Updated Research on CBD and Bipolar with a Comprehensive Review
July 23, 2020
6 million people in the US.
It's a tremendous amount of suffering.
Maybe second only to schizophrenia in terms of the sheer torment.
Interestingly, there's are shared pathways there which we'll get into below.
More importantly, new research is starting to unravel what's happening both in the brain, the gut, and the immune system (yes, the immune system).
There are even some new avenues on reducing suffering in a field with very little improvement for 50 years.
New research on how lithium really works sheds light on one key avenue...neurogenesis, which we'll discuss below.
Clues abound which we'll get into such as:
- Why are people with bipolar 3 ½ times more likely to have migraines?
- Why do the inflammatory markers spike during episodes?
- How can the level of certain hormones predict episodes 3 days prior?
- Why are women 22 times more likely to be diagnosed after pregnancy?
Of course, that dovetails into CBD which we'll spend some amount of time on.
Here are the categories we'll cover:
- New research on what causes bipolar
- Bipolar and the brain
- Bipolar and neurotransmitters
- Bipolar and hormones
- Bipolar and the gut
- Bipolar and inflammation (the gut!!)
- Bipolar and sleep
- The genetics of bipolar
- Current medications for bipolar
- Neurogenesis and bipolar (BDNF, serotonin, etc)
- The endocannabinoid system and bipolar
- Research on CBD and bipolar
- How much CBD for bipolar
- The best CBD for bipolar
Like we said..thorough. We're not messing around.
Let's get started.
New research on what causes bipolar
There is a clear genetic risk for bipolar which we'll cover in a later section but that's not the whole story.
The more fascinating research centers on a system most would not have expected just a few decades ago.
The immune system.
There were already clues for both schizophrenia and bipolar with early exposure to viral infections even in utero.
Look at this recent NIH headline:
Flu in pregnancy may quadruple the child’s risk for bipolar disorder.
We've looked at this in detail at our CBD and neuroinflammation review since it's something we can actually work on.
The immune system is now becoming a shining star in mental health across the board.
New studies are seeing the actual effects directly:
Microglia, immune cells in the brain, play important roles in the process of brain inflammation, and recent positron emission tomography (PET) studies have shown microglial overactivation in the brain of patients with various psychiatric disorders including bipolar disorder (3–8).
Microglia are fascinating. Yes, they are the brain's immune system sentinels but they do so much more.
What's the connection with bipolar disease?
They are intimately tied into the modeling of brain networks!
The birth and death of neurons and connections fall under their sway.
So what happens if early infection "primes" them to be overactive?
Damage. Tissue loss. Impaired connectivity.
This may be the shared lineage that bipolar shares with schizophrenia which both have signs of brain areas being impaired.
As we mentioned, there's a genetic part of the risk (true with everything) and some of those genes directly mirror the ability of the brain to repair and rebuild.
This is needed if the immune system is going scorched earth (very similar to autoimmune diseases).
Even lithium's trick appears to be in support of repair and rebuilding.
We'll touch on all of that at our neurogenesis section below.
There are many ways we can support that pathway including CBD.
Check out the CBD and microglia review...very fascinating research.
A great deal of this appears in certain parts of the brain.
Let's go there now.
Bipolar and the brain
We have to introduce you to the prefrontal cortex.
It's the part of your brain right behind the forehead and it's what makes humans human.
Think of it as your rational brain...as opposed to your "reptilian" brain in the back which much older evolutionarily speaking.
Certain parts of this brain area are implicated in bipolar episodes and risk.
These areas are tied in with impulse control, decision making, and restraining emotional areas of the brain.
Think of them as gates. Information comes from more emotional and let's say "primitive" parts of the brain.
The role of the prefrontal cortex is to determine whether to act on those or not!
This same relationship appears strongly with anxiety (amygdala overwhelms the prefrontal cortex). See CBD and mechanisms of anxiety.
Those signals can very well be for sex, gambling, risk-taking, drug use, etc.
If the prefrontal cortex is impaired as a result of trauma, overactive immune response, or an inability to constantly (meaning by the second) repair, manic episodes can result.
One more stop before your eyes glaze over but it's a critical one.
To the hub of mood control (sounds relevant).
The hippocampus. New research is really pointing to this area as critical to bipolar disease.
Even the little power supplies called the mitochondria here are showing signs:
for about 80% of the bipolar patients, hippocampal mitochondria were smaller than even the smallest of the control subjects’ mitochondria
https://www.psychiatrictimes.com/mitochondrial-clues-bipolar-disorder
This means the hippocampus may not be keeping up and that's not good since it's also the most vulnerable part of the brain due to its plasticity or "changeability" needed for memory (it's the seat of memory as well).
With time, the actual volume of this mood control sub-unit starts to decrease:
A new study found that a volume decrease in certain parts of the hippocampus, a brain region known for mood and memory processing, is linked to bipolar disorder.
Just remember that for when we discuss CBD and hippocampus neurogenesis (building brain!) below.
We can now look at the messengers of this wave of mania to understand the rebound effect (depressive episodes).
Here's where it gets interesting and maybe, actionable.
Bipolar and neurotransmitters
It's been known that there are imbalances with key neurotransmitters bipolar episodes.
The main suspects:
- Serotonin - a master regulator of behavior and brain activity (see CBD and serotonin)
- Dopamine - a driver of focus and drive - the reward circuit manager (see CBD and dopamine)
- Glutamate - the brain's gas pedal - you can't have a manic episode without it (see CBD and glutamate).
- Acetylcholine - Currency of the prefrontal cortex AND the rest/digest part of our autonomic system (see CBD affects acetylcholine).
There are genetic risks associated with how serotonin and dopamine process in the brain for bipolar so that's an interesting clue.
These are all interwoven and finely tuned pathways so too much or too little of any is bad news.
While norepinephrine metabolite levels are normal during mania, other neurotransmitters such as dopamine, acetylcholine, and serotonin have all been implicated in manic and hypomanic episodes, as well as in the depressive symptoms that follow.
The key is not only balance but balance across different brain areas.
For example, schizophrenia shows too much dopamine to the striatum (also implicated with bipolar) and too little in the prefrontal cortex.
Read up on our dopamine, serotonin, and acetylcholine reviews.
It becomes clear that a surge in these would be debilitating.
These are also finite pathways. A prolonged surge in dopamine or serotonin would result in a rebound effect...either by the brain trying to offset the surge or temporary depletion.
We see these effects across almost every pathway. It's the anxiety after alcohol consumption (depletion of GABA and serotonin). It's the basis for withdrawal symptoms for addictive drugs (see CBD and addiction or CBD and withdrawals).
Even migraines are constriction of blood vessels following a surge in dilation. The brain and body can overcompensate!
If you stare at a red dot for too long on a white screen, you'll see the imprint when you look away.
Until the chemicals needed for that color rise back up.
Exhaustion of serotonin will feel like….depression. Exhaustion of dopamine? Well, you can't get out of bed.
That's the short term effect, however. Long term, cumulative manic episodes cause actual damage.
Glutamate is the most finely tuned neurotransmitter since it's the means to every action.
The "gas pedal" if you will.
Here's the issue...too much glutamate for too long is toxic to neurons. Bipolar is marked by cumulative damage to certain brain areas and glutamate definitely underlies this effect.
While research on glutamatergic homeostasis in mood disorders has associated bipolar disorder with excessive levels of glutamate, depressive disorders are thought to show reduced glutamate neurotransmission
Homeostasis means balance.
See how there's a surge of glutamate followed by a drop?
How do we know this?
The studies on NAC (N acetylcysteine) point the way.
We did a full review on NAC since it's so exciting for mental health and addiction.
Basically, it supports the detox system (glutathione) but more importantly for this topic, it acts like a sponge for excess glutamate.
There are big studies going on here but some of the initial trials show promise especially for the mania side:
Fourteen individuals were available for this report, seven in each group. Six people achieved full remission of both depressive and manic symptoms in the NAC group; this was true for only two people in the placebo group (χ(2)=4.67, p=0.031).
https://pubmed.ncbi.nlm.nih.gov/20800897/
Another study looked at NAC and aspirin (inflammation...hello! Immune system response!)
Following a 16-week treatment period, NAC + aspirin was associated with a higher probability of treatment response (67%) compared to placebo (55%), NAC (57%), and aspirin (33%).
https://pubmed.ncbi.nlm.nih.gov/30549489/
Interesting...bring down oxidative stress, soak up excess glutamate, and reduce inflammation.
It takes time for NAC to work but it's safe, cheap, and readily available here.
Again, check out the NAC review which also touches on addiction, unfortunately, a key issue with bipolar.
Then there's acetylcholine.
We'll get into this more with the sleep section since it's a charge of the wake/sleep cycle but the prefrontal cortex (which is lacking or under duress from our immune system/glutamate) relies on acetylcholine.
Studies are looking at supplementing choline to support this pathway with bipolar:
Clinical improvement correlated with higher levels of choline in a part of the brain called the basal ganglia as measured using Magnetic Resonance Imaging (MRI).
Remember...what if the prefrontal cortex can't do its work to keep the more primitive and impulsive areas of our more ancient brain at bay.
Acetylcholine, being the arbiter of prefrontal cortex function and dam against the fight/flight impulses figures into the mania piece:
It has been postulated that abnormal low brain levels of acetylcholine cause some cases of mania. Findings of a small placebo-controlled trial suggest that phosphatidylcholine (15 g to 30 g/day) may reduce the severity of mania and depressed mood in bipolar patients. Case reports and case series suggest that choline reduces the severity of mania.
Choline is also easy to supplement. Eggs and peanuts have it but Choline CDP is a great way to get it (available here).
It's estimate 90% of the population has choline deficiencies.
So...NAC and Choline CDP to start.
Let's turn to another system which is incredibly important for women with bipolar.
You'll see there are connections underpinning this.
Bipolar and hormones
For a subset of bipolar sufferers, this is a huge deal.
This is usually applicable for women with extreme hormone fluctuations of men who readily turn testosterone into estrogen.
You can get a Dutch test to see how your hormone levels are behaving.
This is critical for women over age 40 (progesterone drops to half by then). It's actually how we found CBD - see Dre's story for her perimenopause hell story.
Hormonal shifts are especially important for rapidly cycling bipolar.
Researchers even found that blood levels of certain hormones could predict manic and depressive periods 3 days prior to the event!
https://www.sciencedirect.com/science/article/pii/016503279400094P
Another clue is the tie between bipolar episodes and periods of extreme hormone fluctuation such as pregnancy:
women diagnosed with bipolar disorder are more than 23 times more likely to be admitted for reasons related to their bipolar disorder (e.g. depression, mania, etc.) during the first month after childbirth than during their actual pregnancy.
https://www.focusih.com/estrogen-depression-bipolar-hormones/
A further tie between bipolar and complications of PMS cement this connection:
There are links between PMS, monthly cycle, and worsening bipolar symptoms:
22 to 77 percent of women with bipolar disorder met the criteria for premenstrual dysphoria, and 15 to 27 percent met the criteria for premenstrual dysphoric disorder (PMDD).
https://www.verywellmind.com/effects-of-premenstrual-symptoms-on-bipolar-379963
Make sure to run the Dutch test and work with a naturopath. Most doctors will have no idea what you're talking about, unfortunately.
Next stop...the gut.
Bipolar and the gut
This may seem like a strange departure but all roads to point to Rome and Rome is the gut for mental health these days.
The most exciting studies deal more with the trillions of bacteria in our gut than our actual cells themselves.
80% of your serotonin is made in your gut by bacteria. We saw above how serotonin is directly implicated in bipolar disease.
There's a complicated orchestration between our gut and our brain directly affecting behavior.
For example, the presence H Pylori (often suspected for ulcers) increases mood disorders including depression:
We found that H pylori seropositivity was associated with 2.5 times higher odds of dysthymia among women
Dysthymia just means a depressive episode.
In fact, the numbers and types of bacteria found in gut have a direct effect on multiple numbers of mental health diseases including bipolar (BP):
Decreased diversity of certain gut bacteria have been linked to ASD, BPD, depression, and chronic fatigue syndrome.
http://www.psychiatrictimes.com/article/gut-immune-brain-axis-and-neuropsychiatric-disorders
The more interesting research looks at antibiotic and bipolar disease.
In the study population, 7.7% of the patients with acute mania were found to be prescribed antibiotics.
That was 7 times the level of people who did not display bipolar symptoms!
Remember...the immune system figures large in risk.
Then, we can look at the other side...probiotics or healthy bacteria strains.
During that time, 50% of the patients required rehospitalization, but the rate was lower—by a factor of 3—in the probiotic group. A similar reduction was seen in the duration of hospital stays for patients who were given the probiotic.
We can drill as far into this as you're willing to go.
New research is pointing to the by-product of our gut and mood disorders such as bipolar.
They are called propyl oligopeptides.
Simply put:
This peptidase has been associated with schizophrenia, bipolar affective disorder, and related neuropsychiatric disorders, and therefore may have important clinical implications.
https://pubmed.ncbi.nlm.nih.gov/17295371/
Berberine is a known blocker of these (check out berberine review).
Then there's the obvious connection:
Patients with bipolar disorder exhibit an increased frequency of gastrointestinal illnesses such as inflammatory bowel disease, which mechanistically has been linked to microbial community function.
https://www.karger.com/Article/FullText/504496
That link points to a wealth of information on the connection between gut health and bipolar.
Really fascinating information!
Check out our look at CBD and gut bacteria or CBD and gut barrier health.
Speaking of which...inflammation in our gut leads directly to inflammation throughout the body via a leaky gut barrier.
Let's go there now.
Bipolar and inflammation (the gut!!)
There's a great book called The Inflamed Brain by Edward Buller. We recommend it for anyone with bipolar (or a brain for that matter).
This is the direction of mental health and it dovetails with almost everything we discussed above.
Guess where the scales of inflammation reside? The immune system.
And the gut is a strong determinant in which way that scale is tilting.
As an eye-opener, look at the list of triggers here:
All have something in common. Stress! Acute or chronic stress.
Our body's response to stress is inflammation.
If your skin is stressed (by infection, injury, allergies, etc) the effects are obvious.
Redness. Inflamed. Swelling. Etc.
But what if your nervous system or the brain itself is stressed?
What's the symptom?
The new theory is that many of our psychiatric issues are inflammation of the brain and the central nervous system.
One of the big triggers for bipolar episodes is a disruption in sleep.
A recent study showed that lack of sleep looks just like acute anxiety in scans.
Stress leads to inflammation and guess what carries out the orders from our microglia and immune system in response?
Glutamate...the very thing that can fry out the prefrontal cortex when too high for too long:
Studies show that inflammatory agents in the cross the blood-brain barriers:
Inflammation has also been found to play a major role in glutamatergic neurotransmission involved in mood regulation in depression and bipolar disorder.4-6
Inflammation revs the engine and glutamate is the gas pedal.
In fact, this glutamate activity at the NMDA may be part of the cascading imbalance in serotonin (which drives dopamine):
Imbalances in the metabolites of kynurenine which serve as either N-methyl-D aspartate agonists or antagonists and decreased serotonin production, in turn, may contribute to the onset of manic and depressive symptoms."
Let's translate that because it's really interesting.
Basically, chemicals that drive glutamate pathways specific to serotonin are off-balance prior to episodes.
Researchers have looked at supplementing tryptophan (the precursor to serotonin) for bipolar:
Taking the amino acid L-tryptophan 2–3 gm/day or 5-hydroxytryptophan (5-HTP) 25 to 100 mg up to three times a day may have beneficial effects on anxiety associated with mania.
We covered tryptophan in detail here since it may act as a buffer for social stress.
Sound pertinent?
Let's drill directly into the agents of inflammation. Cytokines.
Is there a connection with bipolar? A smoking gun per se?
The clues are everywhere across studies but a quick look:
The concentrations of IL-4, TNF-α, sTNFR1, and sIL-2R were significantly higher in BD patients in comparison with controls
Those are all cytokines...little immune assassins.
The fascinating part is this:
The immune changes already observed in euthymia are enhanced during mania (Table 2) and depressive state
Think about that...the already existing spike in inflammation gets worse during episodes.
We would expect to see this relationship if there was any kind of connection.
Oxidative stress is a different type of inflammation. It's driven by a separate pathway to remove free radicals that are produced as a waste product from our energy sites (mitochondria).
It's equally implicated:
Several studies have reported that patients with bipolar disorder have significant alterations in antioxidant enzymes, lipid peroxidation, and nitric oxide levels, such as increased lipid peroxidation and increased NO levels
This is where NAC and glutathione (our primary way to remove oxidative stress) comes into play.
Remember the study on NAC (supports anti-oxidant) and aspirin? That's oxidation and inflammation.
Check out CBD and oxidative stress or CBD and glutathione.
CBD and neuroinflammation is also critical.
We're getting there...now on to the interesting connection with sleep. It holds a clue!
Bipolar and sleep
There's a known issue with circadian clocks and bipolar.
This is the internal clock that governs cycles including the sleep-wake cycle.
In fact…
During mania or hypomania, sleep disruptions are commonly presented as a reduced need for sleep with studies finding that 69%–99% of bipolar individuals report a lessened need for sleep during a manic episode or difficulties in falling and/or staying asleep.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4935164/
Interesting. Serotonin figures into sleep modeling, acetylcholine is key for wakefulness and REM sleep while dopamine gets to the heart of it:
Dopamine (basal ganglia) seems to regulate sleep-wake states and helps control when we enter each.
There are actual genes which govern our circadian rhythms and variants of these genes are popping up for bipolar risk.
For example…
Findings suggest that mice with an altered CLOCK gene (eg, a deletion of exon 19) demonstrate manic-like behaviors, increased hyperactivity, reduced need for sleep, and heightened reward-seeking behaviors
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4935164/
Why bring this all up? What can we do about it?
There's interesting new information surrounding vitamin D levels, acetylcholine and sleep.
This may speak to the following:
vitamin D deficiency was found to be 4.7 times more common in a population of 320 outpatients with bipolar disorder, schizophrenia, or schizoaffective disorder compared with the Dutch general population
We'll look at CBD's effect on sleep below but clearly, this is a critical component for bipolar.
A quick stop at the gene store.
The genetics of bipolar
There's new insight all the time on the genetic front which speaks to half the equation (versus environment).
There are four broad family of genes with higher implications:
- Serotonin transporters
- Dopamine transporters
- Neurotropics - BDNF, NCAM, etc which repair/replenish and build brain connections
- Circadian clock - CLOCK, etc
- These all figure into everything we've described above.
Balancing serotonin and dopamine are critical concerns (we'll see CBD's effect below) but supporting repair (BDNF) may be the magic bullet.
There are a few ways to bolster that function which we'll get into with the neurogenesis section.
Remember how the immune system (via its microglia sentinels) can become overactive?
This results in too much "paring" back of the brain's dense connective jungle.
BDNF is on the other side of this frantically trying to rebuild and create new connections.
All the exciting new research (psilocybin, CBD, ketamine, etc) address this and even some old standbys (lithium).
Speaking of which, let's get into the medication front.
Current medications for bipolar
You currently have five general classes of medications for bipolar:
- Mood stabilizers like lithium
- Anti-psychotic medications
- Anti-convulsants
- Antidepressants
- Anti-histamines
Let's start with the other classes before jumping into lithium and the new suite of mood stabilizers.
Anticonvulsants primarily focus on glutamate and GABA levels which makes sense as we've seen above.
Glutamate (excess) is definitely an issue (see CBD and glutamate) and anticonvulsants bring its level down. Or they raise GABA (like benzos do - see CBD versus benzos).
Seizures are essentially the result of too much glutamate.
Next up, antidepressants.
SSRIs are the main class there and they essentially increase serotonin.
This is tricky since a surge of serotonin may be part of the mix with bipolar but the backside, the resulting depression probably reflects a drop in serotonin.
Check out CBD versus SSRI or how do SSRIs really work (hmm hmm...neurogenesis).
Antipsychotics generally work by depressing dopamine. We saw above how dopamine can surge during mania phases which isn't surprising since serotonin governs dopamine (and all behavior for that matter).
Check out CBD and schizophrenia to look at this class in more detail.
Finally, mood stabilizers like Lithium.
Get ready to really be surprise. How on earth do substances like this improve complicated and multifaceted diseases like bipolar?
Brain repair. Neurogenesis.
Yes, it may feel like a wet blanket but the real means of action is to spur repair and re-connectivity in the brain.
Remember, whether it's overactive immune response, excess glutamate, or other trauma that's literally damaging connections in the brain or overrruning the prefrontal cortex (needed to keep impulses in check), there's an entire construction crew that's trying to keep up with the damage.
It's like a hurricane that just keeps hitting the town.
Lithium brings in backup workers and supplies to repair.
Lithium would act by limiting or reversing disease progression directly associated with the activation of neurotrophic effects; these have been widely described in studies evaluating targets such as neurotransmitters, second messengers, signaling pathways, hormones, neurotrophic factors, ion channels, organelles, genes, and others.
That's a mouthful but the key word is "neurotrophic" effects.
Neurotrophic literally means brain builder.
What a great segue...let's meet our #1 neurotrophic.
Neurogenesis and bipolar (BDNF, serotonin, etc)
This may be the most important section of this entire review especially since it's something we can actually act upon.
First, a quick pit stop.
SSRI's boost serotonin which is the # 1 drug class for depression.
How do they really work?
It turns out that serotonin is a major proponent of BDNF, our brain's fertilizer.
In fact, when researchers block out BDNF, SSRI's lose their effect.
This is why it takes a few weeks for them to work.
Again, check out how SSRIs really work or CBD versus SSRIs.
CBD has a powerful effect on serotonin which we'll look at below.
Back to the heavy lifter...BDNF.
This is really the gem behind psilocybin, ketamine, and yes...CBD.
BDNF drives brain repair and growth. It's key to keeping up with the damage we gone to great lengths to describe above for bipolar.
In fact, a gene variant on the BNDF gene (too little activity) is a known risk for bipolar. As are other "neurotrophics".
This may be why some people can be subject to influenza in the 2nd trimester or trauma during critical times of brain development and not get bipolar later.
Robust BDNF and serotonin pathways.
Remember...serotonin drives BDNF. Serotonin also drives dopamine function (partially).
Yes, it's genes are also implicated.
This whole brain repair milieu is going to be the hot topic of the next decade for mental health, addiction, degenerative diseases like dementia, and just good brain health.
- Mindful meditation and exercise both drive BDNF (see mindful meditation and exercise here).
- Psilocybin (which will replace antidepressants in our opinion) are an explosion in BDNF.
And yes...CBD boosts it as well (See CBD and BDNF or CBD and hippocampus neurogenesis).
We'll get to CBD.
One last stop before we get there.
The endocannabinoid system and bipolar
We all have one. It dates back to about 600 million years ago.
This naturally occurring system is tasked with balancing other key systems:
- Endocrine system - hormones such as estrogen (see CBD and perimenopause mood swings)
- Nervous system - neurotransmitters like serotonin, dopamine, and glutamate
- Immune system - cytokines and inflammatory agents plus microglia
Okay..did we just list the who's who of bipolar suspects?
The endocannabinoid system is responsible for homeostasis or balance across the intertwined and powerful pathways.
In fact, a gene tied to this system is implicated in bipolar. It's location is very insightful.
There are two main receptors CB1 and CB2. CB1 is mainly in the nervous system.
This is where THC from cannabis has it's psychoactive effect (which CBD counters - see CBD versus THC).
Where was the gene tied to bipolar?
results suggest that CB2 cannabinoid receptor may play a role in BD.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5042796/#b48-mmr-14-04-2899
CB2 is primarily tied to the immune system. Interesting.
Remember...overactive immune response...essentially autoimmune but in our brain.
We can't go into this system at it would take an entire review but it's deeply involved in the three systems intimately tied to bipolar.
Let's finally meet an agent that works within this system.
Research on CBD and bipolar
CBD works within the endocannabinoid system above but its function is very interesting.
Where most substances (such as THC) push in one direction, CBD works more like a feedback mechanism.
This is especially true for serotonin.
Technically, it's called an allosteric negative modulator but this really means that it sends a signal backwards from neuron to neuron. Feedback!!
This is important as it speaks to why we don't have overdoses and its greatest strength.
A balancing effect.
Let's get into it.
We'll cover the main categories we discussed above for bipolar disease:
- CBD and serotonin for bipolar
- CBD and dopamine for bipolar
- CBD and glutamate for bipolar
- CBD and neurogenesis for bipolar
- CBD and bipolar research
Let's get started...lots to cover.
CBD and serotonin for bipolar
Let's start with the big one. The master regulator of all human behavior.
Brand new research is showing that depletion in serotonin at the hippocampus (a critical gate for mood and mood disorders) may be the driver manic episodes.
These observations suggest that severely impaired 5-HT transmission could lead to a maladaptive increase in synaptic plasticity and dysphoric behavioural conditions that could underlie manic-like states.
https://www.nature.com/articles/s41598-018-30291-2
Basically, serotonin plunges and the hippocampus starts to short circuit which leads to manic states.
This was reversed with valproic acid (which just happens to be the basis for a popular class of mood stabilizers).
So...what about CBD and serotonin?
This may be its most powerful effect.
There are multiple studies on CBD's effect on serotonin balancing but a key one based on what we just read:
CBD induces analgesia predominantly through TRPV1 activation, reduces anxiety through 5-HT1A receptor activation, and rescues impaired 5-HT neurotransmission under neuropathic pain conditions.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6319597/
Researchers essentially depleted serotonin via an injury (serotonin is tied with pain sensitivity).
CBD treatment "rescues" impaired 5-HT (serotonin) pathways.
Goodness...it's exactly what we would hope for based on the prior study.
There's are many studies showing how CBD "normalizes", "rescues" etc.
Some are specific to depression since serotonin is tied to this (via the BDNF effect above).
The key is that it doesn't just push serotonin up in one direction or we would see serotonin syndrome (see CBD and serotonin syndrome).
You can learn all about CBD and serotonin function here with many other studies. Serotonin is fascinating - well worth the read.
Serotonin drives the next big player so let's go there.
CBD and dopamine for bipolar
Imbalances in dopamine are written all over bipolar disease.
A surge is intimately tied to the mania side.
As researchers found:
Converging findings from pharmacological and imaging studies support the hypothesis that a state of hyperdopaminergia, specifically elevations in D2/3 receptor availability and a hyperactive reward processing network, underlies mania.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5401767/
We did a full review on CBD and dopamine since it's so critical to addiction and mental health (intimately connected).
We can look to CBD and schizophrenia for guidance here.
It's even trickier since there is too much dopamine to one area (striatum - also implicated in bipolar) and not enough to the prefrontal cortex (we discussed above in detail).
The antipsychotics, many are the same for bipolar, suppress dopamine function and only address half the equation (striatum and the so-called "positive" symptoms).
Check out the review of CBD and schizophrenia. Both the positive and negative symptoms were affected!
Think about that for a second...two different brain areas. Two different directions.
This gets back to the mechanism at play...the endocannabinoid system which is tasked with balancing neurotransmitters and CBD's feedback mechanism on dopamine's upstream regulator...serotonin.
The CBD and dopamine or CBD and schizophrenia go into the research on this system.
It's also critical to our CBD and addiction review since dopamine drives addiction and the reward circuit.
Next up...the gas pedal to all pathways.
CBD and glutamate for bipolar
Glutamate is the new star for mental health.
Researchers originally thought it was just a basic unit of action for the brain but it's now regarded as a bonafide neurotransmitter.
Much of the cumulative, long-term damage from bipolar episodes may be due to excess glutamate.
It's toxic to neurons and can damage areas of the brain when too high, too often.
The mania phase is driven by a surge in glutamate and both hyperactive immune responses and inflammation drive glutamate levels.
What about CBD there?
We've covered it in detail at our CBD and glutamate or CBD and GABA (the brake pedal).
CBD is showing the same effect of supporting balance in this key pathway.
Look no further than conditions directly tied to this system such as seizures (how CBD originally came to fame) or anxiety (the benzos directly increase GABA - see CBD versus benzos for anxiety).
Simply put:
CBD has multiple targets, but one aspect of its polypharmacy may be to help regulate excitatory glutamate (E) and inhibitory γ-aminobutyric acid (GABA) (I) transmission, which may influence the activity of excitatory and inhibitory signalling pathways:
We cover the research in detail at the reviews above and you can learn more about CBD and hyperactive immune response or CBD and inflammation as well.
Finally, the most important piece (after the do no harm balancing of the above pathways).
Repair!
CBD and neurogenesis for bipolar
Remember that lithium primarily works by spurring repair and regrowth in areas damaged by the sudden swings of chemistry that accompanies (or creates) bipolar episodes.
In fact, most things that "work" rely on this pathway as well.
- SSRI's? Yes, neurogenesis although with side effects and diminishing results due to tolerance
- Mindful meditation - neurogenesis
- Exercise - neurogenesis
- Psilocybin - neurogenesis
- Ketamine - neurogenesis
- Cognitive behavior therapy?? Yes, slow motion neurogenesis
This is THE brain's way to heal. Point blank.
What about CBD here? We know that CBD supports serotonin recovery and serotonin supports BDNF, our brain's fertilizer. You'll want to get to know BDNF...it's going become a primetime player shortly.
Also, remember the hippocampus which loses actual volume with bipolar?
There's lots of research on this now:
These findings support that the anxiolytic effect of chronic CBD administration in stressed mice depends on its proneurogenic action in the adult hippocampus by facilitating endocannabinoid-mediated signalling.
https://pubmed.ncbi.nlm.nih.gov/23298518/
Chronically stressed....this could easily stand in for hyperactive immune response or trauma or periods of excess glutamate.
Remember that the hippocampus is very vulnerable since it's so malleable (due to memory requirements).
Another study in adults:
CBD induced a substantial increase in net neurogenesis by a CB1 receptor-dependent mechanism
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4543605/
What about the prefrontal cortex? Remember that it's not keeping up with controlling impulses via the striatum (dopamine rush).
This may be our favorite sentence in this whole review:
Cannabidiol Induces Rapid and Sustained Antidepressant-Like Effects Through Increased BDNF Signaling and Synaptogenesis in the Prefrontal Cortex
https://pubmed.ncbi.nlm.nih.gov/29869197/
Let's break it down because it's too cool.
CBD created an antidepressant effect (see CBD and depression) by boosting BDNF (brain's fertilizer - our Holy Grail) and created new connections in...the prefrontal cortex.
Goodness. We can drop mic there.
Read more on CBD and hippocampus neurogenesis or CBD and brain repair.
Again, this may be its greatest trick by far for mental health.
Let's look at research available.
CBD and bipolar research
We've covered the components of bipolar with a focus on the neurotransmitters and brain areas involved.
We do not have large, well-carried out studies on CBD and bipolar directly unfortunately.
Better studies have been carried out on schizophrenia which has the closest relationship to bipolar of the mental health issues (both genetic and risk based):
With an odds ratio of 10 considered a strong comorbid association, the ratio of 14 for schizophrenia to be comorbid with unipolar disorders and 46 for bipolar disorder denote a strong, highly significant association between schizophrenia and mood disorders.
For now, we'll have to look at those studies since they also reflect imbalances in dopamine, glutamate, and similar brain areas (striatum and prefrontal cortex).
The study which really sent a shock through the research community had the following result:
Our favorite study deals with a study that showed CBD "reset" the brain and normalized activity (on scans) for people who were pre-psychotic:
In this investigation comparing 33 individuals at clinical high risk of psychosis who were part of a double-blind randomized clinical trial and 19 healthy control individuals, a single oral dose of cannabidiol modulated activation in the striatum, medial temporal cortex, and midbrain.
https://jamanetwork.com/journals/jamapsychiatry/article-abstract/2697762
This is profound and the areas affects are directly in line of fire for bipolar disease.
Furthermore, the levels after a dose of CBD resembled those of the healthy controls.
In fact, they were deemed as no longer being high risk for psychotic break (which is how they started).
This is one study and there are newer ones at our CBD and schizophrenia review.
It should be front page news considering the suffering involved but it's not.
We look forward to the studies directly on CBD and bipolar.
They will likely need to longer term (remember, there's cumulative damage with bipolar) and at a correct dose.
We actually have some research on that front.
How much CBD for bipolar
Let's circle back to the what we described as the most important part to this review.
Neurogenesis.
Although the studies on acute psychosis were at 600-800mg of CBD, neurogenesis appears to peak at around 300 mg of CBD daily.
Beyond that, other pathways are turned on. It's still there...but not as robust.
This would lend to a higher dose for periods of acute swings with longer term amounts at 300 mg between.
We see this with addiction withdrawal symptoms as well.
Exercise, mindful meditation, and NAC are also powerful tools. Really read the NAC and mental health review. It's safe, available, and impressive.
Research we've looked at point to 8-16 weeks for NAC to really kick in (again, it's brain repair) and CBD can have an initial response right away with neurogenesis being long term.
What about the best type of CBD.
The best CBD for bipolar
Some basic requirements are mandatory.
- Organically grown in the US at FDA registered farms
- 3rd party tested
- No THC - THC can actually make things worse
- No Heavy Metals
- No Solvents
- No Pesticides
- No Bacteria
- No Mold
We test our CBD twice.
Next up is the question of CBD isolate versus full spectrum.
First, all the research is on CBD by itself...isolate. That's why we focus on isolate.
More importantly, 40-60% of the population has histamine or allergy issues.
This goes up for women and higher as we get older.
In fact, since there may be an immune system hyperactivation angle to bipolar disease, the last thing we want is an irritant for that system.
There's a good analysis of the different "types" of bipolar here including histamine related
https://www.samanthagilbert.com/bipolar-disorder-underlying-causes-and-dietary-tips/
Finally, let's look at common medications for bipolar disorder like Seroquel.
Guess what their effect is on the histamine system….
They're anti-histamines!
https://www.ncbi.nlm.nih.gov/pubmed/26146015
Again, we want clean CBD isolate. No flavors. Plant material. Etc.
Finally, there's the cost.
If studies are pointing to 600-800 mg for acute issues and 300 mg for long term neurogenesis, we have to be able to afford this.
That's why we price our 6000 mg bottle at the lowest we can find on the market BEFORE various discount options up to 30%.
We've been there (see founders story here) and if there's a better way to avoid suffering, we want people to have it.
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.