ME/CFS, COVID-19 Post-Sequelae & Mental Health

The information in this document is a constant work-in-progress from Brandon Gilles, Electrical Engineer who has brainfog from Long-COVID. It’s for infotainment purposes and/or for spurring ideas in the minds of properly-trained, medically-licensed professionals.  Validate any changes in diet, exercise, supplementation, medication or lifestyle with a licensed physician.  

• Don’t want to learn this yourself?

• Book consult at https://www.foodforyourjeans.com/ (paid; who I’m using) or find equivalent.  After I learned all the below I learned enough to know that this resource is years ahead of me, so I’m using them.
• Go to Born Free Community (free; I’m using tips/tests/tricks) and do their protocol.
• Or have someone without BRAINFOG learn it, do all the testing, and apply it for your individualized needs for recovery.

Postulation Summary:

The root of long-COVID, ME/CFS and many unsolved illnesses is a genetic and lifestyle propensity towards immune system dysregulation and systemic inflammation that is triggered via any event that causes an inflammatory response, such as infection, trauma, (prolonged) stress, diet and/or toxin exposure (detailed below), resulting in a cascade and feedback loops of the following:

• Systemic Inflammation, Oxidative Stress & Ischemic Damage
• Gut Dysbiosis, Epithelial Damage, Nutrient Deficiency, Amyloidosis
• Chronic Infection (Bacterial, Fungal, Viral and/or other)
• Poor Bone Health/Metabolism

• Production of poor quality blood that is “aged and poor quality” and
• Platelet activation with amyloid fibrin micro emboli
• Under-production of blood

• Vascular & endothelial damage including systemic calcification and iron dysregulation (capillaries, smooth muscles, brain, etc.)

There are multiple inflammatory mechanisms. As the disease progresses, the main inflammatory mechanism that causes “aged, clotted blood” seems as a result of senescent T-cells (here) which are behaving as if the body were dying/bleeding out. This is largely in response to persistent gut dysbiosis (LPS-dominant, here) and intestinal barrier degradation, likely as a result of thyroid dysregulation (below), dyslipidemia (and sequelae), and subsequent liver dysfunction (NAFLD).  All of this results in the immune system aggressively releasing inflammatory mediators (which very based on genetics; below), oxidative bursts, and triggering excessive clotting as the immune system (rightly or wrongly) tries to clot-off pathogens.  This aged blood (biomedcentral) which includes high amyloid levels, (produced by overgrowth of gram-negative bacteria which produce lipopolysaccharides) leads to dysfunction of multiple organs, most importantly the liver, with progressive NAFLD as the liver deals with the oxidative stress, the toxins from the gut dysbiosis and increased intestinal permeability.  Increased toxin load body-wide further incites inflammation, causes nutrient/electrolyte deficiency/imbalances and body-wide amyloid-fibrin-calcium deposits in the vasculature.  Which then results in systemic dysregulation.  And all of this together then results in further feedback of the above-mentioned issues, which feeds back into further stress on the T-cells, intestinal barrier, increased gram-negative intestinal LPS/Amyloid production, oxidative stress, vasculature dysregulation… and so the cycle continues feeding in multifarious feedback loops, many of which are not yet discovered in this summary document..

The resultant feedback mechanisms of inflammation, thyroid dysfunction, dyslipidemia, gut dysbiosis infection, immune system dysregulation, amyloid clotting, poor blood quality, vascular damage, and calcium/iron deposits then leads to a dizzying array of secondary problems and symptoms (examples below) - which vary per person based on their genetics, lifestyle, and physical/organ structure.  But nevertheless fit with all the major findings of Long-COVID, Nature.  

For those who do not naturally recover (see divergence of response, below), these feedback loops of multi-system dysfunction sometimes result in a continuous and often precipitous downward cycle, resulting in severe ME/CFS (detailed here).

The progression towards amyloidosis, in conjunction with calcium/iron deposits over the capillaries, which are indicative of the poor blood quality, are so small that they are undetectable via normal scans (CT, MRI, XRAY) and blood tests.  New tests (e.g. WebMD, NIH) and old/discontinued blood tests (e.g. blog) both could catch these.  But normal blood tests cannot. There is now an online symptom-based test (apheriscenter) and a blood test at Mount Sinai in New York, WebMD.  

Put in another way, amyloid, combined with fibrin, the smallest of the clotting factors (see them all here) - in addition to calcium deposits - clot over the capillaries throughout your whole body (biopsies here), which in combination with systemic and chronic inflammation from a dysregulated immune system, and importantly - T-cell induced inflammation (via IL-1β, TNF-α, C-reactive protein, etc., test panel Vectra), which is deleterious to blood production and quality (“aged, clotted” blood (NIH)) - reduce oxygen and nutrient delivery to every muscle and organ - causing feedback cycles of fatigue, muscle pain, infection, further gut dysbiosis, and general organ/muscle/brain dysfunction all the way to the mitochondrial level.  

This inflammation-, fibrin-microclotting- and calcium-deposit- induced low-oxygen environment forces the mitochondria to move from aerobic operation to anaerobic, resulting in the often-observed (but not explained) insulin resistance in ME/CFS (e.g. here) as the mitochondria cannot use glucose without the presence of oxygen.  This also explains why mitochondria dysfunction has so often been observed in biopsies ME/CFS patients (e.g. here).

If/as the condition worsens (see divergence of response, here), progressively severe MCAS (NIH) and associated environmental/food sensitivities are triggered as a result of the ischemically-damaged intestinal barrier (ischemic damage from inflammation, clotting, and calcium deposits; figure below).

The resultant low oxygen environment also makes it significantly easier for pathogens of any kind to evade the immune system (which normally uses oxygen as a primary defense, e.g. here), which can then sometimes result in viral and/or bacterial reactivation (e.g here), and explains why so many can recover using hyperbaric chambers (e.g here, NIH) (if and only if they are treated before the vascular damage is severe) and why more serious sufferers develop POTS (NIH).

The combination and dynamic feedback of concurrent (and potentially progressively-worse) issues including progressively-worse inflammation, blood clotting, rampant infections, MCAS activation, poor blood quality, and vascular damage is part of the reason ME/CFS is considered so hard to treat.  

It is possible to treat.  

But it requires early, aggressive, parallel action and attention to the body’s response in a coordinated and monitored approach to make sure that not just one symptom is being addressed, but the root causes are being addressed in parallel.  

The treatment is multi-pronged (detailed below), involving fixing gut dysbiosis, inflammation, energy production, whole body oxygenation, infections, bone health - poor quality blood production, and stopping and reversing the process of calcium deposits in the vasculature..

Ideally, the treatment should be data-driven and targeted per-patient, taking advantage of:

1. Genetic information on propensities for inflammation (TNF, IL-1B, etc. preferably via here, dnasupplementation.com, geneticlifehacks.com, and/or promethease.com)
2. Thorough analysis of (frequent) fecal (here) for gut pathogens and lack of useful bacteria and how to address them (e.g. here) as well as intestinal permeability testing.
3. Organic acid testing via urine (e.g. here)
4. Mineral status (e.g. vis Oligoscan, here)
5. Blood work with

• Specific markets including rheumatology inflammatory markers (e.g. Vectra) that should include TNF, IL-1B, IL-6, cytokine activity, ferritin (e.g here), usable iron to guide what supplements and/or drugs to use to suppress chronic inflammation as well as a detailed thyroid and parathyroid workup by an endocrinologist, preferably also with a Thyroid ultrasound (NIH).
• Viruses and/or bacteria to include EBV, Herpes, Lyme, RSV to guide suppressing the reactivated viruses/bacteria.
• Standard labs such as comprehensive metabolic panel etc. to look for electrolyte imbalances and full liver function workup.  (Noting that magnesium in tissue can be SUPER low while blood work looks normal.)

A good analogy for treating this disease is like finding and treating cancer:

• Attack it with everything you have, as soon as you can, before it gets worse.
• “Do no harm” in cancer would mean not starting treatment and “just seeing what happens”.
• If this disorder is treated early, it is very easy to recover from.  

And that’s the crux of the problem:

• Nearly always this disease is treated by one symptom at a time - by one specialist doctor at a time - instead of being treated aggressively like cancer in a whole-body and monitored way.
• And for many, this means seeing doctor after doctor until (like me) they end up in a bed-bound existence with the potential of no hope of recovery (what this author looked like is identical to here).
• And for millions (e.g. here) this means living what patients describe as “a continued nightmare version of my life” and removal from the workforce (perhaps permanently), e.g. CNN.

Health Engineering

Overall, I think there’s going to be a huge shift in medicine as a result of Long-COVID/ME/CFS where diseases are treated based on the 3 things mentioned above; genetic information, gut biome status, and blood work - and all 3 are factored in to advise overall non-prescription (food, supplement) and prescription (if needed) treatment.  Where individualized health solutions are engineered (designed) per the patient rather than being prescribed based on rote medical-school learnings.

In my self-treatment, I’m piecing this together using disparate tools, but the whole process can and will be fully automated, which is uniquely possible now that we are in the “Age of AI”, here, where literally millions of data points can be pieced together to produce an engineered health solution (e.g. here, here).  (Note that this author leveraged ChatGPT (3.5, 4.0) extensively in piecing this understanding together.)

The discoveries from the waves of startups that attack this problem and subsequent automation will likely solve most/all mental illnesses and neurodegenerative diseases in the coming decades, resulting in a significantly longer health-span, and likely also productivity-span.

A Note on Severe ME/CFS

If the above postulation holds water then this disorder in its severe form (which effects about 25% of ME/CFS sufferers, here) is of the same nature as Lupus.  Lupus, which carries nearly all the same symptoms and immune dysregulation as severe ME/CFS, is put into remission via CAR T Therapy (e.g. here, details below).

And therefore CAR T Therapy (e.g. here, details below) is likely have a meaningful impact on the quality of life of severe ME/CFS patients (e.g. here), if not put them back into full remission, when used in parallel to treatment of all the parallel facets of the disorder.  

For why the author thinks this:

• T-cell stimulants (such as AHCC, NIH, NIH) (which acts via IL-1B) resulted in:

• The condition overnight getting severely worse.  
• Nearly unbearable pain and flares of all symptoms.

• T-cell suppressants (e.g. Rapamycin, NIH, and supplements below) resulted in:

• The condition overnight improving, and continuing to improve (but at great risk to the author, as Rapamycin carries immunosuppressive risks).

So with proper care, even the most severely impacted patients can likely be recovered.  

And for non-severe, (natural) anticoagulants and natural supplements, below, will bring most back to full health.  

Triggers

The triggers for this disorder seem to be the following:

1. Viral or bacterial exposure (listed in order of severity):

1. SaRS (2003)
2. LymeWest Nile
3. COVID-19
4. Epstein Barr
5. RSV

2. Trauma

1. Surgery
2. Childbirth
3. Internal organ damage

3. Food poisoning

1. Bacterial or Fungal

4. Prolonged Stress
5. Environmental Toxins

1. Mold
2. Heavy metal poisoning
3. Volatile Organic Compounds - VOCs (in water or air)

Most commonly it is 2 or more of the above that trigger the disorder.

For example, in my case, I had COVID-19 in early 2020 with no discernible change in quality of life, aside from “floating” anxiety (a sign of inflammation in the brain) for a month or two after my COVID-19 infection.

But then June 12th 2021 I had trauma to my small intestine, which initiated my downward spiral.  

The Nature of the Disorder

Triggered Chronic Inflammation

Short-form description of the disorder:

1. The triggers result in chronic inflammation, Vagus nerve dysfunction, thyroid dysfunction, resultant GI dysbiosis, high toxin load potential resulting in methylation depletion, poor blood quality, and excess fibrin/calcium/iron clotting of the vasculature including  capillaries resulting in low oxygenation and nutrient delivery to the whole body.  
2. This causes fatigue, brain-fog, and just general malaise that worsens with activity.
3. Opportunistic pathogens take advantage of the thyroid dysfunction, gut dysbiosis, low-oxygen environment and the resultant compromised immune system. here
4. The increased pathogenic load (viral, bacterial, and/or fungal) in the gut and body-wide often result in further triggering of the disorder.
5. The body progressively goes further into a mode of panic as a result of the above, eventually resulting in progressively-more-severe systemic inflammation
6. Eventually MCAS sensitivities occur, poor blood quality (“aged blood”) and severe gut dysbiosis all contribute to vascular damage, more restrictive diets, and worsening energy, methylation saturation and thereby toxin-removal capability of the body.
7. Feedback loops then occur at all levels above.  With a divergence in response based on genetic and lifestyle propensity for inflammation.

There’s a huge divergence in response per patient (more below).  

For some, the cycle self-corrects, for others, they are held at a lowered quality of life (long-COVID), and for the worst, the cycle gets progressively worse until fully bed-ridden or close to bed-ridden (severe ME/CFS, POTS, Fibromyalgia).  For those that self-correct, they may never get to the state of severe inflammation/MCAS.

In all cases, the symptoms vary wildly from patient to patient, depending on which organs or portions of the body are impacted worst by the inflammation and microclotting and the severity of the genetic propensity towards this disorder.  Some have predominantly neurological symptoms, some have predominantly pain, and others suffer primarily from mental symptoms (brain-fog, etc.).  It all comes down to which organs are most severely impacted.  

For me, it all started in the gut after trauma to my small intestine, which was 1.5 years after getting the first-wave COVID.

Long-form description of the disorder:

The triggers result in systemic inflammation which over time causes broad multi-organ dysregulation and eventually full-blown immune-system dysregulation. The “starting state” of each individual determines how the body responds (E.g. what dormant viruses (Epstein Barr, Herpes, Chicken Pox) are residing in the body.)

But generally two significant events occur in most everyone:

Vagus Nerve, Inflammatory Neuropathy, and Acetylcholine Depletion

The ganglionic receptors of the Vagus nerve are depleted as a result of the inflammation itself body trying to fight the inflammation.  This results in initial symptoms of dry eyes, lower gut motility (indigestion), and high anxiety (as the Vagus nerve calms the body, balances fight/flight).

This triggers lower GI motility which increases GI inflammation, and makes the body more prone to intestinal dysbiosis and pathogenic growth.  Which in turn can be a vicious cycle of continued inflammation, worse gut dysbiosis, and so on.  Depending on how the body can cope (e.g. genetic and lifestyle propensities), this is one of the main reasons for the divergence in response/recovery patient-to-patient, detailed below.

In addition to the depletion of Acetylcholine, the nerve itself suffers inflammatory neuropathy, similar to other peripheral (non-spinal-column) nerves.  See below for ways to counteract both of these.

Thyroid Dysfunction

It is seeming more and more likely that of the first-hit organs among the Chronic Inflammation are the thyroid and parathyroid.  

On the daily there are more examples in the literature (found in and reproduced from the Butterfly Method) of thyroid dysfunction in response to the COVID-19 spike protein.  A short list of examples (from Butterfly Method) is below:

• NIH, NIH2, NIH3, NIH4, NIH5, NIH6, NIH7, NIH8
• Springer1, Springer2, Springer3, Springer4, Springer5, Springer6
• ScienceDirect, ScienceDirect2, Wiley, lww, liebertpub, Tandfonline, Oup, ingentaconnect, BMJ, tandfonline, MDPI

And the Butterfly Method, which heavily agrees with Dr. Teitelbaum’s postulations on the disorder (i.e. they’re thyroid-induced) has compiled this amazing comparison of Long-COVID/ME/CFS cases and compared them to thyroid cases.

Butterfly Method Figure 3. Long Covid survey compared to age distribution of thyroid cases in a hospital survey 

Thyroid-Dysbiosis Feedback Loop

And in conjunction with damage from other inflammatory mechanisms and infections, is likely one of the leading contributors to the gut dysbiosis and intestinal damage (NIH).  As thyroid dysfunction causes bile salt production disruption (NIH) which causes improper breakdown and indigestion of all food products, resulting in a shift from digestion in the small intestine to fermentation in the small intestine (NIH), which is also commonly seen in neurological diseases of which ME/CFS/Long-COVID mimics (e.g. Alzheimer’s, NIH) and often results in pathogen overgrowth, notably Candida Albicans, typical of IBS (here), which itself contributes to thyroid malfunction (here).

And if/as the condition worsens, this feedback loop of thyroid malfunction is worsened by the inflammation caused by the GI dysbiosis (NIH), which results in malabsorption. And malabsorption is a key contributor to furthering the gut dysbiosis - as food is left to bacteria to ferment rather than being digested and absorbed by the body (here), resulting in SIBO and subsequent intestinal damage and inflammation.  And malabsorption can further limit the nutrients the thyroid needs to properly function.

Interestingly, and most importantly, the thyroid and the Vagus nerve are the two most important tools at the body’s disposal to maintain motility, proper digestion, nutrient absorption, overall a healthy GI system/microbiome and thereby prevent GI dysbiosis.

And both become compromised as a result in individuals who have this genetic and/or lifestyle propensity for inflammation in response to the trigger(s) above (e.g. COVID spike protein).

And this combination of compromised function then can causes a severe disruption to intestinal motility (e.g. GERD, acid reflux, constipation, diarrhea, reduced appetite, food intolerances, malabsorption, malnutrition, gastro- or intestinal-paresis, etc.), which can become a progressive feedback loop of inflammation, further inflammation and damage to all organs discussed, and further dysbiosis.  

Thyroid-Pulmonary Feedback Loop

Thyroid dysfunction, both hypothyroidism and hyperthyroidism cause respiratory muscle weakness and decrease pulmonary function, and if severe, sleep apnea and pleural effusion (here) in hypothyroidism (which the author of this has often experienced; it’s a horrible feeling).

The low oxygen environment produced by thyroid malfunction then becomes another source of inflammation, which itself has consequences body-wide, but damages both the pulmonary and thyroid/parathyroid systems.

Thyroid-Dyslipidemia Feedback Loop

The Thyroid is the organ responsible for maintaining health lipid levels in the blood and hypothyroidism results in a tendency towards Dyslipidemia (e.g. Mayo).  As the dyslipidemia worsens, increasingly more AGEs are formed as a result of increasingly-more diabetic response to blood sugar, lowered sensitivity to insulin (as from inflammation, clotting, and endothelial damage) which result in oxidative damage, further causing hypothyroidism and Dyslipidemia.

And then this is worsened by a resultant change in diet, often to try to mitigate the short-term effects of the gut Dysbiosis, below.

Dysbiosis-Liver-Diet Feedback Loop

As the SIBO and/or gut dysbiosis worsens, more load is put on the liver.  And as SIBO worsens, the overgrown bacteria in the small intestine consumes the fiber that should be feeding the (beneficial) bacteria in the large intestine.  

Without sufficient fiber in the large intestine, the butyrate-producing bacteria in the large intestine start to die off, and non-butyrate-producing bacteria start to take over (MDPI).  This results in poor intestinal barrier function in the large intestine, as butyrate is responsible for feeding the intestinal barrier and keeping it healthy with tight junctions, which then puts even more load on the liver.

The liver is what is responsible for removing Amyloid from the blood, and with the liver under constant stress, and progressing further into NAFLD, it is progressively unable to do so - resulting in higher an higher concentrations of Amyloid in the blood, and organs body wide.

So the gut dysbiosis worsens, this often drives the sufferer to avoid fiber, as it feeds the bad bacteria in the small intestine, which causes pain and inflammation.  Avoiding fiber generally leads to a progressively higher-and-higher fat diet, which is then harder on the liver, reduces the amount of beneficial bacteria in the large intestine, resulting in non-beneficial bacteria taking over the large intestine, resultant worse nutritional state, resultant poorer performance of the intestinal barrier - all 3 of which independently put more load on the liver, resulting in it being unable to properly detoxify the body and remove Amyloid from the blood.

This also fits with why many have recovered from this condition by going 100% vegetarian, with an aggressive anti-SIBO regime while supplementing good bacteria in the colon (i.e. FMT, probiotics, probiotic enema), as all 3 independently reduce load on the liver.  And why many have recovered (if they have sufficient methylation epigenetics) by aggressive use of Niacin (as it can remove Amyloid from the blood in lieu of the liver doing it).

Multiple Parallel Feedback Cycles

And if the cycles above - and these are just few of likely many not-yet-understood by this author -  are not broken - either by the body itself, or intervention, or both - then this leads into a cascade of further loops of problems, which also are feedback loops to the above dysfunctions.

1. Overproduction of fibrin, the smallest portion of blood clots (made with fibrinogen, see Figure below) in the body concurrent with exhaustion of the enzymes (kinases) that consume the fibrin, and progressively worse blood quality as a result of IL-1β’s impact on the body’s capability to produce high quality blood (see example here).  

1. The above results in capillaries (the smallest of the vasculature in the body) being covered over by fibrin and/or inflamed shut.
2. This results in organs/muscles/etc. not receiving enough oxygen from red blood cells.
3. And this low oxygen state has several negative impacts:

1. General fatigue (oxygen is what allows the mitochondria to operate aerobic instead of anaerobic).
2. Rampant infections, including viral, fungal, and bacterial.  The reason is twofold:

1. As a result of the clotting, the immune system itself has less oxygen to use for energy to fight infections.
2. The immune system has a harder time getting to infected tissues, as similar to the red blood cells, it is blocked at the capillary level by inflammation and/or micro-emboli.

3. Body entering further levels of distress (measurable with low heart rate variability) and visually evidenced by progressively-worse inflammation.
4. Insulin resistance and diabetic-like response to sugar, which fits with the significantly-increased risk of developing diabetes following COVID infection, here.  (Recall that mitochondria in the absence of oxygen go anaerobic, and thereby do not consume glucose, here.)

4. Important Diagnostic Note: One easy way to measure the low oxygen state is to read out the perfusion index say measured at the fingers, or best, toes.  A normal/healthy person will be significantly higher (usually by 10x) than someone suffering with this microclotting/microcirculation disorder.

1. I am 0.3 typically at my thumb (using this), whereas healthy volunteers are typically 5+.  
2. And Sp02 measurement devices cannot get a reading at my toes.  Whereas in healthy volunteers the toe readings are identical to fingers.
3. Both of which are quick/easy indications of microcirculation issues.

2. If 1 is not stopped (see Divergence of Response below), then overproduction of Histamine occurs as the body goes deeper into a stressed/panicked state and begins to enter severe MCAS territory - with associated sensitivities to foods, chemicals, and pharmaceutical fillers/dies/etc..  (Again, you can monitor HRV decreasing over time during this, which I have a full log of myself over 3+ years.)
3. The overproduction of Histamine/MCAS/IL-1β inflammation (more here) results in a vicious cycle:

1. General inflammation body-wide (including the the brain - brain fog)
2. Lower absorption in the small intestine, resulting in malabsorption/malnutrition/vitamin-deficiency.
3. Ischemia-reperfusion injury to the intestines (here) which reduces gut motility - resulting in higher likelihood of SIBO and Candida - and further reducing absorption.
4. Red Blood Cell (RBC) and vascular damage resulting High ferritin levels (400 to 500 in my case) while usable iron in the blood is low as the body tries to keep up with blood production in the face of RBC damage and malnutrition from b.
5. The loss of red blood cells convinces the body that it is indeed bleeding out, the response-to-which is (1) more fibrin is release, and (2) a stronger Histamine/MCAS response, and the cycle continues.
6. The IL-1β inflammation and fibrin deposition leads to multiple mechanisms that result in poor blood quality and low oxygen-carrying blood volume. And the (progressive) MCAS results in inflammation which further reduces oxygen perfusion - perpetuating the downward cycle.
   It is important to note that here we are referring to the total amount of  oxygen-carrying blood in the body, which cannot be measured with blood samples.  The way to measure include radioisotope testing (e.g nuclear medicine imagine as mentioned here and here) or a total blood transfusion where blood volume is measured. NIH on the fibrin deposition here.

1. First is the near-constant overproduction of histamine to fight the clotting.

1. The histamine levels are sufficiently high to damage or destroy red blood cells and damage the vasculature (e.g. here).  
2. And these levels also damage the vasculature.

2. Second is malnutrition.  

1. The inflammation results in intestinal malabsorption which results in malnutrition, and in severe cases (like mine) constant weight loss.  
2. The malnutrition results in the body having a harder time producing red blood cells (and likely equally, plasma).
3. Specifically, in blood tests of those impacted, usable iron will be low (as the body is trying to replace destroyed blood) while ferritin is high (which eliminates hemochromatosis as a cause of the issue - and many doctors will expect hemochromatosis given the high ferritin).

3. Third is the process of blood production itself.  

1. The persistent IL-1β inflammation impacts the mechanisms through which blood is produced from stem cells in bone marrow.  
2. This same phenomenology is observed in regular aging.  See here.  In severe ME/CFS you feel like a 100-year-old, and the blood process seems nearly identical.
3. “Treating elderly patients with anti-inflammatory drugs blocking IL-1B function should help with maintaining healthier blood production.”

7. Interestingly, severe acute COVID cases have resulted in emergency authorization of Kineret® (Anakinra) here in treatment of such patients as it is understood that IL-1β inflammation and commensurate macro-clotting is what quickly results in hypoxemia and death in severe acute COVID-19 patients.

1. Which further reinforces the author’s postulation that a “slower burn” version is at the root of post covid sequelae and ME/CFS.

The Divergence in Response

There seems to be 3 categories of body responses once the disorder is triggered:

1. Natural recovery.  High-anxiety, fatigue/malaise may last weeks, months, or years after COVID, and the body naturally recovers with rest and relaxation.

1. The body over time regains the capability to clear reduce the inflammation, clear the clots, and restore healthy blood production, returning to normal health.

2. Steady-state reduced quality of life/energy.  The body seems to find an equilibrium of malaise and stays there.

1. The body stays at an inflamed/clotted level, getting neither worse nor better.
2. This class is likely treatable with supplements and OTC medications only (i.e. no prescriptions required)

3. Continual downward spiral.

1. In this case, the inflammation, clotting, infection, inability to produce healthy blood and malnutrition continually get worse until organ failure occurs (heart attack, liver failure, intestinal failure, or aneurysm/stroke), usually after years of slowly losing physical and mental capabilities.
2. This case usually requires supplements and prescriptions in an aggressive regimen of anti-inflammatories (MCAS stabilizers), anti-coagulants, immune support, and  IL-1β suppression (e.g. Anakinra or similar; or HELP Apheresis, here) to stop the inflammation, improve blood quality, and improve microcirculation and body-wide nutrient delivery.  
3. Once the cycle is mostly broken, treatment can then be continued with vascular dilators to clear out the remaining excess fibrin.

And it’s worth repeatedly stressing that the impact of the inflammation, poor blood quality, and clotting varies extremely per person.  

This is why the disease is so confusing.  

In some, the brain may be impacted the most (brain fog, or anxiety, non-sequitur thinking, mental disorders, with no other (noticeable) symptoms.  

In others, unexpected heart attacks while otherwise young/healthy may occur (e.g. here) and other symptoms may note even be noticeable.  In others, dysautonomia.  Others, severe food intolerances.  Others, strange neurological symptoms.  

This is because it all depends on which organs, per person, are most susceptible to the clotting and inflammation - as well as the severity of genetic propensity - and the individual’s diet, stress, and environmental factors.  And often the less-severe symptoms may not even be noticed by the patient (in the face of the more severe symptoms).

The Overall Approach to Treatment

Recovering involves going after a cascade of problems, with varying degrees of aggressiveness, depending on the severity of the patient.

The approach involves treating the following in parallel as they all feedback on eachother:

1. Chronic Inflammation
2. Poor/Aged Blood Production Quality
3. Excess Fibrin Coagulation
4. Gut Dysbiosis, Dysregulated Immune System and Thyroid/Parathyroid
5. Damaged and Calcified Vasculature

Note that if the disease is not progressed far, the supplement-only approach will work and likely only A, B, and C are needed.  And in light conditions, even A alone with supplements only is enough.

In fact the supplement-only approach of A, B, and C worked on me very effectively (from 1 minute walk capability to 30 minutes of walking and 30 minutes of biking).  Unfortunately at that time I was not confident in my self-treatment and a team of doctors who were treating me for POTS (a secondary condition) convinced me to abandon this self-treatment plan, and over 10 weeks I got very sick following their treatment.  After which I re-initiated my self-treatment plan and started to improve again - but in those 10 weeks I had become severely ill (lost 45lbs) - so I am now on prescription approach and starting to improve again.

A.   Treating Chronic Inflammation:

The main inflammatory mechanism in this disease is Histamine released from a variety of sources, by the potent proinflammatory interleukin cytokine IL-1β and TNF-α seem to be common.  

The mechanisms vary per person, so performing a blood test for Rheumatology inflammatory markers (e.g. Vectra; and see table below) is advised for targeted treatment in parallel with genetic testing is highly recommended, along with leveraging Genetic Lifehacks, here to decode the meaning for diet, supplements, and drugs to help you recover, based on your genes.  And one requisite aspect of getting inflammation down and keeping it down is rebalancing your gut Microbiome, which often means checking (and understanding) the current state, which can be done with Microbiome Prescription, here, with details below.

Source NIH; found via GeneticLifeHacks, here.

Either way, as the disorder progresses, the inflammatory mechanisms result in progressively poorer blood (clotted, aged) being produced, calcium and ferritin dysregulation, which then triggers even more MCAS/histamine release to break blood clots (NIH).  

So the core focus for anti-inflammatories should be based around your epigenetic inflammation tendencies, but generally involves supplements that reduce or consume histamine, and foods that are anti-histamine (and for sure not high in histamine), but with a particular focus on inhibiting IL-1B, as it seems very common.  A reference on MCAS treatment is here.

However, it is critical to stress that we need to treat not only MCAS.  That is to say, MCAS is a result of the clotting disorder and the clotting disorder is a result of MCAS (and IL-1B).  And one of the trickiest parts is that some of the traditional treatments for MCAS actually trigger the clotting disorder, and vice-versa.  So when taking anything to treat MCAS, double-check to make sure they do not trigger the clotting disorder.  An initial list of which is here.  But please double-check anything you take to make sure it is not a trigger for the clotting disorder - as it is the root of the problem - so triggering it makes all secondary syndromes worse.

And note that this process of getting MCAS/histamine inflammation down is SLOW; 14-30 days to see an impact on histamines in the body, from here (and this fits my experience).  And generally the mast cells (and mast cell signaling system including cytokines and leukotrienes) are having to be retrained over time to be less over-active.  

And before starting any supplements, see Advice on (Self) Treatment here.

Resources

Much of the information below is pulled from the resources below, and then I am in the process of cross-checking the recommendations against if they cause other adverse reactions, here.

• Genetic Lifehacks, here - focus on decreasing inflammation based on genetic propensity
• Hoffman Centre, here - focus on overall MCAS treatment
• Carlos Tello, PhD, here - focus on Leukotriene inhibitors
• Swiss Interest Group Histamine Intolerance (SIGHI), here - excellent overview of histamine triggers for supplements and foods
• Histamine Intolerance: The Current State of the Art, here - concise literature review on histamine intolerance, diagnostics, and recommended treatment options
• Younique Healing and Herbals, here - which has an EXCELLENT summary of various herbs/spices and their impact on Mast Cells, H1, H2, DAO, Leukotrienes, ATP, and Prostaglandins.
• From Fatigued to Fantastic by Dr. Teitelbaum.
• The Butterfly Method, here

Inflammation, Oxidation and (Lack of) Cellular Energy Production

And before jumping into it, a background on energy supplementation, gut inflammation, gut dysbiosis, and excess inflammation and histamine release - as they are all tightly related.

And to explain this, let me use ChatGPT, as it can do it better than me, about what cAMP is, and why it’s important.

“Cyclic AMP (cAMP) is a molecule that plays an important role in a wide range of biological processes in the body. It is a type of second messenger, which means that it acts as an intermediary between external signals and the internal response of a cell.

cAMP is formed from ATP (adenosine triphosphate) through the action of an enzyme called adenylate cyclase. It is involved in the regulation of numerous cellular processes, including energy metabolism, gene expression, and the response to various hormones and neurotransmitters.

When a cell receives a signal, such as a hormone or a neurotransmitter, it triggers the activation of adenylate cyclase, which then catalyzes the formation of cAMP from ATP. cAMP then goes on to activate a variety of protein kinases and other signaling molecules, which ultimately leads to changes in cellular function.

cAMP has been implicated in a wide range of physiological processes, including the regulation of blood pressure, insulin secretion, immune function, and memory formation, among others. It is also an important target for pharmacological interventions, with numerous drugs designed to target cAMP signaling pathways for the treatment of various diseases and conditions.”

And recall that in ME/CFS, mitochondria dysfunction is always found (which is a result of low oxygenation, and inflammation), resulting in low ATP.  So in ME/CFS.  Which means cAMP will be low in ME/CFS patients because of the chronically-low ATP.

And further, activity requires ATP (it's the energy of cells).  And in ME/CFS, there is post-exertional malaise because ATP is used up.  And generally, inflammation is found to be high after activity (which lowers oxygenation and ATP production).  

Now, we’ve established why ATP is low, resulting also in low cAMP.

Now how does cAMP relate to inflammation? 

• cAMP regulates the release of histamine.  
• Low ATP -> Low cAMP -> High histamine release -> high inflammation
• High ATP -> High cAMP -> Low histamine release -> low inflammation

cAMP regulates pro- and anti-inflammatory activities: drugs that elevate intracellular cAMP levels reduce the production of pro-inflammatory mediators and increase the production of anti-inflammatory factors in numerous immune cells. Source: NIH.  

So then the key to getting out of this disease is revolves around all 5 things (Chronic Inflammation, Poor, Excess Fibrin Coagulation, Suppressed Immune System, Gut Dysbiosis and Damaged Vasculature), but one core part of that is supplementing and pacing such that:

1. The body can make more ATP in a day than is consumed.
2. The body has enough nutrients to make cAMP, to then reduce inflammation.

And to further compound the problem, the above indicates that more ATP is needed to prevent histamine release, but more ATP is also needed to clean up the excess histamine in the body.  This is because the methylation cycle is what is used to consume histamine, and the methylation cycle consumes ATP to accomplish this clean up of histamine (NIH).  And worse, depending on your genetics and (restricted) diet, you may not have enough methylation capability, even if enough ATP is present because of the viral/bacterial/fungal toxin load on the body and the necessitated use of methylation (primarily by the liver) to clean out toxins, more below in the Removing Toxins section.

And to compound the problem even further, as yet another example of how and why energy supplementation is needed, during chronic infection (bacterial, fungal, or viral in the GI system, viral in blood/tissue, etc.) the body uses what’s called a respiratory burst as one of the primary ways of fighting infection(s).

And a respiratory burst requires a 10 to 20 fold increase in oxygen consumption through NADPH oxidase (NOX2 in humans) activity. And NADPH is the key substrate of NOX2, and bears reducing power. Glycogen (which has been shown to be short in ME/CFS; NIH) breakdown is vital to produce NADPH. This occurs via the pentose phosphate pathway. (Wikipedia)

And NADPH is one of the key sources of energy in the Citric acid cycle (Krebs cycle) which is how the body produces ATP reproduced below from Wikipedia.

So to fight the chronic infections, the body is:

1. Consuming the key feeding element to the production of ATP, NADPH, which is the core energy source for the body.
2. Consuming 10-20x the normal oxygen during this process.
3. Producing a tremendous amount of reactive oxygen species (ROS), which are then inflammatory and destructive to all tissues around them via oxidation.
4. While in parallel releasing Histamine to fight the infections, which further depletes ATP to clean up.
5. And depleted ATP results in a low cAMP, which triggers even more Histamine release, tissue damage, oxidative stress, ATP use, and and the cycle continues.

And this depletion of NADPH, and its positioning in the Citric Acid Cycle (ATP production cycle) explains why Oxaloacetate supplementation is so beneficial in ME/CFS/Long-COVID patients (NIH), as supplementing that makes up for the virus/bacteria/fungal-infection-inducted deficit of NADPH (as Oxaloacetate is normally made from NADPH, and supplementing Oxaloacetate bypasses this process entirely).

And this further explains the deficiency of Glutathione, Vitamin C, and CoQ10 in ME/CFS/Long-Covid patients (e.g. NIH, NIH2, NIH3) (and why supplementation helps), as these are the anti-oxidants the body utilizes to clean up oxidation after a respiratory burst to attack bacterial/fungi/virus load.

So in short, the persistent infectious load:

1. Uses up your oxygen and energy supply while your body fights the infection.
2. Uses up your antioxidants as your body tries to clean up the oxidation.
3. Causes systemic inflammation from the oxidation.
4. Causes system cell damage and death from the oxidation.
5. Locks the main control-signal for inflammation into inflammatory overdrive.

And all this reinforces that one of the keys to getting inflammation down is helping the body produce ATP, which entails getting the mitochondria what they need to produce ATP.

That sounds simple, but making it happen is the very difficult part, particularly if you (or your loved ones) have severe ME/CFS.

And note that this is why the multi-pronged approach is needed, as Broccoli and Cauliflower extracts (see below for details), for example, are high in the ingredients that the body needs to make cAMP (which suppresses histamine release) from ATP… however, if the body is short on ATP, then it cannot adequately produce cAMP - and so adding Broccoli and Cauliflower would not help (and might hurt).  And this is why the whole picture needs to be taken into account.  Broccoli and/or Cauliflower are a necessary but not sufficient condition to lowering inflammation.  As (1) ATP is needed, and is lacking w/out energy supplementation, (2) gut dysbiosis may actually result in bad bacteria feeding off of broccoli/cauliflower before the host can, and (3) if both are given without energy supplementation, they’re a net energy/digestive consumption of ATP.  

So in parallel to taking supplements that reduce inflammation, as below, it is important to take supplements that help the body produce ATP while also balancing your gut microbiome to make sure helpful bacteria are being fed by the supplementation rather than pathogenic bacteria, while continuously lowering the proportion of inflammatory bacteria (and fungus; Candida) in the intestines.

Given all the above, and since it is well known that ME/CFS and Long-COVID’s main symptom is low energy, post-exertional malaise and lethargy, let’s start with energy supplementation.

Non-Prescription Supplements

Energy Supplementation

Energy supplementation is necessary because of the vicious cycle of inflammation, malabsorption, low oxygenation (switching mitochondria to anaerobic), constrained diet (because of SIBO/SIFO), and many other factors among the feedback loop of this disorder.  

The goal of energy supplementation is to help the body make ATP even in the face of this low oxygenation, to bootstrap the process.  And to do that, supplements that make it easier for the Mitochondria to properly use oxygen to make ATP are necessary.  Summarized below.

A note on timing of mitochondrial enhancers:

They fundamentally increase your metabolic rate (which should be lowest during sleep) as they are forcing your mitochondria to consume oxygen and sugar to make ATP (the primary energy source for the body) and therefore should be taken earlier in the day (depending on their half-life) as otherwise they can:

1. Cause sleep disturbances and/or
2. Cause low oxygenation at night if you have sleep apnea or inflammatory-induced lung damage

Oxaloacetate

• Sources: NIH
• Dosing:

• 500mg to 5grams per day, need one without Vitamin C, like here

Astaxanthin

• Dosing:

• ~12-24mg/day, a mitochondrial antioxidant per NIH, available here, here
• If using ValAsta, here, see vendor-specific notes in the addendum, below

Vitamin K2

• Multifarious multi-system benefits NIH, Science 
• Dosing:

• 100-300mcg Mk7 per day
• 15-45mg Mk4 per day

NMN

• Dosing:

• ~250mg/day

Nicotinamide Riboside (NR; “Niagen”)

• Dosing:

• ~300mg/day

PQQ

• Dosing:

• ~20mg/day, source here
• Best in morning as it may re-align circadian rhythm per ResearchGate, 1 and 2
• Warning: Some sources say decreases glutathione, which is a master anti-oxidant

D-Ribose,

• Dosing:

• 5 to 15 grams per day

Malic Acid (Magnesium Malate)

• Dosing:

• 500mg to 1.5g per day Magnesium Malate

• Warning: Taking Malic Acid directly is the riskiest energy supplementation technique as it can worsen intestinal barrier function as it is acidic (here), and those with this disorder usually have compromised intestinal barrier function and are extremely sensitive to acids.

• Magnesium Malate is the preferred ingestion as it is less acidic in the GI system, while still supplying Malic Acid to the body for energy, and is often the supplement of choice for improved energy production (e.g. here)
• Dr. Teitelbaum recommends this specific Magnesium Malate, MagSRT here from Jigsaw Health as a way to get magnesium, significant amounts of Malic Acid (1.4 grams divided by 4 pills).

• Found via here, which goes into significant depth on the types of magnesium.

Carrots

• Raw Carrots  - Organic preferred, fresher the better, washed, but not peeled (to leave the biome intact)

• Carrots, when fresh, and picked while still growing, are chocked full of all of the energy sources mentioned above.
• And they have multi-organ and multifarious (per-organ) benefits system wide, discussed in pertinent sections in this document below.
• Note that initially carrots will not provide any energy boost, as for the first several weeks to months of consumption they’re value-add will be in helping the body to rebalance the GI microbiome, in a slow, anti-inflammatory way.

• Details and links as to how this is accomplished are in each pertinent section.
• But importantly, if you notice undigested carrot in your stool, that means the process is working… as carrots are very resistant to bacteria and fungus, and are slowly killing the bad bacterial and fungal overgrowth in your small intestine while absorbing the resultant toxins back into the carrot chunk that you will see in your stool.
• Over time, as the GI microbiome starts to restore, you’ll notice progressively more-degraded chunks of carrots until they may entirely disappear.

• Once the GI microbiome is restored, the energy benefits of carrots start to be realized, but more importantly, this rebalance will allow an increased consumption and variety of foods, which becomes a positive-feedback loop to health.

And note that anything that either (1) increases oxygenation (e.g. reducing inflammation and/or reducing clotting) or (2) reduces glycation will help the body produce ATP, as mitochondria will naturally produce ATP in the presence of glucose and oxygen.  The clotting and inflammation is what is preventing the mitochondria from effectively producing ATP (by forcing them into anaerobic, i.e. no-oxygen, cycle, which effectively results in more energy consumption than production).

And this explains why hyperbaric chamber time has been so beneficial in recovering from ME/CFS/Long-COVID (e.g. here) - it helps the body produce ATP, which then enables cAMP production.  (Note that hyperbaric chambers can be harmful if you are far-progressed into endothelial damage; e.g.. have POTS symptoms, as the pressure change can do further endothelial and/or capillary damage and encourage further vascular leakage.)

For reducing inflammation, just like correcting gut dysbiosis below, understanding the following will give you a HUGE leg up on recovery:

• Your genetic propensity to inflammation (with Genetic Lifehacks, here)
• Your current gut microbiome (with Ombre and/or Microbiome Prescription), as SIBO/SIFO and general gut dysbiosis is a HUGE source of inflammation.  And in some cases these bad bacteria can feed off of the energy supplementation above, making your condition worse.

• This can guide targeted removal of specific pathogens
• An excellent example of which here.

• Your current labs including rheumatology panel (e.g. are you high ferritin, TNF-alpha, IL-B), full metabolic panel (low absorbable iron), infectious disease panel (do you have reactivated EBV, etc.?) and also a full Thyroid workup by an endocrinologist.

A targeted approach as above is safest, most effective, and likely the fastest route to recovery. That said, some general recommendations to reduce inflammation are below, and an EXCELLENT table is here, many of which are anti-microbial, anti-inflammatory, anti-fungal and anti-viral.

Vagus and Nervous System Health Support

As above, inflammatory peripheral neuropathy (which seems to be reversible) impacts the Vagus nerve, which exists outside of the spinal column - so is as susceptible as any given peripheral nerve.  Additionally, the body ends up short on acetylcholine through mechanisms this author is yet to determine (on postulation is acetylcholine is consumed during vasodilation, per NIH, and anecdotally during my decline, my vasculature would spasm to huge dilation many times a day).  Either way, the ganglionic receptors of the vagus nerve can be supported via Acetyl-L-Carnitine, which the intestines readily absorb (on an empty stomach), and the body converts to AcetylCholine.

This supplementation will support ganglion body-wide.  So in addition to helping to restore gut motility, it will also help to make the peripheral neuropathy less severe.  

And those with chronically dry eyes as a result of ME/CFS/Long-COVID will quickly notices more moist eyes usually within an hour of taking Acetyl-L-Carnitine.

The supplement Parasym Plus contains a formula that provides all the necessary precursors for the body to make Acetylcholine.

(And to answer the question: Why not just supplement Acetylcholine directly? The reason is that Acetylcholine does not absorb in the intestines.)

In addition to supporting the receptors, the peripheral nerves and the vagus nerve (and also the brain, given the leaky blood-brain barrier that occurs in this disorder) can be supported by supplementing neurprotectant and neurotrophic substances.

Lion's Mane Mushroom

• Lion’s Main Mushroom contains high concentrations of Phosphatidylserine, from here

• Phosphatidylserine is a fatty substance called a phospholipid. It covers and protects the cells in your brain and carries messages between them. Phosphatidylserine plays an important role in keeping your mind and memory sharp. Animal studies suggest that the level of this substance in the brain decreases with age. Here

• The neurotrophic aspect (which allow nerve regeneration, NIH) is important, as it helps in the brain, central, and peripheral nerves to maintain and seemingly regain lost functionality.
• Seems like Lion’s mane is more effective because it contains all the supporting aspects.Many recovered ME/CFS sufferers have noted that mentioned they had to take it to restore their Myelin
• MoreThereThanHere (in recovery) takes it too, with really good notes on it:

• Anti Inflammatory, Immune System, Neuroprotectant, Neurotrophic, Gut health
• On health rising there’s an article about using Phosphatidylserine complex to recover from ME/CFS, here.

• An alternate is a Phosphatidylserine complex, which are popularly available.

Trimethylglycine (Betaine TMG)

For details as to why TMG is anti-inflammatory, see the Supporting Methylation section below.  As usual, checking your genetic tendencies will advise if this is indicated or contra-indicated.  

For this author, there is a genetic tendency (details here) to not be able to convert Choline to Trimethylglycine (TMG) and a genetic propensity towards NAFLD, so TMG is is very beneficial, as over 50% of TMG produced in the body is used by the liver for detoxification.

But to quickly give an idea of its efficacy (in those who benefit from it), from ChatGPT3.5:

TMG (trimethylglycine) has been shown to have anti-inflammatory effects in the body. One study found that TMG supplementation reduced levels of several inflammatory markers in the blood, including C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-alpha) (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3930734/). Another study found that TMG supplementation decreased oxidative stress and inflammation in the liver (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4721581/).

Vitamin K2

Vitamin K2 deficiency deserves special attention therefore and is covered in multiple parts of this document as a result (below in Healing the Intestinal Barrier, here and Healing the Vasculature, here).  

The western diet is often short on vitamin K2 (Healthline and here) and it is therefore even popularly recommended if eating the standard american diet (e.g. foodnetwork).  And this deficiency is progressively being associated with chronic inflammatory and auto-immune diseases, including MS, peripheral neuropathy (NIH), Alzheimer’s (NIH), Parkinson’s (NIH), Type 2 Diabetes (NIH), etc.

And from this excellent Frontiers Immunology article, here and reproduced figure below, Vitamin K2 deficiency in the diet can explain how/why a virus like COVID or a bacterial infection can trigger ME/CFS or Long-COVID - as K2 is so important multi-system wide throughout the body.  

Frontiers Immunology FIGURE 3 Functions of VK in multiple-organ systems, such as testis (9), brain (10–14), intestine (15–17), muscle (18, 19), bone (20–22), liver (7, 23), kidney (24, 25), pancreas (26, 27), fat tissues (28–30), and cardiovascular system (31–34), and biological processes involved in anti-oxidation (3, 4), immune response and anti-inflammation (5, 6), and cancer progression (7, 8), and associated with protective and promoting roles in diverse organs or tissues throughout the human body are summarized above. The figure is in a non-editable format.

And notice that the benefits from Vitamin K2 mirror almost exactly the deleterious effects of ME/CFS/Long-COVID from this excellent Nature article and symptom summary:

Nature figure: The impacts of long COVID on numerous organs with a wide variety of pathology are shown. The presentation of pathologies is often overlapping, which can exacerbate management challenges. MCAS, mast cell activation syndrome; ME/CFS, myalgic encephalomyelitis/chronic fatigue syndrome; POTS, postural orthostatic tachycardia syndrome.

See Healing the Vasculature here for dosing that is commonly used for correcting several of the symptoms shown above in Nature.

Increasing Nociceptive Threshold

And in terms of inflammation and the dysregulated immune response, Vitamin K2’s dose-dependent Antinociceptive effect is very important.

• The Nociceptive Threshold is the level at which the body responds to toxic stimuli like

• harmful chemicals (e.g., capsaicin, formalin)
• mechanical injury (e.g., cutting, crushing, abrasing), or
• adverse temperatures (heat and cold) by the sensory nervous system. Here

• In layman’s terms, it is the threshold at which the immune system treats stimuli as a threat and responds as if it’s a threat and triggers an immune/inflammatory response.

See this NIH for the effect of K2 supplementation demonstrated on diabetic and non-diabetic mice:

• The antinociceptive effect of vitamin K2 (menatetrenone) in diabetic mice was examined using a tail-pressure test.
• Intraperitoneal injection of menatetrenone [Vitamin K2 MK-4] (10-100 mg/kg) produced a dose-dependent increase in the nociceptive threshold in diabetic mice.
• There was no significant difference between non-diabetic and diabetic mice in the menatetrenone-induced changes in the nociceptive threshold.
• The results suggest the therapeutical usefulness of menatetrenone for treating painful diabetic neuropathy and osteoporosis."

So in summary, the dose-dependent Antinociceptive effect of Menatetrenone Mk-4 means  that it increases the threshold of the body reacting (and overreacting) to toxins, stress, trauma, and temperature changes so it's likely useful for reducing inflammation, MCAS and histamine intolerance.

Which then fits with Vitamin K2 reducing food and environmental sensitivities.

Antioxidants

• Astaxanthin, one of the most powerful antioxidants (NIH) and targets mitochondrial antioxidation, improving energy production.

N Acetyl Cysteine

Downregulate NOS2 (iNOS)

This is helpful if you genetic indicate a mutation with NOS2.  This author has a mutation which upregulates NOS2 significantly, causing severe inflammation in response to gut pathogens.  

What NOS2 does when activated:

• Activates platelets (blood clotting)
• super-factory for superoxide
• consumes NADPH, so downregulating it helps a TON!

What activates NOS2:

• Gut pathogens.
• “NOS2 is a fucking flamethrower” per here.

15-20 mins before meals to downregulate NOS2

• 1000-1500mg L-Lysine;

• Bought Life Extension here

• 500mg Boswellia(NOW)

• Bought here

• 1 cap solaray Andrographis;

• Using one I already have, here

• Black Cumin Seed (1 cap Life Extension);

• Bought here
• Going to just stick with it in food/smoothies.
• As one less pill to take!

• Liposomal Vitamin C or Magnesium Ascorbate;

• Using what I already have, here
• Or use liposomal, which might be better.

• Forskohlii (Swanson)

• Need to order Swanson to new place.
• Ordered Nutricost for now, here

Downregulating ALOX 12

ALOX12 is an enzyme that catalyzes the conversion of arachidonic acid to 12-hydroperoxyeicosatetraenoic acid (12-HPETE), which is then converted into various eicosanoids such as leukotriene A4 and 12-hydroxyheptadecatrienoic acid. These eicosanoids play important roles in the regulation of inflammation, immune response, and various cellular processes. ALOX12 has been implicated in the pathogenesis of various inflammatory diseases such as asthma, atherosclerosis, and cancer. Source: ChatGPT

• Life Extension Super Carnosine (1-2 caps 2x per day)

• ordered here

Mast Cell Stabilizers

• Dihydromyricetin (DHM) 

• Downregulates TNF-alpha (TNF-α) and IL-6, per NIH.
• Strongly hepatoprotective.
• Reduces intestinal inflammation and helps promote tight junctions.

• Black Cumin Seed/Oil
• Elderberry Extract
• Vitamin D, probiotics, krill oil:

• “A study using an animal model of gut inflammation found that a mixture of krill oil, Lactobacillus reuteri (probiotic), and vitamin D decreased intestinal inflammation, reduced TNF-α, IL-1β and IL-6 levels (inflammatory cytokines), and increased IL-10 (anti-inflammatory).[ref] This may be important for anyone with IBS.” from here, and more details on probiotics that help below.
• The benefits of Krill oil are likely because Krill eat algae as their main diet, and algae are high in Astaxanthin (above in antioxidants), an extremely powerful antioxidant per NIH.

• Quercetin Phytosome up to 2g+ per day, here,

• More effective than Chromolyn sodium per NIH, and without clotting side-effect
• The Phytosome is by far the best bioavailability, per NIH, at about 20x absorption of regular Quercetin.
• Taken with Vitamin C and Bromelain increases absorption, per here
• Taxifolan, which is Dihydroquercetin, is claimed to be even more anti-oxidative, per here.

• EGCG Mast Cell Stabilizer

• 1g per day, here)

• Curcumin / Turmeric (Highest absorption are Theracurmin here, Meriva here, CuraMed, here)

• And according to here Theracurmin is significantly better than both BCM-95 and Meriva. All 3 of which are higher than regular Curcumin.
• Curamin here has Boswellia additionally.
• WARNING:

• If you have elevated ferritin but normal or towards-the-low-end iron, you have a form of anemia which is the most common kind in hospitalized patients (see here), which is a result of constant/chronic inflammation.
• “Ferritin is an acute phase reactant and a marker of acute and chronic inflammation. It is elevated in a wide range of inflammatory conditions, including chronic kidney disease, rheumatoid arthritis, and other autoimmune disorders, acute infections, and cancer [1, 2].”
• Anemia of chronic disease is the most frequent anemia in hospitalized patients. It develops in people suffering from diseases in which there is chronic activation of cell-mediated immunity, such as chronic infections, immune-mediated inflammatory disorders, or malignancy. It’s characterized by the presence of low iron, but increased blood levels of ferritin [4].”
• This was the case for this author, and Curcumin always sat poorly, which is explained by it being known in the literature that Curcumin blocks the absorption of iron, making the author’s anemia even worse, source NIH 1 and 2.

• Chamomile tea (Apigenin, luteolin) – 1 to 2 cups before bed, here.

• Apigenin prevents the infiltration and degranulation of mast cells and suppressed mRNA and protein expression of IL-31 in the skin of mice. Here.  
  Apigenin reduces IL-1B expression as well, NIH

• CoQ10 ChatGPT

• Research has suggested that CoQ10 may have anti-inflammatory effects through several mechanisms. One way it may work is by reducing the production of reactive oxygen species (ROS) and free radicals, which are molecules that can cause oxidative stress and inflammation in the body. CoQ10 is a powerful antioxidant that can help neutralize these molecules and reduce their harmful effects.
• In addition to its antioxidant effects, CoQ10 may also modulate the activity of certain pro-inflammatory cytokines, including interleukin-1 beta (IL-1β) and tumor necrosis factor-alpha (TNF-α). Research has suggested that CoQ10 can reduce the production of these cytokines and thereby reduce inflammation. NIH
• CoQ10 may also have other beneficial effects on the immune system, such as enhancing T cell function and reducing the production of certain pro-inflammatory enzymes.

• Berberine

• Has the benefit of also being anti-microbial and anti-fungal (here), helping to remove SIBO/SIFO that’s common in ME/CFS (here)

• CBD per here and here, but is VERY risky;

• CAUTION: research drug interactions first!  For example do not use with Zyrtec!
• “Cannabinoids dramatically improve the symptoms of gastroparesis. Furthermore, an improvement in abdominal pain with cannabinoids represents a breakthrough for gastroparesis-associated abdominal pain treatment, for which there are currently no validated therapies.”
• May be beneficial for vasculature, here
• If doing CBD, CBD isolate is recommended as many MCAS patients are allergic to the other parts of hemp oil and THC, source is potentially biased as a vendor, here
• Dosing recommendations from here (the author had/has MCAS)

• For the first 10 days, 600mg daily - that's 3 droppers of the 6,000mg bottle.
• Day 11-30 - 300mg daily - that's 1 1/2 droppers of the 6000mg bottle.
• Beyond that period, adjust according to need. The lowest level that matches any research would be around 50mg daily.

• Like many MCAS treatments, it may not be effective in ME/CFS because of (deleterious) interactions on the other 4 parts of the disease.
• “... evidence has indicated a role for CBD in the modulation of mitochondrial processes, including respiration and bioenergetics, mitochondrial DNA epigenetics, intrinsic apoptosis, the regulation of mitochondrial and intracellular calcium concentrations, mitochondrial fission, fusion and biogenesis, and mitochondrial ferritin concentration and mitochondrial monoamine oxidase activity regulation.”  NIH, found here
• “Thus, under pathological conditions involving mitochondrial dysfunction and Ca2+ dysregulation, CBD may prove beneficial in preventing apoptotic signaling via a restoration of Ca2+ homeostasis” NIH, found here
• And note that where CBD may be beneficial, THC is resolutely deleterious:

• “THC exposure alters brain maximal oxidative capacity. It impairs mainly the complexes I, II, and III of the mitochondrial respiratory chain and mitochondrial coupling. THC also increases brain ROS production and mitochondrial free radical leak.” NIH, found here

Superoxide Consuming Enzymes:

• SOD - Superoxide Dismutase

• SOD Booster by Life Extension

Histamine Consuming Enzymes:

Supplements

• DAO (Diamine Oxidase, ~10mg/day, here)
• Catalase
• Histamine Digest (here) has both

Supporting Endogenous Production

• And here is an excellent resource on the (necessary-during-gut-dysbiosis) supplementation to help the body digest histamine on its own, with figure reproduced below:

• And see Supporting Methylation below for details on the supplements shown above.

Special Pro-Resolving Mediators (SPMs; source of below here)

• SPMs are the body’s natural way to reduce inflammation, Frontiers

• Depending on genetics, environmental factors, and diet, these may become exhausted, but can be supplemented.
• An overview of how they impact the immune system and reduce inflammation is below, from here

• Fish Oil (source for all below below is here)

• Clinical trials using high doses of DHA/EPA and also measuring specialized pro-resolving mediators (SPMs) show:[ref]

• In chronic kidney disease, 4g/day of an omega-3 supplement for eight weeks increased resolvins (RvE1, RvE2, RvE3, RvD5).
• In overweight major depressive disorder patients, supplementing with between 1 and 4 g/day of EPA was investigated. The results showed that all of the supplemental doses increased EPA, DPA, and subsequent SPM levels in a dose-dependent fashion.[ref] (Note that this clinical trial didn’t find that EPA was better than placebo at reducing depressive symptoms – everyone improved, even the placebo group.)[ref]
• In peripheral artery disease, a 4.4g supplement of DHA/EPA for 3 months increased resolvin E3.
• Another study of peripheral artery disease found that a marine oil supplement of 4.5g (DHA/EPA/DPA) increased maresins.
• In people with arthritis, a microalgae oil supplement containing 2.1g DHA/day for ten weeks increased SPMs.

• Vitamin D,  probiotics, krill oil: A study using an animal model of gut inflammation found that a mixture of krill oil, Lactobacillus reuteri (probiotic), and vitamin D decreased intestinal inflammation, reduced TNF-α, IL-1β and IL-6 levels (inflammatory cytokines), and increased IL-10 (anti-inflammatory).[ref] This may be important for anyone with IBS.
• Note that fish oil/SPMs seem to have a combo effect with Aspirin, see below in Treating Excess Microcoagulation
• Fish oil seems to be best taken in the morning. And need 3+ grams to have therapeutic effect, from here/here, as below:

• Summary below of how Fish Oil (and Marine Oil Extracts) impact Resolvins is below, from here.  
• Notice fish oil impacts many anti-inflammatory pathways.

• Traumeel

• An herbal pain relief product offered as an injection or cream, has been shown to increase the production of resolvin D2, resolvin D5, and lipoxin A4 after 24 hours (animal study, injections).[ref].
• Reduces inflammatory markers in RA, per ChatGPT.  Does not impact the function of T-cells and is not immunosuppressent, but reduces IL-1B by up to 70% and other inflammatory markers, per NIH.
• Cream here
• Pill here
• More information from manufacture on it here, particularly its impact on TNF and IL-1B

• Tripterygium wilfordii

• Also known as Thunder God Vine, is a traditional Chinese medicine used for rheumatoid arthritis. Recent research shows that it induced “pronounced formation of specialized pro-resolving mediators (SPM) and related 12/15-LOX-derived SPM precursors, without COX and 5-LOX activation.”[ref] Other research identifies that celastrol is the active component of Thunder God Vine that is responsible for elevating SPMs.[ref]
• Note that Tripterygium wilfordii can be TOXIC to multiple organs, so the author does not recommend using it.  And this information is provided for context only and if it provides clues to other SPMs.

• ​​Zileuton, a leukotriene synthesis inhibitor, also blocks the formation of SPMs.[ref]

• Should be avoided most likely for ME/CFS

Leukotriene inhibitors

These help with shortness of breath, nasal/sinus closing, overview of naturals here (and overall and amazing resource)

• Ginger blocks the production of prostaglandins and leukotrienes [58], here

• May stop blood clotting, here
• Fresh ground ginger is best, added to meals.

• N-acetyl cysteine (no max limit; titrate based on stomach upset)
• Alpha Lipoic Acid found here

• “α-LA acts as an enzymatic cofactor able to regulate metabolism, energy production, and mitochondrial biogenesis.” NIH
• “In addition, co-administration of LA (alpha lipoic acid) with other mitochondrial nutrients, such as acetyl-L: -carnitine and coenzyme Q10, appears more effective in improving cognitive dysfunction and reducing oxidative mitochondrial dysfunction.” NIH
• “Our results showed that FAC results in a significant increase of tissue iron accumulation, oxidative stress, and autophagy and such detrimental effects were reversed by ALA treatment. “ NIH

• Bromelain 

• Helps absorption of Quercetin and other bioflavonoids
• Lowers high LDL and Cholesterol which are often resultant disorders in this condition.

• Luteolin (200-600mg per day, here)

• Shown to reduce blood clots, here

• Boswellia - Gastroprotective, here, anti-inflammatory topically here
• Milk Thistle (Silymarin, here)
• Resveratrol here

• Natural blood thinner here

• Aloe here

• Likely lightly anticoagulatory effect here

• Butterbur -

• Supplement that gives similar effect to prescription Leukotriene inhibitors, per here.
• Shown to reduce blood clotting, here
• Check supplement for liver-toxic pyrrolizidine alkaloids (ChatGPT).  Check for PA-free.  Example here

• Of particular note is interaction with anti-coagulants, e.g. here
• Hesperidin (100-500mg per day here)
• Diosmin
• Copper/Zinc (here)

OTC Drugs

• Good resource on drugs/prescriptions here
• Pepcid AC to block Histamine H2 (40mg/day recommended)

• Warning 1: These can cause worse SIBO long-term.
• Warning 2: These can reduce iron absorption, contributing to various forms of anemia (here)

• Zyrtec Histamine H1 (20mg/day)

• Has advantage of making blood vessels slippery

• Bayer Baby Aspirin (75mg/day Mast Cell Stabilizer here and anticoagulant here^[1])

Prescription

• Rapamycin, details below in Treating Poor Blood Quality Production

• It reduces inflammation by blocking the very-potent inflammatory interleukin cytokine IL-1B.
• Which then also results in newly-produced blood not being so prone to clotting and overall higher-quality (less aged).
• And “poor quality, clotted blood” is being found to be at the root of much of the issue of this disorder, and blocking this inflammation explains it, per NIH here.
• CAUTION: This may be problematic for those with reactivated viruses.

• Other good resource on drugs/prescriptions here
• Mast Cell Stabilizers (from here)

• Zaditor®/Zaditen® (in Europe)*         - Ketotifen

• Recommended: Decreases blood clotting, here
• Also helps to calm T-lymphocytes, per NIH

• Leukotriene Inhibitors (from here)

• Singulair®                     - Montelukast
• Accolate®                     - Zafirlukast
• Zyflo®/Zyflo CR®         - Zileuton

• Cromolyn sodium sodium (Gastrocrom) (here)

• Potentially not recommended for ME/CFS because of GI upset issues.

• Colchicine: (not recommended; high risk) This anti-inflammatory may reduce inflammation around the lining of the heart (pericarditis) and lungs (pleuritis). Colchicine is also used for pericarditis and may reduce chest pain and breathlessness (dyspnea) in Long COVID.[3]

• Used to treat Behçet's disease (which I think Chris has).

Foods that help

• Raw Carrots  - Organic preferred, fresher the better, washed, but not peeled (to leave the biome intact)

• Raw carrots are likely the single-best foot that exists for treating the multi-system maladies that occur in ME/CFS.
• They are rich in antioxidants that help to reduce inflammation.
• They are high in fiber while being uniquely resistant to feeding (bad) bacterial and fungal overgrowth in the small intestine
• From theory, they should be incredibly beneficial in turning this disorder around.

• And indeed there are many many anecdotal tales of someone’s turnaround starting with carrots. So much so that this guy dedicated an entire page to just quoting all the befits of carrots on the GI system, here.

• Super highly recommended for Candida kill-off, e.g: "Carrots contain the powerful, fungus fighting nutrient falcarinol and plenty of antioxidants, such as beta carotene." here

• And Candida is one of the worst-offenders in terms of causing inflammation, food intolerance, and oxidative stress systemically.
• And Candida is one of the worst-offenders in terms of putting a huge load on the immune system and consuming the body’s energy.

• And anecdotally, this author was recovering when eating a diet that included raw carrots, but noticed they were in his stool nearly identical to how the author chewed them and since the author was losing weight, he stopped eating them.

• But this was actually proof of their benefit.
• They’re a highly-resistant form of fiber, and are only digested by good bacteria in the large intestine.  So initially, when in a state of severe dysbiosis they pass through both the large and small intestine effectively untouched.  But over time (weeks, months), the good bacteria in your large intestine will start to grow and digest them.  
• So carrots solve the “I can’t handle ANY fiber” trap that many sufferers end up in, as fiber is a critical part of rebalancing the GI system and overall recovery, as it’s what feeds good bacteria in the LARGE intestine, but during dysbiosis, any given fiber ALSO feeds (bad) bacteria and (bad) fungus overgrowth in the small intestine.

• Carrots are unique or perhaps near-unique in having their own microbiome which prevents them from feeding bacteria in the small intestine (and initially, even in the large intestine, until the good bacteria grows in).

• Collagen Peptides and supplements that encourage collagen production.

• In ME/CFS, collagen production is lowered (e.g. NIH, NIH).
• Correcting this can help pain in the joints, spine, and intracranial pressure (caused by disc atrophy)
• Collagen peptides with no additives anecdotally helped me.  

• So did Biosil, here

• Note that SIBO (and SIFO - specifically Candida form) is very common in this disorder (NIH), which results in low Vitamin A in the body.

• And Vitamin A, specifically retinol, is what stimulates collagen production in the body per NIH.
• So in addition to taking collagen, supplementing vitamin A can be very helpful.
• It’s worth noting that Vitamin A is well-absorbed through the skin.
• See the “Healing the GI System” section for more details.

• MCT Oil

• “MCTs can increase the activity of the histamine-clearing enzyme diamine oxidase (7)” here
• It also helps to tamp down Candida overgrowth (source), which is common.

• Quail Eggs (Prepared fresh, Poached preferred, Organic preferred)

• Chicken Egg whites can be histamine releasers, particularly boxed egg whites.

• Quail eggs however are studied for their anti-histamine properties. For example AllQlear from Integrative Therapeutics, here is derived from Quail Eggs.

• “...from… Quail egg which contains ovomucoids that act as a trypsin inhibitor to support healthy stabilization of mast cells”

• Make sure egg whites are cooked, otherwise they trigger histamine release, per here
• Eggs contain most everything except Creatine, per here.
• Note that chicken egg whites from a box are nearly always high histamine because of how they’re processed and stored, so they hurt.

• So avoid boxed egg whites.

• Ginger

• Antihistamine.  Also anti-microbial.  Petri dish examples here.
• Blocks the production of prostaglandins and leukotrienes [58], here

• Amino acids that don’t contain Histidine, per here

• Example here

• Low-Histamine protein powders, list here
• Very fresh meats can be OK (if you can still handle meats), examples are (from here), cooked sous-vide direct from frozen to minimize histamine.

• Northstar Bison
• White Oak Pastures
• Vital Choice

Things that hurt

The further you progress into MCAS, the more sensitive you become to everything, particularly aged things and artificial sweeteners, chemicals, etc..

• Foods

• Foods that are high in histamine or trigger histamine release (these are the absolute worst for this condition)

• Avocados (8 weeks of 2 Avocados a day destroyed me; lost 40 pounds)
• Foods with MSG (really bad)
• Soy (really bad)
• Example list here, and more thorough, here

• Carbs
• Sugars

• Supplements

• Amino acid blends that contain Histidine, per here
• Stinging nettles

• Source of Quercetin, but likely encourages coagulation because it is high in histamine, per here

• Natural D-Hist (which contains many on this list)

• Contains high-dose Stinging Nettles, high in histamine, per above

• Creatine here

• Helps to build muscle in MCAS
• May contribute to blood clotting, per here

• So likely best to avoid (it made my condition worse) if in a flare

• Thiamine is a histamine liberator and DAO inhibitor, per here

• Drugs per (most of list from here)

• Opioids
• Antibiotics
• Most NSAIDs here 

• For example ibuprofen has been found to block the formation of SPMs (lipoxins, resolvins, and protectins), source here, and found through here (pay wall)).
• Aspirin is a very-notable exception, helping to produce SPMs, see details on SPMs above.

• alcohol-containing medicines and intravenous vancomycin

• Many toothpaste ingredients

• See here 

Stress Management

In addition to the physical and chemical support above for inflammation, stress, of any kind - even about the disease itself can be a trigger for inflammation - which then reduces oxygenation and ATP production.  

And so this stress can trigger your physical condition to worsen - which can trigger more stress.  And this becomes a downward spiral.

Depending on the severity of the disease, using techniques to keep yourself calm and stress-free can be equally important.  These include:

• Deep breathing (6 breathes per minute, into stomach, not chest)
• Yoga, if you are that capable - I am not, yet)
• Visualization (I do this many times a day)
• Calming phrases such as “I’m going to fully recover from this” that you repeat over and over (repetition, whether something is true or not, makes your mind think it is).
• The Gupta Program is strong, and not overly expensive, here (I do this every day)
• The Calm app is fairly great.
• And Amazon has a series of nature and city-view videos that are calming
• Sitting and staring at nature (if you can walk)

Sleep

Overproduction of Histamine (from MCAS) results in poor quality sleep and sleep disruptions.  And this further triggers the downward spiral.  In the literature there are a variety of advised supplements to aid in sleep.  The safest and most effective appears to be Glycine.  It’s well tolerated and seems to have no side effects even at high doses.

• Glycine here

• Helps with sleep and to fight histamine
• 3-5 grams/day, up to 90g/day tested safe (here)
• Glycine is considered very safe even in high doses, both in humans and animals. In rats, high doses over four weeks of 2g/kg were not toxic.10 In some cases, doses of up to 30 (!) grams per day were used in human studies. In one case, nausea with vomiting occurred, which caused the discontinuation of treatment in this individual..11(p)
• More on Glycine and sleep here
• More from NIH, here

• Taurine

• GABA Agonist per NIH, liver support per NIH

• GABA

• Leaky blood-brain barrier allows this to help directly.

• L-Theanine
• L-Carnosine

• Helps reduce sleep disturbances, best taken at night, and it is beneficial for gut and muscle function as well, see below in correcting gut dysbiosis.

• Gut dysbiosis, and histamine release, is one of the primary mechanisms resulting in sleep disturbances.
• And the sleep disturbance further disbalances the gut microbiome.

Glycine (and Taurine) have the added benefit of being beneficial for the liver (hepatoprotective effect, here) which is often struggling in ME/CFS.  Additionally glycine has been shown to help prevent muscle wasting, per here.

Glycine is also used in the biosynthesis of hemoglobin, which is very important in the maintenance of red blood cell integrity and oxygen transport, per here.

• Reduces edema, per here.
• Reduces platelet aggregation per here.
• Shown to help in SIBO per here.
• Helps in bile salt production to fight Candida here.
• Enhances the oxygen supply and blood circulation here.
• Necessary for proper blood production here.

Nutrient Deficiency

The chronic inflammation will result in nutrient deficiency throughout the body.  Most notably, magnesium.  If you’re not already taking magnesium, adding it will make you feel significantly better.

Typical deficiencies include:

1. Vitamin K2
2. Vitamin D, e.g. here

1. This is usually low in ME/CFS patients, which contributes to clotting.  I take 5,000 IU, here

3. Vitamin A, which is required for proper blood production.
4. Boron, which is necessary to prevent and help mitigate Calcium deposits body-wide and is critical in production of energy (Krebs cycle), including SAM-e and NAD+, NIH.
5. Acetylcholine, e.g. here,

1. Acetylcholine cannot be directly absorbed, so to fix this nutrient deficiency, taking Acetyl-L-Carnitine, which the body readily absorbs and converts into Acetylcholine (see here) is the way to get these levels back up.

6. Magnesium, e.g. here

1. Take 400mg of Magnesium Citrate up to 3x per day (titrate based on if you get diarrhea), preferably at night as it is calming.
2. Note that not all magnesium forms will respond equally.  
3. Citrate is the worst form if you have histamine issues (and you very very likely do). here
4. Magnesium L-Threonate seems to be the best tolerated and is the only known to cross the blood-brain barrier, which may help with sleep and brain-fog. here

7. Glutathione, here

1. Supplement using NAC (N-Acetyl Cysteine), ~700mg 3x per day, but no max limit - titrate based on if/when it causes GI upset)

8. B Vitamins, NIH

1. The malabsorption will likely mean you are short on nearly all of the B-vitamins.  Make sure to take a B-vitamin that uses Niacinamide (Inositol Hexanicotinate) instead of Niacin, as Niacin causes flushing which can make this condition worse, explanation at LiveStrong.  
2. The one I use is Nordic Naturals, here

9. General vitamins, e.g. here.  Take a daily (in the morning) multivitamin.  Make sure again that it uses Niacinamide (Inositol Hexanicotinate) instead of Niacin, as Niacin causes flushing which can make this condition worse, explanation here.

1. And try for one without Vitamin K, or little vitamin K, as that vitamin increases blood clotting (NIH).

10. CoQ10 is deficient in ME/CFS, per NIH

1. It is also a powerful anti-inflammatory through multiple mechanisms, see above for details.

11. Ubiquinol is the more bioavailable form of CoQ10.  

1. Better absorption.  
2. CoQ10 may be more gut-inflammation modulatory and Ubiquinal may be more whole-body inflammation modulatory.
3. “These results show that ubiquinol-10 may enhance mitochondrial activity by increasing levels of SIRT1, PGC-1α, and SIRT3 that slow the rate of age-related hearing loss and protect against the progression of aging and symptoms of age-related diseases.” NIH, found here.

12. Malic Acid is reduced in ME/CFS patients because of diet, poor absorption, and typically Candida infection, and is a key part of the Krebs cycle.

1. It’s lacking is suspected by the mitochondrial dysfunction in muscles (NIH), and helps to make the mitochondria less dysfunctional (NIH).
2. Note again that Magnesium Malate is the safest-on-the-intestines way to take Malic acid; delivering the benefits to the body without the deleterious impacts of the acid on the intestinal barrier function

13. Collagen and supplements that encourage collagen production.

1. In ME/CFS, collagen production is lowered (e.g. NIH, NIH).
2. Correcting this can help pain in the joints, spine, and intracranial pressure (caused by disc atrophy)
3. Collagen peptides with no additives anecdotally helped me.  

1. So did Biosil, here

B. Treating Poor Quality Blood Production (Aged Blood):

Novel research in anti-aging (and ME/CFS is like premature aging) has found that blood quality is one of the main causes of (premature) aging.  And specifically, the literature has found the inflammation caused by senescent T-cells is what causes chronic inflammation (e.g. here).  Among the T-cell induced chronic inflammation, and likely the most deleterious, is an overactive inflammatory cytokine interleukin-1β (IL-1β) - which has been shown experimentally to result in aged blood.  And additionally has been demonstrated to be reversible (e.g. here) by blocking IL-1β.   And it is this author’s postulation that using an antagonist to block this will result in drastic improvements for ME/CFS patients, just like has been found for elderly, here.  And this fits with multiple practitioners having success with ME/CFS (and Long-COVID) patients by using treatments that show anti-aging effects, e.g. here.  

But most importantly, addressing the source of the IL-1β (i.e. senescent T-cells) will be even more beneficial, longer-lasting, and carry fewer risks.  

The most effective way to do so is through CAR T Cell therapy, which is usually used for cancer (e.g. here), but has recently been found to be extremely effective in treating auto-immune diseases as severe as Lupus (e.g. here).  

And given that the mechanisms behind Lupus and ME/CFS appear incredibly similar, with ME/CFS being more an immune system dysregulation rather than a full-blow auto-immune disorder, treatment of ME/CFS with CAR T Cell Therapy is even more likely to be successful than with Lupus - where great success has been had!

The author is actively researching the exact T cells impacted, but the literature seems to indicate, CD8 T cells become exhausted/senescent (here).  One patient I’ve interacted with here also has senescent CD57+.  And it is looking like T cell lymphocytes

So then the approach breaks into 3:

1. CAR T Cell therapy

1. Resolves the core issue in this disease, senescent, malfunctioning T-cells

2. Interleukin-1 Receptor Antagonists

1. This can be done via foods in not-severe cases, supplements for those harder impacted, and then prescription drugs for those who are worst impacted.
2. Does not treat the underlying T-Cell senescence and dysfunction, but reduces inflammation and may allow the body (even in sever cases) enough change to recover.
3. Author’s note: Technique 2 is working for me, coming back from being paralyzed nearly completely (including bladder,

3. HELP Apheresis

1. This removes the clots (and other deleterious elements) that the senescent, malfunctioning T-cells are constantly producing.  
2. Since this is furthest from addressing the production of blood that’s high quality, it is the most likely to be of short-term help, or no help at all, e.g. here

1. Albeit the temporary reduction in blood clotting in the body, in combination with parallel treatment of secondary disorders, may be enough for the body to “snap out of it” - which seems to be the case for many who are treated.  

Natural Approach - Foods

Interleukin-1 receptor antagonist (IL-1Ra) is a protein that acts as an inhibitor of interleukin-1, a pro-inflammatory cytokine. IL-1Ra is not a nutrient found in food, but some foods have been shown to have anti-inflammatory properties and may help to regulate levels of interleukin-1 in the body (source: chatGPT):  

• Omega-3 fatty acids found in fatty fish such as salmon, mackerel, and sardines.
• Ginger, turmeric, and other spices that contain anti-inflammatory compounds.
• Fruits and vegetables, especially those high in antioxidants such as berries, leafy greens, and dark, colorful produce.
• Whole grains and legumes, which contain fiber and other nutrients that may help to reduce inflammation.
• Nuts and seeds, which are a good source of healthy fats and antioxidants.

Some patients (the author included) have passed the point where they can eat all the foods on that list (because of gut dysbiosis - SIBO/SIFO - and the inflammatory response caused thereby when the foods are consumed).  So supplementation can be extremely helpful.  Below are supplements of interest.

Supplements for Suppressing IL-1B:

• Akkermansia (from ChatGPT)

• One study published in the journal Cell Reports showed that supplementing with Akkermansia muciniphila in mice reduced the levels of HMGB1 in the blood, improved intestinal barrier function, and reduced inflammation. This suggests that Akkermansia may have potential benefits for reducing inflammation in the body, in part by modulating the levels of HMGB1.
• Studies have shown that HMGB1 can induce the production of IL-1β in various cell types, and that IL-1β can in turn upregulate the expression of HMGB1. This suggests that there is a feedback loop between HMGB1 and IL-1β that can contribute to the persistence of inflammation.
• Elevated levels of HMGB1 and IL-1β have been associated with various inflammatory conditions, such as sepsis, rheumatoid arthritis, and inflammatory bowel disease. Thus, targeting the production or activity of these molecules has been a focus of research into the treatment of these conditions.

And according to ChatGPT (here), all the following should help suppress IL-1:

“Interleukin-1 (IL-1) is a pro-inflammatory cytokine that plays a crucial role in the immune response and inflammation. While there are some supplements that have been shown to have anti-inflammatory effects, there is limited evidence to suggest that any specific supplements can directly block IL-1. However, some supplements may help modulate the immune response and reduce inflammation, which may indirectly lead to a reduction in IL-1 activity.

Here are a few examples of supplements that may help reduce inflammation and potentially modulate the activity of IL-1:

Supplements Summary

1. Omega-3 fatty acids: Omega-3 fatty acids are known for their anti-inflammatory properties and may help reduce the production of pro-inflammatory cytokines, including IL-1.
2. Curcumin: Curcumin is a compound found in turmeric with anti-inflammatory properties. It may help reduce the production of IL-1 and other pro-inflammatory cytokines.
3. Resveratrol: Resveratrol is a polyphenol found in red wine, grapes, and some berries with antioxidant and anti-inflammatory properties. It may help modulate the immune response and reduce inflammation.
4. Quercetin: Quercetin is a flavonoid found in many fruits, vegetables, and herbs with antioxidant and anti-inflammatory properties. It may help reduce the production of pro-inflammatory cytokines, including IL-1.
5. Vitamin D: Vitamin D is known to have immunomodulatory effects and may help regulate the immune response. Some studies suggest that it may reduce the production of IL-1 and other pro-inflammatory cytokines.

It's important to note that while these supplements may have some anti-inflammatory effects and potentially modulate the activity of IL-1, the evidence is still limited, and more research is needed to fully understand their effects on the immune system and inflammation. Additionally, it's always best to talk to a healthcare provider before starting any new supplement or making significant changes to your diet.”

And this author’s experience has been that all of these help substantially.  Before I got severely ill, I was taking all of these up until a team of doctors told me to stop taking them.

Prescription Drugs (treatments) for suppressing IL-1B:

NOTE THAT THESE CARRY SIGNIFICANT RISKS!  

CHECK WITH YOUR DOCTORS ON THESE, PARTICULARLY FOR SIGNS OF EXISTING INFECTIONS.

Specifically, in the research on this phenomenon, it has been found that Kineret®                Anakinra is very effective at preventing this inflammation.

It is however hard to convince a doctor to give you this, even though it is FDA approved for treating acute COVID (but not long-COVID).  See here.  These work by blocking IL-1B (IL-1Beta), which is a potent inflammatory.

Summary

• Likely the safer approaches:

• Aptemer BC 007 (#1 recommendation, but not available until 2024) (details below)

• This may be the only exception WRT risks for existing infections

• IvIg (Intravenous Immunoglobulin supplementation) (details below)

• Likely very risky, particularly if you have existing viral/bacterial re-activation:

• Rapamycin / Rapamune / Sirolimus (details below)
• Kineret® (Anakinra) (details below)
• Ilaris® (Canakinumab) (details below)
• Arcalyst® (Rilonacept) (details below)
• Cartivix®, Matrix® and Verboril® (Diacerein) (Not Available in US) (details below)

Details on Prescription IL-1B-Blocking Drugs

• Likely the safer approaches:

• Aptemer BC 007

• Anti-thrombin, also appears to likely inhibit IL-1Beta
• References here and here
• Looks very effective, but likely not available until 2024, per here
• Need to see if there are other sources for it.

• IvIg

• Shown to reduce inflammation and lower IL-1B
• Needs to be done long-term.

• Note that a 1-time administration to the author had a net positive impact.  But the literature indicates long-term is needed for ME/CFS to keep the inflammation down.

Likely very risky, particularly if you have existing viral/bacterial re-activation:

• Rapamycin / Rapamune / Sirolimus (dosing WIP, seen 4-6 mg one time weekly)

• Big additional risk: High lipids and glucose resistance.
• “Rapamycin is a drug that works by inhibiting a protein called mTOR, which plays a key role in regulating cell growth and metabolism. Interleukin-1 beta (IL-1β) is a cytokine that is produced by immune cells and plays a key role in the inflammatory response. There is some evidence to suggest that rapamycin may have potential benefits for reducing IL-1β levels and mitigating inflammation.
• Some studies have shown that rapamycin can inhibit the production of IL-1β in various cell types, potentially through its ability to modulate the immune response and reduce inflammation. For example, one study published in the journal Frontiers in Pharmacology showed that treating human dendritic cells with rapamycin reduced their production of IL-1β in response to lipopolysaccharide (LPS), a bacterial toxin that can trigger an inflammatory response.
• In addition, some studies have suggested that rapamycin may have potential benefits for reducing inflammation and improving immune function in a range of inflammatory conditions, such as rheumatoid arthritis and other autoimmune diseases. While the exact mechanisms of action are still being studied, it is possible that rapamycin's ability to inhibit mTOR and reduce IL-1β levels may play a role in its anti-inflammatory effects.”
• And it has the benefit of being an antibiotic (NIH) that’s also antifungal (NIH), both of which are helpful for fighting the gut infections that are so common in ME/CFS.
• See here for information about how to buy. Includes info about importing and also for finding Rapamycin-friendly doctors locally who might prescribe it. Note to use SpeedPost EMS for medicine shipments where you do not have a prescription, as other shipping companies require a prescription.
• Potent anti-aging (and ME/CFS is like advanced aging) per NIH
• And this post, originally on reddit but censored, had many helpful links.  Replicated here.
• And it also reduces inflammatory Macrophage activity, which then could be why it is shown to reduce PEM in ME/CFS, per NIH.
• Explains why the blood clotting occurs in ME/CFS, here.2
• More information from Dr. Green, who’s treated thousands, here
• Note that taking it with CBD doubles or triples its activity, here, but can result in toxicity.
• Some note taking Rapamycin off and on can be beneficial, here
• TORC1 is chronically activated, per here
• Ken Lassessen also has a piece on it, here - and the reader notes the exact thing I noticed, VERY strong die-off symptoms from 1mg of it (same dose I’m doing).
• Great post on someone who was housebound for 13 years improving on it, here, but then getting worse over time.
• Recommendation to alternate on and off, here
• Some dosing for Rheumatoid Arthritis, here

• 0.5 mg on alternate days for 24 weeks in a 2 : 1 ratio.
• Low-dose sirolimus immunoregulatory therapy selectively upregulated Tregs and partly replaced the usage of immunosuppressants to control disease activity without overtreatment and evaluable side effect. Further study is required using a large sample of RA patients treated with sirolimus for a longer period. This trial is registered at the Chinese Clinical Trial Registry (http://www.chictr.org.cn/showproj.aspx?proj=17245).

• Dosing for anti-aging, here is 6mg every week or so, just like the reddit post.
• Great post on reddit about immune system dysregulation:

• Post vax or Covid long hauling (they're 99% the same thing!), are immune disorders (dysregulation) at core. Note: this does not always mean auto-immune! It's an immune dysegulation (e.g. T, NK, B cells) that is primarily expressed as various vascular disorders and secondarily as neurological disorders (nuance here between neuo precipitated by vascular and direct effects from immune)
• If you were going directly after vascular, then the focus would be on a mix of anti-platelet, anti-coagulants, and endothelial stabilizing medicines and supplements. Rapamycin would be going after the upstream immune dysregulation.
• Rapamycin has a long half life (50hrs +/-) and it takes 5.5 half lives for a drug to reach peak concentration, so maximal effects would not begin until after 12 days or so. Even then, immune modulation takes time. Any more immediate benefits would be from anti-inflammatory actions (cytokine regulation) and neuro chemical changes that effect signaling.

• In diverse studies, rapamycin extends life span in mice (see for numerous refs. 2,3,4,5). It also improves health not only in rodents, but also in dogs6 and primates7, and its analog everolimus improves immunity in elderly humans without causing side effects8,9. Here
• 
• So mTOR, if over-active (and I postulated it is in ME/CFS), actually blocks Gluconeogensis and lipolysis.  And Gluconeogensis and lipolysis are both way too low in ME/CFS
• “Because mTOR is a nutrient-sensing pathway, it can be deactivated by fasting and severe calorie restriction (CR), which exert metabolic effect that are somewhat similar, but not identical, to those of rapamycin42.”

• This is why I feel better when I don’t eat!
• 

• This scenario is in agreement with the hyperfunction theory125,126, which posits that aging and age-related diseases are associated with cellular (e.g., hypertrophy, hyper-secretory phenotypes, or SASP) and systemic (e.g., hypertension, hyperlipidemia, pro-inflammation, and hypercoagulation) hyperfunction. mTOR-driven hyperfunction eventually leads to organ damage, but it can be suppressed by rapamycin/everolimus125.
• Intermittent rapamycin or a single high dose

• Intermittent rapamycin administration (pulse treatment) was proposed in 2008, as a means of rejuvenating stem and wound-healing cells, thereby improving wound-healing instead of impairing it, as chronic treatment with rapamycin did138. Intermittent administration (e.g., once a week) can be considered a single dose repeated over time. In mice, a single dose of rapamycin does not cause glucose intolerance, but a single dose of a dual mTORC1/mTORC2 antagonist does causes it128. Consistent with that finding, weekly treatments with rapamycin for 22 weeks inhibited mTORC1 and protected against insulin resistance in C57BL/6 mice fed a high-fat diet, whereas mTORC2 activity remained intact70. Higher single doses of rapamycin can be used when administration is intermittent than when it is chronic, and it appears that it is the peak concentration of rapamycin that is especially beneficial2. This is in part because high peak levels enable rapamycin to cross the blood–brain barrier. For example, rapamycin prevents obesity associated with hyperactive mTOR in hypothalamic POMC neurons139. Furthermore, intracerebroventricular injection of rapamycin is sufficient to decrease weight gain140. Intraperitoneal injections of rapamycin produce high blood levels of the drug and prevent weight gain when administered every other week. Indeed, a single intraperitoneal administration decreases weight gain for 10 weeks without additional injections140. By contrast, administration of rapamycin by oral gavage did not prevent weight gain132.

• Kineret® (Anakinra)

• “Treating elderly patients with anti-inflammatory drugs blocking IL-1B function should help with maintaining healthier blood production.” here

“Anakinra is a medication used to treat a range of inflammatory conditions. It is a synthetic version of the naturally occurring interleukin-1 receptor antagonist (IL-1Ra), a protein that helps to regulate the body's immune response.

Anakinra works by blocking the action of interleukin-1 beta (IL-1β), a cytokine that plays a key role in the body's immune response and is involved in many inflammatory diseases. By blocking the action of IL-1β, anakinra can reduce inflammation and improve symptoms in conditions such as rheumatoid arthritis, systemic juvenile idiopathic arthritis (SJIA), and cryopyrin-associated periodic syndromes (CAPS).

Anakinra is given as a subcutaneous injection by a healthcare professional or by the patient themselves. The dosage and frequency of injections depend on the specific condition being treated. Common side effects of anakinra include injection site reactions, upper respiratory infections, and headache. More serious side effects may occur, such as an increased risk of infection or allergic reactions, so it is important to talk to a healthcare professional before taking anakinra to determine if it is an appropriate treatment option.

Anakinra is generally well-tolerated, but it is not recommended for use in people with a history of severe allergic reactions to anakinra or other components of the medication. It is also not recommended for use in people with active or chronic infections, such as tuberculosis or hepatitis B. It is important to follow the healthcare professional's instructions carefully and to report any side effects or concerns promptly.

• Rejuvenates blood in mice, ScienceAlert

• Anakinra works by blocking the inflammatory signal interleukin-1β (IL-1β), which damages the biological machinery used by the stem cells that develop into blood cells.
• "An aging blood system, because it's a vector for a lot of proteins, cytokines, and cells, has a lot of bad consequences for the organism," says geneticist and senior author Emmanuelle Passegué, from the Columbia University Irving Medical Center in New York.

• Ilaris® (Canakinumab)

• “Canakinumab is a monoclonal antibody medication used to treat a range of inflammatory conditions. It works by targeting interleukin-1 beta (IL-1β), a cytokine that plays a key role in the body's immune response and is involved in many inflammatory diseases.

Canakinumab is primarily used to treat a rare genetic disorder called cryopyrin-associated periodic syndromes (CAPS), which includes three different conditions: familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease (NOMID). These conditions are characterized by recurrent episodes of fever, rash, joint pain, and other symptoms.

Canakinumab is also used to treat a type of arthritis called systemic juvenile idiopathic arthritis (SJIA), which is characterized by joint inflammation, fever, rash, and other symptoms. In addition, it has been investigated as a potential treatment for a range of other inflammatory conditions, including gout, atherosclerosis, and certain types of cancer.

Canakinumab is given as a subcutaneous injection by a healthcare professional. It is usually given once every 8 weeks for CAPS and once every 4 weeks for SJIA. Common side effects of canakinumab include injection site reactions, upper respiratory infections, and headache. More serious side effects may occur, such as an increased risk of infection or allergic reactions, so it is important to talk to a healthcare professional before taking canakinumab to determine if it is an appropriate treatment option.” From ChatGPT

• Arcalyst® (Rilonacept) (table 1).

• “Rilonacept is a medication used to treat a rare genetic disorder called cryopyrin-associated periodic syndromes (CAPS), which includes three different conditions: familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease (NOMID). These conditions are characterized by recurrent episodes of fever, rash, joint pain, and other symptoms.

Rilonacept is a recombinant fusion protein that works by binding to interleukin-1 beta (IL-1β), a cytokine that plays a key role in the body's immune response and is involved in many inflammatory diseases. By binding to IL-1β, rilonacept prevents it from activating immune cells and causing inflammation.

Rilonacept is given as a subcutaneous injection by a healthcare professional. The dosage and frequency of injections depend on the specific condition being treated. Common side effects of rilonacept include injection site reactions, upper respiratory infections, and headache. More serious side effects may occur, such as an increased risk of infection or allergic reactions, so it is important to talk to a healthcare professional before taking rilonacept to determine if it is an appropriate treatment option.

Rilonacept is a relatively new medication, and its long-term safety and efficacy are still being studied. It is not known whether it is safe and effective in children under the age of 12 or in pregnant or breastfeeding women. It is important to follow the healthcare professional's instructions carefully and to report any side effects or concerns promptly.

• Cartivix®, Matrix® and Verboril® (Diacerein) (Not Available in US)

• “Diacerein is a medication used to treat osteoarthritis, a degenerative joint disease that is characterized by the breakdown of joint cartilage and underlying bone. Diacerein is classified as a slow-acting drug for osteoarthritis (SADOA) and is believed to work by inhibiting the production of certain cytokines, including interleukin-1 beta (IL-1β) and tumor necrosis factor alpha (TNF-α), which are involved in the inflammatory response in osteoarthritis.

Diacerein is a derivative of rhein, which is a natural substance found in the roots and leaves of some plants, including rhubarb. It is available in capsule form for oral administration and is typically taken once a day. Diacerein is usually well-tolerated, but common side effects may include gastrointestinal symptoms such as abdominal pain, diarrhea, and nausea. Rarely, it can cause liver problems, so liver function tests are usually performed before and during treatment.

It is important to note that diacerein is not a painkiller and may take several weeks to months to produce noticeable effects on joint pain and function. It is typically used in combination with other treatments for osteoarthritis, such as nonsteroidal anti-inflammatory drugs (NSAIDs), physical therapy, and lifestyle changes. As with any medication, it is important to talk to a healthcare professional before taking diacerein to determine if it is an appropriate treatment option.” From ChatGPT

• More information from ChatGPT that’s revealing:

• Interleukin-1 (IL-1) is a pro-inflammatory cytokine that plays a crucial role in the immune response and inflammation. It is involved in many different diseases and conditions, such as rheumatoid arthritis, osteoarthritis, gout, and autoinflammatory syndromes. Therefore, blocking IL-1 signaling can be an effective strategy for treating these conditions.
• There are several ways to block IL-1, including:

• IL-1 receptor antagonist (IL-1RA): IL-1RA is a naturally occurring protein that competes with IL-1 for binding to the IL-1 receptor. It acts as a potent inhibitor of IL-1 signaling and can block the activity of both IL-1α and IL-1β. The recombinant form of IL-1RA, anakinra, is approved for the treatment of rheumatoid arthritis and other autoinflammatory conditions.
• IL-1β monoclonal antibodies: Monoclonal antibodies that specifically target IL-1β can block its activity and reduce inflammation. Canakinumab (Ilaris) and gevokizumab are two such antibodies that have been approved for the treatment of autoinflammatory syndromes.
• Soluble IL-1 receptor type 2 (sIL-1R2): sIL-1R2 is a naturally occurring protein that can bind to IL-1 and prevent it from interacting with the IL-1 receptor. It is not as potent as IL-1RA, but it has been shown to have some inhibitory activity against IL-1.
• Small molecule inhibitors: Several small molecule inhibitors of IL-1 signaling have been developed, such as an orally available selective inhibitor of the NLRP3 inflammasome MCC950. These inhibitors act at various points in the IL-1 signaling pathway and can block IL-1 activity.

• Overall, IL-1RA and IL-1β monoclonal antibodies are the most potent and clinically effective ways to block IL-1. However, the choice of treatment would depend on the specific disease or condition being targeted, as well as the patient's individual needs and circumstances.

Other, likely short-lived options:

• HELP Apheresis e.g. here

So with that, let’s see if we can find supplements that will increase IL-1Ra (Interleukin-1 receptor antagonist) or help the body generate it - to thereby reduce inflammation and support healthy blood production.  

Adiponectin induces the anti-inflammatory cytokines IL-10 and IL-1RA in human leukocytes, per here.  So perhaps there is a way to get that.  Throwing that into Amazon (here), apigenin comes up.  So let’s see what ChatGPT has to say about their relationship:

Apigenin and adiponectin are two biologically active compounds that have been studied for their potential health benefits.

Apigenin is a type of flavonoid that is found in a variety of plant-based foods, including fruits, vegetables, and herbs. It has been shown to have anti-inflammatory, antioxidant, and anti-cancer properties.

Adiponectin is a hormone produced by fat cells (adipocytes) that is involved in regulating glucose metabolism and fatty acid oxidation. Adiponectin levels in the blood are inversely related to body fat levels and have been shown to be decreased in obesity and type 2 diabetes.

Studies have suggested that apigenin may have an impact on adiponectin levels in the body. In animal studies, apigenin has been shown to increase adiponectin levels and improve glucose metabolism. However, more research is needed to confirm these findings in humans and to understand the mechanisms by which apigenin may affect adiponectin.

It's important to note that while apigenin and adiponectin have been shown to have potential health benefits, they should not be used as a substitute for medical treatment. If you have any concerns about your health or nutrition, you should speak with a doctor.

And then to vet if it is pro- or anti- coagulant, ChatGPT was used, and answer marked in the cross-check list here.

Apigenin is a naturally occurring flavonoid that is found in a variety of plant-based foods and has been suggested to have anti-inflammatory and anti-cancer properties. There is limited research on the effects of apigenin supplementation on blood clotting.

In general, blood clotting is a complex process that is regulated by many factors, including the balance between pro-clotting and anti-clotting factors. While some studies have suggested that apigenin may have an anti-clotting effect, other studies have shown no significant effect on blood clotting.

More research is needed to fully understand the effects of apigenin on blood clotting and to determine safe and effective doses for supplementation.

Interestingly, you can buy IL-1Ra here for research purposes.  It is very likely the active component of Kineret/Anakinra.

Daily intake of fish or omega-3 increased adiponectin by a whopping 14-60%. Here.  And other supplements like the ones here all seem to increase adiponectin.  Which fits.  Including Chamomile tea, which is a potent source of apigenin per here.

Now CBD has also shown positive results in this condition, so let’s ask ChatGPT about it:

There is limited research on the relationship between CBD and adiponectin, but some studies have suggested that CBD may have an impact on adiponectin levels. In animal studies, CBD has been shown to increase adiponectin levels and improve glucose metabolism. However, more research is needed to confirm these findings in humans and to understand the mechanisms by which CBD may affect adiponectin.

Interestingly, in normal/healthy adults, the #1 source of IL-1Ra is e-coli, and Kineret/Anakrina is produced by e-coli (see here WRT their note about e-Coli allergy “Proteins made from bacteria called E. coli. Ask your healthcare provider if you are not sure”), and in ME/CFS patients e-Coli in the gut is severely low (see here).  So this all fits.

Additionally, there are other IL-1B blockers, per here:

• Interleukin (IL) 1 is a highly potent proinflammatory mediator that is important in immune defense and in immune-mediated disease.
• Three pharmacologic inhibitors (sometimes termed blockers) of IL-1 are commercially available:

• Anakinra (Kineret)
• Canakinumab (Ilaris)
• Rilonacept (Arcalyst) (table 1).

And blocking IL-1Beta reverses immunosuppression in mouse models, here.

C.  Treating the Excess Micro Coagulation:

Prescription/Drugs

The following are now commonly-used treatments for long-COVID, with some notes sprinkled in from my own research as to effectiveness and experience.

1. One of the following approaches:

1. Heparin (taken as ​​Lovenox)

1. Low Molecular Weight Heparin (LMWH) is Lovenox.  

1. "If insurance will pay for LMWH (Lovenox), use 30 mg. in AM". That's for slender patients like me.  From here.  And it is recommended to be taken sublingually, here.
2. Sublingual is preferred, as injections may trigger the over-active (IL-1Beta) inflammation mechanism, somewhat nullifying the impact of the anticoagulant. (And I’ve confirmed this on myself - I bloat up and turn red immediately after the shot, ears, neck, face, feet, and stomach.)
3. Sublingual is however not common and untested effectiveness, e.g. here. “Nevertheless, it is noteworthy that, although promising, the sublingual route of heparin administration has not been extensively investigated for LMWH.” Dr. Berg however highly recommends sublingual, here.

2. LMWH may be multi-role additionally, as it binds to bacteria, fungi, and viruses, e.g. here

2. Triple Therapy - South Africa Study (here)

1. Apixaban (Eloquis) 5 mg twice a day,

1. “Apixaban is an oral anticoagulant medication that works by selectively inhibiting Factor Xa, which is a key component in the coagulation cascade. Specifically, apixaban binds to both the free and the clot-bound Factor Xa, inhibiting its ability to activate thrombin, which is the enzyme that promotes the conversion of fibrinogen to fibrin, leading to blood clot formation. By inhibiting Factor Xa, apixaban reduces the risk of blood clots in conditions such as deep vein thrombosis (DVT), pulmonary embolism (PE), and stroke in patients with atrial fibrillation.” from ChatGPT

2. Clopidogrel (Plavix) 75mg once a day,

1. “Clopidogrel is an oral antiplatelet medication that works by selectively inhibiting the adenosine diphosphate (ADP) receptor on platelets, which inhibits platelet activation and aggregation. Clopidogrel does not directly act on clotting factors but rather affects platelet function and prevents the formation of blood clots in arteries.
   Platelets are small, disk-shaped blood cells that play an important role in the formation of blood clots. When an injury occurs, platelets are activated and begin to stick together, forming a plug that stops the bleeding. However, in some cases, platelets can become overactive and form clots inside blood vessels, which can cause serious health problems such as heart attacks and strokes.
   Clopidogrel inhibits the activation of platelets by blocking the ADP receptor, which is necessary for platelet activation and aggregation. By reducing platelet activation and aggregation, clopidogrel reduces the risk of blood clots in conditions such as acute coronary syndrome, myocardial infarction, and stroke.” from ChatGPT.

3. Baby Aspirin 75mg once a day, with fish oil and/or SPMs

1. “Aspirin, including baby aspirin (low-dose aspirin), is a nonsteroidal anti-inflammatory drug (NSAID) that works by blocking the activity of an enzyme called cyclooxygenase (COX). This enzyme is involved in the production of prostaglandins, which are molecules that cause inflammation, pain, and fever.
   Mast cells are a type of immune cell that play a role in the body's response to allergens and other irritants. When mast cells are activated, they release a variety of chemicals, including histamine, which can cause inflammation, itching, and other allergic symptoms.
   There is some evidence to suggest that aspirin may have an impact on mast cells. In particular, aspirin has been shown to inhibit the release of histamine from mast cells in vitro (in a laboratory setting). This effect may be due to aspirin's ability to block the activity of COX, which is involved in the production of a type of prostaglandin (PGD2) that stimulates mast cell activation and histamine release.”  ChatGPT.
2. Baby aspirin has multi-fold benefits, as in addition to being an anticoagulant, it helps in the promotion of Resolvins, and long-lasting resolvens from here (payed service)

1. Aspirin is a COX1 inhibitor at lower levels, and at higher levels, it also changes the enzyme function of COX-2 via acetylation.[ref]
2. Aspirin is unique among NSAIDs in that it acetylates COX2, which then triggers the formation of ‘aspirin-triggered specialized pro-resolving mediators‘ or AT-SPMs. These aspirin-triggered SPMs include AT-lipoxin A4, AT-resolvin D1, and AT-resolvin D3.[ref][ref]
3. Aspirin-triggered SPMs are unique in that they have a prolonged half-life and act to resolve inflammation for longer.[ref] It is likely why only aspirin, and not other NSAIDs, helps to prevent heart disease and reduces the risk of colon cancer (for some people).

4. Atorvastatin here to reduce LDL-C which is often too high for fibrinolysis to take hold, as lipid metabolism is disturbed in ME/CFS (see here). (Bromelain also helps, see below.)

3. Rivaroxaban is an anti-clotting drug being investigated as a possible treatment for Long COVID patients with microclots.[1], here
4. The “Berlin Miracle” approach, Aptamer BC 007, here

1. Anti-thrombin, also appears to likely inhibit IL-1Beta
2. References here and here
3. Looks very effective, but likely not available until 2024, per here
4. Need to see if there are other sources for it.

Supplements

• NAC

• From the Butterfly Method:
• Biohackers studying live blood microscopy before and after vaccination have found strong evidence of disruption of blood cell dynamics and were able to treat them with high dose sodium bicarbonate and NAC. The utilize 1 gram of sodium bicarbonate 3 times a day and high dose NAC around 2000mg 3x a day.

• Figure 11. Left - post-vaccine blood under dark field microscopy with “rouleaux” effect, of red blood cells stacking, Right - blood with normal surface charge dynamics after starting high dose NAC and Sodium Bicarbonate.
• Vascular mineralization could be contributing as deposited iron is “leaked” into the blood cause coagulation over time and autoantibodies against blood surface targets and the persistent clotting studies in Long Covid looks identical to the type of clotting expected to be triggered by free iron. In the case of blood clots resistant to enzymatic breakdown it is most likely caused by the presence of iron in the clot, oxidizing enzymes attempting to break them down and curcumin would be an excellent therapeutic approach as it binds iron and acts on blood coagulation.

• Piracetam 

• Dr. Teitelbaum recommends Piracetam- 1200mg twice a day for 2 weeks, then 2400mg twice a day for 2 weeks, then adjust to optimum dose (up to 4800mg a day). He recommends that it be taken with Hydergine.

• In healthy volunteers, piracetam mediated a direct stimulant effect on prostacycline synthesis and reduced the plasma levels of fibrinogen and von Willebrand's factors (VIII: C; VIII R: AG; VIII R: vW) by 30 to 40%, from here, and more details in this doc, here.

• If you get a headache from it, you need more Choline, per here.
• 8 g piracetam daily in 3 divided doses at 8-hourly intervals, here.
• Extremely effective for reducing brain-fog and feeling yourself again, more on why here.

• Serrapetase

• 20,000 SPU to 120,000 SPU total daily dose, with smaller doses at more frequent intervals preferred (i.e., 40,000 SPU three times daily on empty stomach). Enteric coating may improve efficacy. Anecdotally, some are taking much higher doses, but this hasn’t been studied. Here.
• 240,000 SPU’s x 4/day

• Nattokinase

• Start at a subtherapeutic dose to assess tolerability (i.e. 2,000 FU once daily on empty stomach). Some may experience a Herxheimer reaction so it’s best to start slowly.
• Titrate up dose as tolerated to appropriate dose based on medical history & other medications.
• 4000 FU x 4/day, here.

• Lumbrokinase

• Use Boluoke 600,000 IU 3 times daily.  Here.
• 80mg x 4/day, here.

• Taurine

• Anti-fibrin and platelet effects per here: “reducing intravascular fibrin and platelet deposition, which in turn reduces downstream microvascular thrombosis and improves cerebral vascular patency.”
• Hepatoprotective effect (here)
• Also helps reduce SIBO and SIFO via increase in bile salts (here)

• Bromelain

• 500 to 1000 mg/day for Bromelain, from Hemex labs, here.
• 1200 GDU x 4/day, here
• We’re currently doing 2,400 GDU 2x/day
• Helps reduce high Lp(a) or high PAI-1 that is common in ME/CFS because of dietary restrictions, and high Lp(a) or high PAI-1 brock fibrinolysis. here

• Grape Seed Extract, helps with venous insufficiency, here

• Seems to activate uPA system for fibrinolysis (consumption of fibrin), here
• Promotes wound healing
• Often combined with Amla extract (e.g. here), Amla extract was associated with a 36% reduction in platelet aggregation, or blood clotting. here

• Evening Primrose Oil here
• L-Glutamine, here (practically no max dose)
• Vitamin B9 Folate (L-5-MTHF) and B12 Methylcobalamin here
• Rutin, here

• “Rutin proved to be the most potently anti-thrombotic compound that we ever tested in this model,” says Flaumenhaft. Of particular note, rutin was shown to inhibit both platelet accumulation and fibrin generation during thrombus formation.”
• Up to 4 grams per day, here.

• Turmeric with 1% Black Pepper, shown to break down fibrin

• 8 – 16 gm/day of turmeric for therapeutic impact.
• Note this limits iron uptake in the intestines, so do not take if you are anemic.

• Resveratrol, natural blood thinner here
• EGCG, natural blood thinner here
• Fish oil, natural blood thinner here

• Need 3+ grams to have therapeutic effect
• “In peripheral artery disease, a 4.4g supplement of DHA/EPA for 3 months increased resolvin E3.” source here and see SPMs below for additional benefits

• Diosmin/Hesperidin, helps with blood vessel conditions here
• Pycnogenol, here
• “Probiotics. Certain probiotic bacteria, especially the Lactobacillus reuteri NCIMB 30242 strain, have been found to improve markers of thrombosis risk.” here
• Hydrogenated water, here, and see how it helps on cerebral ischemia, here, and here

• Used here to clear urinary blood clots.
• “Inhaled hydrogen gas (H2) has been shown to have significant protective effects on ischemic organs. Clinical trials abroad have shown promise that treatment of patients suffering from stroke, cardiac arrest, or heart attacks may benefit from inhaling hydrogen gas during the early recovery period.” here

• Ginkgo Bilobo, here
• Feverfew, here
• Aloe, here

Light Therapy

• Many who have recovered from ME/CFS have cited the “location effect”, where moving from a darker/colder climate to a sunny/warm climate has lead to a full or mostly-full recovery.

• This may be a result of many factors, one of which could be that intense IR light tends to be anticoagulatory, per NIH

Resources

• Great article on what helps to prevent blood clots, here.  
• NIH summarizing effect of dietary supplements on blood clotting, here

D.   Treating Dysregulated Immune System: (ones in bold are under consideration)

When the clots and MCAS are treated, blood flow to the gut will improve and the immune system will start to improve on its own (note that a big portion of our immune system comes from our gut, here).  Sleep will also improve, which will help the immune system as well.  For example, treating the clots and MCAS alone, my oral thrush completely went away.

But nonetheless the immune system will need help along the way, in the form of direct support and correcting gut dysbiosis.

Immune Support

• IV IG (here) (I had this and it temporarily helped me)

• Shown to reduce T-cell over-activity.

• Hyperbaric chambers (also helps with reperfusion injury from the system low oxygenation).

• Note that for severe cases, the endothelial is too damaged, and this treatment will likely cause more endothelial damage, from the cycling of high and low pressure.

Healing The GI System

As the condition worsens, the body becomes progressively more intolerant to foods containing histamine and any foods that naturally cause a healthy body to inflame (carbs, sugars, etc.), largely as a result of inflammation, under-production of stomach acid, bile salts, and digestive enzymes (NIH), which is likely a result of inflammation-induced damaged to the thyroid (discussed above), subsequent overgrowth of bacteria and fungi in the small intestine (NIH), and resultant toxin- and ischemic- damage to the intestinal barrier (NIH).

As the food intolerance increases, the diversity of the microbiome decreases out of the sufferer’s natural need/desire to eat foods that don’t make them feel sick.  

And the human gastrointestinal (GI) tract contains trillions of bacteria, with estimates ranging from 10^14 to 10^16 bacteria. And this bacterial population in the gut is essential for many aspects of human health, including digestion, metabolism, immune function, and protection against harmful pathogens. (source: ChatGPT)  So once the cycle starts that prevents a properly-varied diet, material and difficult-to-reverse damage is done to these literally this huge community of 100s to 10,000 trillions of bacteria living in the gut.  Which then results in more food sensitivities, and improper immune function, including tendency towards histamine intolerance and MCAS as the gut is progressively overgrown with fungus and LPS-producing bacteria (which in turn trigger platelet activation, e.g. here, found here, and cleave of proteins, NIH)

Details on the biomarkers for histamine intolerance are here. And an excellent view on the difference between the flora of sufferers of this disease and healthy controls is here (tbiomedcentral).

Unfortunately, many (author included) unknowingly make their condition worse by taking standard probiotics which are otherwise may be helpful for those in good health.  

The `why` of this is multifold:

1. Many probiotics either directly or indirectly produce lactic acid in the gut and/or contribute to SIBO/SIFO (small intestinal overgrowth of bacteria and/or fungus).

1. And even some (controversial) recent research is indicating that oral probiotics are harmful to health even for already-healthy people (e.g. here) by reducing microbiome diversity.
2. With fungal overgrowth (common in ME/CFS) and resultant “leaky gut” the lactic-acid produced by most probiotics results in higher lactic-acid in the bloodstream, directly causing fatigue.

2. Many ME/CFS patients already suffer from SIBO (Small Intestine Bacterial Overgrowth) per NIH and Candida, or are prone to SIBO (here).

1. And many probiotics simply make these conditions worse as they will colonize the small intestine in a counter-productive way, instead of doing what is needed, which is to assist in decolonizing the small intestine.
2. And often the typical advice for improving gut health (adding fiber) will make the SIBO worse - which further triggers both clotting and MCAS - if not done in a carefully-coordinated way with the proper probiotic/prebiotic/postbiotic support.

3. Antibiotics, often prescribed to treat gut dysbiosis, are a trigger for inflammation and coagulation (e.g. here) and very-often reduce or eliminate helpful, butyrate-producing (which heal the gut) bacteria while then allowing pathogenic bacteria room to thrive

1. But interestingly, some are actually anti-coagulants, so ME/CFS symptoms can sometimes improve temporarily on antibiotics, depending on which are used and the nature of the antibiotic, only to get much worse after the course of antibiotics is done.
2. There are two HUGE exceptions to this, both minocycline and doxycycline are anti-inflammatory and work well against the bacteria seen in ME/CFS.  Details below in Restoring a Healthy MicroBiome.

4. H2 blockers, while reducing histamine inflammation and having the potential to help, often can CAUSE SIBO because they reduce stomach acid, which is one of the ways the body prevents bacteria from over-growing the small intestine.

1. So then the end goal if you are on H2-blockers is to figure out how to get off of them without a relapse.
2. Spore-based probiotics, Transfer factor, Lactoferrin (caution if low iron), and/or ImmunoSEB (or similar more below) and natural anti-inflammatories (above) may be helpful here.

5. Lack of understanding on what is inflammatory or anti-inflammatory based on your genetics and the status of your current intestinal flora.  These can be understood, and interpreted with the following two resources.

1. Genetic Lifehacks, here - for knowing your genetic propensity for inflammation and recommendations for how to reduce it.

1. Inflammation is the #1 cause of gut dysbiosis, so this information is extremely helpful.

2. Microbiome Prescription, here - for knowing the current state of your gut biome (intestinal flora), and recommendations based on literature review on what probiotics to take to rebalance it.
3. Ombre, here.

1. For example, this author’s worst-offender bacteria is here.  Below is an example, where the author has at least 50-fold the presence of this harmful bacteria compared to a healthy individual:
2. “Corynebacterium, 51x normal. A genus of bacteria characteristically cells are rods with filaments attached and produce filamentous microcolonies; facultative anaerobes; carbohydrates are fermented. The genus has only one type species i.e. Corynebacterium matruchotii. Causative agent of diptheria which affects the nasopharyngeal passageways and in suseptible individuals can produce a toxin which inhibits protein synthesis in the host.
3. Monolaurin is very effective against it per here

6. Ischemic damage to the intestines is common in this disorder, particularly as it progresses.  So typical solutions to low gut motility - such as digestive enzymes - can actually make the condition worse because of the inflammation- and clotting- induced ischemic damage to the intestinal barrier.  Such damage can make digestive enzymes dangerous, as they can actually digest the intestinal lining even further.

1. This specific NIH talks about how in Ischemic conditions the digestive enzymes can digest the intestines themselves.
2. So often supplements for anti-glycation, anti-inflammation, anti-oxidation, ATP production, etc. and then supplements such as tribuyrin are necessary to rebuild the gut barrier are necessary before taking the digestive enzymes, otherwise the digestive enzymes may actually do more damage to the intestines... which the author has personally experienced (it is uncomfortable).

7. Ischemichic damage, gut dysbiosis (including SIBO/SIFO), inflammation, and clotting all result in Vitamin deficiencies systemically, notably:

1. Vitamin K2
2. Vitamin A
3. Vitamin D
4. Vitamin E
5. Vitamin B12

And these errors are particularly bad given that gut health is by far the most important aspect to fix, as it is the key to overall health, and likely the key to longevity (e.g. here).

And that as usual, general advice is often worth what you paid for it.  

The whole picture needs to be looked at when following your genetics and the state of your current intestinal barrier function, and (large-) intestinal flora (recalling the small intestine should have little bacteria in it, in comparison to the large intestine).  

For example, cross-checking what Microbiome Prescription recommends against the recommendations (and contra-indications) from Genetic Lifehacks is recommended - as well as cross-checking against the 5 core pillars of treatment, as done for this author’s recovery, here.

Note that many “How I treated SIBO” articles online actively made my condition worse, as they often include materials which induce an inflammatory response or damage the intestinal barrier (e.g. taking too many powerful digestive enzymes and/or to much pepsin HCL).

Such treatments, in others, is fine - and that’s why these treatments are so successful for patients who are not genetically prone to this disorder - but often materially make Long-COVID and ME/CFS sufferers worse, particularly if not done with gut barrier healing and energy supplementation.

It is only after taking the whole picture into account (e.g. not using any SIBO-killing techniques that CAUSE inflammation) does treating SIBO start to work and improve many sufferers’ conditions.

With all that said, below are techniques, probiotics and supplements that seem to be well-tolerated and in fact help fight SIBO/SIFO in patients with ME/CFS and Long-COVID, which have been used without knowing (a) your genetics or (b) your current gut biome state.  (Knowing your genetics and current biome state will accelerate the recovery and reduce the risk of making yourself worse with treatment.)

Motility Support

The two most important aspects of restoring proper motility are supporting and activating the Vagus nerve and supporting the Thyroid.

For details on supplements to support the Vagus Nerve, see above, and for activation, see below.  And for details on supporting the Thyroid, see below.

Vagus Nerve Activation

In addition to supplementing the Vagus nerve as above, activating the nerve is necessary.  The most effective technique this author has found for that is deep, belly-breathing at 6 breaths per minute.  Often one can feel their GI motility initiate even in a session as short as 5 minutes.  

Deep breathing via the stomach like this is activates the vagus nerve receptors on the heart, which in turn activities part of the brain where the vagus nerve is bidirection.  And this is likely why there are so many questions (e.g. here) on why one poops after yoga (deep breathing through the belly instead of chest is one of the core teachings and practices of yoga).

Vagus Nerve Support

Lion’s Mane Mushroom, see cross-check here for details until this section is flushed out.

Thyroid Support (WIP)

This author has not yet investigated sufficiently to provide proper pointers here, as the Thyroid root of the disorder is a new discovery to the author, found via the Butterfly Method, and fitting exactly with the author’s symptoms.

Testing (WIP)

1. Thyroid and parathyroid workup and analysis by an endocrinologist, preferably also with a Thyroid ultrasound (NIH).
2. Excellent writeup on thyroid testing in The Butterfly Method (here) and From Fatigued to Fantastic.

Foods (WIP)

1. Carrots, Raw (Uncooked)

1. Organic preferred, fresher the better, washed, but not peeled (to leave the biome intact)
2. Raw carrots, for ME/CFS/Long-COVID/IBS/SIBO are a super food.
3. They are one of the few foods that help nearly every malfunctioning part of the body in this condition, and are therefore mentioned throughout.
4. In the case of the thyroid malfunction, raw (uncooked) carrots stimulate the thyroid and can return hypothyroidism back to standard thyroid function (NIH)

1. Note that this is yet another reason to have blood tests and thyroid tests performed by an endocrinologist, as if you have hyperthyroidism (which can also cause ME/CFS, carrots can make your condition worse; same NIH as above).
2. That said, a poor-man’s way to tell which you have is differentiated by your tendency of bowel movements (prior to any interventions/corrections):

1. Hypothyroidism often results in constipation (here)
2. Hyperthyroidism often results in diarrhea (here)

Supplements (WIP):

It’s worth noting that from here and other similar sources, many of the energy and anti-inflammatory supplements discussed above (e.g. vitamin D, quercetin, DHA, phosphatidylserine, curcumin, grape seed extract, and magnesium with malic acid) need to be taken prior to, and maintained during, the support of the thyroid.  As the thyroid needs them in addition to the following to go back to proper homeostasis.

1. Boswellia (also known as frankensents)

1. Shown in combination of Spirulina and Curcumin to reduce nodules on the Thyroid, per here.

2. Beef Liver Extract

1. 500mg morning and evening (or Spirulina for a vegetarian option) per an initial idea on how to supplement from the Butterfly-Method
2. Specifically designed to help lung health because it helps the thyroid
3. Example supplement here
4. Is also an excellent methylation donor, for those who have genetics that result in methylation deficiencies.

3. Artichoke 

1. Helps the thyroid as well, per here

1. And this is likely why it’s used to support motility, as the thyroid stimulates motility.

4. Iodine

1. Per Dr. Teitelbaum in From Fatigued to Fantastic, the standard american diet does not contain nearly enough iodine.

1. The American diet used to have iodine, as it was in bread.  But then bread makers discovered bromine was cheaper.
2. And bromine limits the body’s uptake of iodine, making the problem even worse. NIH
3. Excerpt from his online energy audit materials (here):

1. “Nutritional supplements that provide high quality thyroid glandular extract can promote healthy thyroid function. Optimal iodine levels are also critical for both healthy thyroid and breast tissue function. Iodine deficiency with secondary goiters used to be endemic in the U.S. until manufacturers began adding iodine to wheat flour and, to a lesser degree, salt. This eliminated much of the problem — until flour makers started adding bromine instead of iodine. This not only resulted in iodine consumption dropping by as much as half in the last decade, but even worsened the effects of iodine deficiency, as bromine may block thyroid function. One of the main problems caused by iodine deficiency is hypothyroidism, which can cause fatigue, weight gain and pain.

4. Dr. Teitelbaum recommends the following thyroid support supplements:

1. BMR complex, here (high recommendation)
2. EuroMedica Tri-Iodine, 6.25mg, here (medium recommendation)

2. Example product here used anecdotally by a recovered ME/CFS sufferer.
3. All sources, including the Butterfly-Method recommend starting on iodine SLOWLY and after cofactors that support it, as iodine increases oxidative stress on the Thyroid.

1. Butterfly Method: “...  iodine should be started one week after the cofactors are started to allow thyroid cofactors to stabilize in the system before stimulating the thyroid which can cause oxidative stress. Particularly NAC and selenium are important before blue iodine in the case of an underactive thyroid.
2. Thyroid antibodies should be tested as iodine supplementation stimulating the thyroid can cause it to become overactive in the case of thyroid auto-immune disease.”

5. IP-6 (IP6)

1. Used in subclinical hypothyroid cases, NIH
2. Has the advantage that it binds excess iron in tissues (caused by leaky vasculature) and ALSO binds to excess calcium and iron in tissues and vasculature, per Butterfly-Method

6. Vitamin A

1. Per Buttery-Method, A study found that 45% of the US population does not have adequate vitamin A. Butterfly Method
2. Vitamin A is an incredibly important cofactor for iron transport, with studies showing that vitamin A supplementation was more correlated to hemoglobin production than iron supplementation.  Butterfly Method
3. When supplementing Vitamin A, it is important to consider the ratio of Vitamin A to D and Vitamin D to K2, which is hard to pin down and varies dramatically according to the source.

1. And note that Carrots, just after sweet potatoes, are one of the best sources of Vitamin A, at least according to this region of Canada, here, and have all the benefits listed above and in pertinent sections of this document.

7. DIM 

1. Supports the thyroid as well, apparently, here,

1. And the why turns out to be that high levels of estrogen lowers the thyroid hormone, here, as “excess estrogen levels, aka “estrogen dominance”, causes the liver to produce high levels of thyroid binding globulin (TBG), which, as its name suggests, binds thyroid hormone and decreases the amount of thyroid hormone available to the body.”  Confirmed by multiple scientific publications, e.g. NIH

2. MoreThereThanHere, who has recovered quite well, is taking artichoke extract and DIM, likely for this reason.

8. Spirulina

1. “spirulina helps to fight against physical weakness and thyroid dysfunction.” here

9. Vitamin D & K2

Timing of Thyroid Supplementation (WIP)

As with everything with this order, there’s a tricky balance of getting the right combination of supplements, at the right timing and titration to not cause a Herxheimer reaction or put too much stress on another part of the body.

Iodine seems to be the last step in the process, as it kicks the thyroid into overdrive (from being asleep), causing oxidative stress.  So from the Butterfly method and other readings, it should go last, after everything else is in place.

1. To start make sure are sufficient first (from here)

1. Selenium
2. Zinc
3. Iron

1. And one way to do this is to heal the vasculature, so iron is not leaking into tissues)
2. And all 3 of these are needed by the body for many reasons, so making sure they are at healthy levels is important regardless of the thyroid state.

2. Vitamin A

1. As it is often deficient in SIBO, and is critical for the body making proper use of iron and for blood production.
2. As above, Vitamin A supplementation is higher correlated with reducing anemia than iron (although iron is a necessary condition, just like Vitamin A - it’s just that iron is very prevalent)

3. DIM

1. Doesn’t increase the thyroid, it just makes it so the body isn’t throwing away what the thyroid is producing (via thyroid binding globulin (TBG)).
2. So by adding in DIM, the Thyroid will for sure be no more stressed, and in fact may be less stressed (as it doesn’t have to do as much work to have an impact on the body).
3. So DIM is a logical step after after basic nutrition is in place.

4. Adequate Methylation Support

1. From genetics (some genetics result in excellent methylation capability irrespective of diet), diet, and/or supplements.
2. Methylation is key for reducing toxic load, and toxic load is part of the reason the thyroid shuts down.  
3. And toxic load leads to oxidative stress.  And turning the thyroid back on, increases the oxidative stress of the thyroid, which can then cause further damage to it (it is shut down by the body, most likely, as a protective mechanism).
4. So it is critical to make sure the toxic load is reduced first, which requires making sure your body is setup with sufficient methylation support.
5. For example, the author has a very strong genetic propensity (found via 23andme connected to GeneticLifeHacks) to need heavy methylation support from diet, with almost no capability for methylation without support from diet/supplements.  And this was confirmed via a more thorough analysis via dnasupplementation.com.

5. IP6

1. Removes iron and calcium from tissues and the vasculature and makes it usable to the body, which

1. reduces oxidative stress
2. increases usable iron availability
3. Allows increased blood production
4. May have to do this via enema if gut dysbiosis is too bad.

Some WIP additional notes:

• DIM might be step 1.  As it doesn't put stress on thyroid, it just makes the body stop throwing awake the work the thyroid is doing.  too high estrogen makes the body dispose of thyroid hormones.  The smart dude who's helping me is taking it, and it made his metabolism and thyroid better.
• Artichoke likely step 2.  Helps give thyroid what it needs to thrive.
• Boswellia step 3.  As it also gives thyroid conditions it needs to recover.
• Iodine step 4.  Here's why: From drug researcher who's seen a ton of cases: "
  I didn't add anything to the iodine, but if someone is deficit, aggressive supplementation can be dangerous.
  
  When the UK first started adding iodine to salt, thoudands of people died because of the sudden increase.
  
  So when I started, I only did one drop per day. Then after a few months, increaser it to 2. Decided to stay at 2 because the deficiency was resolved."

Medications:

• Synthroid

Resources:

• Butterfly Method which is extremely specific on the testing needed.

• This is by far the best resource I’ve seen.

• From Fatigued to Fantastic by Dr. Teitelbaum
• One note from Dr. Teitelbaum that stuck out to this author.
• “Normal ranges should always be thought of like shoe sizes.  The normal range for shoe sizes is size 4 to 15.  So when your doctor says your thyroid is in normal range, tell them that their foot is also in the normal range… but that doesn’t mean that size 4 shoes fit them!”
• So in other words, a given thyroid test being in normal range means nothing WRT if your thyroid is functioning properly.  As for example that normal range very well may include people who have severe metabolic syndrome and severe type II diabetes, particularly if it’s a normal range based on the average American.

Daily Iodine Needs

• 140 micrograms per here

Healing the Intestinal Barrier (Fixing Leaky Gut)

A necessary condition of healing the intestinal barrier is to encourage formation of tight junctions while simultaneously reducing inflammation and removing pathogens.  

Image source Frontiers.

One of the core difficulties in implementing this in practice is that removing pathogens often causes inflammation.  So it is highly desirable to find and utilize substances that themselves are anti-inflammatory, or mitigate inflammation, which removing pathogens.  One seemingly-unique substance in this effort is monolaurin, which is found in very high concentrations in the first breast-feedings (colostrum) of a newborn and is what helps clear the newborn baby’s intestines of pathogens, while keeping inflammation down and encouraging tight intestinal junctions.

Tight Junction Supplements

Restoring proper, tight junctions in the intestines is a necessary but not sufficient condition for allowing normal absorption and to reduce and eventually eliminate food intolerances.  

Potassium

Potassium is VERY often deficient in ME/CFS/Long-COVID patients and is absolutely critical for tight-junction support, methylation, thyroid, controlling inflammation, vasculature and literally every function in the body.  Standard blood work should reveal your Potassium levels.  

Potassium Chloride instead of salt with your meals is a good way to increase potassium levels if you cannot do so via diet alone.  Often they can be done as a direct 1:1 substitution, but it is best to use a tool like Chronometer or Google Sheets to calculate how much Potassium, Chloride, and Sodium you are getting in a day to make sure they are in healthy ranges.

One thing that perplexes doctors and patients about this condition is that sufferers, when in a hospital on IV fluids, usually end up being at their best.  Which is part of why the at-home suffering is invalidated.

Part of the reason for this is very likely inadequate Potassium in the body from gut dysbiosis and resultant restricted diet.

So if you notice that you do much better when on IV fluids, the reason is very likely that a single liter of IV fluids gives a full-day’s amount of Potassium (40mEq, NIH).  

In this author’s experience, during my downward spiral, and 9 trips to the emergency room, I would always leave the emergency room feeling good in comparison, for example.

This is potentially also why the disease tends to be ignored… patients are seen on their best days because they are in the ER and on IV fluids which help tremendously.

Low potassium disrupts the gut barrier function per NIH 

"Low potassium diet could increase intestinal permeability and thereby lead to bacterial translocation". This NIH agrees.

ChatGPT is EXTREMELY Bullish on needing adequate potassium to maintain the intestinal barrier function and that leaky gut will occur without enough potassium.

“Potassium chloride (KCl) is a common supplement used to replenish potassium levels in the body. While there is limited research on the direct impact of potassium chloride on intestinal barrier function, potassium is known to play a critical role in maintaining the integrity of the intestinal barrier. Potassium is required for the proper functioning of tight junctions, which are the structures that seal the gaps between intestinal cells and prevent harmful substances from passing through the gut wall.

Low potassium levels can weaken the tight junctions, making the intestinal barrier more permeable and increasing the risk of inflammation and infection. In this sense, potassium chloride supplementation may indirectly support the intestinal barrier by maintaining optimal potassium levels in the body.

However, it's important to note that excessive potassium intake can also have adverse effects on the body, particularly in people with kidney disease or those taking certain medications. As with any supplement, it's best to consult with a healthcare provider to determine the appropriate dosage and potential risks associated with potassium chloride supplementation.”

Vitamin K2

• This Frontiers Immunology article here covers the intestinal benefits of Vitamin K2 better than this author ever could.  From the article (summarizing):

• The lack of Vitamin K2 in the western diet, and the associated lack proper gut bacteria flow well into the excess prevalence of common inflammatory disease in western societies, such as cancer, Type 2 Diabetes, Alzheimer’s disease, Multiple Sclerosis, ME/CFS, and Parkinson’s disease with the figure below explaining the multifarious benefits of Vitamin K2.
• The benefits are full-body, but Vitamin K2 is extremely important for healing the intestinal barrier and restoring the gut biome.
• And antibiotics (which often are a trigger for ME/CFS) often kill off the bacteria in the gut that normally produce Vitamin K2 (Harvard)

Frontiers Immunology FIGURE 3 Functions of VK in multiple-organ systems, such as testis (9), brain (10–14), intestine (15–17), muscle (18, 19), bone (20–22), liver (7, 23), kidney (24, 25), pancreas (26, 27), fat tissues (28–30), and cardiovascular system (31–34), and biological processes involved in anti-oxidation (3, 4), immune response and anti-inflammation (5, 6), and cancer progression (7, 8), and associated with protective and promoting roles in diverse organs or tissues throughout the human body are summarized above. The figure is in a non-editable format.

Astaxanthin

• Shown to help the integrity of the intestinal barrier, increases the expression of tight junction proteins, which help to maintain the integrity of the intestinal barrier, reduces intestinal inflammation and oxidation, which protects the intestine from damange, and shows benefit for microbiota composition. From ChatGPT.
• And from the literature, it seems EXTREMELY helpful. "AMPK helps mitigate increased intestinal permeability. This makes astaxanthin use even more desirable as it turns on AMPK to support gut lining repair, helps modulate autophagy, and helps support the intestinal mucosal barrier." from here

TUDCA

• Hepaprotective and helps reduce gastrointestinal inflammation and promote formation of tight junctions.
• Helps to recover the liver to allow the liver to better remove Amyloid deposits.

Lion’s Mane Mushroom

• See cross-check here for details until this section is flushed out.

Lutein

• "Lutein improves LPS-induced intestinal barrier function and tames the inflammation by decreasing intestinal epithelial cells destruction, strengthening tight junction, and inhibiting TLR4/MyD88 signaling pathway." NIH.
• “Lutein and zeaxanthin are the only forms of vitamin A that affect constipation frequency, as was observed in the present study. This may be attributed to the fact that lutein is a powerful antioxidant that can decrease intestinal oxidation [51,52] and prevent intestinal damage [53,54]. In the animal model of inflammation, lutein was found to be the only retinoid to selectively inhibit the activation of transient receptor potential ankyrin 1 (TRPA1) and the resultant inflammation [55]. Additionally, lutein and zeaxanthin were observed to modulate proinflammatory cytokines (IL-1β, IL-6, and IFN-γ) in the liver, duodenum, jejunum, and ileum, as well as anti-inflammatory cytokine (IL-10) in the liver and jejunum in the animal model [56].” NIH
• ChatGPT is extremely bullish on Lutein, and also mentions it's from Kale and Spinach. "Lutein has been shown to increase the expression of tight junction proteins, which help to maintain the integrity of the intestinal barrier. Moreover, lutein has been shown to have anti-inflammatory properties, which may help to reduce intestinal inflammation and protect the intestinal barrier from damage."

Tributyrin

• Improves intestinal health in multifarious ways per NIH. Protects the intestinal barrier and liver in mice, per NIH. ChatGPT is equally or more bullish on it, mentioning it improves tight barrier function, improves composition of healthy bacteria, is anti-inflammatory, and appears to protect the intestine from damage.
• Useful information from a tributyrin vendor on dosing, and ramping schedule here.
• Butyrate supplementation seems to reduce inflammation and positively increase the number of good bacteria here, found here.

• Which explains why so many recovered MCAS/ME/CFS/Long-COVID patients swear by Tributyrin X, e.g. here and here

• Our current study further demonstrates that butyrate enhances the intestinal barrier function by facilitating the assembly of tight junctions via activating AMPK. NIH
• Also helpful in reducing Candida overgrowth as it is shown to help suppress Candida by attacking its roots, NIH, and here, which then helps to reduce intestinal permeability (as the roots pass through the intestinal wall).

• And note that Candida feeds off of the essential amino acids (e.g. Arginine) that the body needs to maintain and heal the vasculature (more details below).

Sodium Butyrate

• The Butterfly Method here also mentions this, specifying Sodium Butyrate instead of Tributyrin, and linking to this NIH, noting that research shows that taking butyrate supplements actually increase the butyrate producing bacteria (which is a good thing, typically, as butyrate helps to heal the gut lining).

• And from this NIH butyrate protects the kidneys, and kidney pain seems common in ME/CFS.

• And also has an excellent note/analysis reproduced below:
• A paper titled, “Diet, Metabolites, and “Western-Lifestyle” Inflammatory Diseases” discusses the important role of GPR109A in restoring gut homeostasis due to modern challenges. This paper discusses niacin, butyrate and other therapeutic concepts at this mechanism. Anecdotally, experts in gut disruption caused by glyphosate and other modern challenges utilize butyrate, melatonin and other compounds acting at GPR109A with great success for treating gut/brain axis disruption.
• And anecdotally Amazon reviews for supplements talk about glyphosate inducing their ME/CFS with Candida overgrowth and the treatments herein returning their gut to normal, e.g. here.

Sodium Butyrate vs. Tributyrin

• This author is yet to determine which is more effective for Long-COVID/ME/CFS.

• Sodium Butyrate is 7.0 pH (perfectly neutral) so it can be added without changing pH of the GI system.  
• This author is unable to find the pH of Tributyrin
• According to this vendor, the Sodium buffering makes it easier on the intestine than things like Butyric acid and Tributyrin.

• And anecdotally, this author’s whole GI system hurts when Tributyrin is taken.
• The author will report back findings here after taking the Sodium Butyrate instead, here, which has a fascinating review that echos this author’s findings:

• Many of the helpful things for getting out of this disorder come from livestock science, where the incentives are:

• Effective
• Safe at scale
• Low side effect
• Cheap

Butyriticum (Pendulum)

• Butyrate-producing bacteria are notably missing in ME/CFS/Long-COVID patients (NIH)
• To the author’s knowledge this supplement from Pendulum here is the only Butyrate-producing commercial bacteria available

• (Please comment using Google Docs comment functionality if you know of others.)

Melatonin

• Found via MoreThereThanHere and also Butterfly-Method, which cite ScienceDirect for reducing thrombosis and activating GPR109A to help heal the gut

Collagen Peptides

Larazotide

• Heals leaky junctions in the gut, per Wikipedia
• From the literature, it seems like it has promise to cure Celiac disease.
• This author cannot find a source of it though.

BPC-157 Arginate

• BPC-157 may serve as a novel mediator of Robert’s cytoprotection, involved in maintaining of GI mucosa integrity, with no toxic effect. NIH

• Normally produced by the stomach to feed into intestines.

• BPC-157 supplement with Thymosin Alpha-1 here

• This vendor is expensive, but it's also a premium product and includes two peptides, so for a product you can buy in the US, it's not too bad. Especially since the purity on the peptides from this company is generally accepted to be the best available for purchase in retail quantities.

https://www.peptidesciences.com/blog/how-does-bpc-157-work

https://www.peptidesciences.com/blog/how-does-bpc-protect-organs-during-infection

Vitamin C

• Required for collagen production (NIH)
• Actively lowers histamine levels and symptoms (NIH)
• Helps gut motility.
• Note that a non-acidic version will likely be easier on the gut, allowing the epithelium (the intestinal barrier function) to heal quicker and inducing less of a histamine response.

• Magnesium Ascorbate like is often recommended by MCAS sites, e.g. mastcell360 because

• (1) this form is non-citrus and non-fermentation (both of which are a triggers, see below) source of Vitamin C and
• (2) this form is non-acidic, with a Ph ot 7.0, so it’s easier on the stomach.

• Allergy Research Group’s Magnesium Ascorbate, here, has very few additives and is recommended by MastCell360.

• This is similar to why it’s beneficial at least during recovery to take Magnesium Malate instead of Malic Acid directly, as Malic Acid is quite acidic and thereby increases intestinal permeability (a bad thing) whereas Magnesium Malate is not acidic.

Vitamin A

• Used by the body for stimulating collagen production (per NIH), and collagen has been found to be low in ME/CFS patients, 80% below healthy volunteers (e.g. NIH, NIH).
• A key note is that Vitamin A is readily absorbed through the skin (Healthline), while being poorly absorbed in the gut because of the aforementioned issues, so a key workaround to increase vitamin A body-wide is to do so via topical application.

• This can then help the gut heal itself from the inside-out, as collagen is key to the gut lining, regulating the gut biome, and maintaining a healthy intestinal barrier (here)

• Half-life of retinol is 2-9 hours, but Vitamin A is about 12 days, per ScienceDirect.

Vitamin D

• Note that in this condition Vitamin D should not be taken without also taking Vitamin K2.  

• See details above and below on insufficiency of Vitamin K2 in the western diet (and more here), even more severe deficiency in intestinal distress (common in ME/CFS), and the need of K2 to prevent Vitamin D supplements from causing calcium deposits on smooth muscles, the vasculature, and capillaries resulting in worse PEM.

• Helps the body absorb and make use of Calcium and Phosphorous --  both are critical for building bone. (here)
• Vitamin D promotes calcium absorption in the gut and maintains adequate serum calcium and phosphate concentrations to enable normal bone mineralization and to prevent hypocalcemic tetany (involuntary contraction of muscles, leading to cramps and spasms). NIH
• The form of D3 to take is Cholecalciferol, which is the form produced by the skin in response to D3 in the body being exposed to sun.

• Note that this can be applied topically to circumvent the poor gut absorption of Vitamin D in the presence of SIBO.
• Be VERY careful on dosing of Vitamin D, as its half-life is as long as 2 months (NIH), so overdose is hard to correct.
• Be particularly careful when applying D3 Cholecalciferol topically, as it is VERY EASY to go FAR BEYOND safe maximum doses, and the skin absorbs this form very effectively (since the skin normally produces this form).

Vitamin E

• A fat-soluble nutrient found in many foods. In the body, it acts as an antioxidant, helping to protect cells from the damage caused by free radicals. NIH
• It helps keep the immune system strong against viruses and bacteria. MedicinePlus
• It helps form red blood cells and widen blood vessels to keep blood from clotting inside them. MedicinePlus

Vitamin B12

• The factors that enable its absorption are often not present in gut dysbiosis and it is required in many processes in the body, including protein synthesis and healing.

Suppressing Pathogens

Candida

Fungal (Candida) overgrowth is VERY common in ME/CFS and NIH 1, 2, John’s Hopkins, and nearly any institution that has studied ME/CFS.

• And Candida Albicans feed off of the amino acids that are necessary for maintaining healthy vasculature, specifically arginine.  
• “Candida albicans can metabolize and grow on arginine, agmatine, or guanidinobutyrate as the sole nitrogen source.” NIH
• Candida Inhibits Nitric Oxide production (NIH)

Monolaurin

• Laurcidin here
• Extremely beneficial in multiple ways:

• Anti-bacterial
• Anti-fungal (particularly against Candida Albicans)
• Anti-viral
• Anti-inflammatory
• Beneficial for endothelial healing

• What is in the very-first feedings of a new-born human baby from breast-milk (Colustrum).
• ChatGPT sums up the literature on it very well:
  Monolaurin is a chemical compound derived from lauric acid, which is found in coconut oil and other natural sources. Monolaurin is known for its antimicrobial properties, which means it can help fight against certain types of bacteria, viruses, and fungi.  Research has shown that monolaurin can help inhibit the growth of a range of pathogens, including the flu virus, herpes simplex virus, HIV, and some strains of bacteria that can cause food poisoning.  In addition to its antimicrobial properties, monolaurin has also been studied for its potential to boost the immune system, improve heart health, and even reduce inflammation in the body.
• And for full references and more details, see the Cross-Check list here.

Carrots, Raw (Uncooked)

• Contain natural anti-biotics and a powerful anti-fungal agent, falcarinol (ScienceDirect).
• And this is why they are highly recommended for Candida kill-off, e.g: "Carrots contain the powerful, fungus fighting nutrient falcarinol and plenty of antioxidants, such as beta carotene." here.

• And even better, Carrots are high in fiber, so they tend to absorb the toxins that are released when they kill the Candida.
• And initially, during dysbiosis, the carrots will often pass straight out in the stool undigested (as a result of the carrots own microbiome), so the toxins will not re-enter the host and thereby will not induce inflammation.

Olive Leaf Extract e.g. here

• Oleuropein (40% Total Polyphenols), Plus
• 20% Hydroxytyrosol Complex 
• For treatment of Post-COVID syndrome, here
• “Hydroxytyrosol (HT), a peculiar olive and olive oil phenolic antioxidant, plays a significant role in the endothelial and cardiovascular protection associated with olive oil consumption” NIH

Butyric Acid / Tributyrin / Sodium Butyrate

• Shown to help suppress Candida by attacking its roots, NIH, and here

Systemic Enzymes

• Are helpful in multiple ways:

• Cellulase has been shown to attack Candida, e.g here

• Cellulase is present in the Systemic Enzyme blend Holozyme, which is highly recommended for treating MCAS (here).

• Thyroid dysfunction is common and may actually be one of the main contributing factors to kicking off gut dysbiosis (found via Butterfly Method), with TONS of NIH finding thyroid dysfunction after COVID:

• NIH, NIH2, NIH3, NIH4, NIH5, NIH6, NIH7, NIH8
• Springer1, Springer2, Springer3, Springer4, Springer5, Springer6
• ScienceDirect, ScienceDirect2, Wiley, lww, liebertpub, Tandfonline, Oup, ingentaconnect, BMJ, tandfonline, MDPI

• And Thyroid dysfunction cause bile salt disruption (NIH) which causes improper breakdown and indigestion of all food products

• And as the condition worsens, the thyroid malfunction increases, causing worse malabsorption
• And malabsorption is a key contributor to gut dysbiosis - as food is left to bacteria to ferment rather than being digested and absorbed by the body.

Elderberry

• Potent antimicrobial (NIH), antiviral (NIH)
• High in anthocyanin, which when combined with Bromelain, helps improves endothelial function and skeletal muscle oxygenation status in adults per NIH.

Restoring A Healthy Microbiome

Correcting gut dysbiosis is a necessary condition for full recovery, but needs to be done with care and observation while also in parallel healing the intestinal barrier function, as above.

Foods

Carrots, Raw (Uncooked)

• Carrots contain their own microbiome that protects them against harmful bacteria and fungus, including falcarinol which is highly anti-fungal (ScienceDirect).

• As a result, they are unique or near-unique in regards to combinations fibers and carbohydrates in that they do not feed bacterial or fungal overgrowth in the small intestine, and in fact have been shown to reduce both. (NIH)

Ginger, Raw (Grated)

• Similar to carrots, they are anti-microbial and anti-fungal.

Probiotics

It is worth noting that the safest and most effective form of probiotic supplementation for ME/CFS is via enema.  As noted above, SIBO, in addition to a compromised intestinal barrier function and compromised immune system are often a problem in ME/CFS.  So introducing bacteria where they don’t belong (the small intestine) can worsen the condition, or worse, cause pathogenesis of otherwise non-pathogenic probiotics, e.g. NIH.

Further, while many long-term sufferers of ME/CFS have tried oral probiotics time and time again with no success, there is a demonstrated 70% full-recovery rate for enema probiotics, NIH, which is a substantially higher recovery rate than even Fecal Matter Transplant (FMT) (which appears to be the second-highest recovery rate for ME/CFS).

It is likely because most commercially-available probiotics produce lactic acid, which is already severely high in the bloodstream of ME/CFS patients.  Whereas what is needed is butyrate-producing bacteria in the large intestine.

• Spore-based Probiotics

• Helps clear small intestine of pathogens.
• Spurs growth of useful bacteria.
• Combining many different forms of the same spore bacteria appears to be beneficial, and from recovered ME/CFS patients, this has proven anecdotally helpful (.e.g reviewing the regime of MoreThereThanHere, here, which combines many different strains of coagulans, subtilis, and clausii) and a clinical trial linked herein, direct link here, where 4 different strains of Bacillus clausii were used.

• And maybe given the 4-5 ratio of good-to-bad in MegaSporeBiotic, it will be a net positive for me.  I think it might be.
• The major strains that have been found to help are:

• Bacillus subtilis

• Promotes fibrinolysis and reduces clotting per NIH and via the DFE produced by subtilis shown in BioMed
• Inhibits mast cell degranulation per NIH
• Produces Vitamin K2 Mk-7 per here, see details on the benefits/need-for K2 below
• So just like e.Coli Nissly 1917 below makes the anti-inflammatory drug Kineret, Bacillus subtilis makes vitamin K2, which is necessary for removing calcium deposits in the cardiovascular system.

• Bacillus clausii

• “Soil-based probiotics benefits have been investigated in the treatment of small intestinal bacterial overgrowth (SIBO) in patients with IBS. In particular, one probiotic containing all four strains of Bacillus clausii was shown to help control SIBO in a small study with 60 people.”  here

• Bacillus Lichenformis
• Bacillus Indicis
• e.Coli Nissle 1917 (Mutaflor)
• Akkermansia

• Examples products that include these strains, and many who have recovered from ME/CFS or Long-COVID have used these with success, e.g. here and here:

• In MegaSporeBiotic, for example, all except Coagulans are great, even orally.  Coagulans is the only lactic-acid-producing spore.  Several others produce butyrate or acetate, both of which are beneficial, including e.Coli Nissle 1917 and Akkermansia.
• The remaining all produce beneficial things for the intestine and so can live in the small intestine:

• Bacillus Subtilis
• Bacillus Clausii
• Bacillus Lichenformis
• Bacillus Indicis

• So that means in total, the following are probably OK to take orally:

• Akkermansia
• Bacillus Subtilis
• Bacillus Clausii
• Bacillus Lichenformis
• Bacillus Indicis
• e.Coli Nissle 1917 (Mutaflor)

• Deep Immune probiotic has viruses (bacteriophages) that infect bad bacteria, more info here.

• Bacteriophages

• LH01 - Myoviridae
• LL5 - Siphoviridae
• T4D - Myoviridae
• LL12 - Myoviridae

• Spore Probiotics:

• DE111 Bacillus subtilis
• Bacillus coagulans
• Lactobacillus acidophilus
• Bifidobacterium lactis

• Maltodextrin

• ProbioSEB CSC3

• Bacillus coagulans LBSC (DSM 17654)
• Bacillus subtilis PLSSC (ATCC SD 7280)
• Bacillus clausii 088AE (MCC 0538)

• Designs for Health ProbioSpore (one of MoreThereThanHere’s probiotics)

• Bacillus coagulans (Lactospore)
• Bacillus subtilis (DE11)
• Bacillus coagulans (SNZ1969)
• Bacillus coagulans (Lacris-15)
• Bacillus clausii (CSI-08)

• OrthoSpore IG:

• Immonulin 1g

• IgG 480mg

• Bacillus coagulans (SNZ1969)
• Bacillus subtilis (HS43)
• Bacillus clausii (B106)

• SOLARAY Bacillus Coagulans Probiotic (ordered here, from here)

• Bacillus Coagulans (unspecified strain)

• MegaSpore has additional fascinating strains, here

• Bacillus Licheniformis

• Produces proteases that aid protein digestion
• Produces full spectrum of B vitamins

• Bacillus Indicus HU36™
• Produces carotenoids: lycopene, astaxanthin, beta-carotene, and lutein
• Produces quinols and vitamins

• Bacillus Subtilis HU58™
• Produces nattokinase and vitamin K2

• Supports healthy GALT development

• GALT stands for Gut-associated lymphoid tissue, which is a component of the body's immune system that is located in the intestinal mucosa (lining of the gut). GALT plays a crucial role in the development of immune tolerance to food and commensal microorganisms in the gut, as well as in the protection against pathogens.
• GALT development is a process by which the immune system learns to distinguish between harmless substances, such as food and beneficial bacteria in the gut, and potentially harmful substances, such as pathogens. During the development of GALT, specialized immune cells called lymphocytes are trained to recognize and respond appropriately to these substances.
• GALT development begins early in life and is influenced by a variety of factors, including genetics, diet, and exposure to pathogens and environmental toxins. Breastfeeding and early exposure to beneficial gut bacteria are thought to be important for the development of GALT and for establishing a healthy gut microbiome.
• Impaired GALT development has been linked to a number of conditions, including food allergies, autoimmune disorders, and inflammatory bowel disease. Strategies to support GALT development include optimizing gut health through a healthy diet, probiotics and prebiotics, and reducing exposure to environmental toxins.

• Bacillus Clausii

• Supports immune function

• Bacillus Coagulans

• Supports immune function
• Produces L+ optical form of lactic acid

• The L+ optical form of lactic acid is the stereoisomer of lactic acid that has a specific rotation of +3.86°. It is one of two stereoisomers of lactic acid, with the other being the D- optical form which has a specific rotation of -3.86°. The L+ and D- forms are mirror images of each other and have the same chemical formula (C3H6O3), but their physical properties, including their specific rotation and behavior in chemical reactions, differ. Lactic acid is a naturally occurring organic acid that is produced during fermentation and is found in many foods, including yogurt, sourdough bread, and pickles.

• Escherichia coli strain Nissle 1917 (Mutaflor)

• This may seem controversial as e.coli is known popularly as being a harmful bacteria, and like everything in this document, it merits cross-checking against your condition and symptoms (for example the author is chronically constipated).
• E.coli is used to produce Kineret, which is a powerful anti-inflammatory known to improve blood production, details above.

• This author suspects strain Nissle 1917 is used, given this strains very-potent impact on encouraging anti-inflammatory cytokine production in the host (Frontiers-1, and notes from that article below).

• It is also found lacking in ME/CFS sufferers. (Source: Cornell, MEPedia, many others)
• Mutaflor, available for US/Canada here

• “Mutaflor therapy produced an improvement of the irritable symptoms in a majority of the patients. In particular, meteorism and the pain symptoms associated with it could be improved and the quality of life thus increased. 78 % of the patients rated the tolerance of Mutaflor therapy as “good” to “very good”.”, from vendor here
• Helps with IBD and colitis, here

• Some pioneering work on genetic engineering of this strain in Nature.
• From Frontiers-1 it seems to cure both diarrhea and constipation, via stimulation of IL-10 anti-inflammatory cytokine.

• EcN alters host cytokine responses upon stimulation, particularly by inducing high levels of the anti-inflammatory cytokine IL-10 (Cross et al., 2004; Güttsches et al., 2012; Kandasamy et al., 2016).
• In vivo studies using gnotobiotic pigs showed that colonization with EcN mediated greater protection against human rotavirus challenge than Lactobacillus rhamnosus GG (LGG), possibly due to stimulation of the innate immune system and activation of the DC-IL-12-NK immune axis (Kandasamy et al., 2016; Vlasova et al., 2016).

• This NIH shows that it’s almost free of any side effects, helping significantly with idiopathic constipation.
• Escherichia coli Nissle 1917 enhances bioavailability of serotonin in gut tissues through modulation of synthesis and clearance, Nature.

• Our own work has also recently linked alteration of 5-HT signalling with age related decline in gut function, including motility and the onset of chronic constipation40,41.

• E. coli strain Nissle 1917 has been reported to promote gastrointestinal motility and muscle cell contractility (Bär et al., 2009), from Frontiers.
• More positive results published here.
• How exactly E. coli Nissle 1917 is able to inhibit mast cells is currently not known. NIH
• And there are many many more papers that show positive effects on Endothelial function, clotting, inflammation, intestinal barrier function, etc. which are noted in the accompanying cross-check document, here (search “nissle”).

• Other helpful probiotics:

• Akkermansia, per above
• Both DSM17938 strain of Lactobacillus reuteri helps to kill Candida, along with Lactobacillus

• Rhamnosus GG, per here
• Rhamnosus

• Swanson Lactobacillus Rhamnosus (ordered here, from here)

• Lactobacillus Rhamnosus (unspecified strain)

• Particular interest in Lactobacillus rhamnosus GG (LGG) here

• Reuteri

• “NCIMB 30242 strain, have been found to improve markers of thrombosis risk.” here

• available commercially here

• “In this study, 56% of the children taking PPI’s developed SIBO, while only 6% of those taking PPI’s along with this [DSM17938] strain of Lactobacillus reuteri developed SIBO.” per here,

• available commercially here

• BioGaia Protectis Immune Active Probiotic (ordered here)

• Lactobacillus reuteri DSM17938
• Warning this product has additives that may nullify or make a net-negative depending on the severity of your symptoms.
• So you may need to do other reuteri strains first (e.g. NCIMB 30242 strain, available commercially here, improve, then can use this.

• More research and extensive notes on each of these (and other supplements) is in the supplement cross-check document here

• Make sure to read the comments, as they contain additional information on the supplement.

• For example of why cross-check is needed, take for example if you are using Heparin (Lovenox, Low Molecular Weight Heparin, enoxaparin sodium) as a blood thinner/anti-coagulant.  If that’s the case, do not take Lactobacillus Rhamnosus and many other Lactobacillus probiotics as they nullify the anticoagulant effect of Heparin (Lovenox), per NIH, and discovered via here.

• Heparin was degraded by:

• Enterococcus faecalis,
• Lactobacillus animalis,
• Lactobacillus casei,
• Lactobacillus casei subsp. casei,
• Lactobacillus casei subsp. rhamnosus,
• Lactobacillus pantheris,
• Lactobacillus paracasei subsp. paracasei and
• Lactobacillus rhamnosus.

• Heparin was not functionally degraded by:

• Lactobacillus acidophilus
• Lactobacillus aviarius subsp. Aviarius
• Lactobacillus brevis
• Lactobacillus parabuchneri
• Lactobacillus paracasei subsp. Torelans
• Lactobacillus reuteri
• Lactobacillus saerimneri
• Bifidobacterium bifidum.

• This yogurt is highly recommended (by the probiotic advisor, here) for constipation-dominant IBS.  

• Danone Activia. Here 
• Note that this is only recovered enough to tolerate yogurt and sugar, and a FANTASTIC option if you get IBS-D back.

• Bio-Kult (14 strains) (here)

Resources

Custom Probiotics is known for delivering temperature-controlled strains, and also delivering individual strains, here.

Anti-Inflammatory Supplements

• Minocycline and Doxycycline

• Minocycline, NIH, and how it’s also neuroprotective NIH.
• Doxycycline, NIH, how it’s anti-inflammatory, and is used with TUDCA, here indefinitely to treat Amyloidosis, which ME/CFS can mimic.
• Minocycline increases butyrate-producing bacteria in the colon, NIH.
• And this is likely why they lead to remission for this CFS sufferer, here, at Remission Biome, and Doxycycline was used for Ken Lassesen’s recovery at RemissionBiome, and was also (accidentally) used in recovery from MCAS for Keeya, here, with a guess at why it worked, NIH.
• And The Road Back protocol uses minocycline for inflammatory conditions, of which Long-COVID/ME/CFS is certainly one, with their protocol documented here.  So this is validating for the likelihood of minocycline helping.
• And likely why they are so useful in treating Chronic Lyme, NIH, and depressive disorders here, and helps to reduce disease-induced angiogeneis, here as well as promoting many other endothelial-healing impacts.

• Astaxanthin
• Fish oil and SPMs (see details above in Special Pro-Resolving Mediators)
• Low-Dose Aspirin

• Promotes SPMs, works in conjunction with Fish oil and SPMs (as above)
• Downside is worsens leaky-gut

• “Transfer Factor”

• From Colostrum is also recommended, here
• Example here of helping with CFS. (Ordered here)
• This is like Lactoferrin, but more filtered for folks who might have milk allergies because of the severe gut issues/SIBO/SIFO

• Lactoferrin

• Warning: Contains milk

• So depending on your sensitivity to Lactose, you may need to delay taking this until you have recovered enough to handle Lactose

• Anti-inflammatory for gut, lungs and systemically (per NIH, Frontiers)
• Helps iron absorption.
• Reduces gut permeability (NIH)
• Helps clear small intestine of pathogens (NIH)
• Helps reduce immune system inflammatory response to infections (NIH)

• Zinc-L-Carnosine and Carnosine

• Zinc promotes gut health and overall healing, and tighter intestinal barrier.
• Anti-glycation and prevents build of AGEs (Advanced Glycation End products)
• “Carnosine has been shown to prevent AGE formations through reduction of blood glucose, prevention of early glycation, and even reversing previously formed AGEs.” (NIH)
• “We found that carnosine supplementation in 3xTg-AD mice promotes a strong reduction in the hippocampal intraneuronal accumulation of Aβ and completely rescues AD and aging-related mitochondrial dysfunctions.” (NIH)

• “That's removal of brain amyloid beta plaques tied to dementia!” here

• Prevents/reverses age-related brain mitochondrial oxidation per NIH
• Carnosine is a dipeptide of β-alanine and L-histidine.

• The body consumes histidine to make histamine (and make a histamine storm), and it is the author’s guess that muscles (including gut muscles, brain, nerves, etc. end up low in histidine as a result
• And histidine is used in growth, repair of damaged tissues, and making blood cells. It helps protect nerve cells. per Rochester
• So it is the author’s view/guess that supplementing with Carnosine should help restore histidine in the body (and in the gut), which fits with many NIH findings, as above.

• ImmunoSEB (also helps digest blood clots)

• Serratiopeptidase,
• Bromelain,
• Amylase,
• Lysozyme,
• Peptidase,
• Catalase,
• Papain,
• Glucoamylase
• Lactoferrin

• Note that depending on your sensitivity to Lactose, you may need to delay taking this until you have recovered enough to handle Lactose

• Broccoli extract

• Histamine release is controlled via cAMP, which regulates pro- and anti-inflammatory activities: drugs that elevate intracellular cAMP levels reduce the production of pro-inflammatory mediators and increase the production of anti-inflammatory factors in numerous immune cells. NIH
• And broccoli and other cruciferous vegetables have been shown to increase levels of cyclic AMP (cAMP) in the body. This is due to the presence of compounds known as glucosinolates, which are abundant in cruciferous vegetables like broccoli, cauliflower, and kale.
• So by increasing cAMP, Broccoli is potently anti-inflammatory.  

• Cauliflower extract
• Artichoke extract
• Triphala 

• Staple in traditional Ayurvedic medicine for 1,000+ years to support immune system
• Anti-inflammatory, and does not seem to excite T-cells, per ChatGPT:

• Triphala is a combination of three fruits - Amla (Emblica officinalis), Haritaki (Terminalia chebula), and Bibhitaki (Terminalia belerica) - that has been used in Ayurvedic medicine for thousands of years. It has been studied for its potential benefits for digestive health, immune function, and other physiological processes.
• While there is limited research on the specific effects of triphala on T-cells, some studies suggest that it may have immune-modulating effects. Triphala has been shown to have potential benefits for reducing inflammation and oxidative stress in the body, which can help to support immune function. It may also have potential benefits for promoting the growth of beneficial gut bacteria, which can help to improve overall health and immune function.
• In addition, some studies have suggested that individual components of triphala, such as Amla, Haritaki, and Bibhitaki, may have potential immune-modulating effects. For example, Amla has been shown to have potential anti-inflammatory and antioxidant effects, while Haritaki has been studied for its potential benefits for immune function and anti-inflammatory effects.
• Overall, while more research is needed to fully understand the potential impact of triphala on T-cells and immune function, some studies suggest that it may have immune-modulating and anti-inflammatory effects. However, it is important to discuss the use of triphala with a healthcare provider, particularly if you have a history of medical conditions or are taking medications.

• Berberine, per ChatGPT, here

• Berberine is a natural compound that is extracted from various plants, including the Berberis shrub and goldenseal. It has been used in traditional medicine for thousands of years, and recent research has shown that it has a number of potential health benefits.
• Some of the ways in which berberine may impact the body include:

• Regulating blood sugar: Berberine has been shown to help lower blood sugar levels by increasing insulin sensitivity and reducing glucose production in the liver. This makes it a potential treatment for conditions such as type 2 diabetes.
• Lowering cholesterol: Berberine may also help to lower cholesterol levels by reducing the production of cholesterol in the liver and increasing the excretion of cholesterol in the bile.
• Supporting gut health: Berberine has been shown to have antimicrobial properties, which may help to kill harmful bacteria and other pathogens in the gut. It may also help to reduce inflammation in the gut and improve gut barrier function.
• Anti-inflammatory effects: Berberine has been shown to have anti-inflammatory effects, which may make it a potential treatment for conditions such as rheumatoid arthritis and inflammatory bowel disease.
• Supporting cardiovascular health: Berberine may help to improve cardiovascular health by reducing inflammation, improving cholesterol levels, and reducing the risk of blood clots.

• Overall, berberine appears to have a wide range of potential health benefits.

• Glycine is effective, see here
• Taurine increases bile salts, which reduces SIBO and SIFO, here
• IBGard increases bile salts and reduced inflammation, both of which should reduce SIBO/SIFO.
• Melatonin (which is VERY hard to dose properly) decreases intestinal transit times when in small doses (here).
• Oral Igg supplements (OrthoSpore Ig, or similar)
• Toxaprevent (here)

• 3 capsules twice a day empty stomach for 6 months 4.
• Toxaprevent 1 sachet 1 hour before lunch for 2 months

• Acetyl-L-Carnitine (here) to help body product Acetylcholine for proper nerve function (here: https://bioelecmed.biomedcentral.com/counter/pdf/10.1186/s42234-023-00104-7.pdf?pdf=button%20sticky)

• Results in bowel movement ~1.5 hours after taking
• Take first thing in morning
• Note that if your condition is severe, you may need to wait to progress before you can take this, as your intestinal muscles may have too much inflammation and too many clots, resulting in pain/damage when using this.  So the inflammation and clotting may need to be treated before starting this.

Things to avoid (if senescent T-cell problem, as is my case, not viral reactivation issue):

• AHCC

• Increases T-cell activity by stimulating IL-1B, per NIH
• Used in Japan for treatment of over 600 diseases, per here, and here, and improves parasympathetic tone per here.  Eliminated persistent HPV, here at 3g/day.  Full guide on it here.
• And it is recommended for ME/CFS, MCAS, and COVID post-sequelae, here, but not understood as to why it’s effective.
• Helps body deal with physical/disease stress in more productive way.
• Increases parasympathetic tone at rest, per here
• From ChatGPT, it is also good at suppressing one of the root problems of the disorder, the very potent, and very over-active Inflammatory Interleukin Cytokine IL-1Beta:

• “AHCC (Active Hexose Correlated Compound) is a natural extract derived from the mycelium of shiitake mushrooms, which has been suggested to have immunomodulatory effects.
• IL-1B is a pro-inflammatory cytokine that plays a role in the body's immune response, particularly in the regulation of inflammation. Elevated levels of IL-1B are associated with several inflammatory diseases.
• Several studies have investigated the potential impact of AHCC on IL-1B levels. One study published in the Journal of Experimental Therapeutics and Oncology in 2011 found that AHCC decreased the production of IL-1B in human immune cells called macrophages, which are known to produce high levels of this cytokine in response to inflammatory stimuli.
• Another study published in the Journal of Nutrition and Cancer in 2018 examined the effect of AHCC on colon inflammation in mice. The study found that AHCC supplementation decreased the expression of several inflammatory cytokines, including IL-1B.

• And fortunately, according to ChatGPT, it does not seem to cause clotting, and in fact in-vitro it helps to prevent blood clots and particularly useful is improving the lipid profiles, which are found to be off in ME/CFS patients (TO-DO, find the NIH that shows this).

• One study published in the Journal of Experimental Therapeutics and Oncology in 2011 found that AHCC reduced platelet aggregation in vitro, which is a key step in the formation of blood clots. However, it is important to note that this was an in vitro study, which means that the effect was observed in a laboratory setting and may not necessarily translate to the human body.
• There is currently no direct evidence that AHCC can prevent or treat blood clots in humans. However, some studies have suggested that AHCC may have cardiovascular benefits, such as reducing blood pressure and improving lipid profiles, which may indirectly affect the risk of blood clots.

• And from NIH, here, the research agrees that AHCC helps to make T-cells more effective.  Which in concert with reduced inflammation, should help the immune system eliminate pathogens more effectively, thereby having a net result of decreased inflammation.

Fecal Matter Transplant (Colonic)

One of potential core causes of ME/CFS is gut dysbiosis (which can result from any of the trigger(s) that cause inflammation, or from improper diet).  A fecal matter transplant - from the right donor - has canonically been shown to cause complete remission.  

That said, FMTs carry GREAT RISK because the donor may harbor a pathogen which could make you significantly sicker.  This is why, in clinical FMT applications, it is harder to become an approved fecal matter donor than to get into Harvard or MIT (here).

With all that said, below are instructions retrieved from a now-shut-down blog on how to do a DIY Fecal Matter Transplant.

Again, testing is everything.  If you are to do this, the donor needs to have their blood and stool THOROUGHLY tested for any pathogens.  And it is advisable to personally review their entire life, medical, and sexual history.

DIY Instructions (WIP)

• WIP document here

Example Remission Story

• Good story of how this drastically helped, here

Professional FMT

• Puretyclinic.com

• See FMT service here

Resources

• Specialty Enema Store https://enemasupply.com/
• Disposable Enema Bags on Amazon, here

Bacteriotherapy

Similar in concept to an FMT, but potentially safer (less risk of unknown/detected pathogens) and more effective, as noted below from NIH:

• “Moreover, a 70% response rate was obtained when 13 non-pathogenic bacteria were administered via colonoscopy in 60 ME/CFS individuals. Additionally, at 15–20 years follow up, 58% of cases reported maintained response without recurrence [176].”  Compared with:

• In a study of 34 ME/CFS participants who received FMT, 41% showed persistent relief after 11–28 months, while 35% reported only little or late relief [175].

A work-in-progress idea for an enema-based Bacteriotherapy is here.  

Removing Toxins

One of the core reasons the immune system dysfunctions so badly is because of the excessive toxin load from the progressive feedback loops of body-wide dysregulation and resultant toxins buildup, which is constantly being fed by the gut dysbiosis.

And one of the core ways toxins are removed from the body is via methylation in the liver (details here).  And depending on your genetics, you may have a tendency for low methylation capability.  And this can become particularly true when there is gut dysbiosis.

Without sufficient methylation capability, the toxins will not be removed quickly enough, resulting in more cycles of inflammation and oxidative stress to the body.  So it may be necessary, depending on your genetics and diet, to support methylation with foods (if tolerable with gut dysbiosis) or supplementation.

Supporting Methylation

With all of the above dysregulation of normal body functions, and in particular, gut dysbiosis, many toxins will build up, which puts a tremendous load on the methylation in the body.  And worse, often ME/CFS/Long-COVID sufferers have genetics that make them predisposed to insufficient methylation.  For example, this author has a 70% to 80% reduced capability of methylation:

And so as expected, improper methylation is observed in ME/CFS/Long-COVID (NIH) and therefore is and has been an active part of recovery for so many recovered ME/CFS-Long-COVID sufferers, e.g. here, which is a great resource on supporting the methylation cycle (and this author actually found it after writing the below - which is reassuring that the techniques converge from first-principles).

So donors of methylation may be needed - whether from food or from supplementation.  The top methylation donors are summarized below.

A great figure on all that’s required to support Methylation is here and reproduced below.  Note that in ME/CFS, and particularly if you have the genetic deficits for producing methylation components, you may need to supplement the methylation intermediaries (e.g. SAM-e) directly, and perhaps even via injection to avoid GI upset.

So from this figure, the key ingredients that are required for proper methylation are:

• Folate (Vitamin B9) in pre-methylated form:

• Methylfolate (5-MTHF)

• Vitamin B12 in pre-methylated form:

• Methylcobalamin

• Trimethylglycine, TMG so as to not cause excess acidic load in the intestines

• A colloquial name for TMG is Betaine, but the form matters because the mechanisms of action vary wildly depending on how the proteins are folded.
• For example Betaine-HCL is VERY acidic and hard on the intestines (usually a pH somewhere in the 1 to 2 range), for example.
• Whereas Trimethylglycine has a pH of approximately 6.0 to 7.5, so very neutral, and varies primarily based on manufacturing technique.
• So be VERY careful in choosing the TMG for supplementing methylation - so as to not damage your GI system with acid, and it is best to go with the ​​Trimethylglycine form as it provides better cellular protection, and is what is used in livestock for this same reason - to keep them healthy, and to increase yields of healthy livestock.
• From ChatGPT:

• “Trimethylglycine (TMG) and Betaine Anhydrous are chemically related compounds, but they are not exactly the same thing. TMG is also known as betaine, but Betaine Anhydrous is a more concentrated form of betaine that has had the water removed. Betaine Anhydrous is often used in dietary supplements, while TMG is used for various purposes, including as a feed supplement for livestock and as an osmolyte to protect cells from environmental stress. Both TMG and Betaine Anhydrous are known to be involved in methylation pathways in the body and may have similar effects on health and performance, but they have slightly different chemical properties and applications.”

• Allergy Research Group offers a clean, Trimethylglycine (i.e. not Betaine Anhydrous) version, here.

• Allergy Research Group is also trusted for having as many additives as possible.

And then for these to work properly, the body needs to have sufficient of the following:

• Biotin (B7)

• Recommended nearly everywhere for ME/CFS

• Choline

• Eggs, and particularly Quail Eggs are a good SIBO-safe source

• Cysteine

• Eggs, and particularly Quail Eggs are a good SIBO-safe source

• DHA

• Omega3s, either fish or plant based.
• Some genetic profiles need fish-based, some need plant-based.

• Magnesium

• Usually requires supplementation.
• Magnesium Malate is recommended as it includes Malic Acid, which helps in ATP cycle that is used in Methylation.

• Methionine

• Eggs, and particularly Quail Eggs are a good SIBO-safe source

• Niacin (B3)

• Use niacinamide to not accidentally flush
• See Healing the Vasculature for flushing Niacin, which requires Methylation be working before you try it.

• Potassium 

• If you’re diet-restricted because of SIBO Potassium-Chloride added to meals as a powder is a good option, e.g. MORTON SALT SUBSTITUTE, here 
• Make sure to count out your Sodium, Potassium, and Chloride intake when supplementing, including food so as to not go egregiously over the maximum or under the minimum per day of each.
• And see above about why Potassium is so critical.

• pyridoxine (B6) in methylated form:

• Pyridoxal 5'-Phosphate (P5P)
• Will increase histamine production from histadine

• riboflavin (B2) in phosphate form:

• ​​Riboflavin 5'-Phosphate (R5P)
• Will deplete catecholamines by stimulating MAOA and MAOA enzymes

• Sulfur, preferably methylated.  

• Green vegetables, fruits, and certain types of vegetables
• However, the levels of MSM in food sources are relatively low.
• So MSM (methylsulfonylmethane) supplementation is often needed.

• Taurine

• Need to supplement usually.

• Zinc

• Zinc-L-Carnosine has shown to be a dual-benefit by healing the gut and providing zinc to the body, here
• Zinc Picolinate most easily absorbed
• Zinc Sulphate mostly used in studies
• Zinc Testing

• Serum zinc
• RBC Zinc

• Might be more important for people with zinc transport issues

• Omega 3 is crucial for Zinc Transporter function

• https://pubmed.ncbi.nlm.nih.gov/25195602/
• You may have enough zinc, but low omega 3/omega 6 ratio might mean it does not get where it needs to be.

• Zinc is crucial, if not fundamental for the immune system

• https://link.springer.com/chapter/10.1007/978-3-030-16073-9_8
• https://www.hindawi.com/journals/jir/2016/6762343/

• Low Serum Zinc found in ME/CFS

• https://www.sciencedirect.com/science/article/abs/pii/S0165032705003125