Proal AD, Albert PJ, Marshall T
Autoimmun Rev8p677-81(2009 Jul)
This document is a one-article summary of key issues related to the Marshall Protocol, especially those relevant to physicians. Many of the topics covered here are reviewed in greater depth throughout the Knowledge Base.
Without active participation of patients on MarshallProtocol.com site, Autoimmunity Research Foundation does not support or license the public use of this therapy.
Translations of this document (of emerging quality) are available in several languages.
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While the physician is responsible for patient care, patients can do at least some of the footwork, retrieving information so that the physician can make fully informed decisions.
The Marshall Protocol (MP) is the name given to a therapy devised by Professor Trevor Marshall. Based on the pathogenesis Marshall has proposed for chronic inflammatory disease, the MP is aimed at targeting bacteria, fungi, viruses, and other microbes that appear to interact to cause chronic inflammatory diseases.
Marshall (and colleagues) have hypothesized that chronic inflammatory diseases, including many autoimmune diseases, are caused by dysbiosis of a metagenomic microbiotaThe community of bacterial pathogens including those in an intracellular and biofilm state which cause chronic disease.: communities of microbial pathogens, many of which persist intracellularly. A recent peer-reviewed paper describes this Pathogenesis in more detail.1)
Supported by Autoimmunity Research Foundation, the MP has been available since 2002 and has been used in a wide range of chronic inflammatory illnesses.
A significant number of patients diagnosed with sarcoidosis, post-treatment chronic Lyme syndrome, chronic fatigue syndrome, uveitis, Hashimoto’s thyroiditis, rheumatoid arthritis, fibromyalgia, diabetes type II, psoriasis, lupus (SLE), multiple sclerosis, and a number of other diagnoses are showing a promising response from being treated with the Protocol.
In determining whether a patient can be successfully treated with the MP, a specific chronic disease diagnosis is not as important as the clinical assessment by a knowledgeable health care provider, the results of a therapeutic probe, and outcome of the vitamin D metabolites blood test.2)
According to the Marshall PathogenesisA description for how chronic inflammatory diseases originate and develop., chronic inflammatory disease is characterized by dysregulation of the nuclear receptorIntracellular receptor proteins that bind to hydrophobic signal molecules (such as steroid and thyroid hormones) or intracellular metabolites and are thus activated to bind to specific DNA sequences which affects transcription. pathways which control the innate immune responseThe body's first line of defense against intracellular and other pathogens. According to the Marshall Pathogenesis the innate immune system becomes disabled as patients develop chronic disease.. For example, the Vitamin D nuclear receptorA nuclear receptor located throughout the body that plays a key role in the innate immune response. (VDRThe Vitamin D Receptor. A nuclear receptor located throughout the body that plays a key role in the innate immune response.) expresses many of the body's antimicrobial peptidesBody’s naturally produced broad-spectrum antibacterials which target pathogens. (along with TLR2A receptor which is expressed on the surface of certain cells and recognizes native or foreign substances and passes on appropriate signals to the cell and/or the nervous system.). In addition to down-regulation of expression of the VDR itself by many common bacteria and viruses, antagonistic microbial metabolites incrementally block ligands from activating it. Ingested vitamin D slows activity of the receptor in this same manner, preventing the body from killing the pathogens at the heart of the disease state. That is why avoidance of ingested vitamin D (in food and supplements) is essential for the innate immune system to function correctly while patients are on the MP.3) 4)
The MP uses multiple daily dosing of olmesartan medoxomil (Benicar, Olmecip, Olmetec) to re-activate the Vitamin D Nuclear Receptor, dislodging bacterial ligands in the process. This drug was developed as an Angiotensin II Receptor Blocker (ARBA drug which is an angiotensin receptor blocker. One of the ARBs is olmesartan (Benicar). Not all ARBs activate the Vitamin D Receptor.) but it has multiple actions in the human body when dosed as defined by Marshall. In addition to immunostimulation via the VDR, OlmesartanMedication taken regularly by patients on the Marshall Protocol for its ability to activate the Vitamin D Receptor. Also known by the trade name Benicar. also reduces inflammatory cytokineAny of various protein molecules secreted by cells of the immune system that serve to regulate the immune system. production by inhibiting the NF kappa-B transcription pathway. This inhibits, among other things, the release of TNF-alphaA cytokine critical for effective immune surveillance and is required for proper proliferation and function of immune cells., helping to protect the organs from effects of excessive inflammationThe complex biological response of vascular tissues to harmful stimuli such as pathogens or damaged cells. It is a protective attempt by the organism to remove the injurious stimuli as well as initiate the healing process for the tissue..
Additionally, several pulsed, low-dose, bacteriostatic oral antibiotics may optionally be used. Four bacteriostatic antibiotics: minocycline, clindamycin, sulfamethoxazole-trimethoprim (Bactrim DS), and demeclocycline (Declomycin) have been found useful, as also formerly was azithromycin (Zithromax). Minocycline directly acts in an immunosuppressive manner on the PXR nuclear receptor, and this biochemical action may be useful in pulsing immunopathologyA temporary increase in disease symptoms experienced by Marshall Protocol patients that results from the release of cytokines and endotoxins as disease-causing bacteria are killed. to (for example) a 48 hour cycle.
N.B. azithromycin is no longer recommended for use while on the MP.
Seriously ill patients may develop photosensitivityAbnormal sensitivity to sunlight and bright lights. Also referred to as "sun flare" or "light flare." during the healing process, so avoidance of direct and indirect sunlight may be necessary. Patients may need to protect their eyes from bright lights to prevent further retinal damage and reduce neurological symptoms due to inter alia, the effect of ocular 1,25-DPrimary biologically active vitamin D hormone. Activates the vitamin D nuclear receptor. Produced by hydroxylation of 25-D. Also known as 1,25-dihydroxycholecalciferol, 1,25-hydroxyvitamin D and calcitirol. production on the brain.
Patients may also develop sensitivity to skin exposure to sunlight, and/or find that they need to avoid skin exposure to sunlight in order to maintain the low blood levels of vitamin D required by the Protocol. However, some patients do not experience significant photosensitivity during recovery, and those who do often find it more manageable several years into the therapy.
Main article: Science behind immunopathology
When patients on the MP kill bacterial pathogens they experience a reaction called immunopathology. Immunopathology is an increase in one's present symptoms of Th1 inflammationThe complex biological response of vascular tissues to harmful stimuli such as pathogens or damaged cells. It is a protective attempt by the organism to remove the injurious stimuli as well as initiate the healing process for the tissue., or a return of previous Th1 inflammatory symptoms, that is caused largely by cytokinesAny of various protein molecules secreted by cells of the immune system that serve to regulate the immune system. generated by the immune response and endotoxins released from dying bacteria. Occasionally, immunopathology will result in a new symptom or abnormal laboratory value (e.g., elevated creatinine, elevated liver enzymes, low white blood count, etc.). The occurrence of subclinical bacterial inflammation is due to olmesartan's activation of the immune system. Immunopathology appears to be a necessary part of recovery. The amount of immunopathology a patient experiences on the Marshall Protocol (MP) tends to correlate with disease severity and bacterial load. Patients who are less sick will have comparatively less-strong immunopathology.
Immunopathology is sometimes used synonymously with the “Jarisch-Herxheimer reaction” or “herx.”
Many MP patients who have experienced prolonged periods of immunopathology have reached stages of significant improvement or remission. This supports the conclusion that immunopathology is a necessary result of chronic bacterial death, and a precursor to disease reversal. The MP is not unique in this regard. A number of other diseases and/or therapies generate immunopathological or immunopathological-like reactions.5) 6) 7)
Lab work and patient reports can be used to track clinical signs of immunopathology.
The Marshall Protocol has been used in a variety of chronic inflammatory diseases. The gold standard for evaluating whether the MP is warranted is the therapeutic probeA brief trial of the Marshall Protocol to see if it will generate an immunopathological response. The "gold standard" for testing whether a patient is a good candidate for the MP., a brief trial of the Marshall Protocol to see if olmesartan medoxomil and pulsed low-dose minocycline will generate an immunopathological response. The results from a vitamin D metabolites test, while less definitive, may also suggest the presence of treatable condition. For an automated interpretation of the vitamin D metabolites, consult the Vitamin D Metabolite Calculator.
Other patient groups:
Before commencing therapy, physicians and patients should familiarize themselves with the pre-MP checklist, which reviews the medications, eye protection, and possible lifestyle modifications necessary for treatment success and safety.
Main article: Safety warnings for the Marshall Protocol
Main article: Non-MP medications
While there are notable exceptions, the Marshall Protocol (MP) should not be combined with any other protocols, treatments or supplements, especially those which are immunosuppressive or immunomodulatory. Using other treatments while on the MP can impede progress on the MP – or be dangerous to MP patients.
For intolerable symptoms, certain palliative medications such as sleep medication, pain medication, and antidepressants are acceptable. It is generally recommend that MP patients use the lowest dose of medication that is effective.
The following is a summary of common medications that have the potential to interfere with the MP. A more complete list of medications is available in the Non-MP treatments article.
Main article: Food and drink
Patients on the MP must avoid all food and drink that contains supplemental vitamin D or high levels of naturally-occurring vitamin D. MP patients must avoid foods and drinks high in chlorogenic acidAn antioxidant and phenolic compound which in ways that are not yet fully clear can modulate and/or suppress the immune response – particularly coffee, concentrated juices, and supplements and multivitamins containing added folic acid. A low-carbohydrate, insulin-resistant diet is recommended for MP patients but is not required. Specific nutritional imbalances should in some cases be corrected, but this requires proper understanding of both the MP and the nutritional needs of the body by a health professional.
Main article: Photosensitivity
Abnormal sensitivity to sunlight and bright lights is known as photosensitivity and sometimes referred to as “sun flare” or photophobia. In the context of the MP, the ultimate cause of photosensitivity is the Th1 inflammatory disease process – not the treatment itself. Exposure to natural or bright artificial light in a photosensitiveAbnormal sensitivity to sunlight and bright lights. Also referred to as "sun flare" or "light flare." person can lead to flares of internal disease activity, including exacerbation of any inflammatory disease symptoms.
Photosensitivity can occur either when the skin is exposed to bright natural light or the eyes are exposed to either natural or artificial light. Photosensitivity symptoms can occur immediately after exposure or begin 1 to 3 days later, sometimes persisting 5 days or more.
Individuals who are photosensitive prior to the MP will likely become more photosensitive on the MP. Individuals who have no signs of photosensitivity may or may not become photosensitive on the MP. Individuals with limited inflammatory symptoms (suggesting early disease) are the most likely to be able to tolerate more light exposure while on the MP. There is no certain way to tell in advance precisely how photosensitive an individual will be while on the MP. Only after an individual has begun treatment can photosensitivity be assessed.
For many members but not all it is prudent to block sunlight from living space, work space and practice limited sunlight exposure and cover up skin with thick dark layers when going out as well as protect the eyes with the proper NOIRSpecial sunglasses worn by Marshall Protocol patients to block light. glasses.
When in doubt, patients should assume their intolerable symptoms are due to light exposure and reduce sunlight exposure and protect eyes with the proper NOIR sunglassesSpecial sunglasses worn by Marshall Protocol patients to block light..
Patients on the MP often benefit from wearing glasses that block a broader spectrum of light and in many cases must cover their skin when in the sun. Further guidelines are available at the Knowledge Base articles on Eye protection and Skin protection.
Main article: Laboratory tests
Most patients on the MP experience temporary but well-defined increases in various markers of disease state and inflammation, consistent with an immunopathological response. It is helpful, but not necessary, to measure % lymphocytes, C-Reactive Protein, alkaline phosphatase, triglycerides, relevant “autoantibodies”, and serum ACE, to track systemic inflammation. Doctors may want to assess kidney function by testing creatinine or BUN and measure other indicators specific to each patient for a baseline and retest as appropriate. Some lab work – commonly HGB, HCT, eGFR, creatinine and BUN – may become temporarily abnormal, due to immunopathology reactions, until the inflammation resolves.
For example, a higher than usual BUN and creatinine is not an indication that olmesartan should be discontinued but a sign that immunopathology may be occurring in the kidneys or other nearby organs. In most cases where physicians have allowed such levels to remain temporarily out of range, BUN and creatinine have returned to range as microbial die-off in the kidneys subsides. We are not aware of any reports of MP patients needing dialysis, provided they remained on olmesartan.
If these markers indicate dysfunction sustained for more than several months, we advising using one or more methods to lower immunopathology levels.
Related article: Vitamin D metabolite test instructions
There are two main vitamin D metabolites:
If the vitamin D metabolite tests do not indicate Th1 inflammationThe complex biological response of vascular tissues to harmful stimuli such as pathogens or damaged cells. It is a protective attempt by the organism to remove the injurious stimuli as well as initiate the healing process for the tissue. but clinical observation suggests otherwise, a short course of the MP (1 to 2 months) should be used as a therapeutic probe. A longer time period may be needed if 25-D levels remain high, as a therapeutic probe is often not effective unless 25-D levels fall below 25 ng/ml.
Consult the Vitamin D Metabolite Calculator for suggestions on interpreting this lab data.
Main article: Low blood pressure and dizziness
The primary indication for olmesartan (Benicar) is as a mild hypotensive drug. As one can see from the FDA label for Benicar (right), the dose response curve for Benicar is asymptotic, with higher dosages of the drug having incrementally smaller decreases in blood pressure. For example, the difference between 40mg and 80mg of olmesartan results in a decrease of no more than 1mm Hg.
A decline in systolic pressure greater than 15mm Hg of mercury cannot solely be due to olmesartan’s hypotensive action. Instead, the drop is also likely due to the disease processes itself.
For example, the widespread destruction of bacteria and human cells infected by bacteria can lower blood pressure. Although this isn’t true of all bacterial forms, when some forms of bacteria are destroyed, they release endotoxins,11) the bioavailability of which can lead to a steep decline in blood pressure.12)
If a patient suffers low blood pressure before the MP, low blood pressure will return as a symptom of immunopathology while on the MP. In most cases, we find as bacterial die-off subsides, blood pressure levels begin to return to a normal range even as patients continue to take the same dose of olmesartan.
Thus, medications that raise blood pressure, such as fludrocortisone and dopamine, are contraindicated, both because they would do nothing to slow bacterial die-off and because they may have deleterious effects on immune function.
For the purposes of the MP, olmesartan has two primary actions: it reduces inflammation by blocking the Nuclear Factor-kappaB cytokine pathway and it is an agonist of the Vitamin D ReceptorA nuclear receptor located throughout the body that plays a key role in the innate immune response. (VDR). As a VDR agonistA substance such as olmesartan (Benicar) or 1,25-D which activates the Vitamin D Receptor and transcribes the genes necessary for a proper innate immune response., olmesartan activates the innate immune response. Research supports the safety of the doses used by MP patients. Olmesartan has minimal interactions with other drugs and is one of the safest drugs on the market.
The half-life of olmesartan is reported to be 13 hours. This would imply that the drug would remain active during that period of time, however, we have found that in sick patients, olmesartan is most effective when administered every 4-6 hours, with a maximum of every 8 hours. This may be due to the fact that some intracellular infections (notably Shigella), upregulate activity of the caspases, which are proteases that cleave the VDR.13) When the VDR is broken apart by the caspases, it is highly likely that any ligands bound to it (such as olmesartan) would stay bound to the fragments of the protein. Therefore, a VDR agonist would be effective over shorter periods of time in patients with infected cells.
The U.S. Food and Drug Administration has set no safe limit for olmesartan medoxomil (Benicar), as no dose-related adverse events have been identified to this point. FDA post-marketing-experience has shown that Olmesartan has one of the safest profiles of any drug on the market. Note that this does not apply to the combination drugs, such as Benicar HCT, which contains a thiazide and is harmful, and should never be used with an MP dosing schedule.
The label for olmesartan medoxomil states that the drug is well-tolerated. Adverse events were similar to those experienced by the placebo group. Adverse events were generally “mild, transient and not related to dose.” The frequency of adverse events also had no relationship to the dose of olmesartan.
A 2001 study published in the Journal of of Pharmacology found olmesartan to be safe and well tolerated at dosages of up to 160 mg/day.14)
In placebo-controlled trials, the only side effect that occurred in more than 1 percent of olmesartan-treated patients vs. placebo-treated patients was dizziness (3 percent vs. 1 percent).15)
The relevant Knowledge Base article reviews the safety profile of olmesartan/Benicar in greater detail.
The Marshall Protocol has historically emphasized a role for antibiotics. However, as our understanding of the recovery process has progressed, this emphasis has been greatly minimized. This change is gradually being reflected in the guidance available here. In the event of any uncertainty, patients or their physicians should seek guidance on the Protocol forums.
Main article: Managing immunopathology
Patients' goal during the MP should be to maintain tolerable immunopathologyA state in which a patient has maintained an acceptable intensity of bacterial die-off reaction. The primary goal of the Marshall Protocol. as they get well. In cases where IP is becoming intolerable, certain strategies are available including:
Note that three forms of IP are particularly life-threatening and should be handled with an abundance of caution: cardiac immunopathology, neurological immunopathology, and respiratory immunopathology. Patients who are concerned about any of these or other symptoms should not hesitate to call their physician.
Main article: Notice for emergency medical personnel
ARF has prepared a Notice for emergency medical personnel treating a Marshall Protocol patient. Important points from that document include the following:
For the details of these recommendations, please consult the Notice for emergency medical personnel.
In an emergency, physicians may call Trevor Marshall at 1-805-492-3693.
Main article: Length of the Protocol
Related article: Spontaneous remission is a myth
The exact duration of the Marshall Protocol (MP) depends on any number of factors, including degree of illness, amount of fibrosis, subclinical inflammation, the health of the kidneys, and personal preference to remain on Olmesartan.
While someone who is very ill might expect the MP to take five or more years, there is no way to know for sure how long the treatment will take. Due to the nature of immunopathology, feelings of well-being and blood markers of disease tend to be variable in the short-term and improve over the long-term. Also owing to the nature of infection, different symptoms will improve at different rates.
So long as one is responding to olmesartan or olmesartan plus antibiotics with symptoms that wax and wane, there are still bacteria to be killed.
Note that there is no requirement that patients reach the maximum dosages for all antibiotics or do all antibiotic combinations in order to complete the Protocol. In many cases, patients can make considerable progress on olmesartan (Benicar) alone as the drug increases expression of the body's own antimicrobial peptidesBody’s naturally produced broad-spectrum antibacterials which target pathogens.. However, it is considered ideal for patients to stay on the Protocol until they no longer experience immunopathology from any antibiotic combination.
To a large extent, patients who have completed the Marshall Protocol can return to a normal life with the following modifications:
Related article: Taking a break from the Marshall Protocol
Olmesartan will need to be weaned gradually. Note that the immune response may remain activated for a period of time even after discontinuing olmesartan. Patients who stop olmesartan are terminating their recovery.
— Sallie Q 02.20.2017 changed to 'may be' for toleration of fluoroquinolones, and put last after Ceftin & biaxin NOW will need to go back to translations
* added “Rivaroxaban (Xarelto) increases the risk of bleeding and can cause serious or fatal bleeding. A specific antidote for rivaroxaban is not available.” July'15 –Sallie Q
Record of important changes (for translations)
New Danish study on Zith: http://www.nlm.nih.gov/medlineplus/news/fullstory_136424.html