Can CBD Help with General Anxiety Disorder
When perimenopause decided to visit one of our partners, a crushing 24/7 anxiety came along for the ride.
That story is here.
It's not just a question of "Hey, cheer up. You're going to be okay".
It's as if your filter of the world is through an anxiety lens and any feel-good wishes are pointless.
It's very chemical.
We've gone through many aspects of anxiety.
We even looked at the basic pathways of anxiety here.
Everyone feels anxiety at some point in their life.
What if that's all a person feels?
General Anxiety Disorder.
A constant state of worry and anxiety not tied to specific cues.
Let's try to unravel what research is showing there.
We'll then look at how CBD might help with this crushing health issue.
We need to go systemic for this.
Yes, stress, inflammation, hormones, and gut bacteria can have an impact but clearly something is occuring long term.
6.8 million Americans are clawing against and fighting this.
We already have a comprehensive look at how CBD affects the specific pathways of anxiety here.
We want to look at longer term, structural effects for generalized anxiety disorder.
New research is exciting along these lines.
We'll look at the following:
- How is Generalized Anxiety Disorder different from anxiety
- What is happening in the brain with generalized anxiety disorder
- Long term effects of CBD on generalized anxiety disorder
- Comparing CBD versus medications for generalized anxiety disorder
- Best supplements, herbs, and CBD for generalized anxiety disorder
- How much CBD for generalized anxiety disorder (very important)
Let's get started.
How is Generalized Anxiety Disorder different from anxiety?
The real difference is internal versus external causes.
The loss of a family member, a traumatic event, hostile work or home environments can all lead to anxiety.
Gut microbiome imbalances (from antibiotics, pesticides, additives, etc) can also come into play.
Histamine response and infection can also cause anxiety.
These are external causes of anxiety.
Generalized Anxiety Disorder generally deals with an internal system issue in the anxiety pathway.
Women are twice as likely to be affected which may be a clue!
For internal drivers of GAD, we need to look at the following:
- Brain function and GAD
- Neurotransmitters and GAD
- Genetics and GAD
- Hormones and GAD
- Brain mass loss due to infection, inflammation, or developmental history
- Gut Dysbiosis
These are long term, systemic causes of anxiety.
It speaks to the persistent nature of GAD versus anxiety from a test or public speaking.
Let's look at each of these separately.
What is happening in the brain and body with generalized anxiety disorder?
We've explored the anxiety pathway in-depth at our CBD and anxiety article.
A quick recap.
The key players:
- Prefrontal cortex
Think of it as having two separate brains that both work together and oppose each other.
Your Amygdala is a member of our old "reptilian" brain.
Reptiles literally have this same brain area and same basic function.
It's tasked with processing emotional signals such as fear and anxiety.
When processing fear, it acts first to keep us safe.
That signal then gets sent to the prefrontal cortex.
Our prefrontal cortex (just behind your forehead) is a much newer part of the brain specific to humans.
To some extent, it's what makes us human.
This is our rational brain and it takes that initial signal from the amygdala (run, panic, scream!) and determines if that reaction is justified.
Hmmm...it's not a tiger in the bush but a bird. All safe. Stand down Amygdala!
This "circuit" happens all day long in the background to keep you safe.
In generalized anxiety disorder, it's not working correctly.
The amygdala has the upper hand and is running amok.
For the more intrepid souls, a full scientific explanation is here:
This can be because of genetics, structure, or damage.
What about brain structure and pathways specific to General Anxiety Disorder?
Two interesting studies have looked at brain scans to tease out what is going.
First, people with GAD may not have a correct signaling between the fear center (Amygdala) and a part of the brain used to determine the importance of stimuli:
This could mean that people with the disorder have a harder time discerning truly worrisome situations from mild annoyances.
This study and others also found too much connection with the prefrontal cortex and too much activity there:
At the same time, the amygdala was more connected to a cortical executive-control network previously found to exert cognitive control over emotion.
Something in this circuit between the two areas is off-balance.
Another study found:
The results show that worry in normal subjects and in subjects with GAD is based on activation of the medial prefrontal and anterior cingulate regions, known to be involved in mentalization and introspective thinking. A dysregulation of the activity of this region and its circuitry may underpin the inability of GAD patients to stop worrying
Research is here.
This misrouting may be due to weak connection at one key choke point in this whole fear-rational circuit:
In this case, two types of scans showed the amygdala, which alerts us to threat in our surroundings and initiates the “fight-or-flight” response, seems to have weaker “white matter” connections to the prefrontal and anterior cingulate cortex (ACC), the center of emotional regulation.
Hmmm...the ACC connection.
The bottle jam may come down to one little track of white matter:
the imaging showed the brains of people with GAD had reduced connections between the prefrontal and anterior cingulate cortex and the amygdala via the uncinate fasciculus, a primary “white matter” tract that connects these brain regions.
This reduced connectivity was not found in other white matter tracts elsewhere in their brains.
We discussed the anterior cingulate cortex in our CBD for anxiety article.
The uncinate fasciculus is a new actor though.
The plot thickens.
Research is showing this communication tract between our Amygdala and the prefrontal cortex is critical to anxiety:
The UF-amygdala complex may be pivotal for the control of trait anxiety.
The key word there is "trait anxiety".
Not the result of an experience or stressor.
A personality trait. General Anxiety Disorder.
Further evidence is found in children with anxiety:
Tract-based results demonstrated that children with anxiety disorders have significant reductions in uncinate fasciculus FA.
Interestingly, this childhood trait was found for boys only.
What about differences between volume between men and women?
The ICV was significantly larger in males compared to females
Could this partially be at the heart of the different 2.5x increase in general anxiety for women over men?
Remember that the prior study showed this area was (and not others) had reduced signaling in people with General Anxiety Disorder.
This may all be overwhelming but pay off is coming below when we get to CBD.
NO ONE is going this deep into this to get answers than us!
Like we said, this is personal!
We'll stop there but what about the worker bees that do all this signaling between and within brain areas...neurotransmitters.
Neurotransmitters and General Anxiety Disorder
The main players here are the following:
- Histamine (both neurotransmitter and hormone)
The first two are easily implicated in the anxiety pathway but certain genetic susceptibilities might rest heavy on the bottom two as root issues.
Basically, GABA is the main lever for anxiety.
It's critical to the condition in any form including general anxiety disorder.
GABA is our brain's main inhibitory chemical. It's the brake pedal!
Quite simply put...too little GABA and you'll have anxiety (plus insomnia and a host of issues).
Serotonin is trickier and it's more an accomplice to anxiety.
Serotonin is a workhorse of signaling throughout the brain between different areas, within neurons, and between neurons.
It's the little engine that could.
SSRI's, which boost serotonin, are used for anxiety but less effective and with very serious side effects.
There are situations though where serotonin signaling is not working correctly and anxiety can result from this depending on where it's occurring.
Where it gets tricky is this...boost serotonin in an area tied to fear processing such as the CFR, and you'll actually get more anxiety!
That's why there's an increase in anxiety and depression in the first few weeks of using SSRI's.
Learn more about that here.
What about Glutamate and Histamine?
If GABA is the brake we're trying to boost, Glutamate and Histamine are the gas pedal.
Glutamate is the brain's key excitatory chemical (opposite of GABA) and histamine is excitatory in the brain and part of our immune response.
We know its effects when we have allergic responses.
In the brain, it works against the GABA for the sleep/wake cycle.
We'll let you guess which does what. (hint hint - GABA for sleep; Histamine for wake).
These are the most prominent actors of ALL anxiety.
Now let's look at why it might be chronic or ongoing.
We'll start with genes since that's where all these pathways get their beginning.
Genetics and GAD
Some genes definitely are at play with general anxiety disorder.
We'll save the best one for last.
The current list of suspects (growing all the time) are:
- 5HT and 5HT1A (serotonin pathway)
- MAO (breaks down neurotransmitters)
- COMT - degrades norepinephrine (panic response mediator)
- BDNF - helps maintain neuron growth and mass
- CRHR1 - releases stress hormone corticotropin
Interestingly, a study of GABA genes did not show a connection to anxiety:
We're only at the beginning of the genetic discovery phase.
Good news is that with CRSPR, there's a time in the not to distant future where we can sub faulty genes out.
MAO mutations can be brutal for mental health (as are the others).
Genes are also not destiny.
It's 50% genes and 50% environment. We turn genes on and off all the time based on what we do.
For example, I have an MTHFR mutation (as does about 40% of Americans) which means I don't process B9 very well.
A very bad mutation of this gene can be devastating.
We can supplement this pathway with methylated B9 easily to boost its processing.
Same is true for MTRR (B12) and many of the gene pathways above.
First, you have to know what genes you may have mutations on.
23andme used to do a pretty good job but they went away from health related genes last we checked.
Check out the book Dirty Genes by Dr. Ben Lynch. That's a good start.
StrateGene is probably the best way to test now.
You can google any gene and "selfhacked" for a good look at what might support it's function once you know where you have issues.
There are also genes tied to stress response which are very interesting as they pertain to our endocannabinoid system (where CBD works).
We'll get into that below.
Again, this is early days in the gene world for anxiety but it's growing exponentially (please hurry!).
We have a full article on a very particular gene directly tied to "trait" anxiety.
Guess what it does? It's an endocannabinoid and CBD has a direct and positive impact on its pathway.
We'll link here when that article is online.
Hormones are equally powerful for general anxiety disorder.
We discussed how GABA is our calming neurotransmitter.
Progesterone shares some of the heavy lifting here:
Whereas estrogen seems to suppress GABA inhibitory input (Murphy et al., 1998a), progesterone and its neuroactive metabolites (allopregnanolone, pregnanolone) seem to facilitate GABAergic transmission through their action at GABAA receptors
Notice how estrogen actually worked against GABA.
This is huge for anxiety during the cycle, pregnancy, and perimenopause/menopause.
Interestingly, it has been shown that SSRI's boost levels of allopregnanolone which might speak to part of their effects.
Learn about CBD versus SSRI's here.
Basically, by boosting serotonin, more of the progesterone is turned into allopregnanolone:
SSRIs’ ability to enhance formation of allopregnanolone from progesterone by increasing the levels of 5alpha-reductase in the brain
There's also the hormone norexin.
Probably haven't heard of that one!
It's called the "vigilance" hormone and it tied to panic attacks.
We covered it in detail at our CBD and panic attacks article.
Of course, there are the adrenal hormones such as cortisol.
Again, progesterone's effect on GABA is probably the most pronounced and may speak to why women are 2x's more likely than men to have general anxiety disorder.
Let's now dive into the new research on anxiety...the result of an inflamed brain.
Brain mass loss due to infection, inflammation, or developmental history
Judging by the sections above, lots has to go right in our nervous system to NOT have anxiety.
Many things can structurally affect these pathways in the brain which have long term effects such as general anxiety disorder (outside of genetic predisposition):
- Injury to the brain
- Infection or inflammation during key developmental stages or chronically
- Chemical effects on brain mass and circuitry (such as THC!!!)
When you get a chance, check out the book, The Inflamed Mind.
It's very interesting!
Basically, it goes through how inflammation may be at the root of depression and other mental health issues.
Ten years ago, that sounded far fetch but no much with new research.
Let's start with injury:
increased frequency of anxiety disorders after TBI may reflect an overlap between brain regions vulnerable to traumatic brain injury, and the neural circuitry of these disorders.
We've talked about some of the circuits at work (amygdala/prefrontal cortex, the uncinate fasciculus, etc).
What about infection and inflammation?
This is where there's really exciting new research.
The tell-tale signs of both (immune response) is all over general anxiety disorder:
analyses revealed significant differences in serum levels of IL-10, TNF-α, and IFN-γ between GAD and control groups after adjusting for age, gender, body mass index, smoking and alcohol consumption: these group differences were independent of the presence or degree of depression.
GAD is general anxiety disorder of course. Those strange chemicals are all inflammatory immune responders.
Did you notice that last little piece…"independent of the presence or degree of depression".
That's really important.
They found these various immune agents elevated for anxiety by itself!
There are dozens are studies like this all pointing in the same direction.
Immune response (which governs how our body deals with both infection and inflammation) is higher in people with general anxiety disorder!
Put a checkmark next to that for when we get to CBD. Very exciting.
One last stop...the gut!
This is the new Wild West of health...the trillions of bacteria in our gut.
How does this affect general anxiety disorder?
When they compared healthy people's guts versus those with general anxiety disorder, there were marked differences:
Compared with the HCs, we found markedly decreased microbial richness and diversity, distinct metagenomic composition with reduced short-chain fatty acid (SCFA)-producing bacteria (associated with a healthy status) and overgrowth of bacteria, such as Escherichia-Shigella, Fusobacterium and Ruminococcus gnavus
There's a great review of the "gut brain" axis here:
Keep in mind that serotonin and even GABA are synthesized in our gut!
One final note on THC, the other endocannabinoid in the cannabis that gets so much attention for its psychoactive properties.
Remember that all-important communication link between our Amygdala (fear processing) and our Frontal Cortex (rational brain)?
It was the only area showing reduced activity in the brain scans of people with GAD.
People who use cannabis showed reductions in volume for that very important communication link:
Compared to non-users, CU had worse memory performance, decreased fiber bundle length in the UF, and decreased cortical thickness of brain regions along the UF such as the entorhinal cortex and fusiform gyrus.
CU is short for cannabis users. UF is the uncinate fasciculus (the link between two brains).
This is not good!
General anxiety is not the only result of a poorly functioning UF. Again, it connects our "two brains".
Check out "Thinking Fast and Slow" book by Dr. Kahneman. Very fascinating!
Okay...so everything here in enlightening but a bit depressing.
We can't switch out genes yet. What is we have poor circuitry in the brain as a result of injury, illness, or inflammation?
What can we do now!
Long term effects of CBD on generalized anxiety disorder
We've covered the wide array of effects that CBD has on anxiety pathways including GABA and serotonin in linked articles but we want to focus on the long-term effects for general anxiety disorder.
So-called "trait anxiety".
Can CBD help with "structural" issues related to GAD?
The first clues came from studies on schizophrenia.
There's a powerful study where pre-psychotic people were given CBD and brain scans showed that abnormal signaling in brain circuitry "normalized":
Cannabidiol may partially normalize alterations in parahippocampal, striatal, and midbrain function associated with the CHR state.
This is profound. The participants basically had their psychotic states normalized to where a vast majority of them were no longer deemed as pre-psychotic by their doctors.
Learn all about CBD and schizophrenia or psychosis here.
It shows that the underlying endocannabinoid system is governed with "balancing" brain signaling for CBD to have this effect.
Remember that the net result of brain injury, inflammation or genetic variations with general anxiety disorder is irregular signalling (not enough GABA, not enough serotonin in specific areas, etc).
The ability of CBD to boost this balancing mechanism is fascinating.
What about actual brain structure? That's a long term consideration with GAD.
Remember how we noted that THC has been shown to adversely affect brain areas?
Most of the research on CBD on brain structure results from its protective role against these changes from THC.
THC's effects are here:
Across the 31 studies selected for inclusion in this review, neuroanatomic alterations emerged across regions that are high in cannabinoid receptors (i.e., hippocampus, prefrontal cortex, amygdala, cerebellum).
And CBD's effects in the studies?
Preliminary evidence shows that THC exacerbates, whereas CBD protects from, such harmful effects.
Can we reverse brain loss?
The key word there is neurogenesis (building new brain essentially).
This may be our favorite aspect of CBD and the one most important for general anxiety.
CBD induced a substantial increase in net neurogenesis by a CB1 receptor-dependent mechanism
What's the net effect of this reversal of brain loss?
increases hippocampal NPC proliferation via CB1 receptors, which may underlie the anxiolytic effect of CBD
What does anxiolytic mean?
Bear with us here. They are saying that a big part of CBD's effects on anxiety may result from spurring new brain growth in the hippocampus.
Remember that we said brain tissue and pathway loss is showing in new research as a key driver of both anxiety and depression.
All those inflammatory agents we noted above in the brain destroy brain tissue.
Chronic stress literally destroys neurons and their connections.
Both have been directly tied to general anxiety disorder.
Whether it's infection and stress, our body responds with an army and there's collateral damage.
The net effect...general anxiety disorder.
Why do some people react to stress with GAD while others don't?
Let's look at an interesting study which sheds light on this.
There are genes that affect how we will respond to stress.
Some of these are endocannabinoid genes such as FAAH.
In fact, faulty versions of FAAH can affect the very wiring of circuitry of the brain:
Individual differences in frontolimbic circuitry and anxiety emerge with adolescent changes in endocannabinoid signaling across species
we show effects of the FAAH genotype specific to frontolimbic connectivity that emerge by ∼12 y of age and are paralleled by changes in anxiety-related behavior.
This is really important for GAD as opposed to just anxiety.
There are brain changes as a result of this endocannabinoid gene that occur just when anxiety becomes present.
It gets more interesting.
We'll have to translate a bit since it gets very technical.
They found that the FAAH gene variant had a specific effect on the development of a particular piece of gray matter in the brain.
Can you guess what it is!
Ding ding ding. The uncinate fasciculus!! That bridge which showed up on the brain scans solely for people with general anxiety disorder.
Even more fascinating, the effect of this FAAH gene variant caused anxiety behavior (across species) in adolescents and adulthood...but not childhood.
It was tied to the development of general anxiety as result of brain development!
What does the FAAH gene do?
It breaks down Anandamide, our "bliss" molecule (also an endocannabinoid).
Too much FAAH (from gene variant) and you don't have enough Anandamide.
What's the net effect of FAAH on anxiety?
Reduced anxiety-like behaviour induced by genetic and pharmacological inhibition of the endocannabinoid-degrading enzyme fatty acid amide hydrolase (FAAH) is mediated by CB1 receptors
They block FAAH and anxiety goes down!
What does CBD have to do with this?
(we geek out on these reveals by the way)...
cannabidiol may enhance endogenous anandamide signaling indirectly, by inhibiting the intracellular degradation of anandamide catalyzed by the enzyme fatty acid amide hydrolase (FAAH)
It blocks FAAH!
It partially speaks to its anti-anxiety effects but we're curious to see if the combination of reducing FAAH and neurogenesis can repair or strengthen the uncinate fasciculus.
FAAH and Anandamide aren't the only endocannabinoid at play.
Let's introduce 2-AG, the most common endocannabinoid in the brain.
A great deal of our risk for GAD deals with our response to stress.
The endocannabinoid system naturally in our bodies is directly in charge of this response.
2-AG is a key player in this system:
The researchers found that augmenting the supply of 2-AG correlates with a stress-resilient phenotype and increases stress resilience in mice that were previously vulnerable to stress
Phenotype is a critical word.
It's speaks to the engrained, structural nature of a personality trait.
This isn't anxiety in reaction to finals!
This is a persistent anxiety type response.
It's the intersection of genes and environment for anxiety. Aka General Anxiety Disorder.
When they blocked 2-AG, participants were less able to handle stress and more anxiety.
What does CBD do with 2-AG?
CBD has been shown to boost 2-AG signaling by blocking its breaking down.
Again, we go through lots of pathways for anxiety and CBD here.
One final stop...does CBD protect against neuroinflammation?
Remember that infection, auto-immune, and inflammation (all in the immune system's wheelhouse) are directly tied to general anxiety disorder.
Can CBD help there?
Cannabidiol reduces neuroinflammation and promotes neuroplasticity and functional recovery after brain ischemia
A great deal of this research came from CBD's protective effects after brain hemorrhages or strokes (ischemia).
Now let's get specific.
Remember the specific inflammatory markers that were elevated for people with general anxiety disorder?
IL-10, TNF-α, and IFN-γ
It's not Klingon...but our immune responders.
The levels of IL-4, IL-5, IL-13, IL-6, IL-10, and TNF-α were determinate in the serum. CBD treatment was able to decrease the serum levels of all analyzed cytokines except for IL-10 levels.
Interestingly, CBD will boost or lower levels of IL-10 depending on the immune response need.
This is the exciting new world of immunopsychiatry (a new field really).
Since we want long term changes for general anxiety disorder, let look a great combination.
CBD and Meditation (or Yoga)
Stay with us here.
CBD has been shown to be neuroprotection and promote neurogenesis (new brain mass and connections).
Now combine this with new research on mindful meditation:
MBSR participants showed a significant increase in fractional anisotropy in the UNC, while controls did not (group by time interaction missed significance).
The UNC is none other than the uncinate fasciculus we discussed above for general anxiety disorder.
Basically, mindful medication was shown to increase volume in this connection between our fear center (amygdala) and our rational brain (prefrontal cortx).
All the usual anxiety suspects were affected in the brain:
Studies that have examined mindfulness meditation-induced structural and functional changes in the brain have identified a number of implicated brain areas (Hölzel et al., 2011b; Fox et al., 2014; Tang et al., 2015), including limbic regions (e.g., Hölzel et al., 2010, 2011a), and regions in the orbitofrontal cortex (e.g., Hölzel et al., 2008).
The orbitofrontal cortex is studied in our CBD and anxiety article.
The limbic regions include the Amygdala!
All the players are at this party!
These are two very powerful actors for neuroprotection and neurogenesis.
Comparing CBD versus medications for generalized anxiety disorder
The usual suspects come up with generalized anxiety disorder:
Benzodiazepines (Xanax, Ativan, Valium, Klonopin, and others)
SSRI's and SNRI's (Lexapro, Effexor, Zoloft, and others)
We don't mess around (because we personally had to get off of them for anxiety!)
We'll leave the heavy lifting to those articles but let's look at the long term use of those meds since we're talking about general anxiety disorder versus an episodic flare-up.
There is no long term usage!
- Benzos are highly addictive and recommended for short durations.
- SSRI's will normalize as the brain/nervous system adjusts to this boost in serotonin by reducing its own levels.
This is why people eventually have to be changed to other SSRI's and the whole game starts again.
Those are the two main classes that are prescribed for general anxiety disorder.
Not great options.
As for safety, it's no comparison.
This truly is the part that we find so frustrating.
Check out CBD's safety profile but compared to severe addiction and withdrawal (benzos) or a host potential nasty side effects (SSRI's), CBD Isolate has a strong safety profile.
Some caveats there.
It can't have THC.
It should be Isolate (not full spectrum which everyone is selling).
We'll discuss those two items below but first, what about dosage for general anxiety disorder.
Here's where we arm you with research on anxiety specifically!
How much CBD for generalized anxiety disorder (very important)
Research is pointing to both a short term and long term dosage consideration for anxiety.
You can learn all about the process at our how many mgs of cbd for anxiety article.
Start slowly (generally 20-30mg) to test your body.
An NIH study showed tested CBD at 150 mg, 300 mg, and 600 mg.
They found a significant anti-anxiety effect at the 300 and 600 mg level.
The neurogenesis (building new brain connections and neurons) peaked around 300 mg and dropped as we went up to 600 mg.
For general anxiety disorder, we really want this long term effect.
Remember that GAD has systemic roots...damage, poor connections, genetic variances.
Our best approach is to try to correct these structural issues with the neurogenesis effect.
That lies on a bell curve according to the study and starts to decrease above 300 mg.
For that reason, a dosage between 50-300 mg would be ideal depending on the severity of your anxiety.
One more key point for general anxiety disorder.
Best CBD for general anxiety disorder
We discussed how GABA does all the heavy lifting for calming not only our brain activity but also our mood!
It's key to sleep and calm.
Stress, inflammation, excess glutamate will eat it up!
So will histamine!
Histamine and GABA are in a tug of war for sleep/wake cycle as well as calm/alert cycles.
The bulk of the CBD makers are pushing "full spectrum" CBD.
This is basically the full plant material included.
Here's the issue (as our partner found out the hard way)...
40-60% of people have histamine issues and their response to all that plant material may cause histamine responses!
This is especially true for women and people over age 40.
If you have allergies, full spectrum is going the wrong direction.
One other small factor...all the research is based on CBD Isolate by itself!
Learn all about the full spectrum versus CBD Isolate for anxiety argument here.
IndigoNaturals was partially created as a reaction to 3-4 of the biggest CBD brands on the market.
Bad reactions due to histamines!
We base everything on research here.
We take the product for our families after all.
Check out my story for more supplements I found which affect the anxiety pathway.
One final note for people who are truly suffering from general anxiety disorder.
Don't assume tomorrow is like today. The CRSPR technology looks to totally revolutionize medicine and it's coming sooner than the naysayers tell.
We'll take just a slice of that please!
Genetics are at the root of this issue and we'll use CBD to get us there!
Be well and be hopeful even when it's the hardest thing to do.
We've been there!