Long Covid Part 13 Low Dose Naltrexone and MCAS Treatment
Adapted with approval from Dr Jill Carnahan: Dr Graham Exelby January 2023
The major cause of morbidity and mortality in Covid-19 patients is from an exaggerated immune response resulting in hyper-inflammation, or “cytokine storm”. Approximately 15–20% of Covid-19-infected patients suffer a severe form of the acute infection, characterized by activation of mast cells leading to histamine release and hyperinﬂammatory cytokine storms causing far more morbidity and mortality than from any direct viral cytotoxicity.
If you’ve ever spent time reading about allergies, you might have come across people talking about Mast Cell Activation Syndrome (MCAS). People with Mast Cell Activation Syndrome often struggle just to obtain a diagnosis – due to the complexity of the disease and the lack of awareness within the mainstream medical community, patients can go months, if not several years, without relief for their illness.
Drs Lawrence Afrin, Leonard Weinstock and others have written extensively about MCAS, including its links to other conditions like Ehlers-Danloss Syndrome and exposure to chemicals, toxins, mould etc. Research, especially with the linking from Covid pathogenesis has shown the importance of mast cell activation and the inflammatory storms that cause a wide variety of problems that constitute the “Long Covid Syndrome” that affects so many people. It also provides a therapeutic target for MCAS – toll-like receptors.
Mast Cells in Innate and Adaptive Immunity
Mast cells live in our connective tissue. They hold granules of histamine and other inflammatory mediators and are a major part of our protective immune responses and are also involved in allergy, anaphylaxis, and systemic inflammation. Your immune system has two types of response: innate and adaptive immunity.
Innate immunity is a rapid, nonspecific response system that is your first line of defence against invaders. Think cough reflex, your skin, stomach acid, or mucus. All of these are designed to actively clear or eliminate pathogens.
The second response is called adaptive immunity. This is a slower but precisely targeted response mediated by lymphocytes called B and T cells. Adaptive immunity develops over a period of time, but results in the generation of effector cells. Some of these effector cells persist after the infection and form the basis of lifelong immunological memory of the invading pathogen.
Commonly, people think of these as the antibodies that are created after we are exposed to an illness for the first time. The two response systems were once considered separate, with adaptive immunity thought of as more sophisticated and potent of the two. However, researchers are noticing they are extensively interdependent – and one of the key players in this crosstalk is a class of proteins called toll-like receptors.
What Are Toll-Like Receptors?
If mast cells can be thought of as peacekeepers (like our soldiers and police), then toll-like receptors (TLRs) are likely the equivalent of a smart home security system. Similar to how today’s security systems are packed with sensors that alert you to intruders as well as natural disasters, TLRs recognize foreign invaders in your body and send out signals that activate mast cells.
TLRs accomplish this feat by detecting and binding to structurally-conserved molecules unique to foreign microbes, called pathogen-associated molecular patterns (PAMPs). Essentially, TLRs latch on to PAMPs to call attention to them.
Most microorganisms – viruses, fungi, bacteria, and protozoa – express PAMPs, which means TLRs are able to sense just about any infection we might encounter. This is a valuable aspect of our immune systems because backup sensors don’t provide sufficient protections against most infections when TLRs are absent.
Toll-Like Receptors: The Link Between Innate and Adaptive Immunity
When a mast cell encounters an allergen, it releases inflammatory mediators including histamine. These chemicals induce swelling, coughing, sneezing, itchiness, & cramping of the gut to help the body expel pathogens.
Mast cells express multiple classes of pattern-recognition receptors (PRRs), including TLRs. Most people’s mast cells express TLRs 1-10, although there have been variations seen in studies. Upon binding to PAMPs, all known human TLRs except TLR3 activate downstream signalling. This results in cascading reactions where mast cells mount an immune response.
Mast cell activation is the source of symptoms in many chronic illnesses. Mast cell degranulation is a normal part of the neuro-immune response but mast cells can become hypersensitive in some people. Mast cell degranulation is a part of Mast cell activation syndrome (MCAS), mastocytosis, ME/CFS, most post-viral illnesses, long covid, chronic Lyme, severe vaccine reactions, toxic mould exposure, fibromyalgia, IBS, migraine, endometriosis, PMDD, and more.
Mast cell issues are not rare - a fact the mainstream medical industry has barely begun to acknowledge. Medical gaslighting or other mistreatment of patients frequently occurs when patients present with the multi-system sporadic symptoms of mast cell degranulation. Symptoms of mast cell conditions are often incorrectly attributed to psychological conditions.
Mast cells can participate in direct defence against the pathogen in two ways: phagocytosis and reactive oxygen species (ROS) production.
Mast cells can also produce antimicrobial peptides or extracellular traps to kill organisms. However, due to the relatively small number of mast cells, indirect effects of coordinating host innate and adaptive immune responses may be more important.
In the indirect method, mast cells initially release small sacs called granules (degranulation), which contain inflammatory mediators like histamine. These mediators can increase blood flow to the site of infection or enhance epithelial cell mucus production which can physically expel the pathogen. This is followed by the secretion of cytokines, chemokines, and lipid mediators, initiating the process of inflammation.
The secretion of chemokines and cytokines activate the T cells and B cells of the adaptive immune system. Mast-cell derived cytokines and chemokines enhance the migration of dendritic cells to the site of infection, where they ingest the pathogen. This is the start of the adaptive immune response.
In other words, TLRs act as a link between your innate and adaptive immunity.
Chronic exposure to environmental pathogens like toxic mould can trigger the activation of TLRs, which activates mast cells that start the inflammatory process. Without removal of the trigger, mast cells can become overactive in some individuals, leading to the development of mast cell activation syndrome (MCAS). In Postural Orthostatic Tachycardia Syndrome (POTS) DNA imputation has revealed mutations in receptor proteins on mast cells and other areas, major culprits in the MCAS found in POTS and the POTS-like Long COVID syndrome (see DNA Mutations article)
Treatments for Mast Cell Activation Syndrome
While there is no cure for MCAS there are a number of tools you can put into place to control then exaggerated responses. Identifying and avoiding triggers that cause MCAS to flare up is of utmost importance. People with a non-aggressive form of MCAS usually see improvements within the first four weeks of treatment.
Here are some treatment options for patients with MCAS. If you know an environmental toxin or mechanical driver is your trigger, then some of these suggestions might not apply to you.
1. Identify mechanical factors
POTS patients demonstrate defined activation points in their history. Only a detailed history will provide a clue to the mast cell activation, and seldom is there a dramatic and sudden activation, as clues to earlier activation are usually present. Mechanical drivers are the “norm” in POTS, the most common from the Thoracic Outlet Syndrome and scalene pull on the upper cervical spine.
Hypermobility is also very common, but even here there is linking in Ehlers Danloss Syndrome to mast cell activation. The emerging association between the TOS, loss of lordosis in the neck and its effect on the glymphatic system has become a major source of current and future research. Identification and management of these is critical to control of the symptoms. These are often as simple as posture, especially with increasing computer usage, use of backpacks and occupational habits.
2. Eat a Low-Histamine Diet
First things first, you need to get your histamine levels under control. One way to do this is by doing a “low-histamine diet,” which is an elimination diet with the goal of reducing the histamine from the foods and beverages you consume. The link provides an excellent resource to appropriate food choices. This is a critical step, and should be followed as carefully as possible.
There is no guarantee that you will see benefits or that all of the “allowed” foods will not trigger your MCAS symptoms because you have your own list of sensitivities. What makes one person sick may not affect you in any way, so the best thing you can do is to track your own responses as best as possible. Adding low keto diet to this is difficult but is a major part of improving the impaired mitochondrial function critical to fatigue in Long COVID.
To avoid the risk of malnutrition, confusion, or overwhelm, you should seek help from our dietician who is familiar with treating MCAS. It’ll take some experimentation and a lot of patience, but a low-histamine diet could help you understand and identify some patterns in your sensitivities.
3. Use Antihistamines and Mast Cell Stabilizers
Diamine oxidase (DAO) is the main enzyme responsible for degrading histamine. However, in patients with DAO deficiency, or in situations where the mast cell activity is excessive, this degradation activity is impaired, leaving histamine to run amok. The resulting symptoms are those we often associate with an allergic reaction or symptoms such as diarrhoea, headache, rhino-conjunctival symptoms, asthma, hypotension, arrhythmia, urticaria, pruritus, flushing, and other conditions seen in MCAS.
DAO in available in supplements but has such a short half-life, it cannot enter the bloodstream to reduce the amount of histamine produced within the body. This means that excess endogenous histamines need to be addressed by other methods, such as natural antihistamines and mast cell stabilizers.
You’re probably more familiar with antihistamines like Telfast and Zyrtec. These drugs provide relief from allergy symptoms by competing with histamines for occupation of histamine receptors on cells.
I recommend a trial of Telfast 180 mg or Zyrtec initially daily then increasing to twice daily as an adjunct to the low histamine diet. Even brain fog, which reflects altered intracranial vascular pressure, can be relieved with this simple treatment.
There are 4 histamine receptors- H1 to 4. The normal antihistamines block H1. A group of medication used in past decades for reflux oesophagitis and now formally in management of Helicobacter Pylori, have found a very useful place to supplement H1 blockers- H2 blockers, specifically Famotidine
Famotidine is being increasingly used in the management of COVID-19. Low Dose Naltrexone has been found to block the H4 receptors with results in chronic fatigue. This product improves Natural Killer Cell and Glymphatic function.
On the other hand, mast cell stabilizers prevent degranulation and stabilize the cell, preventing the release of antihistamines. Quercetin is a powerful, well-known, natural compound that exhibit mast cell stabilizing activities and a favourite of naturopaths. It is best taken in liposomal form or absorption is poor.
Quercetin (see below) is generally considered safe, although there may be issues in some of the DNA mutations. Other mast cell stabilizers you might be familiar with include resveratrol, luteolin, and curcumin.
Turmeric is widely studied for its health-promoting properties. It has been used in Traditional Chinese Medicine, as well as Ayurvedic medicine, for more than 2,000 years. Curcumin is turmeric’s most active component and provides numerous health benefits, including support for joint function and mobility, liver and gut health, cardiovascular function. Curcumin is also a potent antioxidant and has been found to block the H4 receptors.
5. Identify Sources of Toxins/ cause of mast cell dysregulation
There is no one single factor that has been shown as the definitive cause of MCAS. However, various microbes can disrupt the immune system and cause mast cells to go haywire. The obvious one lately is the SARS virus- Covid 19.
6. Increase Exercise
In general, adults should aim for at least 2 hours of moderate exercise weekly.
7. Promote Good Gut Health
Although we’re still in the early stages of understanding the gut microbiome and its impact on our health, many experts agree that a skewed microbiome often results in illness, including inflammation.
Therefore, moving beyond calming hyperactive mast cells, restoring balance to body’s microbiome is essential. Diet is a huge factor, and in the activated immune state, when you eat a food the body sees as a threat TLRs, mast cell responses are activated with release of cytokines ILs 2,6,8,10 and TNF.
So it is no surprise that change of diet can reduce the glial sensitisation seen in fibromyalgia and the autonomic chaos in dysautonomia and POTS, often with reduction in areas such as brain fog.
8. Get Enough Sleep
In a world that idolizes intense productivity and doing “all the things,” it’s tempting to sacrifice sleep. But doing so can upset the circadian clock of mast cells, which regulates the severity of allergy symptoms throughout the day.
An interesting facet of allergic diseases is the variation in symptom severity throughout the day. Earlier studies showed that serum mast cell histamine levels were lower in the afternoon and highest at night. This is why many patients with allergies report experiencing “morning attacks” or sleep disruptions.
When the newly recognized glymphatic system is looked at closely, there is a close correlation with sleep patterns (see “Cervical Spine with Loss of Lordosis and Impeded Glymphatics and association with the Thoracic Outlet and Jugular Outlet Syndromes”(24). This system provides the background to the emergent work on Chronic Fatigue Syndrome from Griffith University.
The glymphatic system is a macroscopic system for waste clearance in the brain. It uses a system of perivascular channels, formed by astroglial cells, to promote efficient elimination of soluble proteins and metabolites from the CNS. Besides eliminating waste, the glymphatic system may also distribute non-waste compounds, such as glucose, lipids, amino acids, and neurotransmitters, as well as permitting the flow of fluid through the brain. Intriguingly, the glymphatic system functions mainly during sleep and is largely disengaged during wakefulness.
With irregular sleep patterns or poor sleep quality, mast cells can lose their rhythmicity, which means mediator release becomes uniform throughout the day. The bottom line here is that cultivating a good, regular sleep schedule and sticking to it can help keep your mast cells in check as well as improve glymphatic function.
9. Reduce Stress
Stress is a major problem for most of us, and many of us don’t have a healthy way of managing it. Chronic stress can kick your immune system into overdrive and allow troublemaking microbes to flourish. Stress can also contribute to mast cell degranulation, which causes them to release mediators like histamine. It only makes sense, then, for patients with MCAS to minimize stress as much as possible.
Triggers for MCAS patients can be wide-ranging, from physical or emotional stressors to the smell of perfume or even a change in room temperature. The reality is, MCAS is highly variable in its behaviour. Thus, stress management for patients with the disease also needs to be personalized.
10. Low-Dose Naltrexone
Even with all the treatment methods outlined above, some people may continue to struggle with MCAS symptoms. Recent research shows that a novel use of low-dose naltrexone (LDN) may help some of these patients. At first glance, LDN may seem like a strange drug of choice for treatment of MCAS.
Naltrexone is a H4 blocker, a drug that was approved to help prevent narcotics and alcoholics from relapsing. As an opiate antagonist, naltrexone competes with opioid drugs for real estate on opiate and endorphin receptors. This helps patients feel less “high” from opioids or alcohol and reduce cravings.
LDN has a unique action mechanism of suppressing microglial activity. Microglia are the central nervous system’s primary immune cells and are responsible for creating inflammation as a response to injury or pathogens. Microglia when activated secretes various factors, like prostaglandins, nitric oxide, pro-inflammatory cytokines, and excitatory amino acids.
LDN works by reducing inflammation in the brain caused by over-active microglia. Microglia are a type of glial cell of the Central Nervous System (CNS) (brain and spinal cord) and an important line of defence. When there is an assault on the CNS, the microglia are activated and release inflammatory substances (called cytokines) to destroy the foreign invaders.
The inflammatory cytokines created by an assault to the CNS can increase pain sensitivity and fatigue and trigger other inflammation cascades in the body. When the assault is over, the microglia go back to their normal resting state. However, when they react too often from repeated injury, infection, toxins, traumas, or emotional blows, they can remain hyperactive, keeping the brain in a chronic state of inflammation. Research on LDN suggests that it’s able to suppress the inflammatory response of the microglia. Some of the inflammatory conditions that have shown to benefit from LDN include fibromyalgia, multiple sclerosis, Crohn’s Disease (quoted 80% symptom improvement), Complex regional pain syndrome (a disease that often shows evidence of both local and low-level systemic inflammation) and cancer. Overall, while the literature is quite small, there is a consistent theme of LDN efficacy in controlling diseases with inflammatory components.(20)
Low Dose Naltrexone has been demonstrated to exert neuroprotective and analgesic effects. The neuroprotective action appears to result when microglia activation in the brain and spinal cord is inhibited. By suppressing microglia activation, naloxone reduces the production of reactive oxygen species and other potentially neuroexcitatory and neurotoxic chemicals. The anti-inflammatory effect of opioid antagonists may also extend to the periphery, as evidenced by suppressed TNF-alpha, IL-6, MCP-1, and other inflammatory agents in peripheral macrophages.(20)
More importantly, when LDN is used within a specific dosage window (typically between 0.5 mg and 4.5 mg), its binding of opiate receptors on immune cells can have a temporary immunoregulatory effect. The increased levels of endorphins stimulate the immune system by binding to regulatory T cells, which promotes an increase in T-lymphocytes. This up-regulation of T-lymphocytes reduces cytokine and antibody production, restoring a more normal balance.
LDN has anti-inflammatory effects. Recent studies have demonstrated this effect in patients with fibromyalgia, in which inflammation of the central nervous system is a common characteristic. When triggered by inflammation, microglia and immune cells in the central nervous system increase their expression of TLR-4, which leads to an increase in the production of pro-inflammatory cytokines. As a TLR-4 antagonist, LDN blocks this cascade of inflammation.
Fibromyalgia (FMS), is a chronic fatigue and pain disorder that is characterized by diffuse musculoskeletal pain and sensitivity to mechanical stimulation as well as profound fatigue, cognitive disruption, and sleep difficulty. FMS is now known to be glial sensitivity and inflammation driven primarily by ILs 6, 8 and TNFa. Fibromyalgia does not respond to common anti-inflammatories but researchers also found that the patients who took LDN had a 15% reduction of fibromyalgia-associated pain and an 18% reduction in overall symptoms. The serum levels of several pro-inflammatory cytokines, such as interleukin (IL)-6, IL-1β, IL-2, IL-15, IL-17A, and tumour necrosis factor (TNF)-ɑ decreased significantly.(20)
LDN needs to be compounded, and starting dose is typically 0.5 mg daily, increasing by 0.5 mg weekly to a maximum of 4.5 mg.
Because low-dose naltrexone blocks opioid receptors, you should not continue taking narcotic pain medication with LDN without consent of your medical provider. Otherwise, LDN has few side effects and is generally well tolerated by most patients. Most people notice an increase in dreaming and some people notice a bit of sleep disruption during the initial few days of treatment but this improves over time.(23) From our clinic observations, care needs to be taken if patients react poorly to H1/H2 blockade, and in patients with liver enzyme mutations and even lower starting doses seem appropriate, this starting dose may need to be reduced to 0.1 mg daily.
11. Use a DAO Enzyme Supplement
That’s where DAO supplements come in. DAO supplements increase the DAO levels in the digestive tract. By reducing the level of histamine entering the bloodstream, the total level of histamine in the body also decreases. This can provide some people with symptom relief.
You cannot purchase DAO supplements in Australia, but it is readily available at IHerb as “Histamine Block.” Do not be tempted to use Histamine Plus.
12. Other mast cell stabilizers, inhibitors and blockers
Lawrence Afrin(21)describes the various products useful in managing mast cell activation:
Inhibition of mediator production
Corticosteroids may be helpful but limited by toxicities
NSAIDs and aspirin. NSAIDs can be helpful, but these can also trigger flares of activation.
Inhibition of mediator release (mast cell stabilization)
Benzodiazepines to address end organ receptors as well as mast cells, added to potential improvement from reduced anxiety in some inflammatory bowel disease.
Tricyclics eg doxepin have H1 and H2 receptor blocking effects that can be added to traditional antihistamines.
SSRIs may benefit the associated depression but also can affect mast cells via surface serotonin reuptake transporters. However adding antihistamines to SSRIs brings the risk of serotonin syndrome.
Cromolyn (Intal) can stabilize mucosal mast cells- for dosage regime see page 199 of “Presentation,Diagnosis and Management of Mast Cell Activation Syndrome.”
Oral Ketotifen-originally marketed as an inhibitor of anaphylaxis, it inhibits release and/or activity of mast cell and basophil mediators including histamine, neutrophil and eosinophil chemotactic factors, arachidonic acid metabolites, prostaglandins and leukotrienes. (22) It is available in Australia as Zaditen eye drops, and would have to be compounded to be taken orally with a dose of 1 mg twice daily increasing weekly as tolerated
Quercetin is a flavonoid that is poorly absorbed but is thought to inhibit lipooxygenase and cyclooxygenase reducing production of inflammatory mediators eg leukotrienes and histamine. It seems to have general anti-inflammatory effects and impedes PGD2-driven flushing. General dosing is 500 to 1000 mg twice daily. Side effects may include headache and upset stomach. Preliminary evidence suggests that a by-product of quercetin can lead to a loss of protein function. Very high doses of quercetin may damage the kidneys. Care must ne taken with medication interaction, especially anti-depressants. More details available on https://www.mountsinai.org/health-library/supplement/quercetin#:~:text=Quercetin%20is%20generally%20considered%20safe,quercetin%20may%20damage%20the%20kidneys.
Allergen-driven cross-linking of multiple IgE molecules bound to mast cell-surface IgE receptors is a major route of mast cell activation. Omalizumab (Xolair) is a humanized monoclonal antibody which reversibly binds the Fc portion of IgE hindering IgE binding with its mast cell-surface receptor.
Rarely hydroxyurea and immunosuppressants
Blockade of released mediators
Histamine H1 and H2 blockade to address end organ receptors as well as mast cells
Leukotrienes are synthesized and released by mast cells –Selective leukotriene receptor antagonists eg Singulair 10 mg 1-2 times daily may help- limited in hepatic involvement.
Bisphosphonates are helpful in excessive bone resorption. Zolendronic acid has demonstrated a significant reduction in breast cancer recurrence rate. It is interesting to deliberate on the mechanism for this as it is very likely it produces this response via the mast cells.
Tumour necrosis factor (TNF) alpha is a well-established mast cell mediator product, and TNF-alpha antagonists eg etanercept (Enbrel), adalimumab (Humira), and infliximab (Remicabe) are approved for use in a variety of systemic inflammatory diseases increasingly suspected to be of aberrant mast cell origin (eg rheumatoid arthritis, psoriatic arthritis and inflammatory bowel disease). Caution needs to be exercised with these given significant side effect risks
A note of caution when adding any supplements or medications:
It might be tempting to take as many things as possible to relieve yourself of your symptoms, but people with MCAS can react to all sorts of things, even herbs. Slow down and take it easy. Start with one supplement or herb at a time and see how it affects your body.
Living with a chronic illness like MCAS can make you feel pretty discouraged. But there are things you can control. With the addition of healthy lifestyle choices and medications, you can stabilize mast cells and bring balance to your immune system.
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