The realization that Metformin blocks the diamine oxidase enzyme led me to research the medicines that cause histamine intolerance.
Diamine oxidase is the enzyme within the intestine that breaks down biogenic amines (including histamine).
When the level of histamine consumption exceeds the capacity of diamine oxidase to break it down, histamine intolerance occurs.
By blocking diamine oxidase, Metformin can cause histamine intolerance. It did for me.
Seek Medical Advice
Let me make it clear from the outset I am not a medical doctor, and you should not stop any medicines without talking to your doctor.
All medicines have risks and benefits.
I am providing this information so you can partner with your doctor about those risks and benefits and make an informed choice.
It may be that it is best to take medicine and manage the histamine intolerance on balance.
Also, there are many reasons that medicine might be acting promiscuously. Histamine intolerance is merely one.
And finally, while there has been some research into medicines that block the diamine oxidase enzyme or release histamines, this is not a requirement before listing medicines with the regulatory authorities.
Despite my best efforts, this information may be incomplete.
That said, drug allergies are a common cause of histamine intolerance symptoms, at least in my client base.
Medicine’s role in optimizing health and causing unwanted side effects is worth considering.
How Medicines Cause Histamine Intolerance
Metformin is an excellent example of how medicines cause histamine intolerance.
Metformin is the first-line treatment for patients with type 2 diabetes. However, adverse reactions have limited its use. This discontinuation rate led to research identifying that it unknowingly blocked diamine oxidase.
Speaking personally, it dramatically escalated my food intolerances, histamine intolerance symptoms, and my reactivity to histamine-releasing medicines, leading to severe IgE (allergic) reactions to drugs. On one drug, my IgE was 3,000!
My working hypothesis is that in some genetically vulnerable people, the intermittent use of diamine oxidase blocking or histamine-releasing medicines does not cause a long-term destabilization of the histamine system.
Instead, the issue is with the daily and repeated use, which may destabilize the histamine system and even escalate the propensity to IgE reactions to medicines.
This hypothesis fits the emerging hypothesis that the histamine system is usually a tightly controlled process.
For example, the long-term use of antihistamines is thought to alter the equilibrium of this tightly controlled immune system. What’s more, chronic anti-histamine use is also thought to trigger IgE allergies and food sensitivities.
Interestingly, recent research suggests that a low histamine diet plays a role in restoring diamine oxidase and histamine tolerance.
This is certainly my experience.
Once all medicines were withdrawn, my histamine system took about two years to stop hyper-responding and find its equilibrium.
During this time, a low histamine diet and avoiding common allergens were critical parts of my strategy to reset my histamine system.
Diamine Oxidase Blocking Medicines
Some medicines have been shown in the scientific literature to block the histamine degrading enzyme diamine oxidase and limit the body’s ability to degrade excess histamine.
The degree to which the enzyme is blocked can differ. The actual function would also depend on a person’s genetic function.Â
Interestingly, some antihistamines block diamine oxidase.
If an anti-histamine is used to manage diamine oxidase blocking medicines, we should use an alternative anti-histamine.
This is something that personally went wrong for me.
Download my FREE eBook, Histamine Intolerance and Medicines, for a comprehensive list of medicines that block diamine oxidase.
Histamine Releasing Medicines
Certain whole classes of medicines are known more generally to stimulate histamine release. This includes:
Non-steroidal anti-inflammatory agents like aspirin
Antibiotics (which also often block diamine oxidase so are twice as problematic)
Opioids
Contrast agents
Muscle relaxants
Local anesthetics.
Depending on your bio-individual ability to degrade that histamine, these medicines may or may not be a problem.
Download my FREE eBook, Histamine Intolerance and Medicines, for a comprehensive list of histamine-releasing medicines.
Medicines That Alter Gut Function
Many medicines alter gut function with chronic use.
Non-steroidal anti-inflammatories can be associated with significant gut damage.
Other medication classes commonly implicated in adverse gastrointestinal reactions include proton pump inhibitors, cancer chemotherapy, opioid analgesics, antipsychotics, antidepressants, potassium binding resins, and antihypertensive agents.
However, medicines, including many anti-histamines, affect motility, predisposing people to small intestinal bacterial overgrowth (SIBO), which is often linked to histamine and salicylate intolerance.
Download my FREE eBook, Histamine Intolerance and Medicines, for a comprehensive list of medicines that alter gut function.
Other Medicine Issues
While there is limited research on the unwanted side effects of some medicines, there appears to be a high-correlations between adverse event reports and the following:
Fluoroquinolone Antibiotics
While I have not found it in the research, there appears to be a high correlation between fluoroquinolone antibiotics and mast cell activation or histamine intolerance in clinical practice.
What can be said, however, is that there are now FDA warnings on the effects of fluoroquinolone antibiotics on the central nervous system, making it a high-risk alternative when compared to other antibiotics.
Antidepressants
Many antidepressants appear to work through the histamine system and, in clinical practice, appear to be highly correlated with histamine intolerance and mast cell activation. Professor Healy, a leading expert on psychopharmacology, concludes that many antidepressants are not “clean” but interfere with the histamine system.
He states that SRI withdrawal can be viewed as a “histamine over-activity (semi-allergic) state brought around by the fact that the person has been on anti-histamines chronically.”
A 2021 animal study found that SSRIs increased the amount of histamine in the brain, which could better explain this link to histamine over-activity.
Please consider consulting professor Healy if you are struggling with antidepressant withdrawal. He consults with patients remotely.
Estrogen
Estrogen supplementation, specifically when estrogen dominance, relative to progesterone in women and testosterone in men, is histamine-releasing.
Fillers
We should also check fillers for a history of allergic reactions. For this reason, compounded medicines are often better tolerated.I regularly see fillers in medicines causing the symptoms a client wishes to resolve.
Diamine Oxidase Increasing Medicines
Interestingly, heparin has been shown to increase plasma levels of diamine oxidase.
The effect is thought to be due to its anti-inflammatory and immune regulatory properties.Â
Whether this benefits the histamine intolerant community remains to be seen. One study involved continuous administration, so its effect may be temporary.
Basic Strategies
If you have histamine intolerance, you may consider the role of any medicines you have been prescribed in causing histamine intolerance and develop a strategy for managing histamine intolerance symptoms with any essential medicine.
Here are a few strategies I have personally found helpful.
Step 1: Keep a Good History
History is critical. Historically, I have outsourced my medical records to my general practitioner. But I have also moved to countries, cities, and doctors.
I have had severe adverse reactions to medicines throughout my life, but I cannot remember which ones, and I did not take note of them. I’ve also taken medicines without incident and cannot remember which ones.
I now keep a folder with an accurate, up-to-date history and family history.
Step 2: Evaluation of The Risks and Benefits
The common assumption amongst my clients is that all medicine is safe, and their symptoms may be due to some unknown chronic disease. All medicine has risks and benefits. Your doctor is legally obliged to advise you of the risks. So is your pharmacist. Yet rarely do.
Please ask for the Consumer Medicines Information Sheet, read the risks of side effects, and initiate a conversation with your doctor or pharmacist about those risks.
If you wish to initiate this conversation, then The Choose Wisely Organisation has five simple questions to ask.
Step 3: Partner with Your Doctor, and If You Can’t, Find A New Doctor
Did you know that prescription medication errors are the leading avoidable cause of death and permanent disability in Australia? Research shows that “problems related to patient-physician interactions emerged as major contributors… including ignoring patients’ knowledge, disrespecting patients, failing to communicate, and manipulation or deception.”
The “quality use of medicines” depends on the consumer and the prescriber arriving at an agreed understanding of the consumer’s situation through communication.
That is why your involvement in your healthcare and partnering with your doctor is what dramatically reduces that risk to you.
Have you ever been invalidated by a doctor? That is when you should leave and find another doctor. Otherwise, you’ll get the care the doctor perceives you need rather than the care you need.
Step 4: If You Have An Adverse Reaction, Report It
Within Australia, adverse reactions are monitored AFTER the medicine is listed, not before. The regulatory authority and other consumers depend on consumers reporting adverse drug reactions.
So if you have an adverse drug reaction, keep a note of it and report it to the regulatory authority.
With the Therapeutic Goods Administration, it is easy for consumers to do this online in Australia.
Step 5: Get Specialist Advice If You Need It
In my experience, based on the Australian medical system, doctors are trained in a “one size fits all” model. If you don’t fit the mold, your doctor may need to refer you to a specialist Clinical Pharmacologist.
Also, if you have a history of adverse drug reactions, your doctor will most likely not be trained in managing them.
At least within New South Wales, only three medical schools have specialist training doctors on adverse drug reactions. My hospital district has NO doctors currently (as of November 2019) trained in drug allergies.
I have had to do my research and find my team.
I have partnered with a specialist clinical pharmacologist (who specializes in pharmacogenomics), an immunologist (who specializes in drug allergies), community pharmacists (who tend to understand the nuances of medicines more than doctors), and a functional nutrition practitioner (I don’t coach myself!).
Step 6: Have A Plan
Another common issue amongst my clients is that they wait until they are in crisis before getting a plan in place, or they turn up with lists of medicines and detailed explanations of mast cell activation and histamine intolerance, which is too overwhelming to wade through in a crisis.I have a medic alert and an advanced health care directive in place, which is a simple legal document that outlines:
That I have “drug allergies,” which is a simple universal term,
What medicines I CANÂ have for critical categories of essential medicines,
Requests the concurrent treatment with anti-histamines (diamine oxidase enzymes are not readily available in Australia), and
Who they can call with any questions.
It’s a simple plan that gives me peace of mind, gives the doctor confidence, and reduces prescribing errors. It’s also a plan which has seen me successfully have emergency surgery without adverse reactions in circumstances where I previously had repeated hospitalizations.
Conclusion
I am not a doctor and never tell a person to stop taking medicines. And yes, I do take essential medicines where the benefits outweigh the risks.
I am simply providing you with this information so that you can partner with your health professionals about the role that medicines play (if any) in your symptoms.
All medicines have risks. Some medicines are very effective for some people. Some provide little benefit. In other cases, they may cause severe histamine intolerance, drug allergies, and severe harm.
In some cases, it is as simple as switching medicines. In others, it might be about managing the symptoms, including with a low histamine diet. And in other cases, lifestyle interventions may be a better alternative.
What if, rather than an additional disease process, our prescribed medicines were the cause of our histamine intolerance or mast cell activation?
To learn more about how genetics affects our medication choices check out my blog post,  Pharmacogenomics: Drug Intolerances And Genes.
Follow me on Instagram and Facebook to continue the conversation.
Additional Reading
Stenberg, A., “Biogenic amines – nutrition in histamine intolerance”, Environment & Health 2/2007.
Jarisch, Reinhart, ed. Histamine Intolerance: Histamine and Seasickness. Springer, 2014.
Radioextractionassay (REA) for the quantitative determination of DAO-activity in serum and plasma.
Casale, Thomas B., Scott Bowman, and Michael Kaliner. “Induction of human cutaneous mast cell degranulation by opiates and endogenous opioid peptides: evidence for opiate and non-opiate receptor participation.” Journal of Allergy and Clinical Immunology 73.6 (1984): 775-781.
Contributors, Workgroup. “Drug allergy: an updated practice parameter.” (2010).
Demoly, Pascal, et al. “International Consensus on drug allergy.” Allergy 69.4 (2014): 420-437.
Sivagnanam, Soupramanien, and Dirk Deleu. “Red man syndrome.” Critical care 7.2 (2002): 119.
Royal College of Anesthetists, Mastocytosis and Anaesthesia Advice for patients.
