Chronic Stress and The Endocannabinoid System
Some of the physiology behind using the Endocannabinoid System to both address the symptoms of Chronic Stress and help to correct or repair the neurological plasticity after prolonged exposure.
So, I searched for recent videos on the Endocannabinoid System (ECS) and stumbled across a fascinating mini-class. Being over an hour long, it was extraordinarily different from what I’d become accustomed to between 2012-2018. Instead of the usual ECS 101-style presentation from individuals trying to sell hemp CBD online (or teach others how to), it was an accomplished Doctor of Integrative Medicine giving a room full of other doctors a PowerPoint breakdown on how to address Chronic Stress in their patients through the ECS - well, partially.
See that’s the exciting bit! Our ECS is only a single component of a much larger interconnected physiological story rather than the center of a sales pitch. I won’t pretend I understood the whole disquisition as alas I’m far from a doctor, but I went through it over and over, took diligent notes on everything concerning the ECS, studied a handful of connective issues to get a more complete picture and here we are…
Put your hands together and let's dive in.
Chronic Stress Definition: For the purposes of this article, Chronic Stress is defined as the cumulative sustained impact of irregular or maladaptive levels of Fear (a physical response to danger) and Anxiety (a psychological response to perceived danger).
The big players we’ll chat about concerning the ECS and Chronic Stress are:
Cannabinoid Receptor 1 (CB1)
Endogenous Cannabinoid Anandamide (AEA)
Terpenophenolic Phytocannabinoid Cannabidiol (CBD)
The Enzyme Fatty Acid Amide Hydrolase (FAAH)
GABA, Glutamate, Norepinephrine, and Serotonin
The Hypothalamic Pituitary Adrenal (HPA) Axis
I'd like to point out the video lecture this article is based on is among the first solid evidence I’ve found showing ECS Science taking root within mainstream American medicine. Also, when it came time for the doctor to chat about how the audience could obtain non-intoxicating cannabis high in CBD (hemp), they simply advised them to do their homework on any potential provider and take steps to ensure the plant extract is lab-tested to be free of heavy metals, mold, mildew, fungus, bacteria, harmful chemicals and solvents.
The Basic Steps of Stress
Let’s imagine you’re visiting an upscale ‘hair-raising’ Halloween attraction just for fun. Not the usual local $20 creep-show experience, but a special once in a lifetime opportunity from out of town - meaning the scare-crew really pulls out all stops for $80 a ticket. Now, you KNOW what you’re walking into isn’t actually dangerous and you’re safe - not a single patron has ever been so much as scratched (you had to sign a waiver). Plenty of panic attacks though…but what happens in the human brain during one of these experiences?
Here, hold my hand and we’ll go through the eerie basics to set the stage for our journey.
They built the haunted house in a moderate-sized two story home at the end of a dismal cul de sac at town’s edge. You have to enter via the garage, follow a neon-red line on the floor through the entire house of horrors and exit out a far side door. As the axe murderer-looking guy with the ripped and bloody ‘Staff’ shirt collects your ticket and you walk in...
Your Amygdala (contains tons of CB1 receptors) is already in a heightened state of autonomic readiness with increased levels of Norepinephrine expanding alertness, heart and lung capacity for expected oxygen needs, along with tension-communication from the gut preparing you for Fight or Flight responses.
After slowly stepping into the sinister darkness and hearing a door close behind you, sensory nerves throughout your body begin passing perceptions of serious potential environmental threats coming from multiple directions. The Amygdala kicks your Hypothalamus (also contains CB1 receptors galore) into gear.
The Hypothalamus directs neurosecretory cells to secrete and send Corticotropin-Releasing Hormone (CRH) to the Anterior Pituitary Gland (yep, CB1 receptors here too) which then releases Adrenocorticotropic Hormone (ACTH) into your bloodstream telling Adrenal Glands (yep, more cannabinoid receptors) to begin Cortisol production. It’s going to be roughly ten minutes before your body produces the Cortisol needed to tap into glucose energy via protein stores in the liver increasing blood sugar.
Thing is, within about 3 or 4 minutes from the door shutting you start getting genuinely freaked. The brain understands you might not have ten minutes to spare for glucose energy, so when the insane demon-child waves a fake (real-looking) knife and maniacally shrieks right next to you out of nowhere, the Hypothalamus instantly sends chemical messengers and nerve impulses down the spine that cause your involuntary defensive physical reactions and boom, more Norepinephrine is dumped instantly because it’s so readily available to fuel a huge laundry list of physiological processes.
By the time you get through it all, there’s such a neurochemical cocktail floating through your systems it’s no wonder people get addicted to Chronic Stress symptoms - adrenaline junkies. For those with Chronic Stress, it gets serious fast because it means you’re always producing heightened levels of FAAH, Glutamate and Norepinephrine.
The three primary goals of approaching Chronic Stress through the ECS are to:
Target foundational sources of Chronic Stress within the Amygdala.
Further address HPA Axis to decrease Norepinephrine and CRH which lowers FAAH.
Raise Anandamide levels to help lower Glutamate.
An overarching feature of this process has to do with the release of Norepinephrine from synaptic vesicles with stores inside many areas of the brain including the Thalamus, Amygdala, Hippocampus, and Hypothalamus.
Let’s address this component first.
CBD & Norepinephrine
While plant-based CBD has little specific binding affinity to CB1 or CB2 receptors, it’s employed like a free agent of homeostasis control like its endocannabinoid counterpart 2-AG. Through a number of retrograde neural mechanisms, it can safely reduce measured Chronic Stress and overall Norepinephrine production. In this way CBD supplementation is not only a clinically-backed anxiolytic but an anti-inflammatory agent with almost no equal in the plant world.
This is critically important because it’s widely known:
“Chronic Stress damages the body over time through sustained norepinephrine release... its function causes the body to direct resources away from general maintenance, generation, and reproduction. Instead, the focus is on active movement [ADHD symptoms for example], and the consequences can include sleeplessness, libido loss, gut issues, impaired disease resistance, slower rates of healing, depression, and vulnerability to addiction.” 
The other issue is inflammation as a result of how much cellular damage can be taking place. If compounded by an ECS deficiency like we’ll explore below in the Amygdala and HPA Axis, the entire cycle gets continuously worse leading to more serious Fear & Anxiety issues.
2 Core Signs of An ECS Deficiency
Low levels of synthesized AEA and 2-AG (potential for cannabis supplementation).
Level of FAAH enzyme too high (potential for CBD supplementation to lower).
CB1 & The Amygdala: Better GABA Modulation
One primary role cannabis-CBD supplementation plays in modulating stress is by decreasing FAAH, the enzyme the body uses to breakdown AEA. This is fortunate, because AEA (and CBD to a lesser degree) can be employed by the ECS to bind to CB1 receptors within the Amygdala to stabilize Serotonin levels, while modulating inhibitory (GABA) and excitatory (Glutamate) action potentials being sent to the Hypothalamus.
Anyone that’s ever put a tiny amount of hemp-cannabis concentrate - full spectrum, organic plant extract - under their tongue during a panic attack quickly feels a reduction in the impacts of serotonin/norepinephrine on the autonomic nervous system: heart rate slows, less emotional, blood pressure goes down, less involuntary muscle movement, less tension in the gut, etc. Starting in the Amygdala for our discussion, endocannabinoid AEA acts as dimmer via CB1 receptors - less Cortisol production orders (smaller spike in blood sugar) and a calmer disposition!
Supplementing with cannabis CBD improves this overall ECS function.
Quick refresher on this critical area of the brain:
“The amygdala is comprised of at least 13 different subnuclei, the most clearly defined of which are the central (CeA), the basal (BA) and lateral (LA) nuclei. The CeA regulates many aspects of the fear response, including regulation of the release of cortisol through the paraventricular nucleus of the hypothalamus, increase in startle response via the midbrain, and modulation of the autonomic nervous system through the lateral hypothalamus. Lesions of the CeA eliminate fear conditioned responses, such as fear-potentiated startle and freezing in rodents. Thus the CeA can be thought of as the primary output or effector region. The BA and LA are involved in the learning or associative processing within the amygdala.” 
Where are CB1 receptors within the Amygdala? For that we can turn to this international 2001 research conducted by scientists in Hungary, Brussels, and America:
“Here we report that CB1 cannabinoid receptors are expressed at high levels in certain amygdala nuclei, especially in the lateral and basal nuclei, but are absent in other nuclei (e.g., in the central nucleus and in the medial nucleus). Expression of the CB1 protein was restricted to a distinct subpopulation of GABAergic interneurons corresponding to large cholecystokinin-positive cells.” 
Wait, but what does that mean if there aren’t any CB1 receptors in the CEA, which they told us above regulates many aspects of the fear response? Don’t worry, we’ve only scratched the surface of complexity here because, again, I’m no doctor! However, the researchers posited this as a followup:
“The aversive or appetitive nature of a sensory stimulus is processed in part by the basolateral [BA + LA] complex, and afferent inputs from these nuclei to the central nucleus constitute an important pathway in the induction of different kinds of emotional responses (Everitt et al., 2000). Interestingly, recent findings have revealed that GABAergic neurons of the so-called intercalated nuclei may serve as an important intermediate station in this pathway... thus, by reducing the inhibitory tone on basolateral amygdala pyramidal cells, cannabinoids may indirectly enhance the activity of GABAergic cell population in the intercalated nuclei and thereby inhibit neuronal activity in the central nucleus.”
Put another way - better GABA regulation. GABA is made from Glutamate, which we’ll get to in a moment. For now, in contrast to excitatory neurons, GABAergic neurons are inhibitory and characteristically release neurotransmitters Gamma-Aminobutyric Acid (GABA) and glycine. So again, supplementing with either psychoactive (contains THC & CBD in variant ratios) or non-intoxicating (little to no THC, CBD-dominant; typically classified as hemp) cannabis can help reduce FAAH and increase AEA for better modulation of inhibitory/excitatory action potentials = less Chronic Stress.
CB1 & the HPA Axis: Decrease CRH & FAAH
Our focus here is on the production of Corticotropin-Releasing Hormone (CRH) by the Hypothalamus, considered a major excitatory neurotransmitter. With ‘normal’ balanced amounts we experience productive levels of attention (learning), memory recall, and alertness. However, too much results in excitotoxicity which is directly responsible for destroying neurons and neuronal death. With more CRH, comes more FAAH, which means less endocannabinoids like AEA and 2-AG to modulate the situation and return to homeostasis via cannabinoid receptors.
Note: Cannabis-CBD supplementation decreases both, while increasing levels of available endocannabinoids.
Raise AEA to Lower Glutamate
Higher levels of CBD/AEA means less Glutamate. Again, when GABA/Glutamate production is balanced it’s a very good pro-survival situation. When out of balance due to Chronic Stress, prolonged exposure to glutamate like norepinephrine...as the doctor put it in their presentation:
Chronic High Glutamate = Brain on Fire! Neuronal Cell Death
So, the higher your stress response (remember, stress is also cumulative), the more CRH production, thereby lowering AEA which leads to higher Glutamate. For those with Chronic Stress this means their brains/systems are constantly being proverbially set ablaze, then chronic inflammation sets in and weakens the immune systems, among others.
Here’s a basic visual showing how the ECS uses AEA in the overall scheme:
CBD & Chronic Stress Plasticity
The last part I’d like to bring into view here has to do with what’s called plasticity. In those dealing with Chronic Stress, over prolonged exposure the brain has basically carved a path of least resistance so that the Amygdala can quickly respond to the same kinds of stimulus over and over again.
It’s an adaptive nature of our brains, getting programmed to ‘Go to Stress - Fear/Anxiety’ after the Amygdala is constantly being hit by Norepinephrine and Cortisol, and the HPA Axis is taught to churn out CRH. The good news is that this kind of plasticity is changeable; malleable. Through boosting the ECS new paths can be carved so typical Chronic Stress stimulus is better managed (this includes memory recall of stressful or traumatic events; i.e. PTSD).
Conclusions: The ECS & Chronic Stress
In general, phytocannabinoid supplementation boosts the ECS’s ability via CB receptors to modulate overall norepinephrine release via Amygdala and HPA Axis.
CBD-rich cannabis can boost available AEA levels by inhibiting FAAH production.
Less stress leads to lower cumulative amounts of CRH and glutamate in the system via increased AEA levels.
ECS supplementation can also lower Cortisol levels as well, improving overall blood sugar along with reducing negative impacts of concentrations in the brain and body.
Our endocannabinoid 2-AG and it’s mimetic plant-equivalent CBD have been shown effective in disrupting stress-induced plasticity in the brain and helping people re-learn more positive stress responses.
Wow! For those still with me after all that, I hope I did a solid job of making it flow. We’re talking about so many different intertwined systems, neurotransmitters, and neurological processes...but, my goal was to highlight some of the specific ways cannabis supplementation of the ECS can not only treat symptoms of Chronic Stress, but help correct the plasticity that sets in (along with inflammation) after prolonged exposure. In essence, you’re helping the ECS modulate Norepinephrine, Glutamate, CRH and FAAH while protecting it from overexposure.
“Endocannabinoids are the molecules released in our bodies in response to diverse stress stimuli such as injury, temperature change, pathogens, toxins, emotional stress, etc. They have a strong protective role, functioning as guardian molecules, protecting us from the physiological consequences of stress. But if the stress persists over a longer period of time, our defense mechanisms become down-regulated, i.e. weakened, leading to depression-like symptoms. Endocannabinoids (as well as phytocannabinoids) influence the biochemical machinery involved in how we process stress and emotions.” 
And thus our the new developing ECS-based approach to treating Chronic Stress and approaching these issues through that prism instead of the conventional methods of attempting to attenuate Chronic Stress by targeting specific transmitters like serotonin or dopamine.
If you find anything confusing, or perhaps I mis-stated or understated a certain point, please don’t hesitate to leave a comment and I’ll make appropriate iterations.
Thanks for your time.
 "Stress and disorders of the stress system."Chrousos GP, Nature Reviews Endocrinology, 06/02/2009.
 "Amygdala Activity, Fear, and Anxiety: Modulation by Stress" Kerry J. Ressler, Biological Psychiatry, 06/15/2010.
 "Distribution of CB1 Cannabinoid Receptors in the Amygdala and their Role in the Control of GABAergic Transmission" Istvan Katona, Ede A. Rancz, et al, The Journal of Neuroscience, 12/01/2001.
 "The pursuit of happiness and what cannabinoids have to do with it." Tanja Bagar, Fundacion Canna.