Inflammation, Anxiety, and CBD

by Indigo Naturals April 06, 2019

Inflammation is emerging as the new boogeyman for many (if not all) mental health issues.

Chronic inflammation that is.

A new study just came out that tied it directly to depression (as a cause, not a symptom) as well as heart disease.

https://www.medicalnewstoday.com/articles/324748.php

Edward Bullward must feel vindicated with his book, The Inflamed Mind, where he spells out how inflammation drives depression directly.

What about anxiety?

Does it fall in this same bucket of inflammation-driven issues?

We're going to get to the heart of what research (most of it, really new) is saying about inflammation and anxiety.

We'll then look at CBD to see if its well-established anti-inflammatory properties can affect this pathway.

We'll look at these topics in detail:

What exactly is inflammation
Does inflammation drive anxiety
How does the endocannabinoid system moderate inflammation and anxiety in the brain
Can CBD help with inflammation and anxiety
What's the best kind of CBD for inflammation and anxiety
How much CBD is advisable for inflammation and anxiety

Lots to cover.

Let's get started!

What exactly is inflammation

Inflammation seems to be a catch-all term for "badness" in the body.

It's actually a very specific response we have to protect us (in the short term).

The inflammatory response rests in our immune system which spans the entire body and brain.

A good part of it is controlled in our gut which makes sense once you understand the role of the inflammatory process.

Check out CBD and leaky gut or CBD and probiotics for anxiety.

It's basically there to protect us from foreign entities and to repair!

It quite literally is our body's defense force.

The immune system might be the most complicated and beautiful system in the body.

Many different actors (cytokines, T cells, leucocytes, glial cells, etc) and a maddeningly sophisticated pathway.

Unfortunately, it's at the root of most of our 1st world, modern diseases.

Autoimmune diseases are behind almost every scary health issue out there.

Put a checkmark next to "autoimmune" because it's going to play an important part in how inflammation drives anxiety.

Even some kinds of cancers and the process of cancer itself may reside partially in our inflammatory process.

There are really two phases of our inflammatory response:

Seek and destroy foreign entities or faulty cells (pre-cancer)
Repair and rebuild tissue

Most people don't realize the second role that inflammation plays.

That's why NSAID's like Advil can affect how torn ligaments repair and make them more prone to future injury.

They speed up the inflammatory response which also skews the rebuilding itself!

https://academic.oup.com/ptj/article/97/8/807/3826991

The key concern for anxiety specifically is chronic inflammation.

If you get a cut or roll your ankle, a short-term inflammatory response is critical to repairing the tissue.

What if inflammation continues for months or years due to an unresolved issue or environmental factor (chemicals in our food, air, or surroundings)?

That's chronic inflammation and it's literally toxic to our bodies and more importantly for anxiety...to our brains!

Neuroinflammation, inflammation of the brain and/or the nervous system, is where we want to focus on anxiety.

If an inflamed ankle feels the way it does, what does inflammation of our brain or nervous system feel like?

Let's go there now.

Does inflammation drive anxiety?

This is the real question.

It's also really exciting!

Keep in mind that almost none of this was really known 10 years ago.

It still hasn't jumped from the research lab to our medical system.

Get ready to geek out.

So let's give you a quick landscape of the interaction between inflammation and anxiety.

Let's start with the autoimmune angle.

Autoimmune just means that the body's immune system is attacking our own tissue.

This is the root of a wide range of very expensive and growing list of diseases...over 100 and counting:

https://www.aarda.org/diseaselist/

Pick a body tissue and there's probably a corresponding autoimmune disease.

Remember that the immune's system weapon of choice is inflammation!

Where research gets interesting is understanding the mechanics of how autoimmune works.

Almost weekly, there's an article on how bacteria are escaping it confines (our gut, our mouth, etc) and getting out into the body…

And brain!

The plaque that builds up in our arteries has been shown to be from bacteria!

Not your liver or what you eat.

Bacteria from your mouth.

Mouth bacteria are also showing up to make colon cancer worse:

https://www.sciencedaily.com/releases/2019/03/190304100009.htm

We get new examples every month now.

Even bacteria showing up in the brain!

The bacteria behind gum disease is being found in the brain with people suffering from dementia:

https://www.sciencemag.org/news/2019/01/gum-disease-causing-bacteria-could-spur-alzheimer-s

New evidence is pointing to gut bacteria as key to Parkinson's:

https://www.cureparkinsons.org.uk/news/parkinsons-starts-in-gut

Those are a few of a dozen examples of errant bacteria causing issues over the past year.

Our immune recognizes it and unleashes its inflammatory response.

You almost can't have arteriosclerosis WITHOUT inflammation.

Atherosclerosis is an inflammatory disease of the wall of large and medium-sized arteries:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734407/

The first question is this...how are bacteria getting into our bodies?

On a constant basis (chronic)?

We have barriers to keep foreign things out:

Your gut lining and mucus
Your skin (very exciting new research there)
Your blood-brain barrier

That last one looks intriguing for anxiety.

Different causes can cause inflammation in the brain or central nervous system:

Infection such as errant bacteria crossing the blood-brain barrier
Injury
Overexpression of immune response

The net effect is the same for all causes...an inflammatory response.

Interestingly, general inflammation in the body can cross over to create neurodegeneration:

https://www.ncbi.nlm.nih.gov/pubmed/20644946

The mediator of this cross-talk between the body and the brain's response appears to be microglia...our brain's local immune responder.

Like the cop on the beat (the brain), it gets a call from headquarters (immune system) to be on the lookout.

The normal homeostatic role that microglia play in signaling about systemic infections and inflammation becomes maladaptive in the aged and diseased brain and this offers a route to therapeutic intervention.

https://www.ncbi.nlm.nih.gov/pubmed/20644946

This just means that if the microglia respond incorrectly, damage can occur in the brain.

This is critical to anxiety.

We have a full review of CBD and neuroinflammation here.

Let's look at the clues between anxiety and inflammation.

Let's start at a top-level and then zoom in.

A massive study in Sweden looked at stress-related diseases (including anxiety) and autoimmune diseases:

Stress-related disorders were significantly associated with the risk of subsequent autoimmune disease.

https://jamanetwork.com/journals/jama/article-abstract/2685155

Interestingly, they looked at the participants and siblings to separate out obvious negative effects from dealing with an autoimmune disease.

Learn all about Autoimmune disease and CBD here but autoimmune is basically a misdirected and constant state of inflammation in the body and/or brain.

Another animal study separated out the physical impairment from the resulting anxiety and inflammation:

The anxiety-like profile showed higher levels of pro-inflammatory cytokines centrally (hippocampi and spinal cord)

https://www.ncbi.nlm.nih.gov/pubmed/26296565

As they found:

These changes in inflammation were not associated with injury severity; suggesting that the association between inflammation and the expression of behaviors characteristic of decreased psychological well-being was not confounded by differential impairments in motor ability.

Another large study sought to measure the actual component pieces of inflammation in people with anxiety.

They found that inflammation markers were elevated in people with anxiety in two situations:

For men
For people with late-onset anxiety

https://www.nature.com/articles/tp201327

This is very interesting.

We've covered the role of hormones (gender-defining) and anxiety at our comprehensive Anxiety and CBD article and at our CBD perimenopause anxiety here.

If you're part of the 51% of the population where progesterone and the three different versions of estrogen are important, this is a must-read article.

That "late-onset" aspect is also interesting.

This hints at infection and/or inflammatory roots for the anxiety.

The researchers are getting more sophisticated where they can look at specific parts of the brain now.

Now with imaging technology, we can see what's actually happening in the brain in terms of inflammation in people with anxiety:

Inflammation was consistently found to affect basal ganglia and cortical reward and motor circuits to drive reduced motivation and motor activity, as well as anxiety-related brain regions including the amygdala, insula and anterior cingulate cortex, which may result from cytokine effects on monoamines and glutamate.

https://www.ncbi.nlm.nih.gov/pubmed/29173175

If you read our article on CBD for anxiety, CBD for social anxiety, or CBD for teenage anxiety, you'll recognize the Amygdala.

It's our emotional processing center in the brain which is the seat of our fear and anxiety response.

Put a note by the word "cytokine".

These are little inflammatory signallers that are actually very powerful in the brain.

Keep in mind that stress causes inflammation. Chronic stress can cause chronic inflammation.

It's the Holy Grail of health right now and anxiety is not different:

increased inflammation in PTSD, GAD, PD, and phobias is via the activation of the stress response and central and peripheral immune cells to release cytokines.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5143487/

GAD is a General Anxiety Disorder.

There can even be a feedback loop between our body's stress response and our anxiety response:

Dysregulation of the stress axis in the face of increased sympathetic tone and decreased parasympathetic activity characteristic of anxiety disorders could further augment inflammation and contribute to increased symptoms by having direct effects on brain regions critical for the regulation of fear and anxiety (such as the prefrontal cortex, insula, amygdala, and hippocampus).

There's the Amygdala again. Notice how "cytokines" popped up in the prior paragraph?

Let's go there now.

Cytokines are the heavy lifters of the immune system's inflammatory response.

That's a mouthful!

Seriously though.

This is a general catchall for any immune agent that can affect other cells.

It can include:

Interferon
interleukin
growth factors

And more!

It's a zoo of different chemicals our body uses to protect and repair us with.

Do cytokines do other things besides attack bad things in the brain?

cytokine signaling in the brain is known to regulate important brain functions including neurotransmitter metabolism, neuroendocrine function, synaptic plasticity, as well as the neural circuitry of mood.

https://www.sciencedirect.com/science/article/pii/B9780123983145000015?via%3Dihub

Hormones (for gender difference). Check
Ability to rebuild damaged neurons in key areas. Check
Neural circuitry of mood???

That last one seems pretty important for anxiety!

That's all pretty general. What about specifics?

activation of inflammatory pathways within the brain is believed to contribute to a confluence of decreased neurotrophic support and altered glutamate release/reuptake, as well as oxidative stress, leading to excitotoxicity and loss of glial elements

Okay...now we're talking:

Glutamate is our brain's excitatory chemical and it looms large in our research on anxiety. Too much gas pedal!! (See here)
Oxidative stress is highly destructive to neurons (long term) and it's been tied to anxiety see CBD and oxidative stress
Glial elements - those are the microglia immune responders in the brain that go haywire! CBD and microglia here.

https://www.sciencedirect.com/science/article/pii/S0006322308015321

You'll see that these same components (in different measure) are implicated in both anxiety and depression.

The two have a close association (such as side effects for the main anxiety medications!).

Of those with a depressive disorder, 67% had a current and 75% had a lifetime comorbid anxiety disorder. Of persons with a current anxiety disorder, 63% had a current and 81% had a lifetime depressive disorder

https://www.ncbi.nlm.nih.gov/pubmed/21294994

Interestingly, you'll see impacts from inflammation on both throughout the literature for immune stress response.

It's not just physical stress though.

Interestingly, psychological stress is reported to modulate cytokine production, suggesting the potential relevance of this mediator to mental health.

https://www.ncbi.nlm.nih.gov/pubmed/22814704

Let's go deeper down the rabbit hole.

A study looked at specific cytokines to establish a link and to separate it out from other factors:

However, the production capacity of several cytokines was positively associated with the severity of depressive and in particular anxiety symptoms, even while taking lifestyle and health factors into account.

As a specific example...

IL8 (short for Interleukin 8 - a type of cytokine or inflammatory responder) figured prominently:

Elevated IL-8 production capacity in both previously and currently depressed and anxious persons might indicate a genetic vulnerability for these disorders.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5070051/

Another study showed other cytokines elevated:

Comparison of pro-inflammatory to anti-inflammatory cytokine ratios indicated that there were significantly higher ratios of TNF-a /IL10, TNF-a /IL4, IFN-? /IL10, and IFN-? /IL4 in the GAD group compared to the control group.

Again, GAD is General Anxiety Disorder.

Okay...we could go and on from research.

It's clearly showing a link between inflammation and anxiety.

Let's look at the endocannabinoid system before we jump to CBD.

How does the endocannabinoid system moderate inflammation and anxiety in the brain

The endocannabinoid system spans our entire body and there are receptors on almost every type of cell (except red blood cells).

It's tasked with balancing three key systems:

Nervous system - neurotransmitters tied to anxiety-like GABA, Glutamate, and Serotonin
Endocrine system - hormones including estrogen, progesterone, histamine tied to anxiety
Immune system - ding ding ding - inflammatory response including...cytokines!

All three systems interplay with anxiety but the last one is key to our question of inflammation's role in anxiety.

The endocannabinoid system is integral to everything we discussed above.

There are dozens of articles but we'll focus on a few that are key to anxiety and inflammation.

At a summary level:

The endocannabinoid system modulates stress, emotionality, and inflammation

https://www.sciencedirect.com/science/article/pii/S0028390814003293

Here are some specific highlights from one of the studies here:

IL-1ß regulates the synaptic effects of CB1 receptors.
CB1 receptors regulate TNF-mediated potentiation of excitatory synaptic transmission.
TRPV1 channels have a permissive role in the synaptic effects of IL-1ß.
Interplay between ECS and inflammatory cytokines controls behavior.
ECS regulates neurodegenerative processes in multiple sclerosis.

To translate.

CB1 is a cannabinoid receptor in this system generally found in the brain.
IL-1 is short for interleukin 1, a cytokine or immune system responder

More importantly, the endocannabinoid system (eCB) may be the intersection between stress response and inflammation.

eCB signaling seems to determine the value of fear-evoking stimuli and to tune appropriate behavioral responses, which are essential for the organism’s long-term viability, homeostasis and stress resilience; and dysregulation of eCB signaling can lead to psychiatric disorders.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5871913/

Read that again...it's too fascinating. Your response to fear is dependents on endocannabinoid processing!

The keyword in that whole description is "homeostasis" which means balance.

Anxiety is an imbalance in either neurotransmitters, brain area signaling, or increasingly in new research...inflammation response!

What about the immune responders in the brain...microglial cells….how do they interact with the endocannabinoid system?

Cannabinoids regulate the brain–immune axis and inhibit microglial cell activation.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4729885/

Why is this important?

microglial cells could be a target for cannabinoid influence on psychiatric disorders, such as anxiety, depression, schizophrenia, and stress-related disorders.

In fact...the endocannabinoid system may govern how microglia cells respond:

Evidence now shows that microglia, the macrophages of the brain, also express a functional eCBSS and that activation of CB receptors expressed by activated microglia controls their immune-related functions.

https://www.ncbi.nlm.nih.gov/pubmed/18722389

This just means that endocannabinoids have regulation over our immune sentries in the brain.

Another study showed that Microglia are switched to a more aggressive standing in response to inflammation and the net result was high anxiety:

Microglia are polarized to M1 type in high-anxiety inbred mice in response to lipopolysaccharide challenge

Research here.

There's a great summary of direct impacts of inflammation on anxiety here:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4729885/

Just one example…

Stressful experiences such as social defeat activate long-lasting peripheral and central immune response (10–12) and induce microglial activation, myelopoiesis in the bone marrow and spleen, infiltration of monocytes into the brain and neuroinflammation

That might be critical to PTSD, teenage anxiety, and social anxiety.

Again, it's one of many examples.

Let's end with a very specific study on anxiety, the endocannabinoid system, and IL1, a cytokine.

Here's the smoking gun connecting all three:

We found that a single intracerebroventricular injection of IL-1 caused anxiety in mice, and abrogated the sensitivity of cannabinoid CB1 receptors (CB1Rs) controlling GABA synapses in the striatum.

https://pdfs.semanticscholar.org/dfed/3893ddfa1eed331bda924185650be8a121b5.pdf

First, if you've read our summary of anxiety and CBD, you'll know that GABA is the single most important neurotransmitter when it comes to anxiety (and sleep by the way).

The striatum is an incredibly important brain area for anxiety and many other mental health issues.

We geek out on studies like this!

They injected a cytokine (inflammatory immune responder) and the net result was anxiety created by messing up the endocannabinoid system.

In general, our goal is to balance or calm down this inflammation response as it pertains to anxiety.

What a great place to introduce CBD!

Can CBD help with inflammation and anxiety

CBD is a plant-derived cannabinoid.

Research is showing that it bolsters our own endocannabinoid system.

Nowhere is this truer than with our inflammatory response.

Especially in the brain and central nervous system.

There's a lot of information here on related topics:

We're going to focus on brain inflammation and CBD below since anxiety has been tied most closely to this.

We've evaluated different aspects of inflammation and anxiety including:

Cytokines (inflammatory actors)
Microglial cells (the immune actors in the brain)

Let's start generally and work down to these pieces.

First, CBD appears to also aid the serotonin pathway to protect the brain:

CBD demonstrated attenuation of acute autonomic responses evoked by stress, inducing anxiolytic and antidepressive effects by activating 5HT1A receptors in a similar manner as the pharmaceutical buspirone that is approved for relieving anxiety and depression in humans.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5938896/

The key there is "response to stress".

Anxiolytic just means anti-anxiety.

There's the depression link again.

By the way, Buspirone is a medication used to treat anxiety (more here on CBD versus anxiety medications).

That article is interesting because it has lots of different pathways and studies on how CBD affects anxiety but we want to stay with inflammation here.

CBD's effects go directly down into the neurons themselves!

In one study, key components of the cell were protected from stress chemicals by CBD:

These findings suggest that attenuation of the ER stress pathway is involved in the 'oligoprotective' effects of CBD during inflammation.

https://www.ncbi.nlm.nih.gov/pubmed/22739983/

What does the "olio" mean?

It's short for oligodendrocyte which is a type of microglia cell in the brain and nervous system.

Basically, CBD was able to protect these cells during stress response to calm our immune action in the brain.

Remember that overactive microglial cells are tied directly to anxiety:

Hyperactive microglia, a common feature of these neurodegenerative diseases, secrete a number of pro- and anti-inflammatory cytokines, chemokines, glutamate, prostanoids, neurotrophic factors, and a range of free radicals that provide a milieu for oxidative stress.

How does CBD affect this pathway?

CBD has been shown to attenuate oxidative and nitrosative stress in several human disease models

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3386505/

Here may be the most telling effect of CBD for microglial inflammation and anxiety:

CBD was shown to inhibit activated microglial cell migration by antagonizing the abnormal-cannabidiol (Abn-CBD)-sensitive receptor at concentrations

Remember above where anxiety was induced through an immune response to lipopolysaccharide (it's a sugar that coats bacteria...our immune system is primed to respond to it)?

CBD was reported to suppress LPS-induced pro-inflammatory signaling in cultured microglial cells, including NF-?B and STAT1 activation while enhancing STAT3-related anti-inflammatory signaling [26].

LPS is short for lipopolysaccharide mentioned above.

To translate, CBD calmed down the inflammatory response in microglial cells (our brain's immune responder).

Not only does CBD calm the aggressors, but it also boosts the system our inflammatory response uses to walk back the attack.

Researchers found that CBD promoted the increase of inflammatory-suppressor cells called myeloid-derived suppressor cells:

https://multiplesclerosisnewstoday.com/2018/08/24/cannabidiol-increases-inflammatory-suppressor-cells-ms-mouse-study-shows/

This was from a study on MS but MDSC is a system used to calm inflammation in the body.

One more pathway affected by CBD.

Remember that there's a cross-talk between inflammation in the body and inflammation in the nervous system which can drive anxiety.

A great deal of brain inflammation research and CBD was discovered through research on Alzheimer's which see significant effects of microglial cell activation.

CBD is able to modulate microglial cell function in vitro and induce beneficial effects in an in vivo model of AD

https://www.ncbi.nlm.nih.gov/pubmed/21350020

The study shows that CBD slowed down "microglial migration" which is where the microglial activate and start to move towards the site of inflammation.

There are dozens of studies but we'll leave with this one.

Remember how IL1 (interleukin 1), an inflammatory cytokine was directly tied to anxiety? High anxiety to be exact.

Does CBD have an effect there?

CBD was also shown to decrease the measurable quantity of both IL-1 and TNF.

https://www.ncbi.nlm.nih.gov/pubmed/1667651

There are dozens of studies regarding CBD's effect on inflammatory pathways we discussed above for anxiety.

Some good summaries are here:

Let's touch base on a very important part of this equation which may be causing some people more harm than good with CBD.

By some people, just 40-60% of the population!

What's the best kind of CBD for inflammation and anxiety

We have an entire article on Histamine, CBD, and anxiety here.

A key component there is histamine which accounts for an anti-anxiety medication that rivals benzos in effectiveness without the nasty addiction issues.

It's called Hydroxyzine.

Learn all about CBD versus Anxiety medications here.

Interestingly, it's primarily an anti-histamine!

What does this have to do with the best CBD for anxiety and inflammation?

Everything!

90% of what's available on the market is "full-spectrum" CBD.

This is essentially CBD added back into hemp oil.

The problem is that people with allergy or histamine issues will likely not respond well to all this plant material.

That's 40%-60% of the population.

It's higher for women and higher yet if over age 40.

We found out the hard way when originally experimenting with CBD.

Check out our article on how CBD can make anxiety worse here.

We want CBD Isolate for this very reason.

Learn the full reason why at CBD isolate versus full spectrum for anxiety.

Of course, the basic requirements apply:

Organically grown in the US
3rd party tested
THC free (THC can actually cause anxiety)
Solvent-free
Pesticide-free
Heavy metal-free
Bacteria free
Mold free

We literally used anxiety and inflammation as our roadmap for how to craft IndigoNaturals.

Check our story here for all the details.

How much CBD is advisable for inflammation and anxiety

The best approach is to start slow and build up until you have see results.

A starting approach is generally around 20-30mg.

For the 1000 mg bottle, that's about one dropper.

Once you have tested your response, you can go up from there.

The very serious anxiety/panic issues were researched at 300-600 mg so that lets you know the available range.

You most likely will not need to get close to that.

People generally report relief in the 40-100 mg range.

Some of the effects on both inflammation and anxiety are cumulative and will build over time.

Let us know what range works for you.

A major study showed that 300 mg was ideal for serious anxiety and that effects started to go down from there to 600 mg.

Be well. We have a major tool against inflammation and anxiety according to research.

Check out:

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.