At the heart of almost every health and mental health issue is stress.
An exhaustion of stress response in the body and brain to be exact.
This can be sudden (trauma or infection) or a slow grinding down (chronic) but either way, the repercussion is intimately tied to every health issue.
The two biggest drivers of drug relapse???
- Stress
- BDNF levels (we'll cover this below…it's a rock star)
The problem with many of our stress release valves (alcohol, cannabis, benzos, etc) is that they build tolerance over time.
Your stress response system actually gets dialed down with use! Going the wrong way.
CBD isolate doesn't actually have this effect! Let's dive into how it works for stress response with this in mind!
A quick intro to the feedback effect of CBD isolate:
- Way #1 - CBD and GABA
- Way #2 -CBD and serotonin
- Way #3 - CBD and acetylcholine
- Way #4 - CBD and histamine
- Way #5 - CBD and brain inflammation
- Way #6 - CBD and glutamate
- Way #7 - CBD and cortisol
- Way #8 - CBD and corticotrophin-releasing factor
- Way #9 - CBD sleep
- Way #10 - CBD and past trauma, infection, or…stress!
Okay…lots of heavy lifting. Let's get to it!
A quick intro to the feedback effect of CBD isolate
First, stress is not the enemy.
Stress is just a signal that something is wrong…it's there to drive one of 2 actions:
- Stop doing something (knock off that toxic relationship)
- Start doing something fast (get that paper done NOW!)
Stress is just a signal that the current path is not ideal for our well-being.
Great…but occasionally, the source of stress is out of our control and our natural systems to address it are exhausted.
We could use some support in the meantime! We have a massive review of Top 10 Tips for Stress Support but we're going to zero in on one critical player..CBD isolate.
CBD works in the endocannabinoid system but how it works is the key.
Unlike THC (its cousin) which pushes in one direction, CBD acts like a feedback mechanism!
- If stress pathways are too strong, it calms them.
- If stress response is getting too exhausted, it supports them.
We'll dig into the mechanics of it below but this subtle effect is so important to long term stress response.
We don't throw a wet blanket on stress just to have it rebound even stronger!
But…we need some support when outgunned.
Hello CBD! Massive reviews on CBD and stress response or CBD and resilience but let's drill down into CBD and stress pathways directly.
A quick intro to the stress players. First the "bad" guys:
- Corticotrophin releasing factor - hormone starts the whole stress train running
- Cortisol - our primary stress hormone; you KNOW how this feels
- Glutamate - brain's "gas" pedal; rev up…things need to change
- Histamine - excitatory player also moves everything into high alert
- Adrenaline - Okay…jump out of the way of the bus or the mother-in-law…this is serious now
And the opposing forces?
- GABA - the brain's "brake" pedal offsets glutamate, cortisol, and histamine. Good luck with that.
- Serotonin - longer term stress response buffer; manages our "limit" on what we can handle
- Anandamide - "bliss" molecule kicks in as needed to rally the calm troops
- Acetylcholine - our "calm and focus" player that opposes adrenaline
Okay…the field is set. Let's play ball!
We'll start with the monster players. Frontline stress response.
Way #1 - CBD and GABA
GABA is front and center and just happens to be the target of benzos (till tolerance and addiction send things the other way).
GABA is our brain's "brake" pedal and it's intimately tied to calm, sleep, and all versions of slowing down.
Stress directly eats up GABA so this is the first shoe to drop.
CBD is a positive allosteric modulator of GABA. Translation:
It supports when running low!
CBD interacts with CB2 receptors and they're all over GABA function:
There is also evidence that CB2 are present on neurons in stress-associated areas of the brain and regulate the release of GABA, dopamine, and glutamate
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8704602/
We have a whole review on CBD and GABA but the key takeaway is…
GABA is the "right here and now" controller of stress (hence the benzo effect) and CBD supports it when low.
Remember that CBD's original "discovery" was around seizures which reflects a massive imbalance between GABA and its opposing force…glutamate.
Magnesium glycinate is also a great support mechanism here.
What about longer term stress management?
Hello, serotonin!
Way #2 -CBD and serotonin
If GABA is the here and now player, serotonin is the tomorrow and next Wednesday operator.
Serotonin is the manager of ALL human behavior…including how we deal with stress.
In fact, it's a powerful stress (and pain and inflammation) response buffer.
CBD also acts as a feedback mechanism when it's becoming exhausted by stress.
Our favorite study:
Overall, repeated treatment with low-dose CBD induces analgesia predominantly through TRPV1 activation, reduces anxiety through 5-HT1A receptor activation, and rescues impaired 5-HT neurotransmission under neuropathic pain conditions.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6319597/
Let's translate…
An injury causes pain which quickly exhausts serotonin and leads to systemwide pain and anxiety.
CBD…
- "Rescued" serotonin function (5HT)
- Reduced anxiety
- Reduced pain sensitivity
The key word there is "rescue" since too much serotonin can be even worse than not enough! See serotonin syndrome.
Stress exhausts serotonin. CBD supports levels when low.
Check out our big review on CBD and serotonin or serotonin as a social stress buffer.
Tryptophan may also be a support here.
Let's turn to the background nervous system.
Way #3 - CBD and acetylcholine
Acetylcholine is the key component of our "rest and digest" or parasympathetic nervous system.
Notice how your heart races, your pulse quickens, and your palms can get sweaty under serious stress?
That general feeling of "frazzled" is your body's response to stress and is the autonomic nervous system.
Adrenaline! The pushback?? Acetylcholine.
Your "calm and focused" player released from the vagus nerve behind your chest plate (ever wonder why meditation, deep breathing, and gratitude helped??)
More on supporting the vagus nerve here but what about CBD and acetylcholine through its hub, the vagus nerve?
We found CBD exhibited direct excitatory effects on vagal afferent neurons that required TRPA1, were augmented by TRPV1, and attenuated following chronic cannabis vapor exposure.
https://pubmed.ncbi.nlm.nih.gov/32965166/
So CBD supports the hub of rest and digest (calm and focus) and cannabis (THC) offset this.
Interesting! See why CBD is so important to protect against the excesses of THC.
We have a whole review on vagus nerve support and CBD and acetycholine.
Let's turn to a key opponent you may not even know about!
Way #4 - CBD and histamine
Histamine is fascinating. Sure, it's the primary allergic reaction driver but it does so much more in the brain…especially during stress.
When you have acute stress, the body just gushes out histamine from mast cells:
These results suggest that in rats acute stress increases colonic mast cell histamine content. This effect is mediated by the release in cascade in the brain first of IL-1 and secondly of CRF.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2343625/
IL1 is an inflammatory cytokine. CRF??? Just the instigator of the stress response…corticotrophin releasing factor.
So stress drives histamine which is excitatory in the brain.
In fact, the first class of anti-anxiety meds were…anti-histamines! See CBD versus anxiety meds.
Extreme histamine release feels just like anxiety.
So…CBD isolate there?
There are lots of examples where CBD calms mast cell activation (asthma, brain inflammation, gut inflammation, etc) but one example from endometriosis:
CBD has important analgesic effects as showed by the reduced mast cells recruitment in the spinal cord and the reduced release of neuro-sensitizing and pro-inflammatory mediators
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9141153/
Important note….this is CBD isolate. NOT full spectrum and not THC.
See CBD versus full spectrum for histamine to learn why.
Also, for ladies, check out why progesterone is so important for mast cell activation.
One note…histamine directly opposes GABA so your first stress response buffer is getting hit hard when histamine flares up.
Big guide to histamine if this is your issue.
Next up…deep in the endocannabinoid garden that CBD plays in.
Way #5 - CBD and anandamide
Anandamide is one of 2 primary endocannabinoids we naturally in have in our bodies.
Named after Anand, the Hindu goddess of "bliss", it's called on reserve when stress is winning.
THC mimics anandamide but too hard and for too long so there's a rebound effect (and eventual tolerance).
CBD supports anandamide when low…again, the feedback mechanism as an allosteric positive modulator.
It does this by blocking the chemical called FAAH that breaks down anandamide.
- No tolerance
- No addiction
- No "high" of impaired mental function like THC
Let's take an example of extreme (maybe the most extreme) stress response imbalance…psychosis:
Moreover, cannabidiol treatment was accompanied by a significant increase in serum anandamide levels, which was significantly associated with clinical improvement.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3316151/
We have a massive review on CBD and anandamide or even CBD and psychosis since extreme stress can push us to our breaking point.
That's the "hero's" list….let's get back to the "bad guys" of stress.
Way #6 - CBD and glutamate
Glutamate, as the "gas" pedal of the brain, is essential but too much is downright toxic and more importantly, overwhelms GABA.
So…short term:
stress acutely enhances glutamate release in the PFC and hippocampus.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3645314/
Okay…so stress drives the gas pedal. Makes sense (danger! Get going) but it doesn't feel great.
Longer term???
However, chronic stress can lead to malfunctioning of the glutamate system and reduced neuroplasticity.
https://www.frontiersin.org/articles/10.3389/fnhum.2021.722323/
Okay…so too much of a good thing is very bad.
One note…the immune system (inflammation) can just gush out glutamate when hyperactivated…more on that below (point #10).
Love this study because it speaks to the feedback operation of CBD.
They looked at CBD's effects on GABA/glutamate balance between people with autism and a control group.
First...
Preclinical evidence suggests that one aspect of the polypharmacy of CBD is that it modulates brain excitatory glutamate and inhibitory γ-aminobutyric acid (GABA) levels,
https://www.nature.com/articles/s41386-019-0333-8
They found that CBD calmed glutamate but actually increased it in people with autism specifically in the prefrontal cortex (where activity is lacking with autism).
Two different effects depend on the "state" of brain areas. See CBD and autism or CBD and glutamate to learn more.
Magnesium glycinate and NAC are also powerful protection against excess glutamate.
Now…the main stress player.
Way #7 - CBD and cortisol
Cortisol = stress.
No getting around it…what does CBD do with cortisol since it's the powerhouse behind stress response.
A few key takeaways…
First…CBD's effect on cortisol for subjects nearing their breaking point:
CBD treatment attenuated the abnormal cortisol response and reduced the acute stress-associated increase in anxiety, as measured by the STAI [8].
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8704602/
Also…
THC is known to induce stress in healthy people as demonstrated by an increase in cortisol and transient anxiety-like behavior in people with no anxiety disorders [13]. Karniol et al. reported that a single dose of CBD of 15–60 mg significantly reduced THC-induced anxiety, and CBD doses of 30–60 mg significantly reduced THC-induced tachycardia, which like anxiety is part of the stress response
So…THC can actually increase cortisol (our bet is on histamine response) and CBD counters this. The original meaning of the "entourage effect". See CBD to protect against THC.
Another study looked at CBD's effect on people who are pre-psychotic…stress response is almost breaking…while undergoing public speaking test (sounds like torture):
across the participant groups (CHR-P, CHR-CBD and HC), changes in anxiety and experience of public speaking stress (all p’s < .02) were greatest in the CHR-P and least in the HC, with CHR-CBD participants demonstrating an intermediate level of change.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7113209/
To translate…
CBD brought their cortisol levels to in between untreated (max cortisol) and control group (normal response - not pre-psychotic)!
Away from the edge!
See CBD and cortisol or CBD and stress response.
Let's go back to the start of all of this (stress response).
Way #8 - CBD and corticotrophin releasing factor
Remember that CRF starts the whole stress ball rolling.
There's a fascinating tie between serotonin and CRF. In fact, for the first two weeks of starting an SSRI (See CBD versus SSRI), CRF and anxiety can actually INCREASE!
What about CBD and our stress initiator?
Interestingly, cannabidiol at low (5 mg/kg) and intermediate doses (15 mg/kg) successfully blocked the effects induced by acute stress on corticotropin-releasing factor, pro-opiomelanocortin and glucocorticoid receptor gene expression.
https://journals.sagepub.com/doi/full/10.1177/0269881118805495
This speaks to a low-level, maintenance regiment of CBD to keep stress from exploding.
We'll discuss dosages below.
We have a whole review on CBD and corticotrophin releasing factors.
One more stop.
Way #9 - CBD and oxidative stress
All the new exciting research on stress response and anxiety centers around brain energy. In fact, check out the book by that name.
Mitochondria (our cellular power plants) are master regulators of brain function and when they go astray, bad things happen in the stress department.
One big result is increased inflammation and oxidative stress!
Literally, little oxygenated assassins…like running with scissors throughout your sensitive brain material!
This is bigger than stress.
If we don't get the whole stress complex (HPA axis) under control, it leads to damage and aging of the brain:
Hence, this study supports the emerging model that chronic stress exposure promotes oxidative damage through frequent and sustained activation of the hypothalamic-pituitary-adrenal axis.
https://pubmed.ncbi.nlm.nih.gov/23490070/
CBD there?
CBD has been shown to have potent actions in attenuating oxidative and nitrosative stress in several human disease models
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3085542/
Several models indeed.
Check out our full review of CBD and oxidative stress or CBD and mitochondria.
One final but very important note before looking at a stress regiment.
Way #10 - CBD and past trauma, infection, or…stress!
Here's the skinny…early trauma, infection, or stress can dysregulate EVERYTHING we listed above.
- GABA is downregulated
- Serotonin is downregulated
- Anandamide is downregulated
- Cortisol is upregulate
- Oxidative stress is upregulated
- Inflammation and resulting glutamate are upregulated
Goodness…your stress response is literally hijacked and you're "set" to a constant state of vigilance!
We have a whole review on editing your mental health past or how the immune system is the key to mental health.
This may speak to why some people can handle stress better than others and there are ways to "edit" these changes out of our epigenome (where it's stored).
Check out the Top 10 Tips for Stress Response with other important tools that don't build tolerance, addiction, or have nasty side effects.
Our CBD Stress Response QuickStart Guide:
