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Might the Marshall Protocol be an effective treatment for EBV ME/CFS, but not other forms of ME/CFS linked to other viruses?

Hip

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The Marshall Protocol devised by Professor Trevor Marshall is designed to treat chronic diseases such as sarcoidosis, ME/CFS and several other illnesses. Trevor Marshall proposed that these diseases are all caused by L-form bacteria which create an intracellular infection inside cells.

Trevor Marshall theorized that L-form bacteria are able to synthesis proteins which block the vitamin D receptor (VDR) located inside the cell, and they do this in order to evade the immune response.

The VDR is the on/off switch for certain immune responses inside the cell, so by blocking the VDR with a protein, pathogens which live inside cells can thwart the intracellular immune attack, which allows them to survive long-term inside cells.

To address this thwarting of the immune response, the Marshall Protocol (MP) involves taking a blood pressure drug called Benicar (olmesartan), which computer modeling indicates can knock the bacterial protein off the VDR, and then bind to and activate the VDR, thereby switching on the intracellular immune response, and thus killing the intracellular pathogens.


But although Trevor Marshall proposed that ME/CFS is caused by intracellular L-form bacteria, there is no evidence that this is the case: ME/CFS has been linked to various viruses, and also to the intracellular bacterium Chlamydia pneumoniae, but not to L-form bacteria.

But nevertheless some people report that the Marshall Protocol improved their ME/CFS, including researcher Amy Proal (one of Trevor Marshall's colleagues), who had Epstein-Barr virus ME/CFS which was cured by the Marshall Protocol. So if we assume that ME/CFS is caused by chronic intracellular viral infection, and not by L-form bacteria, how does the Marshall Protocol work for ME/CFS caused by viral infection?

Well interestingly enough, Epstein-Barr virus (EBV) is also able to synthesize a protein which blocks the VDR, again for the purpose of thwarting the immune response. This protein is called EBNA3, and this paper describes how EBV makes EBNA3 in order to block the activation and functioning of the VDR as an immune evasion strategy.

This suggests that the Marshall Protocol might be effective for EBV ME/CFS, but may not work for ME/CFS associated with other viruses (like coxsackievirus B or HHV-6).

Unfortunately on Trevor Marshall's forums, the people trying the MP as a treatment for ME/CFS were not was thinking in terms of viral causes of ME/CFS; they were all following Marshall's ideas about L-form bacteria being the cause of ME/CFS. So nobody on these forums paid much attention to the various viral subtypes of ME/CFS, and whether the MP might work for some viral subtypes but not others.

But the fact that EBV blocks the VDR suggests that the MP may work if you have EBV ME/CFS. This form of ME/CFS usually appears after mononucleosis (glandular fever). Mononucleosis is caused by EBV 90% of the time (but more rarely may instead be caused by cytomegalovirus infection).

So for those with EBV ME/CFS, the Marshall Protocol might be worth revisiting. Of course if you have other co-infections alongside EBV, then the MP may not work very well. MP may only work well for ME/CFS patients who have chronic active EBV infection alone (which may be a fairly small subset of ME/CFS patients).

It would thus be an idea to test for the main 7 pathogens linked to ME/CFS, to see which you have. These 7 are: coxsackievirus B, echovirus, EBV, cytomegalovirus, HHV-6, parvovirus B19 and Chlamydia pneumoniae. The appropriate tests for these are detailed here.

Note: in the past antibiotics were used in the MP alongside Benicar, but these days antibiotics are not considered important, so you do not need to take these. Vitamin D avoidance (including from sunlight) I believe is still considered important in the MP; but note that the overall idea of the MP is not to reduce VDR activation through vitamin D avoidance, but to increase VDR activation by taking Benicar.



Note that EBV is not the only virus which thwarts the functioning of the VDR for immune evasion reasons: cytomegalovirus has also been shown to thwart the VDR for survival purposes. However, in the case of CMV infection, this down-regulates VDR expression, rather than blocks VDR activation. Thus the Marshall Protocol may not work for CMV ME/CFS, because the MP only unblocks the VDR, but I don't think it can counter a down-regulation of VDR expression.



More info about the Marshall Protocol in the posts: here, here, here, here and here.

Marshall Protocol websites:
https://mpkb.org/home/mp — Information website
https://www.marshallprotocol.com — MP forum
 
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percyval577

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I searched for relation beween VDR/VitD and other notorious viruses, in this thread:
https://forums.phoenixrising.me/threads/vitamin-d-and-viruses-that-can-trigger-me-cfs.77284/

The thread is still a stub though:
  • The enterovirus that has been shown to be vulnerable by (some) actions of VDR is not known for triggering mecfs.
  • There are more viruses known which need to be added, Zoster virus (some tick), dengue fever (some tick), malaria pathogen (not a virus, but some tick)
  • Other viruses would be nice not to be vulnerable by VDR/VitD, and this seems to be true indeed, as far as I have come

So, optimisticly, an action on VDR/VitD might be one parameter which can trigger mecfs.

On the other side, VDR has such a widespread range of effects, that this itself might seem to be too vague.
Not surprisingly, VitD levels (alone) or VitD alterations (alone) will not cure mecfs:
https://forums.phoenixrising.me/threads/vitamin-d-levels-in-me-cfs-and-other-diseases.77332/
and, many other diseases are associated with VitD deficiency too (not exactly altered VDR´s, not to forget).


In my own recent experience, VDR/VitD is important indeed, though in a concert, and I am sure enough that I am not deficient, so the alteration (in a small time frame) should be responsible for the effect.
 
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gbells

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It is surprising to see the MP brought up again. I thought it had already been debunked.

I tried the Marshall Protocol (MP) for CFS around 2010. In 2007 I was diagnosed with EBV (mononucleosis) and never recovered. MDs at that time expected me to recover within two months. To do the MP you need to have a PCP MD willing to do it and you have to sign up with them as a study participant. That gives you access to the participant section of the website. I found some of his nutritional recommendations to be nonsensical (ie. don't eat EPA) and when I brought up problems in the hidden forum was dropped as a patient.

There are multiple ways that EBV blocks apoptosis, the nuclear pathway is only one of three. So even if taking benecar off label helped one way cells would still be blocked through the other two and not lower the viral load. His protocol bans all Vitamin D, whether from sunlight, supplements and foods. He considers a good response to be worsening of your illness which he says is the body's immune system functioning better. This worsened my fatigue and made me more disabled. When all was said and done, it didn't work.

This poll shows 56% of CFS patients doing the MP get worse. Only 31% say they improved, which is exactly what you would expect from a placebo effect.

https://www.bmj.com/rapid-response/2011/10/31/patient-experiences-marshall-protocol-dangerous

That said, I think his recommendation to limit Vit D isn't total nonsense. Vitamin D acts as a steroid so it inhibits immune response when it is taken. I only dose it once a week taking an entire weeks dose.

Mainstream medicine considers his approach total quackery and it isn't accepted. Even Dr. Mercola warns against it.

https://articles.mercola.com/sites/...y-i-dont-recommend-the-marshall-protocol.aspx \

https://sciencebasedmedicine.org/the-marshal-protocol/

Here is MP founder Trevor Marshall refusing to do quality studies of the method.

https://www.cbc.ca/news/technology/vitamin-d-not-a-simple-case-of-cause-and-effect-1.745493

Oh and Trevor is a true believer so CFS patients will be coached to stay on the method for five years despite their lack of improvement. You never really end it, he continues it for life.

I do not recommend it.
 
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percyval577

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Mainstream medicine considers his approach total quackery and it isn't accepted. Even Dr. Mercola warns against it.
I had a short glance. It´s medicine poesy. No honest reasoning, no patient reports. Possibly dangerous. Recovery rate mecfs: 60%. Antibiotics are no longer considered to be a necessary part of the MP.

(So, I better unlike your post @Hip , but thank you for the information).
 
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Hip

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To do the MP you need to have a PCP MD willing to do it and you have to sign up with them as a study participant.
When I did the MP for a few months approximately a decade ago, in the early years of my ME/CFS, I just bought Benicar from a prescription-free pharmacy and started the protocol. I did not involve my doctor, and I did not really make much use of the MP forum.

The only thing I noticed from doing the MP was perhaps some improvement in my anhedonia and emotional flatness, and I developed a sensitivity to light which required wearing sunglasses on sunny days (this sensitivity ceased once I stopped the MP).

But my ME/CFS is associated with high IgG antibody levels to coxsackievirus B4 and cytomegalovirus, and I do not have any EBV involvement, so according to the ideas presented above, the MP may not work for my non-EBV subset of ME/CFS.



This poll shows 56% of CFS patients doing the MP get worse. Only 31% say they improved, which is exactly what you would expect from a placebo effect.
One of the reasons I started this thread is because if the ideas presented above are correct, then you might expect only EBV ME/CFS patients to improve from the MP. Which would mean that any test of the MP on a broad cross-section of ME/CFS patients would get poor overall results, as it's only the EBV subset that stands a chance of improving, and the rest of the patients would get a negative result. So on average the results would look poor.

So this revisiting of the MP as a possible ME/CFS treatment is from that perspective: the idea that we might want to test the MP on EBV ME/CFS patients only.

I am aware of the criticisms of the MP, and am not arguing against those criticisms. But I just want to be careful about not throwing the baby out with the bathwater, in case the MP might be useful in specific contexts, such as EBV ME/CFS.


As an aside: if I were targeting EBV, I would not just use the MP alone, but would incorporate Dr Lerner's Valtrex or Famvir protocol for EBV at the same time, which may increase antiviral efficiency. There are no interactions between these two drugs on drugs.com.

And I might also add Andrographis paniculata to fight EBV: one paper found Andrographis is antiviral in vitro for EBV; now it often turns out that such in vitro antiviral effects do not pan out in vivo; but in this case, in a pharmacokinetic calculation I performed (not yet posted on this forum), I found Andrographis had a fairly strong in vivo antiviral effect against EBV.



There are multiple ways that EBV blocks apoptosis, the nuclear pathway is only one of three. So even if taking benecar off label helped one way cells would still be blocked through the other two and not lower the viral load.
The first sentence is true: most pathogens have multiple immune evasion mechanisms; but the second sentence does not follow from the first. Immune evasion mechanisms are not individually 100% efficient (if they were, a pathogen would not require multiple immune evasion mechanisms to survive). So if you inhibit one immune evasion mechanism, you reduce the overall ability of a pathogen to survive.



He considers a good response to be worsening of your illness which he says is the body's immune system functioning better.
Yes, the worsening of symptoms Marshall calls the "immunopathology", and he claims it is a Herxheimer reaction, but in fact the cause is unknown.

This immunopathology of angiotensin II receptor blocker (ARB) drugs like Benicar in fact predates the MP. Medical science already knew about the weird effects of ARBs in patients with certain chronic diseases.

It's the strange reaction to ARBs in patients with chronic diseases that Marshall became fascinated with, and I believe this gave him a major clue which led to his investigation of the VDR in sarcoidosis. I think eventually he then came up with this idea of the intracellular bacteria linked to sarcoidosis turning off the VDR for immune evasion purposes, and Benicar switching it back on again, thus leading to a sudden immune response against these bacteria.

Marshall called these weird effects the "immunopathology" symptoms of the Marshall Protocol (like exacerbation of existing symptoms, fever, pain, body aches, light sensitivity requiring dark glasses); but these effects are not specific to the Marshall Protocol; as I understand it, they are what ARBs cause in many patients with certain chronic diseases.



I think his recommendation to limit Vit D isn't total nonsense. Vitamin D acts as a steroid so it inhibits immune response when it is taken. I only dose it once a week taking an entire weeks dose.
I suspect that for antiviral purposes, the vitamin D avoidance would not be necessary anyway. It may only make sense from in the context of sarcoidosis, the disease which Trevor Marshall has, and which he devised the MP to treat.

In sarcoidosis, vitamin D metabolism is abnormal: this disease creates high levels of an enzyme which converts vitamin D into its active form. Marshall noticed that his sarcoidosis was made worse after strong sunlight exposure (this was in Australia), and that's where the sunlight and vitamin D avoidance started. But this may have no relevance to ME/CFS.

So if treating EBV ME/CFS according the theory I outlined above, perhaps Benicar alone would suffice. Benicar may knock the EBNA3 viral protein off the VDR and then, as per the Marshall theory, this drug may activate the VDR, thereby launching the intracellular immune response.
 
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Hip

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Another link between vitamin D and Epstein-Barr virus is multiple sclerosis. MS of course is strongly linked to EBV, and this disease is also significantly more prevalent the further you are from the equator, which is believed to be due to the reduced levels of sunlight in extreme northern or southern climes. See this paper for example.

Thus if Benicar is indeed activating the VDR as Trevor Marshall's in silico computations suggest, then perhaps Benicar might be able to ameliorate multiple sclerosis.
 

Hip

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I searched for relation beween VDR/VitD and other notorious viruses, in this thread:
https://forums.phoenixrising.me/threads/vitamin-d-and-viruses-that-can-trigger-me-cfs.77284/
You might like to add this study to your thread:

Mouse beta-defensin 3 is antiviral for coxsackievirus B3

Beta defensins and human cathelicidin (LL-37) are anti-microbial peptides released in the cell when the VDR is activated (so Benicar should be able to stimulate the secretion of these peptides).

Also of interest:
The amino acid supplement isoleucine induces beta defensins 3 and 4 in mice
Isoleucine, an essential amino acid. induces epithelial beta-defensin expression
Branched-chain amino acids (BCAA) stimulate β-defensins, with isoleucine the most potent

So say 5 grams of isoleucine daily might help augment the effects of the Marshall Protocol.
 
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percyval577

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Another link between vitamin D and Epstein-Barr virus is multiple sclerosis. MS of course is strongly linked to EBV, and this disease is also significantly more prevalent the further you are from the equator, which is believed to be due to the reduced levels of sunlight in extreme northern or southern climes. See this paper for example.
The two risk parameters might be "independent" though:

Rolf et al 2018 (on relapsing-remitting-MS), from the Abstract
Conclusion: High-dose vitamin D3 supplementation selectively reduces anti-EBNA-1 antibody levels in RRMS patients. Our exploratory studies do not implicate a promoted immune response against EBV as the underlying mechanism.
Other studies have shown that VitD and EBV levels are related, but only:
  • during onset of mononucleosis (Maghzi et al 2016), but viral capsid antigen IgM titer are not significantly related to VitD;
  • in the first semester of the year in MS, with 64.3% low VitD (<20ng), but not in the second semester with 28.4% of samples with low VitD, no association with HHV-6 anyway here, no HC´s (Dominguez-Mozo 2017).

Ramien et al 2014 Hypovitaminosis-D and EBV: no interdependence between two MS risk factors in a healthy young UK autumn cohort.
Late Epstein-Barr virus infection and hypovitaminosis-D as environmental risk factors in the pathogenesis of multiple sclerosis are gaining great interest.

We, therefore, tested for in-vivo interdependence between Epstein-Barr-virus (EBV)-status and 25-hydroxyvitamin D3 (25(OH)D3) -level in healthy young individuals from a United Kingdom (UK) autumn cohort. EBV-load was measured by quantitative polymerase chain reaction and 25(OH)D3 levels by isotope-dilution liquid chromatography-tandem mass spectrometry.

This young, healthy UK autumn cohort showed surprisingly low levels of 25(OH)D3 (mean value: 40.5 nmol/L ± 5.02). Furthermore, we found that low 25(OH)D3 levels did not impact on EBV load and anti-EBV nuclear antigen-1 (EBNA-1) titers.

However, we observed a correlation between EBV load and EBNA-1 titers. These observations should be of value in the study of the potential relationship between hypovitaminosis-D and EBV-status in the pathophysiology of multiple sclerosis.
The short paper says, in the Discussion, there wouldn´t be any relation between VitD and the replication of EBV (though there would be limitations in their study, HLA types not looked at, lag effects not looked at).

This holds the possibility, if I am not wrong, that during the first, typically late infection in MS something happens. At least they say (somehow vague), that higher VitD levels than in their cohort "may be needed to see effects on EBV status." And also (vague enough): "whether and how vitamin D supplementation decreases microbial infections by switching on genes involved in anti-pathogen immunity."


Taken together, starting with normal epidemics:
In HC´s VitD would not be related to EBNA1, but in MS (visible only when in high dose).
In both, it seems not to be related to EBV replication.

But during the first infection of EBV low VitD would play a role
in monocucleosis (and in MS?).
 
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uglevod

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Theoretically, Olmesartan could be a partial VDR agonist: maybe it only cleans blocked VDR out of bacterial ligands like Capnine for the further successful D1.25 activation. Also, I'am not sure whether it's active enough within macrophages(is it achieve required tissue concentration to push through macrophage cell-wall or not) or only in blood leukocytes - no research was ever conducted on this.

As for D secosteroid avoidance(light/supplement/food like fish) on the protocol: I hold my own theory that immune activation(and thus, corresponding symptoms) with the Olmesartan alone spikes so high in a majority of sick individuals, that dropping D(D25) is essentially required to avoid D1.25 over-stimulation with the follow up consequences, like septic shock/organ dysfunction.

As for immunopathology itself: well, its a common thing among patients with chronic infection like Lyme which are open to the worsening of their symptoms while being treated - in their case Olmesartan feels like antibiotic with a strong and continuous herxheimer reaction.

I am personally aware of many cases of successful full and partial(50..80%) recovery from CFS/Lyme but with a few exceptions this requires at least 4..6 years of Olmesartan. And for the sickest patients(disabled) up to 10 years.
 

gbells

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Viruses were never really considered by the MP. It's entire theory is based around L-form bacteria. Regarding herpes bacteria's multiple blocking mechanisms, most likely they evolved gradually over time in a competitive environment. First, cells were easily infected by the first mechanism, then evolved resistance so the virus evolved and over again three times. Anyway, these mechanisms are very potent. All it takes is one effective mechanism of the three and you block apoptosis and virus clearance. Several supplements address one of the three blocks. NF-kB inflammation for example, is blocked by curcumin and ashwaghanda. Take this and while it will palliate the inflammation caused by Nf-kB, you still have an inactivated immune response. Actually, if you count nagalase you have four blocking mechanisms at work because nagalase will stop the production of anti-bodies against the virus. So I don't understand this logic of only treating one of the four. It's like saying you have a chest with four locks and only opening one of the four, that isn't going to open the chest. It's a flawed model. Curcumin is useful because it relieves inflammation and the resulting pain. GcMAF restores immune production of antibodies but this doesn't restore antibody killing of the herpes viruses because of the other blocks. Two locks to go.

However, even if we had an effective way to kill off the virally infected cells it would be painful and take a lot of work on the patient's part. Apoptosis involves activating a self-destruct process inside the cell which is perceived as a burning sensation. Yes there are meds to quiet the pain but would people be willing to put the time, effort and suffering necessary to complete the slow kill process? The payoff would be improvement with the CFS symptoms as the latent virally infected cells die off.
 
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uglevod

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ME/CFS has been linked to various viruses, and also to the intracellular bacterium Chlamydia pneumoniae, but not to L-form bacteria.
https://ru.wikipedia.org/wiki/Хламидиоз

Translation:

Chlamydia trachomatis are immobile, coccoid, gram-negative obligate intracellular microorganisms. Chlamydial infection mainly affects the genitourinary system. Currently, urogenital chlamydia is the most common (up to 60%) cause of non-gonococcal urethritis. For a long time, covertly existing, under adverse conditions (exposure to antibiotics, overheating, hypothermia, colds), chlamydia can transform into the so-called L-forms - as if “fall into hibernation." This phenomenon contributes to prolonged intracellular parasitism without conflict with the host immune system. When dividing body cells, sleeping chlamydia are transmitted to daughter cells. Only during immunosuppression (suppression of protective forces) is it possible to actively reproduce and the so-called reversal (awakening) of chlamydia from L-forms.

Research of bacterial L-Forms was independently conducted in USSR around 40 years ago. A lot of different bacteria could persist in L-form - probably most, or even all of them. Another example is Mycobacteria and there is an opinion that M. tuberculosis is infected approximately one third of the Earth’s population.
 
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gbells

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I don't buy it. If chlamydia remained persistent then people wouldn't be easily cured taking the antibiotics for it.

Chlamydia can be easily cured with antibiotic therapy. Antibiotics may be given as a single dose or a 7-day course. Women should abstain from sexual intercourse during the 7-day course of antibiotics or for 7 days after the single dose treatment to avoid spreading the infection to others.
https://www.medicinenet.com/chlamydia_in_women_overview/article.htm\

Trevor isn't a good authority.
 

uglevod

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If chlamydia remained persistent then people wouldn't be easily cured taking the antibiotics for it.
For fresh infection - yes. Just like fresh Lyme is handled with 7..21 days of abx. But chronic Lyme along with chronic chlamydiosis is treated with abx for around 2..3 years and very often with poor result. In fact I'am not aware of a single case where chronic lyme was successfully treated with abx alone.

So we should always distinguish between fresh, active infection and chronic one(which always exists in L-form at least partly). If the immune system is competent enough the infection will persist in L-form for the majority of a person lifetime(without reactivation).
 

uglevod

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I think MP deserves its own subforum(filter) over here, so that others can enter and offer/share their experiences. After all, GCMAF has one and I think MP is more popular that GCMAF. Since MP was empirically proven to be the only CFS therapy with positive results so far, it deserves much more exposure than another thread here and there.
 

pamojja

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I think MP deserves its own subforum(filter) over here, so that others can enter and offer/share their experiences.
I don't think MP posts come even close to the number of posts about supplementing vitamin D here. We don't need to subdivide again, a subforum for every effective vitamin and one for each's avoidance. :headslap:

You are however welcome to share anyway.