An interesting thing happened while researching our comprehensive comparison of CBD and anxiety medications.
We went through about a dozen NIH studies on anti-anxiety medications...anxiolytics as they're called.
Call them what you will as long as they work and we're not taking on a major addiction!
Towards the end of a pretty comprehensive overview of anti-anxiety meds, there was a 1-2 sentence blurb that caught our attention towards the very bottom of the list of meds.
The article first went through:
- Benzodiazepines (the next opioid addiction)
- SSRI's (serotonin boosters with a host of issues)
- Triciclates (old serotonin boosters out of favor due to negatives)
And then there it was….hydroxyzine.
It's a very old medication with fewer side effects.
Since this is personal for us (2017 was a year of intense, rolling anxiety due to perimenopause), we like to turn over every stone.
The more we researched hydroxyzine for anxiety, the more curious we were.
It primarily acted on the histamine receptors, H1 as they're called.
Yet, its effectiveness rivaled benzos for anxiety!
We knew that there was a tie between histamine release and anxiety...especially for the 40-60% of the population that has histamine issues but this was shocking.
Why are we prescribing billions of dollars in SSRIs and benzos with incredibly significant knock-on effects (see the article on anxiety meds versus CBD for the full story), when a simple and effective histamine med has been around for decades?
Our jaded side can answer that question but more importantly, just how deep is the underlying connection between histamine and anxiety?
Now, that's a question we want to get to the bottom of.
Let's go there now!
We'll cover these topics:
A quick look at histamine's function
- Histamine and GABA
- Histamine and Glutamate
- How histamine affects anxiety
- How CBD affects histamine
- The best CBD for histamine and anxiety
- What does CBD do for histamine and anxiety
Let's get started.
First...what is histamine (besides the thing that is "anti" in antihistamine!)?
A quick look at histamine's function
Most of us know histamine from its over-active reaction to pollen, pet dander, and an assorted list of allergens.
Yes, it's in charge of the allergic response we have to many substances (increasingly by the way) but it does so much more.
Histamine is also a powerful neurotransmitter in the brain!
Let's quickly look at both aspects since it will all figure into our discussion of anxiety and CBD.
First, Histamine as an Allergic and Inflammatory agent
This is how most of us know histamine (unfortunately)
It's part of our immune response and its role is straight forward.
Upon detection of foreign entities, get them out quickly!
The result is redness, swelling, itching, sneezing, coughing, and general constriction everywhere.
Again, get an allergen out fast.
Histamine is generally released from Mast Cells located throughout the body.
The name comes from a German word meaning "fattening" since they're jam-packed with histamine ready to be released.
Mast cells can release a host of different inflammatory agents:
histamine, neutral proteinases, proteoglycans, prostaglandin D2, leukotriene C4, and certain cytokines
- Prostaglandins are the cause behind pain during PMS and the monthly cycle.
- Cytokines are little assassins that have been tied to a slew of health issues when released in a chronic fashion.
- Leukotriene is a powerful immune agent which can also cause damage when released chronically.
Again, the new field of medicine is how inflammation is as the seat of many health issues.
A study just the other day showed that inflammation may be a root cause of depression.
For this article, just know that histamine is part of this inflammatory response.
Yes, we need to get the bee venom out (which actually has histamine in it!!) but the constant response to ragweed is overkill!
One note...allergies are on the rise!
This is true for food allergies as well (histamine plays a major role in the gut).
You can get stats and understand more about how it works at these CBD and histamine or CBD and mast cell articles.
Antihistamines work to block H1 receptor activity so that histamine response is lessened.
One knock-on effect of this is drowsiness.
Why would blocking allergies make us sleepy?
That's a great segue into the other major role of histamine.
Histamine and Brain Function
This is the part of our histamine equation that's most pertinent to anxiety!
Histamine operates as a powerful neurotransmitter in the brain.
Here's just a smattering of its effects:
- Histamine orchestrates wakefulness
- Histamine partially controls hunger and satiety
- Histamine is heavily involved in motivation and goal-directed behavior
- Histamine may affect alcohol drive
- Histamine is showing ties to various autoimmune diseases in the gut (IBD, Crohn's, etc)
There are 4 distinct histamine receptors and each one has different responsibilities:
- H1 - control wakefulness and the circadian clock
- H2 - controls gastric acid, smooth muscle, T-cell and cytokine production
- H3 - Decrease Acetylcholine, Serotonin and Norepinephrine Neurotransmitter
- H4 - Mediates mast cell behavior
Did you catch what H3 does?
Those are powerful (very powerful) neurotransmitters
Acetylcholine has its hands in everything from REM sleep regulation, pain sensitivity, and control of hormones!
Serotonin is the workhorse of signaling in the brain and the key target for most of the anti-anxiety medications (SSRI's) on the market.
Check out CBD versus SSRI for serotonin here.
Norepinephrine? What is that?
Oh...just the key chemical behind panic attacks...adrenaline to you.
Clammy hands. Raised heart rate. Feeling of being revved up or even "anxious".
Yes, that chemical.
H3 directly controls these three (and others).
That's a clue and we'll hold on to it for later.
In this way, H1 boosters are excitatory in the brain.
Let's take focus and wakefulness to far...to 11.
What would that feel like?
Think of too much caffeine.
That's a long way towards anxiety!
Interestingly, H1 and H2 can have opposite effects in the brain.
Here's a quick overview which we'll need for later when looking at CBD and anxiety:
- H1 blocking can have sedative and anti-anxiety effects
- H3 boosting can have stimulant effects
Speaking of neurotransmitters and histamine, the other major class of medications (benzodiazepines) deal with GABA.
Let's look at that piece.
Histamine and GABA
GABA really is the main lever for anxiety.
Better said, it's a final lever in the anxiety circuit with many other actors:
- Hormones (Progesterone is key)
- Gut Bacteria
Something downstream is either eating up GABA or causing it not to signal at full strength.
What's the relationship between Histamine and GABA?
First, both are created by the same neuron in the brain which is interesting.
This is one of the few situations in the brain where one neuron makes two different types of neurotransmitters.
Histamine and GABA are intimately tied together in our wake/sleep cycle.
In the brain, histamine is excitatory (the gas pedal) and inflammatory (immune response) while GABA is inhibitory (the brake pedal).
The two are diametrically opposed when it comes to feeling alert, focused, awake (histamine) and feeling calm, drowsy, relaxed (GABA).
It may decrease GABA levels and increase norepinephrine and epinephrine levels.
It is quite common for people with histamine intolerance to report feeling “free-floating anxiety” without situational anxiety.
Maybe more importantly…
H1R anti-histamines are known to reduce excitatory effects in the brain. H3R blockers impair the memory of fear, and avoidance, whilst H3R retains the memory.
GABA is the main inhibitory (slow down) chemical in the brain along with progesterone.
The main excitatory neurotransmitter in the brain is Glutamate.
Let's go there now.
Histamine and Glutamate
Think of anxiety as runaway brain activity in the wrong areas (Amygdala - our fear center) without a check (GABA and prefrontal cortex).
Too much of the gas pedal (Glutamate in the brain).
In that scenario, histamine is like a turbo boost to this system.
Interesting studies have shown that histamine acts to increase glutamate release in the brain:
Activation of histamine H1 receptors caused a concentration-dependent release of [Ca2+]i from internal stores and concentration-dependent increase in glutamate release.
Remember, there's a constant battle between glutamate and GABA in the brain to find "homeostasis" or balance.
The relationship goes both ways between glutamate and histamine:
Infusion of 1 mM glutamate through a microdialysis probe increased histamine release to about 150% of the basal release
This speaks to the roles of both neurotransmitters to be excitatory in the brain.
With a boost of either, GABA is left holding the bag to offset their increase which can result in:
- Racing thoughts
- And yes...anxiety
The second study looked at activity in the hippocampus, which is critical to mood, memory, and emotional state.
Learn all about Glutamate, GABA, and anxiety here.
Let's get to the heart of this discussion now before we jump to CBD's effect.
How histamine affects anxiety
We've discussed some of the players in the anxiety circuit but let's look at histamine directly.
There's a great review of histamine's effect on the anxiety circuit from acute and chronic stress here:
- Acute stress increases the histamine turnovers in the diencephalon, nucleus accumbens and striatum.
- Histamine regulates anterior pituitary hormones.
- Anxiolytic drugs also decrease brain histamine turnover.
- Histamine H1 receptor antagonists and H3 receptor agonists decrease the anxiety state.
- acute stresses increase brain histamine turnover, especially in the diencephalon, which would be partly related to the pathology of anxiety
Goodness, that's a lot of jargon.
A quick translation.
Basically, stress drives the release of histamine in key areas of the brain for anxiety (striatum is crucial).
The fight or flight chemicals like norepinephrine (related to adrenalin) are controlled by histamine
Anti-anxiety drugs decrease histamine levels.
These histamine levels are directly tied to the anxiety circuit.
Another study showed that boosting H3 (histamine 3 receptors) increased anxiety:
H(3) antagonists increased measures of anxiety in wild-type, but not Apoe(-/-), mice
That was H3.
What about H1:
these results suggest that H1 receptor, but not H2, is implicated in anxiety-like behavior and in emotional memory acquisition
Remember that "H" just stands for "histamine".
It's a receptor in the brain for histamine signaling.
If you read about anxiety on our main Anxiety page, you'll see the Amygdala area of the brain written all over it.
Do you know how intense allergic reactions or anxiety can feel like you're coming out of your skin?
We found that acute itch stimuli such as histamine-induced anxiety-like behavior and increased activity (c-Fos expression) in the amygdala in adult male C57BL/6 mice.
They found specific neurons in the Amygdala that were active for both itch and anxiety.
And yes...they were histamine involved:
Electrophysiological characterization of histamine-responsive amygdala neurons showed that this population was active on a behaviorally relevant timescale and partially overlapped with pain signaling
There'a great summary of food sources of neurotransmitters including GABA, glutamate, and histamine here:
We've seen studies where a side-effect of low histamine diets was a reduction (elimination really) in panic attacks.
From that same article is a list of known gut bacteria that can make or influence neurotransmitters.
If we can boost GABA, moderate histamine, and glutamate, that's a big help.
There's a great article here on how histamine causes heart palpitations which most people exhibit with anxiety:
Histamine is known to cause constriction of blood vessels and increase heart rate (get bad things out fast!).
Interestingly, too little histamine can also cause anxiety:
Insufficient intake of L-histidine reduces brain histamine and causes anxiety-like behaviors in male mice.
As with all things in the brain, it's about balance.
That's a great place to jump to CBD.
How CBD affects histamine
We have an entire article on CBD and histamines here.
First, let's get a lay of the land.
We all have an endocannabinoid system which helps to balance other key systems:
- Nervous system
- Endocrine system
- Immune system
The third one is what we're interested in for histamine response.
Ultimately, histamines are part of our innate immune system.
Is there any intersection between the endocannabinoid system and our histamine immune response?
Glad you asked!
CB2 has been shown to play a role in allergic inflammatory responses, being expressed by many immunologic cells including eosinophils, neutrophils and mast cells.
CB2 stands for cannabinoid receptors found throughout the immune system.
To put a point to it…
As a modulator of many immune and inflammatory responses, the ESS could potentially be harnessed for use in the management of a variety of disease processes including wound healing, acute and chronic inflammatory disorders, and cancer.
Let's look at CBD specifically.
A quick recap since we now see the connection between histamine release and anxiety.
First, most of the research is on CBD and "allergies" which is fine since that's just the end result of histamine release.
Let's start with allergic airway diseases (asthma, etc).
In one study:
CBD treatment decreased the inflammatory and remodeling processes in the model of allergic asthma.
Interestingly, CB receptors (where CBD does its work) were integral to the allergic reaction in the lungs and airways.
Let's look at a tell-tale allergic response to histamines...contact dermatitis:
CBD elevates the levels of AEA and dose-dependently inhibits poly-(I:C)-induced release of MCP-2, interleukin-6 (IL-6), IL-8, and tumor necrosis factor-a
Essentially, CBD boosted the signaling of Anandamide, an endocannabinoid we have naturally in our bodies to reduce the allergic response to skin allergens.
Since we're focused on histamines and anxiety, we want to look at controlling overactive histamine release from mast cells.
Together, the results suggest that CBD may induce activation of PPAR in mast cells leading to secretion of G-CSF and consequent MDSC mobilization.
Goodness, can we get a translation, please.
PPAR is a natural "brake" for mast cell release.
MDSC is another brake for runaway histamine release.
Again, the endocannabinoid system (with CBD being a supporter) is about balancing response.
There's a great deal of CBD for mast cell activation here and CBD for histamine release here.
For anxiety, it's about excessive histamine release in the brain.
We need histamine to function correctly but excessive histamine is the issue.
Check out the following for specific detail on CBD's effects:
Once we've established that CBD helps to normalize histamine release, we can go back to hydroxyzine, the anti-histamine which is showing effectiveness similar to benzos.
Its main target is the H3 receptor (histamine receptor) with minor effects on other systems.
That speaks to the power of histamine with anxiety.
It shows in multiple studies:
Compared with placebo, after 3 months of treatment, the hydroxyzine group had superior response rates
That's better than bone-crushing addiction or flatlining feelings (see CBD versus anxiety medications).
If we want to try to adjust this histamine response with CBD, what's the best type?
The best CBD for histamine and anxiety
There's quite a bit of research on CBD's effect on both anxiety and histamine release.
Most of what's being pushed out on the market though might make anxiety worse!
After reading this article, you now know why.
Every big brand out there is pushing "full-spectrum" CBD which has all the plant material in there.
You might as well get a shot of ragweed with your CBD.
Keep in mind that all the research for anxiety or histamine response is on CBD by itself!
That's one of the reasons we focus on CBD Isolate at IndigoNaturals...it's based on research.
We also know first hand how histamines can affect anxiety and other issues.
If you scour the Reddit boards for anxiety, you'll see people all the time who say that CBD made their anxiety worse.
Once we dig a little deeper, we quickly find out that it's one of three things:
- They're using full-spectrum CBD (has the plant material)
- Their CBD has THC in it (up to .3%)
- They have a really bad brand of product and who knows what's in there
Nowhere in the research have we found where CBD Isolate makes anxiety worse.
You can learn more at our CBD Isolate versus Full Spectrum CBD for anxiety article.
Of course, the usual requirements are always present:
- 3rd party testing
- Organically grown in the US
- Heavy metal-free
- Bacteria free
- Mold free
These are the minimum requirements for any CBD product.
This brings up another key concern for anxiety and histamine release...sufficient levels of CBD!
What dose for histamine and anxiety
Generally, you want to start low on CBD and test your body's response.
An introductory level for anxiety and histamine response is usually around 25-30 mg.
For the 1000 mg bottle, that's about 1 dropper (approx 33-40 mgs in a dropper).
Research shows that CBD's effect for anxiety, in terms of neurogenesis, increase up to 300 mg and then starts to drop up to 600 mg.
From there, you can play with the levels to find what brings you relief
Anxiety is a great proxy for CBD since we can tell when it's working.
Some of the benefits should be immediate while others are cumulative.
Immune system balancing can take some time as does neurogenesis (building new neurons).
This has been shown to be key to anxiety and depression long term.
Of course, there's the whole new front of inflammation and anxiety.
We're already a bit long in the tooth for this article!
Feel better and let us know what works for you!
Master overview of CBD and anxiety pathways to look at various aspects we can directly affect.
Links to CBD and anxiety research with dozens of anxiety-specific topics.
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.