Anti-Histamines to Tamp Down Excess Mast Cell Activity in Long Covid
In a previous post, I looked at the idea that much of Long Covid may be due to Mast Cell Activation Syndrome (MCAS). This idea provides an explanation of many (but not all) of the lingering symptoms that can set in after a covid infection. So what are the options for treating that kind of MCAS immune hyperactivity? Here’s one overview:
“Mast Cell Activation Syndrome and Mastocytosis: Initial Treatment Options and Long-Term Management.” The Journal of Allergy and Clinical Immunology, Apr 2019. PMID 30961835.
This article lays out a list of potential options for treating MCAS: H1 and H2 antihistamines, leukotriene blockers, aspirin, zileuton, mast cell stabilizers, (sodium cromolyn), and anti-IgE therapy. I mentioned some others (like dissociated corticosteroids here).
The use of antihistamines for MCAS is common in practice, although little studied:
“H1-antihistamines for primary mast cell activation syndromes: a systematic review.” Allergy, Sep 2015. PMID 26095756.
If one were to be cynical, that review could be summarized with the trite phrase that often appears at the end of studies: “more research is needed.” This review article analyzed all the published studies about using antihistamines for MCAS, and found that there really wasn’t a lot of good research. They concluded that there is an urgent need for large, well-designed studies to investigate exactly how effective antihistamines really are for MCAS. I don’t disagree, and it’s good that science works that way. But my full perspective on that is a bit different…
Certain conditions are suitable for self-monitoring while others are not. If the primary complaint is fatigue or a panic attack, a patient is in a good position to evaluate if a treatment is working for them. That is not true if we are talking about the spread of cancer or the presence of hypertension (the ‘silent killer’) … that type of medical condition needs to be objectively monitored, and how the patient feels from day to day is not the most important thing. But when the primary focus is an impaired quality of life, it is not unreasonable to ask patients how they are doing and make treatment decisions guided by that patient feedback.
This D.I.Y. approach to health-hacking has been explored by some medical researchers like Bruce Charlton, who makes a strong case for self-care by informed patients in certain conditions. 1 2 3 I would add things like chronic fatigue, fibromyalgia, and MCAS to the list of conditions where a patient’s self-reported symptoms are meaningful.
H1 vs H2 Antihistamines
There are different types of histamine receptors in different parts of the body, and different types of antihistamine medicines. Histamine will trigger all of these receptors to be active, but most medicines only block one type of receptor or the other.
The antihistamines that treat allergy and cold symptoms block the H1 type of receptor. These are widely dispersed in our mucous tissues. There are H2 receptors around the stomach that play a key role in releasing acid when food is present. These H2 receptors in the stomach are not very affected by H1 blockers. Medicines like famotidine (“Pepcid”) are quite active in blocking the effects of histamine on the stomach nerves … on the whole, they reduce the release of stomach acid, which is why they can be useful in heartburn and gastro-intestinal reflux disease (GERD).
For many people with MCAS, stomach problems are very often a real concern. The gut is a place where we humans encounter many bacteria, viruses, fungi, and parasites. There has to be a strong wall of defense in the gastro-intestinal system; we need many immune components there to fight against other organisms. Mast cells are one of these components, and the mast cells in the gut can be hyperactive.
Safety of Antihistamines
Antihistamines have been around for over 75 years, and they are considered relatively safe - so safe that most antihistamines are available over the counter. That doesn’t mean they are absolutely safe.
One real concern is that medicines that affect the cholinergic system of neurotransmitters (which includes some antihistamines) might increase the lifetime risk of dementia. This has not been thoroughly studied just for antihistamines, but it is possible that heavy or long-term use of these molecules might make a person more likely to experience cognitive problems as they age. One study found that people who were on any type of sedative medicine when diagnosed with dementia experienced a fast decline. 4
Among the anti-histamines, not all types have an equally large effect on the cholinergic system. The older sedating antihistamines (diphenhydramine and chlorpheniramine) are known to influence the acetylcholine nerves more than the newer non-sedating medications.
Even the H2 histamine blockers (which are mostly active in the gut) somehow increase the risk of cognitive decline and dementia. One study found a 40% increase in the risk of progressing from mild cognitive decline to dementia in people taking H2 antihistamines. 5
A person who has a family history of dementia might be less willing to use something that puts them at greater risk.
“Non-Drowsy” Antihistamines May Not Always Be Best
Drowsiness and sedation are widely recognized as side effects of the first-generation antihistamines like diphenhydramine (“Benadryl”) and Chlorpheniramine (“Clortrimeton”). These can reduce allergic runny nose and itchy red eyes, but if someone keeps nodding off in their cubicle, that is less than ideal.
The brain is surrounded by a protective membrane called the Blood-Brain Barrier (BBB). The BBB has filters that limit what chemicals get into the brain. Things like glucose and oxygen pass through the BBB pretty easily; many larger molecules are kept out because they have no business being in the control center. But this filter system is not perfect, it doesn’t stop every unwanted molecule. The BBB does nothing to keep the first-generation antihistamines from going into the brain (and there they affect how the nerves fire, often causing drowsiness).
Eventually, researchers identified compounds that would block histamine receptors in the sinuses and eyes, and mouth, but which were too big and funky to pass through the Blood Brain Barrier. These newer antihistamines bring down hayfever symptoms, but don’t zombify a person. That’s good, right?
It is good for people with hayfever. But if there is allergic hyperactivity in the brain, the 'non-drowsy’ medicines may not effectively reduce it.
We know that mast cells are present in the brain. 6 We know that they can influence neural activity. And if they kicking out too much histamine and other immune activators, that can have a very large effect on how a person feels. It is possible that some people with mast cell activation in the brain don’t respond as well to the non-drowsy antihistamines as they do to the older ones that have sedating side-effects.
Brain Fog, Mast Cells, and Histamine
Some researchers have suggested (but not yet proved) that ‘brain-fog’ may be due to mast cells in the brain that are kicking out too much histamine and other molecules. 7 In the same way that mast cells in the sinus release histamine and make the surrounding tissue inflamed and itchy, it is plausible to think of mast cells in the brain releasing lots of histamine and interfering with normal function.
Natural Antihistamines
Most of the research I have seen on using natural plant medicines for allergies do not work by directly blocking the histamine receptor in the way that OTC antihistamine medicines do. Many natural compounds can reduce the symptoms of allergy, but they seem to work by stabilizing mast cells, or reducing inflammatory gene expression, or through some other mechanism. I am in the process of searching for natural therapies that are directly analogous to antihistamines, and will post more on that if I come across anything that might be useful.
The Bottom Line
Antihistamines are a potential tool that might reduce some of the hyperactive immune response that seems to be part of the Long Covid Syndrome. There is not yet good research on how effective they are for this. Antihistamines are fairly safe, but are not risk-free; an increased risk of dementia has been documented.
References
“Self-management of psychiatric symptoms using over-the-counter (OTC) psychopharmacology: the S-DTM therapeutic model--Self-diagnosis, self-treatment, self-monitoring.” Medical Hypotheses, 2005. PMID 16111835
“Self-management and pregnancy--safe interventions for panic, phobia and other anxiety-disorders might include over-the-counter (OTC) 'SSRI' antihistamines such as diphenhydramine and chlorpheniramine.” Acta Psychiatra Scandinavia, Oct 2005. PMID 16156843
“Chlorpheniramine, selective serotonin-reuptake inhibitors (SSRIs) and over-the-counter (OTC) treatment.” Medical Hypotheses, 2006. PMID 16413139
“Sedation-Associated Medications at Dementia Diagnosis, Their Receptor Activity, and Associations With Adverse Outcomes in a Large Clinical Cohort.” Journal of the American Medical Directors Association, Feb 2022. PMID 35122733
“Gastric acid suppressants and cognitive decline in people with or without cognitive impairment.” Alzheimer’s and Dementia, Feb 2022. PMID 35169610
“Mast cells in neuroinflammation and brain disorders.” Neuroscience and Biobehavioral Reviews, Aug 2017. PMID 28499503
“Brain "fog," inflammation and obesity: key aspects of neuropsychiatric disorders improved by luteolin.”