First line or “baseline” therapy:

First line therapy consists of the patient's most effective combination of (most often second generation) H1 antagonist and H2 antagonist taken at regular intervals through the day. This “baseline” treatment is important not only to address symptoms, but to stop inflammatory cascades and prevent damage to the body and worsening reactions, which is why it is best to establish as soon as possible after the appearance of symptoms.

Risk of reaction: excepting those to excipients, very low to nonexistent

Long-term risks: very low

As with all classes, if a reaction occurs, consider excipients and the potential need for compounding. It is extremely rare to find a patient who is reactive to the drug (active ingredient) in any one of these options, and in these rare cases, the culprit is almost always fexofenadine. While this may take time, effort, and especially careful sourcing and/or compounding, patients should find an acceptable combination.

Many begin by trying every available second generation H1 antagonist every 12 hours, then adding each H2 antagonist to identify their most effective combination. Unfortunately, there is no way to predict which combination will be best for an individual. Your lack of response to Zyrtec and Tagamet, for example, indicates absolutely nothing about the likelihood you will respond to Xylal and Famotidine. Trials may be short, in the case of no response at all, or up to a couple weeks, in the case of some fluctuations in symptoms. If symptoms are not improving after trialing each available combination at every 12 hours, increase to every 8 hours.

Note that these are “baseline” doses; more of these and possibly other medications are typically necessary to address reactions.

Second generation (non-sedating) H1 antagonists:

Cetirizine (Zyrtec or generic)

Loratadine (Claritin or generic)

Levocetirizine (Xylal or generic)

Desloratadine (Clarinex or generic)

Fexofenadine (Allegra or generic)

H2 antagonists:

Famotidine (Pepcid or generic, also currently “Zantac” in North America)

Nizatadine (Axid or generic)

Ranitidine (Zantac's original ingredient or generic)

Cimetidine (Tagamet or generic)

If you have not tried each second generation H1 antagonist and H2 antagonist that’s available to you,
...both of these, together,

….AT LEAST every 12 hours (and if you haven’t tried increasing to every 8 hours if you were not experiencing enough support at every 12), all of the days,

...or if you have instead jumped to the treatments below...


Rescue medications:

Most mast cell patients, including those who have never experienced a life-threatening emergency, are advised to carry rescue drugs in case they are needed (as well as to increase baseline treatment significantly during reactions and other drugs below as directed). At the very least, patients or suspected mast cell patients should carry epinephrine, and many also carry first generation H1 antagonists and/or steroids, as well.

“Rebound” reactions are common, and it is common for patients to “feel better” for a short period after an initial reaction only to be surprised by a significantly more dangerous rebound. In most cases, reactions which call for the use of epinephrine require a trip to the hospital.

More of the patient's H1/H2 antagonists and sometimes increases in other classes like leukotriene inhibitors and local stabilizers

These are typically used in cases when symptoms of a reaction are relatively mild and do not progress rapidly. For reactions that present with symptoms of the higher grades of anaphylaxis, these are often skipped altogether in favor of multiple options below.

First generation H1 antagonists with additional H2 antagonists

Risk of reaction/adverse event: excepting to excipients, extremely low to nonexistent

Long-term risk when used as rescue: very low

-Diphenhydramine (Benadryl)

-Hydroxyzine (Atarax)

-and others

Low dose benzodiazepines*

Risk of reaction: excepting to excipients, especially when used at these very low doses: low

Long-term risk when used as rescue: low

-Lorazepam (Ativan)

-Alprazolam (Xanax)

-Flunitrazepam (Rohypnol)
-Clonazepam (Klonopin)

-Diazepam (Valium)

*Though you are more likely to know them for anxiety attacks and some kinds of seizures, “benzos” are also mast cell stabilizers. In very low doses, typically a fraction of a milligram, which comprises most of their mast cell uses, they are however, NOT effective for anxiety. For rescue use, Alprazolam (Xanax) is perhaps most common due to its quicker onset of action. However, when used regularly, it does carry greater risk of dependence than some other options (for example, Lorazepam).


Risk of reaction: excepting to excipients, low

Long-term risk when used as rescue: low if tapered when necessary, higher for risk of rebounds when tapers are not undertaken responsibly.

-Methylprednisolone (Sulu-medrol, Depo-Medrol, Medrol)
-Prednisolone (Orapred, Prelone)
-Dexamethasone (DexPak)

-Bethamethasone (Celestone)

*Whether used daily, during flares, or even only in emergencies, corticosteroids should be tapered slowly and with extra caution to avoid issues with “rebounds.”

Epinephrine (auto-injectors or pre-filled syringes)

Risk of reaction: epinephrine typically “works,” when directions are followed, but needs to be followed by other medications and monitoring in the case of most mast cell patients for rebound reactions.

Long-term risk when used as rescue: relatively low when used responsibly

Second line therapies:

Leukotriene inhibitors

You’ll be most familiar with leukotriene inhibitors’ uses for asthma, both in children and adults, and other conditions, such as allergic rhinitis. They can take down inflammation in the lungs, reduce swelling and bronchoconstriction, and decrease mucous production. Leukotriene inhibitors also happen to be helpful for many for overall mast cell stability (leukotrienes are one mast cell mediator) and, as you’d expect, are especially important for those with respiratory symptoms. They are typically taken by mast cell patients twice a day rather than once a day.

Risk of reaction/adverse events/side effects: low to moderate, in the case of past psychiatric diagnoses with montelukast*

Long-term risk: relatively low in general, low to moderate for liver damage (estimated around 2%) in the case of zileuton or zafirlukast. If these are chosen, monitor liver enzymes regularly.

-Montelukast (Singulair)

-Zileuton (Zyflo)

-Zafirlukast (Accolate)

*A note on boxed warnings: As with EVERY drug, supplement, or other change, mast cell patients are advised to begin dosing slowly and under close supervision. This population can respond unexpectedly to any class of drug. Many new patients are made especially anxious, however, by reading about boxed warnings for Singulair (often in support groups) regarding the potential for neuropsychiatric side effects, particularly suicides and derealization and especially at higher doses. Montelukast is the most prescribed drug in the world for asthma and allergic rhinitis in both children and adults and has been available and used by millions without side effects since 1998. The FDA began investigating possible links between it and presumed dose-dependent psychological events in 2008, including 8 reports of suicides of patients on montelukast (a rather low percentage considering the number of patients on the drug and the general prevalence of suicide), even though none of the 11,000 participants in initial safety studies reported neuropsychiatric effects and at least one other study is suggestive of increased psychological well-being on montelukast for asthmatics, possibly because breathing also appears to be important for psychological well-being. It's likely that a history of psychiatric conditions (present in these cases) increases the risk of these extremely rare side effects to this drug, which is otherwise well-tolerated.

Low dose Naltrexone

LDN is not a targeted mast cell treatment. It is, rather, the repurposing of an old drug commonly prescribed for addiction in microdoses as an immune system modulator and general inflammatory help. Small doses of naltrexone essentially biohack the body’s own production of endorphins and other neurotransmitters via a rebound effect, in the process reducing many kinds of inflammation (which of course is often helpful for mast cell reactions. It’s also often prescribed for MS for neuroinflammation.), helping the body to target underlying infections (Some people use the term “calming” autoimmunity by this process.), treating pain (Many EDS patients take it for this reason alone.), or as a supplemental cancer treatment or preventative. It is almost universally tolerated, but many trifecta patients find their optimal doses are in fact in the ultra-low dose range. Each patient has a different optimal dose, and the general practice is to start low (at less than a tenth of a milligram) and to slowly titrate up until symptom improvement is seen. Detox reactions are possible (maybe even likely, depending on the presence and severity of underlying infections like recurrent EBV, mycotoxins, SIBO, parasites, lyme, bartonella, etc.), and some patients need to go even more slowly for this reason. Most EDS or mast cell patients require LDN in either sublingual or topical preparations since absorption and timing are important for the “rebound” effect to take place for this variety of uses. For those using it for pain and its “older” uses for which the rebound is less specific, doses and delivery don't seem to be as relevant, so any recommended “schedules” present no obstacle, and in these cases, microcrystalline cellulose is the only common filler which slows down its absorption and so nixes its effect (if you're *only using it for some pain help, rather than for mast cell and immune needs, you won't need to worry about anything else in the above, as this is pretty much the only way to mess up.)

Risk of reaction, excepting to excipients: extremely low. Even when REGULAR dose naltrexone is accidentally prescribed in its place, often at thousands of times the recommended starting dose of “low dose” Naltrexone. other than an increase in discomfort due to the blocking all opioid receptors and the inability to get high, very few report any substantial side effects. Increasing doses too quickly can, however, lead to herxheimer and other concerns in the case of undelrying infections, and any patient taking more than their optimal “low dose” dose (or typically those taking it orally for immune uses) will not experience benefit, so a VERY slow titration to the patient's INDIVIDUAL ideal dose is necessary.

Long-term risk: negative (Many prescribe LDN as a cancer preventative.)

Local mast cell stabilizers (to address any remaining local symptoms):

These tend to work where you put them, though Ketotifen also has some very weak first generation H1 action. Ketotifen is available as an eye drop in the US but must be compounded in North America for oral use. Cromolyn is not absorbed into the body to any relevant extent, literally perhaps only a few percent well after its half life has passed and it is no longer biologically active. It may be nebulized for lung symptoms, taken orally (slowly, initially, and always in water to help “coat” the gastrointestinal tract, 30 minutes before meals to account for its exceptionally short half life) for GI symptoms, used as an eye drop, a nasal spray, made into “magic masto” lotion for topical symptoms, and so on.


Risk of reaction/adverse event: low, though fatigue is fairly common when increasing dose quickly

Long-term risk: low

-Cromolyn sodium

Risk of reaction/adverse event: orally, moderate, significantly higher if began too quickly (think starting at less than a drop)

Long-term risk: orally, low if tolerated, so long as it is used responsibly (eg not to eat foods which are known triggers to the patient)

Though NSAIDs in general are listed under drugs to avoid, note that Aspirin, when tolerated (and started very slowly and with the awareness of increased bleeding risks in this population) is used successfully by some mast cell patients to help mitigate the effects of prostaglandins.

Risk of reaction/adverse event: moderate, or perhaps reasonable when started appropriately in patients who are not sensitive to salicylates and have tolerated Aspirin in the past

Long-term risk if tolerated: relatively low, but consider bleeding concerns

Third line therapies:

...typically consist of regular use of first generation H1 antagonists, benzodiazepines, and steroids (usually in this order)

First generation H1 antagonists: Please note that certain SSRI's and other drugs common in the Psychiatric field are derived from or act as first generation H1 antagonists:

Long-term risk when used regularly for years: low to moderate (consider anticholinergic risks and tolerance when these are not reserved as rescues)


Long-term risk when used regularly for years at low doses: moderate for taper requirements, typically with lesser risk of dependence.

At higher doses (typically for anxiety and other uses): high for dependence and taper requirements


Long-term risk when used regularly: high for adrenal concerns and inability to safely taper after longer term use of high dose steroids (outside of needs like, for example, Addison's, when these are necessary)

Fourth line therapies:

Some patients also experience benefit from:

Hydroxychloroquine, Jak inhibitors (both DMARD's), interleukin inhibitors, and a wide variety of Biologics that are sometimes prescribed for comorbid RA and other autoimmune diagnoses. These classes are often chosen to treat these conditions and generally are not considered direct therapies for a mast cell disorder.

Risk of reaction/side effects: dependent on the drug chosen

Long-term risk: moderate/variable in general but higher with on presence of underlying infections or exposure to various viral or bacterial triggers these immunosuppressive agents hinder the body from successfully defending against.

TKI's /KIT inhibitors, particularly avapritinib (Ayvakit), imantinib (Gleevec), mastinib (Masivet, Kinovet), Elenestinib (Blu-263), and bezuclastinib (CGT9486 right now) (You'll likely be most familiar with these as the "chemotherapy" drugs.)

Risk of side effects: high, but merited in some cases

Long-term risk: relatively high, but merited in some cases.

Ayvakit is currently approved to treat all forms of systemic mastocytosis due to its inhibition of the KITD816V gene. Imantinib (Gleevec) and mastinib (Kinovet) are sometimes used in patients without this particular KIT mutation. For some, after exhausting other options, these drugs are victories, but they are by no means first line treatments or without risk.


*While not a direct treatment for MCAD, Omalizumab may appropriately be considered higher in this list, perhaps as a third line (indirect) therapy. I include it in fourth line therapies due to the needed level of evaluation of the IgE-sensitive patient's case and consideration of potential risks.

Reaction risk/adverse event risk: high; premedication and individual analysis is always necessary

Xolair, given as a shot at your practitioner’s office every two to four weeks, is an antibody which selectively binds to IgE (decreasing “allergic” responses). It’s approved for more severe cases of allergic asthma which are unable to be controlled by inhaled corticosteroids and chronic idiopathic urticaria (hives). Some mast cell patients who also have elevated total IgE or suffer from allergic asthma or urticaria have found great benefit from this drug.

This is another drug with an FDA warning, in this case a well-deserved one, as it can also cause anaphylaxis immediately, several hours, or even days after patients have left the office, and this is not a particularly rare side effect even among the general (non-mast cell patient) population. Especially in the case of mast cell patients, potential risks and benefits of Xolair should be weighed carefully and the therapy undertaken only if the particular case merits an IgE binder, with a careful plan for adequate premedication and an increase in regular medications, as well as monitoring in the days after administration. It dramatically helps some patients but dramatically worsens the condition of others. Some patients who initially tolerate Xolair also develop worsening reactions to it, in which case it should be stopped immediately. Again, some may very rightly list this as a third line therapy for appropriate patients, but perhaps due to a few bad practitioner apples, some patients are encouraged to try the drug when the question asked is not "Is this patient, currently and in general, a good candidate for this therapy, and how can I increase its chances of success and safety?" but rather, "Will the patient's insurance cover the cost of this drug and its incredibly bottom line-friendly administration in my practice?"

For patients who are also either immunodeficient or suffering from stubborn infections, subcutaneous or immunoglobulins and, after this, intravenous immunoglobulins are sometimes considered.

Risk: high-ish with subcutaneous immunoglobulins, depending on dose and premedication, but extremely high, even with adequate premedication, for IVIG.

For mast cell patients whose cases merit this, most competent practitioners will begin with subcutaneous options, typically after oral options (colostrum), and only consider the progression to IVIG if these prove tolerated and helpful but ultimately insufficient to address the patient's very serious symptoms. For some, this can be a victory or, in the case of those whose immune systems are entirely deficient and this is the root of any number of autoimmune symptoms contributing, go a long way in relieving their issues. For other mast cell patients, IVIG in particular can be deadly or cause permanent harm/a dramatic worsening of their baseline. It's important to consider that, with IVIG, for average mast cell patients, these “better or worse” possibilities are roughly equally likely, and this is why it's often thought of as a “Hail Mary.” This is one reason the rare, but nonetheless extremely irresponsible, profit-driven “let's just try IVIG and see what happens” approach (typically without advising the patient of any of these risks) when either insurance or the patient is able to cover this cost, is never acceptable when treating a mast cell patient.

Help for outbreaks of topical symptoms:

In addition to increasing a patient's regular schedule of medications, these may be useful to help the patient find relief when faced with an outbreak of topical symptoms such as hives, rashes, and itchy skin.

"Magic masto" lotion (topical application of cromolyn sodium

Antihistamine creams (diphenhydramine and other topical preps)

Steroid creams

Cool compresses, cool oatmeal and baking soda baths, or colloidal oatmeal, calendula, and other soothing topical preps

Supplements some mast cell patients find helpful:

As with everything, patients’ individual responses will vary considerably, and nothing is for everyone. Please remember to go slowly with anything new and to always carefully consider excipients, forms, and sourcing.

Quercetin (also luteolin)

Quercetin is a non-citrus bioflavonoid that works as a mast cell stabilizer on the same pathway as cromolyn sodium.

Vitamin D

No one likes a D-eficiency!...but most of the population in the Northern Hemisphere has one. D seems to work best sublingually, especially in populations with malabsorption issues. I have several friends who have been prescribed pills of extremely high doses and have yet to meet an EDS or mast cell patient who absorbed D successfully even this way.

Colostrum is a natural source of many immunoglobulins, lactoferrin, and other immune-modulating compounds with a number of potential therapeutic benefits, as well as acting as a prebiotic for gut health. Colostrum is known to tighten gut junctions (that pesky “leaky gut” everyone seems to have), and some notice it helps in particular with delayed reactions for this reason.

K2 acts as a calcium channel blocker. Calcium channels are intricately linked with mast cell signaling in ways you’re better off learning from dedicated research and discussions with your specialists.

Under normal circumstances, I would add Vitamin C to this list, because while its mast cell stabilization properties are popularly dramatically overrated (some patients I meet have been worsening their condition for months, constantly triggering reactions trying Vitamin C like it's the holy grail when for most patients, it's neither needed nor when tolerated makes a particularly noticeable difference in symptoms), it is an important antioxidant that's essential to many bodily processes and necessary in the production of collagen, and some patients who struggle with fruits and vegetables are not getting enough of it. However, most forms are common triggers, and there is no universal form that is NOT a trigger for many mast cell patients, so I think it's important that this not be the place to start your supplement journey.


When tolerated, cannabinoids are also helpful to some mast cell and EDS patients. There are some social media groups dedicated to this use.

On correcting nutritional imbalances:

Some mast cell patients find themselves with just two or three ingredients they can eat, even for years. Even those on less restricted diets frequently suffer from malabsorption (also common with EDS). I recommend addressing nutritional deficiencies or imbalances as slowly and safely as possible, individually, with evidence from laboratory testing of exactly what is needed. There are many reasons multivitamin and mineral supplements tend to be triggers or cause other issues for this population, though exceptions exist.

One frequently helpful trick for this is the use of whole food powders for when a patient tolerates a food, getting foods “back” after an elimination diet, and general nutritional support. Typically freeze-dried near the site, this process nixes any concerns about stringy fiber and digestability, issues with handling, preservatives, histamine from age, ripeness factors, and other considerations while being incredibly nutritionally dense.

When considering fats, oils, omegas, and protein sources: These things are all important. Unfortunately, meat, fats, and oils are often a problem with gastroparesis, and many are common mast cell triggers to boot. Many are mistakenly told fish oils (sometimes fermented!) are the only way to get omegas, the majority of consumers think “protein powder” is supposed to have a list of ingredients as long as their hand, and….you get the idea. I recommend sourcing single ingredient proteins/ protein powders, pureed foods and soups, balancing fat intake throughout the day, chia, sea buckthorn, and other options for omegas...there are lots of avenues to explore here. None of them need to involve fish or chocolate powders.

Many mast cell patients have also gained insight in some way from hair tissue mineral analysis (HTMA) to identify mineral imbalances and gain a better understanding of what’s happening in their bodies at a more basic level. If you do this, make sure to find a qualified individual to interpret your results, as ratios can be confusing, and sometimes, excesses and deficiencies can look like the opposite. As with almost everything else, slow, targeted corrections are best.

Some complementary therapies and practices which many patients find useful:

Mental health care, meditation, positive visualization, negative feedback disruption, tapping (EFT), and so on. Even good, old-fashioned distraction can be helpful, so long as symptoms are still closely monitored, to help combat the stress chemicals which add to the mast cell mediator burden. Consider seeing a qualified mental healthcare professional and shopping around to find the right fit for you, but avoid “life coaches” and “health coaches” like they’re shellfish.

Infrared therapies (particularly for pain management, for those who tolerate this heat) and for topical inflammation, red light therapy

Halotherapy (particularly for respiratory symptoms)

Massage (Keep in mind that some find triggers in pressure and friction, not to mention the oils most commonly used.)

Pulsed electromagnetic field therapy (PEMF)

Grounding, but perhaps even more so the reduction of problematic electromagnetic fields in the patient's environment, which increase mast cell degranulation

Energy work, including reiki

Acupuncture (Many do find this to be a trigger, however.)

Creative solutions and problem solving:

Not very long ago, mast cell patients would have been called witches and wizards. They are self-made, effective scientists. Once they've exhausted the above options, they often discover unconventional treatments and coping mechanisms to help them manage their unique cases.

They’re also verifiable wizards, tracking down products with excipients they tolerate and harassing with polite aggression businesses for the ingredients in proprietary blends and manufacturing practices. If there aren’t products available that work for them, they make their own, just like they design their own nutritional plans. They are problem-solvers, making lotions out of common OTC meds (See “magic masto” lotion), finding creative ways to exercise and get nutrition, and often doing other impressive things to manage their cases successfully. They learn to sort through research better than many who have spent years in this field and even take on the enormous burden of educating their healthcare professionals (even in emergency settings) while finding ways to enjoy their lives and help others like them in support groups, which in some cases provide much more competent advice than is found even in very specialized clinical settings.

Don’t assume that because your doctor/pharmacist/neighbor/someone else who is an “expert” doesn’t know about it that it hasn’t been done before. If it hasn’t been done before, don’t assume that you can’t be the first to do it.