Covid. Ukraine. Your mother-in-law. Can we please get some relief!?!?
It's estimated that 20% of people (probably higher) are currently dealing with anxiety and the number goes up for children.
Benzos are a nightmare (tolerance, addiction, black box warning). SSRIs also build tolerance and can push serotonin too high.
There are dozens of so-called anxiety remedies with very little research, shiny pitches, and a range of side effects (hello, histamine!).
We do have pretty good research on available options that don't build tolerance, won't send you down addiction and withdrawal alley, and avoid the side effect profile of many herbs.
Yes. please.
First, an introduction to the enemy! Just so you know we mean (research) business.
What drives anxiety?
Anxiety can be thought of at different levels:
- Brain areas not communicating correctly
- Neurotransmitters exhausted or insufficient
- Too many assaults in the form of inflammation, oxidative stress, gut imbalances, histamine, glutamate, stress, etc.
This is a hierarchy if you will.
Meaning, if we can have constant stress (cortisol) as an input, it will exhaust GABA (our brain's "brake" pedal) and with enough time, this will upset the hippocampus (mood manager) and hyperactivate the amygdala (fear and emotional control) while exhausting the prefrontal cortex (rational manager of our emotional response).
Stay with us, we'll dig deeper but it's really important to understand why anxiety happens if we're going to find safe tools to stop it.
So…
Three levels:
- The input (assaults and mother-in-law)
- The messenger (neurotransmitters losing balance)
- The brain's response over time (atrophy and heightened fear response)
Goodness…we're going to need to break that down.
First, the players with anxiety:
- GABA is the "here and now" player. Target of benzos (highly addictive with a side of tolerance)
- Serotonin - stress response buffer and manager of our secret weapon, BDNF (target for SSRIs which build tolerance)
- Amygdala - fear response area can become too strong and overwhelm the rational player…
- Prefrontal cortex - right behind your forehead; keep our fears in check!
So, in the short term, we want to support GABA
- Longer-term, we want to support serotonin (manager of ALL human behavior)
- Longer-longer term, we want to support BDNF to repair, rewire, and regrown brain connections
While doing all this, we want to ratchet down the damaging side. Otherwise, we're fiddling while our anxiety burns.
Stress is obvious. The others need an intro, please.
The new exciting research on mental health all centers on the immune system. Yes, Mother Nature likes to multitask!
The immune system literally manages your brain's ever-changing architecture.
More importantly, the immune system can get hyperactivated. A big cause of this is trauma, stress, or infection, especially during times of brain development (even 3rd-trimester in-utero).
As a result, the brain will upregulate inflammation (immune response) and downregulate GABA and serotonin!
See the connection!
Glutamate is our brain's "gas" pedal and it can also get turbocharged as our immune system's sentinels called microglia can literally spill it out when too fired up.
Glutamate is toxic to nerves when too high and it exhausts GABA!
The pieces are coming together now.
Histamine (key to allergic response) is also excitatory and part of our immune system. It directly opposes GABA in the sleep/wake cycle. The first class of anti-anxiety meds (like hydroxyzine) were actually…anti-histamines!
Ladies…progesterone keeps your immune response under check and it drops by 50% at age 40. Just sayin'
Oxidative stress is just another type of inflammation…a sign that our calming and detox pathway (glutathione) are taxed.
Why bring in the gut? The gut acts like a thermostat of inflammation across the body and directly to the brain via the vagus nerve (right below your lower breastplate).
If the gut has issues, the brain has issues. It also makes a great deal of our serotonin and even GABA. The bacteria (microbiome) actually do this for us…when they're in good shape.
So…that's the landscape…what can we do about it? Safely??
Safe tools to combat anxiety
First, we're going to focus on tools that don't build tolerance since it's the enemy #2.
Tolerance is when substances push a pathway up or down in one direction.
The body doesn't like this and pushes back the other way which means your natural pathway gets weakened over time.
This is why there are such brutal withdrawals for benzos (see benzo review) which pumps up GABA temporarily and SSRIs (see SSRI review) which pumps up serotonin.
Both build tolerance as do many medications and even supplements.
So…no tolerance or addiction is critical.
Based on that, here's the toolkit to knock back anxiety:
There is extensive research at each of those links with dozens of NIH studies but a quick recap (it's hard to deepdive when anxious…we know!!).
Magnesium Glycinate and anxiety
Mag is amazing and so many people are deficient. We primarily get mag from bacteria/fungi in the soil that transport it from the soil to our food BUT…
Pesticide and monocrop farming has disrupted that conveyor belt.
To make things worse, mag is dumped from our bodies (via urine) in times of stress!
Mag directly supports GABA and acts like a stress response buffer in the brain.
Magnesium status is highly associated with stress levels, with both stress and hypomagnesemia potentiating each other’s negative effects.
https://www.ncbi.nlm.nih.gov/books/NBK507250/
Only certain types of mag can cross the blood brain barrier and the "ates" are best at this.
Magnesium glycinate is one of the best plus it has glycine attached which is a supporting "brake" pedal in the brain. Great for sleep as well!
Mag can work very quickly as people with migraines can attest to and 3-4 at 100mg daily spread out is ideal.
You know you have too much mag if things start to move too quickly in your gut since it's a natural laxative.
NAC and anxiety
Longer term, NAC is critical for the brain.
It acts like a sink for excess glutamate which gives GABA a breather.
It also supports our primary detox system (glutathione) which is why it's so important (and popular) in the time of long covid.
There's a tremendous amount of research on NAC and the entire spectrum of mental health as oxidative stress is such a destructive element and glutathione calms the storm in the brain.
You can see this effect on excitability balance across a range of hyperexcitability issues:
On a clinical level, in day-to-day work with patients, NAC seems to help with ruminations, with difficult-to-control extreme negative self-thoughts. Such thoughts are common in depression and anxiety disorders, and also in eating disorders, schizophrenia, OCD, etc.
NAC builds over time (generally 2-3 months) so this is about taking pressure off of GABA, serotonin, and allowing brain communication to function without the static of oxidative stress.
NAC is about righting the long term ship where mag is fast and also builds up.
3 x 600mg daily is a higher dose (but safe) commonly referenced in research.
This is the one we use here.
CBD Isolate and anxiety
We have a massive review on CBD isolate and anxiety here.
CBD is both fast and slow based on different pathways.
CBD isolate supports GABA and serotonin in a feedback mechanism (supports when low) which avoids the tolerance piece.
THC, CBD's cousin, mimics anandamide (at the CB1 receptor) but it hits too hard and stays for too long…so we're back to tolerance (and the side effects with THC).
CBD slows down FAAH which eats up anandamide. More subtle so…
- No tolerance
- No addiction
- No "high"
GABA is the "right now" effect while serotonin builds over 14 days since the real star is BDNF.
BDNF is our brain's fertilizer and it's key to brain repair, rewiring (very important for addiction), and growth.
This speaks to the communication between brain areas and the all important hippocampus (mood controller) which is very vulnerable to stress and other insults.
Serotonin drives BDNF so CBD's support there builds over time! Literally building brain!
Then the assaults!
- Stress - CBD calms cortisol and the trigger of stress called CRF
- Inflammation - CBD calms brain inflammation including microglia hyperactivation
- Oxidative stress - CBD is a more powerful anti-oxidant than Vitamin E or C
- Gut issues - CBD calms gut inflammation and protects the gut barrier
- Glutamate - CBD helps balance the brain excitability balance
- Histamine - CBD calms mast cell release of histamine when excessive
All the research is on isolate (CBD by itself). Full spectrum can actually trigger histamine response which eats up GABA.
A large double-blind, placebo study on CBD for sleep/anxiety:
Anxiety scores decreased within the first month in 57 patients (79.2%) and remained decreased during the study duration.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6326553/
100mg daily is a good start and peak neurogenesis (the BDNF pathway) is 300mg daily, all safe in research.
Let's go down south now.
Berberine and anxiety
The gut is critical to our brain, especially in terms of inflammation.
Why bring in the gut? The gut acts like a thermostat of inflammation across the body and directly to the brain via the vagus nerve (right below your lower breast plate).
If the gut has issues, the brain has issues. It also makes a great deal of our serotonin and even GABA. The bacteria (microbiome) actually do this for us…when they're in good shape.
Berberine is a natural analog for metformin (the longevity wonderdrug) which directly balances gut inflammatory states and supports the gut barrier.
Remember…a great deal of our neurotransmitters are made in the gut and berberines effect:
It is worth noting that berberine regulates biogenic amines in a concentration‐dependent manner. At a low dose, berberine (10 and 20 mg/kg) is effective in depression by increasing levels of NE, 5‐HT and DA
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6307759/
5-HT is serotonin. DA is dopamine. NE is adrenaline.
As for anxiety??
Berberine ameliorates ovariectomy-induced anxiety-like behaviors by enrichment in equol generating gut microbiota
https://pubmed.ncbi.nlm.nih.gov/33493658/
Translating Klingon:
Berberine calmed anxiety after ovary removal (estrogen drives serotonin and progesterone drives GABA) by adjusting the gut bacteria which make our neurotransmitters!
It's our second brain after all (site of most neurons outside of the brain).
Finally, resetting the immune system.
Medicinal Mushrooms and anxiety
The future of mental health including anxiety is the immune system.
A recent study on psilocybin (magic mushroom) which is about to transform mental health, showed that the longer term effects for mental health were actually due to DNA being turned on/off for…immune system genes in the brain!!
In the meantime, we have a range of mushrooms that have been shown to rebalance our immune system and inflammatory states!
Different mushrooms affect different pathways from GABA, to serotonin, to BDNF and all the insults mentioned above.
For example…
Two chemicals in Lion's Mane appear to be the key to its neurotrophic abilities with the following results:
They found that H. erinaceus significantly reduced depression and anxiety, as well as improvement on sleep disorders after 8 weeks of oral administration. The observation was linked to an increase in peripheral pro-BDNF and in the pro-BDNF/BDNF ratio.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6982118/
Neurotrophic just means building back brain better.
Then, there's Reishi, a superstar of GABA support!
Studies there:
The results showed that the methanol extract of G. lucidum at a dose of 200 mg/kg, administered orally, shows a significant increase in the average time spent in the open arms of the EPM when compared with the control; this was comparable to the effect of the standard drug (diazepam, 2 mg/kg by mouth).
https://pubmed.ncbi.nlm.nih.gov/28008811/
We have tons of research here.
Rather than try to source all these different mushrooms, we use the Community Blend one here from Stametz (from the must-see Fantastic Fungi Netflix doc).
Mushroom effects will build with time
Okay…we have our laundry list for anxiety ass-kickers.
The key points:
- No tolerance
- No addiction
- No withdrawals
- No rebound anxiety
These actually calm histamine which brings us to the many items not on the list.
There are dozens of supplements touted for anxiety.
L-theanine. Valerian root. Etc.
These may work for some people but they can also cause the immune system to hyperactivate further as histamine responds to plant material. Keep in mind that much of what the plant material makes (which we tout for health benefits) are natural pesticides to keep predators away.
Our histamine system can react to this since 40-60% of the population has histamine issues and that goes up as we get older and for women (thanks progesterone).
For this reason, we focus on core players (mag, NAC) and substances that balance or calm immune response (CBD, mushrooms, berberine).
The heart of all mental health is the immune system and you're about 5 years ahead of the headlines on this. Check out the fascinating research here.
Balance the immune system and watch anxiety (and depression and…) melt away.
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.