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Increased levels of d lactic acid and acute episodes of d lactic acidosis have been linked to ME/CFS.
Acute episodes of d lactic acidosis typically last hours to days. Symptoms can include confusion, inability to concentrate, fatigue, hallucination, clumsiness, weakness, impaired muscle coordination (ataxia), speech difficulties (apraxia of speech, stuttering, slurred or slow speech), feeling “drunk”, derealization, blurry vision, unsteady gait, nystagmus, irritability, personality changes, and other “stoke-like” symptoms. Severe episodes can involve loss of consciousness.
While previously d lactic acidosis was only considered in short bowel syndrome patients, recent research has also linked elevated d lactic acid levels to CFS and other various diseases including IBS, liver disease, cystic fibrosis, and diabetes. Elevated d lactic acid levels are also found in those with GI irritation and intestinal permeability (leaky gut).
Some have speculated that many CFS symptoms like brain fog, weakness, and fatigue could be due to more persistently elevated levels of d lactic acid - high enough to cause symptoms but not so high as to trigger a full blown acidosis episode. Unlike l lactic acid (the more common form), d lactic acid flows freely into the cerebral spinal fluid, and even small amounts can cause neurological symptoms.
Importantly, d lactic acid and resulting acidosis impair pyruvate dehydrogenase, which can lead to 40% less efficacy of the conversion of l lactate to ATP. So high levels of d lactate not only cause neurological symptoms but can also contribute to low energy, fatigue, and potentially PEM.
PAST RESEARCH - DYSBIOSIS
The vast majority of past research on d lactic acidosis has focused on individuals with short bowel syndrome who develop acidosis due to dysbiosis - overgrowth of d lactic acid producing bacteria in the gut. The overgrowth of bacteria produces too much d lactic acid for the body to clear, and thus acidosis results.
One research study on CFS did indeed find elevated levels of d lactic acid bacteria in CFS patients so some of those recommendations seem applicable to us. D lactic acidosis has also been linked to leaky gut and SIBO.
These studies have been discussed on this forum in the past so I won’t get too much into them beyond noting the treatment recommendations below.
More info on d lactic acidosis caused by dysbiosis here: https://med.virginia.edu/ginutrition/wp-content/uploads/sites/199/2014/06/Parrish-September-15.pdf
NEW RESEARCH - OXIDATIVE STRESS
Elevated oxidative stress has been found in multiple studies of CFS patients, and CFS severity is correlated with oxidative stress. Oxidative stress by itself has a number of negative impacts that can contribute to CFS symptoms, including mitochondrial and DNA dysfunction, widespread inflammation, deterioration of brain neurons, and nerve damage.
Recently, scientists have discovered two new disease processes that are linked to both oxidative stress and d lactic acid.
Methylglyoxal.
Methylglyoxal is a highly toxic molecule that damages cells and DNA and is linked to many diseases. Methylglyoxal can be produced during metabolic processes, consumed in food and drinks (including coffee, tea, and especially manuka honey), and produced by gut bacteria. Gut bacteria that produce methylglyoxal in high quantities include proteus (which is also linked to neuroinflammation and excess histamine), and lactobacillus (!!!!).
When the body breaks down methylglyoxal, d lactate is the end product.
As far as we know, the methylglyoxal pathway is the only endogenous source of d lactic acid in humans. In the past, researchers posited that the amount of d lactate produced by the methylglyoxal pathway is insubstantial. Thus it was assumed that d lactic acid could only accumulate in meaningful quantities through exogenous consumption/production, marking d lactic acidosis as a GI disorder only.
However, recent research has linked excess methylglyoxal to excess d lactate levels. Studies have shown that increasing metabolism of methylglyoxal leads to even higher d lactate levels. This discovery has caused researchers to wonder if some cases of diabetic ketoacidosis are actually cases of d lactic acidosis.
Methylglyoxal (and thus d lactate) accumulates under impaired glucose metabolism and increased oxidative stress - both of which have been found in studies of CFS. While no studies have examined methylglyoxal levels in CFS patients, given we meet the preconditions, it’s not unreasonable to assume our levels would likely be elevated, which would also lead to elevated d lactic acid levels.
The link between lactobacillus and excess methylglyoxal (and thus d lactate) levels could also partially account for why CFS patients often have negative responses to lactobacillus probiotics.
Article on link between methylglyoxal and d lactic acid in several illnesses (2023): https://www.mdpi.com/2227-9067/10/6/945
Ferroptosis.
CFS patients may also be experiencing ferroptosis, a type of cell death that has been recently discovered. Ferroptosis has already been linked to a wide variety of illnesses and can lead to neurological issues and mitochondrial shrinkage (!!).
Necessary conditions for ferroptosis include oxidative stress (which we just learned is high in CFS patients) and high iron/ferritin levels, which are also higher in CFS patients. CFS disease severity is correlated with high iron levels, especially in females, and researchers can even predict which long COVID patients will develop CFS based on their elevated iron levels. (As an aside, fibromyalgia and regular non-CFS fatigue are correlated with low iron levels.)
Ferroptosis is also increased by d lactic acid (but not l lactic acid). In fact, research on cancer has shown that cancer cells will get rid of their d lactic acid (by converting it to pyruvate) in order to prevent ferroptosis cell death so they can continue to multiply.
While ferroptosis has not been examined yet in CFS specifically, researchers have used lipid peroxidation as a marker for ferroptosis in other conditions. Lipid peroxidation is indeed found in CFS patients. If we are already at risk for cell death due to our oxidative stress and elevated ferritin levels, and we are displaying evidence of ferroptosis via lipid peroxidation, one can assume that elevated d lactic acid levels would make us even more susceptible.
Article on ferroptosis in various diseases (2021): https://www.nature.com/articles/s41392-020-00428-9
Another article on ferroptosis in various diseases (2023): https://link.springer.com/article/10.1186/s43556-023-00142-2
Article on the role of d lactate in ferroptosis in cancer (2023): https://www.nature.com/articles/s41392-023-01555-9
NEW RESEARCH - MITOCHONDRIAL DYSFUNCTION?
For a long time it was believed that humans cannot break down d-lactic acid at all. Then research showed that only a very small amount of d lactic acid can be converted to pyruvate.
Within the past few years, however, scientists have been able to identify a specific enzyme in humans that metabolizes d lactic acid, called d-lactate dehydrogenase (shortened to D-LDH or LDHD). This enzyme resides in the inner membrane of mitochondria (!!) and in tissues with high metabolic activity. LDHD deficiencies have also been linked to decreased mitochondrial functioning.
In addition to processing d lactic acid, LDHD produces branched-chain ketoacids (BCKAs), which regulate several different metabolic processes in the body.
Identification of this enzyme has allowed researchers to look at genetic differences in d lactic acid metabolism. Individuals with mutations impacting LDHD have higher rates of d lactic acid in their systems, even in the absence of gut dysbiosis or excess dietary intake. LDHD mutations have also been linked to impairments in metabolic processes and elevated levels of pathogenic organic acids.
Since this research is so new they have not examined LDHD issues in other populations. However one could presume that with the extensive mitochondrial / metabolic dysfunction seen in CFS, in addition to our frequent deficiencies in key LDHD cofactors, we may have impairments in our LDHD functioning, leading to elevated d lactic acid levels, reduced ATP production, and build up of toxins.
It may also be that those of us who have more issues with d lactic acidosis have underlying genetic issues that only became expressed when we got sick; this is a potential theory as to why some people with short bowel syndrome get d lactic acidosis and others don’t. Hopefully more research will be done.
First study identifying LDHD deficiency in humans (2021): https://www.nature.com/articles/s41467-019-09458-6
First molecular analysis of LDHD (2023): https://www.nature.com/articles/s41467-023-42456-3
Article on LDHD genetic mutations and connection to cofactors (2024): https://www.sciencedirect.com/science/article/pii/S0003986124000511
CASCADING IMPACT OF D LACTIC ACID
The cascading impacts of these processes is noteworthy.
Too much d lactic acid causes neurological symptoms on its own. Remember that d lactic acid flows freely into cerebral spinal fluid and is toxic even in small amounts.
Excess d lactic acid then sets off a chain reaction of increased cell death, mitochondrial shrinkage, oxidative stress, impaired ATP production, impaired metabolism, and excess pathogens.
These impairments can further increase d lactic acid levels in at least four separate pathways. First, impaired mitochondrial function and metabolism further limit d lactic acid processing. Second, the acidic environment created impairs LDHD functioning. Third, cell death reduces key cofactors of d lactic acid processing, including glutathione and CoQ10. Fourth, the oxidative stress put on the body further increases methylglyoxal, which in turn converts to more d lactic acid.
D lactic acidosis can thus become a self reinforcing process.
TREATMENT IMPLICATIONS
So there are three primary pathways through which one can develop d lactic acidosis.
One - too much exogenous d lactic acid (focus of old research). This can result from overgrowth of d lactic acid producing bacteria, SIBO, leaky gut, and/or ingestion of d lactic acid containing substances. Treatment is well established and entails use of antibiotics, herbs, and/or probiotics to reduce overgrowth, as well as avoiding triggers.
Two - too much endogenously produced d lactic acid (focus of new research). This is a result of heightened methylglyoxal, which accumulates during oxidative stress and impaired glucose metabolism, and which degrades into d lactate. Treatment is somewhat experimental and entails use of supplements to reduce or prevent oxidative stress in general and methylglyoxal in particular.
Three - inability to metabolize d lactic acid (focus of new research). This can result from impaired functioning of the pyruvate conversion process, genetic mutations in LDHD (the d lactic acid enzyme), and/or impaired functioning of LDHD (due to lack of cofactors and/or as a result of oxidative stress). Treatment is highly experimental and speculative at this point but theoretically entails supplementing cofactors to support d lactic acid metabolism and avoiding substances that inhibit enzyme functioning.
I’ll go over all possible treatment options for all three pathways, and then do a quick bulleted summary at the end.
TREATMENT - REDUCING D LACTIC ACID INTAKE
Avoid medications with d lactic acid.
Ringers lactate and propylene glycol (used in liquid formulations of some medications) both contain d lactic acid and can trigger acidosis episodes in susceptible people.
Avoid d-lactic acid producing probiotics and foods.
Lactobacillus probiotics produce methylglyoxal, which is toxic on its own but also degrades into d lactate, and thus should be avoided. Most lactobacillus probiotics also directly produce d lactic acid. Lactobacillus acidophilus is the most common strain used in commercial probiotics and is a heavy d lactic acid producer.
Almost all fermented foods (yogurt, sauerkraut, etc.) will have d lactic acid in its free form, methylglyoxal-producing strains, AND d lactic acid producing strains and thus should be avoided. Many cheeses are also a source of lactobacillus and d-lactic acid producing probiotics and may be an issue for some.
Lactobacillus probiotics and fermented foods, while healthy for normal populations, are often considered to be quite risky for CFS patients in general anyways. Anyone with significant d lactic acid issues should either avoid entirely or use with caution.
Avoid dietary triggers.
Different overgrowths will come with different dietary triggers. Past research has identified simple carbohydrates, dairy/lactose, and/or sugar alcohols as the most common triggers.
Note that carbs are a particular problem for short bowel syndrome patients due to their unique anatomy (their bowels are too short to properly break down carbs, so undigested food winds up in the large intestine where bacteria can ferment it). Thus discussions of carbs are over represented in the literature. A couple of users on this forum have indeed resolved their acidosis with a keto diet. I personally have zero issues with carbs and worsened on keto. YMMV.
An overly restrictive diet can worsen dysbiosis in the long run. Temporary elimination diets may be helpful to identify your specific triggers. Once you resolve overgrowths you may be able to reintroduce some foods.
Oral or IV sodium bicarbonate.
Sodium bicarbonate effectively neutralizes d lactic acid. (It is not always effective against acidosis caused by l lactic acid, though.)
Studies recommend using oral or IV sodium bicarbonate during a flare to calm things down. One can also take oral baking soda regularly as a preventative measure. Some mix baking soda in with their daily electrolyte water.
However regular use of oral bicarbonate can reduce stomach acid, which can cause SIBO in some, which can worsen acidosis and dysbiosis. Delayed release or enteric coated sodium bicarbonate capsules may help mitigate this risk, as studies have shown they have fewer GI side effects.
Adequate hydration.
Maintain adequate hydration to help flush d lactic acid from the body. During a flare IV hydration is recommended, if possible.
Test for bacterial overgrowth.
Doing a microbiome stool test is critical to identifying the species responsible for overgrowth (if any), so that you can target your treatment.
Short bowel syndrome patients are more likely to have overgrowth of lactobacillus bacteria, whereas CFS patients are more likely to have overgrowth of enterococcus/streptococcus. Treatments are different for each.
Once you do a stool test you can upload your results to https://microbiomeprescription.com (run by a person with ME/CFS) to identify your troublesome bacteria and get personalized recommendations.
You may also want to get a SIBO breath test done if you suspect SIBO. Symptoms can include bloating and pain after eating, diarrhea and/or constipation, nausea, and/or vitamin deficiencies.
Antibiotics.
Antibiotics can help clear out bacterial overgrowth. They should be targeted to your specific overgrowth. Be warned antibiotics can sometimes cause severe crashes in CFS patients.
Ideally you should take CFS-safe probiotics that don’t produce d lactic acid during and/or after antibiotic treatment, in order to prevent colonization in the gaps left by antibiotic treatment by unhealthy bacteria.
Herbs.
The use of herbs can be used in conjunction with, or instead of, antibiotics to help clear overgrowth. Herbs should be rotated every 1-2 weeks to prevent resistance. Herbs should be targeted to your specific overgrowth, and should be carefully planned so as to not kill off any probiotics taken at the same time.
Uploading your sample to microbiome prescription will give you targeted advice for the best herbs to take.
Probiotics.
Most of the old research suggests taking l-lactic acid producing bacteria (such as l. casei) to drown out d-lactic acid producers. However this is based on an assumption of lactobacillus overgrowth, which is less common in CFS patients. This strategy is also risky for CFS patients, who are more likely to have adverse effects from lactobacillus probiotics. We are also are already at risk for elevated methylglyoxal levels due to our high oxidative stress, and since lactobacillus produces more methylglyoxal, we can experience even more inflammation and heightened d lactic acid levels.
Better recommendations for CFS patients are:
E. coli probiotics. E. coli produces 2% as much lactic acid as other bacteria. Drowning out the high producers with low producers helps reduce d lactic acid. The two most recommended probiotics for both CFS and d lactic acidosis are Mutaflor and Symbioflor-2.
Probiotics that metabolize lactic acid. Miyarisan (clostridium butyricum) uses lactic acid to make butyric acid. Miyarisan has shown efficacy in studies in resolving d lactic acidosis, and is also frequently helpful to CFS patients, possibly because low levels of butyrate are correlated with CFS severity. Securil (propionibacterium freudenreichii) converts lactate to propionic acid.
Other probiotics that may be helpful are Equilibrium (many different strains to boost diversity) and Enterogermina (bacillus clausii, one of the only low histamine spore based probiotics, does not produce d lactic acid).
Bifidobacterium may help some, but they produce lactic acid and also boost the growth of lactobacillus, so use with caution. Align is the most well studied and is often recommended for CFS patients.
Prescript Assist used to be highly recommended for CFS patients, but the formula has changed and is now supposedly quite dangerous. Avoid.
Faecalibacterium prausnitzii is a next generation probiotic that might be helpful once it’s commercially available. Low Faecalibacterium prausnitzii levels are correlated with disease severity in CFS.
Many other probiotics might be helpful; doing a stool test can reveal what might help your specific microbiome.
As with herbs, probiotics should be rotated every 1-2 weeks to prevent resistance. A potential rotation might look something like:
His specific posts on d lactic acidosis: https://www.google.com/search?q=d+lactic+site:cfsremission.com
You can also check whether probiotics produce lactic acid (or contribute to the growth of lactic acid producing bacteria): https://microbiomeprescription.com/library/ProbioticMixtures
TREATMENT - REDUCING ENDOGENOUS D LACTIC ACID PRODUCTION
Quercetin.
Quercetin helps reduce oxidative stress and has been found specifically to reduce levels of methylglyoxal (the toxic substance that converts to d lactate). Quercetin is also a strong mast cell stabilizer. It is a strong MAOI which can sometimes pose problems with agitation and insomnia for those with slow MAOI genes or mental health issues. Supplemental doses for MCAS/HIT are often 500mg/day.
Bromelain.
Bromelain helps reduce oxidative stress. Bromelain is also a mast cell stabilizer. It also is a biofilm buster, which can help herbs and antibiotics work better against bacterial overgrowth. Bromelain can be used in addition to quercetin, or instead of quercetin for those who are sensitive to MAOIs. Supplemental doses for bromelain are anywhere between 50-400mg, 1-3 times per day. Can be taken with meals to aid digestion or away from meals to get the maximum anti inflammatory effect.
CoQ10.
CoQ10 helps reduce oxidative stress. It is also a cofactor for LDHD (the d lactic acid enzyme). CoQ10 is used for many metabolic processes and is often recommended to those with CFS. Many CFS medications reduce CoQ10, including beta blockers, other heart medications, tricyclic antidepressants, and birth control.
CoQ10 supplementation can cause profound insomnia, anxiety, and agitation in some so you may want to start with a low dose. If you tolerate it well or have a higher need to supplement, ubiquinol is the bioactive form and is better absorbed.
Vitamin E.
Vitamin E helps reduce oxidative stress. Vitamin E is also a key inhibitor of ferroptosis (cell death), and has been shown to improve the prognosis of other degenerative neurological disorders.
Since vitamin E is fat soluble it can be dangerous to supplement. Vitamin E supplementation is linked to early mortality. Aim for adequate dietary intake instead, 15mg/day. If supplementing, toxicity begins at 400mg/day but can be lower the longer you supplement. Drops may be preferred as you can take very small doses.
Glutathione.
Glutathione (GSH) helps reduce oxidative stress. It has also been shown to help prevent ferroptosis (cell death). Additionally, it is also an important cofactor for LDHD. Its role across multiple d lactic acid pathways makes it particularly important.
Glutathione supplementation is notoriously tricky. There is a blood test for glutathione so you can monitor how effective your supplementation is.
Here is an article on how to increase glutathione: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10215789/
You can also check other threads on this forum for reports and recommendations on supplementation.
Quick summary of options. You should likely only pick 1 or 2 of these to avoid overloading:
Direct supplementation of glutathione. The most effective forms are also the most expensive. Can cause insomnia and agitation. Tricky to get dosage right. If you’re struggling to tolerate it, some people get an expensive effective form and take a tiny dose of it, and others get a cheaper less effective form so not as much is absorbed. If you tolerate it well and see improvement, you can also get nasal sprays or injections. Be warned that direct supplementation has the potential to reduce your body’s ability to produce its own glutathione; some speculate that it may be better to support precursors/cofactors instead.
NAC. Cysteine is a precursor to glutathione. Studies have shown NAC increases glutathione. NAC can also help other CFS symptoms. However it can cause a strong histamine reaction. It’s also a biofilm buster which could help you tackle dysbiosis but can also trigger strong herx reactions. Monitor closely.
Whey protein isolate. This has cysteine and has been shown to be as effective as NAC at boosting glutathione. Histamine safe and also lactose and casein free. Many with dairy issues tolerate whey protein isolate just fine. The brand Immunocal has published a bunch of studies showing their wildly expensive whey protein isolate boosts glutathione, however most experts seem to agree that any old whey protein isolate will work the same.
Glycine. Studies have shown that cysteine + glycine together are more effective at boosting glutathione, so ideally you’d pair NAC + glycine or whey protein + glycine. Many like magnesium glycinate taken at bed to help with sleep. Warning that while glycine itself is calming it does convert to glutamate which is excitatory and releases histamine, especially for those with lots of “tired but wired” symptoms, ADHD or OCD, or MCAS/HIT. Hit or miss. Use with caution and give yourself a full week or two with no other changes to monitor your response.
Milk thistle. Shown to boost glutathione. Also helps with MCAS. May cause allergic reactions in those allergic to ragweed. Is an MAOI. There is no standardized dose; anywhere between 20-300mg/day seems fine. Do not exceed the safe upper limit of 420mg/day.
Support cofactors of glutathione. These are selenium (in desiccated beef kidney which many use as a DAO supplement; aim for 50-200mcg/day, do not exceed 400mcg/day), sulfur (also helps with salicylate sensitivity, can get through diet or epsom salt foot baths), and vitamin C (do not exceed 250 mg / day so it doesn’t convert to oxalate, camu camu is a low histamine source).
Resolve glucose issues.
Glucose issues are linked to oxidative stress, which increases d lactic acid. Some people with CFS have high blood sugar and some have low. This needs to be tested and treated by a doctor.
Some people with CFS respond well to low doses of Metformin, which can both regulate blood sugar and reduce the toxic methylglyoxal. However, Metformin reduces methylgyloxal by converting it to d lactic acid, and indeed Metformin use is linked to acidosis and has been shown in studies to increase d lactic acid. Use with caution.
Resolve iron issues.
High iron levels are linked to ferroptosis (cell death). This must be tested and treated by a doctor. Excess vitamin C increases iron aborption (as well as converting to oxalate) so you may want to avoid if you test as having high iron levels.
Lifestyle.
Studies have shown CFS patients experience an increase in oxidative stress after exercise, so proper pacing/resting may help. Healthy diet and stress management techniques can also help lower oxidative stress.
TREATMENT - SUPPORTING METABOLISM OF D LACTIC ACID
Low oxalates - diet.
LDHD (the enzyme that processes d lactic acid) functioning is significantly impaired in the presence of oxalates. In fact LDHD is the most sensitive enzyme in the body to oxalate.
Maintaining a low oxalate diet can help prevent LDHD impairment. The Facebook group “Trying Low Oxalates” can help with dietary changes. Many report that reducing oxalates too quickly causes “oxalate dumping” which can worsen symptoms; a gradual reduction is better.
We don’t know exactly how many mg of oxalate is okay for those struggling with acidosis. Those with kidney stones are recommended to less than 100 mg per day, ideally less than 50 mg per day. At the very least, avoiding the highest oxalate foods that have hundreds of mg of oxalate per serving (such as spinach, rhubarb, dark chocolate, and many nuts) might help.
You can track dietary oxalates in the free version of the Cronometer app, you just have to turn it on in settings as it’s hidden by default. The app functions best when you choose generic foods (e.g. “oats”); specific brand name products are often lacking in extra data. Make sure there’s an actual value for the nutrients you’re tracking and not a dash (indicating it’s lacking info).
Low oxalate - calcium.
Calcium binds to oxalates and helps your body get rid of oxalates instead of absorbing them. Calcium can be used in addition to a low oxalate diet in order to give LDHD the best chance at optimal functioning, or calcium can be used to mitigate the damage of a higher oxalate diet if one is unable to adhere to a restrictive diet.
It’s recommended to either take 100-300 mg calcium with each meal, or add powder to your water and sip on it all day.
Calcium carbonate can only be taken with meals and can lower stomach acid (which may help with lactic acid bacteria overgrowth but also could lead to SIBO which can worsen dysbiosis). Calcium citrate is preferred as it can be taken any time and does not impact stomach acid, but citrates can be an issue for those with histamine intolerance.
Note that calcium supplementation is no longer recommended for most people as it is associated with early mortality and can lead to heart problems. Consult your doctor. Keeping your calcium supplementation intake under the RDA (1000 mg / day) and taking vitamin K2 (mk-4 has best results in studies and has a lower risk of side effects) may help alleviate risks.
If you are on medication that impacts your calcium levels (like vitamin D, some POTS meds, or lithium), or have any sort of heart/blood problems, you should get blood work done periodically.
You may also try to increase dietary sources of calcium with each meal instead of supplementing. This can be hard, though, as dairy can sometimes be a trigger for acidosis.
Low oxalate - probiotics.
One can also take probiotics that degrade oxalates. The number one bacteria that degrades oxalates is oxalobacter formigenes. Unfortunately only about 30% of people in the west have any of this bacteria left (it’s killed by western diet and antibiotics), and currently there are no viable commercial probiotics available. However there have been a flurry of new studies on oxalobacter formigenes and we can expect a probiotic to come to market soon. (Note that the “oxalobacter” probiotics sold on eBay have been tested and shown to not contain any of the bacteria. Don’t waste your money - wait for a reputable company to release a good product).
Other probiotics that degrade oxalates include lactobacillus paracasei, lactobacillus gasseri (warning some strains make d lactic acid), bifidobacterium breve, and bifidobacterium longum (Align is the most studied and often recommended for CFS). All lactobacillus and bifido probiotics both produce lactic acid of their own AND promote the growth of lactic acid-producing bacteria, so use with extreme caution, if at all.
Low oxalate - avoid excess vitamin C.
Avoid excess vitamin c supplementation (over 250 mg / day), as the body converts it to oxalate. Excess vitamin c can also increase iron levels which can contribute to cell death for those with high iron.
Thiamine.
Thiamine (vitamin B1) is necessary to facilitate conversion of d lactic acid to pyruvate.
Studies on d lactic acidosis recommend 100mg per day. Higher doses will start to deplete your other vitamins and minerals and thus require following a high dose thiamine protocol.
B1 can help with a whole host of CFS symptoms as well. Unfortunately it can cause histamine issues for those with MCAS/HIT. You may need to try each of the three different forms to find one you react the least to - regular thiamine, benfotiamine, and TTFD. Many with CFS believe the benefits of B1 outweigh the negative histamine reaction and thus make an exception for it. Depends on your tolerability and if you find benefit.
Riboflavin.
FAD is perhaps the most important cofactor for d lactic acid processing; FAD binds directly with LDHD and is necessary for its functioning. The body makes FAD from riboflavin (vitamin B2).
Notably, studies have shown that genetic defects in FAD functioning are characterized by repeated episodes of lactic acidosis, which can be resolved with riboflavin supplementation. Big clue there!
MAO activity, which helps clear histamines and some neurotransmitters from the body, is also dependent on FAD and can be boosted by riboflavin supplementation. So histamine issues could be another sign of low FAD/riboflavin in some. (Those with slow MAO genes need extra riboflavin. Caution, those with fast MAO genes may experience depression on riboflavin.)
Riboflavin supplementation is considered safe even in high doses; it’s almost impossible to overdose on. There are no guidelines for dosages for LDHD functioning, but for migraines patients are recommended 400mg of riboflavin per day. Some people do better with the active form of riboflavin, riboflavin-5’-phosphate (R5P), though it can cause histamine reactions in some. Dosages for R5P are usually 1/2 as much as regular riboflavin as R5P is more bioavailable. The body can only absorb a little riboflavin at a time, so it’s better to take smaller doses of riboflavin 2-4 times a day with at least 1 hour between each dose.
Riboflavin is extremely sensitive to light. Leave in its original pill bottle or use an opaque pill organizer.
Note that boron prevents absorption of riboflavin and can lead to riboflavin deficiency. Boron is in most multivitamins and mineral complexes. Either avoid or take at a separate time from riboflavin.
FAD cofactors: iodine, selenium, molybdenum.
The body uses riboflavin + iodine and riboflavin + selenium to make FAD (which is essential for d lactic acid processing). The body uses riboflavin + molybdenum to make FMN, which then gets converted to FAD. Thus you need all three cofactors plus riboflavin to get FAD. Research on autistic children has linked deficiencies in these three cofactors to decreased FAD activity and resulting neurological issues.
Research has also linked deficiencies in the three FAD cofactors to issues with activating B6 and B12. So imbalances in those vitamins could be a sign of low FAD.
Iodine, selenium, and molybdenum can all be dangerous to supplement. It’s best to increase your dietary consumption instead. You can track all three in Cronometer, though you may have to turn some of them on in settings. If you decide to supplement, keep to VERY low doses. You will likely need to break your pills open to get a safe daily dose.
For all three we are not trying to overload, just trying to ensure adequate intake to avoid being deficient.
Iodine. Too much iodine is extremely dangerous and can permanently damage your thyroid. Unsupervised iodine supplementation is not recommended. Only those unable to get adequate iodine in diet should supplement; if this applies to you check your blood levels and consult a doctor. Iodine is a mixed bag for those with MCAS/HIT. It can prevent the conversion of histidine to histamine, but it can also act as a histamine liberator. Some do better with a little iodized salt at each meal, others with once a day drops, others with seaweed or kelp supplements. For those extremely sensitive to iodine you can try applying iodine drops topically, though it’s unclear how much (if any) you absorb this route. Note that iodine needs selenium to function properly. Aim for 150-300mcg/day. Toxicity from diet or supplements starts at 600mcg/day.
Selenium. If unable to get in the diet, selenium is found in high concentrations in desiccated beef kidney, which notably is used as a source of DAO for those with histamine intolerance. You can also get normal selenium supplements. Selenium toxicity can cause organ failure, and the risk of toxicity increases the longer you supplement. Aim for 50-200mcg/day. Toxicity from diet or supplements starts at 400mcg/day.
Molybdenum. Molybdenum is often low in CFS patients. High levels of copper can deplete molybdenum. Salicylate sensitivity could be a sign of molybdenum deficiency and is sometimes resolved with supplementation. Molybdenum deficiency can also lead to thiamine deficiency (which can also worsen d lactic acidosis, and CFS symptoms in general). If you are unable to get enough molybdenum in the diet, low doses of desiccated beef liver can be a good source (be mindful of overdosing on other vitamins in liver, especially vitamin a; typical serving size is 6 pills but you may just need 1-2). One can also get regular molybdenum supplements. Molybdenum is safer to supplement than selenium or iodine, but it’s still generally not recommended. Aim for 50-100mcg/day. Toxicity starts at 200mcg/day.
Manganese.
Researchers found that LDHD (the d lactic acid enzyme) showed the strongest activity in the presence of manganese. Interestingly a study found that out of all the metals, CFS patients are the most deficient in manganese. Connection?
Manganese can be extremely dangerous to supplement. Supplements can cause Parkinson’s like symptoms and permanent brain damage. Additionally too high of a dose can also deplete your CoQ10 which is needed as well for processing d lactic acid.
Increasing dietary sources of manganese is best. There have been no reports of manganese toxicity from diet alone, even though vegans frequently consume 10x the recommended RDA. Low oxalate and low histamine sources include pumpkin seeds, oats, and fruit. You can track your manganese intake in the free version of the Cronometer app as well.
The RDA for manganese is 2mg, the safe upper limit is around 10mg/day, but even as high as 20mg from diet alone is safe. Given manganese’s importance in LDHD processing and our tendency to be deficient it might be smart to aim for somewhere between 2-10mg/day from food sources.
If you must supplement (not recommended), toxicity begins at 10mg/day but it’s wise to not exceed the RDA of 2mg.
Zinc.
Zinc is an important cofactor for d lactic acid processing. Typical dosages for supplementing are 15-30 mg of elemental zinc (the amount on the back of the bottle). Higher doses can be toxic and can also impede glutathione, which is needed for LDHD. We are not trying to overload (zinc is only a cofactor for LDHD, not an activator like manganese) so you may want to stick closer to 15mg.
Zinc carnosine can help resolve leaky gut, which can also contribute to d lactic acidosis, so it may be the preferred form.
Note that zinc and copper compete with each other. Zinc supplementation often leads to depleted copper. Copper is necessary for DAO production so low copper may exacerbate histamine issues. Copper can be extremely dangerous to supplement on its own and lead to neurological issues. Seeking food sources or low doses (1-2 pills) of dessicated liver may be safer. If you want to supplement copper you should consult your doctor and get your blood levels checked regularly. We are not trying to overload, we just don’t want to be deficient. Take copper 2 hours apart from zinc. Aim for 1.5-3mg/day. Toxicity from food or supplements starts at 10mg/day but it’s wise to not exceed the RDA of 3mg.
CoQ10.
Already expanded on above. In addition to reducing oxidative stress, CoQ10 is a cofactor for LDHD.
Glutathione.
Already expanded on above. Glutathione, in addition to reducing oxidative stress and preventing ferroptosis, is a cofactor for LDHD.
SUMMARY - ALL POTENTIAL TREATMENT OPTIONS FOR D LACTIC ACIDOSIS
Testing:
If all of the above is too much… these seem to be the most important to prioritize first (and conveniently are the safest to try):
Acute episodes of d lactic acidosis typically last hours to days. Symptoms can include confusion, inability to concentrate, fatigue, hallucination, clumsiness, weakness, impaired muscle coordination (ataxia), speech difficulties (apraxia of speech, stuttering, slurred or slow speech), feeling “drunk”, derealization, blurry vision, unsteady gait, nystagmus, irritability, personality changes, and other “stoke-like” symptoms. Severe episodes can involve loss of consciousness.
While previously d lactic acidosis was only considered in short bowel syndrome patients, recent research has also linked elevated d lactic acid levels to CFS and other various diseases including IBS, liver disease, cystic fibrosis, and diabetes. Elevated d lactic acid levels are also found in those with GI irritation and intestinal permeability (leaky gut).
Some have speculated that many CFS symptoms like brain fog, weakness, and fatigue could be due to more persistently elevated levels of d lactic acid - high enough to cause symptoms but not so high as to trigger a full blown acidosis episode. Unlike l lactic acid (the more common form), d lactic acid flows freely into the cerebral spinal fluid, and even small amounts can cause neurological symptoms.
Importantly, d lactic acid and resulting acidosis impair pyruvate dehydrogenase, which can lead to 40% less efficacy of the conversion of l lactate to ATP. So high levels of d lactate not only cause neurological symptoms but can also contribute to low energy, fatigue, and potentially PEM.
PAST RESEARCH - DYSBIOSIS
The vast majority of past research on d lactic acidosis has focused on individuals with short bowel syndrome who develop acidosis due to dysbiosis - overgrowth of d lactic acid producing bacteria in the gut. The overgrowth of bacteria produces too much d lactic acid for the body to clear, and thus acidosis results.
One research study on CFS did indeed find elevated levels of d lactic acid bacteria in CFS patients so some of those recommendations seem applicable to us. D lactic acidosis has also been linked to leaky gut and SIBO.
These studies have been discussed on this forum in the past so I won’t get too much into them beyond noting the treatment recommendations below.
More info on d lactic acidosis caused by dysbiosis here: https://med.virginia.edu/ginutrition/wp-content/uploads/sites/199/2014/06/Parrish-September-15.pdf
NEW RESEARCH - OXIDATIVE STRESS
Elevated oxidative stress has been found in multiple studies of CFS patients, and CFS severity is correlated with oxidative stress. Oxidative stress by itself has a number of negative impacts that can contribute to CFS symptoms, including mitochondrial and DNA dysfunction, widespread inflammation, deterioration of brain neurons, and nerve damage.
Recently, scientists have discovered two new disease processes that are linked to both oxidative stress and d lactic acid.
Methylglyoxal.
Methylglyoxal is a highly toxic molecule that damages cells and DNA and is linked to many diseases. Methylglyoxal can be produced during metabolic processes, consumed in food and drinks (including coffee, tea, and especially manuka honey), and produced by gut bacteria. Gut bacteria that produce methylglyoxal in high quantities include proteus (which is also linked to neuroinflammation and excess histamine), and lactobacillus (!!!!).
When the body breaks down methylglyoxal, d lactate is the end product.
As far as we know, the methylglyoxal pathway is the only endogenous source of d lactic acid in humans. In the past, researchers posited that the amount of d lactate produced by the methylglyoxal pathway is insubstantial. Thus it was assumed that d lactic acid could only accumulate in meaningful quantities through exogenous consumption/production, marking d lactic acidosis as a GI disorder only.
However, recent research has linked excess methylglyoxal to excess d lactate levels. Studies have shown that increasing metabolism of methylglyoxal leads to even higher d lactate levels. This discovery has caused researchers to wonder if some cases of diabetic ketoacidosis are actually cases of d lactic acidosis.
Methylglyoxal (and thus d lactate) accumulates under impaired glucose metabolism and increased oxidative stress - both of which have been found in studies of CFS. While no studies have examined methylglyoxal levels in CFS patients, given we meet the preconditions, it’s not unreasonable to assume our levels would likely be elevated, which would also lead to elevated d lactic acid levels.
The link between lactobacillus and excess methylglyoxal (and thus d lactate) levels could also partially account for why CFS patients often have negative responses to lactobacillus probiotics.
Article on link between methylglyoxal and d lactic acid in several illnesses (2023): https://www.mdpi.com/2227-9067/10/6/945
Ferroptosis.
CFS patients may also be experiencing ferroptosis, a type of cell death that has been recently discovered. Ferroptosis has already been linked to a wide variety of illnesses and can lead to neurological issues and mitochondrial shrinkage (!!).
Necessary conditions for ferroptosis include oxidative stress (which we just learned is high in CFS patients) and high iron/ferritin levels, which are also higher in CFS patients. CFS disease severity is correlated with high iron levels, especially in females, and researchers can even predict which long COVID patients will develop CFS based on their elevated iron levels. (As an aside, fibromyalgia and regular non-CFS fatigue are correlated with low iron levels.)
Ferroptosis is also increased by d lactic acid (but not l lactic acid). In fact, research on cancer has shown that cancer cells will get rid of their d lactic acid (by converting it to pyruvate) in order to prevent ferroptosis cell death so they can continue to multiply.
While ferroptosis has not been examined yet in CFS specifically, researchers have used lipid peroxidation as a marker for ferroptosis in other conditions. Lipid peroxidation is indeed found in CFS patients. If we are already at risk for cell death due to our oxidative stress and elevated ferritin levels, and we are displaying evidence of ferroptosis via lipid peroxidation, one can assume that elevated d lactic acid levels would make us even more susceptible.
Article on ferroptosis in various diseases (2021): https://www.nature.com/articles/s41392-020-00428-9
Another article on ferroptosis in various diseases (2023): https://link.springer.com/article/10.1186/s43556-023-00142-2
Article on the role of d lactate in ferroptosis in cancer (2023): https://www.nature.com/articles/s41392-023-01555-9
NEW RESEARCH - MITOCHONDRIAL DYSFUNCTION?
For a long time it was believed that humans cannot break down d-lactic acid at all. Then research showed that only a very small amount of d lactic acid can be converted to pyruvate.
Within the past few years, however, scientists have been able to identify a specific enzyme in humans that metabolizes d lactic acid, called d-lactate dehydrogenase (shortened to D-LDH or LDHD). This enzyme resides in the inner membrane of mitochondria (!!) and in tissues with high metabolic activity. LDHD deficiencies have also been linked to decreased mitochondrial functioning.
In addition to processing d lactic acid, LDHD produces branched-chain ketoacids (BCKAs), which regulate several different metabolic processes in the body.
Identification of this enzyme has allowed researchers to look at genetic differences in d lactic acid metabolism. Individuals with mutations impacting LDHD have higher rates of d lactic acid in their systems, even in the absence of gut dysbiosis or excess dietary intake. LDHD mutations have also been linked to impairments in metabolic processes and elevated levels of pathogenic organic acids.
Since this research is so new they have not examined LDHD issues in other populations. However one could presume that with the extensive mitochondrial / metabolic dysfunction seen in CFS, in addition to our frequent deficiencies in key LDHD cofactors, we may have impairments in our LDHD functioning, leading to elevated d lactic acid levels, reduced ATP production, and build up of toxins.
It may also be that those of us who have more issues with d lactic acidosis have underlying genetic issues that only became expressed when we got sick; this is a potential theory as to why some people with short bowel syndrome get d lactic acidosis and others don’t. Hopefully more research will be done.
First study identifying LDHD deficiency in humans (2021): https://www.nature.com/articles/s41467-019-09458-6
First molecular analysis of LDHD (2023): https://www.nature.com/articles/s41467-023-42456-3
Article on LDHD genetic mutations and connection to cofactors (2024): https://www.sciencedirect.com/science/article/pii/S0003986124000511
CASCADING IMPACT OF D LACTIC ACID
The cascading impacts of these processes is noteworthy.
Too much d lactic acid causes neurological symptoms on its own. Remember that d lactic acid flows freely into cerebral spinal fluid and is toxic even in small amounts.
Excess d lactic acid then sets off a chain reaction of increased cell death, mitochondrial shrinkage, oxidative stress, impaired ATP production, impaired metabolism, and excess pathogens.
These impairments can further increase d lactic acid levels in at least four separate pathways. First, impaired mitochondrial function and metabolism further limit d lactic acid processing. Second, the acidic environment created impairs LDHD functioning. Third, cell death reduces key cofactors of d lactic acid processing, including glutathione and CoQ10. Fourth, the oxidative stress put on the body further increases methylglyoxal, which in turn converts to more d lactic acid.
D lactic acidosis can thus become a self reinforcing process.
TREATMENT IMPLICATIONS
So there are three primary pathways through which one can develop d lactic acidosis.
One - too much exogenous d lactic acid (focus of old research). This can result from overgrowth of d lactic acid producing bacteria, SIBO, leaky gut, and/or ingestion of d lactic acid containing substances. Treatment is well established and entails use of antibiotics, herbs, and/or probiotics to reduce overgrowth, as well as avoiding triggers.
Two - too much endogenously produced d lactic acid (focus of new research). This is a result of heightened methylglyoxal, which accumulates during oxidative stress and impaired glucose metabolism, and which degrades into d lactate. Treatment is somewhat experimental and entails use of supplements to reduce or prevent oxidative stress in general and methylglyoxal in particular.
Three - inability to metabolize d lactic acid (focus of new research). This can result from impaired functioning of the pyruvate conversion process, genetic mutations in LDHD (the d lactic acid enzyme), and/or impaired functioning of LDHD (due to lack of cofactors and/or as a result of oxidative stress). Treatment is highly experimental and speculative at this point but theoretically entails supplementing cofactors to support d lactic acid metabolism and avoiding substances that inhibit enzyme functioning.
I’ll go over all possible treatment options for all three pathways, and then do a quick bulleted summary at the end.
TREATMENT - REDUCING D LACTIC ACID INTAKE
Avoid medications with d lactic acid.
Ringers lactate and propylene glycol (used in liquid formulations of some medications) both contain d lactic acid and can trigger acidosis episodes in susceptible people.
Avoid d-lactic acid producing probiotics and foods.
Lactobacillus probiotics produce methylglyoxal, which is toxic on its own but also degrades into d lactate, and thus should be avoided. Most lactobacillus probiotics also directly produce d lactic acid. Lactobacillus acidophilus is the most common strain used in commercial probiotics and is a heavy d lactic acid producer.
Almost all fermented foods (yogurt, sauerkraut, etc.) will have d lactic acid in its free form, methylglyoxal-producing strains, AND d lactic acid producing strains and thus should be avoided. Many cheeses are also a source of lactobacillus and d-lactic acid producing probiotics and may be an issue for some.
Lactobacillus probiotics and fermented foods, while healthy for normal populations, are often considered to be quite risky for CFS patients in general anyways. Anyone with significant d lactic acid issues should either avoid entirely or use with caution.
Avoid dietary triggers.
Different overgrowths will come with different dietary triggers. Past research has identified simple carbohydrates, dairy/lactose, and/or sugar alcohols as the most common triggers.
Note that carbs are a particular problem for short bowel syndrome patients due to their unique anatomy (their bowels are too short to properly break down carbs, so undigested food winds up in the large intestine where bacteria can ferment it). Thus discussions of carbs are over represented in the literature. A couple of users on this forum have indeed resolved their acidosis with a keto diet. I personally have zero issues with carbs and worsened on keto. YMMV.
An overly restrictive diet can worsen dysbiosis in the long run. Temporary elimination diets may be helpful to identify your specific triggers. Once you resolve overgrowths you may be able to reintroduce some foods.
Oral or IV sodium bicarbonate.
Sodium bicarbonate effectively neutralizes d lactic acid. (It is not always effective against acidosis caused by l lactic acid, though.)
Studies recommend using oral or IV sodium bicarbonate during a flare to calm things down. One can also take oral baking soda regularly as a preventative measure. Some mix baking soda in with their daily electrolyte water.
However regular use of oral bicarbonate can reduce stomach acid, which can cause SIBO in some, which can worsen acidosis and dysbiosis. Delayed release or enteric coated sodium bicarbonate capsules may help mitigate this risk, as studies have shown they have fewer GI side effects.
Adequate hydration.
Maintain adequate hydration to help flush d lactic acid from the body. During a flare IV hydration is recommended, if possible.
Test for bacterial overgrowth.
Doing a microbiome stool test is critical to identifying the species responsible for overgrowth (if any), so that you can target your treatment.
Short bowel syndrome patients are more likely to have overgrowth of lactobacillus bacteria, whereas CFS patients are more likely to have overgrowth of enterococcus/streptococcus. Treatments are different for each.
Once you do a stool test you can upload your results to https://microbiomeprescription.com (run by a person with ME/CFS) to identify your troublesome bacteria and get personalized recommendations.
You may also want to get a SIBO breath test done if you suspect SIBO. Symptoms can include bloating and pain after eating, diarrhea and/or constipation, nausea, and/or vitamin deficiencies.
Antibiotics.
Antibiotics can help clear out bacterial overgrowth. They should be targeted to your specific overgrowth. Be warned antibiotics can sometimes cause severe crashes in CFS patients.
Ideally you should take CFS-safe probiotics that don’t produce d lactic acid during and/or after antibiotic treatment, in order to prevent colonization in the gaps left by antibiotic treatment by unhealthy bacteria.
Herbs.
The use of herbs can be used in conjunction with, or instead of, antibiotics to help clear overgrowth. Herbs should be rotated every 1-2 weeks to prevent resistance. Herbs should be targeted to your specific overgrowth, and should be carefully planned so as to not kill off any probiotics taken at the same time.
Uploading your sample to microbiome prescription will give you targeted advice for the best herbs to take.
Probiotics.
Most of the old research suggests taking l-lactic acid producing bacteria (such as l. casei) to drown out d-lactic acid producers. However this is based on an assumption of lactobacillus overgrowth, which is less common in CFS patients. This strategy is also risky for CFS patients, who are more likely to have adverse effects from lactobacillus probiotics. We are also are already at risk for elevated methylglyoxal levels due to our high oxidative stress, and since lactobacillus produces more methylglyoxal, we can experience even more inflammation and heightened d lactic acid levels.
Better recommendations for CFS patients are:
E. coli probiotics. E. coli produces 2% as much lactic acid as other bacteria. Drowning out the high producers with low producers helps reduce d lactic acid. The two most recommended probiotics for both CFS and d lactic acidosis are Mutaflor and Symbioflor-2.
Probiotics that metabolize lactic acid. Miyarisan (clostridium butyricum) uses lactic acid to make butyric acid. Miyarisan has shown efficacy in studies in resolving d lactic acidosis, and is also frequently helpful to CFS patients, possibly because low levels of butyrate are correlated with CFS severity. Securil (propionibacterium freudenreichii) converts lactate to propionic acid.
Other probiotics that may be helpful are Equilibrium (many different strains to boost diversity) and Enterogermina (bacillus clausii, one of the only low histamine spore based probiotics, does not produce d lactic acid).
Bifidobacterium may help some, but they produce lactic acid and also boost the growth of lactobacillus, so use with caution. Align is the most well studied and is often recommended for CFS patients.
Prescript Assist used to be highly recommended for CFS patients, but the formula has changed and is now supposedly quite dangerous. Avoid.
Faecalibacterium prausnitzii is a next generation probiotic that might be helpful once it’s commercially available. Low Faecalibacterium prausnitzii levels are correlated with disease severity in CFS.
Many other probiotics might be helpful; doing a stool test can reveal what might help your specific microbiome.
As with herbs, probiotics should be rotated every 1-2 weeks to prevent resistance. A potential rotation might look something like:
- Mutaflor
- Miyarisan + herbs
- Enterogermina + herbs
- Symbioflor-2
- Securil + herbs
- Align + herbs
His specific posts on d lactic acidosis: https://www.google.com/search?q=d+lactic+site:cfsremission.com
You can also check whether probiotics produce lactic acid (or contribute to the growth of lactic acid producing bacteria): https://microbiomeprescription.com/library/ProbioticMixtures
TREATMENT - REDUCING ENDOGENOUS D LACTIC ACID PRODUCTION
Quercetin.
Quercetin helps reduce oxidative stress and has been found specifically to reduce levels of methylglyoxal (the toxic substance that converts to d lactate). Quercetin is also a strong mast cell stabilizer. It is a strong MAOI which can sometimes pose problems with agitation and insomnia for those with slow MAOI genes or mental health issues. Supplemental doses for MCAS/HIT are often 500mg/day.
Bromelain.
Bromelain helps reduce oxidative stress. Bromelain is also a mast cell stabilizer. It also is a biofilm buster, which can help herbs and antibiotics work better against bacterial overgrowth. Bromelain can be used in addition to quercetin, or instead of quercetin for those who are sensitive to MAOIs. Supplemental doses for bromelain are anywhere between 50-400mg, 1-3 times per day. Can be taken with meals to aid digestion or away from meals to get the maximum anti inflammatory effect.
CoQ10.
CoQ10 helps reduce oxidative stress. It is also a cofactor for LDHD (the d lactic acid enzyme). CoQ10 is used for many metabolic processes and is often recommended to those with CFS. Many CFS medications reduce CoQ10, including beta blockers, other heart medications, tricyclic antidepressants, and birth control.
CoQ10 supplementation can cause profound insomnia, anxiety, and agitation in some so you may want to start with a low dose. If you tolerate it well or have a higher need to supplement, ubiquinol is the bioactive form and is better absorbed.
Vitamin E.
Vitamin E helps reduce oxidative stress. Vitamin E is also a key inhibitor of ferroptosis (cell death), and has been shown to improve the prognosis of other degenerative neurological disorders.
Since vitamin E is fat soluble it can be dangerous to supplement. Vitamin E supplementation is linked to early mortality. Aim for adequate dietary intake instead, 15mg/day. If supplementing, toxicity begins at 400mg/day but can be lower the longer you supplement. Drops may be preferred as you can take very small doses.
Glutathione.
Glutathione (GSH) helps reduce oxidative stress. It has also been shown to help prevent ferroptosis (cell death). Additionally, it is also an important cofactor for LDHD. Its role across multiple d lactic acid pathways makes it particularly important.
Glutathione supplementation is notoriously tricky. There is a blood test for glutathione so you can monitor how effective your supplementation is.
Here is an article on how to increase glutathione: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10215789/
You can also check other threads on this forum for reports and recommendations on supplementation.
Quick summary of options. You should likely only pick 1 or 2 of these to avoid overloading:
Direct supplementation of glutathione. The most effective forms are also the most expensive. Can cause insomnia and agitation. Tricky to get dosage right. If you’re struggling to tolerate it, some people get an expensive effective form and take a tiny dose of it, and others get a cheaper less effective form so not as much is absorbed. If you tolerate it well and see improvement, you can also get nasal sprays or injections. Be warned that direct supplementation has the potential to reduce your body’s ability to produce its own glutathione; some speculate that it may be better to support precursors/cofactors instead.
NAC. Cysteine is a precursor to glutathione. Studies have shown NAC increases glutathione. NAC can also help other CFS symptoms. However it can cause a strong histamine reaction. It’s also a biofilm buster which could help you tackle dysbiosis but can also trigger strong herx reactions. Monitor closely.
Whey protein isolate. This has cysteine and has been shown to be as effective as NAC at boosting glutathione. Histamine safe and also lactose and casein free. Many with dairy issues tolerate whey protein isolate just fine. The brand Immunocal has published a bunch of studies showing their wildly expensive whey protein isolate boosts glutathione, however most experts seem to agree that any old whey protein isolate will work the same.
Glycine. Studies have shown that cysteine + glycine together are more effective at boosting glutathione, so ideally you’d pair NAC + glycine or whey protein + glycine. Many like magnesium glycinate taken at bed to help with sleep. Warning that while glycine itself is calming it does convert to glutamate which is excitatory and releases histamine, especially for those with lots of “tired but wired” symptoms, ADHD or OCD, or MCAS/HIT. Hit or miss. Use with caution and give yourself a full week or two with no other changes to monitor your response.
Milk thistle. Shown to boost glutathione. Also helps with MCAS. May cause allergic reactions in those allergic to ragweed. Is an MAOI. There is no standardized dose; anywhere between 20-300mg/day seems fine. Do not exceed the safe upper limit of 420mg/day.
Support cofactors of glutathione. These are selenium (in desiccated beef kidney which many use as a DAO supplement; aim for 50-200mcg/day, do not exceed 400mcg/day), sulfur (also helps with salicylate sensitivity, can get through diet or epsom salt foot baths), and vitamin C (do not exceed 250 mg / day so it doesn’t convert to oxalate, camu camu is a low histamine source).
Resolve glucose issues.
Glucose issues are linked to oxidative stress, which increases d lactic acid. Some people with CFS have high blood sugar and some have low. This needs to be tested and treated by a doctor.
Some people with CFS respond well to low doses of Metformin, which can both regulate blood sugar and reduce the toxic methylglyoxal. However, Metformin reduces methylgyloxal by converting it to d lactic acid, and indeed Metformin use is linked to acidosis and has been shown in studies to increase d lactic acid. Use with caution.
Resolve iron issues.
High iron levels are linked to ferroptosis (cell death). This must be tested and treated by a doctor. Excess vitamin C increases iron aborption (as well as converting to oxalate) so you may want to avoid if you test as having high iron levels.
Lifestyle.
Studies have shown CFS patients experience an increase in oxidative stress after exercise, so proper pacing/resting may help. Healthy diet and stress management techniques can also help lower oxidative stress.
TREATMENT - SUPPORTING METABOLISM OF D LACTIC ACID
Low oxalates - diet.
LDHD (the enzyme that processes d lactic acid) functioning is significantly impaired in the presence of oxalates. In fact LDHD is the most sensitive enzyme in the body to oxalate.
Maintaining a low oxalate diet can help prevent LDHD impairment. The Facebook group “Trying Low Oxalates” can help with dietary changes. Many report that reducing oxalates too quickly causes “oxalate dumping” which can worsen symptoms; a gradual reduction is better.
We don’t know exactly how many mg of oxalate is okay for those struggling with acidosis. Those with kidney stones are recommended to less than 100 mg per day, ideally less than 50 mg per day. At the very least, avoiding the highest oxalate foods that have hundreds of mg of oxalate per serving (such as spinach, rhubarb, dark chocolate, and many nuts) might help.
You can track dietary oxalates in the free version of the Cronometer app, you just have to turn it on in settings as it’s hidden by default. The app functions best when you choose generic foods (e.g. “oats”); specific brand name products are often lacking in extra data. Make sure there’s an actual value for the nutrients you’re tracking and not a dash (indicating it’s lacking info).
Low oxalate - calcium.
Calcium binds to oxalates and helps your body get rid of oxalates instead of absorbing them. Calcium can be used in addition to a low oxalate diet in order to give LDHD the best chance at optimal functioning, or calcium can be used to mitigate the damage of a higher oxalate diet if one is unable to adhere to a restrictive diet.
It’s recommended to either take 100-300 mg calcium with each meal, or add powder to your water and sip on it all day.
Calcium carbonate can only be taken with meals and can lower stomach acid (which may help with lactic acid bacteria overgrowth but also could lead to SIBO which can worsen dysbiosis). Calcium citrate is preferred as it can be taken any time and does not impact stomach acid, but citrates can be an issue for those with histamine intolerance.
Note that calcium supplementation is no longer recommended for most people as it is associated with early mortality and can lead to heart problems. Consult your doctor. Keeping your calcium supplementation intake under the RDA (1000 mg / day) and taking vitamin K2 (mk-4 has best results in studies and has a lower risk of side effects) may help alleviate risks.
If you are on medication that impacts your calcium levels (like vitamin D, some POTS meds, or lithium), or have any sort of heart/blood problems, you should get blood work done periodically.
You may also try to increase dietary sources of calcium with each meal instead of supplementing. This can be hard, though, as dairy can sometimes be a trigger for acidosis.
Low oxalate - probiotics.
One can also take probiotics that degrade oxalates. The number one bacteria that degrades oxalates is oxalobacter formigenes. Unfortunately only about 30% of people in the west have any of this bacteria left (it’s killed by western diet and antibiotics), and currently there are no viable commercial probiotics available. However there have been a flurry of new studies on oxalobacter formigenes and we can expect a probiotic to come to market soon. (Note that the “oxalobacter” probiotics sold on eBay have been tested and shown to not contain any of the bacteria. Don’t waste your money - wait for a reputable company to release a good product).
Other probiotics that degrade oxalates include lactobacillus paracasei, lactobacillus gasseri (warning some strains make d lactic acid), bifidobacterium breve, and bifidobacterium longum (Align is the most studied and often recommended for CFS). All lactobacillus and bifido probiotics both produce lactic acid of their own AND promote the growth of lactic acid-producing bacteria, so use with extreme caution, if at all.
Low oxalate - avoid excess vitamin C.
Avoid excess vitamin c supplementation (over 250 mg / day), as the body converts it to oxalate. Excess vitamin c can also increase iron levels which can contribute to cell death for those with high iron.
Thiamine.
Thiamine (vitamin B1) is necessary to facilitate conversion of d lactic acid to pyruvate.
Studies on d lactic acidosis recommend 100mg per day. Higher doses will start to deplete your other vitamins and minerals and thus require following a high dose thiamine protocol.
B1 can help with a whole host of CFS symptoms as well. Unfortunately it can cause histamine issues for those with MCAS/HIT. You may need to try each of the three different forms to find one you react the least to - regular thiamine, benfotiamine, and TTFD. Many with CFS believe the benefits of B1 outweigh the negative histamine reaction and thus make an exception for it. Depends on your tolerability and if you find benefit.
Riboflavin.
FAD is perhaps the most important cofactor for d lactic acid processing; FAD binds directly with LDHD and is necessary for its functioning. The body makes FAD from riboflavin (vitamin B2).
Notably, studies have shown that genetic defects in FAD functioning are characterized by repeated episodes of lactic acidosis, which can be resolved with riboflavin supplementation. Big clue there!
MAO activity, which helps clear histamines and some neurotransmitters from the body, is also dependent on FAD and can be boosted by riboflavin supplementation. So histamine issues could be another sign of low FAD/riboflavin in some. (Those with slow MAO genes need extra riboflavin. Caution, those with fast MAO genes may experience depression on riboflavin.)
Riboflavin supplementation is considered safe even in high doses; it’s almost impossible to overdose on. There are no guidelines for dosages for LDHD functioning, but for migraines patients are recommended 400mg of riboflavin per day. Some people do better with the active form of riboflavin, riboflavin-5’-phosphate (R5P), though it can cause histamine reactions in some. Dosages for R5P are usually 1/2 as much as regular riboflavin as R5P is more bioavailable. The body can only absorb a little riboflavin at a time, so it’s better to take smaller doses of riboflavin 2-4 times a day with at least 1 hour between each dose.
Riboflavin is extremely sensitive to light. Leave in its original pill bottle or use an opaque pill organizer.
Note that boron prevents absorption of riboflavin and can lead to riboflavin deficiency. Boron is in most multivitamins and mineral complexes. Either avoid or take at a separate time from riboflavin.
FAD cofactors: iodine, selenium, molybdenum.
The body uses riboflavin + iodine and riboflavin + selenium to make FAD (which is essential for d lactic acid processing). The body uses riboflavin + molybdenum to make FMN, which then gets converted to FAD. Thus you need all three cofactors plus riboflavin to get FAD. Research on autistic children has linked deficiencies in these three cofactors to decreased FAD activity and resulting neurological issues.
Research has also linked deficiencies in the three FAD cofactors to issues with activating B6 and B12. So imbalances in those vitamins could be a sign of low FAD.
Iodine, selenium, and molybdenum can all be dangerous to supplement. It’s best to increase your dietary consumption instead. You can track all three in Cronometer, though you may have to turn some of them on in settings. If you decide to supplement, keep to VERY low doses. You will likely need to break your pills open to get a safe daily dose.
For all three we are not trying to overload, just trying to ensure adequate intake to avoid being deficient.
Iodine. Too much iodine is extremely dangerous and can permanently damage your thyroid. Unsupervised iodine supplementation is not recommended. Only those unable to get adequate iodine in diet should supplement; if this applies to you check your blood levels and consult a doctor. Iodine is a mixed bag for those with MCAS/HIT. It can prevent the conversion of histidine to histamine, but it can also act as a histamine liberator. Some do better with a little iodized salt at each meal, others with once a day drops, others with seaweed or kelp supplements. For those extremely sensitive to iodine you can try applying iodine drops topically, though it’s unclear how much (if any) you absorb this route. Note that iodine needs selenium to function properly. Aim for 150-300mcg/day. Toxicity from diet or supplements starts at 600mcg/day.
Selenium. If unable to get in the diet, selenium is found in high concentrations in desiccated beef kidney, which notably is used as a source of DAO for those with histamine intolerance. You can also get normal selenium supplements. Selenium toxicity can cause organ failure, and the risk of toxicity increases the longer you supplement. Aim for 50-200mcg/day. Toxicity from diet or supplements starts at 400mcg/day.
Molybdenum. Molybdenum is often low in CFS patients. High levels of copper can deplete molybdenum. Salicylate sensitivity could be a sign of molybdenum deficiency and is sometimes resolved with supplementation. Molybdenum deficiency can also lead to thiamine deficiency (which can also worsen d lactic acidosis, and CFS symptoms in general). If you are unable to get enough molybdenum in the diet, low doses of desiccated beef liver can be a good source (be mindful of overdosing on other vitamins in liver, especially vitamin a; typical serving size is 6 pills but you may just need 1-2). One can also get regular molybdenum supplements. Molybdenum is safer to supplement than selenium or iodine, but it’s still generally not recommended. Aim for 50-100mcg/day. Toxicity starts at 200mcg/day.
Manganese.
Researchers found that LDHD (the d lactic acid enzyme) showed the strongest activity in the presence of manganese. Interestingly a study found that out of all the metals, CFS patients are the most deficient in manganese. Connection?
Manganese can be extremely dangerous to supplement. Supplements can cause Parkinson’s like symptoms and permanent brain damage. Additionally too high of a dose can also deplete your CoQ10 which is needed as well for processing d lactic acid.
Increasing dietary sources of manganese is best. There have been no reports of manganese toxicity from diet alone, even though vegans frequently consume 10x the recommended RDA. Low oxalate and low histamine sources include pumpkin seeds, oats, and fruit. You can track your manganese intake in the free version of the Cronometer app as well.
The RDA for manganese is 2mg, the safe upper limit is around 10mg/day, but even as high as 20mg from diet alone is safe. Given manganese’s importance in LDHD processing and our tendency to be deficient it might be smart to aim for somewhere between 2-10mg/day from food sources.
If you must supplement (not recommended), toxicity begins at 10mg/day but it’s wise to not exceed the RDA of 2mg.
Zinc.
Zinc is an important cofactor for d lactic acid processing. Typical dosages for supplementing are 15-30 mg of elemental zinc (the amount on the back of the bottle). Higher doses can be toxic and can also impede glutathione, which is needed for LDHD. We are not trying to overload (zinc is only a cofactor for LDHD, not an activator like manganese) so you may want to stick closer to 15mg.
Zinc carnosine can help resolve leaky gut, which can also contribute to d lactic acidosis, so it may be the preferred form.
Note that zinc and copper compete with each other. Zinc supplementation often leads to depleted copper. Copper is necessary for DAO production so low copper may exacerbate histamine issues. Copper can be extremely dangerous to supplement on its own and lead to neurological issues. Seeking food sources or low doses (1-2 pills) of dessicated liver may be safer. If you want to supplement copper you should consult your doctor and get your blood levels checked regularly. We are not trying to overload, we just don’t want to be deficient. Take copper 2 hours apart from zinc. Aim for 1.5-3mg/day. Toxicity from food or supplements starts at 10mg/day but it’s wise to not exceed the RDA of 3mg.
CoQ10.
Already expanded on above. In addition to reducing oxidative stress, CoQ10 is a cofactor for LDHD.
Glutathione.
Already expanded on above. Glutathione, in addition to reducing oxidative stress and preventing ferroptosis, is a cofactor for LDHD.
SUMMARY - ALL POTENTIAL TREATMENT OPTIONS FOR D LACTIC ACIDOSIS
Testing:
- Microbiome test to identify potential bacteria overgrowths, upload your results to microbiome prescription to get targeted treatment advice
- SIBO test if suspected
- Blood test for d lactate during a flare, if available (in the US can get through Quest, which sends to the Mayo Clinic)
- Regular blood tests for cofactors / risky supplements / things that easily get out of whack: glutathione (GSH), electrolytes, calcium, zinc, copper, iodine, thyroid, vitamin D, vitamin B6, vitamin B12, glucose, iron/ferritin
- Comprehensive nutrient testing to show all vitamin/mineral deficiencies (expensive, not covered by insurance, and controversial among experts - may not give accurate results)
- Avoid d-lactic acid producing probiotics
- Avoid most/all lactobacillus probiotics (or use with extreme caution)
- Avoid ringers lactate (high d lactate content)
- Avoid propylene glycol (high d lactate content)
- Avoid vitamin c supplementation over 250 mg/day (converts to oxalates and increases iron absorption)
- Adequate hydration
- Low oxalate (oxalate is strongest inhibitor of LDHD), less than 50-100 mg/day
- Avoid your dietary triggers (commonly simple carbohydrates, dairy/lactose, and/or sugar alcohols)
- Avoid d-lactic acid containing and producing foods (yogurt, sauerkraut, and other fermented foods)
- E coli probiotics (produce very little lactic acid): Mutaflor, Symbioflor-2
- Probiotics that metabolize lactic acid: Miyarisan, Securil
- May also be helpful: Equilibrium, Enterogermina, Align, other bifidobacterium
- When commercially available from reputable source: oxalobacter formigenes (to degrade oxalate), faecalibacterium prausnitzii (to produce butyrate)
- Others as recommended by microbiomeprescription based on your microbiome test
- Use microbiomeprescription to see which herbs are best for your overgrowth, and to ensure you couple probiotics with friendly herbs
- Use with caution, can cause severe crashes
- Thorougly research to ensure you get a CFS-safe one and that you’re targeting the correct overgrowths
- High manganese (strongest LDHD activator) - aim for 2-10mg/day from diet, no toxicity reported from dietary sources, do not exceed 10mg/day if supplementing
- Adequate vitamin e (reduces oxidative stress and inhibits cell death) - aim for 15mg/day from diet, do not exceed 400mg/day
- Adequate iodine (FAD cofactor) - aim for 150-300mcg/day from diet, do not exceed 600mcg/day
- Adequate selenium (FAD cofactor) - aim for 50-200mcg/day from diet, do not exceed 400 mcg/day
- Adequate molybdenum (FAD cofactor) - aim for 50-100mcg/day from diet, do not exceed 200 mcg/day
- Adequate copper (to balance zinc) - aim for 1.5-3mg/day from diet, do not exceed 10mg/day
- Quercetin (reduces oxidative stress and methylglyoxal levels) - 500mg/day
- Bromelain (reduces oxidative stress) - 50-400mg taken 1-3 times per day
- CoQ10 (reduces oxidative stress and is LDHD cofactor), dose and form highly dependent on tolerability
- Thiamine / B1 (to convert d lactate to pyruvate) - 100mg/day, try all three forms (thiamine, benfotiamine, TTFD) to see which is tolerated best
- Delayed release sodium bicarbonate (to clear d lactate and prevent/treat acidosis), dosage and frequency dependent on tolerability re: stomach acid and SIBO
- Calcium (to help remove oxalates), no more than 1000mg/day, calcium citrate preferred, take with meals or drink throughout the day, consult with doctor
- Vitamin k2 (if taking calcium to help prevent heart problems), 100mg/day, mk-4 preferred
- Riboflavin / B2 (to make FAD, the strongest cofactor of LDHD), 400mg/day, try both regular riboflavin and R5P, take in 2-4 smaller doses preferred
- Zinc (LDHD cofactor), no more than 15-30mg elemental zinc per day, zinc carnosine preferred
- Direct glutathione supplement/medication, dose and form highly dependent on tolerability
- NAC (+ glycine), dose dependent on tolerability
- Whey protein isolate (+ glycine), dose dependent on tolerability
- Milk thistle, 20-300mg/day
- Supplementation or dietary support of glutathione cofactors:
- Selenium, 50-200mcg/day
- Vitamin C, no more than 250mg / day
- Sulfur, through diet or Epsom salt foot baths / compresses
If all of the above is too much… these seem to be the most important to prioritize first (and conveniently are the safest to try):
- Get a microbiome stool test done
- Avoid d lactic acid containing foods, medications, and probiotics
- Avoid your dietary triggers
- Low oxalate diet
- Rotate CFS-safe and d-lactate free probiotics every 1-2 weeks, potential starting rotation: mutaflor, miyarisan, enterogermina, symbioflor-2, securil, align
- Baking soda as needed to manage acute symptoms, delayed release caps preferred
- High dietary intake of manganese
- Thiamine supplementation
- Riboflavin supplementation
- CoQ10 supplementation
- Glutathione supplementation or support