Lactic acid, lactate in ME/CFS

[Jonathan Edwards]

1) Elevated blood lactate in resting conditions correlate with post-exertional malaise severity in patients with ME CFS

I am not sure how that would relate to going above an anaerobic threshold - I don't see how lactate levels at rest would reflect that.

2) Abnormal blood lactate accumulation during repeated exercise testing in ME CFS

Abnormal lactate levels are also shown in the 2 day CPET
- mind you ME CFS patients that can do 2 day CPET are not severe, but Mild - maybe Moderate

There might well be a correlation between lactate and reduced cardiopulmonary performance on day 2 but that doesn't mean that PEM is specifically linked to anaerobic threshold as far as I can see.
And, as you say, if these people were really in PEM they would not be doing a second test.

 

[Turtle]

I am not sure how that would relate to going above an anaerobic threshold - I don't see how lactate levels at rest would reflect that.


There might well be a correlation between lactate and reduced cardiopulmonary performance on day 2 but that doesn't mean that PEM is specifically linked to anaerobic threshold as far as I can see.
And, as you say, if these people were really in PEM they would not be doing a second test.

Maybe I would be the perfect test case because my AT was extremely low at 1 28 min. Only one CPET.
After doing groceries I always have a day after, off day.
When I know I should postpone my shopping because getting ready to go takes too long, chance of PEM is greater.
Muscle aches in both cases are the same, but cognitive PEM is way worse.
Lactic acid has only been tested once 14.11 and pyruvic acid 0.07 in 24 hour urine sample.

 

[Ferry]

Lactate does not seem to me to be a plausible source of PEM symptoms because the timing is wrong.

But could it be a plausible explanation for intense burning muscle pain that is quickly triggered during routine activities and that forces me to pause or abandon the activity? (Thank you, by the way, for your sustained interest in ME/CFS.)

 

[jnmaciuch]

But could it be a plausible explanation for intense burning muscle pain that is quickly triggered during routine activities and that forces me to pause or abandon the activity? (Thank you, by the way, for your sustained interest in ME/CFS.)

No, that’s been disproven pretty comprehensively. What we know is that lactic acid tends to correlate with the burning feeling during exercise in healthy subjects but does not appear to be the cause (though it likely has a modifying effect on peripheral nerves mediating muscle fatigue more specifically)

 

[Utsikt]

My muscles start burning without me using the as well, so presumably it can happen without having to do with activity.

 

[Arfmeister]

I am not sure how that would relate to going above an anaerobic threshold - I don't see how lactate levels at rest would reflect that.

I’m not so bothered about the anaerobic threshold. I’m interested in the correlation MECFS / PEM and lactate levels.

From that n=123 paper : 45% patients had lactate values around 2 mmol (or sometimes higher) at complete rest:
- “ resting conditions in hospital bed for at least 30  minutes and without preceding exercise “

Also, an important notion is the definition of rest IMO:
- What a healthy person or doctor might consider rest is actually not ‘rest’ for a severe / moderate / even mild ME patient
(I’m bedridden, was an athlete, but I’ve never 24/7 exercised as much as I do now).

What do you think explains these higher lactate levels at rest from that paper?
- I know it’s not the causation, but I’m looking for what explains the correlation (in about 45% of the patients)

 

[tuha]

Are we sure that in this hypothesis we accumulate lactic acid? Cannot it be something else?
I feel every day especially in my calfs something simillar to lactic acid but I think it's different what I felt after overexertion when I was healthy.
So I think lactic acid in a healthy person is different compare to "lactic acid" in ME/CFS.
Or is it a completly different thing? What do you think?
Also what is strange that after walking I feel this "lactic acid" only in my calfs and not in the upper legs. Do you have the same experiences?

 

[Arfmeister]

“Lactic acid” and “lactate” are often used interchangeably, but physiologically they are not the same.

At normal body pH (~7.4), lactic acid (which has a pKa of ~3.9) is almost completely dissociated, meaning it exists as lactate (the negatively charged ion) plus a hydrogen ion (H⁺). As a result, free lactic acid essentially does not exist in the body under physiological conditions; what is actually produced and measured in blood and muscle is lactate.

The distinction matters because lactate itself is not the cause of muscle burning or acidosis.
Lactate is a normal, useful metabolic intermediate that can be shuttled to other tissues and oxidized for energy. The acidic effect comes from the accompanying hydrogen ions (H⁺) generated during rapid ATP turnover, not from lactate. Clinically and scientifically, blood tests measure lactate, even when reports loosely say “lactic acid,” and elevated lactate reflects altered metabolism or stress rather than the presence of an acid poisoning the tissues.

I feel every day especially in my calfs something simillar to lactic acid but I think it's different what I felt after overexertion when I was healthy.
So I think lactic acid in a healthy person is different compare to "lactic acid" in ME/CFS.
Or is it a completly different thing? What do you think?

You can only measure lactate in blood as far as I know, so that’s the data where we have to go from.

Apart from the publication, I posted, I know quite a few patients that tested high for lactate (many through self tested lactate meters /devices)
Also, the burning muscle is a common thing. I started to really suffer from it 10 years into my illness.

For me, it’s very similar to my healthy person experience, with the big difference is that it doesn’t go away and it’s way more intense.

 

[tuha]

Also, the burning muscle is a common thing. I started to really suffer from it 10 years into my illness.

For me, it’s very similar to my healthy person experience, with the big difference is that it doesn’t go away and it’s way more intense.

in my case those feelings are also constant, it doesnt go away even if I walk the same distance every day, it's nothing extreme and my muscles should be use to it.
What I cannot describe good is the feelings in my calfs. It doesnt hurt (only if I get muscle cramps which I can provoke easily by myself) like after overexertion when I was healthy. Also I wouldnt say that it's like burning muscle. I feel it like something very disagreable is accumulating in my calfs and I cannot get out of it. It's also disagreable when someone touch my calfs just a modest touch is disagreable.

 

[Jonathan Edwards]

What do you think explains these higher lactate levels at rest from that paper?
- I know it’s not the causation, but I’m looking for what explains the correlation (in about 45% of the patients)

It is a very peculiar study done retrospectively with PEM judged from old records. Moreover, the lactate levels all look fairly normal and mostly vary with food intake. I don't thin it means much.

 

[Jonathan Edwards]

I think people use 'lactic acid' as a lay term for lactate. When glucose is oxidised one of the hydrogen atoms becomes dissociable, so strictly speaking I think what is produced is lactic acid, but since the pH is clamped at 7.5 all we see is an increase in lactate ion (and probably some conversion of bicarbonate to CO2?).

 

[Arfmeister]

This wearable lactate monitor will be launched in 2026
- monitor working on the same principle as the glucose meter under skin / same principle as the glucose meter in skin
- linked to a smartwatch, as far as I understand

PKvitality’s SkinTaste® micro-sensor technology,

K’Track Athlete is the second wearable to tap PKvitality’s proprietary SkinTaste technology. But unlike the K’Track Glucose, it’s got a fitness bent: Instead of measuring blood sugar, it measures lactate.

The watch uses PKvitality’s SkinTaste® micro-sensor technology, which samples interstitial fluid through tiny micropoints — painlessly and continuously — to monitor biochemical markers like lactate.

“Lactic acid is a key performance indicator for the body and a guide to how well muscles react to long-term exertion and recovery,” PKvitality says. Mostly, it’s about avoiding the Lactic Threshold, or the point at which lactate begins to accumulate in the blood at a faster rate than it can be removed. That buildup triggers fatigue, which in turn affects the body’s ability to perform optimally at activities like long-distance running, rowing, swimming, and cycling.

PKvitality's SkinTaste sensor painlessly penetrates your skin to measure glucose

PKvitality's new SkinTaste biosensor uses microneedles to measure glucose and lactic acid levels in real time. The company has unveiled two wearables, the K-Track Glucose and K-Track Athlete, that use the technology.

www.digitaltrends.com

 

[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.

---

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 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?