Serotonin gets all the glory for helping to repair the brain following stress and injury.
Meanwhile, BDNF does ALL the heavy lifting.
There's even brand new research pointing to a key role for NT-3 with anxiety.
Most people are not going to be familiar with this whole family of chemicals that are in your brain right now.
They should be!
In fact, you can look at BDNF levels as a biomarker for age (or Alzheimer's progression).
We'll go into the key aspects tied to building, repairing, and remapping neuron and pathways as it applies to anxiety (one example).
The same mechanisms are at play for depression, OCD, PTSD, and a range of mental health issues.
BDNF is the superstar of mental health and addiction. Point.
In fact, the two key drivers for addiction relapse:
- Stress levels
- BDNF levels
Goodness.
New genetic discoveries are furthering the connection and we'll look at those as well.
More importantly, we'll look at what can increase neurotrophin expression including CBD.
You won't believe the connection between BDNF and the endocannabinoid system where CBD operates!
We'll cover these topics:
- How do neurotrophins work
- What is doing all the damage that neurotrophins repair
- BDNF and anxiety
- NT-3 and anxiety
- The curious effect of psilocybin and neurotrophins
- Hormones and neurotrophins
- Aging and neurotrophins
- BDNF and serotonin (the lever drive of SSRI's)
- The endocannabinoid system and neurotrophins
- Can CBD increase neurotrophins like BDNF and NT-3
- What else can increase neurotrophins
- How much CBD to increase neurotrophins
- What's the best CBD to increase neurotrophins
Let's get started...there's a brain to rebuild!
How do neurotrophins work
Let's break the word down.
- Neuro - neuron
- Tropin - nourishing, stimulating
We've described BDNF as fertilizer for the brain and that's an apt concept.
Our brain and nervous system have an entire system for breaking down and building neurons and connections.
It's a very dynamic system as we're constantly creating new pathways.
Just reading this sentence is causing new connections in your brain right now.
Those connections are driven by neurotrophins both constructive and destructive (clear out space for new connections).
Some main neurotrophins are:
- NGF - nerve growth factor
- BDNF - brain-derived neurotrophic factor
- NT-3 - Neurotrophin 3 (they ran out of nifty names by then)
- NT-4 - Neurotrophin 4
- DHEA and DHEA sulfate - hormone derivatives from pregnenolone (see full review on pregnenolone for aging and health)
Those are the big players and we'll look at each in context with anxiety with a focus on BDNF and NT-3.
We've written dozens of articles with 100's of thousands of words combined across a wide range topics tied to anxiety and CBD.
A common trend keeps popping up.
Various insults to the brain outgun our brain's ability to repair or our repair system isn't functioning at full tilt.
BDNF pops up throughout the NIH research on anxiety along with serotonin.
You can basically search for BDNF and almost any mental illness to find telling research.
- Depression
- Schizophrenia
- Autism
- OCD
- Bipolar
- And yes...anxiety
Again, BDNF
Neurotrophins not only spur new neurons to be born, they are the mechanism standing between a neuron and cell death:
Neurotrophic factors are secreted by target tissue and act by preventing the associated neuron from initiating programmed cell death – thus allowing the neurons to survive.
https://en.wikipedia.org/wiki/Neurotrophin
This general effect of neurotrophins that we're interested in is called neurogenesis.
We've written extensively on it here:
- CBD and hippocampus neurogenesis (the hippocampus is very vulnerable to damage)
- CBD and long term anxiety
- CBD, meditation, and exercise for neurogenesis and anxiety
Our master review is at CBD and brain repair where we look at how much CBD for peak neurogenesis.
Basically, our repair and growth mechanism in the brain.
And there's lots of potential assassins to the lonely neuron.
Let's go there now.
What is doing all the damage that neurotrophins repair
Check out our CBD and mechanisms of anxiety for more detail but the various adversaries of BDNF are:
- Chronic stress
- Acute stress or trauma (see CBD and trauma)
- Infection and viral activity
- Overactive immune reaction (see CBD and neuroinflammation)
- Chemicals, pesticides, and antibiotics
Some quick examples with references for much more.
Chronic stress (see CBD, stress, and anxiety) and neurotrophins
What's the effect of stress on BDNF levels in research?:
In these animals, BDNF mRNA levels were significantly decreased in the hippocampus after 6 h of restraint
https://www.ncbi.nlm.nih.gov/pubmed/16024125
Essentially, chronic stress showed reduced DNA expression (mRNA) in that vulnerable area of the brain we talked about, the hippocampus.
We'll look at even more interesting detail below in the BDNF section.
Acute stress and neurotrophins
Acute stress (think trauma) is even more devastating to BDNF levels.
Look no further than PTSD for acute stress (See CBD and PTSD).
There's lots of research there:
As seen in Table 1, baseline median level of NGF was significantly lower in patients with PTSD than the trauma survivors with a large effect size
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5969740/
NGF is nerve growth factor, the first discovered neurotrophin.
Infection and virus activity and neurotrophins
The brain's immune system goes defcon 4 at the slightest whiff of bacteria crossing the blood-brain barrier.
For good reason.
Inflammation of your skin is a nuisance. Inflammation in the brain can be fatal!
Here's the rub.
The brain's immune system can actually cause damage to healthy cells which exhausts BDNF activity.
For example, with infection in the body (think flu), the brain will drop tryptophan levels to starve out the raw materials for making new bacteria or virus.
The problem is that our serotonin is made from tryptophan.
Check out a review at our CBD, tryptophan, and anxiety here.
Let's go back even further.
What about infections your mother has while pregnant with you?
That can't have an effect, can it?
Yes.
In fact, there's research on this effect and schizophrenia:
Maternal infection regulates BDNF and NGF expression in fetal and neonatal brain and maternal-fetal unit of the rat.
https://www.ncbi.nlm.nih.gov/pubmed/12742653
Just exposing the mother to the signature of bacteria (called LPS) at specific times would result in overexpression of BDNF and NGF and the effect??:
Abnormal expression of neurotrophic factors represents a potential mechanism through which maternal infection increases risk for neurodevelopmental disorders.
https://www.ncbi.nlm.nih.gov/pubmed/12742653
Check out CBD and child anxiety for more we can blame on mother.
Dad, you're not off the hook. A study just today showed that cannabis (THC) use affects a gene in sperm tied to autism that's passed down to children.
Then, there's the overreaction of our immune system right now!
Overactive immune reaction (see CBD and neuroinflammation)
Let's introduce microglia.
They're the cop on the beat in the brain looking for infection and bad stuff.
Technically, part of our immune system, they reside in our nervous system.
Microglia and neurotrophins are intimately tied together.
In fact:
It is now known that, under certain conditions, microglia may adopt a pro neurogenic phenotype, which involves the expression of neurotrophins and anti-inflammatory cytokines, such as insulin-like growth factor 1 (IGF-1), brain-derived neurotrophic factor (BDNF), and IL-4
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6232769/
This switch from pro-inflammatory (destroy intruders) to anti-inflammatory (Marshall Plan) is called a microglia state (M1, M2, M3, M4).
Once microglia encounter a substance that they sense is foreign or indicative of harm, they enter an ‘activated’ state.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6232769/
Mark our words, aside from the gut microbiome, our brain's immune system is the key to the next big discoveries in mental illness.
And neurotrophins like BDNF will punctuate that story.
The gut and brain are connected of course as are their immune players:
Interferon-γ produced from Th1 cells was found to be instrumental in polarizing macrophages to M1
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4060849/
This requires an entire article of its own but basically, inflammation in the body and gut will push brain responders into an inflammatory state.
- M1 is activated microglia in the brain
- T1 is activated macrophages in the body/gut
This may lie at the heart of most modern diseases (auto-immune) including Alzheimer's, Dementia, Depression, Autism, Parkinson's, and yes...even Anxiety!
Wait till you see what CBD does there and put a mental note next to this:
Evidence is mounting to suggest that PPARγ can inhibit microglial activation, promote M2 polarization and suppress inflammatory cytokines in inflammation-related diseases.
So PPAR can calm the response essentially.
We'll come back to that with CBD.
Just a synopsis...microglia can turn from pro-neuron (makes BDNF) to inflammatory (makes proBDNF) based on signals in the brain and from the body/gut.
Very cool!
Chemicals, pesticides, and antibiotics
Speaking of microglia, they respond to bacteria but really anything foreign.
That includes the host of chemicals, pesticides, and antibiotics we're swimming in daily.
Everyone reading this has PFOA and glyphosate in the blood.
It's even showing up in cord blood for newborns.
Check out our pregnenolone review for how glyphosate impedes all our sex hormones at the very top of the chain.
We just discussed how the microglia will switch to an activated state and actually release a host of inflammatory and destructive chemicals in response.
Our immune system has a sophisticated and complex response but unfortunately, it treats bacteria the same way as any foreign entity.
It didn't grow up in the chemical age!
There was no glyphosate 10,000 or 100,000 years ago.
We're going to end of course with antibiotics but we saw how the gut and brain are intimately linked (via the Vagus nerve).
For example:
Treatment with antibiotics during the first year of life is also closely correlated to depression later in the life of humans
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6182051/
In fact, probiotics can offset some of these effects:
Probiotic supplementation was shown to improve the symptoms of anxiety and depression, especially Lactobacillus helveticus Ns8, which improved the behavioral, cognitive, and biochemical aberrations caused by chronic restraint stress
Check out CBD and probiotics for anxiety to really dive into how we can improve this landscape NOW!
Look...the gut microbiome is intimately tied to how we feel.
A group of researchers used antibiotics to essentially wipe out the gut bacteria and found DNA expression negatively altered in the Amygdala and prefrontal cortex:
These results suggest that the microbiome is necessary for appropriate regulation of miRNA expression in brain regions implicated in anxiety-like behaviors.
https://www.ncbi.nlm.nih.gov/pubmed/21430148
You just described the core of the anxiety "circuit" (see CBD and anxiety or CBD and general anxiety disorder).
- Amygdala - fear and emotional response
- Prefrontal cortex - rational constraint on the amygdala
And your gut bacteria drive DNA expression on those areas!
Why are we even talking about microglia and gut bacteria for anxiety??
Stress-Induced Microglia Activation and Monocyte Trafficking to the Brain Underlie the Development of Anxiety and Depression.
https://www.ncbi.nlm.nih.gov/pubmed/27352390
Basically, the microglia over-react and take out a lot of collateral damage (our neurons!) which BDNF and the neurotrophins can't keep up with or get turned off by...the microglia!!
This is at the heart of inflammation and stress for anxiety and depression.
Welcome to the (less-anxious) future.
Now, let's get to brass tacks.
Our first candidate. BDNF.
BDNF and anxiety
Brain-derived neurotrophic factor.
That's a mouthful.
Simply put…
BDNF is one of the most active substances to stimulate neurogenesis.
https://en.wikipedia.org/wiki/Neurotrophin
In fact, mice born without it don't survive for long.
A quick distinction.
There are two forms:
- proBDNF
- BDNF
The two are diametrically opposed in their activity.
- BDNF is needed to build and repair neurons.
- proBDNF is needed to remove and destroy tissue.
Balance is key of course!
The BDNF pathway is written all over anxiety (and depression for that matter).
Simply put:
Moreover, this neurotrophin has been implicated in the regulation of stress and anxiety-related behaviors: acute and chronic stress lead to decreased BDNF expression in the hippocampus, with subsequent enhancement of anxiety-related behaviors
Research here.
We've covered the hippocampus extensively with anxiety because it's our most vulnerable brain area to stress, trauma, and the other insults we described above.
It may be due to BDNF!
Let's start with genes.
Recently, a single nucleotide polymorphism (SNP) of the coding region of the BDNF gene (Val66Met) has been identified as a risk factor for anxiety disorders, including post-traumatic stress disorder (PTSD)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4513557/
This speaks to other research showing that BDNF levels in the hippocampus are tied to stress response and resilience:
Individuals with the met allele have reduced hippocampal volume (11–14), deficits in hippocampal-dependent memory (15, 16), and altered responses to emotional stimuli
Check out CBD and hippocampus neurogenesis for anxiety here.
"Emotional stimuli" is stress! Psychological stress. We've been there (see our story here).
A simple little switch in this gene makes it harder for the brain to repair and restructure the hippocampus.
It's just the seat of memory and a key "switch" for anxiety.
In fact, SSRI's (see CBD versus SSRI for anxiety) boost serotonin till tolerance kicks in.
Serotonin does a lot of things in the brain...what does this have to do with BDNF?
Well...you need BDNF to "fertilize" serotonin neurons:
BDNF promotes the survival and differentiation of 5-HT neurons.
https://www.ncbi.nlm.nih.gov/pubmed/17882234
5-HT is shorthand for serotonin.
People...this may be the biggest takeaway from this whole article.
BDNF supports serotonin functioning. That's a billion-dollar industry with SSRI's.
This gets to the heart of how SSRI's actually increase serotonin levels (whether your low or not - see CBD for serotonin withdrawal here):
Conversely, the administration of antidepressant selective serotonin reuptake inhibitors (SSRIs) enhances BDNF gene expression.
Goodness! What did we just unravel?
Again, check CBD versus anxiety meds like benzos and SSRI's here.
When an SSRI does work (until the brain normalizes the other way), BDNF increases are reflected:
Patients who met response and remission criteria (with either treatment) had greater mean increases in BDNF at endpoint from baseline
https://www.ncbi.nlm.nih.gov/pubmed/23313564
Check out exactly how SSRIs work here.
Meaning...when it worked...it worked because of resulting BDNF levels.
Going back to early trauma and stress' effect on later anxiety, researchers found an effect of BDNF which is critical during key periods of brain development (and pruning):
We found that hippocampal BDNF expression plays a critical role in resilience to chronic stress and that reduction of hippocampal BDNF expression in young, but not adult, rats induces prolonged elevations in corticosterone secretion.
https://www.ncbi.nlm.nih.gov/pubmed/21430148
The same was found for acute stress in terms of the effect on younger brains.
Aside from the repair of neuron damage, BDNF is a learning enhancer!
It's jacked up when we're young and foreign languages seem to come with ease.
Could its effect on anxiety risk be tied to learning?
A pretty interesting study looked at two different types of rats.
One of them is genetically bred to be anxious.
They found that BDNF differences in the anxiety breed were altered and that this affected their ability to learn (along classic rat learning tests).
They postulated that reduced BDNF function creates anxiety by making new learning more difficult.
Think of how you feel when you're thrown into a test or situation where you don't know anything about what you're doing.
Anxious might be the word.
Now magnify that across your daily living!
This is a current theory for autism anxiety (see CBD and autism anxiety) where social rules seem so arcane.
Their summary:
Facilitated associative learning may represent a vulnerability factor in the development of anxiety disorders.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4513557/
This could also explain why anxiety becomes so epidemic for the elderly (see CBD and elderly anxiety).
BDNF is going down over time and everything just gets harder.
With parents in their 70's, I can see it.
The result is usually frustration and anxiety. This also ties in with the hippocampus association:
When the answer was revealed, activations generally were found in structures associated with learning and memory, such as parahippocampal gyrus and hippocampus.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4635443/
Learning and memory. Hmmm.
On a side note, as our brain's primary landscaper, BDNF directly regulates GABA and glutamate activity and balance.
GABA is the main lever for benzo's, the most common anti-anxiety medication.
Kind of a big deal and worthy of its own article.
This all sounds like horrible news!
Don't worry, we'll touch on ways to increase BDNF function below.
Next up, some very exciting news in terms of anxiety research.
NT-3 and anxiety
Neurotrophin 3.
All the neurotrophins have important interactions with mental health in general and anxiety specifically but new research is really shining a light on NT-3.
It's one thing to have anxiety as a result of stress, trauma, and outside influences.
The new study found a direct tie between NT-3 and "trait" anxiety.
This is an internal anxiety "lens" through which a person views the world.
This gets to extreme anxiety or inhibited temperament.
In a study of primates, researchers narrowed down substances tied to anxiety (or the lack thereof).
Landing on NT-3, they then used a virus to increase its levels in the primates.
The results:
Overexpression of the transcript for NTRK3's endogenous ligand, NTF3, in the dorsal amygdala resulted in reduced AT and altered function in AT's neural circuit.
AT is short for anxious temperament which is a critical early signature of anxiety.
Interestingly, brain scans later showed changes in the brain tied to the anxiety circuit we described above.
Hopefully, this will open up the floodgates for NT-3 and the other neurotrophins as these are still early days.
Next, let's look at another interesting clue from a very surprising source.
Magic mushrooms (research only...for now).
The curious effect of psilocybin and neurotrophins such as BDNF
Psilocybin is the psychoactive chemical in psychedelic mushrooms. We have a massive review of psilocybin since it's going to revolutionize mental health.
It's similar in function to LSD (the synthetic).
Why are you even bringing this up in an article on BDNF?
Psilocybin has shown remarkable effects on very intractable cases of anxiety, depression, addiction, and other mental health issues where the brain appears to be "stuck".
Stuck is just another way to say unable to rebuild, repair, and change.
It sounds like something we just spent quite a bit of time discussing.
Neurogenesis.
As for anxiety, in a study of people facing a terminal illness, a double-blind study was performed with psilocybin:
Anxiety significantly decreased as measured by the State-Trait Anxiety Inventory at 1 and 3 months post-treatment in the psilocybin group compared to niacin. Mood improved for 2 weeks after treatment and reached statistical significance on the Beck Depression Inventory at the 6-month point with the same comparison.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6007659/
This is just one study. Check out the New York Bestseller, How to Change Your Mind by Michael Pollan or the new Netflix show with the same name.
So...how is a few hour psychedelic trip causing long term effects on anxiety and depression (plus PTSD, OCD, and more).
This seems unfathomable.
Neurogenesis!
The chemical psilocybin creates an explosion in neurogenesis across the brain.
There are actual pictures where you can the little dendrites (think of tree roots) creating new "tentacles" out to each other.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6082376/
Back to BDNF.
Psychedelics increase BDNF (2 fold) but more importantly, they appear to affect Trkb, a critical step in BDNF function.
In fact, when they blocked TrkB's function, the neurogenesis from psychedelics is blocked!:
When cortical cultures were co-treated with ANA-12 (Cazorla et al., 2011), a selective antagonist of BDNF’s high-affinity receptor TrkB, the ability of psychedelics or BDNF to stimulate neuritogenesis and spinogenesis was completely blocked
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6082376/
"Completely blocked".
That also points to BDNF's powerful influence on Serotonin which was thought to be the main driver of neurogenesis (see CBD versus SSRI for serotonin).
Psilocybin is going be big news over the next decade so we did a full review of it here: Psilocybin and mental health.
Of course, both serotonin and BDNF are closely associated with anxiety, depression, and a host of mental health issues.
We bring this up to shed light on the power of neurotrophins...not to encourage everyone to run out and do psychedelics.
Now that Colorado has legalized them, hopefully, we'll finally get more research with today's sophisticated tools.
John Hopkins already has an entire department dedicated to this reserach.
Next up...hormones and neurotrophins.
Hormones and neurotrophins
First, check out our review on pregnenolone (the precursor of all hormones and an endocannabinoid!).
Next, up let's look at DHEA in particular.
It's a neurosteroid and hormone that derives from pregnenolone.
There's some interesting research that DHEA may be pulling the strings for NGF and BDNF function.
In fact:
Overall, DHEA might induce NGF and BDNF neurotrophins overproduction in cortical neurons which promotes neural cell protection, survival, and proliferation.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3867952/
DHEA is all over the anxiety pathway in terms of resulting effects:
It protects hippocampal cells from oxidative stress [9] and antagonizes the neurotoxic effects of corticosterones in primary cultures of neurons
Did you catch that? The hippocampus. Protection from stress, it's nemesis!
We've covered that quite a bit up above as it's the most vulnerable brain area to stress and inflammation.
Also, the BDNF levels were shown to be protective there:
Resilience to chronic stress is mediated by hippocampal brain-derived neurotrophic factor.
https://www.ncbi.nlm.nih.gov/pubmed/21430148
Interestingly, they found this effect was more pronounced early in life during development.
DHEA is very interesting (as is pregnenolone) for another key factor:
Aging!
In fact, DHEA is one of those biomarkers for age where researchers can estimate age just by DHEA levels.
In fact, calorie restriction, which is known to slow aging, can increase DHEA.
As for our story on neurotrophins:
ELISA results showed that treatment of DHEA increased NGF and BDNF levels, 7- and 5-fold (Figure 1(b)) compared with control, respectively
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3867952/
Speaking of aging…
Aging and neurotrophins
DHEA was a good place to drop off.
We know that BDNF and the other neurotrophins drop as we age.
BDNF levels in plasma decreased significantly with increasing age or weight, whereas platelet levels did not.
https://www.sciencedirect.com/science/article/abs/pii/S0197458004001071
Did you catch that last part...increasing weight drops our BDNF!
If you look at pictures from 70's almost no one is overweight (just saw one on Twitter yesterday).
It's actually shocking to see it.
Thanks big Ag for the estrogen, antibiotics, seed oils, and pesticides.
Back to age, the other big determinate in BDNF levels.
Men and women had the same level of BDNF but the number platelets differed (fewer in women) and they also fluctuated during the monthly cycle.
This figures into another known biomarker for aging...decrease in hippocampus volume!
Check out CBD for hippocampus neurogenesis or CBD, meditation, and exercise for neurogenesis.
In fact, researchers have found a gene tied to reduced BDNF activity which leads to brain loss in age:
In humans, circulating levels of BDNF decline with advancing age, and genetic polymorphism for BDNF has been related to gray matter volume loss in old age.
https://www.ncbi.nlm.nih.gov/pubmed/20392958
Sure this affects memory, cognitive, function and many age-related neurodegenerative diseases but what about anxiety!
We know that GABA is a key lever for anxiety (see CBD versus benzos for GABA).
Remember how BDNF was a controller of GABA and its opposing force, glutamate pathways in the brain?
If BDNF levels are going down, what does that mean for GABA:
The reduction of BDNF results in GABAergic neuroplasticity dysfunction and contributes to late-life anxiety disorder.
https://www.ncbi.nlm.nih.gov/pubmed/30714802
More importantly in the experiment with mice, they directly tied the level of BDNF in the hippocampus to age-related anxiety.
In fact, they were able to reverse it by boosting BDNF in the hippocampus:
We demonstrated that the basic function of BDNF in the hippocampus was negatively correlated with GND and anxiety-like behavior of aged mice.
GND is Gaba neuroplastic disorder or the loss of flexibility and function in the GABA pathways.
All this age-related loss in BDNF function (as well as other neurotrophins) mirrors what's happening upstream.
DHEA also drops and it's a big player here as we saw above.
In fact, DHEA directly interacts with NGF receptors (which is why technically, it's also called a neurotrophin as well as a steroidal hormone):
Neurosteroid dehydroepiandrosterone interacts with nerve growth factor (NGF) receptors, preventing neuronal apoptosis.
https://www.ncbi.nlm.nih.gov/pubmed/21541365
Apoptosis is a technical word for cell death.
Remember the balance between growth and death?
One study even found that calorie restriction, known to slow aging, also boost DHEA levels!
Pregnenolone is the precursor to DHEA and it drops with age as well.
In fact, it may be the beginning spot for the cascade.
One important note...estrogen and testosterone both drive serotonin (and therefore, bdnf).
Testosterone drops about 1%/year and estrogen falls off a cliff late 40's!
One more stop before we get into CBD's realm.
BDNF and serotonin (the lever for the SSRI's)
SSRI's are quickly becoming the go-to drug for anxiety despite their side effects and less-than-stellar effect for anxiety.
Check out CBD versus SSRI for anxiety.
They basically make serotonin more available to neurons.
Researchers found that they also boost BDNF levels.
What's going on there?
BDNF and Serotonin (5-HT) are intimately linked:
These two signals co-regulate one another such that 5-HT stimulates the expression of BDNF and BDNF enhances the growth and survival of 5-HT neurons.
Why is this important for anxiety?
Impaired 5-HT and BDNF signaling is central to depression and anxiety disorders,
We'll see what CBD does for both below.
Finally, we're getting to CBD's neck of the woods.
The endocannabinoid system and neurotrophins
Every living animal has one.
It's tasked with balancing other key systems:
- Nervous system - including neurotransmitter like GABA, serotonin and neurotrophins
- Endocrine system - hormones such as DHEA, cortisol, and more
- Immune system - microglia, cytokines, and gut microbiome
Literally the cross-section of systems tied to anxiety.
We have CB1 receptors primarily in the nervous system and CB2 receptors throughout the body.
This is the primary location for cannabinoids to exert their influence.
What about the endocannabinoid system and neurotrophins like BDNF?
They're intimately tied of course!
Researchers are just starting to tease out both of these relatively new (to research) players.
For example:
BDNF potently inhibited CB1R function in the striatum, through a mechanism mediated by altered cholesterol metabolism and membrane lipid raft function.
https://www.jneurosci.org/content/30/24/8127
This involved the dopamine and GABA systems in a key part of the brain called the striatum (just recently tied more strongly to schizophrenia).
What about the anxiety circuit.
As we'll see below with CBD, the endocannabinoid system is all over the neuron growth-death balance.
You could argue it's role IS balance or homeostasis.
There's a rather complex review of how intertwined the two systems are below but their summary will suffice:
Disruption of either BDNF or endocannabinoid signaling is associated with an overlapping set of neurologic and psychiatric diseases, and both systems are currently major targets for the development of novel therapeutics, particularly in relation to depression, anxiety, autism, and schizophrenia.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4415885/
Since BDNF and other neurotrophins are primarily growth factors, let's look at the hippocampus since we spent so much time there for anxiety:
Endocannabinoids (eCB) are one of the main systems controlling both excitatory and inhibitory neurotransmission, as well as neuroplasticity within the hippocampus.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5742214/
One of our favorite studies is where scientist blocked CB1 activity (in knock out mice) and BDNF levels drop:
Accordingly, decreased BDNF levels have been observed in the hippocampus of CB1KO mice
https://www.frontiersin.org/articles/10.3389/fnbeh.2011.00063/full
There's that hippocampus again.
Can we support or boost this system's role in balancing?
Finally...CBD.
Can CBD increase neurotrophins like BDNF and NT-3
Let's get into it.
We've established how neurotrophins like BDNF and NT-3 are critical for brain function and aging.
We also looked at how various insults and even cruel time itself can decrease these levels.
Finally, we established that CBD's primary playground, the endocannabinoid system directly governs neurotrophin levels and vice versa.
So...can CBD affect levels and function?
Let's first look at a study on depression (tied to the same brain-wasting result as anxiety):
Cannabidiol Induces Rapid and Sustained Antidepressant-Like Effects Through Increased BDNF Signaling and Synaptogenesis in the Prefrontal Cortex.
https://www.ncbi.nlm.nih.gov/pubmed/29869197
Goodness...I feel like we just showed all our cards at the poker table!
- CBD (cannabidiol) check
- Increased BDNF check
- Synaptogenesis (literally building new pathways in the brain) check
- Prefrontal cortex - the constraint on our fear center in the brain. Check!
We could probably stop there but what's the fun in that.
Remember how BDNF and serotonin were intimately tied together?
BDNF creates more serotonin pathway and serotonin boosts BDNF levels.
What does CBD do for serotonin:
Cannabidiol modulates serotonergic transmission and reverses both allodynia and anxiety-like behavior in a model of neuropathic pain
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6319597/
Allodynia is system-wide nerve pain.
Let's look at a study of CBD head to head with a antidepressant:
Administration of cannabidiol and imipramine induces antidepressant-like effects in the forced swimming test and increases brain-derived neurotrophic factor levels in the rat amygdala
Imipramine is a tricyclic anti-depressant known as Tofranil.
Check out CBD versus anti anxiety medications to understand the stark difference in the side-effects and other issues.
Remember how infection or false alarm immune responses can also cause damage that needs to be repaired from neurotrophins?
This study looked at that piece.
Lipopolysaccharide (LPS)-induced neuroinflammation leading to microglial activation was reported previously to be responsible for disrupted neurogenesis in the dentate gyrus region of the hippocampus [6] and for a decrease in the hippocampal level of brain derived neurotrophic factor (BDNF) [7].
Study is here.
LPS is the protein shell of bacteria that our microglia are on the lookout for.
You see the knock-on effects from their over-activity...decrease in BDNF and decrease in hippocampus.
In a nasty experiment that approximates chronic liver disease where they sever the bile duct, CBD had impressive results:
However, BDL reduced expression of the brain-derived neurotrophic factor (BDNF) gene, which was increased by CBD.
Study is here.
How did it do this?
BDL is bile duct ligation, the injuring procedure.
BDNF is the most researched of the neurotrophins (by a landslide).
What about the others? Are CBD's effects family wide?
Here's a study on NGF (nerve growth factor...the first one discovered).
CBD increased the viability of cells treated with the neurotoxin N-methyl-4-phenylpyrimidine (MPP+), and prevented the MPP+-induced increase in caspase-3 activation and decrease in levels of nerve growth factor (NGF)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5958190/
Basically, they administered a nerve toxin and CBD was able to offset the decrease in NGF (as well as other positive effects).
Here's where things get interesting.
Remember how CBD bolsters the endocannabinoid system which is about balancing other key systems.
What if we have neurotrophin levels that are too high and actually detrimental?
In the study below, they injected NGF to actually cause muscle pain.
Cannabidiol, cannabinol and their combinations act as peripheral analgesics in a rat model of myofascial pain.
https://www.ncbi.nlm.nih.gov/pubmed/31158702
CBD offset the pain effects of too much NGF.
This speaks to why we don't have a case of CBD overdose (high quality isolate only...can't speak for everything else the market is trying to push).
As for reducing the damage (reducing the load on neurotrophins):
But we want people to feel better generally! Look...we study CBD and we see first hand what research shows for its benefits.
Let's look at other things that promote healthy BDNF levels.
What else can increase neurotrophins in addition to CBD:
- Exercise (see CBD, meditation, and exercise for neurogenesis)
- Sleep
- Sunlight (Vitamin D doesn't have the same effect)
- Calorie restriction and intermittent fasting
- Soy (estradiol boosts BDNF) - try to get organic to avoid glyphosate (90% of US soy uses glyphosate or worse).
- DHEA (see pregnenolone)
- Niacin (B3)
- Curcumin
- NAC (see CBD and glutathione since it directly boosts that pathway)
- EGCG (green tea extract)
- Caffeine
Of these, exercise is probably the most powerful.
They even found the chemical released from exercise which upregulates the BDNF gene.
Electrophysiological measurements indicate that β-hydroxybutyrate causes an increase in neurotransmitter release, which is dependent upon the TrkB receptor.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4915811/
Remember that TrkB activity may be more important than actual BDNF levels from the study above.
There's a great list of natural substances and research for BDNF support:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5804326/
Back to CBD...how much should we take for BDNF?
How much CBD to increase neurotrophins
We actually have some definitive research here.
It's all comes down to neurogenesis...brain repair.
Remember that serotonin and BDNF drive the brain building business after injury, infection, stress, and age.
A study found that the peak level for this effect was at 300 mg of CBD.
That aspect actually starts to go down from 300 to 600 mg even though the anti-anxiety (immediate effects) might continue.
Studies like the public speaking study for social anxiety used 600 mg and and some studies on schizophrenia even go up to 800 mg.
Most people start at about 25-30 mg and go up from there.
Based on the study at how many mgs of CBD for anxiety, neurogenesis effects (BDNF and serotonin) peak at 300 mg!
What kind of CBD is best for BDNF and neurotrophins?
What's the best CBD to increase neurotrophins
We need the best quality CBD which meets these requirements:
- Organically grown in the US (you can't buy CBD on Amazon despite all the bogus product there now)
- CO2 extracted (cleanest method)
- 3rd party tested free of:
- No THC (see THC versus CBD for anxiety or better yet, how CBD offsets THC negatives)
- No Heavy metals
- No Pesticides
We actually test IndigoNaturals (our kids take it!) twice...once at the manufacturer and then we run a second test for the final product (available at top of any page).
Finally, CBD isolate versus CBD full spectrum (the bulk of what's sold on the market).
We've written extensively on this at our CBD isolate versus full spectrum for anxiety article.
Look...all that research up above and the 100's of articles we reference are based on CBD isolate.
Not full spectrum. Not hemp oil. Not THC (actually has countering effects).
Isolate.
The "entourage effect" sounds great but we based IndigoNatural on research like above.
Hopefully that's obvious or all this work is for naught!!
Then there's histamine.
It's the hormone behind allergies but also incredibly excitatory in the brain (see CBD, histamines, and anxiety).
It can also cause mayhem just like the overactive microglia which eats up BDNF reserves.
All that plant material in full spectrum is going the wrong way for anxiety.
40-60% of the population has histamine issues!
You can count us in that lucky bunch. CBD isolate can actualy calm histamine response.
Finally, there's cost. Cost per mg of CBD is the key which is why we offer discounts up to 50% on 2-3 cents per mg (6000mg bottle) already.
We were there so it's important that we make this accessible to the most people.
We'll keep our eyes out for options that support BDNF without building tolerance or causing safety issues.
CBD isolate is front and center there.
Related Research
Neurogenesis and brain repair
Psilocybin and neurogenesis
Hippocampus neurogenesis
Why immune system is future of mental health
CBD and anxiety pathways
CBD and anxiety research
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.