CBD, Microglia, Neuroinflammation, and Anxiety
This really is cutting edge.
- The standard anxiety circuits
- Stress and brain area repair
- Neurotransmitters such as serotonin and GABA
The immune system's effect on anxiety however is groundbreaking.
It's even spawning a new discipline called immunopsychiatry and when you see the studies on how our immune system is wrapped around brain function, you're going to geek out.
You might actually see a pathway to reducing anxiety.
That's the goal after all.
The clues trickled in at first but it's only sped up in recent years.
If you think this is all speculation, what about the new study showing that Parkinson's may be an immune response from bacteria in gut:
Bacteria in Gut Can Promote Parkinson’s by Altering Brain’s Immune Reactions
The "marks" of our immune response occur across a range of mental health issues including anxiety.
We danced around it our CBD and inflammation for anxiety article but let's zero in on brain immune response.
We'll cover these areas:
- An introduction to your brain's immune response
- How prior infection and immune response can cause overactive immune response for anxiety
- The endocannabinoid system and brain inflammation response
- Can CBD help with overactive microglia and immune response in the brain
- How much CBD to take to calm immune response in the nervous system
- What's the best CBD to take for immune and microglia response
Let's get started. We have years (and lifetimes) of immune response to attend to.
An introduction to your brain's immune response
Let's get to know ourselves first.
We can't go too deep or we'll never make our way back.
Our immune system is incredibly complicated and none more so than the part in our brain and nervous system.
We'll focus on key players that are intimately tied to mood states including anxiety.
Our key players in the neuroimmune landscape:
- Glia- astrocytes, microglia, and oligodendrocyte cells are the brain's primary immune responders
- Cytokines - inflammatory agents designed to attack intruders (and do so much more)
- Mast cells - another key player which releases histamines for allergic response
- Blood-Brain barrier - key to keeping bad things out
These agents (and others recruited when needed) are key to protecting our brain and nervous system from pathogens...bacteria, viruses, and more.
They're also key to clearing out damage, dead neuronal material, and repair!
Let's look at Glial cells first….with a focus on anxiety.
Microglia are fascinating and increasingly showing their importance in NEW research.
Simply put, they're the maintenance and security departments of the the brain:
Microglia are key cells in overall brain maintenance—they are constantly scavenging the CNS for plaques, damaged or unnecessary neurons and synapses, and infectious agents.[
CNS is short for central nervous system.
They make up about 10-15% of total brain cells and are distributed throughout.
The issue is when microglia are over-active and actually damage healthy tissue which can lead to anxiety or depression.
There's interesting research in how our neuroimmune system responds to chronic psychological stress.
One study found that psychological stressed caused the ramping up of microglia and a specific cytokine, IL-1B:
Collectively, the development of anxiety during stress was caused by microglial recruitment of IL-1β-producing monocytes that stimulated brain endothelial IL-1R1.
When the researchers blocked the microglia activation, the anxiety effects went away.
Later on, we'll discuss the connection between IL-1B and the endocannabinoid system.
For now, just put a mark next to that.
It's not just anxiety of course. Depression follows a similar trajectory:
That inflammatory response, in turn, led to "the atrophy and impaired response of neurons in the medial prefrontal cortex [part of the brain's executive control center], causing depressive behavior."
Check out CBD and inflammation for anxiety for further information.
By the way, inflammation is just our immune response to injury or infection.
Here's where it's interesting.
The microglia are generally in charge of brain immune response.
In chronic situations, microglia call for reinforcements from the body.
These are the monocytes mentioned above that make their way to the brain from bone marrow.
Usually, our body's immune responders like monocytes can't cross the blood/brain barrier.
It's the chronic aspect that triggers this panic response from microglia.
"We can't seem to control the situation by ourselves...call in the mercenaries!"
Monocytes can be very destructive to brain tissue though.
In terms of survival, infection/injury takes precedent but it's not without collateral damage to neurons:
The cells surrounded blood vessels and penetrated brain tissue in several areas linked to fear and anxiety, including the prefrontal cortex, amygdala and hippocampus, and their presence led to anxiety-like behavior in the mice.
In another study with gene knockout mice, the damage was limited by reducing monocyte recruitment (by the microglia) after seizures:
Importantly, preventing monocyte recruitment accelerated weight regain, reduced BBB degradation, and attenuated neuronal damage.
BBB is the blood brain barrier which we'll get to later.
The main area they saw this recruitment to was the hippocampus!
The hippocampus is a key player in the anxiety circuit. Check out CBD to boost neurogenesis in the hippocampus here.
Other studies point to the intersection of our immune response and the hippocampus for both anxiety and depression:
The results show that 12 weeks of chronic mild stress induced remarkable depressive- and anxiety-like behavior, simultaneously causing hippocampal microglial activation
There's that key…"microglial activation".
By the way...the "chronic stress" applied before was social defeat.
Check out CBD for social anxiety here.
The key is that the brain's immune system sees psychological stress the same as infection:
The research indicates that stress--maybe even the stress of being cold--appears to tap into the same immune systemnervous system loop that triggers symptoms of the common cold,
Read that study if you get a chance...it's pretty fascinating!
It uses pretty original studies to tease out how the brain and gut communicate via cytokines.
In fact, the feeling of "sickness" when you have a cold is the result of cytokines rushing to the brain after signals of infection.
They could "stop" the sickness feeling by blocking the cytokines!
For example, when Maier and his colleagues inactivate these cytokines or block the receptors in the brain that bind them, animals show no sign of sickness after infection. And if they administer these cytokines to the brain, the animals show all the signs of infection even when no infection exists.
As another study succintly put it:
Certain core symptoms of major depression, especially the somatic symptoms, resemble the “sickness behavior” that is produced by systemic infectious or inflammatory conditions
That brings up an interesting tangent.
When the neuroimmune system senses infection, it responds by dropping tryptophan to thwart future bacterial growth.
The problem is that our brain uses tryptophan to make serotonin!
That directly affects anxiety and depression as you can find from our CBD and tryptophan for anxiety article.
Check out CBD versus SSRI's for serotonin and anxiety to understand why it's so important.
What's fascinating is that stress leaves a mark on microglia that persists for a while:
researchers at The Ohio State University have shown that the immune cells of the brain, called microglia, hold unique signatures of chronic stress that leave the animal more sensitive to future stressful experiences, evident by increased anxiety and immune responses.
It's not just in microglia where there's a lasting mark.
Microglia also remodel the brain. They're in charge of pruning and growing...the landscapers of the brain if you will.
This is a dynamic process that's occurring from you reading this sentence.
Stress also causes the microglia to "shape" key areas of the brain:
The team’s experiments showed that under conditions of stress, neurons in the brain’s prefrontal cortex—a region involved in complex functions such as decision making and social behavior—produce a signal that triggers microglia to begin remodeling neural circuits.
The interesting piece to our discussion is what happens when they blocked microglia's signal:
The research team found that when they prevented neurons from producing their microglia-stimulating signal, mice exposed to chronic stress did not develop signs of anxiety or depression.
What are these signals?
Powerful and potentially toxic chemicals.
Microglia can actually take different forms depending on the threat level surrounding.
In one state, they release a ton of oxidation (like molecular scissors in the hands of a 3 year old).
Check out our article on CBD and oxidative stress for anxiety.
We spent a lot of time on microglia...what about astrocytes and oligodendrocytes?
That's a mouthful.
We'll go quicker but they figure in as well.
Astrocytes and Anxiety
These guys outnumber neurons 5-1 and they have just a small (sarc) role:
Astrocytes help form the physical structure of the brain, and are thought to play a number of active roles, including the secretion or absorption of neural transmitters and maintenance of the blood–brain barrier.
Okay..form physical structures in the brain...so big role.
They have their hands in so many pots, we'll focus on the anxiety.
Let's start here:
Recently, it was demonstrated that astrocytic GLT-1 blockade leads to an anxiety-like phenotype.
Essentially, they block astrocyte activity and "trait" anxiety is displayed.
Any synthroid or levothyroxine users out there?
Turns out that it can interfere with astrocytes functioning which may result in anxiety or depression:
Here we report that mice with astrocyte-specific Dio2 inactivation (Astro-D2KO) have normal serum T3 but exhibit anxiety-depression-like behavior
That's pretty technical but it looks at one piece of the thyroid chemistry set which is affected in astrocytes.
The real focus we want to look is astrocytes "management" of GABA and glutamate.
Even though these are immune agents, they also can govern neurotransmission especially during quiet times (low infection or injury).
GABA is the primary lever of benzo's for anxiety (see can CBD boost GABA for anxiety).
It has an immediate effect on anxiety.
What does this have to do with an immune responder like astrocytes?
There are powerful neurosteroids such as allopregnanolone.
Where is it made?
These are synthesized by cytochrome P450 enzymes in oligodendrocytes, astrocytes, and possibly in neurons
The relationship between allopregnenoline and GABA is powerful:
Allopregnanolone is a potent positive allosteric modulator of GABAA receptors, which allows it to facilitate and fine-tune the activity of GABA at these receptors.77 Through its action on GABAA receptors, allopregnanolone exerts anxiolytic, antidepressant, and anticonvulsant activities when administered to experimental animals
Let's translate a bit there.
Basically, allopregnanolone (as well as progesterone and estrodiol) govern GABA release and have anti-anxiety (anxiolytic) results!
Interestingly enough, that new post-partum depression medication at $25,000 a pop is a synthetic version of allopregnanolone.
You can get it's precursor, pregnenolone for $10 down at Whole Foods but our health care system is fine.
Also, synthetic always has nasty side effects. Check our complete review of Pregnenolone.
Look...we focus on CBD but if people are suffering, we want to research and get the word out.
Our feathers have settled...back to our immune system and anxiety.
Astrocytes and anxiety.
SO why would a key brain remodeler be important for anxiety (or depression or a host of issues)?
Certain areas like the amygdala (our fear and emotional center) are dynamic regions that are constantly being remodeled.
In fact, anxiety has been tied to enlarged amygdala volume and activity.
Check out CBD for general anxiety disorder.
One study looked at astrocytes in just one specific area for fear avoidance:
Avoidance learning is an adaptive mechanism, but can become maladaptive and lead to the development and persistence of many specific anxiety disorders like post-traumatic stress and social anxiety disorders
By turning astrocytes on and off in a specific region, they could directly affect fear avoidance:
Using genetic and optical dissection strategies in vitro and during behavior we report that VTA astrocytes tune glutamatergic signaling selectively on local inhibitory neurons to drive a functional circuit for learned avoidance.
What about it's easy to pronounce cousin, oligodendrocytes?
Oligodendrocytes and anxiety
Another member of the brain's immune system, these cells have the important task of constantly wrapping nerves in protective sheathing called myelin.
We know all too well when this process goes wrong (multiple sclerosis, cerebral palsy, schizophrenia, etc).
What about anxiety?
When oligodendrocytes are are genetically blocked, anxiety results in 7 days:
Supporting the idea that OPCs can influence anxiety, the focal genetic ablation of OPCs from the prefrontal cortex of young, adult NG2-Cre :: iDTR transgenic mice was sufficient to produce anxiety-like behaviors within 7 days
What's really interesting is what happens from early stress on these cells.
We'll look at that below in our causes section.
Again, they also help to regulate neurotransmitters (remember GABA the "brake" and glutamate...the "gas pedal"):
ErbB knockdown increased evoked dopamine release in the striatum (Roy et al., 2007), while Olig2 knockout increased glutamate expression in the cortical gray matter and increased the density of glutamatergic vesicles at synaptic terminals (Chen et al., 2015), suggesting that oligodendrocyte loss may precipitate an anxiety-like phenotype by dysregulating neurotransmitter signaling in the CNS
Essentially, when oligodendrocytes were blocked genetically, the gas pedal was left on and anxiety "trait" behavior would result.
We keep seeing "cytokines" in the mix with these different immune responders and anxiety.
How do they figure in?
Cytokines and anxiety
Cytokines are inflammatory agents and they're about as confusing and complicated as you get in the body.
They can have different responses in different settings from different stimuli.
Let's stay out of the weeds and focus on those tied to anxiety in research.
You'll usually recognize them by "IL" in the beginning which stands for interleukin.
Let's hit some highlights.
We're going to combine IL-1 and our last section on oligodendrocytes:
Meghan Jones, of the University of North Carolina, found chronically stressed mice possessed elevated levels of a molecule called interleukin-1-β (IL-1) in the astrocytes of the hippocampus, a brain area critical to learning and memory.
The hippocampus is key to anxiety and depression (See CBD and hippocampus neurogenesis here).
SO...IL-1. That's on our radar.
On the flip side, IL-10 is protective and anti-inflammatory.
When microglia are "turned on" or activated for attack, they release different chemicals:
M1-polarized microglia are associated with the production of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), superoxide, nitric oxide, reactive oxygen species and proteases
Don't worry, we'll create a little cheat sheet of the cytokines and their effects below.
It's a zoo!
The key is that anxiety is tied to elevate levels of inflammatory cytokines and reduced levels of anti inflammatory cytokines.
This will really come into play with CBD later!
Another study showing both the good and bad from chronic stress (which we established above in terms of anxiety):
Likewise, activation of NLRP3 inflammasome and upregulation of inflammatory mediators, such as interleukin-1β (IL-1β), IL-6, and IL-18, were also observed in the hippocampus after exposure to chronic stress.
Before we start to glaze over, we'll summarize with this;
Results show that LPS-stimulated inflammation was associated with increased odds of current depressive/anxiety disorders
When they ruled out lifestyle and health, one market stood out:
In fact, you can create an anxiety state just by administering the shell protein of bacteria call lipopolysaccharide:
When normal volunteers were injected with lipopolysaccharide, a well-known immune activator, they exhibited acute increases in symptoms of anxiety
What's the tie with overactive microglia?
Overactive microglia continue to release pro-inflammatory mediators (IL-1β and IL-6)
Another study looked at general anxiety disorder which is a good proxy for long term "trait" anxiety.
Generalized Anxiety Disorder Linked to High IFN-γ and TNF-α but Low IL-10 Peripheral Levels
Remember that IL-10 was anti-inflammatory. The other two are definitely inflammatory.
We could go on and on so let's try to make some sense of it. It's very complicated!
First our pro-inflammatory cytokines that at least correlate with anxiety states if not drive them:
Next, our anti-inflammatory cytokines that appear to calm and "resolve" the immune response:
Again, this is just a smattering...we could fill books with this topic.
Just put a note next to them for later when we look at trying to calm the immune response as it pertains to anxiety.
One last piece…
The blood brain barrier and anxiety
We have a protective layer which separates the brain from the body.
Only certain things can get past this barrier which is essential.
The damage that pathogens can do in the brain is tremendous since our neuron environment is so sensitive and complicated.
Swelling in the knee is one thing.
Swelling in the brain can be catastrophic.
It's increasingly important with modern diseases of the brain (such as the Parkinson's connection above).
As researchers put it:
His team also found that microglia reinforce the BBB, which is composed of endothelial cells, pericytes, and astrocytes. Microglia fill in spaces left by astrocytes killed or damaged during injury. Without a robust barrier, McGavern says, unwanted immune cells may flood the parenchyma and do more harm than good.
Newer studies are find the actual mechanisms behind the blood brain barrier and anxiety such as this one:
Restraint Stress Induced Hyperpermeability and Damage of the Blood-Brain Barrier in the Amygdala of Adult Rats
It's a pretty sophisticated setup where they showed that chronic stress broke down the barrier in one of the most important brain areas tied to anxiety..the amygdala.
And then there's the cytokine impact:
In addition, increased IL-1β contents in serum and amygdalar tissues were observed in the restraint-stressed groups.
There's that IL-1B again.
We have to move on or we'll never get to how to calm this system.
So we'll leave off with the title of another study:
Peripheral and Central Effects of Repeated Social Defeat Stress: Monocyte Trafficking, Microglial Activation, and Anxiety
- Chronic stress (psychological). Check
- Breaching blood brain barrier (monocytes). Check
- Microglial activation. Check
Let's now look at one more piece of the puzzle...early exposure and "training" our immune system to overreact.
Just one more thing you can blame your mother for!
How stress, infection, and immune response can cause anxiety
We'll touch on this quickly but it's very important and fascinating.
Prior exposure to pathogens, antibiotics, stress, and trauma can "shift" your immune response and make you more likely to have anxiety or depression.
In fact, through epigenetics, these effects can go on for generations!
We'll look at a few examples.
Remember how microglia can "remember" past interactions?
How about back to when we were in the womb:
Conversely, events that activate microglia can have long-lasting behavioral consequences. Neonatal exposure of rats to LPS produces significantly increased anxiety-like behavior and hippocampal microglial activation in adulthood
LPS is that protein shell from bacteria that we saw above.
The same is true with antibiotics:
Treatment with a single antibiotic course was associated with higher risk for depression with all antibiotic groups, with an adjusted OR (AOR) of 1.23 for penicillins (95% CI, 1.18-1.29) and 1.25 (95% CI, 1.15-1.35) for quinolones.
We're really getting into the heart of the immune response which is our gut.
We have to move on to where CBD has its effect.
The endocannabinoid system and neuroimmune inflammatory response
We're almost to CBD.
Let's first introduce the endocannabinoid system which we all have.
It's tasked with balancing key systems including:
- Nervous system - neurotransmitters such as GABA and serotonin
- Endocrine system - hormones including cortisol (stress hormone) and histamine
- Immune system - cytokines, glial cells, and more!
Did you catch that one?
Yes...the very subject of everything you read above.
This evidence has suggested that the endocannabinoids production by glial cells may constitute an endogenous defense mechanism preventing the propagation of neuroinflammation and cell damage.
Let's finally get to CBD to see it's role in this system for neuroinflammation and anxiety.
Can CBD help with overactive microglia and immune response in the brain
Finally, we're here.
Let's review studies for CBD's effect on the following tied to neuroinflammation and anxiety:
- Too much microglia activation
- Too much oxidative stress
- Weakened blood brain barrier
- Too high levels of destructive cytokines (IL-1, IL-6, IL-8, INF-y, and TNF)
- Too low levels of protective cytokines (IL-4, IL-10, IL-13)
We'll start with microglia since they are the bosses that start the whole inflammatory process (call in cytokines, monocytes, etc).
What does CBD do there?
Cannabidiol and Other Cannabinoids Reduce Microglial Activation In Vitro and In Vivo: Relevance to Alzheimer's Disease
Interestingly, THC was shown to dysregulate microglia activity which CBD helped to offset.
In pilot experiments we have replicated the finding that adolescent, low-dose THC activates microglia in the prefrontal cortex via CB1 cannabinoid receptors and increases IL-6 mRNA. The increase in IL- 6 was prevented by concurrent cannabidiol.
Re-read that last part.
Low dose THC (psychoactive chemical in cannabis) activates microglia inflammatory response in the prefrontal cortex...the very seat of reason which has to counter the amygdala in our anxiety circuit.
It's also the part that develops last in puberty...very critical if you're a human!
CBD (cannabidiol) prevented the resultant increase in IL-6.
This needs to get out in the media as the market currently has products that are ALL THC.
In this way, CBD is an absolute MUST to protect from the effects of THC or cannabis use as this same process mirrors what occurs in schizophrenia for certain people.
What about astrocytes that protect and guide or brain remodeling job?
CBD blunted neuroinflammation sustained by astrocytes through PPARγ selective activation in vitro and in vivo
And oligodendrocytes? Those the very important cells that make protective sheaths for neurons among other things.
Cannabidiol protects oligodendrocyte progenitor cells from inflammation-induced apoptosis by attenuating endoplasmic reticulum stress.
We picked ONE example for each cell type but the general trend should be apparent.
CBD is a powerful anti inflammatory in the brain.
Let's look at one of the most traumatic and inflammatory events in the brain...stroke or ischemia.
That's a great proxy since all inflammatory agents explode on the scene. This is life or death after all.
First, the bad news:
Using a multi-tiered behavioral testing battery during 21 days, we found that BCCAO mice exhibited long-lasting functional deficits reflected by increase in anxiety-like behavior (day 9), memory impairments (days 12-18) and despair-like behavior (day 21).
BCCAO just means that they blocked an artery to a part of the brain in mice resulting in a traumatic stroke.
The catastrophic results above are expected. Notice the anxiety behavior (not surprising considering the ties we've seen above between inflammation and anxiety!).
Now the good and quite honestly, ridiculous news:
Short-term CBD 10mg/kg treatment prevented the cognitive and emotional impairments, attenuated hippocampal neurodegeneration and white matter (WM) injury, and reduced glial response that were induced by BCCAO.
Um...do we drop the mic now?
To follow up:
In addition, ischemic mice treated with CBD exhibited an increase in the hippocampal brain derived neurotrophic factor (BDNF) protein levels. CBD also stimulated neurogenesis and promoted dendritic restructuring in the hippocampus of BCCAO animals.
This is all techno speak for building and repairing new brain!
Check out CBD for neurgenesis here.
Did we forget to mention the cytokines? Those little inflammatory tasmanian devils in the brain?
Looking at asthma response:
The levels of IL-4, IL-5, IL-13, IL-6, IL-10, and TNF-α were determinate in the serum. CBD treatment was able to decrease the serum levels of all analyzed cytokines except for IL-10 levels.
Remember that IL-10 was protective for the brain.
What about the protective cytokines like IL-10?
You want to see how complicated the cytokine garden can be?
We and others have shown that CBD upregulates the anti-inflammatory cytokine IL-10 [71,78,130], the immunoregulatory genes in autoimmune T cells mediating EAE/MS [72,73], and induces inhibitory cell phenotypes resolving inflammation, including myeloid-derived suppressor CD11b+Gr1+ cells  and CD4+CD25+LAG3+ T cells [72
There will be a test!
Actually, the net net of the above is that CBD boost levels of protective cytokines.
What about the all important blood brain barrier?
Cannabidiol protects an in vitro model of the blood–brain barrier from oxygen‐glucose deprivation via PPARγ and 5‐HT1A receptor
5HT is the serotonin pathway by the way which is key to repairing brain damage tied to anxiety and depression.
In fact, that's the primary way that SSRI's work.
Check out CBD versus SSRI for serotonin and anxiety.
You can also check out CBD and oxidative stress for anxiety.
The gut-brain axis is a whole separate article here.
So...some practical matters on CBD and neuroinflammation.
How much CBD to take to calm immune response in the nervous system
There isn't hard research on immune response with CBD.
Obviously, the equivalent treatments for more serious issues like schizophrenia (has an overactive microglia component) and ischemia are at high levels of CBD.
600 - 800 mg.
Even the CBD for public speaking anxiety was at 600 mg.
That being said, the peak for anxiety is generally around 300 mg since the neurogenesis effect goes down after that point.
For general neuroprotective effects, it may be as low as 40-80 mg.
It always makes sense to test first at about 20-30 mg and go up from there.
One good clue is if you get relief from histamine (allergy) release.
That brings up a great point.
What's the best CBD to take for immune and microglia response
We purposely missed one of the biggest immune responders in the brain tied to anxiety.
Those lovely mast cells.
We covered CBD's effect on histamine release at our CBD, histamines, and anxiety article.
Needless to say, we don't want to poke the dragon with lots of plant material or THC.
That's the primary reason we only deal with CBD isolate in MCT (coconut oil) extract.
Everyone out there is pushing full spectrum even though 40-60% of people have issues with histamines.
Histamine release is about as inflammatory as you can get in the brain!
It also eats up GABA which is a key lever for anxiety.
Maybe more importantly, all the research (above and beyond) is based on CBD isolate.
Check out why CBD isolate is better for anxiety here.
We found this out the hard way after having bad reactions to about 4 big CBD full spectrum brands.
That's a big reason we made IndigoNaturals.
We wanted CBD built on research.