Boo! Hiss! It’s Histamine!

Often cast as the villain, histamine actually plays a complex role in our lives.

Photo from Candid Flaneur/Pexels

We seem to be at war with histamine. Or at least having a big hissy fit over it.

Antihistamines that soothe hay fever and block other allergic reactions are among the most popular over-the-counter medications. Drugs that block histamine-2 receptors and reduce stomach acidity are widely prescribed. And now many individuals are seeking treatment for MCAS — mast cell activation syndrome, where too much histamine is released and causes nausea, rashes, itching, fatigue and a number of other symptoms.

But histamine doesn’t just cause trouble.

Histamine plays a major role in our immunologic defense system. It’s also an essential neurotransmitter, promoting alertness and regulating our circadian rhythms. It works as a neuromodulator, influencing the release of other neurotransmitters, including dopamine, serotonin, acetylcholine and neuropeptides.

Medications that work on histamine-3 receptors are being investigated for treating dementia and a number of other neurodegenerative conditions.

Having a more nuanced view of what histamine does in the body and brain, especially when too much is available, provides a deeper understanding of why so many people take antihistamines. It may also help you in determining whether you should be concerned about MCAS, since it is a condition right now that is both frequently missed by doctors, and too often identified as the culprit by misleading online medical forums.

Histamine’s immune system role

Almost all of the histamine contained in your body comes from histidine, one of the amino acid building blocks of proteins. A single chemical modification converts histidine to histamine.

Histamine is a fairly small molecule, classified as a monoamine. It bears some structural resemblance to other monoamines, such as dopamine, norepinephrine and serotonin.

Some foods, most commonly fermented products like sake, wines, sausages and aged cheeses, contain small amounts of histamine. The micro-organisms living in your digestive system can also manufacture histamine. Usually both of these sources produce only small, safe amounts of histamine.

A powerful enzyme in the digestive system, DAO, inactivates and starts the breakdown of histamine. Only a small fraction of histamine in your digestive system ever enters the blood stream. In the brain, a different enzyme, HNMT, is primarily responsible for deactivating histamine within cells.

The vast majority of histamine in humans is packed into granules inside of mast cells. Mast cells are a type of white blood cells, sprinkled in tissues throughout the body, that serve as a primary surveillance system for detecting and neutralizing foreign chemicals that invade the body. Mast cells are particularly prevalent in potential entryways: skin, lungs, and the mucosa lining the digestive system, mouth, nose and throat.

When allergens enter the body, a special type of antibodies, called IgEs, bind to them. The IgE-allergen complex then binds to receptors on mast cells, prompting them to release their granules. These granules contain not just histamine, but also the blood thinner heparin, as well as other chemicals.

Other triggers can also activate mast cells to release their histamine-rich granules; these triggers include:

• temperature changes
• UV/sunlight exposure
• extreme exercise
• friction or other pressure
• stress
• fatigue
• infections
• venoms (usually insect bites and stings)
• some medications

Histamine acts quickly to dilate small blood vessels and make them more permeable, so that other cells of the immune system can rush in to ward off threats. Histamine also causes small airways in the lungs to constrict, and promotes acid secretion in the stomach, which are both defensive mechanisms to prevent potentially dangerous chemicals from harming the body.

Histamine release produces the classic symptoms of allergic reactions:

• flushed, red skin
• hives
• itching
• nasal congestion
• watery eyes
• runny nose
• wheezing
• nausea

Most often, histamine reactions are short-lived, because within minutes DAO and HNMT inactivate it. But if the triggering exposure persists, or when mast cells become sensitized over time, histamine release becomes more persistent or severe.

Monoamine oxidase (MAO), which degrades other monoamines, and is the target of MAO-inhibitor antidepressants, doesn’t play a prominent role in the initial degradation of histamine.

In the extreme case of anaphylactic shock, dilation of blood vessels leads to a collapse of blood pressure, while tissue swelling and airway constriction cut off oxygen. Although this is a potentially fatal condition, more than 99% of individuals hospitalized for anaphylaxis survive.

What’s going on in the brain?

Mast cells exist within the brain. Histamine release in the brain is thought to play a central role in neuro-inflammatory processes. Brain inflammation contributes not just to nerve cell destruction leading to dementia and Parkinsonism, but also occurs in many mental health conditions including schizophrenia, depression, and ADHD.

Histamine also acts like a classic neurotransmitter in the brain. Neurons in a posterior part of the hypothalamus synthesize histamine. These neurons send projections throughout the brain, and release histamine at synaptic connections. This histamine binds to specific receptors on the receiving neurons, encouraging them to fire.

Histamine also acts more diffusely as a neuromodulator. Those same posterior hypothalamic histamine neurons can release enough histamine that it spreads beyond the synaptic connections after it is released. Histamine then binds to slow-acting receptors on neurons, fine-tuning the activity of these other nerve cells. In particular, histamine helps coordinate the firing of dopamine, serotonin, and acetyl-choline systems in the brain.

Histamine promotes arousal and alertness. It also helps synchronize the circadian clocks that create our sleep-wake cycle and other 24 hour rhythms in the body.

In early development, histamine is one of the first neurotransmitters detectable, where it helps coordinate the basic wiring of the brain.

Histamine is the prefrontal cortex is involved in many of the executive functions of the brain, beyond just alertness and arousal. It plays a role in goal-directed behaviors and behavioral flexibility. It also helps regulate body temperature, appetite and feeding patterns, and responses to stress.

Being receptive to histamine

Histamine exerts its effects in the body and brain via specific receptors. Four different receptors have been identified, although relatively little research has been conducted on the fourth type, so I won’t mention it further.

H1 receptors are present throughout the body and brain. They mediate many of the symptoms of allergic reactions, as well as many of the arousal and cognitive actions of histamine in the brain.

Diphenhydramine (Benadryl) was one of the most widely used antihistamines, primarily blocking the H1 receptors. It was effective for treating hives, itching, runny nose, and wheezing. Because it easily reached the brain, it also tended to cause sedation.

In the days before Ambien, diphenhydramine was the most widely used drug in hospitals to help patients sleep. It did so by shutting down the histamine-based arousal system.

Some people have paradoxical reactions to diphenhydramine, and become revved up and agitated, rather than sleepy from it. Also, in many cold medicine formulations, antihistamines were combined with mild stimulants, like pseudoephedrine or phenylephrine, in order to combat sedation. Some people are more sensitive to the activating stimulant component of these medications than to the sedating antihistamine effect.

So-called second generation antihistamines, which include:

• cetirizine (Zyrtec)
• loratidine (Claritin)
• fexofenadine (Allegra)

are all H1 receptor blockers, but differ from diphenhydramine in that in most people they aren’t able to cross the blood brain barrier. This means they work effectively to block allergic responses in the body, but don’t tend to reach the brain and cause sedation.

However, there is considerable person to person variability regarding whether an individual feels groggy from these second generation H1 blockers. Both physiologic and expectation effects contribute to this variability.

Two many receptors?

The histamine-2 receptors have a more restricted localization and action in the body. They’re primarily found in the stomach, where they promote production and release of hydrochloric acid.

In smaller numbers H2 receptors are found in the heart, blood vessels and brain. Within the brain H2 receptors are particularly abundant in the hippocampus and cortex, and play a role in cognitive functioning and the regulation of the body’s energy.

H2 blockers cimetidine (Tagamet), famotidine (Pepcid), and ranitidine (Zantac) are widely used for heartburn, acid indigestion, and treating ulcers. Cimetidine enters the brain far more readily than does famotidine, which is why it is more likely to cause side effects like sedation, dizziness and confusion.

Three’s a crowd

Speaking of confusion, that leads us right to the third histamine receptor. Unlike H1 and H2, H3 receptors are more common in the brain than in the rest of the body. H3 receptors are often autoreceptors located on the very histamine cells that make and release histamine. When histamine binds to H3, it tends to shut off further release, in a negative feedback loop.

In addition, H3 receptors modulate mast cells in the brain, providing feedback signals that prevent too much histamine from being released. This can help prevent hyper-inflammatory states in the brain.

Antihistamines that specifically block the H3 receptor actually promote the release of more histamine by halting the negative feedback. Not only do H3 blockers increase availability of histamine, they can also boost levels of dopamine, serotonin, norepinephrine and acetylcholine.

One attractive feature of H3 blockers is their relative specificity for the central nervous system. Compared to H1 of H2 blockers, they have a lower likelihood of causing immune system side effects in the rest of the body.

Pitolisant is the only H3 blocker currently on the market, although several more are under development. There’s a good chance you haven’t heard of it, because it is quite expensive ($4K a month) and only approved for the treatment of daytime sleepiness associated with narcolepsy.

Researchers have sought to use H3 blockers for other mental health conditions where boosting arousal and alertness seems to be desirable, such as in ADHD. But so far, H3 blockers have not proven beneficial for such conditions.

However, there is growing laboratory and clinical research indicating that for some types of dementia and other degenerative conditions, H3 blockers can improve alertness, memory, sleep-wake rhythms, and cognition. Boosting histamine appears to help some brains function better.

Too much

Although the H3 auto receptors regulate the availability of histamine, and the DAO and HNMT enzymes usually prevent an overabundance of histamine, sometimes they’re not enough.

Tuna, mackerel, and mahi-mahi contain abundant amounts of histidine, which is normally not a problem. However when tuna goes bad, (there’s that villain again) the bacteria can produce excessive amounts of histamine from this histidine.

Eating spoiled tuna can result in scombroid poisoning. Although this might sound like a good name for a punk rock band, scombroid poisoning consists of severe nausea, vomiting, flushing, rashes, sweating, headache, dizziness, low blood pressure, and trouble breathing.

Cooking spoiled tuna will stop the bacteria from producing more histamine, but it doesn’t degrade or eliminate the existing histamine. It may sound fishy (without even smelling fishy) but consumption of such tuna can still result in scombroid poisoning.

Some individuals have genetic variants of the DAO or HNMT genes which code for less efficient versions of the enzymes that degrade histamine. These individuals may be more susceptible to having toxic reactions when histamine is released during allergic reactions or when consuming histamine-rich foods.

In other individuals, control of immune system processes can go awry, contributing to allergic reactions being triggered more easily than usual, or greater amounts of histamine being released. Some of these cases stem from inappropriate up or down regulation of histamine receptors.

Mast cell activation syndrome is defined by mast cells too readily releasing too much histamine. Experts consider it to be uncommon (less than 1/10,000 individuals) which means that many doctors are unfamiliar with it, and don’t recognize it when present. Furthermore, it can occur on a spectrum of severity, with less dramatic cases being harder to detect.

Reflecting the multitude of histamine’s effects on the body, MCAS symptoms can include:

• abdominal pain
• burning pain in the skin
• itchiness
• flushing (red) skin
• excessive sweating
• chest pain
• bruising
• bone pain
• memory loss
• impaired concentration
• tickle in throat, throat clearing
• weakness
• low energy
• fatigue
• weight loss
• rapid heart
• high or low blood pressure

One challenge with this list is that many of the symptoms are non-specific, and can arise from numerous conditions. Many online health influencers blithely diagnose MCAS for almost anybody with ongoing problems with fatigue, poor concentration, blood pressure control, or abdominal distress. MCAS is not only commonly under-diagnosed, it is also currently being widely over-diagnosed.

Laboratory tests can be quite useful to detect problems with histamine levels or metabolism that indicate MCAS is a problem. They can also reveal whether mast cells are overabundant or aberrant in other ways. The absence of any signs of itching or flushing make it less likely that histamine or MCAS explains one’s symptoms. A thorough workup involves searching for other possible culprits.

Treatment of MCAS usually entails minimizing exposure to foods, allergens, and other triggers for histamine release. Judicious use of antihistamines and other medications can be helpful.

It’s all connected

Histamine highlights the interconnectedness of our immune and nervous systems. The common origin of both immune and nervous system cells from the same ectodermal layer of the early embryo helps explain some of this connection.

The immune and nervous systems shape how an individual communicates with and defends itself against the outside world.

The immune and nervous system interact intimately throughout our lives. Autoimmune conditions are strongly associated with a wide range of mental health conditions. Inflammation impairs our thinking and mood, and appears to play a significant role in creating and perpetuating many mental health conditions.

Histamine helps protect us, even if it can cause suffering when its regulation goes awry. Even if you have an itch and with to flush all histamine out of your body, you depend on it for your very survival.

No histamine was blocked or AI utilized in the writing of this story.

If I’m not promoting nuance, I’m probably creating new angst.