CBD and Acetylcholine - the Best Kept Secret Neurotransmitter
July 02, 2020We just wrapped up our review on CBD and nicotine addiction.
After pulling back the curtain a bit, it's clear from the research that acetylcholine is a primary driver of why people are drawn to nicotine.
This is the self-medicating aspect of it.
Acetylcholine and its dietary precursor, choline are fascinating in terms of what they do.
Yes, it's the neurotransmitter of focus and mental firepower but it's also the primary pathway for our parasympathetic nervous system - the rest and digest side of things.
Two seemingly opposite poles if you will.
They're also popping up in research for a range of mental health and neurodegenerative issues.
We'll dig into acetylcholine's function along these lines but equally important, what does CBD do to this pathway?
These are the areas we'll cover:
- What is the role of acetylcholine
- Acetylcholine and the parasympathetic nervous system
- Acetylcholine and mental health
- Acetylcholine and age-related brain diseases
- Does CBD boost acetylcholine
Let's get started. You're going to need some acetylcholine for this one!
What is the role of acetylcholine
Acetylcholine is needed to trigger muscle activity but we want to focus on its role in the nervous system and brain.
There are two seemingly different pathways here:
Acetylcholine drives focus, attention, learning, and memory
Acetylcholine also drives involuntary body responses tied to rest and digest.
These are seemingly two different directions which is fascinating.
Mother nature tends to multitask chemical pathways it likes and choline receptors are dated back to about 2.5 billion years ago.
This pathway has been interwoven through nervous systems far and wide.
Classically, acetylcholine is best thought of as a neuromodulator.
This means it can affect how other neurotransmitters work in the brain and nervous system.
Presynaptic nAChRs induce the release of a number of neurotransmitters including GABA, glutamate, dopamine, serotonin, norepinephrine, and acetylcholine.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3466476/
That's basically the who's who of neurotransmitters.
Acetylcholine acts as an equal-opportunity gear shift.
Where glutamate only pushes in one direction (gas pedal), acetylcholine is a key player in fine-tuning activity not only among neurotransmitters but in brain areas and even clutches of neurons themselves.
The most fascinating piece to us for mental health is brain plasticity.
This is the key to maintaining a healthy brain.
We covered this in detail at our CBD and neurogenesis or brain repair.
Researchers were able to turn neurogenesis on and off by simply blocking the acetylcholine pathway:
Our data provide evidence that forebrain ACh promotes neurogenesis, and suggest that the impaired cholinergic function in AD may in part contribute to deficits in learning and memory through reductions in the formation of new hippocampal neurons.
The hippocampus is especially important for mood and mental health as we'll see below.
Check out CBD and hippocampus to learn more about its function.
Let's turn to the opposite end of the spectrum...away from focus, attention, and growth.
Look...neurogenesis is the linchpin for mental health and addiction. Point!
Acetylcholine and the parasympathetic nervous system
This is the half of the autonomic nervous system that's tasked with calming down and recovery.
It's typically called "rest and digest" as opposed to "fight or flight".
All the background activity needed to keep our brain and body balanced lies here.
Acetylcholine is THE neurotransmitter of this pathway involving:
- Dilating blood vessels
- Slowing heart rate
- Moving the digestive tract
This speaks to why people can feel both focused and calm with nicotine (see CBD and nicotine addiction review above).
The "calm" part is from the parasympathetic nervous system.
Let's jump into the mental health side which is fascinating.
Acetylcholine and mental health
Tobacco use is a great clue here.
Epidemiological studies have long shown that schizophrenics exhibit higher rates of tobacco smoking than the general population, suggesting that patients may use nicotine (an agonist of nAChRs) for self-medication.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4268065/
Nicotine fits in nicely at the acetylcholine receptor...in fact, that's it primary pathway.
Check out the full review of CBD and schizophrenia for more detail.
Depression is also getting more scrutiny these days with acetylcholine.
In this case, it's a question of heightened or imbalanced acetylcholine, especially in the prefrontal cortex.
Consistent with a role for increased ACh signaling in affective disorders in humans, clinical trials have suggested that blockade of either mAChRs (Furey and Drevets, 2006; Furey et al., 2010) or nAChRs (George et al., 2008; Shytle et al., 2002) can decrease symptoms of depression.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3466476/
In this case, they're blocking it...speaking to reduced sensitivity. Giving it a break can actually allow it to function and we see this in many pathways (ketamine and GABA, etc).
Nicotine also reflects this self-medication:
For instance, the overall incidence of smoking in depressed patients is twice as high as in the general population.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4486625/
What about anxiety, the other epidemic following the pandemic?
Studies are pointing to too much acetylcholine activity in the amygdala (see CBD and anxiety):
In the hippocampus, another brain region critical for an antidepressant response (Santarelli et al., 2003), increasing cholinergic tone induces anxiety- and depression-like behaviors that can be reversed by systemic administration of a nicotinic antagonist.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4486625/
There's the lovely hippocampus we've covered in detail since it's the seat of memory and mood.
Repair in that area is turning out to be one thing we can really influence on mental health.
See CBD and brain repair or CBD and hippocampus neurogenesis.
Mindful meditation and exercise also exert their positive effects on mental health via this pathway.
A range of new studies from aggression to social stress response has pinpointed acetylcholine as a key player.
For example, this study:
Knockdown of AChE in the Hippocampus Increases Anxiety- and Depression-Like Behaviors and Susceptibility to Social Stress.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3587265/
This shouldn't be surprising when looking at its effect on serotonin, our master mood and behavior regulator:
Nicotine, signaling through nAChRs, can influence serotonergic transmission in a complex manner, generally acting to increase serotonin release in many brain regions.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4486625/
We covered serotonin in detail at our CBD and serotonin review or CBD and tryptophan as a social stress buffer.
Very interesting since stress drives a great deal of what we've covered above.
Then there's anger. Rage. Irritability.
Fascinating research is pointing to a lack of acetylcholine and this whole subset of behavior.
Remember...it's the stuff of our rest and digest the autonomic system.
Ever notice how rage seems to be out of our control? Like we're riding a big nasty wave that only becomes apparent afterwards?
A nasty, red dream.
That's the autonomic nervous system. It runs in the background and half of it designed to calm down after fight or flight (rage).
It's primary currency? Acetylcholine.
The results:
Emerging data suggest that nicotinic agents may have a significant role in addressing ARBS across a variety of diagnoses.
ARBS is short for Aggression related behavioral states.
A full review of the research is here:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4486625/
The net net...when the calming side of our background nervous system runs low, adrenalin, and the "fight or flight" system can run amok.
There's a delicate balancing act or tug-of-war between these two systems where one needs to temporarily win for a bit (say if a tiger attacks) and then come back to balance.
One particular study caught our attention which leads to our next section.
The particular study:
This is supported by data from a case series in which transdermal nicotine was an effective treatment for agitation in four patients with severe dementia.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4486625/
Let's go there now.
Acetylcholine and age-related brain diseases
You can see from above that acetylcholine is a jack-of-all-trades across many brain areas.
Muscle control. Focus and thinking. Calming the nervous system down and repair.
We didn't even get into its powerful effect on sleep.
Let's look at what happens when it invariably goes down with age.
We'll also pinpoint a reason why women may be hit hardest by Alzheimer's and Dementia.
Most of the early Alzheimer drugs work by blocking the enzyme which breaks down acetylcholine.
Then, just look at the risks associated with drugs that reduce choline and Alzheimer's.
These include common meds like Benadryl (and Tylenol PM), Pepsid AC, and SSRIs.
All are tied to increased risk for Alzheimer's and Dementia.
Acetylcholine naturally decreases as we get older. Vitamin D, which is essential for proper choline processing, also decreases and may be the linchpin there.
Vitamin B5 is also needed to process and absorption of vitamins decreases as we get older.
Newer research is pointing to the loss of choline neurons as a key driver of Alzheimer's and Dementia. To the detriment of the old theory involving plaque buildup and tangles.
In fact:
Cholinergic neurons located at the nucleus basalis of Meynert are the main neurons affected in AD.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4787279/
Interestingly, Vitamin E was shown to increase the number of acetylcholine receptors.
This is important for diseases like depression where there may be too much excess acetylcholine (due to not enough receptors).
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4268065/
Let's turn to women since they get hit so hard by dementia (not just age-related).
In fact, there's a direct correlation of risk for Alzheimer's and hormone replacement.
We've covered this whole effect in detail since it was perimenopause that triggered our founder's initial scramble to find CBD, to begin with.
If you really want to see why estrogen is so important to how your brain functions, check out CBD, and perimenopause brain fog.
Why does this matter for acetylcholine?
Estrogen drives choline function!
In fact, researchers are zeroing in to the actual mechanism:
Loss of p75NTR receptors that are modulated by estrogen (Bora et al., 2005) on basal forebrain cholinergic neurons is associated with early evidence of cognitive dysfunction even without evidence of cellular loss.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4573353/
Serotonin may be a key player and estrogen directly drives serotonin function as well!
These results suggest that the positive effects of estrogen on cognitive functions might be mediated through ACh-5-HT interactions.
https://pubmed.ncbi.nlm.nih.gov/12020863/
Ya think!
5HT is serotonin. Serotonin is just the master regulator of all human behavior so we're not surprised.
Just a head's up...testosterone also drives serotonin and acetylcholine for men and it drops 1% each year from about age 20.
Check out CBD and serotonin for more insight.
This may also be CBD's key switch to throw for mental health!
More on that below.
So...ladies, really research hormone replacement to protect the brain. Check out our estradiol review to look at the sad history of how millions of women were sent into the abyss (literally) by faulty research in 2002.
Everything we've read points to choline dietary requirements (most people don't meet since organ meats aren't exactly flying off the shelf and the US govt crushed egg consumption with incorrect, initial info) needing supplementation.
Citicoline is the best absorbed and we personally use Choline CDP (available here).
As we mentioned, Vitamin D is essential (make sure to run labs to keep track of your levels - 50 - 60 is a general range).
B vitamins are also essential but watch out for too much B5.
Vitamin E supports acetylcholine receptors
Some more guidance:
https://www.health.harvard.edu/staying-healthy/a-possible-brain-food-that-youve-probably-never-heard-of
https://bebrainfit.com/acetylcholine-neurotransmitter/
Finally...the question at hand (sorry for the many detours - hopefully interesting!)
Does CBD boost acetylcholine
We clearly don't want to impair this pathway.
First, animal studies point to CBD increasing acetylcholine during wake times (critical since it should rise then):
Here, we demonstrate that systemic injections of CBD (0, 5, 10 or 30 mg/kg, i.p.) at the beginning of the lights-on period, increase the extracellular levels of ACh collected from the basal forebrain and measured by microdialysis and HPLC means.
https://pubmed.ncbi.nlm.nih.gov/29876791/
"The forebrain"...where our most taxing "thinking" happens. Exactly where we need acetylcholine.
Another study looked at CBD versus THC for choline uptake following electroshock:
One hour after administration of CBD, 60 mg/kg i.p. in vitro choline uptake was not altered in any brain region. In contrast, 1 hr after administration of delta 9-THC, 10 mg/kg i.p., in vitro choline uptake in the hippocampus and hypothalamus was significantly reduced.
https://pubmed.ncbi.nlm.nih.gov/6245205/
This could speak to THC's effect on memory and thinking.
Remember how we showed above that serotonin drives acetylcholine function?
There's a definite effect on CBD and serotonin.
This may be CBD's crown jewel of effects in fact.
It's been shown in multiple studies to balance serotonin.
Such as this one:
Seven days of treatment with CBD reduced mechanical allodynia, decreased anxiety-like behavior, and normalized 5-HT activity.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6319597/
The keyword there is "normalized".
So...
- reduced pain
- reduced anxiety
- normalized serotonin function
Check out CBD and serotonin to dive deep into the research but the key is balance.
We don't want serotonin (or acetylcholine) too high or too low.
By the way, in the above study, allodynia is increased pain sensitivity and anxiety is...well...we all know it after the pandemic.
The issue with acetylcholine is that some issues appear to be due to too high levels (depression) while others are due to too low levels (schizophrenia, ADHD, etc).
Even different brain areas come into play.
With powerful brain players like serotonin (and its downstream henchmen like acetylcholine and dopamine), it's all about balance.
Probably the biggest example of this with CBD is schizophrenia.
Check out the review on CBD and schizophrenia.
This horrible disease is so difficult because it reflects dopamine being too high in one brain area (striatum) while too low in another (prefrontal cortex).
The current antipsychotics reduce dopamine thus improving one set of symptoms while potentially making another set worse (the so-called "negative" symptoms).
CBD's effect was positive on both sets of symptoms!
How on earth is this possible?
CBD technically is called a negative allosteric modulator...especially for serotonin.
This means it works like a feedback mechanism from the receiving cell to the sending cell.
Usually, chemicals push a pathway up or down.
This is why we don't see overdoses on CBD.
Cancer is another great example of this.
Three different responses depending on the state of the system:
- Healthy cell or neuron with low inflammation - no effect
- Healthy cell or neuron with high inflammation - CBD reduces oxidative stress
- Cancerous or virally infected cell - CBD INCREASES oxidative stress
Read that back over!
The third instance doesn't make sense until you understand that oxidative stress is the body's (immune system actually) way to get rid of faulty cells!
We look forward to more studies on CBD and acetylcholine directly.
For now, the research points to having very little direct impact unless it's during times when acetylcholine needs to be high (such as during wake cycles).
CBD has not been shown to impair memory, cognitive functioning, or any other process that relies heavily on acetylcholine.
In fact, the big study on CBD and public speaking for people with social anxiety disorder showed no negative impact on verbal or cognitive function but a big drop in self-perceived anxiety!
The real behind the curtain player may be serotonin and we have lots of research there in our CBD and serotonin review.
To really get into the calming aspect of acetylcholine, check out our big review on the vagus nerve below. It's must read in today's hectic world.
Also, early trauma, infection, life stress can downregulate acetylcholine later in life which might speak to imbalances.
This can be reversed and it may be the most exciting new advance in mental health. More below.
Related Research:
the vagus nerve and acetylcholine
early trauma and acetycholine
brain inflammation and mental health
gut health and probiotics
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.