We need to talk about histamine
If only it was just about sneezing from ragweed!
Histamine is a powerful force in the brain and body across very different pathways and it rarely gets the respect it deserves.
We found histamine the hard way when full spectrum CBD caused negative side effects but that only prompted the beginning of our journey.
Histamine is the canary in the immune system coal mine.
A very tangible signal that our immune system might be hyperactive…perhaps from prior trauma, infection, or stress.
Even in utero or from past generations!
The repercussions of this ramp up is powerful.
The first class of anti-anxiety meds were…anti-histamines! They were actually pretty effective.
The tie between histamine and insomnia is even more telling. It literally governs the sleep/wake cycle with GABA! More below!
Its role in the brain and gut drive powerful effects…both good and bad.
We're going to finally get to know this powerful player and how to range-bound it when hyperactive!
Here are the topics we'll cover:
- A quick intro to histamine
- Histamine in the brain
- Histamine in the gut
- Histamine and steroidal hormones (big big deal)
- Histamine as a neurotransmitter
- Histamine and GABA
- Histamine and insomnia
- Histamine and serotonin
- Histamine and anxiety
- Histamine and medications
- The whole Histamine intolerance mid-direction
- The problem with anti-histamines (acetylcholine)
- How to calm histamine when too active
- Past trauma, infection, and stress for histamine response
Let's get started!
A quick intro to histamine
We all know histamine as the driver of allergic reactions.
Histamine is released from mast cells, swollen cells of our immune system that receive signals of foreign or bad actors that gain access to our bodies.
Mast cells then "activate" and just spill out histamine plus a range of cytokines…chemical inflammatory assassins.
A slew of effects result from histamine release all tasked with getting bad things OUT FAST!
- Heart rate speeds up
- Gut movement increases
- Blood vessels dilate
To the extreme…itching, vomiting, and nausea all push to get foreign interlopers (bacteria, viruses, chemicals, etc) out of the body.
That's just the start!
Mother Nature is all about efficiency and she likes to multitask.
That's where we'll focus!
Histamine is a powerful player in the nervous system and gut. Most people have no idea just powerful histamine is in how they feel and think.
Let's go there now!
Histamine in the brain
Histamine is a powerful neurotransmitter in its own right!
Aside from its immune system's sentry role (the foot soldier), histamine can be thought of as an excitatory agent in the brain.
This makes sense since this general pattern of "revving things" matches its effects on the body.
Something's wrong (intruder alert)...mobilize!
As a result, histamine manages other powerful excitatory players in the brain:
Histamine is also known as a neuromodulator, since it regulates the release of other neurotransmitters, like acetylcholine, norepinephrine, and serotonin.
Those are some heavy hitters:
- Acetylcholine - the "calm and focused" player - rest and digest
- Norepinephrine - the "fight or flight" adrenaline player
- Serotonin - master regulator of ALL human behavior
So..we have both the calm and fight players of our autonomic nervous system (background manager).
Then there's serotonin. We'll dive into all of these below.
Histamine's role as an immune sentry in the brain is also critical to the entire inflammatory complex.
All the new research on mental health points to the immune system being hyperactivated and histamine is the first line of defense there.
Here's the rub. The immune system is a one-trick pony.
It responds to psychological stress and trauma pretty similarly to a virus!
Stress conditions activate mast cells to release prestored and newly synthesized inflammatory mediators and induce increased blood-brain barrier permeability, recruitment of immune and inflammatory cells into the brain and neuroinflammation.
Goodness. Read that back over
- Stress increases histamine in the brain
- Stress activates neuroinflammation
- Stress allows things to cross the blood-brain barrier more easily
Think of when you're really stressed...how that feels. Pretty similar to an allergy attack!
Agitated. Revved up. Flustered. Twitchy!
Below, we'll look at the very powerful effect of early life stress, trauma, or infection on this whole complex!
Neuroinflammation is the enemy of mental health and brain function microglia (brain immune managers) just leak out glutamate, our brain's "gas" pedal.
Check out our review on neuroinflammation.
Glutamate, when excessive, is toxic to neurons in the brain. There are tools to keep glutamate in check which we'll cover and we have a whole review on glutamate.
We've set the stage though so let's go south… its first contact. The gut!
Histamine in the gut
The brain has no real interaction with the real outside world… there are no tactile nerve endings and it sits in a dark, enclosed bony cage.
How does its immune system know there's a problem?
If you think about it, our gut has the most interaction with potential intruders with hitchhiking bacteria/viruses hopping on everything we eat.
It's literally the outside world brought in!
In fact, ingeniously, the gut is filled with its own bacteria arsenal, the microbiome, which turns out to be a powerful force in mental health and how the brain works.
Most of our serotonin is made in the gut and other neurotransmitters are directly managed here as well. See our review on probiotics and anxiety as examples.
Histamine and mast cells are big gut players… a form of advance scout.
This is why DAO is such a big deal as it breaks down histamine in the gut but the question is why we have to supplement it?
After all, we all naturally make DAO in the gut. Until we don't. HIT or histamine intolerance.
First...the gut bacteria.
De Palma and colleagues show that histamine, a known neuroimmune modulator, is produced by gut bacteria and that it induces abdominal pain in a mouse model of irritable bowel syndrome (IBS).
Hmm. So the gut bacteria act like little foot soldiers to trigger an immune response when they see the enemy!
Check out gut inflammation review or our new review on seed oils.
We're soooo out-gunned!
Now…here's the interesting piece.
The vagus nerve sits at the center of gut-brain communication and new research is pointing to it as a manager as well!
The vagus nerve regulates histamine mobilization from enterochromaffin-like cells of the stomach
See our guide on the vagus nerve but understand that it acts like the "brain" for the body and gut. Heart function is directly managed by it which is why your heart will race when histamine spikes.
This is also how the brain gets its "signal" from the front line…the gut.
Let's take a detour further south.
Histamine and steroidal hormones (big big deal)
We learned this the hard way. Our founder started having trouble with certain foods, cosmetics, and just about everything mid-40s.
It got worse and worse. She tried DAO, probiotics, and a host of different "fixes" from doctors and naturopaths.
In the end…it was just progesterone.
Progesterone calms the immune response but here's the rub...
Progesterone drops by 50% at age 40 and continues down from there.
Interesting that autoimmune and histamine issues hit women 8 to 1 and creep up during the '40s.
Progesterone inhibits mast cell secretion
Goodness…it's a break pedal on histamine.
And DAO in the gut?
Progesterone stabilizes mast cells, up-regulates DAO, and can therefore reduce histamine.
We have a whole review on progesterone and mast cell activation.
Interestingly, estrogen has the opposite effect…it boosts immune function. They work in a yin-yang function but progesterone has left the scene mid-late 30's with continuing dropping from there while estrogen stays relatively stable till late 40s.
10 years of histamine hyperactivation!
That's a lot of damage (and symptoms).
A quick backstory. Why does progesterone calm immune response including histamine?
It's a trick nature built in to keep the mom's immune system from attacking the amniotic sac which is actually made by dad's DNA (and therefore…foreign to the histamine system).
Low progesterone is now the key to preemie birth. What happens when progesterone spikes during pregnancy?
For mast cells (and histamine):
They have also been implicated in inflammatory conditions, such as painful bladder syndrome/interstitial cystitis (PBS/IC), irritable bowel syndrome (IBS) and migraines, all of which occur more often in women and are exacerbated during ovulation, but are suppressed during pregnancy.
"suppressed during pregnancy". Hmmm.
Read our progesterone guide to look at all the interesting effects but histamine is front and center.
Get your hormones tested and support progesterone (bioidentical) as needed. More on estradiol here.
As for testosterone, it wears both hats. Immune modulation. It generally suppresses immune response (and histamine) but can also support it.
Generally…it calms histamine (hence the 8:1 ratio for women and auto-immune)
Testosterone administration, by contrast, affected a striking reduction of histamine excretion.
Ladies…support progesterone. All our histamine responses to food, etc went away once progesterone was replaced. Everything else is fiddling while Rome burns.
Okay…Let's go back up to the brain.
Histamine as a neurotransmitter
Histamine can both increase and reduce the function of:
- Serotonin - manager of all human behavior
- Dopamine - your drive and reward circuit
- Opioid system - pain...including resilience
- NMDA (glutamate - brain's "gas" pedal)
- Acetylcholine - the calm and focus player
- Adrenaline (norepinephrine) - energy, drive, zest!
Goodness…that's a who's who in brain function.
In fact, in the brain, histamine has been suggested to be a regulator of “whole brain” activity
Generally, we can think of histamine as being the immune's translator to the brain as an excitability agent.
This all fits with histamine's primary immune response. Ready the forces…we're going to battle.
Nature just gerry-rigged this effect for other results which will become apparent below.
Let's start that journey.
Histamine and GABA
The opposite of excitatory is GABA. GABA is the brain's "brake" pedal.
GABA and histamine (with cortisol) govern the sleep/wake cycle in a push/pull antagonistic effect.
Nothing to do with allergies. Just wake up!
This was the first clue that histamine was a powerful player in the brain.
We mentioned above that immune cells in the brain (called microglia) release glutamate…sometimes too much when hyperactivated.
Glutamate is the directly opposing force to GABA. So…the enemy of my enemy is my friend!
Activation of histamine H1 receptors caused concentration-dependent release of [Ca2+]i from internal stores and concentration-dependent increase in glutamate release.
So…histamine drives glutamate (which it borrowed from its immune function) to increase activity in the brain.
We need glutamate, within limits, to run every activity in the brain. It's the true gas pedal!
The problem is when GABA is not able to keep glutamate under wraps.
Let's turn to histamine and sleep (or the lack thereof).
Histamine and insomnia
It's been known for a while that histamine opposes GABA to wake us up!
Histamine release in the hypothalamus and other target regions is highest during wakefulness.
So…Nature took the "vigilance" red alert signal and used a water-down level of it…to make us awake!
And GABA is there to keep it in check (unless it's overrun):
The new research suggests that the chemical GABA acts against histamine, like a chemical “brake” preventing wakefulness being too intense.
Think of the effects of antihistamines. Just look at the side effect profile.
Most prominent: Drowsy
In fact, there are millions of people (mainly women in their 40s and beyond - the steroid loss effect) that use Benadryl or Tylenol PM to get to sleep.
With really dire risk effects later on for dementia and more (we'll cover below).
Histamine release in the hypothalamus and other target regions is highest during wakefulness. The histaminergic neurons display maximal activity during the state of high vigilance, and cease their activity during non-rapid eye movement (NREM) and rapid eye movement (REM) sleep.
So…histamine rises during wakefulness and it drops (or stops) during deep sleep.
We did a whole review of histamine and insomnia. In fact, looking at the research, histamine may be THE key.
The net net…histamine when hyperactivates shifts our entire immune "setting" from T1 to T2 and T2 is associated with insomnia.
Check out the review. Very interesting! So maybe that meal DID keep you up at night!
Let's hit another big player…serotonin.
Histamine and serotonin
Okay…this is fascinating.
You have two of the biggest brain managers in a ring together: serotonin and histamine.
Serotonin is the manager of ALL human behavior. No hype there. It's a big deal!
Does histamine affect serotonin when released?
With normal levels of histamine (like the wakefulness or cognitive activity level), histamine can increase serotonin.
This makes sense…get the motor running and serotonin is the driving wheel.
Now…with inflammation level (hyperactivated) histamine, it's quite the opposite.
Histamine can actually reduce serotonin function.
A fascinating study looked at how inflammation-driven histamine prevented SSRIs (which boost serotonin) from increasing levels:
Inflammation-Induced Histamine Impairs the Capacity of Escitalopram to Increase Hippocampal Extracellular Serotonin
This also makes sense. Good serotonin levels make you feel…good! Grounded really.
It's a powerful mood and self-esteem manager.
Histamine is our brain signaling agent from the immune system's department (headquarters in the gut??) and if it's detecting danger…that should feel pretty bad.
This begs the question…are SSRIs just calming hyperactivated histamine (inflammation) to raise serotonin levels??
Our results demonstrate that selective serotonin reuptake inhibitors selectively require the integrity of the brain histamine system to exert their preclinical responses.
We looked at how SSRIs only work when neurogenesis (brain repair) can function but the histamine may be up-river.
It's really about reducing inflammatory load first!
Now…it's gets even more curious.
What about extreme levels of histamine and serotonin?
Serotonin syndrome is actually quite dangerous. Our founder experience it as a result of Lexapro combined with an anti-nausea drug (boosts serotonin) which almost killed her. That whole story of a brutal perimenopause.
Serotonin Syndrome (also known as Serotonin Toxicity) occurs when there is a build-up of too much histamine or tyramine in the body.
You can actually get serotonin syndrome from taking drugs that block the breakdown of…histamine!
More on serotonin syndrome but we've seen 3 different responses now!
Read our master serotonin guide…it's so interesting and hyperactivated histamine is the enemy of feeling…well.
In fact, it can feel downright horrible. Let's go there now.
Histamine and anxiety
The first class of anti-anxiety meds were actually antihistamines!
Hydroxyzine is the big name and looks at it versus benzos:
Compared to other anxiolytic agents (benzodiazepines and buspirone), hydroxyzine was equivalent in terms of efficacy, acceptability and tolerability
But wait…benzos became the go-to for anxiety and they have a nasty addiction effect plus tolerance (see CBD versus benzos).
Maybe…that's exactly why they became the go-to. What a great legal drug market.
Sorry…we're jaded after reading all the research on benzos and SSRIs.
So…back to histamine and anxiety.
First…GABA is our first defense against anxiety (benzos drive GABA till tolerance kicks in).
Histamine directly opposes GABA in the brain.
Remember histamine is a red alert from the immune system…danger! Intruder alert.
Anxiety is actually the correct response to danger. That's its correct use.
Histamine actually drives up our background (autonomic) nervous system to be ready for this.
That's the increased heart rate, blood pressure, etc that comes with allergy response.
The brain picks up on these signals of danger from adrenaline (norepinephrine) and voila…anxiety!
The whole thread through all of this is…stress and our response to it.
Histamine is a powerful foot soldier of this stress cascade:
Acute stress increases the histamine turnover in the diencephalon, nucleus accumbens, and striatum.
So…stress spikes histamine in critical areas of the brain.
What about chronic stress?
Moreover, chronic restraint stress continued to increase the histamine turnovers in the nucleus accumbens and striatum, not in the diencephalon.
Think of layers of the stress response:
When these are exhausted, anxiety is there to tell us…Change something! This isn't working.
Histamine is a key signal to the brain from stress of this need to address a danger.
See…mother nature just multi-tasked our allergic reaction player to respond to psychological stress! Very efficient.
We have a deep dive into histamine and anxiety.
Let's turn to medications.
Histamine and medications
We already looked at how histamine may be the lever that SSRIs use to actually increase serotonin (temporarily) in the brain.
That's just the start!
Many medications directly impact histamine for better and for worse.
Interestingly, benzos increase histamine which is counterintuitive. So they jack up GABA but then send opposite signals via the histamine system.
What about blood pressure meds?
Remember that histamine causes vasodilation…more room in your veins equals less blood pressure.
Histamine attenuates BP, vascular resistance, and the work of the heart via activation of H2 receptors and these effects occurred primarily in the vasculature and not in the myocardium.
So blood pressure meds.
First…the beta-blockers like metipranolol.
Betaxolol and metipranolol induce substantial histamine release from human leucocytes, probably as a result of their cytotoxic effect.
Okay…so these medications jack up histamine (which we know drops blood pressure) but…because they're toxic! The body is trying to get rid of a poison!
Seems to be a bad trade-off.
The next big class…ACE inhibitors?
ACE-inhibitor-induced enhancement of spontaneous and IgE-mediated histamine release from mast cells
Remember…histamine has direct effects on the entire cardiovascular system!
Let's now zoom in on the disease-du-jour.
The whole Histamine intolerance mid-direction
First, we'll set the table.
Histamine Intolerance (HIT) is meant to describe an inability to eat certain foods due to their histamine content.
This is largely attributed to a reduction in DAO and a plethora of "products" to address this from DAO supplements to pig kidney extract to very strict histamine diets.
After all, any "real" food starts to break down almost immediately and histamine is there to respond to bacteria and decay, right?
Aged meats, cheese, fermented food, etc.
Okay…here's where we get angry. Let's look at powerful clues of what's really driving the train.
- Women are hit much more than men by "HIT"; 2:1 matching allergy, auto-immune and more
- Increase sensitivity during pre-menstrual phase (when progesterone plummets)
- Significant fluctuations in DAO activity values have also been reported in women associated with different stages of the menstrual cycle
Just a head's up…the DAO levels (supposedly the main driver) are the same in men and women despite women getting hit much harder.
progesterone works against degranulation of mast cells . Correspondingly, fluctuation in intensity of allergic diseases (especially asthma and eczema) in relation to intake of oral contraceptives, hormone replacement therapy, along the menstrual cycle as well as during pregnancy (high values of DAO improve allergy) was confirmed.
Goodness. Ladies, your progesterone drops by 50% by age 40. And continues down.
Our founder was on the DAO, porcine kidney, etc merry-go-round. After bioidentical progesterone replacement, she can eat whatever she likes. Peppers, etc that were unheard of 5 years ago.
Her story is here but progesterone is THE immune calming player and HIT is just a part of this.
Check out the progesterone guide to see why this is just the tip of the iceberg.
So…why not just take anti-histamines like Benadryl or Tylenol PM?
The problem with anti-histamines (acetylcholine)
Researchers realized much later that classic antihistamines have a serious knock-on effect.
They rip acetylcholine.
This is a critical neurotransmitter - our "calm and focus" player released primarily from the vagus nerve.
Huge player for:
- Dementia risk
- ADHD and other focus issues
- Learning and cognitive function
Let's zero in on the dementia risk.
Taking an anticholinergic for the equivalent of three years or more was associated with a 54% higher dementia risk than taking the same dose for three months or less.
This is longer term and revolves around the older class of anti-histamines.
Acetylcholine naturally decreases as we age so…let's not jumpstart that.
Among the antihistamines, PYR showed the highest reversible inhibition of acetylcholine (100 µM)-induced responses with IC₅₀ of 6.2 µM.
So…are there ways to calm histamine response that don't build tolerance or have knock on effects?
Let's turn there now.
How to calm histamine when too active
Here's are histamine toolkit:
We have deep dives on all of these but here is a quick recap.
- Can't build tolerance (cause immune system to rebound as a result)
- Can't have knock-on effects like ripping acetylcholine
- Shouldn't cause drowsiness or impact waking hour function
Okay…that leaves a few options. Here they are.
Magnesium glycinate and histamine
Mag is our first line mineral stress response buffer and this includes histamine:
Blood histamine levels increased 4--5-fold by 14 days of Mg depletion and subsequently declined to levels similar to those in pair-fed Mg-adequate controls.
Stress just eats up mag so it's all intertwined!
CBD isolate and histamine
CBD has powerful effects on histamine and the immune system generally! This gets to the root of the issue where early trauma, stress, and infection can upset the apple cart later in life.
CBD's effect on histamine is more sophisticated…it directly acts on mast cell activation which calms the histamine explosion when hyperactivated!
The 'when hyperactivated" is critical as histamine is essential to normal, wakeful functioning.
That's why we don't see the drowsiness and other issues as with anti-histamines.
The technical piece (we'll translate):
the results suggest that CBD may induce activation of PPARγ in mast cells leading to secretion of G-CSF and consequent MDSC mobilization.
So…CBD triggers an anti-inflammatory pathway called PPAR which boosts other key elements that "resolve" histamine release. Pushes back the other way!
Hormone support and histamine
Get your levels tested:
- Estradiol and progesterone for women
- Testosterone for men
The Dutch Test is the gold standard but blood tests at least show trajectory over time.
For women in their 40's and older, this is THE critical piece. Progesterone directly calms immune function...and it's dropping.
Must be bioidentical as synthetic hormones have side effects that bioidentical don't.
If your doctor doesn't know or care about this…
Progesterone was associated with lower breast cancer risk compared to synthetic progestins when each is given in combination with estrogen, relative risk 0.67; 95 % confidence interval 0.55–0.81.
Just a head's up…the immune system governs cancer (see cancer guide)
Prometrium is bio-identical progesterone. Estrace is bio-identical estradiol. Both are oral and we looked at the whole oral versus topical below.
Speaking of steroidal hormones!
Vitamin D and histamine
D is a steroid we get from the sun…a major manager of immune response. And histamine which comes from mast cells?
Mast cells activated automatically in a VitD-deficient environment.
Goodness…low D and mast cells just run amok.
The data demonstrate that VitD is required to maintain the stability of mast cells. The deficiency of VitD results in mast cell activation.
So many people are deficient and endocrinologists want us closer to 60 ng/ml (not the 30 RDA limit for deficiency).
We have a whole review on Vitamin D. Get tested!
Medicinal mushrooms and histamine
Medicinal mushrooms (all mushrooms really) are fascinating for balancing our immune response.
Just a few examples.
Chaga has a direct effect on histamine response as shown in studies on food allergies:
The in vivo mast cell-stabilizing activity was also found only in EE and DF whereas the activities to suppress Th2 and Th17 immune responses and cOVA-specific IgE production in the small intestine were observed in all three treatment regimens, implying that inhibition of the mast cell function by lipophilic compounds was vital for the therapeutic effect.
To translate, in live bodies, Chaga components were able to stabilize mast cells (calm histamine) and shift the immune setting to less inflammatory!
Remember…the gut sets our general inflammatory and histamine setting for the rest of the body and brain.
We could go on and on…check our big review on medicinal mushrooms and immune function.
We use this one which has a blend of the most popular mushrooms species.
PEA and histamine
Remember, PEA is a backup endocannabinoid in the body. Called-in reinforcements.
PEA is a big wet blanket for histamine response when excessive!
For example, with asthma (an explosion of histamine and inflammatory agents):
Evaluation of pulmonary sections evidenced a significant inhibitory action of PEA on pulmonary mast cell recruitment and degranulation, an effect coupled to a reduction of leukotriene C4 production.
Okay…that's a wrap. A series of tools that don't build tolerance, addiction, or rip acetylcholine or other key pathways!
Let's get to the real exciting news though. Getting to the root of why our histamine response might be hyperactivated (outside of the loss of steroidal hormones).
Past trauma, infection, and stress for histamine response
At first, it sounds depressing.
Our histamine response may be nothing more than remnants of early trauma, infection, or chronic stress.
In utero, during times of development, or even past generations!
This early interaction causes our immune system to hyperactivate throughout life. Little "mark ups" that affect our histamine setting…for life!
This is especially true in the brain, nervous system, and…gut:
Early-life stress increases the potential for interactions between enteric glia and mast cells, and histamine is a potential mediator of mast cell-glial interactions through H1 receptors.
The research is really pointing to this being the root of mental health issues generally and mast cells are just a great signal for immune hyperactivation.
A study on early life stress and anxiety or depression:
“We found that stress at different times had different effects – chronic exposure to stress is where we saw the significant differences in mast cell activity in the brain"
So…great…the die is cast!
Not really…these "markup" to our immune system can be "edited". We looked at that process here.
Check out our related research and please…give histamine the respect it deserves!
Always work with a doctor or naturopath with any supplement!
The information provided here is not intended to treat an illness or substitute for professional medical advice, diagnosis, or treatment from a qualified healthcare provider.