This isn't your dad's review of anxiety.
We already know the symptoms...all too well.
We're looking for answers on why it happens and how we can make it stop happening.
CBD is all the rage right now in the news and anxiety is the #1 reason people are seeking it.
Can CBD really do anything to help with anxiety?
Good thing we've read through 100's of NIH studies on anxiety and CBD.
We're going to walk through what new research shows on the pathways of anxiety.
Some of it is brand new and very exciting such as ways to boost neurogenesis to repair damage in the brain across the anxiety "circuit".
Yes, we're going to address what CBD does along these pathways but even without that, you'll learn some of the core drivers.
We're also going to explain how the vast majority of CBD that is being sold may be a very bad fit for 40-60% of the population.
We've received countless pieces of feedback similar to this…
"I tried CBD brand X and it makes my anxiety worse!"
There are a few reasons this may be the case.
We'll get into all of them.
This isn't going to be your run-of-the-mill article with a bunch of fluff and some sales pitch at the end.
We're going to get our hands dirty (and hopefully, our nerves calm!)
If you or a loved one is suffering from anxiety (I've seen it first hand with family...that story here), it's important to wrap our heads around it.
These are the general topics we'll cover:
- Modern look at anxiety
- Brain areas tied to anxiety
- Neurotransmitters and anxiety
- New research on THC and anxiety
- Histamine release and anxiety
- Brain inflammation and anxiety
- Medications for anxiety
- Endocannabinoid system and anxiety
- Research on CBD and anxiety
- Best CBD for anxiety
- How much CBD to take for anxiety
Like we said...no stone left unturned!
Let's get started by meeting the different players at work.
Updated look at anxiety
We're not going to get into the symptoms.
If you're reading this, you are already well acquainted.
We want to go a few levels deeper and try to make the confusing world of the brain understandable.
Think of anxiety as a cross-section between different forces:
- Stress response
- Differences in brain area strengths
- Imbalances in neurotransmitters (the agents of brain signaling)
- Imbalances in hormones which interact with the brain
- Histamine release in the brain (same thing that's responsible for allergic reactions)
Of course, genetics underpins all of this but genes are turned on and off by the environment all the time!
It's the newest and most fascinating part of genetics called epigenetics.
You actually have gene expression which was influenced by prior ancestors!
Not to mention that processed fast food from yesterday.
One, some, or all of these facets can conspire to produce anxiety.
Let's zero into each one and eventually, we'll get to the research on CBD.
For that research to pack a punch, we first need to look at these facets.
It will help later!
Let's start with the brain.
Brain areas tied to anxiety
We're going old school.
Deep into the "reptilian" part of the brain called the Amygdala.
It's the seat of emotion, impulse, fight or flight, and fear.
There's a pretty cool introduction to it here:
If the amygdala is firing too strongly, you can have anxiety.
What keeps it in check?
The typical dominion of practicality is the prefrontal cortex.
That's the part behind your forehead and it's roughly the seat of logic and rational thought.
It's really what makes humans...human.
We share the Amygdala with most other creatures...it's one of the oldest parts of our brains. The prefrontal cortex is a newer addition!
One more note...there's an interchange between these two areas called the cingulate cortex.
If activity is too low or reversed in this interchange, anxiety can result.
The hippocampus also comes into play as it's the seat of memory.
Not just numbers, dates, and places but emotional memory.
Anxiety can reflect a loop of fear-based memory within this system.
All of these become very important for anxiety and CBD as we'll find out later.
If these are the parts of the brains at play, the actors are neurotransmitters.
For more information on brain areas, check out CBD and general anxiety disorder here.
Neurotransmitters and anxiety
Research is showing that the key neurotransmitter for anxiety is GABA.
GABA acts as a "brake" in the brain to calm the specific parts of the nervous system tied to a panic reaction.
Adrenaline and glutamate are usually the opposing force to GABA but a balance is ideal.
In mice that have a gene for GABA signaling knocked out, they display the expected fear and anxiety response:
mice represent a model of anxiety characterized by harm avoidance behavior and explicit memory bias for threat cues, resulting in heightened sensitivity to negative associations
Look no further than the current regimen to treat anxiety...benzodiazepines.
What do they do?
BZDs act as positive allosteric modulators on the gamma-aminobutyric acid (GABA)-A receptor.
Simply put, they boost the activity of GABA.
With some pretty serious side effects as well (see CBD versus benzos here).
We'll look at that below.
To recap...GABA is the calming "brake" of the brain!
We have an entire article on CBD, GABA, and Anxiety here.
So...what can exhaust or eat up GABA? Let's start with hormones.
Hormones and anxiety
You can't discount hormones.
They're incredibly powerful in regards to the symptoms of anxiety as well as the cause.
First, some of the henchmen of anxiety are actual hormones.
Cortisol. Adrenaline. Both hormones.
They do the dirty work in the body (if excessive) when anxiety hits.
Increased heart rate. Rise in blood pressure. Sweaty palms... Hormones.
Changing hormones or imbalances in that system can also drive anxiety.
There's a direct tie between large fluxes in estrogen and testosterone with anxiety.
Puberty. Monthly period. Pregnancy. Perimenopause.
Check out CBD and perimenopause anxiety to really get into this effect.
This entire website was born out of an incapacitating anxiety response from perimenopause (progesterone and estradiol plummeted).
There's a good run-through of some key hormonal impacts on anxiety here:
Progesterone has been shown to have a powerful anti-anxiety effect via its boosting of GABA:
The anxiolytic effect of progesterone is associated with increases in cortical allopregnanolone and GABA-A receptor function
The very same GABA we looked at above which benzo's boost (along with addiction).
Estradiol, the dominant version (out of three) of estrogen, has been shown to help balance and moderate the signaling of GABA:
Just to round it out, testosterone has a powerful anti-anxiety effect as well.
This may get to the heart of why women have an 85% higher risk for anxiety than men.
Testosterone is an androgen or a hormone that drives masculine traits.
Women have testosterone as well but if estrogen is dominant, it can reduce testosterone levels.
As for testosterone's effect on GABA…
testosterone metabolites, androstanediol, and androsterone have little or no affinity for androgen receptors (11), but they are potent GABAA (gama aminobutyric acid A) receptor agonists and have GABA-mediated functions
None of this is surprising given the anxiety connection to monthly cycles for women.
Also, take a look at CBD and teenage anxiety for a better understanding of hormone influences.
There's another interesting hormone to consider especially for anxiety.
Histamine release and anxiety
Histamine is the hormone responsible for allergic reactions as well as a host of different effects in the brain and body.
It's used to get bad things out of the body.
Histamine release in the brain is even more interesting.
It's called a neuromodulator which means that it interacts with many other neurotransmitters in the brain.
Let's look at some of the clues.
First, inflammatory chemicals released from mast cells (where histamine also is released) are out of balance in people with General Anxiety Disorder (GAD):
The findings indicate a relatively increased pro-inflammatory response and decreased anti-inflammatory response and provide the first demonstration of an altered cytokine balance in GAD.
Learn all about the powerful effects of CBD and inflammation with anxiety here.
Then there's the study with mice which showed that GABA is used to reduce the levels of histamines in the brain. It acts as a moderator of the excitatory response:
GABA May Act as Chemical “Brake” Preventing Histamine Wakefulness from Being Too Intense
We can even see where the benzo's (common anti-anxiety medication) directly reduces the metabolism of histamine (called turnover):
Anxiolytic drugs also decrease brain histamine turnover.
Diazepam-induced decrease in histamine turnover in mouse brain
Other benzodiazepines such as chlordiazepoxide, nitrazepam, and estazolam in high doses also decreased histamine turnover.
Interestingly, GABA and Histamine are both created in the same type of neuron.
Granted, this effect may only apply to a subset of anxiety conditions but the fact that the benzos (leading medication for anxiety) have this effect is worth noting.
Remember this whole histamine element when we get to what is the best CBD for anxiety.
It's crucial for 40-60% of the population.
Just a head's up...many of the physical effects of anxiety (rapid heartbeat, sweaty palms, feeling of constriction, etc) are partially under the direct control of histamine.
There's a whole slew of studies on histamines, mast cells, and anxiety here:
An entire review of CBD, histamine, and anxiety can be found here.
Let's look at the other theory gaining credibility.
Inflammation in the brain.
Brain inflammation and anxiety
It's one thing when your elbow or gums are inflamed.
What about inflammation in the brain or central nervous system?
What would that feel like?
Anxiety is a pretty good guess.
There's plenty of research to back this up.
Keep in mind that the hub of our inflammatory response is in the gut where our immune system's control center works.
Learn all about it at our CBD for inflammation and anxiety article.
On to the studies.
We're just going to look at a few of them.
There are clear signs of inflammation in the brain with anxiety:
Biomarkers of inflammation, including inflammatory cytokines and the acute-phase reactant C-reactive protein (CRP), are reliably increased in a subset of patients with depression, anxiety disorders and post-traumatic stress disorder (PTSD).
Remember that brain area that's the seat of fear, anxiousness, and emotional context...the Amygdala:
Administration of innate immune stimuli to laboratory subjects and the associated release of inflammatory cytokines has been shown to affect brain regions involved in fear, anxiety and emotional processing such as the amygdala.
They gave immune response agents (inflammation basically) to subjects and the negative effects were found in the Amygdala.
In one subset, inflammatory agents affected the communication between the Amygdala and Prefrontal Cortex (basically, your fear center and your rational center).
Does that sound familiar from our brain section above?
We have an entire system for dealing with inflammation and stress in the body or brain.
Let's zero in on one kind of inflammation in the brain.
This is basically the waste byproduct of using energy in our brains.
Keep in mind that our brain uses the vast majority of our energy by body weight.
It creates lots of ROS (or Reactive Oxygen Species).
Too much of this or a failure to neutralized it is directly tied to anxiety in research.
There's an entire summary of different studies linking anxiety not only to this oxidative stress but the genes that govern our systems for clearing it out!
In a nutshell..Oxidative Stress in the brain may equal Emotional Stress
It always starts with the poor mice:
Hovatta et al.25 identified a close relationship between antioxidative defense mechanisms and anxiety-related phenotypes in six inbred mouse strains.
Genes tied to the antioxidant process were directly associated with high anxiety responses.
Check out CBD and oxidative stress for anxiety.
Interestingly, one of those genes governs how glutathione processes.
Glutathione is one of the body's most important and potent antioxidants.
The researcher was able to create or remove an anxiety response just by either reducing or increasing the function of this and another gene.
We go deep in the CBD and glutathione for anxiety here.
Another comprehensive study of oxidative stress (inflammation) and anxiety can be found here:
All this talk about antioxidants and anti-inflammatories in a perfect segway into the most commonly prescribed medications used for anxiety
Medications for anxiety
Everyone knows their names.
Valium, Ativan, Xanax, etc.
They're all over the Soundcloud rap music scene now.
For good reason….they're extremely habit-forming and powerful mood affecting agents.
But how do they work?
We need to look at this before we get into CBD.
Here are the main effects of the benzos as it applies to the sections above...
They increase the action of GABA in the brain (our "brake" if you will)
Put it this way...there are actual sites on GABA receptors called benzodiazepine receptors (obviously named after the class of drugs).
There are serious long term and even short term effects on benzodiazepines.
They are known to be highly addictive.
GABA isn't the only neurotransmitter affected.
Benzo's also boosted dopamine similar to opioids.
Dopamine is the reward neurotransmitter and lies at the heart of almost all addiction.
It's estimated that 44% of users eventually become dependent!
The side effects of withdrawal are extremely nasty!
One of the key side effects…
Anxiety and Panic attacks.
Great...isn't that why we're taking them to begin with?
On a side note, CBD is not habit-forming and does not normalize (need more and more for the same effect) according to research.
Check the CBD safety page here.
We've looked at the results of CBD versus these options in detail (get ready to get angry):
- CBD versus anxiety medications
- CBD versus benzos such as Ativan, valium, and Xanax
- CBD versus SSRI like Lexapro, Zoloft, and Effexor
We're going to get deep into research with those three articles!
Next up...the gut...our microbiome...the bacteria in our gut that function almost like a separate organ.
Let's see how they affect anxiety.
The gut microbiome and anxiety
It's called the second brain for a reason.
You have an entire nervous system intermeshed through your digestive tract and it's busy producing all sorts of things you need to feel well.
If it gets out of balance, psychiatric issues like anxiety can occur.
Remember the serotonin neurotransmitter from above?
How much is made in the gut?
Oh, just 90%.
In case you're wondering, serotonin is our "feel good" neurotransmitter.
What about GABA?
It could be your new best bacteria friend!
They isolated what it does and remarkably, it appears to synthesize GABA!
It wasn't the only species of bacteria involved.
Keep in mind that 20-60% of our gut bacteria have never been cultured!
Genome-based metabolic modeling of the human gut microbiota revealed multiple genera with the predicted capability to produce or consume GABA
They even found bacteria that appeared to reduce or "eat" GABA and other neurotransmitters:
By coupling 16S ribosomal RNA sequencing with functional magnetic resonance imaging in patients with major depressive disorder, a disease associated with an altered GABA-mediated response, we found that the relative abundance levels of fecal Bacteroides are negatively correlated with brain signatures associated with depression.
Like we said before, this really is the wild west of health.
Here's a great visual of GABA involved bacteria here:
We've written specifically on actual probiotics you can supplement at our CBD and probiotics for anxiety here.
Here's a summary if you want to see just how intricate and involved this system is:
One last stop before the endocannabinoid system, CBD, and anxiety.
New research on THC and anxiety
We've had research on THC and anxiety for a while now.
First, people with allergy or histamine issues have a much higher risk of being allergic to THC.
Roughly 24-36% of the greater population has a THC allergy.
This speaks to the side effects people can have:
- Heart palpitations and other effects
- Increase heart rate
- Panic attacks
In fact, research is showing that CBD helps to offset the negative effects of THC.
This was the original underpinning of the "entourage effect".
Check out specific information on cannabis or THC versus CBD for anxiety here.
The new research is even more interesting.
There's a great book called Never Enough which goes through the process in a way we can actually understand it.
Basically, THC has been shown to thicken the Amygdala (seat of fear and anxiety response).
This effect is especially prevalent in teenagers with one user having an effect.
Maybe, more importantly, is THC and normalization or tolerance.
This means that your brain adjusts to the heightened state that THC creates by reducing the neurotransmitters involved.
The net effect is that THC will make you feel less and less and eventually, without THC, you're more at risk for depression and anxiety.
Even if you are not prone to addiction, these downshifts in mood are still happening.
Let's now finally get into the realm of CBD and anxiety.
Endocannabinoid system and anxiety
CBD is an actor on a powerful stage in the body.
The stage is the endocannabinoid system.
This system is over 600 million years old and spans all known animals.
It's tasked with balancing other key systems in the body:
- Nervous system (neurotransmitters like GABA)
- Endocrine system (hormones like estrogen, cortisol, adrenaline, etc)
- Immune system (inflammatory responders like cytokines, and histamine)
To put it simply, this system's responsibilities are written all over anxiety!
It's also the system that CBD works within...more on that later.
Let's check out research on the matter.
We'll start with the basics.
Are there endocannabinoid receptors even on GABA and Glutamate neurons?
In fact, they could directly affect the anxiety feeling by boosting or reducing how this system worked...either way:
In anxiety, a bidirectional influence of the ECS has been reported, whereby anxiolytic and anxiogenic responses have been obtained after both increases and decreases of the endocannabinoid tone.
ECS is short for the endocannabinoid system. Anxiolytics means anti-anxiety while anxiogenic means anxiety causing.
When researchers knocked out genes for the CB receptors, the results were anxiety:
Several studies using CB1 receptor knockout mice have reported anxiogenic responses in classical anxiety paradigms
Read that over again to understand just how relevant this is to anxiety.
Three specific endocannabinoids (cannabinoids that we naturally make in our bodies) appears to be critical to anxiety:
- Anandamide (AEA) - appears to reduce anxiety
- FAAH - elevated levels appear to increase anxiety
- 2-AG - appears to reduce anxiety
Remember that the goal of the endocannabinoid system is balance.
You need anxious feelings sometimes!
Like if the proverbial tiger jumps out of the bush or you're acting in a risky way.
It's there to protect you.
That requires a TEMPORARY imbalance to elicit that effect.
It's when the imbalance is long term or not due to any threatening issue that we have a problem.
Stress in excitatory. It boosts glutamate which eats up GABA.
Long term stress can exhaust this calming neurotransmitter and create anxiety.
The three endocannabinoids are trying to balance out this system.
There's a slew of research on how endocannabinoid systems govern this but a few studies...
A plethora of studies involving pharmacological blockade of FAAH by the specific inhibitor URB597 demonstrated anxiolytic behaviors in a variety of species using different anxiety paradigms
They used a specific chemical to block FAAH from working which reduced anxiety.
Check out FAAH's effect in the study of the woman who can't feel pain, depression, or anxiety here.
Next, Anandamide (the so-called "bliss" molecule)
The effects of diazepam (benzo) were increased with the addition of Anandamide:
These results suggest a possible synergistic action on glutamatergic inhibition (by the increase in AEA) and GABAergic enhancement (by the activation of GABA A receptors).
This basically means that Anandamide appeared to take the foot off the gas (glutamate) in the brain and boost GABA at the same time (apply the "brake").
2-AG was proposed as the endocannabinoid responsible for the tonic inhibition of excitatory neurotransmission, and interaction with the inhibitory network was excluded using GABA A and GABA B receptor antagonists
2-AG appeared to calm the excitability in the brain and boost the GABA networks.
There's an entire summary of all the different studies here:
The net-net is this…
- The endocannabinoid system is intricately involved in the system imbalance that drives anxiety
- The endocannabinoid genes are involved in anxiety when faulty
- The endocannabinoids (AEA, FAAH, and 2-AG) are key players in balancing this system.
So...what about CBD?
This is all well and good but what can we do to bring back balance to this system?
Can we possibly add one or more sets of letters to our alphabet soup and get relief??
Research on CBD and anxiety
First, for post-traumatic stress disorder, check out our CBD and PTSD here.
There are very specific pathways there and CBD appears to boost the innate system we have for forgetting negative memories and emotions!
Not to mention building new neurons (called neurogenesis) which may have a significant role for some people with anxiety.
That's important for anxiety in all its forms.
For example, there's a part of the brain that can have a significant role in anxiety.
It's called the DPAG (dorsal periaqueductal gray).
It's the seat of dread and impending doom. Literally!
This is one aspect of CBD's effect in the brain.
these findings suggest that repeated treatment with CBD induces anti-panic effects by acting on 5-HT1A receptors in DPAG.
5HT is a pathway for serotonin which is our feel-good neurotransmitter and common pathways for anxiety.
What does CBD do for this pathway?
It helps to balance or moderate this pathway following an injury to this pathway:
Seven days of treatment with CBD reduced mechanical allodynia, decreased anxiety-like behavior, and normalized 5-HT activity.
It also affected pain and inflammation but the anti-anxiety effect was via the 5ht pathway.
Of course, serotonin pathways are key to depression as well!
This partially accounts for the close association between anxiety and depression.
Same pathway in many cases.
We've discussed GABA quite a bit with anxiety.
It's the "brake" in our brain.
What does CBD do with GABA:
these results reveal a mode of action of CBD on specifically configured GABAA receptors that may be relevant to the anticonvulsant and anxiolytic effects of the compound
Maybe, more importantly, it did not affect this change via the benzodiazepine receptors:
The potency of CBD increased and efficacy preserved in binary α1/α2β2 receptors indicating that their effects do not involve the classic benzodiazepine site
This is huge!
The last thing we want is another chemical that uses the same pathways as benzos.
Let's look at the three endocannabinoids we discussed above.
Anandamide. (helps reduce anxiety symptoms)
They found CBD's effect on Anandamide in connection to schizophrenia:
Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia
And FAAH (higher levels showed anxiety effects)??
We noted that CBD inhibits FAAH more potently than the (+)-enantiomer.
Those are some of the neurotransmitters.
Let's look at other complicit pathways we looked at above.
Inflammation in the brain and CBD.
CBD is showing itself as a powerful anti-inflammatory in the brain:
Cannabidiol reduces neuroinflammation and promotes neuroplasticity and functional recovery after brain ischemia.
They actually found this out while looking at brain injury following strokes.
You're about to be on the cutting edge of anxiety science.
CBD, Neurogenesis, and Anxiety
There's new research that speaks to reduced brain mass and anxiety.
This reduction can be due to stress, injury, an autoimmune attack, or genetics.
Either way, CBD is showing the amazing result of increasing neurogenesis...growing new neurons.
Why is this important??
Increasing Adult Hippocampal Neurogenesis is Sufficient to Reduce Anxiety and Depression-Like Behaviors.
Read that again. It's really important and quite telling as to what's actually driving anxiety in many cases.
CBD's effect on neurogenesis:
CBD induced a substantial increase in net neurogenesis by a CB1 receptor-dependent mechanism
You're going to be hearing about BDNF a lot more soon.
One final but important stop that has a direct impact on the type of CBD you take.
Histamines and Anxiety
We showed the connection between histamine release and anxiety for a good percentage of the population (growing by the year).
CBD Isolate has powerful calming effects on histamine.
Full-spectrum CBD or CBD in hemp oil, however, may actually trigger histamine response.
It's pushed everywhere based on scant research.
We covered the differences at our CBD Isolate versus Full Spectrum for anxiety review.
Best CBD for anxiety
Based on the histamine tie with anxiety, it's important to consider CBD Isolate.
We see so many initial results from people using CBD for anxiety with full spectrum that has side effects consistent with allergy and histamine issues.
CBD Isolate usually takes care of this.
It's one reason we focus on Isolate.
The bigger reason is that research is based on CBD.
Not full spectrum. Not hemp oil.
Of course, the CBD has to be:
- 3rd party tested
- Organically grown in the US at an FDA registered farm
- THC free (histamine issue)
- Heavy metal-free
- Bacteria and Mold free
CO2 extraction is the cleanest process and very important as well.
We basically designed our CBD at IndigoNaturals to meet these requirements.
We take it for our families!
It was crafted after perimenopause sent one of our partners into an anxiety tailspin (her story here).
What about the dosage for anxiety?
How much CBD to take for anxiety
There's a lot of confusion around the dosage of CBD and anxiety.
We're written a complete article on how much CBD to take but let's look at anxiety specifically.
The starting amount is generally 20-30mg of CBD to test how your body reacts.
You can then go up from there.
The research above is generally around 300mg of CBD but you may not need to go that high.
There's actually research that shows that the neurogenesis tied to CBD for anxiety decreases from 300 to 600 mg. See more detail here.
The responses we've seen are across the board in terms of what works.
This can be a function of weight, liver function, and what's driving the anxiety.
Our recommended approach is to listen to your body.
Since these amounts are higher, we need to get the best value by mg of CBD.
That's our goal as well at about 2-3 cents per mg before discounts up to 30%.
Some of the best on the market so people can actually get the relief they need.
Let us know what works for you below.
Hopefully, you can see that we put our heart and soul into this article and subject matter.
Anxiety from perimenopause is how we found CBD, waded through bad options (very big brands), and eventually crafted our own based on research.
It's exactly what we needed to find back when anxiety was our most unwelcome guest!
Practical questions on CBD and Anxiety:
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.