We could all use some backup here these days.
Brain pathways of resilience are very fascinating and actually accessible but the areas may be surprising.
We're going to drill down into these areas and look at ways to support them.
There's amazing research on how early trauma/infection (even in utero) can directly affect our resilience later in life.
We'll look at how to unwind this effect which primarily operates in the immune system and our epigenome (where our environment affects our genetic playbook).
The downstream effects then percolate through stress and neurotransmitter pathways.
We're going to look at these pathways as a cascade.
Think of a set of dominos that fall as each system is overwhelmed which then pressures the next system.
The systems in question:
- GABA - the brain's brake pedal and buffer from stress
- Serotonin - powerful stress response buffer
- Anandamide - backup stress buffer tasked with balancing other systems
- Acetylcholine - your "calm and focus" player with key ties to the gut via the vagus nerve
Yes, we're complicated and there are other areas that drive our basic resilience such as steroidal hormones, gut inflammation states, basic nutrients, genetics, and more. We'll touch on those as well.
We want to focus on the main drivers of resilience and most importantly, ways to bolster our response to stress.
Okay, here are the topics we'll cover to get to the bottom of how to support resilience:
- An intro to the pathways of resilience (the stress cascade)
- The GABA pathway and resilience
- Serotonin and resilience
- Anandamide and resilience
- Acetylcholine and resilience
- How to support resilience
Let's get started!
An intro to the pathways of resilience (the stress cascade)
Resilience is really the ability to handle stress well. Period.
Sure, there are many definitions of resilience and lots of inspiring quotes but in terms of our body, it's all about stress.
Stress is not the enemy. It's important to our survival and even our ability to function.
Resilience is the ability of our body and brains to address stress and re-balance from it.
Let's first introduce the stress side of things.
There are key players in this "cascade" as well:
- CRF - corticotropin-releasing factor - hormone trigger for stress response
- Cortisol - the main hormone which drives stress
- Epinephrine (adrenaline) - the fight or flight player
From this stress pathway, other systems come into line - remember that stress may be life-threatening so all hands on deck.
The neurotransmitters then ramp up with two big ones:
- Glutamate - the brain's "gas pedal"
- Histamine - key to an allergic reaction but also excitable in the brain (and body)
Inflammation is also part of the equation since it ramps up with stress.
Inflammation is the fight and repair pathway and if stress is being triggered, there's the potential for danger and injury.
Call in the army (inflammation) to get ready!
This is really important and it's a big way that prior trauma/infection can affect our resilience today.
No one is talking about this. We will!
The immune system is the future of mental health (more here) so any discussion without addressing this is…old hat. We'll cover that below.
So….stress occurs. Let's look at the domino's falling.
- CRF is released first and this starts the whole ball rolling.
- Cortisol is then triggered and acts as our primary stress hormone
- If severe enough, epinephrine ramps up as part of the fight or flight pathway
Stress is supposed to be short-term. After the "danger" has passed, these pathways should slow down.
The brain is all about opposing forces and the other side (the side of resilience) can generally manage stress and move on.
This is the GABA, serotonin, anandamide, and acetylcholine (among others).
Here's the key point…our resilience lasts as long as these players do.
Meaning…when they're exhausted (short term or from chronic stress), our resilience drops.
We can't always change stress but we can look at these resilience players and even support them WITHOUT tolerance.
Let's introduce your best friends for resilience below.
The GABA pathway and resilience
Think of GABA as our first line of defense against stress. It's the right here and now form of resilience.
GABA is our nervous system's "brake" pedal. The most important thing to know is that it directly opposes cortisol (our stress hormone), histamine (allergy and excitatory), and glutamate (the "gas pedal" and ramp-up of nervous activity).
You can think of all of those as "gas" pedals in different pathways (stress, immune, excitability).
GABA is a major player holding back the dam.
We have a huge review on GABA here and just a sidenote…benzos and alcohol are both drivers of GABA (but with tolerance and addiction).
A study looked at GABA and resilience specifically in the context of stress within a critical brain area called the habenula:
the expression of GABA(B) receptors, including both GABA(B1) and GABA(B2) subunits, was significantly down-regulated in the LHb of the susceptible mice.
So…less GABA, less resilience to stress.
The habenula is fascinating. We looked at it in detail in our panic attack review.
All you need to know:
A tiny part of the brain can keep track of your expectations about negative experiences—and predict when you will react to an event—researchers at University College London say.
It essentially predicts…dread!
As for the stress hormone:
GABA reduces the secretion of corticoliberin (corticotropin-releasing hormone, CRH), which triggers a series of consecutive hormonal changes, leading to secretion of cortisol by the adrenal cortex
That's the cascade of stress!
GABA opposes histamine in a delicate balance as well that governs the sleep/wake cycle (with cortisol as well).
Then there's glutamate and inflammation. GABA's primary opposing force is glutamate and too much glutamate is toxic.
As the imbalance goes up, you may see anxiety, and insomnia. Then agitation, irritability. Excessive levels of glutamate and you can have seizures.
We have a full review of glutamate here but resilience falls when glutamate is excessive.
It starts with the feeling of being "frazzled" or "janky". We've all been there.
Again, GABA and glutamate are worker bees…the two most prevalent neurotransmitters in the brain.
Once that first dam falls and resilience begins to crack, we have to look at longer-term players.
Serotonin and resilience
Serotonin is the master regulator of ALL human behavior. Yes. All.
Stress, pain, trauma, etc can all exhaust serotonin.
As for resilience, look no further than recent gene studies:
Studies of polymorphic traits of the serotonin transporter gene SLC6A4 and receptor genes have led to several discovOur focus is on its role as a stress buffer.eries regarding the effects of gene × environment interactions on resilience.
Translation…more serotonin function…more resilience.
Luckily there are ways to support serotonin without tolerance (SSRIs build tolerance with time which reduces your natural serotonin pathway).
In the end…serotonin shapes how you will respond to stress across all pathways:
The brain serotonergic system plays a key role in coordinating autonomic, behavioral and neuroendocrine stress responses.
Goodness. That's fight or flight (autonomic). Behavioral (brain area). And hormonal (cortisol, etc).
The bigger secret to serotonin for long-term resilience is BDNF.
BDNF is our brain's fertilizer. When low, our brain becomes less connected, robust, and able to repair and grow in response to the damage of stress.
Especially in key brain areas like the hippocampus (key to mood management):
Resilience to chronic stress is mediated by hippocampal brain-derived neurotrophic factor
For long-term resilience, BDNF is your new best friend. Exercise, mindful meditation, psilocybin, CBD, and other tools abound. Serotonin drives BDNF so support there is crucial.
More on that below.
If our short-term and long-term resilience players start to fail, call in the backup!
Anandamide and resilience
Anandamide is one of two key players in the endocannabinoid system which we all have.
It's named after the Hindu goddess of bliss, Anand.
The body makes anandamide as needed and breaks it down almost as quickly.
It's a stopgap when stress is overwhelming the main players.
The endocannabinoid system is really a key player in resilience.
After all, it's tasked with balancing other systems when they're impacted by stress:
- Nervous system - neurotransmitters like GABA, serotonin, glutamate, etc
- Endocrine system - hormones such as cortisol and CRF
- Immune system - inflammation, BDNF, and cellular birth/death cycles
The key is righting the ship after it's stretched from stress:
Specifically, under conditions of acute stress, the eCB system plays an important buffering role by limiting the magnitude of the stress response and facilitating recovery to basal function after cessation of stress exposure
In fact, when researchers block FAAH, the substance that breaks down anandamide, look at the results:
URB597 treatment induced behavioral changes indicative of a shift towards active coping with challenges.
Our favorite part:
This behavioral change appears compatible with the previously suggested role of endocannabinoids in emotional homeostasis.
"Homeostasis" means balance. Emotional balancing. Goodness.
That's anandamide's primary role in terms of resilience and it's a key safety valve when stress is starting to erode our primary buffers.
Okay…let's take a quick detour from hormones and neurotransmitters…deeper into the autonomic systems around resilience.
To the vagus nerve!
Acetylcholine and resilience
Acetylcholine is the primary driver of the "rest and digest" part of our autonomic (not under our conscious control) nervous system.
This is opposite of the fight or flight. Sound relevant for response to stress and resilience?
Acetylcholine can be thought of as the "calm and focused" player in the brain and nervous system but its roots run much deeper.
The vagus nerve sits right behind your lower breastplate and it's a fascinating hub between the brain and the gut…the largest concentration of neurons outside our skull.
Our second brain!
The vagus nerve (named after the "wanderer" since it branches out across the body) is a primary source of acetylcholine.
What comes to mind when you think of resilience.
Calm. Collected. Able to think clearly. That's acetylcholine!
It's also why so many people self-medicate with nicotine which plugs right into the acetylcholine receptor.
See our full review on acetylcholine or the vagus nerve (must read!!!).
- What about resilience?
- Cholinergic signaling in the hippocampus regulates social stress resilience and anxiety- and depression-like behavior
There's that hippocampus again.
The hippocampus is especially vulnerable to the stress pathway.
As the seat of memory, it's very malleable but this flexibility also makes it prone to outright damage from cortisol, glutamate, inflammation, and trauma.
Back to the vagus nerve…is there a connection?
Treatments that target the vagus nerve increase the vagal tone and inhibit cytokine production. Both are important mechanism of resiliency.
Let's take one more detour which is incredibly important for people who find their resilience lacking.
Early trauma and infection's effect on resilience
We have a whole review on the mechanisms behind early (even in utero) trauma/infection and the entire pathway of resilience.
A quick recap.
Early infection or trauma (the immune system "records" both) can directly downregulate GABA, serotonin, BDNF and upregulate glutamate and inflammation.
Read that back over. We just laid out how early trauma/infection can make a person more susceptible to stress.
Any pathway above that we looked at is affected.
The literature abounds:
Childhood adversity was associated with reduced adjustment, social support, and resilience.
Changes in threat-related social and emotional processing and accelerated biological aging serve as transdiagnostic mechanisms linking childhood trauma with psychopathology.
To translate…with early trauma, our "vigilance" goes up and this is…stressful.
Get ready to get blown away…it's not just trauma.
Infection is a big one:
Men and women exposed in utero to abnormal levels of pro-inflammatory cytokines and to an imbalance of pro- to anti-inflammatory influences showed dysregulation of stress response circuitry 45 y later, with sex-dependent effects.
Again, the immune system responds to both infection and trauma. The future of mental health is the immune system (more here).
We go into the actual components and research in the big studies referenced but we clearly need to re-balance the immune system (brain and gut inflammation) if we're going to give resilience a fighting chance.
Speaking of fighting, let's put the gloves on.
How to support resilience
A few rules before we start.
We absolutely must stay away from anything that builds tolerance.
It's the enemy long-term and almost everything out there will eventually cause the body to push back (and go backwards).
You would be surprised at how many meds and supplements fall under this category.
Secondly, our tools should have a pretty spotless side-effect profile. Otherwise, we're upending some other key pathway.
Based on that, here's the list of tools outside of behavioral effects (which we'll comment on after):
- Magnesium glycinate
- CBD isolate
- CDP Choline
- Medicinal Mushrooms
- Steroidal hormone support (including Vitamin D)
Let's get started!
Magnesium glycinate and resilience
We love mag! It basically took away our migraines (a GABA/glutamate excitability imbalance) and is great for sleep and anxiety.
It's a huge supporter of GABA when low.
We have a whole review of mag here but essentially, it's a stress response buffer in mineral form.
In the modified intention-to-treat analysis (N = 264 subjects), both treatment arms substantially reduced DASS-42 stress subscale score from baseline to Week 8 (Mg–vitamin B6, 44.9%; Mg 42.4%);
A 45% reduction in stress effects!
It's estimated that 75% of people are meeting daily requirements since mag is usually absorbed via soil bacteria into our food. The bacteria aren't there due to pesticides and mono-crop farming.
Worse yet, stress causes the body to dump out magnesium via the kidneys (in urine) and this creates a vicious cycle:
This overlap in the results suggests that stress could increase magnesium loss, causing a deficiency; and in turn, magnesium deficiency could enhance the body’s susceptibility to stress, resulting in a magnesium and stress vicious circle.
In times of emotional of physical stress, magnesium is a must.
The "ates" such as magnesium glycinate cross the blood-brain barrier much better. Threonate is a runner-up.
I take 100mg 3 times daily and if I feel a migraine coming on (always stress induced).
You know it's too much if the gut is moving too fast since it's a natural laxative.
No tolerance. Just great resilience support.
There's a great review of the process here.
This is the mag we use based on quality and cost.
CBD isolate and resilience
CBD isolate affects all the pathways above and does it in a very specific way.
CBD supports our endocannabinoid system (where anandamide works) as a feedback mechanism.
This is critical and we can look at its cousin, THC, as a contrast.
THC imitates anandamide but it pushes too far and for too long (hence the side effects, high, and eventually…tolerance).
CBD doesn't build tolerance. It's technically called an allosteric positive modulator with supportive effects on:
- Serotonin (and hence, BDNF)
- Glycine (backup to GABA)
So short term, CBD supports GABA and anandamide.
Longer-term it, supports serotonin and calms gut and brain inflammation (even the vagus nerve).
No tolerance, addiction, or high.
We focus on CBD isolate versus full-spectrum since they can have such different histamine responses and histamine is excitatory (eats up GABA) in the brain.
Learn more about CBD and anxiety here.
Peak neurogenesis is around 300mg daily, but the range is generally from 100mg to that level.
This is the CBD level that addresses that range here.
Let's now move into the longer-term immune response piece we touched on above.
Berberine and resilience
Berberine is a fascinating analog for metformin (without the b12 rip and other issues).
Our focus with berberine is on the gut and inflammation.
One example of the research (much more here)
It has powerful effects on the microbiome which is the new direction in research on mental health.
recent studies show that berberine has a protective effect on central nervous system disorders, such as Alzheimer's, cerebral ischemia, mental depression, schizophrenia, and anxiety
The gut is a key player in brain inflammation states and berberine offers a way to calm this entire axis with no tolerance and a strong safety profile.
The effects on longevity pathways AMPK and mTOR are just added benefits (see AMPK to learn more).
Full review here. This is the one we use here.
Immune remodeling takes time so this is longer-term (2-3 months).
Another powerful player in this area next.
We have a master review of medicinal mushrooms and mental health.
Different species directly drive a range of pathways mentioned above:
- GABA production in the gut
- Brain inflammation
- Brain growth factors like BDNF
- Serotonin balancing
Some of these effects are in the gut and radiate up to the brain via the vagus nerve while others cross the blood-brain barrier and operate there.
The immune system is the key to our focus here though.
Just one example of just one species:
Reduction of depression and anxiety by 4 weeks Hericium erinaceus intake
That's the lion's mane which can support neurogenesis in the hippocampus.
We cover the biggest species here and we attempt to get exposure to all the large ones.
Again, it takes 4-6 weeks to kick in so this is a longer-term tool.
Let's turn to the autonomic nervous system (rest and digest) now.
CDP Choline and resilience
We've focused on the immune system and neurotransmitters.
Most sources don't focus on the autonomic nervous system where acetylcholine functions and that's a real disservice.
The long covid research is really pointing to the vagus nerve as a source of both heart palpitations and anxiety as a result of inflammation there.
That's the hub for acetylcholine. Is there a way to support this pathway directly?
First, check out our review of the vagus nerve as there are many ways to provide backup (some of them, downright weird).
CPD choline is a supplement we can take directly to support our pathway if you're not eating eggs (huge source of choline).
The lowest choline quintile was significantly associated with high anxiety levels (odds ratio: 1.33; 95% CI: 1.06, 1.69) in the fully adjusted (age group, sex, time since last meal, educational level, and smoking habits) logistic regression model.
Panic attacks are even more tied to choline deficiency which makes sense given the rest and digest offset to fight or flight (literally panic response).
We use this one here and the full review on acetylcholine is here.
One last stop. Maybe the most important depending on age.
Steroidal hormone support (including Vitamin D)
Get past the thought that estrogen, progesterone, and testosterone are about reproduction, libido, and muscle building (respectively).
Every cell in your body has a receptor for each of these (whether male or female).
Especially the brain!
- Estrogen and testosterone drive serotonin (and BDNF as a result).
- Progesterone drives GABA
They all manage the immune system (inflammation) and the ability to repair and replenish in the nervous system.
Our founder learned the hard way about this in her late 40's when estrogen went into a tailspin and rolling panic attacks and 24-hour anxiety was the result.
Benzos, SSRIs, and a range of heart meds just made things worse.
Get your levels tested and support with bioidentical hormones if deficient.
Our entire metabolic profile (cholesterol, glucose, etc) all improved as a result.
Vitamin D is actually a steroid and many people are deficient. Get your levels tested and support as needed.
Find a naturopath, get tested, and support!
There's no band-aiding loss of steroidal hormones.
Otherwise, we have a full range of tools above to support your stress response system.
We left off psilocybin but have a full review here as it's going to be a monster in the mental health space and resilience specifically.
It's a master at removing the artifacts from trauma/infection and newer research is showing genes tied to the immune system are front and center.
Be well. Take care of each other. Take care of yourself!
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.