate metabolism is maintained by an interaction between astrocytes and neurons known as the astrocyte - neuron lactate shuttle. Astrocytes generate and release lactate into the brain interstitial fluid. Neurons import the lactate and convert it to pyruvate for use in mitochondrial oxidative phosphorylation. Lactate is a more efficient starting point for oxidative respiration than glucose since the neuron has a net gain of one ATP molecule, and the glucose can be reserved for skeletal muscle ATP production.

Lactate derived from exercising muscles is another energy source for neurons. Proton – coupled monocarboxylate transporters (MCT) shuttle lactate across the blood – brain barrier and through astrocytes to neurons and other cells. Under normal conditions, astrocytes supply lactate by glycolysis followed by lactate export, and during muscular exercise by absorption of lactate from across the blood – brain barrier into the neuropil. The flux is efficient so importation matches neural energy needs and brain lactate levels do not rise.

Lactate in the cerebral ventricles of CFS subjects is significantly higher than anxiety, major depression, and healthy volunteers.

Exercise proved to be a critical stressor that perturbed the baseline state of [GWI] compensatory adaptations to more clearly reveal distinctions from controls as well as by Increaser and Decreaser cognitive – prefrontal lactate status. These [GWI] subjects also met CFS criteria

During increased neural synaptic activity, lactate is the preferred energy source even in the presence of glucose. Mono-carboxylate transporters (MCT) are responsible for shuttling lactate in the brain. MCT-2 is the predominate neuronal lactate transporter. MCT-1 and MCT-4 are the primary astrocytic lactate transporters. The relationship between lactate and working memory scores in Increasers was consistent with preferential lactate metabolism by neurons during highly demanding cognitive situations.

the persistently elevated prefrontal lactate levels of Decreasers implied an inability to import or utilize lactate by neurons. MCT-2 transporter dysfunction is one potential explanation. […] Extrapolation of our data would suggest that cerebral glucose may have played a compensatory metabolic role in Decreasers so that their baseline 2-back accuracies were comparable to Increasers.

Mitochondrial dysfunction provides an alternative hypothesis to explain the significantly elevated prefrontal lactate levels before and after exercise in Decreasers. Loss of oxidative capabilities in neurons and astrocytes may cause a shift to glycolysis for ATP generation.

Lactate dehydrogenase (LDH) is responsible for the catalytic conversions between pyruvate and lactate. The isoform LDH-A is responsible for converting pyruvate to lactate whereas iso form LDH-B is responsible for converting lactate to pyruvate. Mitochondrial dysfunction leads to increased transcriptional activity with higher relative levels of LDH-A. This facilitates the regeneration of NAD+ substrates that can be reused in glycolysis to maintain ATP generation. This compensatory dependence on glycolysis may explain the increased lactate levels in Decreasers.

During vigorous exercise, skeletal muscles dramatically increase glucose uptake in order to generate ATP for sustained contractions. This depletes plasma glucose availability leading to a 32% decrease in brain glucose uptake. In the normal brain, the lower glucose availability as a fuel is met by compensatory replacement with lactate.

Our results suggest Increasers were able to metabolically shift to the use of lactate as an energy source […] However, Decreasers were not able to utilize lactate in the post-exercise setting when glucose would be preferentially sequestered to muscle. Inability to use lactate may have required decreasers to rely more heavily on glycolytic metabolism.

 

[SNT Gatchaman]

Since high lactate in the brain in ME/CFS seems to be a finding that keeps coming up

So lactate might be a good thing, produced to help neurons do hard cognitive tasks?

It all seems rather complicated and I have a nasty suspicion that people doing studies on lactate, wherever, in ME/CFS work on the simplistic assumption:

lactate = bad = metabolic failure = ME/CFS = bingo.

Hmm… we should pursue this discussion. Some initial questions —

Do we fail to demonstrate elevated plasma lactate (from muscle use) in ME/CFS because in part it's preferentially cleared from the blood pool and sequestered for use as fuel in brain?

If brain lactate flux in healthy people is efficient "so importation matches neural energy needs and brain lactate levels do not rise" what happens in ME/CFS when we're asleep and brain energy levels are lowered? Do lactate levels rise? Could this be / has this been measured? Overnight MRI and sleeping in a noisy magnet doesn't sound feasible, nor does prolonged direct access for CSF sampling.

But could that be part of the unrefreshing sleep phenotype, the waking in the middle of the night with heart racing? See eg Experimental induction of panic-like symptoms in patients with postural tachycardia syndrome (2006).

 

[Violeta]

Elevated blood lactate in resting conditions correlate with post-exertional malaise severity in patients with Myalgic encephalomyelitis/Chronic fatigue syndrome​

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"The study included 123 patients. Elevated (n = 55; 44.7%) and normal (n = 68; 55.3%) lactate groups were comparable except for PEM, which was more severe in the elevated lactate group after adjusting for age at disease onset, sex, and comorbidities (OR 2.47, 95% CI: 1.10–5.55). ME/CFS patients with elevated blood lactate at rest may be at higher risk for more severe PEM. This finding may be of interest in ME/CFS management."

PKM2 accelerated the progression of chronic fatigue syndrome via promoting the H4K12la/ NF-κB induced neuroinflammation and mitochondrial damage​

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"Serum lactate levels increased in the model group compared to the control group, but there was no significant difference between the Model + PKM2-OE and Model + PKM2-KD groups. Brain tissue lactate levels increased in the model group, further elevated in the Model + PKM2-OE group, but decreased in the Model + PKM2-KD group. PKM2 in hippocampal cells enhances glycolysis, lactate accumulation, and H4K12la/NF-κB-mediated neuroinflammation, leading to mitochondrial damage and accelerating the progression of chronic fatigue syndrome."

Lactate in the brain​

Lactate in the brain

A recent overview of neurocognitive research into ME/CFS found that attention span, memory and reaction time were impaired, a finding that is consistent with the memory and concentration problems that patients themselves complain about. Given that some neuropsychiatric disorders also show...

www.meresearch.org.uk

"The scientists point out that high brain lactate levels are consistent with reports of areas of low blood flow to the brain in ME/CFS patients, and also with reports of increased oxidative stress in ME/ CFS leading to mitochondrial dysfunction, anaerobic glycolysis and lactate production."