We just wrapped a huge review on how early trauma, infection, and stress can downregulate serotonin...for life!
As a result with the symptoms, serotonin figured in strongly:
- Stress response
- Anger and Irritability
Of course, estradiol (our main estrogen) and testosterone (via estrogen conversion in the brain) drives serotonin function which is how we "ran" into it. That brutal story.
But that's just the start of serotonin.
It may be the most fascinating and misrepresented chemical in our body (and gut!).
It's also the target of arguably the most popular class of medications out there called SSRIs (see CBD versus SSRIs for serotonin).
The interactions with CBD and serotonin are both very interesting and revolutionary (compared to the meds out there).
We're going to look at all of it.
If there's one neurotransmitter to really wrap our heads around in terms of mental health and well-being, it's serotonin.
The real secret behind serotonin is likely BDNF, our brain's fertilizer! More on that below.
We'll cover these areas:
- What is serotonin and what does it do in the body
- What happens when serotonin is too high or too low
- Serotonin and tryptophan
- Serotonin and BDNF
- Serotonin and Estrogen
- Alcohol and serotonin
- What do SSRIs do with serotonin
- How does CBD work with serotonin
- Can CBD increase serotonin
- Can CBD cause serotonin syndrome
- CBD and serotonin in the gut
We're going to look at elements of serotonin that most people don't know about but are incredibly important to tease out its role in the brain and body.
This is a story of balance and we'll see what research is showing on that front with CBD.
Let's get started.
What is serotonin and what does it do in the body
We'll start with the basic understandings of serotonin.
It's commonly called the "feel good" neurotransmitter but that belittles its real role in the body and brain.
Serotonin is a master messenger and regulator across all brain aspects that affect... human behavior.
Yes, that's a broad category but that speaks to just how widespread serotonin function is.
As researchers put it:
Serotonin has been implicated in practically every type of behavior, such as appetitive, emotional, motor, cognitive and autonomic.
You'll commonly see it referenced at the 5HT pathway (5-hydroxytryptamine).
Remember that "tryptamine" in the end there for later with our tryptophan section.
Serotonin has a host of housekeeping functions (gut movement, heart function, etc) but the more fascinating effects are on shaping and molding our behavior.
There are three powerful levers directly under its control with important relevance for mental health (our primary focus with anxiety and depression at epidemic levels):
- Brain repair and growth via the BDNF pathway
- Stress response
- Shaping self-esteem and positive outlook
These are just a few avenues to look at but they'll shine a light on just how integral serotonin is to how you feel.
An example is so much more powerful than just telling you that serotonin is the "feel good" chemical!
Let's look at each of those.
Brain repair and growth via the BDNF pathway
You have a constant battle going on in your nervous system (and body really) between forces that destroy and those that rebuild.
On the destroyed side in the brain, we can have:
- Inflammation (especially chronic)
- Immune response
- Chemicals (like alcohol or drugs - see CBD versus alcohol)
- Trauma (even early psychological or social trauma)
- Stress...especially chronic
- Overactive glutamate or histamine (both gas pedals in the brain)
You'll notice that the immune system is involved in a lot of the insults (see CBD and neuroinflammation for anxiety).
Fighting the tides is our repair and replenishing side.
Serotonin is a major player in this process called "neurogenesis".
It turns out that what it's really doing is "regulating" a downstream player called BDNF which is our brain's fertilizer.
Check out CBD and BDNF to learn more about this unsung hero.
In fact, with studies on SSRI's, when they block BDNF pathways, the neurogenesis (the real star there) and their anti-depressant effects go away!
More relevant to our article here is that this also happens when the block endocannabinoid receptors (that CBD works through).
A great deal of research is showing that anxiety, depression, and a host of mental health issues can arise from the following mix:
- The insults (inflammation, trauma, chemicals, etc) are too high
- The repair system (serotonin, BDNF, etc) are too low
That's why chronic stress can literally cause brain damage and loss!
As we mentioned above, estrogen/testosterone is a major supporter of serotonin and this may speak to why women's risk of dementia goes up when estrogen goes away (see estradiol review or CBD and perimenopause brain fog).
Originally, researchers pointed to serotonin for this neurogenesis effect but it was really BDNF doing the heavy lifting.
Now you know (even if your doctor doesn't).
Next up...part of how we actually process or deal with the insult side.
Serotonin and Stress response
We wrote an entire article on how serotonin (via tryptophan) might be sort of stress buffer.
In fact, serotonin is pivotal all along the stress response pathway.
Think about it...some people can take tremendous amounts of stress with very little impact.
What is that??
Serotonin figures strongly.
There's a study where they reduced oxygen in the air for participants.
Some of them had tryptophan (the raw material for serotonin) depleted and others did not.
The lack of serotonin directly impacted their stress response to the restricted oxygen situation:
ATD influenced the HPA axis (associated with higher cortisol levels), apparently independent of CO(2) or air inhalation stressors.
HPA is your fight or flight center which affects how your body will respond to fear and stress.
In fact, chronic stress can reduce serotonin levels naturally and this even speaks for social and psychological stress.
This has huge ramifications for social anxiety, teen anxiety, and really….any anxiety.
Serotonin appears to be a tool used to craft social interaction, behavior, and even status!
Let's go there now.
Shaping self-esteem and positive outlook
What originally fascinated us were studies on how serotonin was used as a reward for higher social status and self-esteem and a stick for lower social self-esteem.
Researchers would literally watch primate groups where a member would ascend to the top of the hierarchy and their serotonin levels would rise accordingly.
The opposite would happen for those that fell in status.
Recent primate studies suggest that fluctuations in the neurotransmitter serotonin helps regulate our level of self-esteem and place within the social hierarchy.
Look...there are dozens of bizarre studies on tryptophan, serotonin, and social interaction.
For example, a person is more likely to reject an unfair offer in a game if supplemented with tryptophan (direct precursor to serotonin).
Increasing serotonin through TRP supplements increased the rejection of very unfair offers.
Without tryptophan, participants were more likely to accept bad offers.
Think how strange this is!
Impulsivity was not affected (although that's under the control of serotonin partially as well).
You could argue that serotonin is the chemical that makes you stand up for yourself!
These are just a few examples of how serotonin shapes our behavioral response.
It's only a smattering! The word "behavior" is a ridiculously broad one but that speaks to how powerful serotonin is and we're even looking at its housekeeping roles in the gut and body.
We could geek out on this all day such as with this study:
One study found that after 2 weeks’ treatment with citalopram, participants were significantly less likely to behave in a self-interested manner in a modified version of the prisoner's dilemma that allowed participants to act selfishly, cooperatively, or charitably.
Selfish. Giving. Moral judgment. Goodness.
Let's look at what happens when levels go too low or too high.
What happens when serotonin is too high or too low
First, there's no good way to test your brain serotonin levels.
When doctors prescribe SSRIs (which make more serotonin available), they're guessing by your symptoms.
I was put on Lexapro after intense anxiety at age 47.
Rather than first looking at hormones (duhhh...I'm in the middle of perimenopause - see Why some women have horrible perimenopause transitions), they went right to benzos and SSRIs.
That's pretty typical these days.
Any way, withing about 3-4 weeks, I had full-blown serotonin syndrome (too much serotonin).
We'll talk about that below in more detail.
It's actually a very serious (as in go to the ER) issue.
The more prevalent state is that of too little serotonin.
After looking at some of the pathways affected by serotonin above, you can see how this would be a big issue.
The most obvious (but not limited to) results could be:
- Depression (loss of brain repair)
- Anxiety (loss of stress response and resilience)
- Insomnia - serotonin is converted to melatonin which manages the sleep/wake cycle
Again, the full range of "mood" can be affected.
There's a full range of gut issues that occur as well as most of our serotonin is actually made and used in the gut!
What about the other side, too much serotonin?
That's the nasty serotonin syndrome I mentioned above which is almost exclusively caused by medications that boost serotonin.
It's very serious and brutal (I experienced it with Lexapro).
We look at the symptoms at our How I Used CBD to wean off SSRI's article.
So….the key is balance fo serotonin.
Not too much or too little.
This is where CBD is so interesting and we'll look at that in detail below.
First, it's important to understand where serotonin comes from since we actually have control over that.
Serotonin and tryptophan
Tryptophan is an amino acid and it's the sole source of serotonin!
We've all heard how Turkey at Thanksgiving can make you sleepy because of serotonin.
Sorry to disappoint but food sources (such as meat) will not significantly boost brain tryptophan.
The reason is that tryptophan has to compete with all the other amino acids to cross the blood-brain barrier.
In fact, carbohydrates help to carry it across the barrier which is why one symptom of low serotonin is craving starchy foods. Tryptophan supplementation, however, is showing interesting effects on research.
We really went deep into it with our Are CBD and tryptophan a stress buffer we can use with Social Anxiety?
Very interesting studies!
There's another interesting aspect with tryptophan.
When we're fighting infection, our brain will naturally limit tryptophan which suppresses serotonin.
This is partially why you feel so low when sick.
It does this because the bacteria or viruses also use tryptophan to make more of themselves!
Just a head's up...our immune system isn't really good at deciphering between inflammation from bacteria or from chronic stress! Or even psychological trauma!
This is partially why stress can cause serotonin levels to drop.
The immune response is a one-trick pony in that case!
In fact, early stress, trauma, or infection can "prime" the system to have lower serotonin later in life!
We looked at the whole connection at our Tryptophan, inflammation, and anxiety article.
Let's look at the real workers behind serotonin's management. BDNF!
Serotonin and BDNF
Many people have heard of serotonin but very few know of BDNF.
That's a shame because it's really holding back the forces of destruction between your ears right now.
It's described as the brain's (nervous system really) fertilizer.
We did an in-depth look at psilocybin since it's primary effect was on BDNF for anxiety and depression.
That was our first sign that this was a key player.
This is pretty well established now with SSRIs (till tolerance kicks in):
In summary, current data suggests that conventional antidepressants and ketamine mediate their antidepressant-like effects by increasing BDNF in forebrain regions, in particular the hippocampus, making BDNF an essential determinant of antidepressant efficacy.
Why the forebrain?
That's the prefrontal cortex and it's the rational player in the anxiety circuit (see CBD benefits for anxiety) as well as the reduced player in depression.
Again...under assault. Call for back-up!!
What's interesting is that they can chemically or genetically block the activity of BDNF and the anti-depressive and neurogenesis effect is blocked!
Again, check out BDNF and CBD here. There are ways to boost it in addition to CBD which is critical.
Next up...an unexpected player (unless you have a monthly cycle).
Serotonin and Estrogen (or Testosterone)
As we mentioned above, we were becoming bored with describing the serotonin pathway with each and every symptom of perimenopause.
Most people don't realize that estrogen has powerful pro-growth effects (through the ERa receptor).
One way it does this is via serotonin and ultimately, BDNF as we just learned.
Estradiol (E2 - our primary estrogen) directly controls both the production and removal of serotonin:
Estradiol is especially nurturing towards serotonin – it stimulates TRPH expression to ensure that enough serotonin is made and suppresses MAO A levels to prolong the longevity of the neurotransmitter.
TRPH is a tryptophan from before. MAO is a powerful enzyme with ties to many mental health issues (for certain genetic variants).
When estradiol goes on a roller-coaster ride during puberty, perimenopause, or monthly cycles, we see that effect all over the body and brain.
Fluctuations in estradiol would then naturally lead to fluctuations in serotonin.
Goodness. No one's talking about this!
What about when estradiol flees the scene altogether (menopause)?
Those symptoms are even more serious (dementia, heart disease, osteoporosis, etc).
Read the review on estradiol to understand why it's so critical.
For men, a great deal of testosterone is converted (via heavy aromatase levels) into estrogen in the brain where it does the same thing. In fact, libido is actually driven by...estrogen! Even for males!
Interestingly, the drug of choice for ladies in their 40's and going into perimenopause appears to be alcohol. Wine, to be exact.
Let's go there now.
Alcohol and serotonin
The body is all about balance.
Is serotonin is suddenly leaving the scene because no one really lived past age 50, 100 years ago, the female body will try to make up for it.
First, body fat will increase since fat cells are a secondary source of estrogen.
Another fascinating boost to estrogen is none other than alcohol.
Check out the CBD versus alcohol for serotonin article to see how wine specifically was shown to increase estrogen levels in US and European women.
It also directly boosts serotonin in both genders...with a caveat!
In the short term, there's a boost to serotonin (which partially accounts to the feeling of alcohol):
In humans, for example, the levels of serotonin metabolites in the urine and blood increase after a single drinking session, indicating increased serotonin release in the nervous system.
That's short term or acute alcohol exposure.
The effects look very similar to SSRIs where more serotonin appears to be available for use in the brain.
There's another shared trait though from prolonged exposure.
The brain fights back any time an outside force is trying to push one way or the other.
It's called homeostasis...a fancy word for balance.
With long term alcohol exposure:
For example, if alcohol exposure inhibits the function of a neurotransmitter receptor, the cells may attempt to compensate for continuous inhibition by increasing the receptor numbers or by altering the molecular makeup of receptors or cell membranes so that alcohol no longer inhibits receptor function.
This has been shown to happen to the 5HT2 receptors after prolonged alcohol exposure.
That's not good.
Essentially it means that your brain is down-regulating serotonin function to compensate.
Guess what happens when the alcohol (or SSRI) wears off or if you stop using it?
Withdrawal symptoms. Since that would be bad for a billion-dollar industry (SSRIs), they call it Serotonin Discontinuation Syndrome.
Orwell would be so proud (and probably medicated).
Your "new" serotonin level is now lower than before you started and this tit for tat continues with usage.
Of course, juicing serotonin levels is showing a mechanism by which alcoholism (and addiction) occur as well.
In fact, when the genetically knock out serotonin processing genes in mice, they display less withdrawal and tolerance:
Compared with normal mice, the knockout mice showed less evidence of tolerance to alcohol’s effects.
Interestingly, they also showed more aggressive behavior with the loss of that receptor.
Again...serotonin is tied in with all behavior!!
Let's look at the biggest player on serotonin levels around now.
What do SSRIs do with serotonin
The primary lever of SSRI, the most common class of anti-depressants on the market, is none other than serotonin.
The most common ones are:
Fascinating data both in terms of how they work, how they're different, and the strange history of their rise to prominence.
We now know better on the mechanics behind their effect.
On a surface level, SSRIs allow more serotonin to be available in the brain. They stop the process that "recycles" serotonin so that neurons have more to use.
This may be temporarily great if you have low serotonin and the first thing you doctor will do is test your serotonin levels.
Yes, that's not going to happen.
There are metabolite tests but nothing very accurate for the brain and the doctors will just go based on symptoms.
Most likely, it will be a GP or general practice doctor after a 10-minute visit.
Bam...out the door you go with a medication that tinkers with the neurotransmitter that governs all human behavior.
It should be fine.
It's estimated to be effective for 30-40% of the people treated for depression depending on the research you look at.
A big reason for this low number is that the list of side effects is both vast, varied, and horrifying.
Check out the CBD versus SSRI review for more info.
The bigger issue is the whole tolerance issue we mentioned above.
It's common knowledge in the medical and research community that SSRIs generally lose their effectiveness (if effective).
The dosage is usually increased and/or other SSRIs are tried or layered on top.
The inevitable endgame is...tolerance.
The brain doesn't take kindly to outside influence with such a critical pathway.
This happens anytime we try to boost or decrease the hard levels of a critical component in the brain.
The doctor may actually warn you in that 10-minute visit not to come off of an SSRI quickly (if ever).
The effects can actually be dangerous.
I discuss this in the article, How I used CBD to wean off SSRIs.
Your entire serotonin pathway has been changed...remapped if you will.
It can take weeks, months, and even years for that to normalize as we hear from many customers.
Interestingly, guess what system is tasked with this balancing act?
The endocannabinoid system!
The very system that CBD operates in.
Let's go there now?
How does CBD work with serotonin
We first have to understand the endocannabinoid system to truly appreciate what CBD does (and doesn't do!).
We all have this system and it's dated back to 600 million years ago evolutionarily speaking.
All animals have one (insects were too early for the party).
It's tasked with balancing other key systems in response to stress (a general meaning of anything that pushes on a system one way or the other):
- Immune system - inflammation and repair
- Endocrine system - hormones such as estradiol and many others
- Nervous system - neurotransmitters like….serotonin!
This balancing act is really important for CBD's mechanism on serotonin.
Again, we don't want to just pump up serotonin levels (long term) like with SSRI's or alcohol - the brain will push back.
Even THC (CBD's cousin) pushes in one direction and can cause tolerance longer term.
What exactly does CBD do for serotonin?
CBD appears to strengthen the endocannabinoid system's ability to do its job.
That's a bold statement but we'll tease it out with actual research on serotonin function.
Let's look at some of these studies now.
Researchers created a nerve injury in mice that resulted in increased system-wide pain and anxiety.
Overall, 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.
Let's break that down because it's fascinating with a little guidance.
5HT1A is a primary serotonin receptor. The researchers were able to show that by blocking this receptor, the positive effects went away.
This ties CBD's effect to serotonin function.
The interesting piece is towards the end…." rescues impaired 5-HT".
Here's the deal...the injury exhausted proper serotonin function.
Keep in mind that serotonin thas a powerful effect on pain sensitivity (like we said...all behavior).
This acute or chronic pain basically runs serotonin dry. CBD was able to "buffer" or restore this serotonin pathway.
It's a back-up!
This study shows that CBD can bolster serotonin….WHEN LOW.
That's critical since too much serotonin is equally bad (if not worse)t than too low.
Check out serotonin syndrome here if you need an example.
The positive effects seen on CBD for depression are also pointing to buttressing these levels when too low:
Results showed that CBD (10 mg/kg), FLX (10 mg/kg) and DES (5 mg/kg) induced antidepressant-like effects in mice submitted to FST. I
In that study, they compared it to the original SSRI, fluoxetine (Prozac).
When they used another chemical to block serotonin function, the effects of CBD went away.
Serotonin also acts as a brain message lubricant for a lack of a better word.
It's intimately involved in regulating other key neurotransmitters (dopamine, norephedrine, glutamate, GABA, etc).
There's a school of thought based on research with depression that a lack of glutamate (gas pedal) in the prefrontal cortex may be at play.
This area of the brain is what makes humans, human. It's what makes you, you. Literally.
Right behind your forehead.
People that have depression can show reduced activity there.
In vivo microdialysis revealed that the administration of CBD significantly enhanced serotonin and glutamate levels in vmPFCx in a different manner depending on the emotional state and the duration of the treatment.
So...increasing activity in the area of the brain that keeps our more primail emotional/impulse centers (like the amygdala) in check!
The net effect of this:
Cannabidiol induces rapid-acting antidepressant-like effects and enhances cortical 5-HT/glutamate neurotransmission
5-HT is serotonin.
Here are two really important takeaways from this that require noting:
Moreover, adaptive changes in pre- and post-synaptic 5-HT1A receptor functionality were also found after chronic CBD
In vivo microdialysis revealed that the administration of CBD significantly enhanced serotonin and glutamate levels in vmPFCx in a different manner depending on the emotional state and the duration of the treatment.
The first basically says that CBD is shaping the pathway of serotonin itself as opposed to just jacking up levels.
Not to be sensationalist but this avoids how the brain builds tolerance (as with outside interlopers like SSRI and alcohol).
The second is more telling.
The effect of CBD depended on the state of the system.
This may be the most important thing you've read yet (assuming you've lasted this long...sorry).
We see this all over the pathways affected by CBD.
It's called a biphasic (two different responses depending on the state of the system).
There's even a tri-phasic effect with cancer that drives home the point:
- Normal cell with low inflammation - no effect
- Normal cell with high inflammation - anti-inflammatory effect
- Cancerous cell - INCREASES inflammation!
Read that back over. It's amazing. More on CBD and cancer.
Keep in mind that the way the body (immune system to be more precise) kills cancer naturally is to jack up inflammation in the cancerous cell until it dies.
That's the same mechanism that chemo and radiation use.
Sorry for the detour but this varying effect on serotonin is seen elsewhere….everywhere really with CBD.
Back to serotonin.
Remember how we said that serotonin is a master regulator of stress response?
Rats were subjected to restraint (RS or restraint stress) and tested 24 hours later.
Half were given CBD.
Exposure to RS increased blood pressure and heart rate and induced an anxiogenic response in the EPM 24 h later. These effects were attenuated by CBD.
Anxiogenic means boosting anxiety.
They used a second chemical to block serotonin function and the positive benefits of CBD went away.
Newer, more sophisticated is actually showing that CBD can substitute for serotonin in certain pathways:
Overall, these studies demonstrate that CBD is a modest affinity agonist at the human 5-HT1a receptor.
That's technical speak for saying that CBD can plug directly into the 5HT lock.
All told, CBD appears to buffer serotonin levels, function, and activity when LOW.
Let's look at some practical questions below and address if it can raise serotonin too high!
A common question first.
Can CBD increase serotonin
The studies above pointed to a balancing of serotonin function...especially when low (injury, depression, stress, etc).
Does CBD actually increase serotonin?
It depends...and that's the beauty (and the reason we write 100's of thousands of words on it).
The better question is this...can we just keep increasing CBD and get too much serotonin?
Is it a one-way train like SSRIs?
If you keep boosting SSRI dosages, you're likely to end up with Serotonin Syndrome...a very dangerous situation.
Along the way, you'll start to see a host of nasty symptoms.
What about CBD?
There has not been a documented case of overdose or serotonin syndrome for CBD.
A high dose is around 600-800 mg (seen in research on schizophrenia and CBD here).
Researchers have tested it up to 1500 mg with no side effects and even higher.
The peak dosage for neurogenesis (assumes serotonin and BDNF pathway) is 300 mg.
We would expect with very high doses to see the side effect profile of SSRI's but that doesn't reflect the research (See CBD safety here).
So...as we showed with the bi-phasic effects:
- If serotonin levels are low, CBD appears to increase serotonin levels and function (it may actually function as fill-in for missing levels)
- If serotonin levels are high, CBD may actually bring function down
For the latter, we actually need studies on CBD and serotonin syndrome
Again, that's the role of the endocannabinoid system.
Until we get better research, let's look at the symptoms of too much serotonin to see if they match anything seen with CBD.
That leads us to the topic of serotonin syndrome.
Can CBD cause serotonin syndrome
Serotonin syndrome is a very serious condition caused by too much serotonin. Extreme levels.
Take a look at the first-rung symptoms:
- Agitation or restlessness
- Rapid heart rate and high blood pressure
- Dilated pupils
- Loss of muscle coordination or twitching muscles
- Muscle rigidity
- Heavy sweating
In the study above on stress restraint, the actually measure heart rate and blood pressure at 3 doses:
- 1 mg/kg weight
- 10 mg/kg weight
- 20 mg/kg weight
A 160-pound person weighs about 70 kg.
That 20 mg level is the equivalent of 1400 mg...almost a gram and a half!
In that study, the heart rate and blood pressure continue to go down (following restraint stress) as the dose goes higher.
You would expect it to go the other way judging by the listed symptoms of rapid heart rate and increased blood pressure from excessive serotonin.
That's a good signal to look at since we don't have much control over it as part of our autonomic nervous system (unless you're a yogi or Jedi).
With higher doses up to 1500mg, those symptoms above do not appear.
Again, we look forward to more research but remember the takeaway from the study above:
"different manner depending on the emotional state and the duration of the treatment."
Again, this speaks more to the beauty of the endocannabinoid system and how CBD interacts with it as a constraint on both the low and high end.
Just a head's up...you can't say the same for THC which directly boosts CB1 activity like it's analog, anandamide.
You can get too much activity via THC and indeed, long term use will cause tolerance (see why you need CBD to protect against THC).
One final note which is important.
CBD and serotonin in the gut
Most of our serotonin is made in the gut.
That's why so many of the side-effects of SSRIs are gut-related.
It is a fascinating clue that so much of our primary neurotransmitter resides in the gut...our so-called "second brain".
It has many functions there and is directly implicated in motility (movement), vomiting, nausea, and diarrhea.
Hopefully, you have a good understanding of the basics surrounding CBD and serotonin now.
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.