Comparing CBD and Anxiety Medications

The "state of the art" hasn't changed much in 30 years for anxiety medications.

It definitely hasn't caught up with all the new avenues of investigation we show in our comprehensive CBD benefits for Anxiety article.

• Gut bacteria
• Inflammation
• Brain connections
• BDNF
• Early trauma/infection
• Specific genes

 

We're going to dig down deep into how the major classes of anxiety medications work.

We'll then look at if and how CBD works on those same pathways but without the pesky side effects (addiction, depression, suicidal thoughts, tolerance, and yes...anxiety!!!).

If you've already read our Anxiety Mechanisms and CBD article, you'll realize that we go all in and more importantly…

This is personal for us.

Yes, we'll base everything on research but the whole reason we started IndigoNaturals was the result of crushing 24/7 anxiety and panic attacks brought about by hormone flux in perimenopause.

 

That story is here but we know first hand what the medications feel like for anxiety.

It's not a place we want to go back to.

After 12-18 months of scrambling and trying everything under the sun, we found bioidentical hormones, CBD Isolate, other tools (more on that below) and finally...relief.

Like we said...this is personal so we're going to give it everything we got.

We'll touch base on these topics:

• A quick summary of contributors to anxiety
• The four classes of medications for anxiety
• How CBD works for anxiety
• Other supplements and tools for anxiety
• Can you take CBD with anxiety medications
• Side effect comparison between anxiety meds and CBD
• Addiction differences between anxiety meds and CBD
• Safety comparison between anxiety meds and CBD

Let's get started.

A quick summary of contributors to anxiety

The full story is here on what research is showing for anxiety but it's not what you expect.

Yes, we have the usual culprits which current anxiety medications attack:

• Neurotransmitter imbalances
• Brain region signaling

 

Keep in mind that the general class of anxiety meds has been around for decades with very little change.

This is true for depression as well.

They basically aim to address the levels of specific neurotransmitters.

Let's introduce those now since we'll see them over and over again (even with CBD).

• Serotonin
• GABA (the brake)
• Glutamate and Cortisol (the gas pedal)
• Histamine (a secret star..more on that below)

 

We'll try to keep it out of the thick grass but we need to wrap our heads around what these do.

Serotonin and Anxiety

This is our "feel good" neurotransmitter in the brain.

It's also the target of many anxiety medications on the market.

The so-called SSRI's dominate the market. That's short for Serotonin Serum Reuptake Inhibitor.  We have a whole review on CBD versus SSRIs here. 

 

We'll look at it more closely later but for right now, just know that these aims to increase the levels of serotonin available in the brain.

One note..serotonin is not just a "feel-good" chemical.

It's a huge workhorse for signaling between different areas of the brain.

Very powerful chemical.  It's greatest trick is managing BDNF, our brain's fertilizer. 

This is actually what drives how SSRIs work until they don't due to tolerance.  More on how SSRIs actually work here.  

This is the key to long term anxiety states!

Next up...GABA

GABA and Anxiety

GABA is our calming chemical.

Both literally (inhibits activity in the brain) and figuratively (makes us feel calm).

It's the opposite of anxiety!

 

 

Obviously, this is critical to anxiety and it's the target of the other big class of anxiety medications - benzodiazepines.

 

They've been around even longer than the SSRIs!!

Huge review on CBD versus benzos here.  

Again...not much improvement in almost half a century.

The newer class of benzos like Xanax and Ativan come on fast, hit hard, and drop off quickly with nasty addiction effects.  Hence the street names (and values).   

 

The brain rarely works in one direction.

If GABA is the calming (or inhibitory) chemical that acts as a brake, what's the gas pedal?

Next up…

Glutamate and Cortisol

 

Glutamate and GABA work to counter each other in the brain.

Glutamate is the excitatory chemical responsible for revving things up.

A little bit of it is good for making you alert, focused, and functional.

Cortisol carries out the orders of our fight or flight and stress response.

Also, a boost is needed when we're jumping out of the way of an oncoming bus!

Too much of these for too long can lead to anxiety.

This can be the result of constant stress or even inflammatoin exhausting the brake (GABA) or not enough GABA being produced.

 

Either way, the flight or fight response is partially controlled by Cortisol (with help from adrenaline).

Finally...a less known actor...but very important

Histamine and Anxiety 

Histamine is a powerful chemical.

Most people know it as based on resulting effects of an allergic reaction.

It's also excitatory in the brain with the management of wakefulness, focus, and alertness.

Sounds a bit like Cortisol above, doesn't it?

Too much histamine release can feel like anxiety.

 

 

For the 40-60% of the population with allergy or histamine issues, you know exactly what this feels like.

 

This number goes up as we get older and for women when progesterone leaves the scene (drops by 50% at age 40).  

Okay….so we laid the groundwork on the neurotransmitters intimately tied to anxiety and also the prime targets for current anxiety medications.

There's so much more!

Check out the Anxiety page for details on:

• Inflammation - the new kid on the mental health block
• Gut bacteria - specific strains directly tied to anxiety
• Brain mass - infection or injury can affect neuron health in specific parts of the brain
• Early trauma/infection - this is really where the exciting research is 

 

We'll leave the further reading to the main Anxiety page but we're here to understand the medications for anxiety versus CBD.

Let's look at the classes of medications.

The main classes of medications for anxiety

Valium was patented in 1959 (benzodiazepine). Prozac (SSRI) was released in 1988.

Everything since has been incremental versions of the same thing.

So we're looking at roughly 60 years for benzos and 30 years for SSRI's.

We're on the cusp of editing genes with CRISPR and this is all we have for increasingly the most common mental health issue out there??

 

Goodness.

Let's look at the main classes in more detail by volume of use.

Benzodiazepines

 

Benzodiazepines include:

• alprazolam (Xanax)
• chlordiazepoxide (Librium)
• diazepam (Valium)
• lorazepam (Ativan) 

 

Benzo's work by boosting the effect of GABA in the brain.

There's actually a benzodiazepine receptor on the GABA-producing neuron in the brain.

The science behind benzos can be found here:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3684331/

Here's the issue...they also boost the release of Dopamine.

Dopamine is our reward neurotransmitter.

It's why you get up in the morning, go to work or school, and try to learn Chinese.

 

It's also the root of all addiction.

That's the main issue with benzo's...they're incredibly addictive.

This isn't your garden-variety habit like coffee or donuts.

They're on par with opioids - it's estimated that roughly 44% of people who use benzos will become addicted

Some less than flattering results: 

• Benzo's cause a rush of dopamine in the brain
• They alter brain structure over time to increase dopamine rush
• Benzos are intended only for short durations - up to 1 month
• Severe withdrawal symptoms occur including panic attacks and anxiety
• Benzos can result in cognitive impairment for young and old
• Alzheimer's risk roughly doubled for long term users of benzos
• Risk of dying early doubled for benzo users

 https://drugabuse.com/worried-benzos/

Look...we're not trying to scare people but know the risks.

I was prescribed 3 of these (plus another one, Klonopin, used more as a sedative).

Coming off of these was the hardest thing I've ever had to do.

Bar NONE.

It was a brutal process and the doctors barely mentioned this risk when they wrote the scripts after 5 minutes.

Here's my story on how I used CBD to wean off of benzos. 

Be careful!

This is the next opioid crisis and we see more and more deaths as a result.

Here's a pertinent story of the addiction to benzos:

https://www.healthline.com/health/addiction-drug-problem-benzos#1

More importantly, you generally start to build a tolerance in 2 weeks.

https://www.ncbi.nlm.nih.gov/pubmed/2908516

This means that the drug will have less and less effect with use.

A need to increase dosages or pills taken generally result and anxiety is one of the key withdrawal symptoms.

Think of it...this medication was putting your calming neurotransmitter in overdrive.

When it's pulled away, the rebound effect is...an exaggerated anxiety (since there was already a deficit to begin with and our brain adjusts to the boosting effect of the benzo).

This is one reason why it's so hard to stop them (plus the whole dopamine effect).

It's estimated:

• 30 million Americans use benzos - roughly 13% of the population
• Suicide rate increased for benzo users - even more than for opioid users! Here
• Prescriptions increased 67% between 1993 and 2015 here
• The market is expected to be $3.8B by 2020
• 3 benzos are in the top 10 most prescribed psychoactive medications in the US with Xanax currently the most prescribed (and abused).

https://psychcentral.com/blog/top-25-psychiatric-medications-for-2016/

We go into CBD versus benzos specifically here with lots of research.   We have a tips guide to tapering off benzos here.

That's a good place to jump to our next big class...SSRI's.

Why???  Because they round out most of the rest of the top 10 drugs. 

SSRI's and SNRI's

SSRI is short for Selective Serotonin Reuptake Inhibitor.

SNRI  just adds Norepinephrine (adrenaline) to the mix.

Both attempt to make more serotonin available to neurons.

"Uptake" just means that the brain will not recycle serotonin...it will allow it to stay present and available to the neurons.

Classically, this class of medications is used more for depression than for anxiety.

Again, as we saw from the benzo topic above, if we're only looking at neurotransmitters (which we shouldn't be but that's our healthcare system), then GABA is the more direct route.

 

SSRI's are partially used to avoid the long term and very significant addiction issues with benzos.

So how do they work for anxiety?

Mixed.

A study at Harvard looked at the effectiveness of SSRI's for anxiety specifically (not including depression):

They found that there was a 2.3 point improvement out of 56 total variances from placebo.

https://www.anxiety.org/how-effective-are-antidepressants-treating-anxiety

In other words, placebo (sugar pill) was about 80% as effective as SSRIs for a standard anxiety test score.

There are studies where different SSRIs were more effective than placebo but this class of medication generally has to be prescribed much higher for anxiety than for depression to have an effect.

This increases the chance of side effects which can be pronounced for SSRIs.

70% of people who use SSRI's experience sexual dysfunction and reduced libido.

https://www.anxiety.org/how-effective-are-antidepressants-treating-anxiety

This is one item in a laundry list of potential side effects:

• Drowsiness
• Nausea
• Dry mouth
• Insomnia
• Diarrhea
• Nervousness, agitation or restlessness
• Dizziness
• Sexual problems, such as reduced sexual desire or difficulty reaching orgasm or inability to maintain an erection (erectile dysfunction)
• Headache
• Blurred vision

https://www.mayoclinic.org/diseases-conditions/depression/in-depth/ssris/art-20044825

Then there's Serotonin syndrome and increased suicidal thoughts.

We did an entire review of SSRIs and homicidal or suicidal thoughts since it's so important.  

I actually had suicidal thoughts out of nowhere with Lexapro (my story is here). 

We love how many of the big sites won't show all the side effects (because we've been there!!)

Here's a more thorough list:

https://www.webmd.com/drugs/2/drug-63990/lexapro-oral/details/list-sideeffects

The first thing we are struck by reading that list is just how integral serotonin is to our entire body and brain's function!

 

A study just yesterday showed an entirely new aspect of serotonin which blew open the doors on how scientists view it.

Serotonin can actually turn genes on and off in our DNA within neurons:

https://www.sciencedaily.com/releases/2019/03/190313143312.htm

It literally unwinds our tightly packed DNA to expose regions to more expression!

The researchers don't even know what to make of this.

The point is this...serotonin is incredibly powerful and if we look at the diverse list of potential side effects, directly hammering the levels of it will likely seem like using leeches someday in the future.

We apologize if we're a bit jaded but it's from our experience.

Most doctors will tell you to take a benzo for the first two weeks so that the SSRI can ramp up.

At best, that's misguided.

What they're not telling you (or don't know) is that there can actually be an increase in anxiety and depression as a result of SSRI use for the first two weeks.

 

The benzo is just to mask that feeling.

Why on earth would an increase in serotonin cause an increase of anxiety and depression initially?

We'll assume that you actually have too low a level of serotonin (which a doctor can't even test for).

They just assume you do.

That's why some people get serotonin syndrome (too much serotonin) which is potentially fatal.

Remember...serotonin is not just a mood stabilizer.

It's a brain signaling workhorse between neurons, between brain areas, between body and brain, and even with the DNA within neurons itself (brand spanking new research).

 

It's like changing aspects of your blood and wondering why your foot starts to hurt.

Read all about the initial 2-week increase in anxiety at our CBD and corticotropin-releasing hormone article.

Fascinating!

We have an entire article on CBD's effect on serotonin since the rabbit holes goes quite a bit further down.

There's even research showing that serotonin can increase anxiety for people with social anxiety:

Individuals with social phobia have too much serotonin -- not too little

https://www.sciencedaily.com/releases/2015/06/150617115327.htm

What gives??

We actually have multiple serotonin receptors (HT1, HT2, HT3, etc).

Think of serotonin as a signal booster.

• If HT1 is boosted, it can reduce anxiety.
• However, if HT2 receptors are boosted, it can actually increase anxiety!

https://psychopharmacologyinstitute.com/antidepressants/ssris/role-serotonin-5-ht-impulsivity-aggression-anxiety-stress-cognition/

It's a very complicated system which is why we have the crazy list of side effects (really...giant hives and yawning??).

  

Just remember that they increase the levels of serotonin available to neurons in the brain.

If you want to see just how complicated the serotonin process is, go there:

https://www.futurity.org/serotonin-system-map-neurons-1851232/

There's one sentence in that article that's especially interesting:

Rather than just transmitting messages with serotonin, the cortical-projecting neurons also released a chemical messenger called glutamate—making them one of the few known examples of neurons in the brain that release two different chemicals.

 

Glutamate! One of the key "gas pedals" in the brain that has a direct effect on anxiety (see anxiety summary here). It eats up GABA, our main calming pathway.

That will come back around below with CBD.

Moreover…

Taken together, these findings indicate that the brain’s serotonin system is not made up of a homogenous population of neurons but rather many subpopulations acting in concert. 

 

This speaks to the HP1 and HP2 differences above but also to how serotonin can create different...even opposite results...depending on what area of the brain you're boosting!

We could geek out all day on this but we'll save for a separate article.

We have to get to CBD eventually, right??

The other classes of anti-anxiety meds

The other various offshoots are really just more of the same two above.

The older triciclates also attempt to make more serotonin available

They include:

• Amitriptyline
• Imipramine
• nortriptyline

 

These have largely been replaced by the SSRI's above as they have more serious issues.

SNRI's work on both the Serotonin and Norepinephrine systems.

They are similar to SSRI's in that they make more of each available to neurons.

The SSRI's by far dominate what is prescribed for anxiety.

Another medication, BuSpar is also used for anxiety.

It works to boost serotonin and dopamine activity in the brain.

The issue with BuSpar is whether it's effective for anxiety and it's rarely prescribed by itself.

However, a double-blind placebo-controlled study of 30 patients with SAD in 1997 showed no improvement compared to the placebo.

https://www.verywellmind.com/buspar-treatment-of-social-anxiety-disorder-3024958

There's a full analysis of various anxiety medications here:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3181684/

There's a very curious sentence in that overview of anxiety medications:

Hydroxyzine, an antihistaminic compound, has been reported to produce improvement in 60% to 90% of patients with GAD

 

Wait a minute. Hydroxyzine is a simple antihistamine. GAD is shorthand for General Anxiety Disorder...or persistent anxiety.

The safety profile is much better than any of the other anti-anxiety medications.

60-98% of patients in another study. How does that compare to benzos which are driving our new addiction crisis?

Compared to other anxiolytic agents (benzodiazepines and buspirone), hydroxyzine was equivalent in terms of efficacy, acceptability, and tolerability

https://www.ncbi.nlm.nih.gov/pubmed/21154375

Now, there are some issues with this class of meds (including Benadryl and the active ingredient in Tylenol PM) and dementia...especially for older adults.

This is from ripping acetylcholine, our "calm and focused" workhorse.  

Benzos and tricyclics also have the same risk, albeit higher.

https://www.health.harvard.edu/mind-and-mood/two-types-of-drugs-you-may-want-to-avoid-for-the-sake-of-your-brain

Recent studies have shown that hydroxyzine main effect is on histamine with very weak effects on serotonin, dopamine, and acetylcholine (the dementia tie above):

Unlike many other first-generation antihistamines, hydroxyzine has very low affinity for the muscarinic acetylcholine receptors, and in accordance, has low or no propensity for producing anticholinergic side effects

https://en.wikipedia.org/wiki/Hydroxyzine

The histamine connection is very interesting though.

A double-blind test looked at hydroxyzine effectiveness specifically for anxiety:

After four weeks, hydroxyzine, but not buspirone, was superior to placebo on the primary outcome variable (the Hamilton Anxiety Rating Scale).

 

Hydroxyzine might have mild effects on serotonin but its primary function is to block H1 or histamine receptors.

Keep that in mind when we get to CBD. It's a lovely connection!

It also speaks to the theory of brain inflammation being a root cause of mental health issues including anxiety.

What about hydroxyzine against aripiprazole (Abilify, etc)?

However, hydroxyzine showed better anxiolytic activity when compared to control, aripiprazole monotherapy, and combination groups.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5153890/

Anxiolytic is just a fancy way to say anti-anxiety.

Okay...that drug (Abilify) is used for a range of issues including anxiety from autism, schizophrenia, Tourettes, and depression.

So histamine and brain inflammation. Make a note by that for later!

Quick question...why are billions of very expensive, addictive, and potentially unsafe benzos and SSRI's being prescribed for anxiety with an old, safe, and effective medication sitting there?

 

Hmmmm.  No patent???

Speaking of SSRI's, we're about to introduce you to the future of mental health with a very specific example.

Most new research is showing the role of brain inflammation in a host of mental health issues.

 

 

Follow this train of thought and get ready to geek out (we sure are).

We mentioned above that serotonin operates via 5HT receptors.

That's short for 5-hydroxytryptamine.

That "tryp" might look familiar.

Yes, serotonin is made from tryptophan, a very basic amino acid.

Here's where it gets downright freaky.

When the body is fighting infection (or inflammation/stress), part of its natural response is to reduce tryptophan.

The bacteria/viruses also need tryptophan to make more of them and they grow really quickly!

The body drops production of tryptophan and NAD (ours and the bacteria's source of all cellular energy) to thwart the bacteria's ability to grow.

 

A side effect of this is...less serotonin production or signaling.

Also, less energy which is why you feel so sluggish when fighting the flu.

Now...over the last few years, researchers are finding ties to bacteria escaping our gut, mouths, and other areas... traveling around the body and our immune system attacks them there.

Much to our bodies chagrin.

It's the whole basis of autoimmune.  see CBD and autoimmune here.  

A study today just showed that narcolepsy is autoimmune!

THAT tryptophan starvation is a KEY tie between brain inflammation and anxiety!

We explored this in detail at our CBD, tryptophan, and serotonin review or our CBD and neuroinflammation for anxiety review. 

Or depression or a host of other issues.

A study just came out that definitively tied inflammation to depression and heart disease:

https://www.sciencedaily.com/releases/2019/03/190318222147.htm

More detail on that here as it relates to autism:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3729335/

One more stop.

CRF and Anxiety

Short (thank goodness) for Corticotropin-Releasing Factor.

Stick with us...this is very interesting.

This chemical is at the heart of our brain's anxiety and fear signaling circuit.

Why do we get that burst of anxiety and depression when starting an SSRI at first?

The serotonin wears many different hats and one of them is to stimulate this CFR release.

 

Make one more note there for later. 

Later is now by the way!!

How CBD works for anxiety

We touched base on many different pathways for anxiety.

 

 

Look...this is chemistry and brain architecture. It can be fixed.

I've seen it first hand.

My specific issue was hormones:

• Estrogen (or testosterone) drives serotonin
• Progesterone drives GABA and calms histamine

 

I had rolling 24/7 anxiety and panic attacks as a result.

Just to recap, we've covered the following pathways affected by anxiety medications:

• GABA and Glutamate pathways (Benzos)
• Serotonin pathways (SSRI's, SSNI,'s, Buspar, triciclates)
• Histamine pathways (hydroxyzine, Tylenol PM, etc)
• Inflammatory pathways (histamine, CFR, tryptophan, etc)

 

So...how does CBD affect these different pathways?

A quick introduction to the stage CBD operates on.

The endocannabinoid system.

 

We all have one and it's tasked with balancing other key systems:

• Nervous system - neurotransmitters like GABA, Glutamate, Serotonin, etc
• Endocrine system - hormones like histamine, estrogen, progesterone, etc
• Immune system - inflammatory response as well as cell growth/death cycles

 

Let's start with the neurotransmitters.

CBD and GABA, Glutamate, and Serotonin

GABA is such a better proxy for anxiety than Serotonin.

It's more direct in its action and activity in the anxiety circuit.

What does CBD do there?

It was shown to directly increase GABA signaling:

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, more than twice the potentiation seen with other α-subunit receptor combinations

https://www.ncbi.nlm.nih.gov/pubmed/28249817

Let's translate the Klingon a bit.

2-AG is a naturally occurring endocannabinoid in our brain.

In fact, it's the most prominent in our nervous system.

The researchers wanted to test both their effects on GABA signaling.

To translate...CBD doses increased the signaling strength of GABA receptors by 4 times.

Maybe more importantly for this article:

The potency of CBD increased and efficacy preserved in binary α1/α2β2 receptors indicating that their effects do not involve the classic benzodiazepine site.

 

They are not hitting the benzo receptor site that can cause issues above.

There was a direct dose impact on GABA expression seen here:

https://www.researchgate.net/figure/Potentiation-of-GABA-current-responses-by-CBD-at-12-and-22-GABAA-receptors-expressed-in_fig4_314109989

CBD likely does this by strengthening or replenishing our naturally occurring 2-AG signaling.

There's a very thorough (and difficult) analysis of all the ways 2-AG stimulates GABA function.

Interestingly, 2-AG may be the safety net or back up for GABA in our brains.

Its action is especially prevalent at LOW levels of GABA (anxiety levels)!

The fact that modulation of GABAA receptors by 2-AG is exclusively observed at low concentrations of GABA may be the reason why we were not able to establish conditions to measure the robust effects of 2-AG in brain slice experiments.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3207709/

When levels come back up...2-AG backs down.

Hmmmm.

So, CBD's effect on boosting GABA appears to be partially from its interaction with 2-AG.

There's a great walkthrough of this subtle process here:

https://lift.co/magazine/discovery-cannabidiol-acts-gaba-neurons-explain-antiepileptic-properties/

We looked at CBD and GABA for anxiety in detail.

This brings up a much more interesting question...why is our GABA low to begin with for anxiety?

GABA is your brain's main "inhibitory" chemical.

It slows things down.

Let's look at the culprits for depleted GABA.

Many things can "eat up" GABA levels:

• Too much Glutamate, the brain's main excitatory chemical
• Histamine, a secondary excitatory chemical from the immune system
• Cortisol, an excitatory chemical from the nervous system
• Stress and inflammation response
• Early trauma and infection...even in utero

 

The big culprit is Glutamate.

90% of our brain's gas pedal resides with this chemical.

There's a rich interplay between glutamate and the endocannabinoid system.

Learn all about the glutamate pathway at our CBD and Anxiety article.

Here's a pretty good explanation of the glutamate pathway with our endocannabinoids:

Upon activation by 2-AG and Anandamide, CB1 drives cellular cascades that block the flow of calcium into the presynaptic terminal. This then causes a significant reduction in glutamate release, downregulating the activity of glutamate on the postsynaptic neuron.

http://www.phytecs.com/tour-the-ecs/cannabinoid-signaling-at-the-synapse/

To translate, the endocannabinoid system keeps a check on glutamate activity.  We already talked about CBD's effect on 2-AG.

What about Anandamide?

Anandamide, the so-called "bliss molecule" was named after Anand, the Hindu goddess of bliss.

It's a very prominent, naturally occurring endocannabinoid.

CBD is just a cannabinoid from a plant but its effect is through our own endocannabinoid system and its actors.

So...2-AG and Anandamide calm the glutamate response.

What's the connection between CBD and Anandamide?

Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3316151/

There's a great article on excess Glutamate below including tips like supplementing Vitamin D, Vitamin K, Zinc, and Magnesium (all known to help with anxiety by the way):

http://www.rlcure.com/glutamate2.html

We have a whole separate article on all this (available at anxiety tips page here) but we need to move on.

What about Histamine, the other excitatory chemical with ties to anxiety?

We thought you would never ask!

CBD has been shown to directly calm histamine response and mast cell release (where the histamine comes from).  More on that here:

Look...Histamine may be the most overlooked actor in the whole anxiety question.

 

In fact, the neuron that makes GABA also makes Histamine!

Too much histamine will automatically reduce the amount of GABA produced (only so much production capacity).

A great deal of this was discovered while researching sleep since histamine also governs wakefulness.

https://www.imperial.ac.uk/news/166875/study-finds-brain-chemicals-that-keep/

In fact…

The new research suggests that the chemical GABA acts against histamine, like a chemical “brake” preventing wakefulness being too intense.

http://www.sleepreviewmag.com/2015/08/gaba-may-act-chemical-brake-preventing-histamine-wakefulness-intense/

Learn all about CBD, histamines, and anxiety here.

Let's look at CBD versus the other big class of anxiety medications...SSRI's.

CBD versus SSRI's - Serotonin pathways

Most of the research for CBD and serotonin is along the lines of depression.

As we mentioned above, GABA is a better proxy for anxiety and serotonin is more aligned with depression.

The endocannabinoid system is deeply involved in the balancing neurotransmitters like serotonin.

CBD helps to support this system.

For example...

Our results suggest that the antidepressant-like effect induced by CBD in the FST is dependent on serotonin levels in the central nervous system (CNS).

https://www.ncbi.nlm.nih.gov/pubmed/29885468

In this study, they directly studied the effects of CBD which appear to operate on the 5HT system (serotonin).

Further studies confirmed CBD's powerful effect here:

Both the antidepressant-like effect and enhanced cortical 5-HT/glutamate neurotransmission induced by CBD were prevented by 5-HT1A receptor blockade.

https://www.ncbi.nlm.nih.gov/pubmed/26711860

So...the antidepressant effect of CBD occurred through serotonin pathways.

Maybe, more importantly, the effects were found to be fast-acting and long-lasting:

our findings indicate that CBD could represent a novel fast antidepressant drug, via enhancing both serotonergic and glutamate cortical signaling through a 5-HT1A receptor-dependent mechanism.

 

Remember that most SSRI's will eventually stop working and require switching to other medications or increasing dosages.

The brain adjusts to the increased serotonin levels that those meds create by...reducing serotonin!!

That's why it is so hard to come off of them.  Can you imagine the feeling of suddenly having the serotonin rug pulled out from under you.

It's no different than any other addiction or drug withdrawal except maybe worse.

Serotonin governs so much in the brain and body!

Coming off of Lexapro was the second worse process behind Xanax (and actually, #2 was a common blood pressure med they put everyone on!)

 

I went through the whole process at our review on how I used CBD to get off SSRI's.

Brand new research is pointing to how serotonin actually offsets both anxiety and depression.  

 

Check out CBD and BDNF for anxiety.  You're about to be light years ahead of your doctor!

The key is that CBD supports serotonin when low but doesn't boost it in one direction.  Technically, it's called an allosteric positive modulator.

 

Let's touch base on CBD and other pathways of anxiety quickly.

CBD, brain inflammation and anxiety

Yes, histamine is part of this but our immune-inflammatory response may be key to anxiety, depression, and a host of mental health issues.

CBD has been found to be a powerful neuroprotective and anti-inflammatory in the brain and nervous system!!

Much of this research was found following significantly brain injuries such as following stroke:

CBD treatment results in global functional recovery in ischemic mice and impacts multiple and distinct targets involved in the pathophysiology of brain ischemic injury.

https://www.ncbi.nlm.nih.gov/pubmed/12509806

One of the symptoms displayed by the animals after the injury in this test was anxiety.

CBD helped with this as well.

 

Maybe more importantly for anxiety, is CBD's effect on microglia in the brain.

This is the immune responder in our central nervous system which is showing to be key to a host of mental health issues:

Cannabinoids ablate the release of TNFalpha in rat microglial cells stimulated with lipopolysaccharide.

https://www.ncbi.nlm.nih.gov/pubmed/12509806

TNF (tumor necrosis factor) is a powerful inflammatory chemical in the brain and body.

Check out CBD and microglia for anxiety here. 

Remember that people suffering from anxiety and depression show reduced brain mass in key areas.

This can be the result of injury, stress, trauma, infection, illness (including autoimmune response), or genetics.

Maybe the most powerful effect of CBD is neurogenesis.

 

 

This is the ability to build new neurons in specific and important brain areas.

A great deal of SSRI's power with anxiety may be from this observed result.

This may be our favorite study on CBD and anxiety because it speaks to the root of what's going today.

The anxiolytic effect of cannabidiol on chronically stressed mice depends on hippocampal neurogenesis: involvement of the endocannabinoid system.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3386505/

The key words there…"Chronic stress".

A new study just came out which showed that the youngest generation's rate of anxiety has skyrocketed.

Under age 26.

Chronic stress (since 2008) is basically a hallmark of our current society.

Chronic stress eats up GABA, increases Glutamate, increases inflammatory response (cytokines, histamine, etc), and slowly causes neuron death.

Excess glutamate alone can kill neurons as can the inflammatory responders.

The study showed that the anti-anxiety effect of CBD (anxiolytic is the term) was due to neurogenesis in the hippocampus.

 

What's the hippocampus (besides a very cool word?)

Just a key area of the brain in charge of balancing mood and tied to anxiety/depression:

CBD for neurogenesis and anxiety

Very cool!

Again, SSRIs have been shown to have a similar effect and countering the ravishes of brain stress may be the real positive for anxiety and depression.

We just don't want the nasty side effects and tolerance.

Speaking of stress response….

Remember that chemical CFR from above (we won't blame you if you don't!)

It's the chemical messenger between our brain and the stress response organs.

Stay with us...this gets very cool and no one is really talking about it.

Remember how SSRI's initially increase anxiety and depression?

The reason is that serotonin is a general messenger across many pathways.

One of them is this CFR pathway.

Boost CFR = feel stress and eventually, anxiety

 

It's that simple.

What does this have to do with CBD?

If you boost CFR, it increases an endocannabinoid called FAAH which eats up Anandamide in the Amygdala (our fear and emotional center of the brain -very important to anxiety, addiction, and other issues).

 

What does CBD do for anandamide?

It boosts its signaling and reduces FAAH back to baseline!!!

https://www.ncbi.nlm.nih.gov/pubmed/25740517

The word baseline there is key.

Remember how some people get Serotonin Syndrome from SSRI's or how benzos normalize and eventually require higher and higher amounts for the same effect?

CBD in the endocannabinoid system works completely differently.

It's not a hammer in one direction (up with serotonin for SSRI's or up with GABA for benzos).

Important note:  THC, CBG, and CBN (other cannabinoids) push pathways in one direction and cause tolerance.  See CBD versus THC to learn more.

 

 

It's like a rubber band that pushes too much or too little on a given pathway.

That brings up the safety of CBD for anxiety versus other medications.

Let's go there now.

Safety comparison between anxiety meds and CBD

This, for us, is really the key difference between almost all anxiety medications and CBD.

The profiles are significantly different.

The vast majority of what is prescribed on the market is either in the benzodiazepine or SSRI classes.

Both have some pretty heavy baggage.

Benzodiazepine:

You can google the side effects for any given medication (they can be slightly different) but the main concern is addiction.

Benzo's are not encouraged for long term use.

Any good doctor will explain this and be concerned about use over 15 days to 1-2 months.

 

It's well established in the medical community that this class of medication has a high rate of addiction.

There's a reason why it's called the next opioid crisis and that Xanax has a "street value" on the illegal market now.

In addition to the serious risk of addiction from long term use, there are other issues:

• Cognitive impairment
• Motor vehicle crashes
• Hip fractures

https://www.aafp.org/afp/2013/0815/p224.html

Just how prevalent is the use of this class?

In 2016, Reuters Health noted that benzo prescriptions had tripled that year and overdoses involving benzos more than quadrupled since 1996.

• In 2015, Xanax was called the world’s most popular pill, with tens of millions of prescriptions being dispensed globally
• American doctors are writing 12% more Xanax prescriptions every year
• In 2011, 49 million alprazolam prescriptions were written worldwide

https://www.therecoveryvillage.com/benzodiazepine-addiction/#gref

Those are old stats now.

Check out slightly updated information here:

https://en.wikipedia.org/wiki/Benzodiazepine_overdose

Again, this is pretty well established in the medical community and your doctor BETTER explain the backside of these meds to you. 

There's a Black Box warning after all.

 

Ours didn't.

In light of these downsides with benzos, there's been a big move to SSRI's in the last few years for anxiety.

What about their safety?

SSRI safety

SSRI's are a completely different ball of wax.

Technically, they are less addictive than benzos in the traditional sense.

They are not hitting the dopamine system (our reward circuit) like benzos but that doesn't mean that coming off of SSRIs will be easy.

One way around it is to call it something other than withdrawal.

How about….

SSRI discontinuation Syndrome!

Ding ding ding!

https://en.wikipedia.org/wiki/Antidepressant_discontinuation_syndrome

Yes, the symptoms are the same as addiction (including anxiety) but it's a different name so we're all good. 

Basically, it's a brutal tolerance and withdrawal.

The duration is usually a few weeks to months.

Up to half of the people who stop SSRI's experience these symptoms and half of them call them "severe".

 

This usually ends with them going back on the medication to stop the symptoms.

But it's not addictive!

https://www.health.harvard.edu/newsletter_article/what-are-the-real-risks-of-antidepressants

Walks like a dog. Barks like a dog. But it's a cat.

So, why would people want to come off of SSRI's, to begin with?

We listed the side effects of an SSRI of choice, Lexapro above.

Let's look at another very popular SSRI, Zoloft.

A slightly different list of side effects but pretty comparable.

When they put me on an SSRI, I had a range of these effects.

It culminated in 3 days of not sleeping which landed me in the ER.

 

Prior to that, everything flatlined.

• There was no feeling of anything.
• Food. Sex. Anything.

 

That's a listed possible side effect from SSRIs.

Again, serotonin is a master signaller in the brain (and gut).

No one can even test whether your serotonin is low!

They're just guessing based on the anxiety (which is more of GABA issue).

What happens if you get too much serotonin?

There's a name for it...Serotonin syndrome.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3865832/

Apparently, if you put syndrome in the name, it's less threatening.

Interestingly, many of the symptoms of this very serious but less common result are similar to the standard list of side effects.

https://www.health.harvard.edu/newsletter_article/what-are-the-real-risks-of-antidepressants

It's really difficult to get good stats on the probability of this result.

The only stat we could find was just under 10,000 official diagnosis back in 2004 but the number of prescriptions has skyrocketed since then and it's very difficult to test for it.

 

Insult to injury...guess what is usually used to address Serotonin syndrome..

You guessed it...Benzos!

Benzos are used to mask the anxiety/depression of new SSRI's and they're used on the back end of the SSRI's cause serotonin syndrome.

For now, that leaves us with the standard side effect of any given SSRI and there's quite a bit there.

Always work with your doctor but weaning slowly is MANDATORY with SSRI's

We did a tips guide on tapering off SSRIs here.

Stopping SSRI's cold turkey can be downright dangerous. 

Are SSRI's even effective for anxiety?

As we mentioned, serotonin is more targeted to depression.

New studies are not looking great.

the analysis showed a difference between treatment with an antidepressant and treatment with a placebo of 4.0 points on the Hamilton Anxiety Rating Scale for patients with severe GAD. For patients with mild GAD, the antidepressant-placebo difference was just 1.4 points.

https://www.psychcongress.com/article/antidepressants-less-effective-mild-anxiety-panic-disorder

1.4 points over the placebo effect. That's out of 70 points!

At least we'll have the benzos for coming off of the SSRI's (sarc)

One note...before CBD safety….we mentioned hydroxyzine above.

An antihistamine.

Its safety is much better than either of these two classes with drowsiness being the main side effect. 

The only issue with antihistamine is that they rip acetylcholine, our key "calm and focused" neurotransmitter with big implications for dementia.  

That's a good jumping-off point for CBD safety.

CBD safety for anxiety

The most common side effects of CBD are:

• Dry mouth
• Lower blood pressure
• Drowsiness
• Lightheadedness

 

Keep in mind that these side effects are for CBD Isolate by itself (not full spectrum).

That's why we focus on CBD isolate to only match the research.

Here's the interesting point...

There is not a reported overdose on CBD

How is that possible?

In research on anxiety, CBD has been tested between 300-600 mg.

 

Safety tests have run up to 1500 mg and higher with a strong profile.

You can learn all about the safety of CBD here.

Studies are pointing to 300mg daily for peak neurogenesis:

A few notes when comparing CBD to benzos or SSRI's.

CBD has not been found to be habit-forming, addictive, hedonic (pleasure creating), or prone to normalization.

Normalizing means that you need more and more of it for the same effect.

This speaks to the function of the endocannabinoid system in our body to balance other key systems.

It's used as needed.

In fact, research is showing that CBD may be a valuable aid for addiction to other substances such as Benzos and/or SSRI withdrawal or "syndrome".

 

Learn all about CBD and addiction here.

Maybe most importantly for anxiety, it doesn't pound serotonin or GABA levels in one direction.

This requires a more involved discussion of exactly how the endocannabinoids (Anandamide, 2-AG, FAAH, etc) work in the brain.

The endocannabinoid system review is here

Otherwise, some key pages:

• CBD safety profile
• CBD for anxiety
• CBD and the gut (gut bacteria are key to anxiety)
• CBD and inflammation
• CBD and neurogenesis
• CBD and the markup of early trauma/infection

 

The question comes up often, can you use CBD to transition from benzos or SSRIs?

Can you take CBD with anxiety medications

CBD may help with the transitioning from other anxiety medications.

Some key points on this.

First, you want to take CBD at least 4 hours away from any medication since they can use the same pathway in the liver.

 

Always work with your doctor (Not sure about the one who gave you benzo or SSRI after a 10-minute discussion).

Ideally, you find a naturopath or sympathetic doctor who will work with you on this front.

Sorry...check out our story  as to why we're a bit skeptical!

Deep dives here (along with other tools):

CBD to taper off benzos
CBD to taper off SSRIs

We've gone through the different pathways that CBD works on with anxiety.

These hold true with or without the other anxiety medications.

Just make sure to take them away from each other so it doesn't boost a medication's levels in the blood (because the liver is busy processing CBD).

Ideally, CBD will help mitigate some of the negatives from coming off of benzos or SSRI's if that's your intent.

The main side effect can be anxiety and sleep issues so we definitely want relief there.

Make sure to take CBD Isolate so we don't create more histamine.

Remember that hydroxyzine was as effective as benzos for anxiety and it's primarily an antihistamine!

Full-spectrum CBD has lots of plant material which can cause more histamine for the 40-60% of people (higher in women and higher yet over age 40) that have histamine/allergy issues.

CBD Isolate is our best match for what research is showing.

Learn about CBD and histamines here.

• Test a 1000 mg bottle to see how your body responds.
• A starting dosage is usually around 25-30 mg to test how your body responds.
• Neurogenesis peaks at 300 mg according to research.

 

I take 150 mg at night and 150 mg in the morning now that I'm completely off of Valium and Lexapro.

Why put all this effort into comparing CBD and anxiety meds?

 I suffered for a full year trying to find what works.

I've never experienced anything like that and there's no way another person can understand unless they've been through it.

That's why we put so much into this article and others.

That's why we crafted IndigoNaturals to help people.

  

The goal is simple...reduce suffering.

Be well and you will feel better. I did. You will get there too.

Related Research:

Top 10 tips for tapering benzos

Top 10 tips for tapering SSRIs

Comparing CBD and benzos

Comparing CBD and SSRis

How SSRIs really work (till tolerance kicks in)

 

 

 

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.