There's interesting new research in the process of our brain's response to brain injury.
Our immune system's response can be a double-edged sword after injury.
We tend to think of our immune system as just responding to infection but it has a much broader role with injury...both immediate response and more importantly...repair.
We're going to get into this whole process based on research.
CBD has interesting effect in these pathways along with a few other tools.
That's all on the table below.
These are the topics we'll cover:
- A quick introduction to traumatic brain injury
- Inflammation and brain injury
- Immune response and repair
- The rebuild phase after traumatic brain injury
- Research on CBD and traumatic brain injury
- How much CBD do you need for traumatic brain injury
- What's the best CBD for traumatic brain injury
Let's get into it!
A quick introduction to traumatic brain injury
Let's walk through the process that occurs in the brain following injury. It's not so different than a bruise to your arm...except the real estate is so much more precious!
Yes, the original injury can cause damage but look at the immune response fallout:
Primary brain damage that occurs at the time of injury can be exacerbated and prolonged for months or even years by chronic inflammatory processes, which can ultimately lead to secondary cell death, neurodegeneration, and long-lasting neurological impairment.
The immune response is in charge of both cell birth and death...critical components to recovery from traumatic brain injury.
In fact, the current state of research is looking at how to calm the immune response after injury.
Before we jump into the different aspects of this, let's set the stage.
- Following an injury, the immune system sets off a cascade of inflammatory responders.
- This response can actually be too strong and cause more damage or prevent repair (like a bruise!!)
- The inflammatory response should then switch to a recovery mode and repair/rebuild
This last piece is fascinating.
Most people don't realize that the repair side is built right into our inflammatory process!
That's why NSAIDs can actually lead to more risk of future injury because they interrupt (speed up technically) the repair process.
The suppression of PGE2 also occurs with excessive wound scarring and therefore NSAIDs may increase scar formation, especially if they are used during the proliferative phase of healing
You can shorten the time but the work will be shoddy!
Let's turn our attention to the brain.
It's a story of inflammation.
Inflammation and immune response for brain injury
Following brain injury, the immune system jumps into action.
An onslaught of inflammatory agents rush to the scene with various tasks:
They guide a sequence of events including expression of adhesion molecules, cellular infiltration, and additional secretion of inflammatory molecules and growth factors, resulting in either regeneration or cell death.
The key bit there is "regeneration or cell death".
Literally, making a decision on whether a cell should live or be removed depending on its level of damage.
The issue is that this inflammatory process can last for years and actually cause more damage than the original injury.
However, activated microglia and astrocytes and elevated levels of inflammatory cytokines can be detected for months to years following brain injury
Microglia are the managers of our brain's immune response (see CBD and neuroinflammation).
Remember that the brain is cut off from the rest of the body by the blood brain barrier.
All responders have to be in-house!
What's interesting is that the immune response in other parts of the body rarely last beyond a few weeks.
The breakdown of the blood brain barrier from traumatic brain injury is a key concern for long term recovery.
During the inflammatory stage, we can focus on cytokines, the little messengers of our immune response.
Interleukin-1 is a potent pro-inflammatory cytokine that has been implicated in numerous inflammatory and neurological disorders. Secretion of IL-1 must be tightly regulated in the brain, as unchecked IL-1 production has been shown to provoke neuroinflammation and neurodegeneration.
There's a great balancing act here. Addressing the original injury but resolving the inflammatory response.
Otherwise, it can do even more damage!
Turns out that the great balancer of immune response is the endocannabionid system (where CBD works).
This is a mouthful but we'll translate after:
manipulations of endocannabinoid degradative enzymes (e.g., fatty acid amide hydrolase, monoacylglycerol lipase, and α/β-hydrolase domain-6), CB1 and CB2 receptors, and their endogenous ligands have shown promise in modulating cellular and molecular hallmarks of TBI pathology such as; cell death, excitotoxicity, neuroinflammation, cerebrovascular breakdown, and cell structure and remodeling.
Basically, the individual chemicals that make up the endocannabinoid system guide every step of the response (good and bad) to TBI!
Inflammation figures strongly into this since it's the active process of response.
The problem with recovery from TBI is that the immune response can get stuck!
We demonstrate that increased microglial activation can be present up to 17 years after TBI.
The immune response is not "resolving"...a key step in the process.
Again, check out CBD and neuroinflammation to really get into this process since it's present in anxiety, depression, and various mental health issues.
Let's turn to the messengers that lie at the intersection of the brain and immune response.
Neurotransmitter and TBI
Part of the equation with TBI recovery (or the lack thereof) is due to imbalances in neurotransmitters that result.
There are some key players in this process:
- GABA/Glutamate (the brake and gas pedal of the brain)
- Serotonin (critical to our rebuilding process)
We'll just focus on these for now since they're so critical.
Following brain injury, glutamate is over-expressed by the microglia (brain immune managers from above).
Glutamate is important to get the response/repair processing moving but too much is a bad thing:
Neuronal disruption spills excitatory amino acids into the interstitial space, producing glutamate-mediated excitotoxicity
It's overkill and this is very dangerous in the brain.
In fact, we have multiple failsafes to guard against excessive glutamate.
We've covered in detail at our CBD and glutamate process.
NAC is an important supplement to support this process as is glycine.
We'll look at CBD's role below in the balancing act between Glutamate and GABA (see CBD and GABA for anxiety).
Serotonin is very fascinating (see CBD and serotonin).
Serotonin is our master regulator for all human behavior. It directly manages other key pathways such as dopamine, our reward circuit player and downstream chemicals that drive focus, arousal, and more.
That's just the obvious role.
Serotonin drives the repair process!
Here's the interesting piece...the brain will starve out serotonin production (from tryptophan) during times of infection.
It does this to starve out the potential bacteria/viruses from building more of themselves (tryptophan is a basic building block for many life forms it turns out).
This drop in the tryptophan pathway leads to reduced serotonin!
Here's the rub...the immune system can't tell the difference (very well) between infection and injury.
It has roughly the same response and downregulates serotonin after TBI:
Effects on the serotonin system were essentially confined to changes in the 5-HT synthesising enzyme TPH2
5-HT is serotonin and TPH2 is the enzyme we mentioned above that turns tryptophan into serotonin.
Check out our review on whether tryptophan is a stress buffer and tied to self esteem.
So...serotonin gets "exhausted" by the injury.
Here's the problem for long term recovery from TBI...serotonin drives BDNF, our brain's primary agent for building and repairing tissue.
It's our brain's fertilizer!
Let's go there now.
The rebuild phase after traumatic brain injury
We've looked at the destructive side of TBI:
- Inflammatory agents like IL1
- Immune response hyperactivity (microglia) over years
- Excessive glutamate
Let's look at the other side of the coin. The repair process!
As we mentioned above, serotonin drives this activity but the real star is BDNF.
BDNF is literally our brain's fertilizer and will be THE big star over the next 10 years.
This dance between cell destruction (TBI, stress, glutamate, immune response, drugs, chemicals, etc) and repair/rebuild is key to almost every mental health issues we've investigated. See CBD and mental health.
For example, the two key determinants to relapse with addiction?
- BDNF levels
Goodness...this should be front page news.
By the way, serotonin is a key stress responder as is anandamide (our endocanninoid).
In fact, researchers point to BDNF genetic differences as the key to recovery and even survival after severe TBI:
BDNF GRS was significantly associated with acute mortality, regardless of age.
After the dust (cytokines) clears, BDNF figures strongly into the process of recovery from TBI:
BDNF has been implicated in reducing secondary brain injury, with elevations providing neuroprotection and restoring connectivity after TBI.
BDNF is the star but there's a slew of different players downstream.
For example GFAP is tied to the blood brain barrier and it becomes elevated following TBI:
GFAP has excellent specificity for TBI-associated intracranial hemorrhage and focal mass lesions.14,15 Elevated values are associated with increased mortality.1,16
We'll look at all of this with CBD. Speaking of which.
Research on CBD and traumatic brain injury
Let's turn our attention first to CBD's effects on the various pathways we've seen above.
We'll cover the following:
- CBD and inflammatory agents
- CBD and immune response resolution
- CBD and excess glutamate
- CBD and serotonin rescue
- CBD and BDNF support
- Research on CBD and TBI
Before we get started, a lay of the land is in order.
CBD works within our naturally occurring endocannabinoid system.
This system is generally tasked with balancing other key systems:
- Immune system - cytokines and microglia
- Endocrine system - hormones
- Nervous system - including players like serotonin, glutamate, and BDNF
You can see that TBI is right in the wheelhouse of this system.
In fact, studies show that many of the endocannabinoids (like anandamide and 2-AG) are elevated following TBI in an attempt to offset the inflammation.
CBD's role is more nuanced than THC which drives activity like anandamide in the brain.
CBD acts like a feedback mechanism on key pathways.
This means it can have different results depending on the state of the system.
You can learn more at exactly how CBD works but let's jump into the research.
We'll start with inflammation.
CBD and inflammatory agents
So...what is CBD's effect on the pro-inflammatory cytokines, our little chemical assassins?
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.
What's the deal with IL-10?
It's part of the clean up crew to "resolve" the inflammation.
IL-10 plays a role in controlling the early influx and the later efflux of macrophages out of the injured nerve, reduces the expression of proinflammatory chemokines and cytokines, and is required for myelin-phagocytosis-induced shift of macrophages from proinflammatory to anti-inflammatory.
This study was from a study of direct crushing injury.
IL10 is critical to wrapping up the inflammatory party and moving towards rebuilding!
What about IL1 which was specifically mentioned above with TBI?
One of earliest effects reported with CBD was in human mononuclear cells,111,112 in which TNF-α, IFN-γ, and IL-1α were all suppressed (0.01–20 μg/mL CBD or 0.03–64 μM CBD).
There are so many players in our inflammatory response that we can quickly go down the rabbit's hole but the key take away is this.
CBD is generally anti-inflammatory in nature UNLESS the cell is cancerous, virally infected, or otherwise damaged (say from brain injury).
In those cases, CBD can actually lead to an increase in oxidative stress which is the immune system's natural way to kill off cells (called apoptosis).
That's part of the feedback aspect of how CBD works.
One final piece on the inflammation side...adenosine.
Here's the connection with TBI:
There is evidence that adenosine regulation is a significant factor in traumatic brain injury (TBI) onset, recovery, and outcome, and a growing body of experimental work examining the therapeutic potential of adenosine neuromodulation in the treatment of TBI
Adenosine is fascinating. It works likes a powerful "modulator" in the brain. Unlike GABA (brake pedal) or glutamate (gas pedal), adenosine's effects differ depending on the state of the system.
It's very important to the brain in terms of blood flow and oxygen loss, both of which are significantly hurt by TBI.
In fact, a good part of the "damage" from TBI is the loss of oxygen and blood flow to key areas of the brain.
Adenosine is a major signaling nucleoside that orchestrates cellular and tissue adaptation under energy depletion and ischemic/hypoxic conditions
Iscemis is stroke. Hypoxia is loss of oxygen.
CBD's effect here?
CBD increases brain adenosine levels by reducing adenosine reuptake. Increased adenosine is associated with neuroprotection and decreased inflammation after brain trauma.
Check out CBD and neuroinflammation to really get into it.
Let's zoom out now to the greater immune system response and CBD following TBI.
CBD and immune response resolution
We'll look at two major factors from 30,000 feet.
- Microglia activation - our brain's immune response commanders
- TH immune response setting - key to transitioning from injury response to repair
First, we need to calm the drivers of immune response down after the injury.
Remember, the cure can be worse than the disease with immune response and TBI.
Pro-inflammatory activated microglia are known to exacerbate TBI-induced neuroinflammation
A study of CBD and alzheimer's (amyloid beta are little immune responders by the way - see CBD and dementia) found the following:
In summary, CBD is able to modulate microglial cell function in vitro and induce beneficial effects in an in vivo model of AD
This was attributed partially to the adenine angle above (remember, starving brain areas from oxygen and blood flow is the driver with adenosine).
The two main endocannabinoids in the brain, 2-AG and anandamide are both shown to protect neurons during and after injury.
If we can target the enzymes (FAAH and MAGL) that break them down, this would be positive as follows:
However, FAAH inhibition, similarly has been found to protect against TBI-induced microglial activation
MAGL inhibition protects against TBI-induced microglial activation
Okay...so what about CBD there?
CBD increases anandamide levels by inhibiting its transporter-mediated reuptake and degradation by FAAH
There is also evidence that CBD reduces MAGL-mediated degradation of 2-AG
Again, check out CBD and microglia which has huge impacts on all the symptoms of TBI (anxiety, seizures, etc).
What about the immune "setting"?
- TH1 (inflammatory - respond to injury)
- versus TH2 (antiinflammatory - repair and rebuild).
So...following a brain injury, the immune system is set to defcon 4:
Th17 cells to brain diseases associated with cognitive impairment, including multiple sclerosis (MS), ischemic brain injury and Alzheimer’s disease (AD).
If it can't get out of this, more and more damage accumulates.
More importantly, we can move into the repair phase. It's stuck.
From an autoimmune study:
cannabidiol (CBD), markedly reduce the Th17 phenotype which is known to be increased in inflammatory autoimmune pathologies such as Multiple Sclerosis.
See CBD and autoimmune for more info.
Let's turn to neurotransmitters in play.
CBD and excess glutamate
Glutamate is one of the factors released by overactive microglia.
Again, it's very important to keep glutamate within a certain range in the brain or it becomes toxic to neurons.
This is a hallmark of TBI.
CBD is technically an allosteric negative modulator for GABA, the constraint to glutamate activity.
Just one example of many:
The maximal level of enhancement seen with either CBD or 2-AG were on α2-containing GABAA receptor subtypes, with approximately a 4-fold enhancement of the GABA EC5 evoked current
Essentially, CBD increased the potential of GABA receptors by 4x's!
GABA is the target of benzos (See CBD versus benzos) so you can guess the general result of its action but in the brain, it's a dominant player to slow down activity.
We did a review on a fascinating basis for why some people may chronically use cannabis.
THC substitutes for anandamide in the brain and anandamide slows everything down in the brain.
Anandamide essentially calms down glutamate.
The better study for TBI however is one involving infection.
Essentially, researchers cause excessive glutamate levels as a result of heightened immune response due to bacteria.
- Immune response Check
- Excess glutamate Check
There's a huge tie into early exposure to infection (even in utero) and mental health later on as the immune system is "primed" to run hot (similar to TBI but injury instead of infection).
CBD's effect there:
Overall, these findings show that CBD can restore cannabinoid/GABAergic signalling deficits in regions of the brain implicated in schizophrenia pathophysiology following maternal poly I:C exposure.
Let's turn to serotonin which a a curious connection with immune response and TBI as well.
CBD and serotonin rescue
Many of the knock-on symptoms of TBI are tied to serotonin dysfunction.
This is why SSRIs are commonly prescribed (see CBD versus SSRIs).
The problem is that SSRIs build tolerance as the brain pushes back.
CBD's greatest trick may be on the serotonin pathway.
We've covered this in detail at our CBD and serotonin review.
It doesn't just boost it in one direction which can lead to serotonin syndrome (as bad as not having enough).
It works like a feedback mechanism.
There's actually a great experiment which sheds light on TBI specifically.
Rats were given a spinal cord injury.
This resulted in a series of expected effects including generalized pain, the rat equivalent of anxiety and depression, and exhausted serotonin levels.
repeated treatment with low-dose CBD induces analgesia predominantly through TRPV1 activation, reduces anxiety through 5-HT1A receptor activation, and rescues impaired 5-HT neurotransmission under neuropathic pain conditions.
The most important piece there (for this review) is "rescues impaired 5-HT neurotrransmission".
5-HT is serotonin.
Remember, the brain and immune system have a hard time deciphering between physical injury, infection, and even psychological injury (see Trytophan as social stress buffer or tryptophan and infection).
It has certain tools in its arsenal (glutamate, inflammation, etc) and they're applied pretty similarly whether it's bacteria, a blow to the head, or social rejection/isolation.
See our CBD and self esteem review (very fascinating).
The bigger effect for TBI of bringing serotonin back on line is the downstream boost to BDNF.
CBD and BDNF support
Serotonin drives (manages really) BDNF, our brain's fertilizer which is key to the rebuilding process following TBI.
BDNF is so important that we did a full review at our CBD and BDNF.
A study looked at CBD's antidepressant effects (see CBD and depression) and found the following:
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).
Basically, CBD drove BDNF and cohorts in key areas of the brain!
This is at the heart of how SSRIs (antidepressants) really work and it's why it takes 2 weeks to kick in. Check out How SSRIs really work to get into it.
The problem is that SSRIs build tolerance while CBD does not (see CBD and tolerance) which means your natural serotonin system is downregulated over time.
It's not just depression!
As we mentioned above, this repair pathway is key to almost every mental health issue.
This study with schizophrenia dovetails nicely with TBI:
CBD attenuates the decrease in hippocampal neurogenesis and dendrite spines density induced by chronic stress and prevents microglia activation and the decrease in the number of parvalbumin-positive GABA neurons in a pharmacological model of schizophrenia.
Essentially, chronic stress can cause the immune system (microglia) to hyperactivate and cause damage.
CBD blocked this effect by stimulating new brain and pathway growth.
Key to repair after TBI as well!
Another example of the brain repairing after damage via this pathway:
In addition, in animal models of encephalopathy, CBD improved cognition, motor activity, and restored 5-HT and BDNF levels via 5HT1A receptor activation
Encepthalopathy literally means damage or disease of the brain!
All the exciting new breakthroughs (psilocybin, ketamine, etc) revolve around BDNF and neurogenesis.
TBI is no different once we calm the immune response.
Let's look at any research specific to CBD and TBI.
Research on CBD and TBI
We're still waiting for trials on CBD and TBI in a clinical setting.
Let's start with the animal studies.
Rats were exposed to a spinal cord injury and tested for motor skill deficits following.
Apply CBD to one group of the rats had the following effect:
Cannabidiol-treated rats exhibited a higher Basso, Beattie, and Bresnahan locomotor score at the end of the first week after spinal cord injury:
Those are all measures of motor skills.
Another study looked at the many resulting symptoms of TBI on mice and found the following:
CBD oral treatment restored the behavioral alterations and partially normalized the cortical biochemical changes.
This is important because it speaks to both the symptoms (behavior) and the underlying damage (cortical changes).
Their net takeaway:
our data show some of the brain modifications probably responsible for the behavioral phenotype associated with TBI and suggest the CBD as a pharmacological tool to improve neurological dysfunctions caused by the trauma.
Please..can we get some trials!
Let's turn our attention to stroke which is a good correlation of TBI in terms of runaway damage in the brain.
A study looked at CBD or THC delivery both before and following stroke:
Both pre- and post-ischemic treatment with cannabidiol resulted in potent and long-lasting neuroprotection
Interestingly, THC only helped afterwards.
This is fascinating. CBD not only primed the system to respond better but helped in repair after an injury occurred.
It also does not build tolerance like THC.
Another study tied CBD's effect on stroke and brain damage (following the blockage main artery -MCA) directly to serotonin function:
Cannabidiol significantly reduced the infarct volume induced by MCA occlusion in a bell-shaped curve.
Infarct volume is literally the footprint or size of the injury in the brain.
Part of the damage caused by TBI is a reduction or break in the blood brain barrier.
CBD (10 μM) prevented the increase in permeability caused by 4 h OGD. CBD was most effective when administered before the OGD, but protective effects were observed up to 2 h into reperfusion
This is critical because the blood brain barrier protects the integrity of the brain.
Look at the net effect of this CBD protection:
CBD also reduced cell damage, as measured by LDH release and by markers of cellular adhesion, such as the adhesion molecule VCAM‐1.
As for TBI lite...concussions?:
CBD can therefore potentially provide treatment to enhance neuroprotection by reducing inflammation, regulating cerebral blood flow, enhancing neurogenesis, and protecting the brain against reactive oxygen species.
All hallmarks of concussion and TBI..
Again, we need trials soon.
Let's turn to practical questions.
How much CBD do you need for traumatic brain injury
We actually have some guidance here from the neurogenesis aspect of TBI.
Studies show that peak neurogenesis (repair and rebuilding brain tissue and connections) is at 300 mg/daily.
Above that, neurogenesis starts to go down as other pathways kickin.
That puts ideal levels at 300 mg long term (see can you take CBD long term).
In our studies of addiction (a different need of rewiring), research was pointing to 6-8 weeks at these levels after an initial 6-10 days at higher levels of 600 mg.
Remember...one of the two biggest determinants of relapse is the level of BDNF!
Also check out the following:
- NAC - supports our detox system (see CBD and glutathione) and keeps excess glutamate at bay
- Magnesium - powerful calming agent in the brain
- Vitamin D- powerful steroid involved in neuroprotection (make sure to get tested)
- Fisetin - another key detox supporters for oxidative stress
What about the type of CBD?
What's the best CBD for traumatic brain injury
There are basic requirements for any CBD:
- Organically grown in the US at FDA registered farms
- CO2 processed
- 3rd Party Tested
- No THC - THC pushes in one direction be it immune suppression or otherwise.
- No Pesticides
- No Heavy metals
- No Solvents
- No Bacteria
- No Mold
We test ours twice since the whole family uses it.
Then there's the question of full spectrum versus CBD isolate.
All the research above and the dozens of NIH studies referenced across the site are based on CBD isolate.
We go into full spectrum versus CBD isolate here but the bigger issue is histamine response.
40-60% of the population has histamine issues (goes up for women and as we get older).
TBI already leads to an exhaustion of histamine responders which we don't want to further reduce with plant material:
These significant decreases delineate the extent of cellular damage because of trauma and may underlie sustained cognitive and motor deficits displayed by these animals.
The goal with TBI to calm response and repair.
Then there's the question of cost.
We noted that peak neurogenesis is at 300 mg.
The key then is cost per mg of CBD.
That's why we price our 6000mg bottles at about 2-3 cents per mg of CBD before discounts up to 30%.
The reason is simple...we've been there.
If you read the founder's story here, it is one of trauma and recovery from a brutal perimenopause.
We've been there and want to make CBD available to as many people as possible.
Be well. Take care of each other. Take care of yourself.
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.