The COVID-19 era was a game-changer. Many people lost many loved ones to strokes, heart disease, cancers, severe inflammation, etc. The usual killers but, this time, “on steroids”. Suddenly, lots of people started having problems that until then only a relative few had, i.e. those with connective tissue disorders.
When people got a mild cold that left them brutally tired afterward, I often joked, “welcome to my world!” I was born with a connective tissue disorder that has made my life very interesting, to say the least. And it’s something I don’t wish on anyone. The positive side is that dealing with chronic problems of the kind in the spectrum of “Long COVID” and connective tissue disorders does tend to increase people’s knowledge base. When mainstream therapies are seldom useful, you’re forced to think outside the box and take measures that improve your quality of life in order to stay functional on a daily basis.
Today, we’ll shine a light on a subject that remains largely unknown among mainstream practitioners due to chronic ignorance of the function and role of connective tissue in our bodies.
This subject is mast cell activation syndrome, MCAS for short, which is extremely common. It’s an inflammatory condition and immunological disease characterized by mast cell dysregulation at the level of the connective tissue.
MCAS is the kind of affliction that leaves you totally dysfunctional in daily life, though you might recognize it as “histamine intolerance” instead.
Mast cells originate from stem cells in the bone marrow, which then pass into the bloodstream as “progenitors” and finish their maturation process in connective tissue – in the skin, but also in the mucous membranes of the digestive, respiratory, ear, nose and throat tracts, the urogenital mucosa and all organs in general. There is connective tissue everywhere in our bodies, and it’s our body’s most sensory organ. See my prior post for more information:
Mast cells are sentinels, and they protect us from possible aggression.
They provide immune defense, they protect us against tumor proliferation, promote wound healing, contribute to fibrosis processes and angiogenesis. These are all good things when it’s in good measure and for a good reason.
When mast cells are stimulated, they locally release (and eventually into the bloodstream) substances they have synthesized including histamine, heparin, prostaglandins, leukotrienes, platelet activation factor, angiotensin converting enzyme, proteolytic enzymes, cytokines, chemokines, tumor necrosis factor alpha, etc.
The problem arises when they release their content (degranulate) when they shouldn’t, or when they’re hyperactive, as is often the case in connective tissue disorders.
Then there’s a lot of inflammation, both localized – lungs, digestive tract, urinary bladder and genitals, skin, eyes, nose throat, etc. – and generalized: a lot of retention of liquids, and you’re literally miserable with brain fog, fatigue, and pain.
In the skin there might be redness, urticaria, dermographism and Darier’s sign (provocation of characteristic redness and edema by rubbing a skin lesion – you can write your name in your skin!).
In the digestive tract there’s irritable bowel syndrome, nausea, vomiting, bloating, flatulence, belching. Digestive pain is of the kind that can lead a person to the emergency room.
At the cardiovascular level there are palpitations, vasovagal reactions, low blood pressure, anaphylactic reaction, postural tachycardia or dysautonomia, or what is now commonly known as postural orthostatic tachycardia syndrome (POTS). Some researchers are convinced that POTS is just a manifestation of MCAS.
At the level of the musculoskeletal system there are all types of joint, bone, muscle and/or tendon pains. These pains may be entirely due to MCAS. It’s the type of pain that feels as if your tissues are tearing apart.
At the urogenital tract level there’s frequent urination (> 6 per day), overreactive bladder, urinary burning sensations, interstitial cystitis, libido disorders.
At the level of the lung and ear-nose-throat tracts there’s coughing, respiratory issues, conjunctivitis and sinusitis. These can favor sleep disorders such as chronic obstructive sleep apnea or upper airway resistance syndrome (UARS), which can then favor more vasovagal reactions, palpitations, POTS, nocturia (peeing throughout the night), fatigue, daily somnolence, etc.
At the systemic, neurological and psychological level there’s severe fatigue, restless leg syndrome, sleep disorders, insomnia, headaches, dizziness, tinnitus, mood disorders such as unusual sadness, anxiety, irritability, concentration and memory difficulties, muscle pain or weakness, sleep attacks, acoustic startle, light sensitivity, eating disorders, tremors, non-epileptic seizures, Tourette’s syndrome, hallucinations, bipolar disorder, agoraphobia, post-traumatic stress disorder, etc.
Notice how MCAS resembles Long COVID and Ehler-Danlos Syndrome. They’re practically interchangeable, and this is because the problem is at the level of the extracellular matrix, fascia and/or conjunctive/connective tissue.
Some authors estimate that MCAS is present in 70 to 75% of Ehler-Danlos patients, and that 30% of MCAS cases have Ehler-Danlos syndrome.
Triggers for MCAS include bug bites, drugs (opioids, imaging contrast media, aspirin and nonsteroidal anti-inflammatories, muscle relaxants, some antibiotics such as ciprofloxacin/fluoroquinolones and vancomycin), changes in temperature (heat, cold), mechanical friction (tight clothes, massages, pressure), invasive procedures (surgeries, endoscopy, biopsies), emotional stress, exercise, infections (viral, bacterial, parasitic), fever, alcohol (even in herbal remedies, but mostly beverages) and foods. Mold infection triggering MCAS can be practically interchangeable with CIRS or Chronic Inflammatory Response syndrome. In those with classical connective tissue disorders, however, treating mold will only improve the problem so far.
Common food triggers are gluten and dairy, nuts, chocolate, fish, smoked meats or fish, strawberries, pineapple, kiwis, and literally ANY spicy food. This is why a carnivore diet is so healing for people with extracellular matrix dysfunction or connective tissue anomalies. It is also the reason why, even on mainstream guidelines, a low FODMAP diet is practically mandatory for people with Ehler-Danlos syndrome. This should enlighten those dealing with connective tissue spectrum disorders, including those with MCAS and Long COVID, as to the importance of doing a low FODMAP diet – short for Fermentable Oligo-, Di-, Mono-Saccharides And Polyols. You can check out any guide about it on the web. This diet eliminates the worst offenders from the diet. Restless leg syndrome and practically all the symptoms listed above can be made much more manageable by reducing MCAS-triggering foods in those susceptible, something that most neurologists and mainstream practitioners ignore.
The following study, “Prevalence and treatment response of neuropsychiatric disorders in mast cell activation syndrome (MCAS)”, published in June 2025, does a great job in increasing awareness about MCAS. They discourage the term “histamine intolerance” because it really doesn’t quite describe the problem. In the article, the authors explain how individuals with MCAS are at a high risk for neuropsychiatric (NP) disorders and may see symptom improvement using MCAS-targeted therapies. That is, mast cell dysregulation affects the brain and peripheral nervous systems.
Among the most useful therapies to calm down neuropsychiatric symptoms secondary to mast cell dysregulation were antihistaminics and low-dose naltrexone therapy. The following concepts from the study, are key and largely unknown for mainstream practitioners:
Mast cell activation syndrome (MCAS) remains unrecognized as the primary cause for many complex patients with a multisystemic disorder.
Although allergic, dystrophic, and other phenomena are commonly seen in MCAS, chronic multisystem inflammation is the universal constant, or sine qua non, of MCAS.
The diagnosis of MCAS is often delayed for decades. Reasons for this include: 1) the relative absence of MCAS education in medical school and residency curricula, 2) the common misconception that an increased serum tryptase level is needed to establish the diagnosis, and 3) the marked heterogeneity of the disease’s clinical presentation (consequential to its marked heterogeneity at the genetic mutation level and the mediator expression level).
In the largest series of prospective MCAS patients (N = 413), the prevalence of various neuropsychiatric disorders and symptoms included fatigue (83 %), fibromyalgia-type pain (75 %), pre-syncope/syncope (71 %), headaches (63 %), cognitive dysfunction (49 %), insomnia (35 %), vision abnormalities (30 %), anxiety and/or panic attacks (16 %), depression (13 %) and involuntary movements (13 %) (Afrin et al., 2017). In 2010, an article listed headache, syncope, and psychiatric conditions that were associated with mast cell activation (Akin et al., 2010).
The most common physician-diagnosed comorbid diagnoses were POTS, irritable bowel syndrome (IBS), and urticaria.
Other than a low FODMAP diet or carnivore diet for those most sensitive, many supplements that decrease inflammation need to be taken. There are many supplements and protocols described. For congenital connective tissue disorders, at least five grams of vitamin C is generally the rule. I have found that plasmalogens are quite essential, and I’ve written a post about it:
Mainstream treatments for MCAS are also very helpful. Notice above how many report improvements in psychiatric symptoms with anti-histaminics. MCAS initial protocol (before resorting to costly immunotherapy) includes montelukast, sodium cromoglycate, famotidine, and antihistaminics such as bilastine at maximum doses. Low-dose naltrexone is also a very good option.
Check out the tables in the study above to help you think outside the box in relation to neuropsychiatric disorders in our world today. Many vaccine-injured children and adults have an immunological predisposition that left them with something akin to MCAS or generalized inflammation. This just got worse after the COVID-19 era.
About the Author:
A countryside family medicine doctor and former heart surgeon in service of the Hippocratic Oath.