We've already gone deep into the chemical issues surrounding benzos with tolerance and addiction here.
Benzos boost GABA, our brain's "brake" pedal but too hard and the body pushes back by squashing natural GABA production.
GABA (along with glutamate) is a workhorse in the nervous system…not a good way to go.
Throw in dopamine spiking, our reward pathway, and addiction follows shortly behind which is why there's a black box warning on benzos.
That's all pretty well understood.
The electrical side is fascinating….and completely contradictory.
We're going to dive in the brain waves and show how benzos actually are telling the nervous system to panic!
Not exactly advertised on the box (not enough room with the black box warning??).
Here are the topics we'll cover:
- A quick into brain waves
- Benzos and brain waves
- The chemical electrical disconnect with benzos
- Alternatives to benzos for GABA support
Let's get started.
A quick into brain waves
We focus so much on neurotransmitters that we forget there's a whole separate system running in tandem.
Neurotransmitters can't travel across the brain instantly…it's all local communication (neuron to neuron).
The electrical system can radiate across the brain and coordinate large-scale action.
Researchers have pinpointed specific wavelengths for this electrical field tied to brain activity with the dominant ones being:
Anxiety dominant, active, external attention, relaxed
Very relaxed, passive attention
Deeply relaxed, inward-focused
This alone is fascinating and there are many ways to "hack" this system for better health.
Meditation is intimately tied to theta waves for example.
When you wake up in the morning, try not to look at the phone for 20 minutes.
There's a brief period of theta wave between delta (sleep) and Gamma (focus) that can set the tone for how you feel throughout the day.
Turning to the phone bypasses this theta interval as you go right to focusing.
Anyway, our background nervous system (called autonomic) is tied into this electrical system which makes sense.
If a tiger jumps out of the bush and you had to rely on neuron to neuron chemical communication, you would be dead!
Too slow. The brain wave "information highway" can propagate at the speed of light to cause your body to jump out of the way.
There are two sections of this system that oppose each other:
- Sympathetic nervous system - fight or flight system (think adrenaline, glutamate, etc)
- Parasympathetic nervous system - rest and digest system (calm, repair, etc)
Again, we can hack this with deep breathing…especially long outbreathes and support of the vagus nerve where acetylcholine is released. A big review on the vagus nerve here since it's the hub between the gut (our "second" brain) and the brain in our head.
Acetylcholine is our "calm and focused" neurotransmitter. More on it here.
Take a guess which brain wave is associated with fight or flight…
Yes! Extreme Beta waves! Anxiety and panic as well.
This is the "tiger in the bush" network that allowed our ancestors to survive so we can be reading this right now.
Here's where it gets really strange for the most commonly prescribed medication for anxiety, panic, and sleep.
Benzos and brain waves
You would think the primary medication for anxiety and panic would result in a brainwave tied to relaxation…theta (calm) or at least alpha (relaxed).
BZZZZZT (buzzer sound)
While a decrease in high frequency EEG activity is associated with a decrease in arousal in drug-free conditions, sedative benzodiazepines increase beta activity
Wait a minute.
Benzos increase beta wavelengths. Just a reminder of what that's telling the man behind the curtain of your nervous system:
Prominence of this wave causes anxiety, high arousal, an inability to relax, and stress, whereas its suppression can lead to ADHD, daydreaming, depression, and poor cognition.
Let's go deeper:
There was a significant association (p-value <0.001) between the symptoms related to amygdala activation, expressed in the temporals (Beta >17% and High-Beta >10%).
Conditions? Anxiety. Phobias. Panic. Insecurity. The usual suspects.
Even more interesting:
Finally, all drugs induce a reduction of the amplitude of the hippocampal theta rhythms
A reduction in theta waves (deep relaxation) in the hippocampus, a key hub for mood control (see hippocampus and anxiety).
So…benzos are telling our chemistry one thing but our background nervous system the opposite.
Do see telltale signs in the autonomics system?
So…acetylcholine (the primary neurotransmitter of the rest and digest system):
The benzodiazepine (BZ) site agonist eszopiclone, indicated for treatment of insomnia, decreases acetylcholine (ACh) release in sleep-promoting regions of the pontine reticular formation.
And the seat of addiction:
Acetylcholine in the accumbens is decreased by diazepam and increased by benzodiazepine withdrawal: a possible mechanism for dependency
What about the all-important "vagal tone" - i.e. general function of the vagus nerve (why deep breathing, chanting, singing, humming, gratitude, etc has a calming effect)?
This is the factory for acetylcholine after all.
Vagal tone decreases following intravenous diazepam
They used to give benzos to patients following heart attacks, etc as a calming agent but the vagus nerve directly manages the heart!
Lorazepam reduces cardiac vagal modulation in normal subjects
So this is hitting the background manager of our nervous system….why the sedation and calming effect (temporarily till tolerance builds up).
The chemical electrical disconnect with benzos
Clearly, benzos have an immediate calming effect. What gives?
Basically, GABA is our nervous system "brake" pedal and benzos directly drive GABA activity.
Of course, there's a rebound effect and the newer class of benzos (like Ativan and Xanax) come on strong, last a short while, and then drop off a cliff compared to the older ones (like Valium).
So our electrical system (subconscious but maybe more powerful) is heightened like in a state of anxiety but our chemical system is so downregulated, our conscious (what we're aware of) response is muted…like a wet blanket.
It's a total mismatch and this is a strange quirk of the benzo class.
GABA is so ubiquitous in the nervous system that our background management system may be panicking that an outside influence is monkeying with such a critical player.
Or perhaps, the increased GABA is downregulating some pathways which keep anxiety in check.
For example…GABA is the brake for ALL systems…including serotonin, our master stress response buffer and manager of ALL human behavior.
What happens if we suppress it as a knock-on result of the benzos?
Although central serotonin neurons are thus implicated in the therapeutic actions of benzodiazepine tranquilizers, it is quite possible that the drugs actually act indirectly to reduce serotonin activity.
Playing around with such a fundamental neurotransmitter always has knock-on effects.
For example, SSRIs boost serotonin but they can actually INCREASE anxiety and depression for the first 2 weeks since serotonin drives the stress cascade via corticotropin-releasing factor (more on how SSRIs really work).
Doctors will generally address this first 2 weeks with…you guessed it…benzos.
Alright…the tolerance and addiction is the real issue with benzos but the electrical cross-talk doesn't help.
Are there ways to support GABA and maybe even the root of why GABA is getting overwhelmed (see ways to fight back anxiety or GABA review).
Alternatives to benzos for GABA support
Before we jump into the toolkit, let's quickly address what's drawing down GABA, to begin with.
Otherwise, we're just treading water.
The usual suspects abound:
- Hyperactive immune system
Early trauma/infection (even in utero) can actually downregulate GABA (and serotonin) later in life.
There are ways to "unwind" that and the immune system is front and center.
- Magnesium glycinate
- CBD isolate
- CDP choline
- Medicinal mushrooms
- Steroidal hormones
We have big reviews on all of these but a quick look.
Magnesium glycinate versus benzos
Mag is a natural stress response buffer in the nervous system.
It directly supports GABA:
Magnesium may additionally modulate anxiety via increasing GABAergic availability by decreasing presynaptic glutamate release .
Glutamate is the opposing "gas pedal" to GABA. Mag calms the engine down which supports GABA.
Glycinate crosses the blood-brain barrier much better than other forms of mag.
More on that here.
CBD is an allosteric positive modulator of GABA.
Essentially, it works like a feedback mechanism when GABA is low.
This is why you don't see the cascade of decreasing brain activity like with benzos and/or alcohol.
In fact, CBD can cause energy during wake cycles and drowsiness during sleep cycles.
CBD also modulates specifically configured GABAA receptors that may be relevant to anxiolytic effects (Bakas et al. 2017; Deshpande et al. 2011). CBD is anxiolytic under experimental conditions in animals, healthy humans and in those with generalised social anxiety disorder
Importantly, CBD also addresses the culprits - stress, brain inflammation, histamine response, immune hyperactivation, etc.
It doesn't build tolerance since it doesn't push GABA in one direction like benzos.
NAC is fascinating for mental health.
In the nervous system, it acts as a sink for excess glutamate.
A note…one of GABA's primary roles is to balance against glutamate.
For example…a study with autism (where glutamate is hyperactivated…immune system!!!):
The effect of NAC on behaviors relevant to ASD was examined in a separate cohort. NAC induced a time-dependent decrease in striatal glutamate, which recapitulated findings of lower striatal glutamate reported in ASD
We have a full review on NAC for mental health here.
Let's turn to the vagus nerve!
Get to know your vagus nerve. It's cutting edge for mental health right now.
It connects the gut and brain with connections to all your organs (especially the heart).
The vagus nerve is the seat of acetylcholine, the master player for the "rest and digest" system.
We have big reviews on the vagus nerve here and acetylcholine here.
We can support this pathway in multiple ways (see the review…some are fascinating) but choline is a great precursor.
Look at some of the connections:
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.
Eggs are a great source of choline (it's actually a B vitamin) but supplementation also helps.
Take it in the morning since it can help with energy (albeit…calm and focused).
Let's look at longer-term players to rebalance the immune system which is critical as to why GABA might be outgunned.
The immune system is the future of mental health.
Remember how early trauma/infection can downregulate GABA later in life? The immune system is the vector for that.
In fact, this epigenetic programming can go back 14 generations.
Mushrooms have a fascinating way to balance our immune response across multiple pathways….including GABA.
Extract of Ganoderma lucidum potentiates pentobarbital-induced sleep via a GABAergic mechanism
However, we're more interested in the modulation of hyperactivated immune response which is at the core of why GABA might be drawing down.
There's tons of research as well on the repair side such as BDNF (our brain's fertilizer).
The big review is here.
Finally…if you're in your 40s or older…this is essential.
Estrogen and testosterone drives estrogen. Progesterone drives…GABA!
Our results showed that progesterone significantly increased the α1 subunit mRNA in both hemispheres of male and female rats. Moreover, there was an inverse correlation between depressive-like behaviors and GABA(A)R α1 subunit mRNA expression in the right hemisphere in female rats.
Again…if GABA is run down, damage occurs in the brain from glutamate (which is toxic at higher levels) and depression is the result. See big review on depression.
Here's the issue…progesterone drops by 50% at age 40! Progesterone is a powerful calming agent for immune response (see big review here).
Steroidal hormones are so so important to GABA function and pretty much every cell in our body.
We learned this the hard way from a brutal perimenopause (that story is here).
That's a wrap. In addition to exercise, meditation, forest bathing, and good nutrition, we have a toolkit to support GABA without triggering the beta wave panic button.
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.