MEDICINES THAT CAUSE HISTAMINE INTOLERANCE

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.

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 that you can partner with your doctor about those risks and benefits and make an informed choice.

It may be that on balance it is best to take the medicine and manage the histamine intolerance.

Also, there are many reasons that medicine might be acting promiscuously. Histamine intolerance is merely one. 

And finally, whilst there has been some research into medicines that block the diamine oxidase enzyme or release histamines, this is not a requirement prior to listing medicines with the regulatory authorities.

This means that despite my best efforts this information may be incomplete.

With that said, drug allergies are a common cause of histamine intolerance type symptoms, at least in my client base, and the role that medicine plays in both optimizing health, and causing unwanted side effects is worth considering.

How Medicines Cause Histamine Intolerance

Metformin is a good example of how medicines cause histamine intolerance. It did for me.

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 that identified that it unknowingly blocked diamine oxidase.

Speaking personally, it dramatically escalated my food intolerances, and histamine intolerance symptoms, and also my reactivity to histamine-releasing medicines and even led 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, do not cause a long-term destabilization of the histamine system.

Rather, the issue is with the daily and repeated use, which may destabilize the histamine system, and may even escalate to the propensity to IgE reactions to medicines.

This hypothesis fits with the emerging hypothesis that the anti-histamine system is normally a tightly controlled process.

The long-term use of anti-histamines, for example, 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 therefore histamine tolerance.

This is certainly my experience.

Once all medicines were withdrawn it took about two years for my histamine system to stop hyper-responding and find its equilibrium.

During this time a low histamine diet and avoidance of common allergens was a critical part of my strategy to reset my histamine system.

So here is the available research.

Diamine Oxidase Blocking Medicines

These medicines have been shown in the scientific literature to block the histamine degrading enzyme diamine oxidase and in so doing limit the ability of the body to degrade excess histamine.

Where the research indicates the degree to which the enzyme is blocked I have provided that information. I have not included any weak (that is less than 20%) inhibitors. The actual function would also depend on a person's genetic function.

Here is the list:

Interestingly, some anti-histamines block diamine oxidase.

If an anti-histamine is being used to manage the use of any of these diamine oxidase blocking medicines then an alternative anti-histamine should be used.

This is something that personally went wrong for me.

Histamine Releasing Medicines

Certain whole classes of medicines are also known more generally to stimulate the release of histamine.  This includes:

  • Non-steroidal anti-inflammatory agents like aspirin
  • Antibiotics (which also often block diamine oxidase are twice as problematic)
  • Opioids
  • Contrast Agents
  • Muscle Relaxants
  • Local anesthetics.

 

These medicines may or may not be a problem depending on the individual's ability to degrade that histamine.

Fluoroquinolone Antibiotics

Whilst I have not been able to find it in the research, in clinical practice there appears to be a high correlation between fluoroquinolone antibiotics, and mast cell activation or histamine intolerance.

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 anti-depressants, 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 anti-depressants 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.”

Please consider consulting professor Healy if you are struggling with antidepressant withdrawal. He consults with patients remotely.

Estrogen

And finally, estrogen supplementation, and specifically when there is estrogen dominance, relative to progesterone in women and testosterone in men, is histamine releasing.

Fillers

Fillers should also be checked for a history of allergic reaction. For this reason, compounded medicines are often better tolerated.

Diamine  Oxidase Increasing Medications

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. 

Whether this is of benefit to the histamine intolerant community remains to be seen.  The one study involved continuous administration such that its effect may merely be temprorary. 

Medications That Alter Gut Function

Many medications alter gut function with chronic use. 

Non-steroidal anti-inflammatories can be associated with significant gut damage. 

Other medication classes commonly implicated in adverse reactions involving the gastrointestinal tract include proton pump inhibitors, cancer chemotherapy, opioid analgesics, antipsychotics, antidepressants, potassium binding resins, and antihypertensive agents.

However, medications, including many anti-histamines, affect motility predisposing people to small intestinal bacterial overgrowth (SIBO) which is often linked to histamine and salicylate intolerance. 

The following medications are known to alter motility:

Basic Strategies

If you have histamine intolerance, then you may like to consider the role of any medicines you have been prescribed, in causing histamine intolerance, and also develop a strategy for managing any 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 really important.

Historically, I have outsourced my medical records, to my general practitioner. But I have also moved 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 a 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

A common assumption amongst my clients is that all medicine is safe and that their symptoms may be due to some unknown chronic disease.

In fact, 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 either your doctor of phamacist about those risks. 

If you wish to initiate this conversation, then the choose wisely initiative has 5 simple questions to ask. 

Step 3: Partner with Your Doctor, and If You Can't, Find Another Doctor

Did you know that prescription medication errors are the leading avoidable cause of death and permenant 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 own 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 actually need. 

Step 4: If You Have An Adverse Reaction Report It

Within Australia, adverse reactions are monitored AFTER the medicine is listed, not before. 

This means that both the regulatory authority and other consumers are dependent on consumers reporting any adverse drug reactions. 

So if you do have an adverse drug reaction, not only keep a note of it, but also report it to the regulatory authority. 

In Australia, it is really easy for consumers to do this online, with the Therapeutic Goods Administration

Step 5: Get Specialist Advice If You Need It

In my experience, which is based on the Australian medical system, doctors are trained in a "one size fits all" model. 

This means if you don't fit the mold then your doctor may need to refer you to a specialist. 

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 3 medical schools, have specialist doctors training doctors on adverse drug reactions, and within my hospital district there are NO doctors currently (as of November 2019) trained in drug allergies. 

I have had to do my own leg work and find my team. 

I personally have partnered with a specialist clinical pharmacologist (who specializes in pharmacogenomics), immunologist (who specializes in drug allergies), community pharmacists (who tend to understand the nuiances 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, 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 in the case of an emergency

  • That I have "drug allergies" which is a simple universal term,
  • What medications I CAN have for key categories of essential medicines,
  • Requests the concurrent treatment with anti-histamines (diamine oxidase enzymes are not readily available in Australia), and
  • Who to 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 I don't ever 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 are playing (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 even cause severe histamine intolerance, drug allergies, and even 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 or our histamine intolerance or mast cell activation? 

 

Additional Reading

Goriacko, P., & Veltri, K. T. (2019). Adverse Drug Effects Involving the Gastrointestinal System (Pharmacist Perspective). Geriatric Gastroenterology, 1–44. doi:10.1007/978-3-319-90761-1_10-1 

Lackner, Sonja, et al. "Histamine-reduced diet and increase of serum diamine oxidase correlating to diet compliance in histamine intolerance." European journal of clinical nutrition(2018): 1.

Sattler, J., et al. "Inhibition of human and canine diamine oxidase by drugs used in an intensive care unit: relevance for clinical side effects?." Agents and actions 16.3-4 (1985): 91-94.

Leitner, Roland, Eva Zoernpfenning, and Albert Missbichler. "Evaluation of the inhibitory effect of various drugs/active ingredients on the activity of human diamine oxidase in vitro." Clinical and translational allergy 4.3 (2014): P23.

Yee, Sook Wah, et al. "Prediction and validation of enzyme and transporter off-targets for metformin." Journal of pharmacokinetics and pharmacodynamics 42.5 (2015): 463-475.

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Kovacova-Hanuskova, E., et al. "Histamine, histamine intoxication and intolerance." Allergologia et immunopathologia 43.5 (2015): 498-506.

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Agúndez, José AG, et al. "The diamine oxidase gene is associated with hypersensitivity response to non-steroidal anti-inflammatory drugs." PLoS One 7.11 (2012): e47571.

Jarisch, Reinhart, ed. Histamine Intolerance: Histamine and Seasickness. Springer, 2014.

Sutter, M. C., Guy Beaulieu, and A. R. Birt. "Histamine liberation by codeine and polymyxin B in urticaria pigmentosa." Archives of Dermatology 86.2 (1962): 217-221.

Bushby, S. R. M., and A. F. Green. "The release of histamine by polymyxin B and polymyxin E." British journal of pharmacology and chemotherapy 10.2 (1955): 215-219.

Baxter, Alexander B., Stephen C. Lazarus, and Robert C. Brasch. "In vitro histamine release induced by magnetic resonance imaging and iodinated contrast media." Investigative Radiology 28 (1993): 308-308.

Kun, Tomasz, and Lucjusz Jakubowski. "Influence of MRI contrast media on histamine release from mast cells." Polish journal of Radiology 77.3 (2012): 19.

Radioextractionassay (REA) for the quantitative determination of DAO-activity in serum and plasma.

Ellis, Harry V., Alice R. Johnson, and Neil C. Moran. "Selective release of histamine from rat mast cells by several drugs." Journal of Pharmacology and Experimental Therapeutics 175.3 (1970): 627-631.

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 nonopiate receptor participation." Journal of Allergy and Clinical Immunology 73.6 (1984): 775-781.

Sniper, W. "The estimation and comparison of histamine release by muscle relaxants in man." British journal of anesthesia 24.4 (1952): 232-237.

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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.

Roujeau, Jean Claude, and Robert S. Stern. "Severe adverse cutaneous reactions to drugs." New England Journal of Medicine 331.19 (1994): 1272-1285.

Joseph T. DiPiro, Robert L. Talbert, Gary C. Yee, Gary R. Matzke, Barbara G. Wells, L. Michael Posey, Pharmacotherapy: A Pathophysiologic Approach, 9th Edition, Chapter 22.

Horton, John R., et al. "Structural basis for inhibition of histamine N-methyltransferase by diverse drugs." Journal of molecular biology 353.2 (2005): 334-344.

Lorenz, Wilfried, et al. "Histamine release in man by propanidid and thiopentone: pharmacological effects and clinical consequences." BJA: British Journal of Anaesthesia44.4 (1972): 355-369.

Royal College of Anesthetists, Mastocytosis and Anaesthesia Advice for patients.

Klocker J, Perkmann R, Klein-Weigel P, et Continuous ad- ministration of heparin in patients with deep vein throm- bosis can increase plasma levels of diamine oxidase. Vascul Pharmacol 2004; 40: 293-300.

Giardina, Traber Davis, et al. "Learning from patients’ experiences related to diagnostic errors is essential for progress in patient safety." Health Affairs 37.11 (2018): 1821-1827.

Hamrosi, Kim K., David K. Raynor, and Parisa Aslani. "Enhancing provision of written medicine information in Australia: pharmacist, general practitioner and consumer perceptions of the barriers and facilitators." BMC health services research 14.1 (2014): 183.

Kakolyri, Maria, et al. "Increased Basal Blood Histamine Levels in Patients with Self-Reported Hypersensitivity to Non-Steroidal Anti-Inflammatory Drugs." International archives of allergy and immunology (2019): 1-7.

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