We've covered many aspects of CBD's benefits for anxiety.
Dozens of NIH studies.
While researching how CBD and Anxiety medications compare, we came across an interesting piece of the puzzle.
CRF. Corticotropin-Releasing Factor.
We understand if your eyes glaze over but stick with us.
See our article on Does CBD reduce cortisol for stress and anxiety
The payoff is there for anxiety.
It's a critical piece of the anxiety pathway and CBD can have a direct (and positive) effect.
We'll cover these aspects below:
- What is CFR?
- The curious effect of CFR and SSRI's for anxiety and depression
- The endocannabinoid system and CFR with anxiety
- Does CBD help with CFR's effects on anxiety
Let's get to it.
What is CFR?
CFR is a chemical deeply tied to stress response in the brain and nervous system.
See our article on CBD and GABA and How CBD affects acetylcholine the best kept secret neurotransmitter.
We have an entire system dedicated to responding to stress.
It's called the HPA axis (short for Hypothalamic - Pituitary - Adrenal).
These are the three areas that generate stress response chemicals such as adrenaline, norepinephrine, and other glucocorticoids.
CFR is a master regulator of these chemicals.
A big result of CFR is cortisol!
Learn all about the importance of cortisol with anxiety in our CBD for stress and anxiety article.
Simply put for CFR:
Corticotrophin-releasing hormone also acts on many other areas within the brain where it suppresses appetite, increases anxiety, and improves memory and selective attention.
As with all things, it's the chronic exposure to CFR that can lead to anxiety and other issues.
The mechanism should be familiar if you've read our article on CBD benefits for anxiety here.
Stress toxicity could also favor hyperactivity in the amygdala which may enhance fear responses to environmental cues while decreasing neural inhibition in dlPFC and ventromedial PFC; chronically stressful conditions can fail to maintain effective executive control over limbic overdrive.
Let's translate that since it's important.
The amygdala is a key suspect in anxiety.
It functions as our fear (and emotional center).
It's countered by the prefrontal cortex (PFC in the above sample).
Essentially, too much stress and CFR makes the amygdala bigger and stronger.
The watchdog of fear, our prefrontal cortex is no longer able to "maintain effective executive control" as they put it.
The net effect...anxiety!
Learn all about this anxiety "circuit" at our CBD and anxiety article.
Now, let's look at why SSRI's, commonly prescribed for anxiety, can boost anxiety and depression in the first few weeks.
The curious effect of CFR and SSRI's for anxiety and depression
SSRI stands for Selective Serotonin Reuptake Inhibitor.
It's a popular class of medications prescribed for both anxiety and depression.
You can learn all about CBD versus SSRI's for anxiety here.
See our article on a complete guide to CBD and serotonin.
They basically boost levels of serotonin available to neurons in the brain.
The problem is that serotonin is a workhorse of signaling in the brain.
- Boost it in one area and you might get a reduction in anxiety.
- Boost it in another, and might get an increase in anxiety.
This is exactly what happens with SSRI's and CFR.
There's a curious result of a person just starting SSRI's for anxiety.
For the few two weeks, there can be an INCREASE in anxiety or depression.
If SSRI's, and more importantly, serotonin, is so ideally suited for the condition, why would we see an initial increase in the very thing we're trying to address?
It's a cascade effect the net result is more CFR which causes more anxiety:
Kash and his team observed that the anxiety-mediating BNST neurons expressed the stress-signaling molecule corticotropin-releasing factor (CRF). When they added a compound to block CRF activity, they witnessed those fearful behaviors -- which had been triggered by fluoxetine -- were greatly reduced.
Fluoxetine is a popular SSRI (Prozac).
Interestingly, when the CFR is blocked separately, the anxiety effects of the SSRI are reduced: When the team added a compound to block CRF activity, the fear and anxiety that had been triggered by the Prozac were greatly reduced.
This is why many doctors will prescribe benzodiazepines (like Xanax, Ativan, or Valium) for the first few weeks.
They'll often say this is because it takes time for SSRIs to kick in but that's not entirely true.
It's to mask the increased anxiety or depression:
Combine this with the fact that SSRI's normalize (effect goes away with time), have significant side effects, and are generally helpful in 30% of those prescribed.
That's for depression.
See our article on CBD and brain repair for anxiety
In general, the SSRI's work better for people who have anxiety along with depression.
The two are known to travel together or share a "comorbidity".
This doesn't surprise us if you look at the new research on inflammation and anxiety or neurogenesis and anxiety.
New research is pointing to inflammation as a key driver of mental health issues in general.
Overactive CFR activity has also been shown in depression as well:
In depression, hyperactivity of corticotropin-releasing factor (CRF)--producing neurons contribute to the well-characterized hypothalamic-pituitary-adrenal axis hyperactivity of depression.
Is there another way to address this CFR piece of our anxiety puzzle?
The endocannabinoid system and CFR with anxiety
If you read our CBD and stress response for anxiety article, something becomes apparent from the research.
The endocannabinoid system is a key regulator of our stress response.
The CFR is a key initiator of our stress response.
Do the two intersect?
We all have an endocannabinoid system which is tasked with balancing key systems:
- Nervous system - neurotransmitters such as serotonin, CFR, and GABA
- Immune system - inflammatory response
- Endocrine system - hormones such as leptin (which reduces CFR levels)
It's a mouthful but we're going straight to the heart of it:
Corticotropin-Releasing Hormone-Mediated Induction of Intracellular Signaling Pathways and Brain-Derived Neurotrophic Factor Expression Is Inhibited by the Activation of the Endocannabinoid System
Basically the researchers found that CB1 receptors (endocannabinoid sites in the brain) are needed to reduce CFR levels!
In fact, when other researchers knocked out these CB1 genes, anxiety was a result:
Mutant mice lacking CB1 receptors show anxiogenic-like and depressive-like phenotypes in several tests, as well as profound alterations in their adrenocortical activity.
That's the "anxiogenic" word...it means anxiety!
The adrenocortical activity speaks to our stress response chemicals.
There are two main endocannabinoids found naturally in the brain:
Let's look at anandamide in relation to CFR.
If you read our article on the woman who can't feel pain or anxiety (or depression) here, you'll recognize the importance of anandamide.
Here's what researchers found in regards to anandamide and CFR:
Preclinical models reveal that stress-induced amygdala activity and impairment in fear extinction reflect reductions in anandamide driven by corticotropin-releasing factor receptor type 1 (CRF1) potentiation of the anandamide catabolic enzyme fatty acid amide hydrolase.
Basically, CFR was driving down Anandamide after stress caused damage to the amygdala, the key brain area for anxiety.
To put a point to it:
interactions between anandamide and CRF1 represent a fundamental molecular mechanism regulating amygdala function and anxiety.
Ummm...did you just read that? Try it on one more time for size.
More research makes it clearer yet:
Corticotropin-releasing hormone drives anandamide hydrolysis in the amygdala to promote anxiety.
"Hydrolysis" just means the process of breaking something down or reducing it.
CFR breaks down anandamide and the result is....anxiety!
Can we boost anandamide to offset CFR and anxiety?
Glad you asked…
Central anandamide deficiency predicts stress-induced anxiety: behavioral reversal through endocannabinoid augmentation
These data indicate that central anandamide levels predict acute stress-induced anxiety, and that reversal of stress-induced anandamide deficiency is a key mechanism subserving the therapeutic effects of FAAH inhibition.
To translate..boost anandamide by blocking the chemical that breaks it down...FAAH. Anxiety from stress is reduced.
That's the same chemical the woman has very low levels who are unable to feel pain or anxiety.
So..that begs the question.
How can we "augment" anandamide and the endocannabinoid system?
Does CBD help with CFR's effects on anxiety
First, we'll jump right to the question of anandamide support.
The originally studied CBD's boosting of anandamide while studying schizophrenia:
Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia
See our article on CBD and schizophrenia and psychosis.
What about anxiety specifically and CFR?
Reduction of AEA–CB1R signaling in the amygdala mediates the anxiogenic effects of corticotropin-releasing hormone , and CB1R activation is essential to negative feedback of the neuroendocrine stress response and protects against the adverse effects of chronic stress
If the stress is chronic, you can see actual changes in brain structure across key areas tied to anxiety:
Finally, chronic stress impairs eCB signaling in the hippocampus and amygdala, leading to anxiety
See our article on Can CBD stimulate hippocampus neurogenesis for anxiety.
A more sophisticated study looked at actual gene expression:
Interestingly, cannabidiol at low (5 mg/kg) and intermediate doses (15 mg/kg) successfully blocked the effects induced by acute stress on corticotropin-releasing factor, pro-opiomelanocortin, and glucocorticoid receptor gene expression.
This effect appears to occur via the serotonin (5HT) pathway.
Which brings us full circle back to why SSRIs cause anxiety and depression in the first few weeks.
Serotonin is boosting CFR release which can lead to anxiety.
CBD above is shown to inhibit CFR release...through serotonin effects!!
The beauty of the endocannabinoid system (which CBD supports) is that it's one of balance.
It doesn't just push in one direction!
As one (of 100's of examples), when they exposed the mice to restraint stress, the gene expression did not reflect a stress response after CBD dosing.
Simply put, CBD improved their "resiliency".
Let's look at a very important consideration for a good half of the population in terms of the best CBD to help with the stress response.
Best CBD for stress response via corticotropin-releasing hormone
Roughly 40-60% of the population has histamine issues (think allergies).
That number goes higher for women and even higher if over age 40.
Histamine is excitatory in the brain. In the opposite direction, we want to go with anxiety.
See our article on Why you should only take isolate for histamine and allergy issues.
In fact, histamine is shown to drive the release of corticotropin-releasing hormone:
We conclude that HA stimulates hypothalamic CRH and OT neurons by increasing mRNA levels, and this effect seems to be mediated via activation of both HA H1 and H2 receptors.
Why does this matter for the type of CBD we take?
The vast majority of the market is pushing full-spectrum CBD.
It's essentially hemp oil with CBD added back to a certain level.
All that plant material can send a person with histamine issues in the wrong direction.
That's why so many people have bad initial reactions to CBD oil.
CBD isolate usually clears the side effects right up in our experience.
Learn all about why CBD isolate is better for anxiety here.
The histamine-CFR connection is just one more piece of the puzzle.
The full puzzle can be found at our histamine, CBD, and anxiety article above.
We crafted IndigoNaturals based on research and the research is all for CBD by itself.
Master overview of CBD and anxiety pathways to look at various aspects we can directly affect.
Links to CBD and anxiety research with dozens of anxiety-specific topics.
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.