While pouring over studies for our general anxiety disorder and CBD article, we came across a range of research dealing with stress.
This gets to the heart of why two people can go through war and one has PTSD while another doesn't appear to.
See our article on the complete guide to CBD's benefits for anxiety.
Its importance in general anxiety as opposed to episodic (due to a specific trigger) is also very important.
Even more fascinating is that the endocannabinoid system (where CBD does its heavy lifting) is integral to our "stress response".
Stress response and anxiety are directly linked.
Think of when you didn't get much sleep or have 100 things coming at you.
Your general mood shifts.
Maybe to irritability. Most likely to anxiety or an anxious state.
You just can't handle it as much.
We're going deep into the research to look at how stress impacts anxiety.
Most importantly, we'll touch on what CBD can do for this stress response if anything.
Simply put...chronic stress can literally shrink your brain!
The repercussions of this are significant with anxiety and depression front and center.
We'll see what new research says about all of this!
The topics we'll get into are as follows:
- What is stress in the body and brain
- Neurotransmitters and stress
- Can stress cause brain loss
- Stress and Anxiety
- Genes and Stress Response for anxiety
- The endocannabinoid system and stress
- Research on CBD and stress response and anxiety
- CBD and oxidative stress
- How much CBD for better stress response anxiety
- Best type of CBD for stress response and anxiety
Lot's to cover...we don't mess around.
What is stress in the body and brain for anxiety
We've covered the pathways of anxiety extensively in our CBD for anxiety article. 4000+ words.
You can think of stress as discount fear in terms of how the body processes it.
Heck, look at the title of this NIH study on the matter:
The Neurocircuitry of Fear, Stress, and Anxiety Disorders
We'll refer to it often below.
Small doses of stress are actually important to keep us alert and safe.
The brain's response to stress is similar to what runs amok in anxiety.
The issue is really with chronic stress or acute stress that is overwhelming for a given person's stress response.
We're going to leave all the other websites for generic descriptions of stress.
A good description is here:
We're going deeper based on new research on the relationship between stress and inflammation.
Prepare to dive!
There are chemicals released during any stress response:
- Adrenaline (also called Epinephrine)
Cortisol is our main suspect and it's fascinating.
Cortisol is a steroid in the body.
Simply put, it's the body's main stress hormone!
Imagine, you turn the corner and a person on a bike nearly misses crashing into you.
That's cortisol with some adrenaline thrown in for good measure.
Stress causes the release of this same chemical albeit in lower doses.
That's not all cortisol does though:
- Manages how your body uses carbohydrates, fats, and proteins
- Keeps inflammation down
- Regulates your blood pressure
- Increases your blood sugar (glucose)
- Controls your sleep/wake cycle
- Boosts energy so you can handle stress and restores balance afterward
All of those are important but let's focus on the second one.
When we're faced with a threat right now, the body shifts resources to right now!
Get out of the way of that bike!!
What's the point of a good immune response or proper digestion if we're going to be dead from a bike crash.
It's a trade-off earned over millions of years of evolution so apparently it works.
That's acute stress.
The problem is when we have a constant release of cortisol due to ongoing stress.
This is where things get interesting.
Cortisol exerts a powerful control over our immune response (hmm hmm...inflammation).
A research team led by Carnegie Mellon University's Sheldon Cohen has found that chronic psychological stress is associated with the body losing its ability to regulate the inflammatory response
They went on to say:
"Inflammation is partly regulated by the hormone cortisol and when cortisol is not allowed to serve this function, inflammation can get out of control,"
Essentially, the immune system becomes less responsive to Cortisol's balancing act if it's always present.
Very similar to our body's response to constant sugar...diabetes!
They went on to say...
When under stress, cells of the immune system are unable to respond to hormonal control, and consequently, produce levels of inflammation that promote disease.
Other studies have shown this same effect with cortisol having so-called "biphasic" effects on inflammation.
Excessive cortisol (from chronic stress) poses its own issues in terms of anxiety:
Exaggerated or recurrent negative cognitions, rumination or worry, magnification, and helplessness are all maladaptive catastrophizing responses to pain or non–pain-related stress that may prolong cortisol secretion
Can we just call "rumination or worry" what it is, please. Anxiety.
This article is interesting in that it finally ties in pain sensitivity to this whole equation.
The key is this...
Chronic stress translates to inflammation in the body and brain.
Inflammation in the brain has a slew of knock-on effects tied direction to anxiety
We have an entire article on inflammation and anxiety here.
In terms of cortisol and inflammation:
Cortisol is a potent anti-inflammatory, and its failure to function results in an unmodulated inflammatory response to physical pathogens, unrecognized proteins, or psychological stressors
That last bit is interesting.
Cortisol is anti-inflammatory but if it's chronic, the system won't respond to it anymore.
And what does all that inflammation result in:
Inflammation induces oxidative and nitrosative stress, free radical damage, cellular death, aging, and systemic tissue degeneration
Then there's the connection to autoimmune diseases.
See our article on CBD and neuroinflammation and anxiety.
With excess cortisol, our immune response moves to a different footing which is tied to histamine response called T2:
an enhanced Th-2 mediated humoral immune response could increase vulnerability to autoimmune and allergic diseases
Long term stress has a more lasting result.
Let's turn to the brain.
Neurotransmitters, brain, areas, and stress for anxiety
We've looked at the key pathway for anxiety in many of our articles based on research.
The Amygdala and Prefrontal cortex are two main players.
Our old reptilian seat of fear (amygdala) and our more rational (and newer) brain area...the prefrontal cortex.
The "circuit" lies at the heart of anxiety in the brain.
In our article on CBD and general anxiety disorder, we even looked at a main connector between the two which showed in brain scans with anxiety:the uncinate fasciculus
What does stress do in these areas?
Scientists have learned that animals that experience prolonged stress have less activity in the parts of their brain that handle higher-order tasks — for example, the prefrontal cortex — and more activity in the primitive parts of their brain that are focused on survival, such as the amygdala.
This is the wrong direction.
Studies show that a thicker amygdala makes a person more prone to anxiety.
In fact, recent research showed that THC thickens the amygdala in such a manner.
THC has been known to cause anxiety in a percentage of the population and this may be the means.
The biggest differences in gray matter were in the amygdala, which is involved in fear and other emotion-related processes, and in the hippocampus, involved in memory development and spatial abilities.
Remember that powerful thoroughfare of communication between our scaredy-cat (amygdala) and voice of reason, the prefrontal cortex.
The uncinate fasciculus (say that 5 times fast).
Chronic stress early in life can affect this communication link as well:
Exposure to intense and chronic stressors during the developmental years has long-lasting neurobiological effects and puts one at increased risk for anxiety and mood disorders
This early stress during development may be due to changes in that communication link which pops up in people with general anxiety.
We found that higher sensitivity to ELS predicted both reduced fractional anisotropy in right frontal UF and higher levels of anxiety symptoms.
To translate, early life stress caused issues in that communication link which resulted in anxiety.
So...chronic stress has the following effects in regards to anxiety
- Enlarges fear center - amygdala
- Shrinks the competing, rational center - prefrontal cortex
- Shrinks the connector between the two - uncinate fasciculus
There's an amazing explanation of the entire process here:
Let's look at the neurotransmitters which do all the signaling with these areas.
We'll focus on two big ones for anxiety:
- GABA - calming chemical - main lever for anxiety
- Serotonin - workhorse signaler throughout the brain
Let's start with GABA since it's the most direct proxy for anxiety:
Stress and fl-Carbolines Decrease the Density of Low-Affinity GABA Binding Sites
This makes sense and is fine in the short term.
When that bike is about to crash into you, calm is not the response that will keep you (or your ancestors) alive.
Adrenaline and Cortisol are more needed!
Long term, chronic stress, however, will depress GABA levels which is directly tied to anxiety.
Chronic stress causes disinhibition of the hypothalamus-pituitary-adrenal axis. Consequently, the brain is overexposed to glucocorticoids which in humans may precipitate stress-related disorders, e.g. depression.
What about serotonin (more tied to depression but also present with anxiety circuit).
An interesting study showed that in healthy subjects, cortisol (our main stressor chemical) would boost serotonin but not in subjects with depression or anxiety:
A significant increase in serotonin uptake (+37% + 14, M + SD) was observed in the control group, whereas neither the generalized anxiety disorder nor the major depression group exhibited changes in serotonin uptake upon incubation with cortisol.
Serotonin is a tricky beast which is why the side effects of SSRIs can be so varied.
- If it boosts signaling in the Amygdala (fear center), anxiety can result.
- It boosts signaling in the frontal cortex or between brain regions, anxiety can go down.
Again, GABA is the better proxy for anxiety.
Let's make one last stop before CBD for stress and anxiety.
The endocannabinoid system and stress
This system is especially important to our discussion on stress and its effects (such as anxiety).
We all have this system and it's tasked with balancing other key systems including:
- Nervous system - GABA, Serotonin, and brain area signaling
- Immune system - inflammatory response (ding ding ding)
- Endocrine system - Hormones like Cortisol and other key components of stress
It should be pretty obvious that this system may be the intersection of stress and anxiety based on our discussion above.
Why do two people go through the same situation and one has anxiety while the other seems unscathed?
This system may be the grand balancer of our stress response!
As this study puts it:
A growing body of work indicates that the endocannabinoid (eCB) system is an integral regulator of the stress response.
We naturally have endocannabinoids that act as checks and balances of all these actors.
The two big ones in the brain are:
- Anandamide - the "bliss" molecule
Why do they matter?:
Across a wide array of stress paradigms, studies have generally shown that stress evokes bidirectional changes in the two eCB molecules, anandamide (AEA) and 2-arachidonoyl glycerol (2-AG), with stress exposure reducing AEA levels and increasing 2-AG levels.
The various chemicals interact at specific receptors throughout the brain and body known as CB1 and CB2 receptors.
The research went on to say:
Additionally, in almost every brain region examined, exposure to chronic stress reliably causes a downregulation or loss of cannabinoid type 1 (CB1) receptors.
Let's put the pieces all together now:
With respect to the functional role of changes in eCB signaling during stress, studies have demonstrated that the decline in AEA appears to contribute to the manifestation of the stress response, including activation of the hypothalamic-pituitary-adrenal (HPA) axis and increases in anxiety behavior
At an extreme, check out the article on the lady who can't feel pain or anxiety to see the power of anandamide.
Incapable of feeling anxiety or depression.
Put a note next to Anandamide for when we discuss CBD below (very exciting).
Back to the question, we had at the beginning...why do some people have one stress response while another person has a completely different stress response?
translational studies have shown that eCB signaling in humans regulates many of the same domains and appears to be a critical component of stress regulation, and impairments in this system may be involved in the vulnerability to stress-related psychiatric conditions, such as depression and posttraumatic stress disorder.
When they blocked CB1 gene expression, anxiety-like behavior resulted in mice:
The vehicle‐injected CB1‐knockout mice from the second experiment also showed increased anxiety as compared with wild types.
In terms of stress, Anandamide appears to be a key driver of anxiety:
These data indicate that central anandamide levels predict acute stress-induced anxiety, and that reversal of stress-induced anandamide deficiency is a key mechanism subserving the therapeutic effects of FAAH inhibition
FAAH is the endocannabinoid that breaks down Anandamide.
Too little Anandamide may be a key driver of anxiety as a result of stress.
That's all well and good but what can we do about it?
Especially the early adolescent stress-induced damage to the brain!
Time machines are still a work in progress.
Research on CBD and stress response and anxiety
Let's look at CBD.
CBD, short for cannabidiol, is a cannabinoid that can interact with the endocannabinoid system we just discussed.
It has a strong safety profile (see here) but can CBD help with our stress response...especially as it pertains to anxiety?
We're going to cover the key topics:
- Can CBD support stress response
- CBD and Anandamide for stress and anxiety
- Can CBD support brain areas damaged by chronic stress and anxiety
- CBD and neurotransmitters following stress and anxiety
- CBD and oxidative stress in the brain
Let's get started!
First, stress response and CBD.
We know that our main stressor Cortisol has immediate effects across the body.
One of those raises heart rate and blood pressure (getting ready to jump back from the bike!).
An early clue is CBD's effect on these physical manifestations of stress:
This data shows that acute administration of CBD reduces resting BP and the BP increase to stress in humans, associated with increased HR.
The keyword there is "stress". The effect was different in people not under stress.
Remember, our endocannabinoid system is one of balance.
Let's get right to the heart of our stress response...cortisol!
Does CBD have an effect on cortisol levels?:
This decrease in cortisol levels was significantly attenuated after CBD (basal measurement = 10.5 +/- 4.9 micrograms/dl; 120 min after 300 mg CBD = 9.9 +/- 6.2 micrograms/dl; 120 min after 600 mg CBD = 11.6 +/- 11.6 micrograms/dl).
Interestingly, CBD does not affect verbal and mental processing while bringing down cortisol as seen in our CBD and public speaking article.
You still need to jump out of the way of that bike (what's with bikes these days!).
Remember that chronically elevated cortisol wreaks havoc on the immune system, cardiovascular system, and eventually...the stress response system itself!
Let's start to drill into CBD's effect on the stress response.
Think of this as emotional resiliency!
Let's look at stress' effect on serotonin (key target for half of the anxiety meds on the market).
We'll translate this study a bit but the headline:
Activation of postsynaptic 5-HT1A receptors improves stress adaptation.
Essentially, they first depleted serotonin levels and then used stress to stimulate the body's natural stress chemicals.
When serotonin was boosted back up, the stress chemicals went down.
It shows that serotonin was critical for our ability to handle stress.
It improved our resiliency:
In preclinical studies, 5-HT1AR agonists are anxiolytic in animal models of general anxiety , prevent the adverse effects of stress , and enhance fear extinction
We have an entire article on the effects of CBD on serotonin for anxiety but a quick take away:
CBD significantly enhanced serotonin and glutamate levels in vmPFCx in a different manner depending on the emotional state and the duration of the treatment.
Again, serotonin is a better lever for depression but the impact on anxiety above still applies.
Most importantly...that "depending on emotional state" part.
We discussed Anandamide (our natural endocannabinoid which partially governs stress response) above.
What does CBD do to affect anandamide (if anything)?
cannabidiol treatment was accompanied by a significant increase in serum anandamide levels, which was significantly associated with clinical improvement
See our article on how a women who never felt pain or anxiety.
It does this by blocking FAAH which breaks down anandamide.
The FAAH gene mutation is actually what's behind the woman who never feels pain or anxiety (or depression!!).
CBD reduces FAAH expression!
Next, let's look at the result of stress in the brain. Oxidative stress.
When everything is in hyper mode (translation...cortisol), the brain is ratcheted up for fight or flight.
Everything speeds up.
This creates a great deal of waste material called ROS (short for Reactive Oxygen Species).
It's the thing that antioxidants are "anti" to.
Stress drives up ROS and even NOS.
Why does ROS matter?
However, during times of environmental stress (e.g., UV or heat exposure), ROS levels can increase dramatically. This may result in significant damage to cell structures.
Collateral damage to surrounding tissue and since it's in the brain, that's valuable real estate.
To be more specific:
They also trigger numerous molecular cascades, leading to increased blood-brain barrier permeability (through activation of matrix metalloproteinases and subsequent degradation of tight junctions), alterations of brain morphology, neuroinflammation, and neuronal death
The blood-brain barrier breakage is especially interesting considering our explosion of autoimmune diseases.
We're going to wrap with this research (as there are dozens of CBD's effects on stress response).
This one ties it all together:
The anxiolytic effects of cannabidiol in chronically stressed mice are mediated by the endocannabinoid system: Role of neurogenesis and dendritic remodeling.
- First, anxiolytic just means anit-anxiety.
- Cannabidiol is CBD
What they found is amazing.
A big part of CBD's effects on anxiety comes from its ability to spur new brain connections in key areas tied to mood.
These are the very same areas that chronic stress damages!
In all our research, the only other thing that causes brain growth (neurogenesis) to help strengthen our stress response is mindful meditation:
...and exercise. We have an entire article coming.
Why is this so important?
You can take a benzo for immediate relief but it does nothing for the underlying structural causes of anxiety.
- Brain area communication links
- Neurotransmitter levels
- Inflammation and immune damage
- Elevated stress chemicals
The benzos stop boosting GABA and not only are you right back to the same pathways but we now have added withdrawal anxiety heaped on top.
See our article on how CBD can boost GABA for anxiety.
That's why the addiction problem for benzos is so severe!
Learn all about CBD versus benzos for anxiety here.
SSRI's boost serotonin in one direction but have many side effects, Serotonin Discontinuation symptoms (please...can we call it was it is, Orwell), and normalization (goes away with time).
The above mechanism (neurogenesis) is starting to chip away at the root deficiency in the brain for anxiety!
Long term effects.
For now, CBD may be THE weapon we have against damage caused by stress in our brains and bodies.
Of course, the other usual suspects are also in play:
- Exercise (150 minutes a week has significant effects)
- Avoid processed food and eat well (see CBD and gut bacteria)
- Healthy social interactions (see CBD and social anxiety here)
- Sleep sleep sleep (see CBD and sleep here)
- Supplements as needed (magnesium, B vits, Vitamin D, Selenium, etc See Dre's pick of supplements)
One final takeaway.
Research is pointing to the endocannabinoid as a reactive and dynamic system governing stress response in our body and brain.
There are many other studies we didn't here (as they support the same facts).
You can find more here:
Also, check out CBD for PTSD….the ultimate expression of stress' effect on the brain.
So….how much CBD should we use for stress response support?
How much CBD for better stress response anxiety
We're going to look at this in two parts:
- Preventative and general wellness
- Stress-related anxiety
For preventative and wellness, the generally accepted dose is from 25-50 mg
Anxiety is pointing to 200-300 mg for both short term and long term support (see how many mg of CBD for anxiety here).
You don't want to go higher than 300 generally since the neurogenesis (building new pathways and connections in the brain) is on a bell curve.
It starts to go down between 300 and 600 mg according to one study.
Of course, always start small to test on your body (generally 20--30 mg) and then go from there.
CBD can even be taken prior to a stressful event.
Just check out our CBD and public speaking article for insight into how that works.
Let's cover a crucial item for stress since it's intimately tied to inflammation and revving things up in the body.
Best type of CBD for stress response and anxiety
We have an important consideration here (since we actually look at research) which most other brands are not paying attention to….Histamines!
This directly ties to stress response.
Histamine, like glutamate, is excitatory in the brain.
This study shows how Histamine and ROS go hand in hand:
Cortisol and Histamine are also directly connected.
Think about what an allergic attack feels like.
It has all the telltale signs of cortisol.
Why does this matter for our type of CBD?
A good majority of the CBD pushed on the market may raise histamine release.
For 40-60% of the population with histamine issues, that's the wrong direction.
See our article on histamine anxiety and CBD.
Simply put, it's a stressor in terms of how the brain sees it.
The percentage goes higher for women and higher yet for women over 40!
For this reason, we want CBD Isolate (by itself with a base oil).
Everyone and their mother is pushing full-spectrum CBD.
Learn more about CBD Isolate versus Full Spectrum for anxiety here.
Again, we focus on research (hopefully obvious from this one article out of dozens).
That's why IndigoNaturals is CBD Isolate with the cleanest MCT (from coconut oil) base.
The research is all based on CBD Isolate!
To be safe, shouldn't the product we put in our bodies mirror this same research!
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.