Top 6 Medication Triggers for Histamine Intolerance

Uncover hidden medication triggers behind histamine intolerance symptoms

It would be delightful if we all stayed healthy enough that we never needed to take a trip to the pharmacy to fill a prescription. But we live in an imperfect world and sometimes we need prescription medications to treat symptoms and manage chronic conditions.

These conditions range from diabetes and hypertension to depression and chronic pain. Yet some medications have hidden downsides if you have histamine intolerance. If you struggle with histamine overload, you may discover that certain medications trigger or worsen histamine intolerance symptoms.

Patients often don’t realize that common prescriptions fall into the category of histamine intolerance medications that trigger mast cell release.

This is how one patient described it. “I feel trapped between managing my diabetes and enduring debilitating symptoms that feels like an allergic reaction without the allergy.” ​

Uncover the Hidden Pharmacological Triggers of Histamine Intolerance

First, a brief review. Histamine intolerance occurs when the body accumulates more histamine than it can break down, so histamine builds up in their bloodstream and tissues. One cause is inadequate activity of diamine oxidase (DAO), the primary enzyme that degrades histamine in the gut.

While we know that dietary histamine sources like aged cheese and fermented foods reliably trigger these symptoms in people with this condition, we know less about the role medications play in histamine intolerance symptoms.

Regulatory authorities don’t require pharmaceutical companies to test drugs for their effects on histamine pathways. This leaves doctors and patients with a frustrating gap in their understanding of medication-induced histamine reactions.

3 Ways Medications Disrupt Histamine Balance

​Still, we’re starting to understand some of the mechanisms by which medications disrupt histamine balance. They seem to do so in 3 ways:

• Directly triggering histamine release from mast cells. (histamine-producing cells)
• Suppressing the DAO enzyme that breaks down histamine
• By disrupting the integrity of the gut lining, where mast cells produce histamine.

Let’s look at medications that can worsen histamine intolerance symptoms. And the first one, I’m sure you’re very familiar with because you can buy them at your local drugstore.

NSAIDs and Histamine: The Pain Relief Paradox

There are few people who haven’t taken a NSAID (non-steroidal anti-inflammatory drug) for pain or fever. They’re one of the most prescribed medications in the world, but that doesn’t mean they’re not risky.

Beyond the harm they can cause your kidneys if you take them long-term and causing a rise in blood pressure, they’re tricky if you have histamine intolerance as well.

Aspirin, ibuprofen, diclofenac, and naproxen can all trigger direct histamine release from mast cells. At the same time, they damage the intestinal lining where mast cells congregate and make DAO.

When you don’t make enough DAO, histamine starts to build up and cause those old familiar histamine intolerance symptoms.

Unfortunately, some people need these medications to relieve pain, especially those who have debilitating arthritis. Arthritic patients often tell me that taking a NSAID is the one thing they can get at the drugstore that reigns in their pain.

So, the trade-off is temporary pain relief but also the risk of triggering histamine overload symptoms, skin flushing, digestive distress, and fatigue.

Metformin: A Histamine Intolerance Medication Trigger

​And what about people taking medications for type 2 diabetes and have histamine intolerance? Over 500 million people with type 2 diabetes take a common, blood-sugar lowering medication called metformin. While metformin does its job of lowering blood sugar well, it has an unfortunate downside.

Research shows it blocks the activity of the DAO enzyme, thereby causing histamine to stay in your system longer. This may be why up to 75% of people who take metformin complain of digestive side effects, such as nausea, vomiting, or bloating. ​

I talked to a functional medicine practitioner who said starting metformin was the initial trigger for her own histamine intolerance. Despite it helping to manage her blood sugar, the histamine surge that resulted created inflammatory cascades that disrupted metabolic pathways that metformin is designed to improve.

Heart Medications and Histamine: Hidden Cardiovascular Risks

And, yes, medications that lower blood pressure and relax blood vessels for heart health can also worsen histamine intolerance symptoms. These include beta-blockers doctors use to manage hypertension, anxiety, and irregular heart rhythms.

Research published in the British Journal of Ophthalmology found that certain beta-blockers, particularly betaxolol and metipranolol, trigger dose-dependent histamine release from human leukocytes (white blood cells)

Even more concerning, some research suggests that beta-blockers and ACE inhibitors (another group of medications that treat high blood pressure) work together to reduce the threshold mast cells need to produce more histamine. ​

As discouraging as it sounds, medications prescribed for PROTECTING the heart can make people who take them more vulnerable to histamine-mediated cardiovascular symptoms like a drop in blood pressure and fast heart rate.

​Antibiotics and Anesthetics: How They Affect Histamine Level

Even antibiotics aren’t immune to affecting your body’s histamine balance. A number of antibiotics, including clavulanic acid (found in Augmentin), cefuroxime, and isoniazid, suppress DAO activity. But here’s the good news.

Using antibiotics short-term limits the damage they do. However, it takes your gut microbiome many months to recover from a single antibiotic prescription. That’s why it’s important not to take them for viral infections.

Pain meds and anesthetic agents, used to put you to sleep during procedures, Opioid analgesics and anesthetic agents used to put you to sleep for procedures can also cause potent release of histamine from mast cells. This can cause adverse reactions like a drop in blood pressure. ​

Antidepressants, Antihistamines, and DAO: A Surprising Connection

Fortunately, most commonly prescribed psychotropic medications, including ones doctors prescribe to treat depression and anxiety sertraline, paroxetine, pregabalin, lorazepam, and alprazolam and citalopram don’t appear to reduce DAO activity in laboratory studies.

But there’s another group of medications prescribed for depression called monoamine oxidase (MAO) inhibitors that are more problematic. This group of medications appear to slow the breakdown of histamine.

And strangely, certain antihistamines, including cimetidine and promethazine, can inhibit DAO, activity and increase the risk of triggering histamine overload. ​

Strategies to Reduce Histamine Overload While Taking Medications

Knowing all of this, it’s not surprising that histamine intolerance sufferers often find themselves in a tough spot if they need take medications.

The usual go‑to strategy is a low‑histamine diet, followed for about a month until symptoms settle down, then slowly reintroducing foods. But if certain medications keep blocking DAO or triggering histamine release, diet changes alone may not be enough.​

So, what can you do to avoid problems? Work with knowledgeable healthcare providers to identify histamine-interfering drugs and explore alternatives.

For instance, research suggests that ADHD stimulants like methylphenidate and lisdexamfetamine do not inhibit DAO activity, with lisdexamfetamine actually increasing DAO gene expression. So, not all medication classes pose problems.​

Supplementing with DAO has shown encouraging results in clinical studies. For example, Komericki and colleagues looked at 39 patients with confirmed histamine intolerance and found that taking DAO capsules (10,000 histamine‑degrading units each) improved symptoms compared to placebo.

Similarly, an eight‑week trial by Schnedl reported benefits with smaller 0.3 mg DAO capsules. That said, the degree of success can vary quite a bit, depending on individual tolerance levels and the timing of the supplements.​

And mind your gut health too! ​Because the intestinal lining produces DAO, treating underlying gut issues, like inflammatory bowel disease, small intestinal bacterial overgrowth, or increased intestinal permeability, helps restore the body’s own DAO production.

Managing Medications with Histamine Intolerance

So, if you find yourself in this dilemma where you need to take medications, work closely with a healthcare provider you trust and who has knowledge of histamine intolerance.

Reviewing medications, adjusting diet, and using supplements backed by research are practical steps that can improve quality of life while still managing underlying conditions.

References

• Barke KE, Hough LB. Opiates, mast cells and histamine release. Life Sci. 1993;53(18):1391-9. doi: 10.1016/0024-3205(93)90581-m. PMID: 7694026.
• Nassiri M, Babina M, Dölle S, Edenharter G, Ruëff F, Worm M. Ramipril and metoprolol intake aggravate human and murine anaphylaxis: evidence for direct mast cell priming. J Allergy Clin Immunol. 2015 Feb;135(2):491-9. doi: 10.1016/j.jaci.2014.09.004. Epub 2014 Oct 16. PMID: 25441633.
• van Beek LM, Mulder M, van Haeringen NJ, Kijlstra A. Topical ophthalmic beta blockers may cause release of histamine through cytotoxic effects on inflammatory cells. Br J Ophthalmol. 2000 Sep;84(9):1004-7. doi: 10.1136/bjo.84.9.1004. PMID: 10966954; PMCID: PMC1723656.
• Yee SW, Lin L, Merski M, et al. Prediction and validation of enzyme and transporter off-targets for metformin. Journal of Pharmacokinetics and Pharmacodynamics. 2015;42(5):463-475. doi:https://doi.org/10.1007/s10928-015-9436-y
• Yaiza Tobajas, Alemany-Fornés M, Samarra I, et al. Interaction of Diamine Oxidase with Psychostimulant Drugs for ADHD Management. Journal of Clinical Medicine. 2023;12(14):4666-4666. doi:https://doi.org/10.3390/jcm12144666

‌

‌