Mast cell patients often end up on a wide mix of different medications, aimed at stopping the constant release of mast cell mediators or blocking how cells respond to them.
One challenge is the anticholinergic effect of certain medications used for this purpose. These effects can add up when medications are combined, increasing the risk of side effects over time. Anticholinergic effects, particularly from older-generation antihistamines, show up mainly in the central nervous system.
What are anticholinergic side effects?
Acetylcholine is a chemical messenger in the nervous system. It's especially important in the brain, where it functions as a neurotransmitter.
In the involuntary, or autonomic, nervous system, acetylcholine mediates many bodily processes and is the main neurotransmitter of the parasympathetic nervous system. Saliva production, gut motility, heart rate, and blood pressure all depend on it.
This explains why strongly anticholinergic medications, such as tricyclic antidepressants like amitriptyline and older-generation antihistamines, which significantly block acetylcholine's effects, commonly cause constipation and dry mouth as side effects.
Other side effects linked to anticholinergic activity include dry mouth, blurred vision, dizziness, fatigue, difficulty urinating, and, in more severe cases, memory problems and hallucinations.
Treating allergic symptoms
In patients with mast cell conditions, whether mast cell activation syndrome (MCAS), mastocytosis, urticaria, or pseudoallergies like NSAID intolerance, symptom severity often requires combining several medications and taking higher daily doses. This is necessary to control symptoms and keep them manageable.
This is also the right approach for preserving quality of life and supporting patients. The anticholinergic effects become a real concern specifically when antihistamine doses keep climbing and other anticholinergic medications get added on top.
It is often hard for patients to imagine that an antihistamine they have always tolerated well could suddenly cause side effects once combined with an antidepressant, and that the resulting dizziness or fatigue is not necessarily a symptom of their underlying condition this time.
That is why it is important to review every medication with a doctor, and to regularly reassess together whether each one is still providing real benefit. Anticholinergic effects are cumulative, meaning they add up and reinforce each other.
Side effects of medications used for histamine-mediated conditions
New versus older generation antihistamines
Most people with allergies are probably familiar with loratadine and cetirizine (both available over the counter). Many MCAS patients, especially those more severely affected, take fexofenadine, rupatadine, or other newer-generation antihistamines long term, which require a prescription in some countries.
"Newer generation" means these drugs act less on the central nervous system, making them less sedating than older antihistamines. Older antihistamines include dimetindene and diphenhydramine. Diphenhydramine is particularly well known in English-speaking countries, where it is sometimes used intravenously to control severe MCAS flares. It can also be used short term for sleep difficulties.
Antidepressants with high anticholinergic potential
Tricyclic antidepressants like amitriptyline, imipramine, and doxepin have anticholinergic effects and can cause unwanted symptoms such as dry mouth, urinary retention, constipation, or an elevated heart rate.
These medications are used, among other things, for fibromyalgia, chronic pain, and depression.
Anticholinergic burden as a measure of anticholinergic potential
To assess how much anticholinergic risk a medication carries, researchers use a point-based scoring system: 0 means no anticholinergic potential, 1 is weak, 2 is moderate, and 3 is strong anticholinergic potential. This is known as the ACB (anticholinergic burden) scale.
These points are added together across a patient's full medication list. Once the cumulative score exceeds 3, especially in older adults, this has been linked to cognitive impairment and an increased risk of developing dementia, which is why doctors and pharmacists pay particular attention to it.
A team of German researchers [1] published a paper attempting to classify commonly used medications on this scale, drawing on multiple existing sources. Their goal was to help reduce the cumulative anticholinergic burden that can build up in vulnerable patient groups, along with its potential long-term consequences.
| Low (score = 1) | Moderate (score = 2) | High (score = 3) |
| Celecoxib, cetirizine, desloratadine, diazepam, famotidine, lorazepam, midazolam, mirtazapine, and others | Cimetidine, opipramol, ranitidine, tramadol, and others | Amitriptyline, clemastine, diphenhydramine, hydroxyzine, doxepin, trimipramine, and others |
Anticholinergic potential of specific medications
This research also highlights disagreement among scientists and organizations about the anticholinergic potential of certain drugs. Fexofenadine, a commonly used antihistamine in mast cell conditions, is classified as moderate (2) in two scientific sources, while two other research teams classify it as 0, meaning no anticholinergic effect at all.
Desloratadine and other antihistamines are similarly rated anywhere from mild (1) to moderate (2), depending on the source.
Averaging across the various sources they reviewed, the German research team ultimately placed fexofenadine and desloratadine in category 1 (weak anticholinergic activity). The H2 blockers cimetidine and ranitidine were listed under moderate activity (2).
Benzodiazepines generally show mild to moderate anticholinergic activity.
Conclusion
Combining H1 and H2 blockers with other medications can quickly add up to a high anticholinergic burden for mast cell patients, which can itself cause side effects. These side effects are sometimes mistakenly interpreted as symptoms of the underlying condition instead.
That said, for some conditions or very severe symptoms, medication combinations with a higher anticholinergic burden are genuinely necessary, and may need to be used in the absence of good alternatives, as long as the side effects remain manageable.
It is worth regularly reviewing your full medication list with your doctor to check whether each medication is still needed. Lifestyle adjustments and dietary changes are also worth considering alongside this.
References
[1] Kiesel EK, Hopf YM, Drey M. An anticholinergic burden score for German prescribers: score development. BMC Geriatr. 2018;18(1):239. doi:10.1186/s12877-018-0929-6
