CBD and Probiotics for Anxiety - the 1-2 Punch
Talk about two emerging prospects for anxiety.
It's about time!
It's been 50 years since benzos came out and 30 since SSRI's came out for anxiety and they both have significant issues (See comparison of CBD and anxiety medications here).
Most importantly, they don't address the root driver of anxiety (SSRI's do by one mechanism but with lots of collateral damage).
Exciting new research is showing how CBD and probiotics can directly affect the anxiety circuit and do so with our own internal systems.
Don't underestimate the power (not of the dark side) of those trillions of gut bacteria.
One of many examples:
if they colonized the intestines of one strain of germ-free mice with bacteria taken from the intestines of another mouse strain, the recipient animals would take on aspects of the donor's personality. Naturally timid mice would become more exploratory, whereas more daring mice would become apprehensive and shy.
We'll get into lots more below.
The situation in our gut is pretty different however.
We're only scratching the surface of how the trillions of gut bacteria directly drive levers tied to all manners of mental health including anxiety.
- 90% of your serotonin is made in the gut by these bacteria
- Certain species are direct synthesizers of GABA (benzos), glutamate, and other neurotransmitters
- Our inflammatory response is partially governed by gut bacteria
The last one is fascinating since a subset of anxiety/depression may be the result of runaway inflammation in the brain.
We're going to look at all of it!
This really is the new frontier of health.
We'll cover these topics:
- Introduction to your microbiome
- How the gut bacteria affect anxiety
- CBD's effect on gut bacteria for anxiety
- The endocannabinoid system and the gut
- B Infantis and anxiety
- B rhamnosus and anxiety
- Additional gut bacteria strains of interest
- Best CBD and probiotic options for anxiety
Let's get started!
Introduction to your microbiome
It's often referred to as our "second brain".
The gut and its trillions of inhabitants (bacteria for the most part).
In fact, when the human fetus is early in development, the brain (including spinal cord) and gut split from the same initial tissue!
Research is still really new.
We're starting to see specific strains tied to almost every modern medical disease.
Bacteria in our gut can turn genes on and off in our cells to change inflammatory response.
Inflammation is the key topic-du-jour across a range of health issues.
This teaming pool of competing bacteria species are constantly in flux.
They can be knocked out by a range of outside inputs:
- Artificial colors, flavors, and additives
- Stress and inflammation
- Introduction of highly destructive bacteria "pathogens".
The bulk of our microbiome is made of "good bacteria" which we need for a host of different activities.
You have trillions of bacteria, protozoa, fungi, and viruses in and on you right now.
There can be some that are very destructive introduced from outside.
Most of them do benefits and key things for our health:
- Make vitamin b12, thiamin, riboflavin, and vitamin K.
- Make over 90% of our serotonin (the "feel good" neurotransmitter)
- Synthesize GABA (calming neurotransmitter) and Glutamate (excitatory neurotransmitter)
- Turn genes on and off in our gut and immune system
- Send signals to the brain to control hunger, satiety, blood sugar, energy usage, and more
There's a comprehensive overview of the importance of these bacteria:
Research is picking up fast.
Specific species of bacteria are being tied to:
- Full range of mental health issues
- Histamine response
- Autoimmune diseases
To see what we mean, just google "gut bacteria" + a health issues to see what research is showing.
Make sure to narrow the range to "past year" since it's an emerging field and most information is brand new!
As a simple but powerful example, a study showed that the removal of one species of bacteria from the gut of mice would explode their fat creation and weight…
Even with identical calories and activity!
We tend to think of "neurons' as being only available in the brain.
There are about 500 million neurons lining the gut and surrounding tissue.
That's our first clue for anxiety and mental health in general.
It's called the enteric nervous system and it's the only place you'll find neurons outside the brain and spine.
It's only since the 90's that we realized we have a semi-autonomous second brain in the gut!
So who are actors that reside in our gut?
There are about 1000 species of bacteria on average.
They generally fall into two main families:
You also have a host of protozoa, fungi, and viruses in the gut but the bacteria are the workhorses of this system.
Of course, an occasional "bad" bacteria rushes the community.
Think 5 second rule, doorknobs, and food poisoning!
Guess what causes that violent reaction after food poisoning?
Yes...you're gut bacteria.
One important aspect of the gut bacteria is their influence in protecting the barrier between what goes through our digestive tract and the rest of us.
The most important aspects of gut health that affect anxiety and mental health are:
- Breakdown in the gut barrier which allows bacteria to travel around the body and brain
- Inflammatory response going out of control and attacking our own tissue
- Synthesis of neurotransmitters and nutrient metabolism key to anxiety
Let's look at the microbiome and anxiety now.
How gut bacteria affect anxiety
Let's start with the bigger picture and then we'll drill down into actual research on specific bacteria strain.
We'll then look at how CBD comes into play.
First, the three different pathways that gut bacteria use to affect anxiety.
The first two are intertwined.
We have an entire article on CBD, inflammation and anxiety here but some key takeaways.
We'll start with "leaky gut".
Yes, it sounds terrible.
There's a highly coordinated series of "junctions" or gates between our gut and our bloodstream.
Think of how tricky this is.
The nutrients from our food must get into the bloodstream without allowing the hitchhiking pathogens (bad bacteria, chemicals, viruses, fungi, etc) from getting in.
Each has a chemical signature and our immune system has to figure out what to let in and what to keep out.
You're talking about trillions of interactions each meal!
If that barrier is functioning correctly, our body does a pretty good job.
The problem is that it is under assault by our modern (mostly Western) life:
probable culprits such as: food production and refinement, overuse of xenotoxins (e.g. fertilizers, carbon emissions, and pesticides), vaccines, antibiotics, and various types of medications, particularly the third generation of antidepressants, commonly known as selective serotonin reuptake inhibitors, SSRIs.
Did you catch that last one?
SSRI's are commonly prescribed for depression and anxiety (see CBD versus SSRIs for serotonin and anxiety).
The clues began to build up at a connection between our two brains:
a growing consensus in psycho-behavioral research recognizes that disorders, specifically anxiety and depression, are often co-expressed with physiological symptoms, particularly digestive and bowel disorders.
So, the gut is at play but what about the microbiome...our gut bacteria?
Studies in germ-free animals and in animals exposed to pathogenic bacterial infections, probiotic bacteria or antibiotic drugs suggest a role for the gut microbiota in the regulation of anxiety, mood, cognition and pain.
There's an interesting communication going on between your gut and brain in both directions.
It's call the gut - brain - axis or GBA.
The primary communication hub is the vagus nerve.
The key there is that bacteria can escape out into the body and brain which creates an immune response when finally detected.
Let's now go to the interesting parts for anxiety.
Let's start with basic mechanics of mental processing:
Cryan's research shows that when bred in sterile conditions, germ-free mice lacking in intestinal microbes also lack an ability to recognize other mice with whom they interact.
This plays into autism and anxiety as well.
Maybe more interestingly, scientists were able to create anxiety and remove it in the other direction:
In other studies, disruptions of the microbiome induced mice behavior that mimics human anxiety, depression and even autism. In some cases, scientists restored more normal behavior by treating their test subjects with certain strains of benign bacteria.
Once researchers started to see these powerful effects of gut bacteria on anxiety and a range mental health issues, the term "psychobiotics" came into fashion.
Gut bacteria that directly affect mental health for better and worse.
Psychobiotics have their effects along a few key pathways:
- Psychological effects on emotions and thinking
- Inflammation and immune response (see CBD for inflammation and anxiety)
- Neurotransmitters and proteins which drive brain function
Some quick examples of many.
For the inflammation piece:
For example, injection of interferon-α, a pro-inflammatory cytokine, has been shown to induce depression,
Neurotransmitters directly implicated in anxiety (see CBD for GABA and aniety or CBD for serotonin for anxiety):
In particular, strains of Lactobacillus and Bifidobacterium are found to exert a profound anxiolytic influence through the production of γ-aminobutryic acid (GABA), 5-HT, and SCFAs, and by dampening HPA adrenergic reaction
Let's look at a few of these key players.
If you read our CBD for anxiety, GABA is a key "immediate" lever of anxiety.
In fact, the benzos directly drive up its levels (see CBD versus Benzo's here).
What about the gut bacteria and GABA?
Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve
As for long term anxiety pathways (stress, inflammation, and damage reducing key brain areas), serotonin is key.
Learn all about CBD and serotonin for anxiety here.
Serotonin is key to neurogenesis or repair and replenishing (even growing) new brain neurons and connections.
So is BDNF.
What about gut bacteria and that pathway?:
Indigenous spore-forming bacteria (Sp) from the mouse and human microbiota promote 5-HT biosynthesis
5-HT is the serotonin pathway.
Keep in mind that 90% of our serotonin is actually made in our gut!
Those are the two big players but you can find interaction between almost any neurotransmitter or chemical tied to anxiety and gut bacteria.
GABA, Serotonin, Glutamate, Dopamine, and more.
Let's turn our attention to the other part of the anxiety equation (from neurotransmitters) to brain inflammation.
We've discussed inflammation and stress' role in anxiety with detail here:
There's a direct effect of stress on the gut bacteria:
It has been shown that different types of psychological stress including maternal separation, chronic social defeat, restraint conditions, crowding, heat stress, and acoustic stress can alter the composition of gastrointestinal microbiota
By the way, that article is a ridiculously thorough walk through of the entire process by which gut bacteria interact for stress and anxiety.
In animal studies, when they raise mice without gut bacteria, they develop a "trait" anxiety display:
Furthermore, germ-free animals display an anxiolytic phenotype in mildly stressful novel and aversive environments including elevated plus maze, light/dark box and open field test
See CBD and general anxiety disorder to understand when anxiety is more a personality trait than a response to acute stress.
Interestingly, when they add gut bacteria in, the anxiety traits go away!
There are multiple studies now where nervous system inflammation is turned on and off by introducing or removing specific strains of anxiety:
Indeed, oral administration of specific microbial metabolites to germ-free mice promotes neuroinflammation and motor symptoms.
Then there's the microglia.
Microglial cells are the immune systems vanguards in the brain and nervous system.
They're intimately tied to a range mental health issues when not working correctly (overactive essentially).
When microglial are over-expressed, it can lead to actual neuron death and brain loss.
The resulting effect:
Microglial Over-Activation by Social Defeat Stress Contributes to Anxiety- and Depressive-Like Behaviors
We've discussed in detail how neurogenesis (new neuron and connection creation) is key to anxiety at our CBD, meditation, and exercise for neurogenesis here.
Our neuroinflammatory process is incredibly complex.
The microglia are one (albeit major) player in this response.
Here's the key takeaway for anxiety:
Overproduction of these molecules may cause cellular damage and loss or decreased function of neuronal activity by excessively pruning synaptic connections that ultimately contribute to the development of anxiety- and depressive-like states.
So...what does the gut microbiome have to do with microglial function?
Temporal eradication of host microbiota severely changed microglia properties. Limited microbiota complexity also resulted in defective microglia. In contrast, recolonization with a complex microbiota partially restored microglia features.
One more stop in the inflammation process...on the stress response side.
We want to show just how intimately involved gut bacteria are in almost every step in the stress-inflammation-anxiety pathway.
We discussed NPY as a neuroprotective agent in our CBD for performance anxiety article.
Essentially, soldiers sent to war who had PTSD responses had lower levels of NPY than those who did not.
It's a chemical of "resiliency" essentially.
What about gut bacteria and NPY?
NPY is found at all levels of the gut-brain and brain-gut axis.
In fact, it appears to govern the gut bacteria's effects on stress response:
NPY may control the impact of the gut microbiota on inflammatory processes, pain, brain function and behaviour.
Did you catch the "pain" part?
There's an interesting intersection of pain, anxiety, and depression.
We digress (unless you have a lot of pain with associated anxiety/depression)!!
Interestingly, NPY has a direct anti-bacteria effect against E.Coli and….
Yes...the very probiotic that everyone is slinging out there will reduce your NPY levels which may be detrimental for stress resilience!
That's not on the label.
We're going to get into the actual bacteria strains associated with different pathways of anxiety below.
First, let's look at the second part of our 1-2 punch for anxiety.
CBD's effect on gut bacteria for anxiety
We've studied and written extensively about CBD and anxiety here.
Here's why it's such a good partner to gut bacteria support.
CBD supports the endocannabinoid system which research is showing to be a powerful balancer of other key systems:
- Nervous system - neurotransmitters like GABA, glutamate, serotonin, and more)
- Endocrine system - hormones including stress mediators like cortisol, adrenaline, and NPY
- Immune system - inflammatory agents like cytokines and microglial.
See why this is so important for our topic!
The gut bacteria are powerful agents for control of these various systems.
They can be knocked off balance by a host of different factors (pathogens, stress, chemicals, etc).
The endocannabinoid system is our internal checks and balances.
CBD has been shown to support this system and its components when they are exhausted or under duress.
Let's look at some of the same examples on the pathways we covered above with gut bacteria:
- Stress response
- Microglial overactivity
We have entire articles on each of these but some highlights to show the importance.
CBD and GABA for anxiety:
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 significantly increased the GABA potential release.
CBD and Serotonin
One of the most powerful effects CBD has is on the Serotonin (5HT) pathway.
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.
By the way, FLX is short for fluoxetine or Prozac.
Check out the side effects and other issues of the SSRI class of medication at this CBD versus SSRI for serotonin and anxiety here.
DES is another type of antidepressant medication.
We go into detail as to how SSRI's even work (it's neurogenesis!!)
Speaking of which…
CBD for neurogenesis and anxiety.
So...stress, infection (either during critical times of brain development or in utero), chemicals, trauma, etc can all conspire to actually cause brain damage and loss.
The hippocampus (watchdog for anxiety response) is keenly susceptible to this onslaught.
So...what's the highlight there:
Cannabidiol Reduces Aβ-Induced Neuroinflammation and Promotes Hippocampal Neurogenesis through PPARγ Involvement
That's a 2 for 1 - neurogenesis and anti-inflammatory in the brain!
Let's look further upstream at our stress response.
We've written extensively on CBD and cortisol levels here.
What about the resiliency chemical, NPY we discussed above.
We're going to take a quick stroll down brain chemistry lane.
There's a powerful, naturally-occuring endocannabinoid called Anandamide.
It's the so-called "bliss" molecule named after the goddess of bliss, Anand.
There's an interesting connection between levels of Anandamide and NPY:
The cannabinoid agonists anandamide (AEA) and CP55,940 both significantly augmented resting and KCl-evoked NPY release.
This isn't surprising since Anandamide (really...it's remover in the body call FAAH) is key to the woman who can't feel pain or anxiety (or depression).
More on that here.
Does CBD have any effect there?
Studies on schizophrenia and CBD lead the way here:
Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia
That is one example but check out CBD, stress, and anxiety for more research.
What about microglial (brain immune responders) activity which our gut biome manages?
CBD and microglia activity
Cannabidiol and other cannabinoids reduce microglial activation in vitro and in vivo: relevance to Alzheimer's disease.
That study is interesting.
They threw a range of different synthetic endocannabinoids or CBD at the brain in both lab and live settings.
This is also very relevant for Alzheimer's and Dementia which are turning out to be autoimmune diseases where the microglia are part of the problem.
So, we've looked at pathways for both gut bacteria and CBD for anxiety.
Let's zero in on specific strains that are getting specific attention.
B Infantis and anxiety
If you read enough NIH studies on anxiety (or depression), you see some common themes.
Brain injury as a result of early life (even in the womb) stress, infection, or injury can come back later in life as anxiety or depression.
Of course, our genetics have a say in how we're able to "respond" to these insults.
It can either be poor connection between brain areas in the circuit, reduced/elevated neurotransmitters or genetic differences (most likely a combination).
That's what makes b. Infantis so interesting.
The name should partially give it away.
B. infantis is a major first orchestrator of our newly formed gut biome.
Newborn babies get a flood of it from breastfeeding.
There's a reason for this interchange:
In vitro, B. infantis grows better than other bacterial strains in the presence of human milk oligosaccharides, displays anti-inflammatory activity in premature intestinal cells, and decreases intestinal permeability.
Read the article...very interesting on what b infantis does in the developing baby's brain.
Interestingly, it's presence is dropping significantly in the developed world.
The suspected reasons:
- An increase in cesarean births;
- Use of commercial formulas instead of breast milk; and,
- Heightened use of antibiotics.
We could spend quite some time here but we'll leave further reading for you on the side.
Why b infantis for anxiety?
Two interesting things happen when researchers introduced b infantis to babies fed formula.
The bacteria quickly established themselves in the babies, crowding out other gut bacteria that are associated with intestinal problems and immune-related diseases such as asthma, allergy and autoimmune disease
The second has to do with PH balance in the gut and brain.
In the first article (here), they talk about how the ph in infant's gut are significantly higher without the b. Infantis:
An analysis of 14 clinical studies performed between 1926 and 2017 showed a startling increase of pH from 5.0 to 6.5 in infant stools.
There's some interesting research in how acidic conditions in the body and brain (especially our fear center...the Amygdala) may be primary to panic response and anxiety:
A hypersensitivity to acid in the brain appears to be part of the inherited vulnerability to panic attacks.
It's a very interesting read if panic attacks are an issue (also see CBD and panic attacks).
Interestingly, for this reason, the "L" bacterias may not be a good fit for anxiety and panic attacks as they produce lactic acid.
Recent studies have shown that patients with panic disorder consistently build up excess lactate in their brains during ordinary mental activities.
The research on infantis and anxiety (or depression) then gets really interesting.
So...B infantis (we only scratched the surface but that requires a separate dive into the weeds).
B rhamnosus and anxiety
Where infantis appears to do heavy lifting in gut health and inflammation, rhamnosus is more aligned with anxiety and mental health directly.
For good reason.
It's a major synthesizer of neurotransmitters:
chronic treatment with L. rhamnosus (JB-1) induced region-dependent alterations in GABAB1b mRNA in the brain with increases in cortical regions (cingulate and prelimbic)
GABA is the key lever of anxiety as we described above and in our CBD and GABA article.
So how does that translate into actual effects in the body?:
Importantly, L. rhamnosus (JB-1) reduced stress-induced corticosterone and anxiety- and depression-related behavior.
Ding ding ding.
Check out CBD and cortisol (our main stress chemical or corticosterone).
Guess what cortisol does with GABA?
It's eats it up. The two actually oppose each other for the sleep/wake cycle.
Other interesting gut bacteria strains for anxiety
Infantis and Rhamnosus are two interesting strains to look at but needless to day, it's a virtual zoo down there!
There's an interesting look here:
B longum and B helvetica are both showing promise.
Longum is the strain you can typically find at retail locations now for "mood".
Infantis is actually a subspecies of longum.
What does research show for these two?
In yet another study, healthy participants who ingested Lactobacillus helveticus and Bifidobacterium longum showed less self-reported negative mood and decreased urinary cortisol
Cortisol is an important player in the stress to anxiety pathway (check CBD and cortisol for anxiety here).
Interestingly, one study on L casei showed no difference with control groups EXCEPT when they broke out the people who initially had worse scores for mood:
However, when only participants whose baseline mood scores were lower (indicative of an antidepressive state), probiotic supplementation resulted in significantly more of this group of participants self-scoring as happy rather than depressed compared with placebo
Two other interesting strains for GABA production are:
- L brevis
- B dentum
They were both found to be efficient synthesizers of GABA.
Finally, what about human, double-blind studies:
humans specific strains of Lactobacillus and Bifidobacterium for 30 days yielded beneficial psychological effects including lowered depression, less anger and hostility, anxiety, and better problem solving, compared with the placebo group
You can get a great list of what bacteria strains make what nutrients (b vitamins, folate, etc) here:
Below, in our best probiotic section, we'll share some options we've found that targeted and we'll designed.
Best CBD and probiotic options for anxiety
In light of everything we've looked at above, here's a good approach to picking the best.
For CBD, there are some deal-breaking requirements.
It must be:
- THC free (see THC versus CBD for anxiety)
- 3rd part tested
- CO2 extraction process
- Organically grown in the US
- No pesticides
- No solvents
- No mold
- No bacteria
- No heavy metals
Those are the basic requirements and we built IndigoNaturals with this in mind.
We actually test twice (once at the biomass level and once at the finished product).
For anxiety, there's some research which shows that the long term neurogenesis effect drops after 300 mg.
For that reason, it doesn't make sense to go higher than the 300 mg.
Also, based on the histamine connection to anxiety (see CBD, histamine, and anxiety here), we want to focus on the CBD isolate.
Here's the deal...all the research above (and across NIH studies) is on CBD isolate.
CBD by itself.
All the sales pitch for CBD full spectrum is not supported by research.
Again, we base everything we do at IndigoNaturals on NIH research.
Afterall, our entire families use it!
What about probiotics?
It's actually tough to get the strains we want for anxiety from retail stores.
There's a lot of B longum out there which is not bad.
We just weren't able to find the infantis subset and rhamnosus.
There are two options that look good there.
SeekingHealth.com is a massive source for supplement and they have a pretty good blend.
LiftedNaturals.com is a smaller company but we were impressed by their focus on the right strains plus low histamine gut bacteria strains.
We'll keep an eye out for any new additions (and research)!