
This document is a one-article summary of key issues related to the Marshall ProtocolA curative medical treatment for chronic inflammatory disease. Based on the Marshall Pathogenesis., especially as it is relevant to physicians. Many of the topics covered here are reviewed in greater depth throughout the Knowledge Base.
An active community of recovering patients has been a cornerstone of our success. While the physician is responsible for patient care, patients can do a lot of the footwork, retrieving information so that the physician can make fully informed decisions. Indeed, without active participation of the patients in our study, we do not support or license the public use of this therapy. We urge physicians to encourage patients to take advantage of the following three websites:
The Marshall Protocol (MP) is the name given to a therapy devised by Professor Trevor Marshall, and is based on the pathogenesis he has elucidated for chronic disease.
Marshall (and colleagues) observed that chronic inflammatory diseases, including many autoimmune diseases, are caused by a metagenomic microbiotaThe community of bacterial pathogens including those in an intracellular and biofilm state which cause chronic disease.: communities of bacterial pathogens, many of which persist intracellularly. A recent peer-reviewed paper describes this Pathogenesis in more detail.1
The Marshall Protocol, a medical treatment supported by Autoimmunity Research FoundationNon-profit foundation dedicated to exploring a pathogenesis and therapy for chronic disease., has been available since 2002 and has applicability to 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, 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 receptor 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.. The Vitamin D nuclear receptor (VDR) 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 pathogens, antagonistic bacterial 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 four-times daily dosing of the ARB olmesartan medoxomil (Benicar, Olmecip, Olmetec) to re-activate the Vitamin D Nuclear Receptor, dislodging bacterial ligands in the process. Additionally, several pulsed, low-dose, bacteriostatic oral antibiotics are used to help the immune system recognize the pathogens in the metagenomic microbiota. Olmesartan also reduces inflammatory cytokine production by inhibiting the NF kappa-B transcription pathway. This inhibits, among other things, the release of TNF-alpha, helping to protect the organs from effects of excessive inflammation.
Patients on the MP ultimately will use up to five bacteriostatic antibiotics: minocycline, azithromycin (Zithromax)Bacteriostatic antibiotic used by Marshall Protocol patients. Has relatively long half-life., clindamycin, sulfamethoxazole-trimethoprim (Bactrim DS), and demeclocycline (Declomycin)Bacteriostatic antibiotic used by patients on the Marshall Protocol. to help their immune system weaken and attack components of the systemic microbiota.
Seriously ill patients may develop photosensitivity 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-D production on the brain. Some patients do not experience any significant photosensitivity during recovery, and those who do often find it more manageable after 12 to 18 months.
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 inflammation, or a return of previous Th1 inflammatory symptoms, that is caused largely by cytokines generated by the immune response and endotoxins released from dying bacteria. Occasionally, immunopathology will consist of a new symptom or abnormal lab value (e.g., elevated creatinine, elevated liver enzymes, low white blood count, etc.) due to the occurrence of subclinical bacterial inflammation that has been revealed by Olmesartan's activation of the immune system. Immunopathology is a necessary part of recovery. The amount of immunopathology a patient experiences on the Marshall Protocol (MP) is correlated 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 serves to validate 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 minocyclineBacteriostatic antibiotic used by Marshall Protocol patients. 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.
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 has the potential to interfere with the MP. A more complete list of medications is available in the Non-MP treatments article.
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.
Abnormal sensitivity to sunlight and bright lights is known as photosensitivity and sometimes referred to as “sun flare.” 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. Sometimes a reaction to light can be instantaneous. Photosensitivity symptoms can occur immediately after exposure or begin 1 to 3 days later, sometimes persisting 5 days or more. The amount of acceptable light exposure an MP patient can get is based on individual tolerance of symptoms.
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.
Patients on the MP often benefit from wearing special 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.

Most patients on the MP experience temporary but well-defined increases in various markers of disease state and 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., 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 bacterial die-off in the kidneys subsides. For as long as they remained on Olmesartan, there has been no dialysis needed in the MP cohort.
If these markers indicate dysfunction sustained for more than several months, it may be advisable to use one or more methods to lower immunopathology levels.
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.

The primary indication for olmesartan (Benicar)Medication taken regularly by patients on the Marshall Protocol for its ability to activate the Vitamin D Receptor. 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.
It is important to understand that olmesartan’s effect on blood pressure is limited if we are to appreciate that a decline in systolic pressure greater than 15mm Hg of mercury cannot solely be due to olmesartan’s hypotensive action, but is also likely to include the result of disease processes.
The widespread destruction of bacteria and human cells infected by bacteria can lower blood pressure. Though 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 these cases, we have observed that patients who remain on the MP dosage of olmesartan see their blood pressure eventually return to a normal range as immunopathology subsides.
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.
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.13
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).14
The relevant Knowledge Base article reviews the safety profile of olmesartan/Benicar in greater detail.
The Marshall Protocol (MP) employs rotating combinations of bacteriostatic antibiotics at pulsed low dosesAdministration of an antibiotic periodically such as every 48 hours and in amounts small enough that the immunosuppressive effects of the antibiotics are minimized. for maximum effectiveness. The type of bacterial pathogens the MP targets are chronic forms, bacteria that grow much more slowly than acute forms.
Antibiotics are typically dosed at levels above the minimum inhibitory concentrationThe lowest concentration of an antimicrobial that will inhibit the visible growth of a microorganism after overnight incubation. Dosing at well below the MIC improves the MP's effectiveness against slow-growing chronic pathogens and reduces the likelihood of resistance. (MIC) so as to reduce the likelihood of bacterial resistance. While the MIC may be relevant for acute infections, dosing at that level can still suppress the immune response and aid the growth of chronic infections including those implicated in chronic inflammatory disease. For instance, some antibiotics, when administered at high dosages, have been widely recognized as being able to inhibit various functions of phagocytes.15 These effects seem to be independent of their antibacterial effect.16
The Marshall Protocol uses subinhibitory dosage levels of antibiotics. Dosing at well below the MIC improves the MP's effectiveness against chronic pathogens and further reduces the likelihood of bacterial resistance. Pulsed dosing greatly reduces the incidence of biofilm persister cells.17 The presence of a sustained immunopathological response is evidence that the MP uses antibiotics in such a way that it does not suppress the immune system.
Patients who are still experiencing significant immunopathology from 100mg of minocycline alone are not yet ready to add a second antibiotic because the two antibiotic combination, especially when ZithromaxBacteriostatic antibiotic used by Marshall Protocol patients. Has relatively long half-life. is used, is much stronger than minocycline alone.
When ready to experience additional immunopathology, patients begin to take a second antibiotic in conjunction with their minocycline (which is still taken q48h). Typically, that second antibiotic is Zithromax (azithromycin)Bacteriostatic antibiotic used by Marshall Protocol patients. Has relatively long half-life.. But often, patients and their physicians choose to use clindamycinBacteriostatic antibiotic used by patients on the Marshall Protocol. .
A special consideration for patients with high levels of 25-D – For those patients who have been supplementing for years, vitamin D can remain in the tissues for months or years even when they are abstaining from further vitamin D consumption and outdoor light exposure. In the case of patients who are severely ill, it may be prudent to wait until their 25-D levels have dropped below 12 ng/ml before administering Zithromax. However, in less serious cases, physicians may use their discretion to increase antibiotics even in the presence of a higher level of 25-D so long as patients are aware they may have to take measures to control higher levels of immunopathology when their 25-D levels do drop.
After completing a two-antibiotic combination, patients may add a third antibiotic and rotate combinations as desired. Appropriate dosing combinations include:
For a more detailed discussion on the MP antibiotics including combination strategies, examples of progression through the MP, and general tips, please read the Knowledge Base article, Dosage and administration of Marshall Protocol antibiotics.
Patients' goal during the MP should be to maintain tolerable immunopathology as they get well. In cases where IP (also known as herx) 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.
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 805-492-3693.
The exact length of time the Marshall Protocol (MP) takes depends on any number of factors, including degree of illness, amount of fibrosis, subclinical inflammation, the functionality of the kidney, and personal preference to remain on the MP.
While someone who is very ill can expect the MP to take in the range of 3-5 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 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 olmesatan (Benicar) alone due to production of the body's own antimicrobial peptides. However, it is considered ideal to stay on the Protocol until one has tried all the combinations and no longer experiences immunopathological reactions from the antibiotics.
To a large extent, patients who have completed the Marshall Protocol can return to a normal life with the following modifications:
The length of time it takes for antibiotics to no longer have an effect is variable. Determining factors include how long the antibiotics stay in one's system. Due to its unusually long half-life, Zithromax can remain in the tissues for a month or more. In addition, the self-sufficiency of the immune system is an important factor. Some patients may find their immune response is relatively self-sustaining due to the body's own increased antimicrobial peptide production, and thus it will take longer for the immunopathology to wane. If the patient is stopping antibiotics for the purpose of minimizing immunopathology, in some cases it may be preferable to stay on either 100 mg minocycline every other day or take it daily for its palliative effects (many of which are the result of its effect on the PXR nuclear Receptor, see Bioessay, Figure 1).
To discontinue both antibiotics and olmesartan, patients should first discontinue their antibiotics following the above instructions. If necessary, olmesartan should be weaned gradually, only after the antibiotics have been discontinued and over the course of several weeks. Note that the immune response may remain activated for a period of time even after discontinuing olmesartan.
An alternative to discontinuing olmesartan alone is to wean the patient across to another ARB, valsartan (Diovan), 80mg every 6 hrs (80 mg is one quarter of a 320mg Diovan tablet). The patient reduces the olmesartan dosage (e.g., from 40 mg to 30mg to 20mg to 10mg to 0) while simultaneously ramping the valsartan (e.g. 0 to 20mg to 40mg to 60mg to 80mg). The length of time the organ protection from the valsartan will be needed depends on how long it takes the immune system to shut down again. This ARB does not activate the immune system, but does protect organs and provide a little palliation. The patient can be weaned across in 2 to 3 days.
Patients who stop olmesartan are terminating their recovery.