Is Histamine the Key to Insomnia?

December 6, 2021

We don't usually equate an allergic reaction with those periods at night where we're just wide awake.

We should!

Histamine is a powerful neurotransmitter in the brain that's intimately tied to the sleep/wake cycle.

We'll let you guess which side of the table it's on.

The more we dig into histamine, the more powerful the argument that it's a key player to rule out (or address) insomnia.

Changes in steroidal hormones with age have a very powerful effect on this pathway as well.

Hence the increasing issues around sleep as we get older.

Let's get into it.

Here are the topics we'll cover:

A quick intro to the neurotransmitter role of histamine
Histamine and the sleep/wake cycle
Histamine is part of the immune system
Steroidal hormones and histamine
Anti-histamines and sleep (plus their downside for dementia)
Tools to calm histamine response for insomnia

Let's get started (before morning arrives)!

A quick intro to the neurotransmitter role of histamine for the sleep/wake cycle

Let's take bee stings and allergies off the table for now.

Histamine is a powerful excitatory neurotransmitter.

This means that it speeds things up in the brain and nervous system.

There is a huge role it plays in the sleep/wake cycle with GABA being the opposing force:

Strong and consistent evidence exists to suggest that histamine, acting via H₁ and/or H₃ receptor has a pivotal role in the regulation of sleep-wakefulness. Administration of histamine or H₁ receptor agonists induces wakefulness, whereas administration of H₁ receptor antagonists promotes sleep.

https://pubmed.ncbi.nlm.nih.gov/20851648/

Simply put...histamine is the promoting agent for wakefulness.

Let's dig deeper.

There's an important hub in the brain called the hypothalamus...a very old (evolutionarily speaking) part of the brain that manages basic bodily functions (energy, temperature…..sleep!).

There's actually a specific control switch in that hub to initiate sleep.

Yes...that point where you drop off!

It's called the VLPO:

Neurons in a part of the hypothalamus called the ventrolateral preoptic nucleus (VLPO) connect directly to the many arousal-promoting centers. Rather than stimulating activity in these areas, signals from VLPO neurons inhibit their activity. By shutting down the arousal centers, the VLPO promotes sleep

https://healthysleep.med.harvard.edu/healthy/science/how/neurophysiology

Check out glycine which is a key player there.

What does this have to do with histamine?

Moreover, a bath application of histamine to acute brain slices inhibits the majority of VLPO neurons, which are also inhibited by noradrenaline.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3002444/

Goodness...histamine turns off the sleep switch.

This makes sense...notice how they mentioned adrenaline as having the same effect.

You don't want to be nodding off to sleep when under attack by a tiger (adrenaline) or internal poison (histamine).

Histamine's primary role is to get foreign and potentially dangerous particles out of our bodies as fast as possible.

It's an emergency situation.

The problem is that a flood of histamine (say from aged food) will flood the brain as well.

The gut (our second brain) is highly connected to the brain via the vagus nerve.

Think of the gut-brain as a sensor for what's going on in the body while the brain senses the outside world.

Before we move on...there's no better explanation than histamine's role than this:

Histaminergic neurons in the tuberomammillary nucleus (TMN) of the hypothalamus form a widely projecting, wake-active network that sustains arousal.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4509551/

"Sustained arousal". Sound familiar? Hello, insomnia!

Let's turn to the balance between histamine and GABA for insomnia.

Histamine and GABA balance for insomnia

GABA is one of our favorite playgrounds due to its effect (calming) on anxiety, sleep, pain, and just about every mental health issue there is.

GABA is our primary brake pedal in the brain. Second, only to glutamate (the gas pedal), it's key to keeping pathways from redlining.

The foes are many and fierce.

Glutamate is toxic when too high so we have powerful systems to keep it in check (see CBD and glutathione).

Cortisol, our primary stress hormone also directly opposes GABA...especially in the sleep-wake cycle.

You have a daily cortisol rhythm that peaks in the morning (wake up), drops at night, and has a slight kick up around 4 am (that get up and use the bathroom period).

This rhythm can be upside down as we found out the hard way during a brutal perimenopause (progesterone and estrogen both guide sleep).

See CBD and cortisol or CBD and stress response.

The point is...GABA has its hands full.

If GABA is exhausted by too much glutamate, histamine, and/or cortisol, good luck with sleep.

We'll look at tools to support GABA that don't build tolerance (translation...not sleep aids or benzos!!).

Look what happens when the genetically dampen GABA activity in the adjoining area of that hypothalamus:

Selective siRNA knockdown of the vesicular GABA transporter (vgat, SLC32A1) in histaminergic neurons produced hyperactive mice with an exceptional amount of sustained wakefulness.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4509551/

"Exceptional amount of sustained wakefulness".

Histamine eats up GABA when activated in the brain.

Okay...let's now figure out what is driving this histamine response.

Histamine is part of the immune system

We mentioned that histamine's primary role is to remove potentially dangerous and foreign entities out of the body as quickly as possible.

Think about an allergic reaction.

Swelling. Itching. Sneezing. Coughing.

That's the physical.

Unfortunately (if it's 2 am), histamine has dual roles as we've noted above.

Really pay attention to certain foods and insomnia.

Basically, anything that's "aged" be it wine, cheese, or even meat will trigger this system since organic material starts to break down almost immediately.

The histamine system is highly tuned to this process which usually involves bacteria or pretty foreign preservatives (chemicals not known to the body) to prevent it.

After all, histamine is part of the immune system!

Histamine is released by mast cells, large repositories of this chemical just waiting to be released.

Check out CBD and mast cell activation or CBD and histamine response for more.

We don't get into the list of things to avoid (there are many online) but a few notes.

We have general immune system settings such as TH1 and TH2.

TH1 is generally pro-inflammation while TH2 is generally anti-inflammatory.

Guess what controls the setting system-wide?

Histamine regulates antigen-specific Th1 and Th2 cells, as well as related antibody isotype responses.

https://pubmed.ncbi.nlm.nih.gov/16354958/

Histamine literally has its hand on the trigger of our inflammatory response including...the brain!

A study looked to see if there was a connection between this immune "state" and insomnia.

The results:

The present results showed a link between insomnia unrelated to medical disorders and a shift in the Th1/Th2 balance toward Th2 dominance, indicating that the relationship between sleep quality and the etiology of immune-related diseases should be reconsidered.

https://www.karger.com/Article/Abstract/71474

Hello, histamine:

Thereby, histamine regulates the effective balance between Th1 and Th2 cells by assisting a shift toward Th2

https://www.frontiersin.org/articles/10.3389/fimmu.2018.01873/full

Interesting. Insomnia is tied with a shift to TH2 states while histamine pushes in this same direction.

Check out CBD and sleep or CBD and neuroinflammation to dive deeper into how the immune system is at play.

Okay..we have to dive into one more really important aspect before looking at ways to calm histamine and insomnia directly.

Steroidal hormones and histamine

We need to touch on estrogen, progesterone, and testosterone.

Progesterone and testosterone drop slowly but surely starting around the early '20s.

About 1% a year with progesterone reaching 50% by age 40.

Estrogen goes into a roller-coast ride late 40's and then plummets.

What does this have to do with histamine and insomnia?

Just about everything.

FIrst…

Other hormonal changes, such as premenstrual syndrome (PMS) or menopause, can also can affect sleep. Insomnia becomes more common over the age of 60.

https://my.clevelandclinic.org/health/diseases/12119-insomnia

Let's face it...we slept much better when we were younger. Why?

We did a big review on why the loss of steroidal hormones may be the first shoe to drop with aging.

How does this affect sleep?

First, progesterone.

Progesterone is a major supporter and mediator of GABA function via its metabolite, allopregnanolone.

Progesterone stimulates benzodiazepine receptors, causing the release of gamma-aminobutyric acid (GABA), a sedating neurotransmitter that can potentially facilitate sleep

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4607064/

Did you catch the "benzodiazepine" part? You know...valium, Xanax, Ativan, Klonopin, etc.

See CBD versus benzos to learn more.

It does this without the tolerance and brutal addiction risk from benzos.

In fact, benzos appear to be a common go-to for prescribing to women for sleep issues...that arise in late 40's and beyond.

Go figure.

Check out our full review on progesterone for sleep here.

Ambien and it's class are just a different way to get to the GABA receptor with the same tolerance issues. See CBD versus Ambien or CBD versus alcohol (boosts GABA and serotonin but with tolerance/addition).

Then there's estrogen.

Estrogen is excitatory BUT it's also a huge supporter of serotonin, the master sleep regulator.

Serotonin is the only source for melatonin, which we slowly lose as we get older.

Check out estrogen and mental health or CBD and serotonin to learn more.

What about testosterone?

We think of testosterone as pro-growth and excitatory (which it is) but its effect is quite the opposite for sleep.

In fact, peak testosterone production and release occurs...when we sleep!

We're talking about supporting low levels...not muscle-head gym levels!

Low testosterone may affect overall sleep quality which is improved by replacement doses.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3955336/

Testosterone also supports serotonin.

What does any of this have to do with histamine?

Everything!

Histamine is a part of our immune system and progesterone is a powerful calming agent for the immune response and histamine release.

Pregnancy is a tell-tale clue:

These results suggest that mast cell secretion may be regulated by progesterone and may explain the reduced symptoms of certain inflammatory conditions during pregnancy.

https://pubmed.ncbi.nlm.nih.gov/17166400/

Many women will notice their sensitivity to foods, cosmetics, etc all start to creep up during the '40s.

That's progesterone going down and histamine response going up as a result.

When the cat's away.

On a more serious note, autoimmune, cardiovascular problems, mental health issues, etc all rely on this same reduction.

Estrogen actually boosts immune response and histamine release as a result.

There's a delicate dance between estrogen and progesterone and progesterone is losing that battle up till perimenopause (late 40's).

Interestingly, testosterone helped women keep histamine under wraps but had less effect on men.

Keep in mind that men get estrogen by conversion from testosterone and vice versa for women.

The real crux is for women, especially as they get older.

There's a great review of the relationships here:

https://www.larabriden.com/the-curious-link-between-estrogen-and-histamine-intolerance/

One last stop.

Anti-histamines, medications, and sleep (plus their downside for dementia)

Just look at the side effect profile for Benadryl or Tylenol PM.

Sedation. Drowsy.

If you calm the histamine storm, GABA is able to gain the upper hand.

It's a direct confirmation of everything we've discussed.

In fact, one of the first anti-anxiety meds was an antihistamine (hydroxyzine) which allowed GABA to function more prominently.

See CBD versus anxiety meds.

Simply put:

Blocking histamine-1 (H1) receptors successfully dampens cortical arousal, and fatigue and sleepiness result.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3884958/

Other meds come at it from the other angle...they jack up GABA.

These are barbituates, benzos, and the newer sleep aids like Ambien, etc.

The problem with this approach is tolerance (and then addiction).

GABA is so critical to the working of the brain that any medication that pushes it up in one direction quickly creates an opposing effect by the body.

The body will literally reduce the number and sensitivity of GABA receptors in the nervous system.

This means your natural level of GABA just keeps going down and the medication has less and less effect.

Ambien and other newer agents boost GABA but not through the specific port (benzodiazepine).

Still, others work on other pathways like Orexin, etc.

Again, tolerance is the enemy of any long-term medication that impacts GABA.

What about anti-histamines?

Same problem, different pathway.

With longer-term anti-histamine use, we slowly rip or deplete acetylcholine, the effects of which are really serious:

Common anticholinergic drugs like Benadryl linked to increased dementia risk

https://www.health.harvard.edu/blog/common-anticholinergic-drugs-like-benadryl-linked-increased-dementia-risk-201501287667

Acetylcholine (released from the Vagus nerve which connects gut and brain architecture) is the key to dementia risk.

See CBD and dementia or our acetylcholine review.

Statins, SSRIs, anti-acids, and a host of medications all hit (negatively) this pathway.

There are millions of women that take anti-histamines like Tylenol PM and Benadryl to fall asleep.

We personally know many women who do this. The risk is not worth it...not to mention effects on the gut barrier and autoimmune (see CBD and gut inflammation or CBD and pain).

So...all bad news. How about some good news.

Tools to calm histamine response for insomnia

So, are there ways to calm histamine response and support GABA/serotonin without the nasty tolerance and addiction (benzo's, etc)?

Yes!

Let's look at these tools:

CBD and Magnesium glycinate
CBD
Glycine
Vitamin D
HRT

Let's get started.

We listed these in a specific order...from immediate effects to longer-term ones.

First up...mag.

Magnesium Glycinate for Histamine and Insomnia

Magnesium glycinate is a huge player in sleep. We did a full review here.

Mag directly supports GABA especially when exhausted. Mag deficiency is one of the most common out there since our topsoils are so depleted.

Don't take our word for it:

As compared to the placebo group, in the experimental group, dietary magnesium supplementation brought about statistically significant increases in sleep time (P = 0.002), sleep efficiency (P = 0.03), concentration of serum renin (P < 0.001), and melatonin (P = 0.007), and also resulted in significant decrease of ISI score (P = 0.006), sleep onset latency (P = 0.02) and serum cortisol concentration (P = 0.008).

https://pubmed.ncbi.nlm.nih.gov/23853635/

We take 3-4 daily (100mg) and at night if we can't get back to sleep. The "ates" like glycinate cross the blood-brain barrier better. Glycinate also has glycine built right in (more on that later).

Look at mag deficiency and histamine response:

Blood histamine levels increased 4--5-fold by 14 days of Mg depletion

https://pubmed.ncbi.nlm.nih.gov/6445415/

Mast cells (where histamine comes from) increased by 6-7 times with mag deficiency!

Mag is a powerful dam against rampant immune and histamine response.

Then there's CBD, closest to our heart.

CBD and Histamine for Insomnia

We have a comprehensive look at CBD and sleep here but a few key takeaways.

CBD works like a feedback mechanism for key pathways when they run low.

The big ones for sleep are GABA (immediate effects), Serotonin (longer-term sleep architecture), and glycine (the "sleep" switch).

It also reduces oxidative stress and neuroinflammation (see CBD and oxidative stress or CBD and neuroinflammation) in addition to calming the stress response system (CBD and stress response).

More importantly to our discussion, CBD ISOLATE calms histamine response when too high (see CBD and mast cells).

As for insomnia:

In a study among individuals with insomnia, results suggested that administration of 160 mg/day of CBD increased total sleep time and decreased the frequency of arousals during the night

https://www.med.upenn.edu/cbti/assets/user-content/documents/s11920-017-0775-9.pdf

160mg is a good indicator for levels based on sleep research.

One important note...there's a HUGE difference with histamine response between Full/Broad Spectrum CBD and CBD isolate.

In fact, histamine may be THE difference! Big review here but look at the reviews...it's all about bad responses from full spectrum going away with isolate.

Next up is glycine.

Glycine and Histamine for Insomnia

Glycine is also inhibitory in the brain (slows things down). It counters glutamate, our primary gas pedal in the nervous system.

We have a whole review on glycine here but it's really important for starting sleep.

This is all about the sleep clock and we all know-how about insomnia can throw us off and have self-referential effects (worry about sleeping again).

Hello Glycine!:

Research shows oral glycine elevates serotonin, reduces symptoms of insomnia, and improves sleep quality. Other studies suggest it may help you bounce back to healthy sleep cycles after a period of disrupted sleep.

https://www.psychologytoday.com/us/blog/sleep-newzzz/201902/4-sleep-benefits-glycine

And the glycine-histamine connection?

Oral exposure to the free amino acid glycine inhibits the acute allergic response in a model of cow's milk allergy in mice

https://pubmed.ncbi.nlm.nih.gov/30340819/

It's a hammer on neuroinflammation especially in the brain stem!

We take mag, CBD, and glycine before bed along with melatonin which has many other attributes beyond just sleep (longevity being a big one).

Then there are the longer-term players.

Vitamin D and Insomnia

Vitamin D is a monster actor in every pathway of your body...especially sleep.

It's a steroid we get from the sun but the majority of people are deficient and that gets worse as we get older.

Studies on D and insomnia such as:

Symptoms were improved starting from the first week and there was no need of increasing the dosage or adding another hypnotic agent. No withdrawal effect was seen. Patients are currently on follow-up with prescription of melatonin 0.5 mg/night in case needed and vitamin D 1000UI/day for a month.

https://n.neurology.org/content/90/15_Supplement/P5.320

It can take months for Vitamin D levels to get up higher. I take 10K daily and it slowly budges (up to about 70 ng/mL now finally).

Get your levels tested and act accordingly. Even the newest guidance is at 3K daily for adults.

We have a whole review of Vitamin D here for sleep and mental health.

Also, D modulates our immune system including histamine! Big shocker.

Vitamin D helps manage our other steroidal hormones so let's go there.

HRT and insomnia

We covered this a bit already but long term (especially for women in the mid/late 40's and beyond), it's a total game-changer for all pathways described.

No wonder so many women in the 40s/50s are thrown on sleep aids, SSRIs, and benzos.

Progesterone drives GABA while estrogen drives serotonin.

The two work in concert to manage all systems including sleep AND histamine response.

Testosterone (especially for men) has similarly powerful effects.

Any HRT (work with your doctor or better yet, naturopath since they're more in tune with hormones) should be bioidentical. Synthetics carry risks not present with bioidenticals.

You got to love comments like this:

Research also suggests that progesterone and estrogen may protect women against sleep apnea, but menopause cancels out that benefit.

https://www.yalemedicine.org/news/women-are-your-hormones-keeping-you-up-at-night

Really? Does it? Next time they say "Your numbers are fine for your age"...find a new doctor.

We did deep dives on estradiol safety, estrogen and mental health, and progesterone.

Testosterone is due but it's effects mirror estrogen in women for sleep (serotonin), growth, repair, etc.

Most interestingly, the steroidal hormones all manage immune response which is also histamine.

Progesterone is the heavy lifter there.

As a bow around the "histamine = insomnia" premise, let's look at PEA, a member of the endocannabinoid family (like THC without the high and tolerance).

It's a powerful dampener of mast cells (histamine) in the body.

The effect on insomnia?

Overall, the results of this study support PEA as a potential sleeping aid capable of reducing sleep onset time in individuals with sleep latency issues and improving cognition on waking.

https://sleep.biomedcentral.com/articles/10.1186/s41606-021-00065-3

The immune system (histamine) and sleep go hand and hand!

Check out the immune system and mental health review which has more tools for rebalancing our immune response which can be primed "hot" from early infection or trauma (even in utero).

Be well. Take care of each other. Take care of yourself!

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