. Elevated concentrations of TNF-alpha are related to low serum magnesium levels in obese subjects. Magnes Res. 2004 Sep;17(3):189-96.
[PMID: 15724867]
Related articles: Immunopathology, Science behind immunopathology
Table of Contents
Managing immunopathology (IP)
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:
- Adjust olmesartan (Benicar) - Depending on which of olmesartan's two main properties a patient experiences most strongly during a particular period of treatment, increasing or decreasing the dose may help manage immunopathology. For some, taking olmesartan sublingually (under the tongue) can provide immediate relief.
- Minocycline as a palliative – Minocycline taken more frequently such as every 12-24 hours, it may help reduce symptoms of immunopathology.
- Take palliative medications – A range of symptom-specific palliative medications can be relied upon in the case of intolerable immunopathology - enquire in the forums at MarshallProtocol.com
- Light restriction. Sunlight to the skin and eyes can exacerbate symptoms and make symptoms intolerable. This is individual. However, if experiencing intolerable symptoms one will want to reassess their response to every type of light exposure. Indoor lighting above 30 lux or any type of fluorescent lighting has been enough provoke intolerable symptoms for some patients, even when wearing NoIR sunglasses.
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.
Goal of tolerable immunopathology
Patients should strive to achieve and maintain tolerable physical and mental immunopathology (IP). Failure to take the requisite precautions against intolerable IP, including proper light avoidance, can mean putting one's very life in jeopardy. Patients are required to take responsibility for the choices they make, which ensure their IP is at a tolerable level.
To this end, it's important that patients learn which strategies work for them. The start of the Protocol is an excellent time for this.
Learning early the key ways to assess immunopathology will help address symptoms proactively.
Those who have had to bear strong disease symptoms may have more difficulty defining the line between tolerable and intolerable IP symptoms. A cautious approach is best.
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Emergency or not?
Main article: Hospitals and emergencies
Is a set of symptoms worthy of a trip to the emergency room? It depends. Patients with intolerable immunopathology (IP) are advised to first assess the severity of their symptoms. Sometimes patients can make adjustments immediately to improve intolerable symptoms.
The following kinds of IP, and the examples of intolerable symptoms which sometimes accompany them, may become life-threatening, and should be taken very seriously:
- cardiac immunopathology – slow or rapid heart rate, syncopal (fainting) episodes, chest pain, irregular rhythm, heart skipping beats, or palpitations
- neurological immunopathology – strong feelings of wanting to hurt oneself or others
- respiratory immunopathology – sudden or increased shortness of breath, throat tightening
Patients who have intolerable cardiac, neurological, or respiratory symptoms should take immediate and decisive action. Follow your instincts. Seek help or call for emergency assistance if you think you need it. If you are not thinking clearly or worried, ask someone to stay with you and help you problem solve. Do not drive yourself to the hospital.
Strategies for immunopathology management
Patients should never hesitate to make adjustments to keep all symptoms at a tolerable level. The following are a list of adjustments or strategies patients can use to limit the amount of immunopathology (IP) at any one time. Patients should always try to provide themselves a margin for error such that their symptoms aren't continually on the brink of intolerable. Patients should try to learn which of these strategies are most effective at controlling IP.
Note that patients weaning from corticosteroids face the prospect of particularly strong IP and may need to be familiar with these strategies as much as anyone in later stages of the MP.
If these strategies don't work, patients should call their physician.
Strategy #1: Adjust olmesartan
Taking more frequent or higher doses, or less frequent and lower doses, of olmesartan (Benicar) is often effective at managing immunopathology. Olmesartan has two actions: an anti-inflammatory effect and an immune-stimulating effect. For this reason, most Marshall Protocol patients – roughly 80% or so – feel either substantially better or worse when taking olmesartan. Knowing which kind of patient a person is can help decide which course to take in case of intolerable immunopathology. It is important to experiment during times of relative well-being to see which strategy is most successful.
Increasing olmesartan increases its anti-inflammatory effect
A potent anti-inflammatory, olmesartan decreases levels of Nuclear Factor Kappa B, a protein that stimulates the release of inflammatory cytokines - proteins that generate pain and fatigue.
Olmesartan has been shown to be safe in higher than typical doses. As a temporary replacement for standard dosing for olmesartan, which is 40mg every six hours, patients can:
- take 40mg of olmesartan every four hours or more frequently; some patients have reported a benefit from taking olmesartan as frequently as every three hours
- lower the dose to 20mg every two to six hours, but only if that reduces symptoms
When in a crisis, never discontinue Benicar, or increase the dosing interval beyond 6 hours.
Also, there is the option of taking Benicar sublingually, that is, under one's tongue. Some people in the midst of a crisis situation have found it helpful to combine 40mg oral doses at the regular time with an additional 20mg of sublingual Benicar (at minimum three hour intervals) around the clock.
Swallowed olmesartan, which in non-emergency situations is preferred, usually takes between 90 and 300 minutes to be absorbed by the GI tract, depending on whether the stomach is full. Chewing and then putting Benicar under one's tongue can drastically cut the amount of time it takes for the medication to be absorbed.
The sublingual route of medication administration uses the thin epithelium and rich network of capillaries on the underside of the tongue to gain rapid absorption and drug action. Drugs absorbed from the sublingual route have a rapid effect since they enter the bloodstream directly without being metabolized by the liver or being affected by gastric and intestinal enzymes.
Note that the FDA has not approved sublingual use of olmesartan and it is uncertain what effect its routine use would have on local soft tissues and tooth enamel. Also, it is not recommended to routinely use sublingual administration of Benicar during the protocol since swallowed Benicar is distributed in a manner that is considered more effective for maintaining the reduction of body-wide inflammation levels.
Decreasing olmesartan lessens its immune-activating effect
A Vitamin D Receptor agonist, olmesartan turns on the immune response, which usually leads to immunopathology. Ideally, a Marshall Protocol patient would take 40 mg of olmesartan 4-6 times a day. The dosing interval is most important, as VDR receptors are quickly liganded and/or broken down by bacterial kinases, with a mean useful lifespan of 3-6 hours. Provided the dosing is kept frequent, every 4-6 hours, immunopathology can sometimes be reduced if the Benicar (olmesartan medoxomil) dosing is lowered to 20 mg every 4-6 hours. More often, the loss of palliation at the lower dose makes this approach untenable.
A patient or physician should never stop olmesartan in a crisis situation without a slow weaning schedule. The innate immune system remains active after the olmesartan is withdrawn, but the organ-protection offered by the olmesartan is lost, leading to potential organ failure. If discontinuation of the Protocol is necessary, a physician should consult Prof. Marshall to discuss therapeutic options.
Olmesartan has multiple effects: anti-inflammatory, immune stimulating and anti-hypertensive. Activation of the innate immune system via olmesartan activation of the VDR can on its own cause immunopathology (IP) or herx. Early on, this impact may dominate, and the anti-inflammatory effects may not be sufficient to lessen the intensity of the IP. In these circumstances or in anticipation of the possibility of that occurring, ramping up olmesartan over a few days is a wise option. If though the lower dose of olmesartan cause an increase in symptoms, upward adjustment of olmesartan is initiated.
In conclusion, there can be circumstances where some variation in the established protocol may be necessary but this is uncommon and should not be seen as a change of treatment direction for the vast majority of patients. This lower dose is only temporary and almost everyone will ultimately tolerate and benefit from higher dose olmesartan.
Greg Blaney, M.D.
Strategy #2: Adjust minocycline
Another successful strategy for managing strong immunopathology (IP) is to adjust the dosing frequency of minocycline.
On the other hand, like many antibiotics, minocycline partially suppresses the immune system in the hours after it is taken. In fact, the very rationale for taking pulsed doses of antibiotics is that the immune system is most effective and generates the most IP when the concentration of the drug is lowest.
Patients have had success adjusting minocycline in a variety of ways. Note that the lowest and highest recommended doses for minocycline are 25mg and 100mg, respectively.
- If taking lower doses of minocycline, try 25mg every 6, 12, or 24 hours. Note the advice on how to divide a dose.
- If taking higher doses of minocycline, try 50mg every 12 or 24 hours.
This “frequent minocycline” option is more likely to be palliative if the patient typically has less immunopathology symptoms during the first 6 to 24 hours after taking a dose of minocycline and more IP toward the end of the 48 hours
When symptoms are again tolerable, minocycline dosing can be extended gradually (by the hour if needed) out to 24 hours and then 48 hours. When symptoms have settled back and you feel like you can tolerate a little more you can increase the mino to the next dose level.
Other options worth considering:
- Stop minocycline for a while with the idea that you will resume if the IP becomes too strong.
- Extend minocycline from every other day dosing out to three days or longer.
Please note: minocycline is not palliative for all people. For some, increased frequency of minocycline results in more immunopathology. This is more likely to be the case if one experiences less immunopathology toward the end of the 48 hours between doses.
Strategy #3: Take palliative medications
A range of symptom-specific palliative medications can be relied upon in the case of intolerable immunopathology.
- mental and neurological – anti-anxiety agents and antidepressants; sleep medications
Note that many of these medications, especially steroids, can interfere with recovery. It would be much better, if possible, to control symptoms with your increased Benicar. Discontinue the use of these medications as soon as symptoms become tolerable.
Strategy #4: Take quercetin
Quercetin taken around the clock may be helpful once a patient has been established on MP. It is usually not helpful in the first few months.
Strategy #5: Take guaifenesin
The expectorant Guaifenesin may help dampen inflammation a bit as well as liquefy mucus. Use a product that does not contain any other ingredients. One might find a slight surge of symptoms during “withdrawal” from periods of intense guaifenesin use.
Strategy #6: Re-examine food/supplement/medication intake and changes in response to light
Several foods, beverages and supplements contain substances that may modulate immune response and some patients have altered their intakes to moderate immunopathology. You might also be entering Stage 5 and this may have changed your response to light. Also, an adverse effect of some non-MP medications may have developed (e.g., gastrointestinal symptoms and/or anemia from NSAIDS). It is worth considering the possibility that what one is experiencing is not truly IP and is actually an acute infection. In addition, patients may want to consult their doctor about other conditions, such as celiac disease – the symptoms of which can easily be minimized by avoiding gluten.
Strategy #7: Re-examine sources of emf in your surroundings.
Strategy #8: examine Magnesium status
Deficiency signs and symptoms:
General Anxiety, lethargy, weakness, agitation, depression, dysmenorrhea, hyperactivity, headache, irritability, dysacusis, low stress tolerance, loss of appetite, nausea, sleep disorders, impaired athletic performance.
Muscle spasm, cramps in the soles of the feet, leg cramps, facial muscles, masticatory muscles, and calves, carpopedal spasm, back aches, neck pain, urinary spasms, magnesium deficiency tetany.
Nervousness, increased sensitivity of NMDA receptors to excitatory neurotransmitters, migraine, depression, nystagmus, paraesthesia, poor memory, seizures, tremor, vertigo.
Constipation.
Risk of arrhythmias, supraventricular or ventricular arrhythmias, hypertension, coronary spasm, decreased myocardial pump function, digitalis sensitivity, torsade de pointes, death from heart disease.
Hypokalaemia, hypocalcaemia, retention of sodium.
Dyslipoproteinemia (increased blood triglycerides and cholesterol), decreased glucose tolerance, insulin resistance, increased risk of metabolic syndrome, disturbances of bone and vitamin D metabolism, resistance to PTH, low circulating levels of PTH, resistance to vitamin D, low circulating levels of 25(OH)D, recurrence of calcium oxalate calculi.
Asthma, chronic fatigue syndrome, osteoporosis, hypertension, altered glucose homeostasis. Pregnancy Pregnancy complications (e.g., miscarriage, premature labor, eclampsia).
Elevated concentrations of TNF-alpha are related to low serum magnesium levels in obese subjects. 1)
These data shows that low serum magnesium levels and elevated TNF-alpha are related in the obese subjects.
Magnesium Decreases Inflammatory Cytokine Production: A Novel Innate Immunomodulatory Mechanism 2)
Following in vivo MgSO4[magnesium sulfate] treatment, we observed a reduced frequency of monocytes producing TNF-α and IL-6 in women receiving MgSO4[magnesium sulfate] for clinical indications.
The potential influence of magnesium (Mg) on inflammatory responses was assessed using an ex vivo model–human whole blood incubated with and without lipopolysaccharide (LPS). Addition of LPS leads to higher levels of cytokines including TNF-alpha and IL-6. No significant effect of Mg was observed following LPS stimulation whereas high concentration of Mg inhibited the baseline level (without LPS) of TNF-alpha and IL-6 production. 3)
This observation contrasts with that of a previous one on Mg-deficient animals. Therefore, the weak efficiency of increasing Mg concentration in this study on the whole blood from healthy volunteers suggests that the efficiency of Mg supplementation on cytokine production induced by endotoxin challenge depends on Mg status.
During the progression of Mg deficiency in a rodent model, we have observed dramatic increases in serum levels of inflammatory cytokines [interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha)] after 3 wk on a Mg-deficient diet. 4)
Bacteria use their own pumps to collect magnesium
Magnesium is a mineral found in all living organisms. Your body contains 20–30 grams of this element, most of which is in the skeleton. We humans are supplied with magnesium through our daily diet or as a supplement.
Magnesium deficiency is not especially common, but occurs in patients with intestinal diseases such as Crohn's disease. These patients often have to live with cramps and various rheumatic illnesses. Other symptoms typical of magnesium deficiency are muscular spasms, cramp, anxiety or abnormal heart rhythms.
Researchers at NCMM, the Centre for Molecular Medicine Norway at UiO and Oslo University Hospital have shown exactly how sensitive the bacteria's transport system is. 5)
Researcher Jens Preben Morth says, “We have identified a nano-sized magnesium pump.”
The researchers manipulated an E. coli bacterium so that it overproduced using its own magnesium pump.
“The pump was isolated in the bacterium's cell membrane.”
Magnesium deficiency can be deadly for bacteria. This has led to our own cells developing a mechanism that removes magnesium and other metals from bacteria when they start to attack us.
“In order to counteract this mechanism, the bacteria have developed a unique system to detect and attract magnesium. The bacteria manage to do this even if the amounts of magnesium in their environment are only minimal,” says Morth.
Magnesium is bound to several proteins within a cell. It is used by many of the enzymes that are involved when sugar is broken down into energy. This process is known as glycolysis.
“Magnesium also stabilises genetic material in both humans and bacteria,” Morth elaborates.
Bacterial Growth at the High Concentrations of Magnesium Sulfate Found in Martian Soils 6)
The Influence of Magnesium on Cell Division
SUMMARY: In simple chemically defined media all of 15 bacteria failed to grow in the complete absence of magnesium. The concentration of magnesium for maximum growth was dependent upon the Gram reaction of the individual species examined, the magnesium requirements of the Gram-positive organisms being some ten times greater than the requirements of the Gram-negative organisms. In contrast to the observations made in more complex media (peptone water), normal cell division occurred in chemically defined media containing suboptimal amounts of magnesium. It is suggested that magnesium is involved in the synthesis of bacterial protoplasm as well as cell division and, in simple chemically defined media, the synthetic reactions require the higher magnesium concentration.
Myth or Reality—Transdermal Magnesium? 7)
Planning for strong immunopathology
Patients need to determine which strategies are effective for them, so that they will be prepared the next time symptoms flare. In addition to the strategies previously mentioned, patients may want to know how to:
- send for support and emergency care
- notify their doctor
Also, it makes sense to get to know and have at the ready a printed copy of the Hospitals and Emergencies Information Sheet.
Note that immunopathology is very likely to increase as a patient's blood level of 25-D approaches and declines below 20ng/ml (48nmol/L).
Pain control
Physical methods include acupuncture, yoga, Reiki, Tai chi, meditation and other practices.
Pain control substances
Products containing THC are only available in states where cannabis is legal. The CBD only products can sometimes be purchased locally.
Importance of a positive attitude
Main article: Keeping a proper attitude
It is not as if Benicar won't bind to patients' Vitamin D Receptor if they don't have the proper attitude. But, a positive attitude about the MP does color the perception of one's symptoms. Patients who are able to or choose to see their immunopathology as serving a purpose in their recoveries seem to do much better.
My mantra with my MP patients is “Great, you are effectively eliminating the bugs and their toxins and with such a safe therapy (no IVs etc) and it will pass.” I think every practitioner using the MP should do it so they can confidently reassure their patients and/or anticipate the reactions that they will likely experience.
I also, during follow up, identify the positive changes that have occurred but which are often ignored by the tendency of patients to focus on their symptoms.
Greg Blaney, MD
Another key part of having a positive attitude is resisting the temptation to complete the MP in world record time. This is sometimes very hard for certain patients, especially those with obsessive compulsive tendencies, to accept.
There is no point in pushing your body too hard, and you might do damage to it. There is no need to keep the pedal flat-to-the-floor, this is an endurance race, not a sprint.“
Trevor Marshall, PhD
Posting and working with more experienced members of our support community
It's important that you post your progress regularly to get support regarding managing immunopathology (IP) from more experienced members of our support community.
Patients will be assisted, if needed, in determining the options to use to achieve and maintain tolerable IP. By posting regularly, Often more experienced members of our support community can tell if patients are heading towards problems and need to make adjustments.
Patients should ask for help before they take any action that is unfamiliar to them.
If for some reason you find that you need more help and posts are not responded to in a timely manner, please send an email to our Support Staff.
Patients experiences
I have successfully used Guaifenesin for excruciating menstrual cramps - the cramps became unbearable after starting the MP, things are improving now.
I originally used Quercetin which also sorted the cramps, however I found it messed with my hormones, and my cycle became irregular.
With Guaifenisin I found it didn't work immediately, like a painkiller, rather I had to dose for a couple of days to build up the effect. I found if I took it a day or so before my period (every 8 hours), this would stop the cramps.
Nyima, MarshallProtocol.com
I think it might worth a try for you to try palliating with frequent mino doses. After a 3 week break from minocycline, I started taking 25mg mino every 24 hours for a few days and then upped it to every 12 hours after a few days. I did this for 3 weeks and then went to 50mg minocycline once every 24 hours for a month. About 20 days on this dose, I suddenly had the best 6 days I've had in years…far from perfect, but it felt amazing. After this, I gradually added a few hours to my minocycline dosing each time, until I was at 50mg every 48 hours and now I'm tolerating it.
PoochyMama, MarshallProtocol.com
Don't forget time with IP adjustments too.
Benicar is the fastest intervention. Even if it is not totally effective all by itself to quell an IP, it is my first step no matter what because it can be done immediately. 20mg sublingual bolus and every 3-4 hours 40mg is the take away I get when I read instructions at MPkb.org. But your doctor has to make sure you have enough on hand to use this strategy.
If not already dosing these (most shouldn't need these all the time anyway), quercetin and basic guafenisen (basic mucinex) may provide some rather quick assists for some.
Next in the time frame is the 48hr abx. In your case, one might consider halving or dropping Clindy first, if needed, while keeping a vigilant olmesartan blockade in place.
After that, then remember that deme acts a bit like mino. You may actually find some relief by increasing as opposed to decreasing, but unless you know your own pattern is definitely to increase deme (or mino) to get more relief, it might be safest to decrease first.
Finally, Zith is the one that should make a huge difference if you land in stage 5. It can be halved and then halved again. Unfortunately, I just described what could be a 2 week to 20 day turnaround time frame. The good news is most of the interventions above are helped out by halving zith to nothing this way if you are easing into stage 5. Remember, some actually have a little more kick about day 18 if they drop Zith outright. You may appreciate a smoother transition.
Janet Foutin
N.B. azithromycin is no longer recommended for use while on the MP.
I could not manage the immunopathology from 100mg mino. I wound up with about 50 active boils on my back and off-the-scale kidney numbers. I then dropped to 50mg every 48 hours, but still had no improvement. Then, I went off minocycline entirely for 14 days and kidney numbers got even worse. Finally, I hit upon starting the frequent mino, 50mg q12h, and that sent the kidney numbers to “normal.”
Over the next month I stretched it to 50mg every day and have been taking that for 14 months now. I have noticeable IP and a noticeable pulse. I have about 3-4 small active boils on my back at any given time. Various other obvious but tolerable IP. Stretch it 6 hours either way and the IP gets worse (see my progress thread for gory details).
Chef Bama, MarshallProtocol.com
When a wise MP support person suggested maybe my “helper” meds weren't helping any more, I was scared to discontinue them. I expected that I'd be back where I started, in too much pain to sleep. But I did stop them–and to my surprise found that that my symptoms were no worse than when I was taking the helper meds!
Since then, even if I have truly needed to take an extra medication for some situation that arises, I have made it my mission to try to then wean off of it as soon as possible. Sometimes I find I have to continue the extra med for awhile longer. But I eventually have been able to wean off of it. Result is that I'm the only 70+-year-old person I know who takes only one medication–olmesartan–, and no supplements, and after being wheelchair-bound for almost a year at age 61, was able on the MP to return to full-time work till I was almost 70
Grateful Survivor, MarshallProtocol.com
2)
. Magnesium decreases inflammatory cytokine production: a novel innate immunomodulatory mechanism. J Immunol. 2012 Jun 15;188(12):6338-46. doi: 10.4049/jimmunol.1101765. Epub 2012 May 18.
[PMID: 22611240] [PMCID: 3884513] [DOI: 10.4049/jimmunol.1101765]
[PMID: 22611240] [PMCID: 3884513] [DOI: 10.4049/jimmunol.1101765]
3)
. High-magnesium concentration and cytokine production in human whole blood model. Magnes Res. 2009 Jun;22(2):93-6.
[PMID: 19658279]
[PMID: 19658279]
4)
. Pathobiology of magnesium deficiency: a cytokine/neurogenic inflammation hypothesis. Am J Physiol. 1992 Sep;263(3 Pt 2):R734-7. doi: 10.1152/ajpregu.1992.263.3.R734.
[PMID: 1384353] [DOI: 10.1152/ajpregu.1992.263.3.R734]
[PMID: 1384353] [DOI: 10.1152/ajpregu.1992.263.3.R734]
5)
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6)
. Bacterial growth at the high concentrations of magnesium sulfate found in martian soils. Astrobiology. 2012 Feb;12(2):98-106. doi: 10.1089/ast.2011.0720. Epub 2012 Jan 16.
[PMID: 22248384] [PMCID: 3277918] [DOI: 10.1089/ast.2011.0720]
[PMID: 22248384] [PMCID: 3277918] [DOI: 10.1089/ast.2011.0720]
7)
. Myth or Reality-Transdermal Magnesium?. Nutrients. 2017 Jul 28;9(8):813. doi: 10.3390/nu9080813.
[PMID: 28788060] [PMCID: 5579607] [DOI: 10.3390/nu9080813]
[PMID: 28788060] [PMCID: 5579607] [DOI: 10.3390/nu9080813]