Can CBD Stimulate Hippocampus Neurogenesis for Anxiety (and other issues)?
Thank goodness the original researchers were wrong.
For decades, science has been telling us that the neurons we are born with are all we ever get.
It's only downhill from there.
Any damage from inflammation, infection (during critical times of development), injury, or chemical exposure is locked in.
Turns out that isn't true.
Pretty recently, scientist have determined that the adult brain can make new neurons and has an entire system for this undertaking.
Nowhere is this more prevalent in the brain than the hippocampus.
This is especially important for anxiety, depression, PTSD, and a host of mental health issues.
Not to mention memory!
Interestingly, our hippocampus naturally shrinks about 2% each year from age 30 on.
Are there ways to offset or even push the needle the other way?
We're going to look at all of it!
We'll then look at CBD and two other ways to actually spur neurogenesis in the hippocampus.
The focus will be on hippocampus effects on anxiety but the same calculus applies for many issues since the hippocampus is such an interconnected system.
Here are the main topics we'll get into:
- What does the hippocampus do
- How is hippocampus brain loss tied to anxiety
- What can damage or shrink the hippocampus
- Can damage to the hippocampus be repaired
- How is the endocannabinoid system involved in hippocampus neurogenesis
- Can CBD help with hippocampus neurogenesis
- Other things that help with hippocampus brain repair
- The best CBD to take for hippocampus repair
- How much CBD to take for hippocampus neurogenesis and brain repair
Lot's to cover.
What does the hippocampus do?
The name is greek for "sea horse" due to its similar look.
The hippocampus is best known for its role in memory formation and spatial mapping.
In fact, the hippocampus is one of the first brain areas to show damage or loss with Alzheimer's.
Injuries to the hippocampus can result in a type of amnesia where memories are able to form or be placed in long term memory.
We're more focused on its role in emotional processing.
The hippocampus is part of our limbic system which is the oldest part of the brain.
It's sometimes referred to as the "reptilian" brain since we share this system with most living things including reptiles!
It's that old evolutionarily speaking.
The hippocampus function in anxiety is pretty new and very fascinating!
Stay with us...the payoff is worth it.
First, it was found to be the seat of approach-avoidance behavior.
This is a setup where we (or a poor test mouse) has to make a decision that might result in reward or punishment.
There's a state of anxiety that's caused by this decision which is natural.
Think of blackjack. Dealer's showing 18. You have 12. Do you get another card knowing that it's likely a 10 but also knowing that 18 will beat you now?
There's a blip of anxiety there.
In fact, they found two areas in the hippocampus tied to this.
If you block one, you tend to seek confrontation or approach (draw card). If the scientist block the other one, you tend hold (don't draw card). The two areas generally compete against each other.
The "fight" or "approach" area is C3. The "flight" or "avoid" area is C1.
The results of one area being dominant are fascinating.
- Too much "conflict" might be tied to addiction, impulsivity, ADD.
- Too much "avoidance" might be tied to anxiety or depression.
More info here:
That was the first clue that the hippocampus was even in play with anxiety circuits which tend to be associated more with the amygdala and prefrontal cortex.
When scientists injected GABA (see CBD and GABA for anxiety),our "brake" neurotransmitter into the hippocampus:
Specifically, γ-aminobutyric acid type A receptor agonists, both direct and indirect, reliably inhibit a number of animals' untrained anxiety reactions when microinfused into the hippocampus,
Other neurotransmitter injections also created an antianxiety effect.
In another study on social anxiety (see CBD and social anxiety), activity in the hippocampus was the difference between treatments helping or not:
In treatment-responders, irrespective of type of treatment, improvement was accompanied by a decrease in regional cerebral blood flow in the hippocampus, amygdala and the periamygdaloid, rhinal and parahippocampal cortices.
Finally and maybe more importantly, there's this…
‘Anxiety Cells’ Identified in the Brain’s Hippocampus
The scientists were able to turn "anxiety" on and off by stimulating those cells.
When the anxiety cells were stimulated, the mice exhibited more fear behaviors even when they were in “safe” surroundings.
These cells are found in the part of the brain tied to our "avoidance" area above.
Everything's a threat!
Sound like something we know?
So...it appears that two separate areas of the hippocampus act as proxy for fight or flight.
We can even see the effect of this in our stress response:
The hippocampus exerts strong regulatory control of the hypothalamic-pituitary-adrenal axis.
The HPA is the hub of your stress response. Fight or flight.
We'll also see how the arrow goes the other way...stress can negatively impact your hippocampus (a vicious cycle).
So...to our original question...can hippocampus loss cause anxiety?
How is hippocampus brain loss tied to anxiety?
The clues have been building.
PTSD (an acute form of stress related illness under the anxiety umbrella) showed obvious results:
A study of Vietnam War combat veterans with PTSD showed a 20% reduction in the volume of their hippocampus compared with veterans having suffered no such symptoms
Trying to get to the root of this, researchers then bred mice who had hippocampus damage:
These results suggest that hippocampal dysfunction enhances the development of persistent avoidance responding and, thus, may confer vulnerability to the development of anxiety disorders and PTSD.
Another study took twins where there was a difference in hippocampus volume who were both exposed to war:
Importantly, the twin sibling of the combat-exposed PTSD subject had reduced hippocampal volume compared to the twin sibling of the combat-exposed non-PTSD subjectshttps://indigonaturals.net/blogs/news/can-cbd-help-with-social-anxiety
Remember the CA3 area above (the "fight" area in our hippocampus)?
A recent study, using high resolution MRI, showed that reduced hippocampal volume in PTSD patients is localized to the CA3/DG region of the hippocampus
It's not just PTSD though. Anxiety is a discount version.
Excessive avoidance is a core feature of all anxiety disorders and is a core component of PTSD diagnosis
That's right from the Manual of Mental Disorders.
Another study found that reduced hippocampus function in rats did not affect acquiring new "fears" but interfered with forgetting old ones!
The net effect on hippocampus tissue:
hippocampal and cortical volume was reduced in WKY rats compared to SD rats
As for anxiety directly…
Depression and anxiety are commonly comorbid (Kessler et al., 2003), and a smaller hippocampus has been associated with both disorders
Too much flight signaling and not enough fight. A fear-centric hippocampus.
- When they caused damage in the approach area, anxiety resulted.
- When they caused damage in the avoid area, risky behavior resulted.
It's a beautiful system really. When it's in balance.
Let's look at the primary drivers of hippocampus loss and imbalance.
What can damage or shrink the hippocampus?
Yes, there can be hippocampus loss due to a variety of reasons besides age:
- Infection (in utero or after birth during critical periods)
- Genetic predispositions
But by, far the biggest culprit these days is stress.
The entire brain is under the same assault from chronic stress but the hippocampus really gets hit hard.
As researchers sum up:
Chronic stress is a pathological state that is caused by prolonged activation of the normal acute physiological stress response, which can wreak havoc on immune, metabolic and cardiovascular systems, and lead to atrophy of the brain's hippocampus (crucial for long-term memory and spatial navigation).
It's not just the hippocampus though and the link between chronic stress and anxiety is written all over in the anxiety "circuit":
The researchers noted similar patterns of abnormal brain activity with fear/anxiety and chronic stress -- specifically an overactive amygdala (associated with emotional responses) and an under-active PFC (thinking areas of the brain that help regulate emotional responses through cognitive appraisal).
But why does the hippocampus take so much punishment from long term stress?
As we mentioned, cortisol is our main stress hormone.
It's effects on the hippocampus are very clear when applied chronically.
Remember when we said that the hippocampus is a primary regulator of the HPA axis (our stress pathway in the body)?
For this reason, the network of our stress response is heavily wired into the hippocampus:
The hippocampus contains high levels of glucocorticoid receptors, which make it more vulnerable to long-term stress than most other brain areas
As you can learn from our CBD and cortisol for anxiety, cortisol is our primary glucocorticoid.
There's actually a feedback loop where more cortisol or stress chemicals should start to dampen the hippocampus response.
This is to eventually find balance again after a stressful situation has passed.
What happens when stress is chronic?
These adaptational effects of the hormones may become maladaptive if the stressful event is associated with other challenges of the network (like ischemic insults) or when stress occurs repetitively, in an uncontrollable and unpredictable manner.
That feedback loop where cortisol is so supposed to go back down starts to fail.
Enough stress for a long enough time actually leads to loss of hippocampus volume:
Studies are described to show that chronic stress or prolonged exposure to glucocorticoids can compromise the hippocampus by producing dendritic retraction, a reversible form of plasticity that includes dendritic restructuring without irreversible cell death.
A slew of bad things happen:
- Serotonin levels drop
- Levels don't come back to normal as well
- Overall function reduces with time
The controller of stress response and anxiety is off the clock!
That first one is really important.
Serotonin is key to neurogenesis or the ability to repair and regrow brain tissue (especially in the hippocampus).
In fact, new research is showing that SSRI's (which boost serotonin) may have their effect on anxiety (and depression) because of this boost to neurogenesis:
5-HT1A and 5-HT4 receptor signaling, either independently or cooperatively, modulates the function of the hippocampal DG at multiple levels, any of which could play a critical role in the antidepressant actions of 5-HT-enhancing drugs.
5-HT is the serotonin pathway. DG is the dentate gyrus where new neurons are created for the...hippocampus!
That's not on the label! The many side effects are however.
What a great segue into the next question...
Can damage to the hippocampus be repaired?
This is where new research is so exciting (and hopeful!).
As we mentioned before, scientists use to think that adults couldn't build new brain.
Turns out it happens all the time!
There are three things that we have found in research which can repair brain issue including the hippocampus:
- Mindful Meditation
Yes, it's a strange triumvirate but the research is solid.
You can find details and the research at our CBD, meditation, and exercise for neurogenesis article.
We'll leave that article to dive into each one's effect on the neurogenesis pathway.
It helps to look at the mechanisms that spur this activity in the brain (besides bringing down the inflammatory stress response which is causing it).
Two key players show prominently:
- Serotonin - mentioned above
These are both chemicals found naturally in the brain which support the creation of new tissue.
Serotonin is usually thought of as the lever for depression (and to a lesser degree, anxiety).
Interestingly, when scientist deplete serotonin and tryptophan (its precursor) in healthy individuals, they do not become depressed (or anxious).
See Tryptophan and Serotonin for anxiety for more information on that.
This speaks to lots of new research showing that inflammation and stress chronically applied or early in life when the brain is developing may be the culprit.
There's a great summary of this evolving theory of serotonin here:
Is serotonin important for neurogenesis?
One of the most important factors regulating proliferation in the DG is serotonin. Brezun and Daszuta (1999) 192 R.L. Djavadian found, that depletion of serotonin in the brains of adult rats decreased the numbers of the BrdU-labeled (newly generated) neurons in both SVZ and DG
If you want some heavy lifting, that article is pretty thorough on this entire interaction.
What about BDNF?
Brain-derived neurotrophic factor (BDNF) is required for the enhancement of hippocampal neurogenesis following environmental enrichment.
Like we said...two critical players. Wait till you see the effects of CBD on both (and consequently neurogenesis and hippocampus repair).
The brain has systems for building new tissue and destroying tissue which hopefully are in balance.
The minute we say balance, the endocannabinoid system figures prominently.
Let's go there now.
How is the endocannabinoid system involved in hippocampus neurogenesis?
We all have an endocannabinoid system naturally in our body.
It has its own players such as anandamide and 2-AG in the brain.
Think of this as a checks and balances system for other key systems:
- Nervous system - including neurotransmitters like serotonin and chemicals like BDNF
- Endocrine system - hormones like cortisol
- Immune system - important inflammatory agents which can damage nerves if excessive
So you can see how it's intimately involved in balancing cell birth/death in the brain and hippocampus.
Just a few key studies on their interaction.
When scientists blocked CB1 receptors (where cannabinoids do their work):
Cannabinoid receptor signaling may regulate the balance of progenitor cell survival and proliferation in adult mouse olfactory epithelium.
Another study went further:
Defective Adult Neurogenesis in CB1 Cannabinoid Receptor Knockout Mice
What area were they looking at?
The DG and SVZ (two prominent areas of the hippocampus for new neurons).
There are dozens of studies that effect.
We'll leave with this for the system itself before jumping into CBD's effects on hippocampus neurogenesis:
Endocannabinoids (eCB) are one of the main systems controlling both excitatory and inhibitory neurotransmission, as well as neuroplasticity within the hippocampus.
"Neuroplasticity" is just a fancy word to say that the brain can change and repair over time.
In fact, this system's duress under stress may be a big part of our hippocampus damage problem:
Also, chronic stress modulates hippocampal CB1 receptors expression and endocannabinoid levels.
There's that stress effect again!
So, we have damage whether from in utero infection from our mother or years of stress.
Can CBD help there?
Can CBD help with hippocampus neurogenesis
CBD is a cannabinoid which can support the system above when it's under duress.
We'll look at the facets of CBD's effect on neurogenesis in the hippocampus with more detail but a summary level:
CBD did not impair learning but increased adult neurogenesis
We found the neurogenic effect of CBD to be dependent on the CB1 receptor, which is expressed over the whole dentate gyrus
The dentate gyrus is the same DG we've seen up above and is where new hippocampus neurons are born!
Now, let's drill down a bit.
What about the intersection of stress and anxiety?
Glad you asked:
The anxiolytic effect of cannabidiol on chronically stressed mice depends on hippocampal neurogenesis: involvement of the endocannabinoid system
Anxiolytic just means anti-anxiety.
Let's translate this interesting study because it's too important.
They basically stressed out mice and gave them CBD which had an anti-anxiety (anti-stress if you think about it) effect.
They found an increase in neurogenesis as a result of the CBD (where stress usually impairs this growth).
They then blocked the neurogenesis with a specific chemical and the anti-anxiety effect was significantly reduced!
Think about that.
Research is showing that anxiety (and depression) may partially be a result of damage to our hippocampus not being able to be repaired or replenished at the same rate it's under attack.
Picture mickey mouse with the buckets of water (stress hormones like cortisol in this case).
He's unable to catch up.
CBD is a like an extra set of hands to support this repair system.
Interestingly, the same can't be said for THC which can actually distort various brain regions.
The good news is that CBD actually helps to protect against this effect.
See THC versus CBD for anxiety article for full detail.
Let's go even one level deeper.
To serotonin and BDNF for hippocampus neurogenesis.
We'll start here:
Cannabidiol modulates serotonergic transmission and reverses both allodynia and anxiety-like behavior in a model of neuropathic pain
Allodynia is basically neuropathic pain or increased pain threshold.
By the way, new research is tying this together with depression and anxiety.
Learn all about CBD and serotonin here.
What about BDNF?
We're going to end with this because it basically ties it altogether:
Cannabidiol Induces Rapid and Sustained Antidepressant-Like Effects Through Increased BDNF Signaling and Synaptogenesis in the Prefrontal Cortex.
Synaptogenesis means to create new brain pathways and connections.
The prefrontal cortex is the rational counterweight to the fear center (amygdala)...key to the anxiety circuit.
Wait a minute...we're talking about the hippocampus. Oh yes…
The acute antidepressant effects (30 min) were associated with increased expression of synaptophysin and PSD95 in the medial prefrontal cortex (mPFC) and elevated BDNF levels in both mPFC and hippocampus (HPC).
All are directly tied to what can damage brain areas...especially the hippocampus.
There we go. Again, these are a few of dozens of NIH studies on CBD and hippocampus neurogenesis.
Other things that help with hippocampus brain repair
We mentioned exercise and mindful meditation which have also been shown to increase volume in different areas of the brain.
The three combined should speed the process and increase the effect!
Check out research and detail including how much, how often, and how long for each based on research here:
The best CBD to take for hippocampus repair
A few important tips here.
We want NO THC.
THC can actually have the opposite effect.
In fact, studies show that CBD may offset the negatives of THC on brain function including enlargement of the amygdala (key to anxiety) and increased cortisol release.
As for THC itself:
Delta-9-tetrahydrocannabinol (Δ-9-THC) was hypothesized to produce dose-related increases in plasma cortisol levels and decreases in plasma prolactin levels. F
Learn all about CBD versus THC or cannabis for anxiety here.
We also want CBD isolate instead of full spectrum.
40-60% of the population has histamine issues (higher for women and higher if over 40).
Histamine is excitatory in the brain and that's going to cause an inflammatory response which is the opposite direction we want to go with an already stressed out system.
Check out research on CBD, histamine, and anxiety for more detail.
Everyone out there is pushing full spectrum CBD but based on what??
The 100's of studies we've reviewed are based on CBD isolate (by itself) including those above for neurogenesis.
At IndigoNaturals, we base everything on research and we dig deep (hopefully that's obvious).
Here are vetted options for neurogenesis based on the research above (with an interesting note on dosage below specifically for neurogenesis):
How much CBD to take for hippocampus neurogenesis and brain repair
Here, we actually have some good data.
Studies that looked at anxiety found a dose dependent effect on anxiety but a bell curve for neurogenesis.
They found that neurogenesis increased up till about 300 mg of CBD and then trailed off up to 600 mg of CBD.
For this reason, we likely do not want to go higher than 300 mg.
A good starting dose is around 25-50 mg to test how it feels for you.
These studies reflect higher amounts and cost is an issue.
For that reason, we price all our CBD at between 3-6 cents per mg of CBD isolate.
It's the best on the market for a reason.
Our company was born out of a devastating anxiety caused from perimenopause hormone drop and an adverse reaction to a typhoid oral vaccine (that story here).
It was a full year of suffering that finally brought us to CBD after benzos, SSRI's and the like almost did us in.
We want to reduce similar suffering. Point.