The Controversy

Should patients with MCAD be concerned about continual use of over-the-counter antihistamines like H1 and H2 blockers? Some resources cite that long-term regular use of antihistamines can, over time, lead to cognitive problems such as dementia. I decided to dig a littler deeper to see what the literature supported.



In order to discuss these medications, it’s helpful to have an overview of some of the lingo. There are two main categories of antihistamines, H1 and H2 receptor antagonists.

According to The Mastocytosis Society1, H1 Receptor Antagonists (sometimes called H1 blockers) help with “itching, abdominal pain, flushing, headaches and brain fog.”

Below are some generic H1 receptor antagonist medication names accompanied by (one example of) a name brand of medications in each class. This is not an all-inclusive list.

Examples of First Generation (“sedating”) Antihistamines2:

chlorpheniramine (Chlor-Trimeton), diphenhydramine (Benadryl), promethazine (Phenergan), hydroxyzine hydrochloride (Atarax), meclizine (Bonine), clemastine (Tavist), doxepin hydrochloride (Sinequan)

Examples of Second Generation (“non-sedating carboxyl group”) Antihistamines2:

loratadine (Claritin), cetirizine (Zyrtec), levocetirizine (Xyzal), desloratidine (Clarinex), ketotifen (Zaditor/Zaditen in Europe)

Example of Third Generation (“non-sedating carboxyl group”) Antihistamines2:

fexofenadine (Allegra); additional third generation medications are in formulation but have not been released to the market yet.

“First generation” antihistamines were initially effective but had heavy sedating properties and side effects because they cross the blood brain barrier, which inspired the development of “second generation” antihistamines in the 1980’s.3 The second line of drugs have more selectivity for H1 receptors, a longer bio-availability and less interference with cognitive function.4  Second generation antihistamines also have stronger anti-inflammatory actions, less anti-cholinergic effects, and less risk for adverse cardiovascular reactions when compared to first generation versions.4 However, a few second-generation drugs (terfenadine and astemizole) exhibited serious cardiac complications and were removed from the US market3 and from there, a new “third generation” became available to replace them that were free of cardiac toxicity (which are often labeled “second generation.”) Second and third-generation antihistamines have a carboxylic acid group substituted molecularly are therefore considered “non-sedating carboxyl group” medications.4

The second and third generation medications tend to cause less drowsiness than first generation antihistamines, but some of them still do cause some degree of fatigue or tiredness.

According to The Mastocytosis Society1, H2 Receptor Antagonist medications (sometimes called H2 blockers) helps with “gastrointestinal symptoms and overall mast cell stability (all mast cell activation symptoms).”

Examples of H2 Receptor Antagonists2 include:

famotidine (Pepcid), ranitidine (Zantac), cimetidine (Tagamet), nizatidine (Axid)

While H1 receptor antagonists suppress generalized histamine-mediated effects in the body, H2 receptor antagonists are more specific to the parietal cells and the suppression of gastric acid secretion by blocking histamine receptors in the stomach. They are commonly used for the treatment of gastroesophageal reflux disease (GERD), but can also be effective for both chronic management of MCAS and during acute flare-ups. H2 blockers are different than proton-pump inhibitors which act by a separate mechanism.


What does the evidence say?

A 2017 review article by Yanai and colleagues4 clarified that in terms of this debate, one of the key aspects to evaluate is whether the antihistamine is anticholinergic or not. Anticholinergic medications cross the blood-brain-barrier and tend to have more sedating and anti-anxiety effects.

Antihistamine medications that are considered in the anticholinergic class include: diphenhydramine (Benadryl), hydroxyzine (Atarax), cyproheptadine (Periactin), and chlorpheniramine (Chlor-Trimeton). Second and third-generation antihistamines are generally considered to have low anticholinergic activity.5

A 2014 review on urticaria published guidelines that state that the dosage of non-sedating antihistamines may be increased 2-4 times the typical dose when the typical dose is insufficient to manage symptoms. These dose-increase guidelines only apply for non-sedating carboxyl group antihistamines that do not have anticholinergic action. In other words, additional dosing (within reason) of second and third-generation antihistamines are permitted as needed to manage mast cell-related skin symptoms according to these guidelines.6

A 2015 study of over 3400 patients evaluated medications that have anticholinergic effects, including antihistamines, and found that higher use of such medications was associated with an increased risk of dementia. However, this study classified other types of drugs such as incontinence medications and antidepressants as anticholinergics, so the study was not directly specific to the sole use of antihistamines.7

A study in 2016 further investigated the use of anticholinergic medications including antihistamines on executive function test scores and brain scans and found increased brain atrophy and reduced brain glucose metabolism accompanied a clinical decline in cognitive function in patients using anticholinergic medications. This study also failed to separate patients based on which exact medication they were taking, considering a number of different drugs as anticholinergic. 8

On the other hand, while a lot of the research has focused on the potential negative long-term consequences of antihistamine use, one recent study found that clemastine fumarate appeared to improve optic nerve function and possibly contribute to re-myelination of nerves in patients with multiple sclerosis. Subjects reported fatigue, as is common with antihistamine use, but no adverse events were reported.  Medication use was 10-72mg/day in twice-daily doses. The group that received the drug for three months followed by a two-month period without it had beneficial carry-over effects into the months that they were not taking it. Dosing was not standardized and long-term effects were not determined in the study; future research will likely aim to further investigate these areas and replicate findings.9

In summary, it appears that the anticholinergic and sedating potential (ie, “first generation” classification) of certain antihistamines are what are currently believed to pose the greatest threat for long-term side effects. The 2017 review4 on antihistamines concluded that in terms of suppressing allergic activity,

“from this perspective, long-term use of non-sedating antihistamines in monthly regimens is desirable as adverse reactions are uncommon. Carboxyl group-containing non-sedating antihistamines are particularly suitable for long-term use due to their reduced anticholinergic activity.”

While there is great concern about the development of dementia with H1 receptor antagonists, H2 receptor antagonists may not pose the same risk. A 2002 study in the journal of Neurology found no associations between H2 blocker use and the development of Alzheimer’s Disease.10 However, a 2007 study of an African American population found that continuous H2 receptor antagonist use was associated with greater risk of cognitive impairment, even after controlling for a number of factors including additional anti-cholinergic medication use.11 That being said, when compared to the research on the use of an H1-receptor antagonist, there is a scarcity of peer-reviewed evidence in the area of H2-receptor antagonist use and it’s 1) association with dementia and 2) utility in patients presenting with symptoms of MCAD.

H2 receptor antagonists are frequently part of acute attack/anaphylaxis management recommendations by allergists. Surprisingly, based on a 2014 meta-analysis, it’s unclear whether H2 receptor antagonists are effective in these scenarios.12 The majority of research with H2 receptor antagonists focuses more on associations with the gastrointestinal system and stress ulcers. More research is certainly needed in the area of the role of H2 blockers in the management of allergic conditions and anaphylaxis.


The Take-Home Message

The bottom line is that every patient is different, and the pros and cons need to be weighed out, keeping in mind that there’s a sort of “ebb and flow” to MCAS treatment and that some medication regimens may be temporarily necessary for certain time frames. If the patient is stable enough to have the choice, based on the research it appears that avoidance of first-generation H1 receptor antagonist antihistamines may possibly reduce the risk of dementia development. Recommendations for H2 receptor antagonist use for MCAS remain less clear, according to the literature.

Not all patients with MCAS use H1-blocking antihistamines, but they are recommended to be trialed as first-line treatment for MCAS by all. A 2015 review notes that second generation non-sedating H1 antihistamines given twice a day is a proper initial treatment trial for prophylactic therapy in MCAS.13 Experts in MCAD concur with the recommendations from the urticaria research that “doses to 4 times what is considered normal may be needed if urticaria is present.”13

Flare-ups and “breakthrough symptoms” may be managed by first generation (sedating) medications such as diphenhydramine and hydroxyzine.13 Other patients with severe MCAS may necessitate anti-cholinergic drugs on a chronic basis (particularly Benadryl), and in those patients, the benefits and impact on quality of life likely strongly outweigh the potential risks, as highlighted by case studies supporting the utility of a continuous IV drip of diphenhydramine in patients experiencing continual anaphylaxis.

A third sub-group of patients with MCAS may find a place where once they have symptoms better under control, they can successfully transition from regular antihistamines to more natural compounds that have antihistaminic effects on the body and may opt for antihistamines during flares only. And lastly, there are patients who may not respond to antihistamines at all and may opt for other types of medications.

All medications and supplements have the potential for side effects and interactions with other drugs and should be under the same scrutiny as the H1 receptor antagonists.

If a patient with MCAS is concerned about long-term consequences of H1-receptor blocking antihistamine use, according to the research, they should talk to their doctor about second-generation carboxyl group-containing non-sedating antihistamines and/or other mast cell medications and may also want to look into different more natural treatment options with their medical team.



  1. The Mastocytosis Society Webpage. Accessed June 16, 2018.
  2. Carson S, Lee N, Thakurta S. “Drug Class Review: Newer Antihistamines: Final Report Update 2.” Portland (OR): Oregon Health & Science University; 2010 May.
  3. Handley DA, Magnetti A, Higgins AJ. “Therapeutic advantages of third generation antihistamines.” Expert Opin Invest Drugs. 1998;7(7):1045-54.
  4. Yanai, Kazuhiko, Takeo Yoshikawa, et al. “The clinical pharmacology of non-sedating antihistamines.” Pharmacology & therapeutics. 2017;178:148-156.
  5. Monthly Prescribing Reference Webpage. Accessed June 16, 2018.
  6. Zuberbier T, Aberer W, Asero R, et al. “The EAACI/GA(2) LEN/EDF/WAO guideline for the definition, classification, diagnosis, and management of urticaria: the 2013 revision and update.” European Academy of Allergy and Clinical Immunology; Global Allergy and Asthma European Network; European Dermatology Forum; World Allergy Organization. Allergy. 2014;69:868–887.
  7. Gray SL., Anderson ML, Dublin S, et al. “Cumulative use of strong anticholinergics and incident dementia: a prospective cohort study.” JAMA internal medicine.2015;175(3): 401-407.
  8. Risacher S, McDonald B, Tallman EF, et al. “Association between anticholinergic medication use and cognition, brain metabolism, and brain atrophy in cognitively normal older adults.” JAMA Neurol. 2016;11(34):E1-E12.
  9. Green AJ, Gelfand JM, Cree BA, et al. “Clemastine fumarate as a remyelinating therapy for multiple sclerosis (ReBUILD): a randomised, controlled, double-blind, crossover trial.” The Lancet. 2017;390(2):2481-2489.
  10. Zandi PP, Anthony JC, Hayden KM, et al. “Reduced incidence of AD with NSAID but not H2 receptor antagonists: The Cache County Study.”  2002;59(6):880-886.
  11. Boustani M, Hall KS, Lane KA, et al. “The Association Between Cognition and Histamine‐2 Receptor Antagonists in African Americans.” Journal of the American Geriatrics Society2007;55(8):1248-1253.
  12. Nurmatov UB, Rhatigan E, Simons FER, Sheikh A. “H2-antihistamines for the treatment of anaphylaxis with and without shock: a systematic review.” Annals of Allergy, Asthma & Immunology2014;112(2):126-131.
  13. Soderberg, ML. “The Mast Cell Activation Syndrome: A Mini Review.” MOJ Immunol. 2015;2(1): 00032.


This content is Copyright © Mast Cells United and is not intended to diagnose or treat anyone. Always consult your medical professional for any health guidance or advice.

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