MCAS or Mast Cell Activation Syndrome is a condition in which mast cells release excessive amounts of mediators. The digestive tract or skin are often affected, but there can also be psychological effects, which - vice versa - may then affect the digestive system.
Taking pills can be a challenge for people with MCAS, though there are a number of antidepressants available that have a stabilizing effect on mast cells or even an antihistaminergic effect. The latter means, that these antidepressants counteract histamine, which is often released in excessively high concentrations in MCAS or histamine intolerance syndrome (HIS).
Overview of different types of antidepressants
| Type of Antidepressant | Characteristics | Examples |
|---|---|---|
| Tricyclic antidepressants (TCA) | TCA increase the concentration of neurotransmitters, serotonin and norepinephrine, which helps improve mood and alleviate depression. | Amitriptyline, Nortriptyline, Imipramine, Doxepin |
| Mirtazapine | Classified as a noradrenergic and specific serotonergic antidepressant (NaSSA) and typically used to treat major depressive disorders. | Mirtazapine |
| Selective serotonin reuptake inhibitors (SSRIs) | SSRIs increase the levels of the neurotransmitter serotonin in the brain. | Fluoxetine, Sertraline, Citalopram, Escitalopram |
| Selective serotonin and norepinephrine reuptake inhibitors (SNRIs) | SNRIs block the reuptake transporters in the brain for the neurotransmitters serotonin and norepinephrine. Both neurotransmitters remain in the synaptic cleft longer, and signal transmission between nerve cells is enhanced. | Venlafaxine, Duloxetine, Milnacipram |
| Pregabalin (Gabapentinoids) | Pregabalin works by binding to the alpha-2-delta subunit of voltage-gated calcium channels in the central nervous system. This reduces the release of various neurotransmitters, including glutamate, norepinephrine, and substance P, which play a role in pain signaling and seizure activity. | Pregabalin |
Tricyclic antidepressants (TCA)
Tricyclic antidepressants are the oldest generation of antidepressants. Of particular interest to MCAS patients: some of them have antihistaminergic properties, meaning they have a stabilizing effect on mast cells.
Tricyclic antidepressants are also used to treat common comorbidities of MCAS, such as neuropathic pain, migraine, or irritable bowel syndrome.
The specific medication used has different properties and side effects. Common side effects may include:
- Dry mouth
- Blurred vision
- Constipation
- Urinary retention
- Drowsiness
Mirtazapine
Mirtazapine occupies a unique position among tricyclic antidepressants. It has only mild anticholinergic effects and therefore the impact on the nervous system is reduced.
Another advantage is its role as an antagonist at histamine H1 receptors. This means that mirtazapine acts like an antihistamine, which is often used anyway to treat allergies, MCAS, and histamine intolerance.
By blocking H1 receptors, mirtazapine, too, has a mild sedative effect and can thus help with sleep disorders.
Nausea and vomiting are reduced (1), and another side effect that is viewed positively by many people with chronic illnesses is that mirtazapine stimulates appetite and can therefore lead to weight gain.
For those suffering from chronic urticaria, taking mirtazapine can also have a positive effect by dampening the overactivity of mast cells and thus reducing the severity of hives and itching. (2)
Selective serotonin reuptake inhibitors (SSRIs)
SSRIs can have side effects, including gastrointestinal complaints, sexual dysfunction, and, in some cases, increased anxiety or restlessness, especially when first starting the medication.
In individuals with MCAS, these symptoms may overlap with psychiatric symptoms such as depression and anxiety. SSRIs can be effective in treating these aspects. However, it is important to distinguish whether these symptoms are a direct consequence of MCAS or an independent psychiatric disorder. The lines can sometimes be difficult to draw.
In a rat model with depressed rats, fluoxetine was able to reduce the release of mast cell mediators caused by chronic stress (3). Stress itself already leads to mast cell degranulation, which is why antidepressants can target this mechanism.
At the same time, mast cells can also release serotonin (4). Some patients report that an excess of serotonin can lead to both, a temporary and a permanent, worsening of symptoms.
Selective serotonin and norepinephrine reuptake inhibitors (SNRIs)
Among SNRIs, milnacipran has the most potent norepinephrine reuptake inhibition, while venlafaxine has the least.
Some of the side effects overlap with those of classic SSRIs, such as sexual dysfunction or gastrointestinal complaints. However, nausea, dry mouth, dizziness, and increased sweating may also occur.
In a rat model, venlafaxine led to elevated levels of estrogen, the female sex hormone, and consequently to an increased number of mast cells in the tissue. This is because estrogen generally promotes increased mast cell activation and formation (5).
On a positive note, however, venlafaxine possesses anti-inflammatory properties. In animal models, inflammatory parameters such as TNF-alpha and interleukin-1ß were reduced (6). Of course, the results from animal models can only be applied to humans with extreme caution, but unfortunately, there are too few studies in humans on this topic.
In general, tolerability varies among mast cell patients, and it is best to try these medications with caution.
Pregabalin (Gabapentinoids)
Pregabalin is a medication primarily used to treat neuropathic pain, fibromyalgia, and as an adjunct treatment for certain types of seizures (epilepsy). It is also approved for the treatment of generalized anxiety disorder.
It is important to be aware of the side effects of pregabalin, which may include dizziness, drowsiness, blurred vision, weight gain, and difficulty concentrating or paying attention. In patients with MCAS, who may be more sensitive to the effects of medications, these side effects must be carefully monitored.
Because pregabalin can lead to physical dependence, abrupt discontinuation may result in withdrawal symptoms. When discontinuing the medication, the dose must be gradually reduced under medical supervision.
The dosage of pregabalin for MCAS-related symptoms is similar to that used for neuropathic pain or fibromyalgia. It typically starts with a low dose and is titrated upward depending on response and tolerability.
Although pregabalin is not traditionally used to treat MCAS, it may be helpful in managing certain symptoms associated with the condition, such as neuropathic pain or fibromyalgia-like symptoms that can occur in some MCAS patients. Additionally, blocking calcium channels may prevent mast cell activation. There is a reported case in which the use of pregabalin led to a reduction in antihistamines in MCAS.
A study on pruritus showed that pregabalin can also be used to reduce itching, which is sometimes a distressing symptom of MCAS and histamine intolerance (7). Another companion symptom of MCAS and HIS, sleep disorders, can likewise be treated with pregabalin (8).
General information on antidepressants and MCAS / Histamine Intolerance Syndrom
Antidepressants can be a useful tool to treat MCAS or HIS when these conditions are accompanied by psychological symptoms and physical symptoms such as nausea, vomiting, or insomnia. Mirtazapine, in particular, can be helpful in such cases due to its sleep-inducing and antihistamine effects.
References
[1] Nutt DJ. Tolerability and safety aspects of mirtazapine. Hum Psychopharmacol. 2002;17 Suppl 1:S37-41. doi:10.1002/hup.388
[2] Bigatà X, Sais G, Soler F. Severe chronic urticaria: response to mirtazapine. J Am Acad Dermatol. 2005;53(5):916-917. doi:10.1016/j.jaad.2005.05.040
[3] Chen ZH, Xiao L, Chen JH, et al. Effects of fluoxetine on mast cell morphology and protease-1 expression in gastric antrum in a rat model of depression. World J Gastroenterol WJG. 2008;14(45):6993-6998. doi:10.3748/wjg.14.6993
[4] Nautiyal KM, Dailey CA, Jahn JL, et al. Serotonin of mast cell origin contributes to hippocampal function. Eur J Neurosci. 2012;36(3):2347-2359. doi:10.1111/j.1460-9568.2012.08138.x
[5] da Silva AAS, de Santi F, Hinton BT, Cerri PS, Sasso-Cerri E. Venlafaxine increases aromatization, reduces apical V-ATPase in clear cells and induces increased number of mast cells and smooth muscle cells death in rat cauda epididymis. Life Sci. 2023;315:121329. doi:10.1016/j.lfs.2022.121329
[6] Hajhashemi, Valiollah; Minaiyan, Mohsen; Banafshe, Hamid Reza; Mesdaghinia, Azam; Abed, Alireza. The anti-inflammatory effects of venlafaxine in the rat model of carrageenan-induced paw edema. ProQuest. Accessed July 24 2026. https://www.proquest.com/docview/1704355922?sourcetype=Scholarly%20Journals
[7] Ahuja RB, Gupta GK. A. A four arm, double blind, randomized and placebo controlled study of pregabalin in the management of post-burn pruritus. Burns. 2013;39(1):24-29. doi:10.1016/j.burns.2012.09.016
[8] Roth T, Arnold LM, Garcia-Borreguero D, Resnick M, Clair AG. A review of the effects of pregabalin on sleep disturbance across multiple clinical conditions. Sleep Med Rev. 2014;18(3):261-271. doi:10.1016/j.smrv.2013.07.005
