Low Dose Naltrexone and MCAS Treatment
Content adapted with approval from Dr Jill Carnahan: Dr Graham Exelby June 2023
This includes a personal management protocol for POTS, Long Covid and other MCAS-associated conditions. There are no Cochrane Guidelines at this point, and all treatments are based on research from around the world. Jill Cochrane describes the importance of MCAS, in an understandable way.
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.
As the DNA studies reap more information the mutations found in the “first responders” TLR 2 and TLR4 mutations are likely to be critical in the individual patient response.
Dong et al (1) demonstrated that brain inflammation plays a critical role in the pathophysiology of brain diseases. They demonstrated that in the brain, activation of mast cells triggers activation of microglia, whereas stabilisation of mast cells inhibits the CNS inflammation that would otherwise result from activation of microglia.(1)
Microglia, the resident immune cells in the brain, play an important role in brain inflammation, while brain mast cells, rather than microglia, are the "first responders" to brain injury. They showed that site-directed injection of a “mast-cell degranulator” compound in the hypothalamus initiated the acute inflammatory response by inducing mast-cell degranulation, activating microglia, and triggering the production of inflammatory factors.
When considering treatment in MCAS, especially in Long Covid, you may have to decide whether to target the TLR4 or Mast cells, or both. A personal approach is to decide on direction from history.
Mast Cells in Innate and Adaptive Immunity
Jill Carnahan describes that 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)
Management requires to stop the ongoing inflammatory processes. Each area of inflammation from the Covid and pre-Covid state needs to be identified and managed. Then our protocol is to reduce the desensitization and reduce the inflammatory activation:
1. H1 blockade -mast cell stabilization.
Fexofenadine 180 bd or Cetrizazine 10mg bd or equivalents
Ketotifen (see below)
2. H2 blockade:
Famotidine 40 bd, but may need to be increased to 80mg bd. Famotidine is limited by arrythmias and QT prolongation. Extra magnesium is thought to counter these.
3. TLR4 modulation -Toll-like receptor 4 (TLR4) plays a crucial role in the innate immune system, recognizing pathogen-associated molecular patterns and initiating inflammatory responses. When TLR4 is overactivated, it can contribute to excessive inflammation and the development of various inflammatory and autoimmune diseases. Modulating TLR4 signalling can have significant effects on immune responses and inflammation.
Low Dose Naltrexone -improves glymphatic function (and probably Natural Killer cell function). If H1/H2 not tolerated, caution with Low Dose Naltrexone. A study by Wang et al. (9) demonstrated that naltrexone could attenuate TLR4 signalling in glial cells, leading to reduced neuroinflammation
Nigella Sativa contains several active compounds, in particular thymoquinone, that have been found to modulate TLR4 signalling. Studies have shown that thymoquinone can down-regulate TLR4 expression and inhibit TLR4-mediated signalling pathways, reducing inflammation and oxidative stress. It increasingly looks to be a reasonable adjunct to above treatments, especially when D-Dimer remains elevated as it has anti-thrombotic activity, and may be a reasonable replacement when LDN is not tolerated.
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 modulate TLR4 signalling.
PPARg agonists eg pioglitazone and rosiglitazone, have been shown to inhibit TLR4 expression and signalling in various cell types
Other products that can influence TLR signalling include:
Glutathione indirectly by regulating redox state and mitigating oxidative stress (5)
Nicotinamide mononucleotide (NMN) appears to indirectly influence TLR4 signalling and inflammation by increasing NAD+ levels and promoting sirtuin activation. Sirtuins especially SIRT1 and SIRT6 can modulate TLR signalling and related inflammation.(6)
Amitriptyline is a tricyclic antidepressant (TCA) commonly used to treat depression, neuropathic pain, and other chronic pain conditions. While the primary mechanism of action of amitriptyline is the inhibition of serotonin and norepinephrine reuptake, it has also been shown to have other effects, including anti-inflammatory and immunomodulatory properties. While there is no direct evidence of amitriptyline acting as a TLR4 modulator, it appears to have anti-inflammatory and immunomodulatory effects that could be indirectly related to TLR4 signalling. (7)(8)
Doxycycline- is a broad-spectrum antibiotic that has been used to treat various bacterial infections. However, in addition to its antimicrobial effects, doxycycline has been found to have immunomodulatory properties, including the ability to inhibit TLR4 signalling. Several studies have demonstrated that doxycycline can reduce the expression and activity of TLR4 and its downstream signalling molecules, such as NF-κB and MAPKs, in various cell types. This can lead to a decrease in the production of pro-inflammatory cytokines, such as TNF-α and IL-6, and an overall dampening of the immune response. Therefore, doxycycline has been proposed as a potential therapeutic option for diseases that involve dysregulated TLR4 signalling and excessive inflammation, such as sepsis, inflammatory bowel disease, and autoimmune disorders.
In the POTS patients, especially when it has been triggered by COVID, we have found there is a high percentage that have QT prolongation shown in lying and standing ECGs. This makes the use of H1/H2 blockade with antihistamines and famotidine potentially risky until the prolongation can be controlled (which can be with sympathetic overactivity control with Japanese [Kiiko-Matsumoto in our studies] style acupuncture. In this situation consideration should be given to TLR4 modulation (see below) and/or oral ketotifen.
Ketotifen- H1 antihistamine/H1 blocker and mast cell stabilizer
Ketotifen requires compounding as it is not available in oral form in Australia. As it has no effect on the QT prolongation it provides a useful part of the armoury to manage Long Covid/POTS/MCAS pathways.
Ketotifen reduces antigen-induced mast cell degranulation and decreases the release of histamine, tryptase, and various prostaglandins. Ketotifen also stabilizes calcium permeability in mast cell membranes(2) making it a valuable product in MCAS and Long Covid management. It is known to interact with several ion channels and receptors that are involved in mast cell activation and the release of inflammatory mediators. One such target is the Transient Receptor Potential Melastatin 3 (TRPM3) ion channel, which has been shown to play a role in the regulation of mast cell degranulation and histamine release.
The Transient Receptor Potential Melastatin 3 or TRPM3 is a calcium-permeable ion channel that is expressed in a variety of cells, including mast cells. It plays a role in various physiological processes, including calcium homeostasis, pain perception, and temperature sensing. The activation of TRPM3 leads to an influx of calcium ions into the cell, which can trigger the release of inflammatory mediators. Ketotifen has been shown to inhibit TRPM3 activity, thus reducing the influx of calcium ions and ultimately leading to a decrease in mast cell degranulation and histamine release. In addition to TRPM3, ketotifen has also been shown to interact with other Transient Receptor Potential (TRP) channels, such as TRPV1 and TRPA1. These channels are also involved in the regulation of mast cell activation and the release of inflammatory mediators, and their inhibition by ketotifen can contribute to its overall anti-inflammatory effects. At the clinical level, the inhibition of TRP channels by ketotifen has been implicated in its efficacy in the treatment of various allergic and inflammatory conditions, including MCAS. It also reduces TNFa, macrophage-derived chemokines and IL-8.(2)
Ketotifen can be used in children as well as adults. The typical dose for children is 0.5mg to 2mg daily to twice daily. The adult dosage is typically 2mg to 4mg daily to twice daily.(3)
The main side effect is drowsiness, which affects 10%-20% of patients. This side effect tends to diminish with time, typically in about 2 months. Most patients begin treatment with a bedtime dose then increase to twice daily once the drowsiness subsides. Weight gain may occur.
Use of the eye drops commonly triggered eye pain, sensitivity, photophobia, dry mouth. Similar reactions in both adults and young children, but percentage of adverse effects lower in children eg sedation 14% in adults, 6% in children.(4)
Low Dose Naltrexone (LDN)- dosage 0.5 to 4.5 mg daily
Naltrexone is 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 is thought to work primarily through its interaction with opioid receptors, particularly the mu-opioid receptor, modulating the immune system and reducing inflammation.
There is some evidence suggesting that naltrexone, and potentially LDN, may modulate Toll-like receptor 4 (TLR4) signaling. TLR4 is a pattern recognition receptor that plays a key role in the innate immune system, recognizing pathogen-associated molecular patterns and initiating inflammatory responses. LDN has also been shown to repair TRMP3 function.
A study by Wang et al. (9) demonstrated that naltrexone could attenuate TLR4 signalling in glial cells, leading to reduced neuroinflammation. 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. Thus LDN works by reducing inflammation in the brain caused by over-active microglia.
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. Some of the inflammatory conditions that have shown to benefit from LDN include multiple sclerosis (10), Fibromyalgia (11), Crohn’s Disease (12) (quoted 80% symptom improvement), Complex regional pain syndrome (13) (a disease that often shows evidence of both local and low-level systemic inflammation). It has been suggested LDN may also be helpful in rheumatoid arthritis, SLE, and Griffith University has confirmed its application in CFS/ME. It may have applications in cancer management. Overall, while the literature is quite small, there is a consistent theme of LDN efficacy in controlling diseases with inflammatory components.
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 upregulation 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 or infection, 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.
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. We have found improvements in fatigue are usually seen between 2 and 3 mg daily.
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. Nausea, dizziness, drowsiness, anxiety, fatigue and loss of appetite can occur. 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.
Potential interactions can occur with opioid medications, as naltrexone is an opioid antagonist, and blocks the effects of them. It can lead to opioid withdrawal if used together. This includes codeine, morphine, oxycodone, hydroxycodone and may cause an increase in pain controlled by those medications. It may interact with buprenorphine, naloxone, and it has immunomodulatory effects, it may interact with other immunosuppressive medications potentially altering the medication’s effectiveness. This may include methotrexate, corticosteroids and cyclosporine. It’s use must be discussed with your medical advisor.
Other mast cell stabilizers, inhibitors and blockers
Lawrence Afrin (14) describes other various products useful in managing mast cell 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. 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. As it can inhibit COMT and increase symptoms, DNA should be sought first. 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 be 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.
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.
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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