Changes Include Addition of Nattokinase As First Line Therapy and Reordering of First-And Second-Line Therapies
Changes Include Addition of Nattokinase As First Line Therapy and Reordering of First-And Second-Line Therapies
Changes Include Addition of Nattokinase As First Line Therapy and Reordering of First-And Second-Line Therapies
Since Phase 3 and Phase 4 clinical trials are still ongoing, the full safety and toxicity profile for COVID-19
vaccines cannot be fully determined. From a bioethical perspective, cases of any new-onset or worsened
signs, symptoms, or abnormalities following any dose of COVID-19 vaccine must be considered as an
injury caused by the vaccine, until proven otherwise.
Note that there are significant overlaps between the symptoms and features of long COVID/long-hauler
syndrome and post-vaccine syndrome. However, a number of clinical features appear to be
characteristic of post-vaccine syndrome; most notably, severe neurological symptoms appear to be
more common following vaccination. To complicate matters further, patients with long COVID are often
also vaccinated, making the issue of definition more difficult.
Epidemiology
The Centers for Disease Control (CDC), National Institutes for Health (NIH), Food and Drug
Administration (FDA), and World Health Organization (WHO) do not recognize post-COVID-19 vaccine
injuries as a specific medical condition, [1] even though there is a specific ICD-10 code. Curiously, the
code U12.9 is recognized in Europe but not in the United States. There have been no prospective studies
that have accurately classified and logged the incidence of this complication; therefore, the true
magnitude of post-vaccine syndrome is unknown.
However, as of December 2nd, 2022, nearly 1.5 million adverse events had been reported. This includes
over 30,000 deaths, 185,000 hospitalizations, 15,000 heart attacks, 35,000 cases of myocarditis, and
60,000 cases of permanent disability according to OPEN VAERS, which tracks data recorded in the U.S.
Vaccine Adverse Event Reporting System (VAERS). Note that VAERS data is limited by underreporting, by
a factor of at least 30-fold. [2]
The true incidence of adverse events following COVID-19 injections, including deaths and serious vaccine
injuries, is unknown; this is complicated by the deliberate and willful manipulation of data
(underreporting) by governmental agencies in the United States, United Kingdom, Israel, and many
other countries. [2,3].
As the mainstream medical community does not recognize this serious humanitarian disaster, these
patients have been shunned and denied access to the care they need and deserve. Furthermore, there is
limited clinical, molecular, and pathological data on these patients to inform an approach to treating the
condition. Consequently, our approach to the management of vaccine-injured patients is based on the
presumed pathogenetic mechanism, pharmacologic principles, as well as the clinical observations of
physicians and patients themselves.
Pathogenesis
The spike protein, notably the S1 segment, is likely the major pathogenetic factor leading to post-
vaccine syndrome (see figure 1). [4-6] The S1 protein is profoundly toxic. Multiple intersecting and
overlapping pathophysiologic processes likely contribute to the vast spectrum of vaccine injuries: [1,7]
• The acute, immediate reaction (within minutes to hours) is likely the result of an acute type I
IgE-mediated hypersensitivity reaction. The type I response may be due to preformed antibodies
against mRNA, polyethylene glycol (PEG) [8,9], or other components of the nano-lipid particle. In
addition, PEG activates multiple ‘complement components,’ the activation of which may be
responsible for both anaphylaxis and cardiovascular collapse. [9-11] A prospective study on
64,900 medical employees, in which reactions to their first mRNA vaccination were carefully
monitored, found that 2.1% of subjects reported acute allergic reactions. [12]
• The acute myocarditis/sudden cardiac death syndrome that occurs post-vaccination (within
hours to 48 hours), noted particularly in young athletes, may be caused by a “stress
cardiomyopathy” due to excessive catecholamines produced by the adrenal medulla in response
to spike protein-induced metabolic aberrations. [13]
• The subacute and chronic myocarditis is likely the result of a spike protein-induced
inflammatory response mediated by pericytes and macrophages. [14,15]
• The subacute (days) and chronic (weeks to years) vaccine-related injuries likely result from the
overlapping effects of an S1-induced inflammatory response, the production of autoantibodies,
activation of the clotting cascade, and secondary viral reactivation.
• The inflammatory response is mediated by spike protein-induced mononuclear cell activation in
almost every organ in the body but most notably involving the brain, heart, and endocrine
organs.
• Patients with long COVID and those post-vaccination may have spike protein circulating in the
blood for as long as 15 months. [16-18] Spike protein inhibits natural killer (NK) cell activity, [19-
22] cytotoxic T-cells, and inhibits autophagy [23]; this may account for the persistence of the
spike protein.
The spike protein is highly thrombogenic, directly activating the clotting cascade; in addition, the clotting
pathway is initiated via inflammatory mediators produced by mononuclear cells and platelets. [6]
Activation of the clotting cascade leads to both large clots (causing strokes and pulmonary emboli) as
well as micro clots (causing microinfarcts in many organs, but most notably the brain). Emerging data
suggest that the vaccines can induce an allergic diathesis (eczema, skin rashes, asthma, skin and eye
itching, food allergies, etc.) This appears to be due to a unique immune dysregulation with antibody
class switching (by B cells) and the production of IgE antibodies. There is an overlap with Mast Cell
Activation Syndrome (MCAS) and the distinction between the two disorders is not clear. [55,56]
However, by definition MCAS has no identifiable causes, is not caused by allergen-specific IgE, and has
no detectable clonal expansion of mast cells. [55]
The common factor underlying the pathogenic mechanism in the vaccine-injured patient is “immune
dysregulation.” The development of immune dysfunction and the severity of dysfunction likely result
from several intersecting factors, including:
• Genetics: First-degree relatives of patients who have suffered a vaccine injury appear to be at a
very high risk of vaccine injury. Those patients with a methylenetetrahydrofolate reductase
(MTHFR) gene mutation [61] and those with Ehlers-Danlos type syndromes may be at an
increased risk of injury. MTHFR C677T polymorphism is the most common MTHFR single
nucleotide polymorphism (SNP) and the most common genetic cause of hyper-
homocysteinemia. [62] Increased homocysteine levels have been linked to worse outcomes in
patients with COVID-19. [63,64] Increased homocysteine levels may potentiate the
microvascular injury and thrombotic complications associated with the “spikopathy”. [62,65]
• mRNA load and quantity of spike protein produced: This may be linked to specific vaccine lots
that contain a higher concentration of mRNA. [1] The Moderna vaccine is reported to contain
100 ug of mRNA as compared to 30 ug mRNA for the Pfizer vaccine (10 ug in children 5-11 years
of age), however, it is likely that the true concentration varies widely.
• Sex: It appears that about 80% of vaccine-injured patients are female. Furthermore, treatment
with estrogens has been reported to worsen or precipitate an event/relapse. Women are known
to be at a much higher risk of autoimmune diseases (especially SLE) and this likely explains this
finding. Estrogens interfere with glucocorticoid receptor signaling. [66] In addition, estrogens
modulate B and T cell function.
• Underlying nutritional status and comorbidities: Certain preexisting conditions may likely have
primed the immune system to be more reactive after vaccination. This includes those with
preexisting autoimmune disorders and chronic inflammatory diseases such as Lyme disease.
Those patients with a poor nutritional status including those with deficiencies of nutrients such
as Vitamin D, Vitamin B12, folate, and magnesium may be at an increased risk of injury.
It is important to emphasize that there are no published reports Patients should notify their
detailing the management of vaccine-injured patients. Our anesthesia team if using the
treatment approach is, therefore, based on the postulated following medications and/or
pathogenetic mechanism, pharmacologic principles, clinical nutraceuticals, as they can
observation, and feedback from vaccine-injured patients. increase the risk of Serotonin
syndrome (SS) with opioid
The core problem in post-vaccine syndrome is chronic “immune administration:
dysregulation.” The primary treatment goal is to help the body
• Methylene blue
to restore and normalize the immune system—in other words,
• Curcumin
to let the body heal itself. We recommend the use of immune-
• Nigella Sativa
modulating agents and interventions to dampen and normalize
• Selective Serotonin
the immune system rather than the use of immunosuppressant
Reuptake Inhibitors
drugs, which may make the condition worse. However, the
(SSRIs)
concomitant use of a controlled course of an
immunosuppressant drug may be appropriate in patients with
specific autoimmune conditions.
The treatment strategy involves two major approaches i) promote autophagy to help rid the cell of the
spike protein and ii) interventions that limit the toxicity/pathogenicity of the spike protein.
Treatment must be individualized according to each patient’s presenting symptoms and disease
syndromes. Not all patients respond equally to the same intervention; this suggests that the treatment
must be individualized according to each patient’s specific response. A peculiar finding is that a
particular intervention (e.g., Hyperbaric oxygen therapy) may be lifesaving for one patient and totally
ineffective for another.
Patients should serve as their own controls and the response to treatment should dictate the
modification of the treatment plan. One (or at most two) new interventions should be added at a time in
order to evaluate what helps the patient and those interventions that are not helpful.
Early treatment is essential; the response to treatment will likely be attenuated when treatment is
delayed.
Patients should be started on the primary treatment protocol; this should, however, be individualized
according to the patient’s particular clinical features. The response to the primary treatment protocol
should dictate the addition or subtraction of additional therapeutic interventions. Second-line therapies
should be started in those who have responded poorly to the core therapies and in patients with severe
incapacitating disease.
Patients with post-vaccine syndrome must not receive further COVID-19 vaccines of any type. Likewise,
patients with long COVID should avoid all COVID vaccinations.
Patients should avoid unscientific and poorly validated “Spike Protein Detox” programs.
Hyperbaric oxygen therapy (HBOT) should be considered in cases of severe neurological injury and in
patients showing a rapid downhill course (see below).
Once a patient has shown a clinical improvement the various interventions should be reduced or
stopped one at a time. A less intensive maintenance approach is then suggested.
Baseline Testing
Post-vaccine patients are often subjected to an extensive battery of diagnostic tests. These tests are
rarely helpful, usually confusing the situation and leading to inappropriate therapeutic interventions.
Patients frequently undergo diagnostic tests that are “experimental,” unvalidated, and clinically
meaningless; patients should avoid getting such tests. Remember the dictum: Only do a test if the
result will change your treatment plan. We recommend a number of simple, basic screening tests that
should be repeated, as clinically indicated, every 4 to 6 months.
Dr. Steven R. Gundry, a cardiac surgeon, performed a biomarker-based cardiac risk assessment score
(the PULS Cardiac Test now available as the SMARTVascular Dx provided by SmartHealth Dx
https://www.smarthealthdx.com) in 566 patients 2 to 10 weeks following the 2nd mRNA COVID shot
and compared this score to the PULS score drawn 3 to 5 months prior to the jab. [69] The PULS score is a
marker of endothelial inflammation. In this study, the 5-year Acute Coronary Risk Score (ACS) increased
from a baseline of 11% to 25% after the jab. This study clearly demonstrates that the mRNA ‘jabs” lead
to progressive endothelial inflammation.
To complicate matters further, the clots (micro-clots and macro-clots) that develop in patients with
spike-related disease are distinctly different from “usual clots” and have a number of unique
characteristics. These clots are rich in fibrin with amyloid-like fibrils and are more resistant to
fibrinolysis. Immunohistochemical staining demonstrates a high concentration of spike protein within
the clots; this is important as spike protein via multiple mechanisms activates clotting as well as altering
the structure of fibrin resulting in amyloid-like fibrils.
Based on this information, it would seem intuitive that the use of anti-coagulants and the approach to
treatment would be different for these three phenotypes; however, the ideal approach has yet to be
determined. A provisional approach to anticoagulation is provided below. A review of the
pharmacological properties of the various anticoagulants available to the healthcare provider is
provided. The general approach to the management of the multi-symptom vaccine syndrome is then
reviewed.
The greatest risk with the use of anticoagulant drugs is clinically significant bleeding. A number of
factors increase the risk of bleeding; [70-72] these include age > 65 years (advanced age is a major risk
Antiplatelet drugs:
Aspirin (ASA): ASA produces a clinically relevant antiplatelet effect by irreversibly acetylating the active
site of cyclooxygenase-1 (COX-1), which is required for the production of thromboxane A2, a powerful
promoter of platelet aggregation. These effects are achieved by daily doses of 75 mg (and higher). The
major adverse effect is bleeding. Bleeding most commonly occurs in the gastrointestinal tract and is
rarely fatal. Bleeding also occurs at other sites, with intracranial bleeding being the rarest
(approximately 4 per 10,000) but the most serious (with a 50% case fatality rate).
Clopidogrel (Plavix): Clopidogrel requires in vivo biotransformation to an active thiol metabolite. The
active metabolite irreversibly blocks the ADP receptors on the platelet surface, which prevents
activation of the GPIIb/IIIa receptor complex, thereby reducing platelet aggregation. Similar to ASA,
platelets blocked by clopidogrel are affected for the remainder of their lifespan (~7 to 10 days). The
usual dose is 75mg daily.
Apixaban (Eliquis): Inhibits platelet activation and fibrin clot formation via direct, selective, and
reversible inhibition of free and clot-bound factor Xa (FXa). FXa, as part of the prothrombinase complex
consisting also of factor Va, calcium ions, and phospholipid, catalyzes the conversion of prothrombin to
thrombin. Thrombin both activates platelets and catalyzes the conversion of fibrinogen to fibrin. Typical
dose is 2.5 to 5mg twice daily.
Rivaroxaban (Xarelto): Mechanism of action similar to apixaban. Typical dosage is 10–20 mg once daily
with the evening meal.
Nattokinase: Nattokinase (NK) is a serine protease purified and extracted from natto, a traditional
Japanese (cheese like) food produced from the fermentation of soybeans with the bacterium, Bacillus
subtilis. [74-76] Recent studies demonstrated that a high natto intake was associated with decreased
risk of total cardiovascular disease mortality and, in particular, a decreased risk of mortality from
ischemic heart diseases. [77]
Nattokinase has potent fibrinolytic, antithrombotic, and antiplatelet activity. [74,75,78-81] NK degrades
fibrin directly and also increases the release of tPA with a subsequent increase in the formation of
plasmin. [82] Furthermore, NK enhances fibrinolysis through cleavage and inactivation of PAI-1. [76,81]
In a study comparing the antiplatelet effects of NK and aspirin, NK was shown to display excellent
antiplatelet aggregation and antithrombotic activities in vitro and in vivo, inhibiting thromboxane B2
formation from collagen-activated platelets. [83] In addition, in both animal and human studies, NK also
has antihypertensive, anti-atherosclerotic, lipid-lowering, and neuroprotective actions. [75,81,84] Of
particular relevance to patients with spike-related clotting, nattokinase causes the proteolytic cleavage
of both spike protein and amyloid proteins. [85] In a randomized study, NK proved to be more effect
than statins (simvastatin) in reducing carotid artery atherosclerosis. [86]
Studies indicate that an oral administration of NK can be absorbed by the intestinal tract. [84,88] NK,
unlike most proteins, is more resistant to the highly acidic gastric fluids in the stomach and can be
absorbed in the later sections of the digestive tract.
The optimal dose of nattokinase is unclear, however, a dose of 100-200 mg (2000- 4000 FU/day) twice
daily has been suggested.
While NK appears to have an excellent safety profile, [87,89] bleeding has rarely been reported in
patients with risk factors for bleeding (advanced age, renal failure, hypertension, concomitant ASA, etc).
[90,91] High concentrations of vitamin K2 in natto can reduce the INR when coadministered with
warfarin; this may also occur with nattokinase supplements if vitamin K2 is not removed during the
production process. Information regarding safety and efficacy in pregnancy and lactation is lacking.
Lumbrokinase: Lumbrokinase derives from a group of enzymes extracted from earthworms. The
enzymes are sourced mostly from the earthworm Lumbricus rubellus. Lumbrokinase has very similar
pharmacodynamic properties to Nattokinase, i.e., it directly breaks down fibrin clots, inhibits PAI-1
activity, enhances t-PA activity, has antiplatelet activity, and proteolytically cleaves amyloid. [92-94] The
recommended dose is 300,000 to 600,000 IU/day (20-40 mg). Lumbrokinase has been widely used for
patients with acute ischemic stroke in China; however, because rigorously designed studies are lacking,
the safety and efficacy of lumbrokinase remains largely unknown. [95] As the pharmacology, clinical
effectiveness, and safety of nattokinase has been assessed in a number of experimental and clinical
studies, this agent is preferred over lumbrokinase.
It is important to stay well-hydrated during fasting periods; drink lots of water and/or an electrolyte
solution. In his book the “Complete Guide to Fasting,” Jason Fung, MD recommends drinking coffee with
added coconut oil (medium chain triglycerides)/heavy cream (no CHO or protein) during fasting. [98]
Remarkably, caffeine stimulates autophagy, [106-108] while coconut oil has numerous health benefits.
[109-111]
Mechanisms
Autophagy plays an important role in preventing Alzheimer’s disease by removing amyloid protein.
Autophagy likely removes spike protein and misfolded proteins induced by the spike protein. Autophagy
may therefore play a critical role in reversing the “spikopathy” induced by COVID injections. Indeed,
activation of autophagy may be the only mechanism to remove intracellular spike protein.
Proton pump inhibitors (PPI) should be avoided as they prevent the acidification of lysosomes and block
autophagy. [112] Patients may develop rebound esophagitis if a PPI is suddenly discontinued. H2-
blockers (famotidine, ranitidine, etc.) may be an alternative. Aloe Vera Stomach Formula (Aloe Vera
contains over 200 biologically active components) and diluted Apple Cider vinegar (tastes awful) have
been suggested as an alternative to a PPI; however, there is limited data to support these interventions.
[113,114]
Paradoxically, while autophagy may prevent cancers, autophagy may promote the growth of cells that
have already undergone malignant transformation. Cancer cells, which have an increased metabolic
demand for energy and macromolecular building blocks to proliferate, show elevated levels of
autophagy to recycle nutrients. [117] High-dose HCQ (more than 800 mg/day) has been demonstrated
to improve the outcome of patients with certain cancers by inhibiting autophagy. [118-122] This data
suggests caution in activating autophagy (fasting) in patients with cancer. However, “fasting mimicking
diets” as an adjunct to chemotherapy have been reported to improve quality-of-life indicators. [123-
125] Patients should discuss fasting and fasting protocols with their treating oncologist.
Although there are no comparable human studies, experiments in rats have shown that 3–6 months of
alternate-day fasting caused a reduction in ovary size and irregular reproductive cycles in female rats.
[126] Similarly, in a murine model, Kumar and Kaur demonstrated that intermittent fasting negatively
influences reproduction in young animals due to its adverse effects on the complete hypothalamus-
hypophysial-gonadal axis. [127] However, it should be noted that, in this study, the female rats were
very young (3 months old), which corresponds to a human aged 9 years old. [128] Heilbronn et al
reported that alternate-day fasting adversely affected glucose tolerance in nonobese women but not in
nonobese men. [129]
Changes in gonadotropins during fasting have only been assessed in one clinical trial to date. In this trial
by Li et al., young women with obesity and polycystic ovarian syndrome (PCOS) followed an early 8-hour
time-restricted eating regimen for 5 weeks. [130] At the conclusion of the study, LH and FSH remained
unchanged. It is possible that alternate-day fasting results in greater disruption of the hypothalamus-
hypophysial-gonadal axis than does 8-hour time-restricted eating. In addition, the timing of time-
restricted eating may be important. Jakubowicz et al demonstrated that a large meal later in the day (at
dinner) augmented estrogen levels in women with PCOS as compared to eating earlier in the day. [131]
There are many anecdotal stories of women who have experienced changes to their menstrual cycles
after starting intermittent fasting (likely alternate-day or fasting > 24 hours). For this reason, pre-
menopausal women may need to follow a modified approach. To reduce any adverse effects, women
should take a mild approach to fasting: shorter fasts and fewer fasting days. We would suggest
beginning a program of time-restricted eating consisting of fasting for 12 hours for two to three days a
week and increasing from there (see Figure 4). Furthermore, the fasting window should begin at least 4
hours before going to sleep.
Fasting days should be nonconsecutive and spaced evenly across the week (for example, Monday,
Wednesday, and Friday). With time, the fasting window can slowly be increased to 16 hours and the
number of fasting days per week increased. It has been suggested (with no published data) that the
cycle of intermittent fasting be linked to the menstrual cycle; namely, with a 16-hour fasting window
from day 1 to day 10 (including Keto), a 12-hour fasting window on days 11-16 (with Keto), and a
“normal” dietary pattern on days 17-28 (including more carbohydrates with a less strict Keto diet). In
“I started 14:10 daily for a couple of weeks (14 hours fasting, eating for 10 hours); Then 16:8
daily for another two weeks (16 hours fasting; eating for 8 hours); Finally,18:6 for 3-4 days
out of a week with the rest of the week 16:8.
I try to stop any oral intake other than water three hours before bedtime — I found this is the
most critical factor in how I feel the next day. I have not noticed any side effects from
intermittent fasting other than a few pounds of unintentional weight loss. However, I have
experienced an improvement in my health.”
____________________________
It appears that vaccine-injured patients can be grouped into two categories: i) ivermectin responders
and ii) ivermectin non-responders. This distinction is important, as the latter group is more difficult to
treat and requires more aggressive therapy.
Based on the most updated clinical experiences in our collaborative network, we propose the following
treatment approach:
o Initiate therapy with 0.3 mg/kg daily. Reassess for improvements in 2-3 weeks.
▪ If the patient reports additional benefit with doubling the initial dose, continue patient
on 0.6mg/kg daily.
▪ If the patient does not report additional benefit at the higher dose, reduce ivermectin to
the initial dose of 0.3mg/kg daily.
o For ivermectin responders, prolonged and chronic daily treatment is often necessary to support
their recovery. In many, if the daily ivermectin is discontinued worsening symptoms often recur
within days.
For example: A 160 lb. person needs to take a daily dose of 0.3 mg/kg. Her doctor has provided her with 3 mg
tablets. Based on this table, her daily dose should be 21-23 mg, so she should take 7 tablets.
Mechanisms
Similar to patients with chronic fatigue syndrome, post-exertional fatigue may be related to
mitochondrial dysfunction and the inability to augment production of ATP. [139,141,142] Magnetic
resonance–augmented cardiopulmonary exercise testing suggests failure to augment stroke volume as a
potential mechanism of exercise intolerance in patients with long COVID. [143]
Nattokinase
Dosing and administration
100-200 mg (2000-4000 FU) twice daily. Aspirin/ASA 81 mg daily can be added in low-risk patients.
Mechanisms
Nattokinase is a highly effective fibrinolytic and antiplatelet agent which targets the abnormal clotting in
the spike injured patient. In addition, nattokinase has been demonstrated to lyse extracellular spike
protein; this may further enhance the anti-clotting action of nattokinase.
Melatonin
Melatonin has anti-inflammatory and antioxidant properties and is a powerful regulator of
mitochondrial function. [146-150]
Magnesium
Dosing and administration
A starting dose of 100 to 200 mg daily is suggested, increasing the dose as tolerated up to 300 mg
(females) to 400 mg daily. Endpoints of treatment include an RBC-Mag at the higher end of the normal
range (between 4.2 and 6.8 mg/dL to be about 6.0 ng/dL).
Mechanisms
There are at least 11 different types of magnesium that can be taken in supplement form with varying
bioavailability. Generally, organic salts of Mg have a higher solubility than inorganic salts and have
greater bioavailability. [151] Magnesium citrate is a widely used type of magnesium in salt form and is
often recommended to treat constipation; high doses may cause diarrhea and prolonged use should be
avoided. Magnesium oxide and magnesium citrate compounds, commonly prescribed by physicians,
have poor bioavailability. [152] Magnesium Malate, Taurate, Glycinate, and L-threonate have good
bioavailability and will readily increase RBC magnesium levels. Magnesium taurate and magnesium L-
threonate significantly increase magnesium levels in brain cells; hence they are used in the treatment of
depression and Alzheimer’s disease. [152,153]
It is important that patients and/or their healthcare providers purchase high-quality, impurity-free,
pharmaceutical-grade methylene blue. Patients may purchase a 1% methylene blue solution (e.g.
https://www.bphchem.com/product/methylene-blue-1-usp-grade-50-ml-1-drop-contains-0-5-mg-of-
methylene-blue/), MB in a powder form requiring reconstitution into a 1% solution (e.g. from CZTL at
https://cztl.bz/?ref=Lwr85 ) or MB Buccal Trouches (https://troscriptions.com/products/) (will cause
blue staining of mouth and teeth; trouches can be swallowed to avoid this effect).
Dosing of LDMB:
• Start with 5 mg (.5 ml) twice daily for the first week.
• Gradually increase the dosage every 2-3 days (guided by symptoms - i.e., improvement in
fatigue and/or cognitive improvement) until you reach a maximum of 30 mg (3 ml) per day.
• Take the 7th day off every week to allow the body to “reset”.
Mechanisms
Methylene blue (MB) has a number of biological properties that may be potentially beneficial in vaccine-
injured patients. MB induces mitophagy (mitochondrial autophagy) and has anti-inflammatory,
antioxidant, neuroprotective, and antiviral properties. [154,155] A study in 2013 found that methylene
blue-induced neuroprotection is mediated, at least in part, by macroautophagy through activation of
AMPK signaling. [156]
MB easily crosses the BBB and preferentially enters neuronal mitochondria. MB has high bioavailability
to the brain with brain tissue levels tenfold higher than serum levels. [157,158] Low-dose methylene
blue (LDMB) stimulates mitochondrial respiration by donating electrons to the electron transport chain.
MB can reroute electrons directly from complex I to complex III, avoiding electron leakage and
subsequent ROS production.
MB and photobiomodulation (PBM) have similar beneficial effects on mitochondrial function, oxidative
damage, and inflammation. Treatment with MB is therefore often combined with PBM therapy.
[159,160]. However, because PBM and MB exert beneficial effects through distinct mechanisms,
combining the use of these two therapies is expected to improve therapeutic outcomes synergistically.
Numerous studies indicate an improvement in brain mitochondrial function and neurological function
following treatment with MB and PBM for a spectrum of neurological diseases. [158,159,161]
LDMB will cause your urine to be blue or blue-green. Some patients may experience a Herx reaction. A
Herx reaction may cause fatigue, nausea, headache, or muscle pain. If you experience a Herx reaction,
stop the protocol for 48 hours and then resume again slowly.
MB is a potent monoamine oxidase inhibitor (MAOI) that, in conjunction with an SSRI, can potentiate
serotonin syndrome, a life-threatening medical emergency. This combination of medications is to be
strongly avoided. Do not take FLUVOXAMINE, FLUOEXETINE or BUPROPION or any other SSRI -NDRI
(norepinepine-Dopamine Reutake Inhibitor) with MB.
MB increases toxicity of hydrocodone bitartrate by increasing serotonin levels in the blood. This
combination should be avoided.
Individuals with glucose-6-phosphate dehydrogense deficiency (G6PD) should not be treated with MB as
it can cause hemolytic anemia.
Those interested in this therapy are recommended to read the book by Ari Whitten entitled “The
Ultimate Guide to Red Light Therapy.” [163]
A number of LED panels with multiple red and IR lights are commercially available (e.g.
https://mitoredlight.com/, https://hoogahealth.com/, https://platinumtherapylights.com/. The
disadvantage of LED panels is they do not mimic that of solar radiation as they deliver 1-10 nm wide
spiked emissions of red light at 660 nm and NIR-A at 830 nm. In contrast, ThermaLight® bulbs
(SaunaSpace® Saunas™) have a radiation spectrum closely resembling that of solar radiation, but
without UV radiation. About 39% of the emitted spectrum of the ThermaLight® bulb is NIR-A (the solar
spectrum has 41% IR-A) and about 41% of the radiation is in the IR-B range; part of IR-A and IR-B (1000-
3000 nm) contributes to the thermal effects of emitted radiation, which promotes induced
hyperthermia (sauna therapy) and is discussed below under “Other Potential Therapies”.
Mechanisms
PBM is referred to in the literature as low-level light therapy, red light therapy, and near-infrared light
therapy. The spectral radiance of solar radiation extends from 10 nm to about 3000 nm i.e., the
spectrum from ultraviolet (10-400 nm), visible (400-700 nm with red light 600-700 nm), near-infrared
radiation (750-1500 nm (NIR-A)) and mid-infrared radiation (1500- 3000 nm (NIR-B)).
A more recent large prospective study demonstrated that avoiding sun exposure is a risk factor for all-
cause mortality. [165] In this study, the mortality rate amongst avoiders of sun exposure was
approximately twofold higher compared with the highest sun exposure group. Apart from UV radiation
stimulating vitamin D synthesis, red and near-infrared (NIR) radiation have a profound effect on human
physiology, notably acting as a mitochondrial stimulant and increasing ATP production. [166]
The most well-studied mechanism of action of PBM centers around enhancing the activity of
cytochrome c oxidase, which is unit four of the mitochondrial respiratory chain, responsible for the final
reduction of oxygen to water. In addition, one of the most reproducible effects of PBM is an overall
reduction in inflammation. PBM has been shown to reduce markers of M1 phenotype in activated
macrophages. [166] Many reports have shown reductions in reactive nitrogen species and
prostaglandins in various animal models. In addition, PBM activates a wide range of transcription factors
leading to improved cell survival. It has also been suggested that NIR light increases the production of
melatonin in mitochondria. [167]
In an outstanding in vitro study, Aguida et al demonstrated that infrared light caused a marked
reduction in the TLR-4-dependent inflammatory response pathway in a human cell culture line. [168] In
this study, infrared light exposure resulted in a significant decline in NFkB and AP1 activity as well as a
marked decrease in the expression of proinflammatory genes. The increased body temperature induced
by NIR-A and NIR-B activates the production of heat shock proteins (which increase autophagy) as well
as essential cell stress survival pathways.
Emerging data suggest that transcranial PBM has beneficial effects in a range of neuro-psychiatric
diseases including stroke, traumatic brain injury, Alzheimer's disease, Parkinson’s disease, and
depression. [169-172] PBM has been suggested to have a role in the prevention and treatment of
COVID-19. [173] A recent double-blind, sham-controlled study using an LED device demonstrated a
marked improvement in the condition of hospitalized patients with acute COVID-19 infection. [174]
Quercetin, a plant flavonoid with many of the biological properties of resveratrol, acts synergistically
with resveratrol and increases the bioavailability of resveratrol. [180-182] Pterostilbene, is another plant
flavonoid similar to resveratrol in structure with similar biological properties. [183-185] However,
pterostilbene's unique structure makes it more oil-soluble than resveratrol, which increases its
absorption and cellular uptake while reducing the rate of elimination from the body. Research has
shown that pterostilbene has seven times the half-life of resveratrol and has greater bioactivity in
reducing the effects of oxidative stress. We, therefore, suggest a “high quality” combination supplement
with resveratrol and quercetin and ideally also containing pterostilbene.
The safety of these phytochemicals has not been determined in pregnancy and they should therefore be
avoided.
Due to the possible drug interaction between quercetin and ivermectin these drugs should not be taken
simultaneously (i.e., should be staggered morning and night).
The use of quercetin has rarely been associated with hypothyroidism. [187] The clinical impact of this
association may be limited to those individuals with pre-existent thyroid disease or those with
subclinical thyroidism. Quercetin should be used with caution in patients with hypothyroidism and TSH
levels should be monitored.
Probiotics/prebiotics
Patients with post-vaccine syndrome classically have a severe dysbiosis with loss of Bifidobacterium.
[188-190]
• Vitamin D (4000-5000 units/day) and Vitamin K2 (100 mcg/day); The dose of Vitamin D should
be adjusted according to the baseline Vitamin D level. However, a dose of 4000-5000 units/day
of Vitamin D, together with Vitamin K2 100 mcg/day is a reasonable starting dose.
• N-acetyl cysteine (NAC); 600-1500 mg/day [192-194] NAC is the precursor of reduced
glutathione. NAC penetrates cells where it is deacetylated to yield L-cysteine thereby promoting
GSH synthesis. [194] Based on a broad range of antioxidant, anti-inflammatory, and immune-
modulating mechanisms, the oral administration of NAC likely plays an adjuvant role in the
treatment of the vaccine injured. Several studies showed that NAC is well absorbed by the
intestine and that a supplementation with NAC is effective for increasing GSH levels.
Oral glutathione is poorly absorbed and is generally not recommended. [195,196] However,
acetyl glutathione is more lipophilic than glutathione, sufficiently so to be taken up intact by
cells, and has been shown to rapidly raise intracellular GSH levels. A combination supplement
that contains acetyl glutathione, NAC and Vitamin C may enhance the bioavailability of
glutathione. In addition, liposomal glutathione has been demonstrated to increase tissue levels,
antioxidant capacity and immune function. [197]
• Omega-3 fatty acids; we suggest a combination of EPA/DHA with an initial dose of 1 g/day
(combined EPA and DHA) and increasing up to 4 g/day (of the active omega-3 fatty acids). The
omega-3 fatty acids have anti-inflammatory and cardioprotective effects and play an important
role in the resolution of inflammation by inducing resolvin production. [200,201] Furthermore,
omega-3 fatty acids are believed to afford potent vasculoprotective effects, by improving
endothelial function, limiting vascular inflammation, reducing thrombosis, and limiting reactive
oxygen species production. [202] Fish, particularly wild Atlantic (or Alaskan) salmon, are a good
source of omega-3 fatty acids. Omega-3 supplements include Vascepa™ (icosapent ethyl; an
ethyl ester of eicosapentaenoic acid [EPA]), Lovaza™ (a combination of ethyl esters of EPA and
docosahexaenoic acid [DHA]) as well as “regular fish oil supplements” containing a combination
• Nigella sativa; 200-500 mg encapsulated oil twice daily. Nigella sativa is a small shrub native to
Southern Europe, North Africa, and Southeast Asia. The seeds and oil of Nigella sativa have been
used as a medical agent for thousands of years. The most important active component is
thymohydroquinone. Nigella sativa has antibacterial, antifungal, antiviral (SARS-CoV-2), anti-
inflammatory, antioxidant, and immunomodulatory properties. [217,218] A dose of 200-500 mg
twice daily of the encapsulated oil is suggested. [217-220] It should be noted that
thymohydroquinone decreases the absorption of cyclosporine and phenytoin. Patients taking
these drugs should, therefore, avoid taking Nigella sativa. [221] Furthermore, two cases of
serotonin syndrome have been reported in patients taking Nigella sativa who underwent
general anesthesia (probable interaction with opiates). [222]
• Vitamin C; 1000 mg orally two to three times a day. Vitamin C has important anti-inflammatory,
antioxidant, and immune-enhancing properties, including increased synthesis of type I
interferons. [223-227] Avoid in patients with a history of kidney stones. Oral Vitamin C helps
promote the growth of protective bacterial populations in the microbiome.
• Intravenous Vitamin C; 25 g weekly, together with oral Vitamin C 1000 mg (1 gram) 2-3 times
per day. High-dose IV vitamin C is “caustic” to the veins and should be given slowly over 2-4
hours. Furthermore, to assess patient tolerability the initial dose should be between 7.5-15 g.
Total daily doses of 8-12 g have been well-tolerated, however, chronic high doses have been
associated with the development of kidney stones, so the duration of therapy should be limited.
[103-108] Wean IV Vitamin C as tolerated.
• Hydroxychloroquine (HCQ); 200 mg twice daily for 1-2 weeks, then reduce as tolerated to 200
mg/day. HCQ is a potent immunomodulating agent and is considered the drug of choice for
systemic lupus erythematosus (SLE), where it has been demonstrated to reduce mortality from
this disease. Thus, in patients with positive autoantibodies or where autoimmunity is suspected
to be a prominent underlying mechanism, HCQ should be considered earlier. Further, it should
be noted that SLE and post-vaccine syndrome have many features in common. HCQ is safe in
pregnancy; indeed, this drug has been used to treat preeclampsia. [265-269] With long-term
usage, the dose should be reduced (100 or 150mg/day) in patients weighing less than 61 kg (135
lbs.). It should be noted that HCQ will limit the effectiveness of intermittent fasting.
• Low dose corticosteroid; 10-15 mg/day prednisone for 3 weeks. Taper to 10 mg/day and then 5
mg/day, as tolerated.
• Valproic acid [280,281]; Depakote, 250mg 2-3 times daily. Valproic acid has anti-inflammatory
effects and polarizes macrophages towards an M2 phenotype. [282] Histone deacetylase (HDAC)
inhibitors are being studied for neural regeneration. In addition, valproic acid has important
anticoagulant and anti-platelet effects [283] and is an inducer of heat shock proteins. [284]
Valproic acid may be helpful for neurological symptoms. Treatment should be limited to less
than 6 to 9 months due to the concern for the loss of brain volume particularly in those patients
with cognitive dysfunction. [285] In a cerebral ischemia/hypoxia model resveratrol markedly
enhanced the neuroprotective effects of valproic acid. [286] Furthermore, resveratrol has been
reported to reverse the toxicity of valproic acid, [287,288]. These data suggest that resveratrol
(in a dose of 500 mg – 1000 mg twice daily) should be recommended in patients prescribed
valproic acid.
• Induced hyperthermia and Cold Hydrotherapy. The role of sauna bathing and cold therapy
(cold showers, cold baths) in patients with long COVID and the vaccine-injured is unknown.
[289,290] Regular sauna bathing has been proven to reduce all-cause and cardiovascular
mortality, prolong the lifespan, improve exercise performance, and improve the outcome of
patients with neuropsychiatric disease. [291-295] Induced hyperthermia increases the
expression of heat shock proteins, which activates autophagy. In addition, heat therapy
increases the expression of cell stress pathways, has antioxidant and anti-inflammatory effects,
and improves mitochondrial function. [289] Sauna bathing has very similar physiologic effects to
that of aerobic exercise (increase heart rate, stroke volume, and cardiac output). [296,297] As
patients with long COVID and the vaccine-injured are exercise intolerant (they cannot increase
cardiac output) [143] sauna bathing may be poorly tolerated. However, sauna bathing and
induced hyperthermia have been shown to improve endothelial and cardiac function in patients
with chronic heart failure. [298] Furthermore a recent meta-analysis reported that sauna
bathing improved cardiac function in patients with chronic heart failure. [299] Waon therapy
(infrared dry sauna) has shown promising results in patients with chronic fatigue syndrome.
[300,301] Patients interested in sauna bathing should determine their tolerance to short
sessions (5-10 mins) and increase the duration as tolerated (up to 20 minutes) three to four
times a week. Similarly, the role of cold therapy in the vaccine-injured is unknown; patients
should similarly determine their tolerance to this treatment approach. [302,303]
• Pentoxifylline (PTX); PTX ER, 400 mg three times daily, should be considered in those patients
with severe microcirculatory disturbances. PTX is a non-selective phosphodiesterase drug that
has anti-inflammatory and antioxidant effects. [224] In addition, PTX improves red blood cell
deformability and reduces blood viscosity, so can mitigate the hyper-viscosity and RBCs hyper-
aggregation, which is linked with the development of coagulopathy in the vaccine injured.
• Maraviroc; 300 mg orally twice daily. If 6 to 8 weeks have elapsed and significant symptoms
persist despite the above therapies, this drug can be considered. Note Maraviroc can be
expensive and has a risk of significant side effects and drug interactions. Maraviroc is a C-C
• Sulforaphane (broccoli sprout powder) 500 mcg – 1g twice a day. While sulforaphane has many
potential benefits in patients with COVID, [305-307] long COVID and post-vaccine syndrome,
there is limited clinical data to support this intervention. Sulforaphane has immunomodulatory
effects by targeting monocytes/macrophages, suggesting a benefit in chronic inflammatory
conditions. [305-307] Sulforaphane is a beneficial supplement that may be useful for reducing
microglial-mediated neuroinflammation and oxidative stress. In addition, as has been well-
popularized, sulforaphane has an important role in cancer prophylaxis. The pharmacology and
optimal dosing of sulforaphane are complex. Sulforaphane itself is unstable. The supplement
should contain the two precursors, glucoraphanin and myrosinase, which react when the
supplement is consumed. Broccoli “extracts” are produced in a way that completely destroys
the activity of the myrosinase enzyme. As such, these extracts are incapable of producing
sulforaphane when consumed in a supplement or food. [308,309] We recommend a 100%
whole broccoli sprout powder, which maximally retains both glucoraphanin and myrosinase
whilst, at the same time, deactivating the inhibitors.
• Dandelion (Taraxacum officinale). The root, flower, and leaves of dandelion contain an array of
phytochemicals that have anti-inflammatory, antioxidant, hypolipidemic, antimicrobial, and
anticoagulant properties. [310,311] It is widely reported that dandelion is effective for
‘detoxifying’ spike protein. An in vitro study demonstrated that a dandelion leaf extract altered
the binding of SARS-CoV-2 spike protein to the ACE receptor. [312] It would appear that this
effect was due to alterations (binding) of the ACE-2 receptor rather than binding to the spike
protein. It, therefore, remains unclear whether dandelion extract actually binds to the spike
protein and would potentiate clearance of this protein. The European Scientific Cooperative on
Phytotherapy recommends a dose of 4-10 g TID (20-30mg/ml in hot water). [313] It should be
noted that Dandelion extract is considered contraindicated in those with liver and biliary
disease, bile duct obstruction, gallstones, cholangitis, and active peptic ulcer. [313] Furthermore
dandelion is rich in potassium and should be used cautiously in patients with kidney failure.
• C60 or C60 fullerenes [315,316]; C60, short for Carbon 60, is composed of 60 carbon atoms
forming something that looks like a hollow soccer ball and is considered as a “free radical
sponge.” C60 is considered the single most powerful antioxidant ever discovered. Robert Curl,
Harold Kroto, and Richard Smalley were awarded the Nobel Prize for chemistry in 1996 for its
discovery.
• Intravenous immunoglobulin (IVIG) treatment; The role of IVIG in the treatment of the vaccine
injured is unclear. The response to IVIG in the general population of vaccine-injured patients is
mixed, with very few showing long-term improvement. Many patients who report an initial
IVIG is, however, recommended in specific autoimmune syndromes, which include Guillain Barré
Syndrome, transverse myelitis, and immune thrombocytopenia. These patients should
concomitantly be treated with the core immune-modulating therapies. IVIG proved to be
ineffective in an RCT that enrolled patients with small fiber neuropathy. [317]
The fact that many patients report an initial response to IVIG supports the notion that many
aspects of this disease are due to autoantibodies. IVIG will remove preformed antibodies, but
they do not prevent the B cells from ongoing antibody production; hence the response is likely
to be short-lived, and interventions that limit the production of autoantibodies are therefore
required (core immune-modulating therapies).
Depression
• Depression is a serious problem in long COVID and post-vaccine patients and, unfortunately, suicide
is not uncommon. [332-334] Patients with a history of depression and/or those taking SSRI
medications appear to be at particular risk of severe depression.
• Patients with depression are best managed by mental health providers with expertise in this area.
Long-term SSRI medications are generally not recommended due to the long-term effects of these
drugs on serotonin receptors, intracellular messenger pathways as well genetic and epigenetic
effects. [335,336] It should be noted that most SSRI/SNRI agents, but notably sertraline,
fluvoxamine, paroxetine, venlafaxine, and duloxetine are associated with severe anxiety which may
progress to mania, self-inflicted harm, suicide, anger outbursts, physical violence, homicidal
thoughts, and homicide. [337-340] Patients who are treated with antidepressant agents, therefore,
require close monitoring for the development of these serious adverse reactions.
• There appears to be an interaction between vaccination, COVID-19, zinc levels, and depression.
[341-344] COVID-19 infection and COVID vaccines may lead to low zinc levels. Zinc deficiency is
associated with an increased risk of depression. Treatment with zinc has been shown to have
antidepressant effects and to act synergistically with SSRI medication. [345] 25 mg zinc daily
(elemental), together with the zinc ionophore quercetin is therefore suggested. [344]
• Non-invasive brain stimulation (NIBS) using transcranial direct current stimulation or transcranial
magnetic stimulation has been demonstrated to be highly effective in the treatment of depression.
[346-350] Indeed, The Fisher Wallace Stimulator® is FDA approved for the treatment of depression,
anxiety, and insomnia. NIBS is painless, extremely safe, and easy to administer. NIBS is a recognized
therapy offered by many Physical Medicine and Rehabilitation Centers. Patients may also purchase
an FDA-approved device for home use (https://www.fisherwallace.com/).
• Methylene blue (dose as indicated above) has been proven to be beneficial in patients with
depression.[351,352] Do NOT TAKE FLUVOXAMINE, FLUOXETINE, BUPROPION or any other SSRI-
NDRI with MB.
• Photobiomodulation and sauna bathing have been shown to be highly effective for the treatment of
depression. [294,353-355]
Vaccine-induced myocarditis/pericarditis
• ACE inhibitor/ARB, together with carvedilol as tolerated to prevent/limit progressive decline in
cardiac function.
• Colchicine in patients with pericarditis – 0.6 mg/day orally; increase to 0.6 mg twice daily if
required. Reduce dose if patients develop diarrhea. Monitor white blood cell count. Decrease
dose with renal impairment.
• Magnesium to reduce the risk of serious arrhythmias (see dosing above).
• Coenzyme Q (CoQ) 200-400mg/day. [369-372]
• Omega-3 fatty acids – EPA/DHA 2-4 g/day [373-375] Increase dose slowly as tolerated.
• Resveratrol/flavanoid combination for its anti-inflammatory and antioxidant properties.
• Referral to a cardiologist or ER in case of persistent chest pain or other signs and symptoms of
cardiac events are observed.
Tinnitus
• This a frequent and disabling complication reported in post-vaccine syndrome.
• Tinnitus refers to the sensation of sound in the absence of a corresponding external acoustic
stimulus and can, therefore, be classified as a phantom phenomenon. Tinnitus sensations are
usually of an unformed acoustic nature such as buzzing, hissing, or ringing. Tinnitus can be
localized unilaterally or bilaterally, but it can also be described to emerge within the head. [386]
• Ideally, patients should be evaluated by an ENT specialist or audiologist to exclude underlying
disorders.
• A number of treatment approaches exist to manage this disabling disease including: [386-388]
o Cognitive behavioral therapy [389]
o Specialized therapy including tinnitus retraining therapy, hearing aids, sound therapy,
auditory perceptual training, and repetitive transcranial magnetic stimulation. [386]
o A number of pharmacologic agents have been used to treat tinnitus. Anticonvulsants
including carbamazepine have generally been disappointing. The following drugs have
shown some clinical benefit.
• Tricyclic antidepressant agents particularly nortriptyline and amitriptyline.
[390,391] In addition, the SSRI sertraline has shown some efficacy. [392]
• Clonazepam and or other benzodiazepines. These drugs may provide temporary
relief, however, due to issues of dependence, long-term use is not
recommended. [393]
• Melatonin slow release 2-6 mg at bedtime. [394]
• Oxytocin nasal spray. Oxytocin acts as a neurotransmitter affecting several neural circuits,
particularly in the hypothalamus and amygdala. [324] Oxytocin nasal spray has shown promising
results for the treatment of tinnitus (one puff to each puff nostril two times a day; a total dosage
of 16 IU per day). [395] Oxytocin must be avoided in pregnancy. Oxytocin nasal spray should be
compounded at 12 to 15 units/0.1ml (spray) and administered at onset aggressively to
upregulate receptors at 2 sprays each nostril BID (8-sprays per day) for the first week and then
maintenance at 2 sprays ea. nostril (4/d) once daily. [329] Oxytocin can also be delivered via SL
liquid or via lozenge.
• Non-invasive brain stimulation (NIBS) has proven to be effective in controlling treatment-
resistant tinnitus. [240,241]
Patients with new onset allergic diathesis/features of Mast Cell Activation Syndrome
(MCAS)
• The novel flavonoid luteolin is reported to be a potent mast cell inhibitor. [401-404] Luteolin 20-
100 mg/day is suggested.
• Turmeric (curcumin); 500 mg/day. Curcumin has been reported to block H1 and H2 receptors
and to limit mast cell degranulation. [405,406] Curcumin has low solubility in water and is poorly
absorbed by the body; [407] consequently, it is traditionally taken with full-fat milk and black
pepper, which enhance its absorption. Nano-curcumin preparations or formulations designed to
enhance absorption are encouraged. [408-411]
• H1 receptor blockers. Loratadine 10 mg/day, Cetirizine 5-10 mg/day, Fexofenadine 180 mg/day.
• H2 receptor blockers. Famotidine 20 mg twice daily as tolerated. [412]
• Montelukast 10 mg/day. Caution as may cause depression in some patients. The efficacy of
montelukast as a “mast cell stabilizer’ has been questioned. [55]
• Ketotifen. 1 mg in 5 ml. Start with 0.5 ml at night. Once they get used to it, as it has a strong
hypnotic effect, increase by 0.5ml increments up to 5ml. Some patients can increase up to 10 ml
daily (1 mg BID). Ketotifen has antihistamine effects and is a mast cell stabilizer. Ketotifen may
be particularly useful in patients with GI hypersensitivity. [413,414]
• Vitamin C; 1000 mg twice daily. Vitamin C is strongly recommended for allergic conditions and
MCAS. Vitamin C modulates immune cell function and is a potent histamine inhibitor.
• Low histamine diet.
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