CBD, Glutathione, and Anxiety

by Indigo Naturals August 21, 2019

We just wrapped up a massive article on CBD, neuroinflammation, and anxiety here.

Somewhere buried in those few thousand words is a quick blip about glutathione and CBD's effect on it.

It's worth expanding on the role of glutathione by itself.

It is your most powerful antioxidant after all!

This is incredibly important in the most energy-hungry, waste-producing, and oxidative part of your body...the brain!

The connections between destructive oxidation and anxiety (any mental health issues for that matter) is well established.

We'll look at ALL of it!

Finally, we'll see if CBD can boost glutathione in the body and BRAIN.

Let's get started!

We're going to cover these topics:

A quick introduction to glutathione
Glutathione in the brain for anxiety
Glutathione and GABA
Does CBD boost glutathione for anxiety
How much CBD to take to boost glutathione for anxiety
The best type of CBD to boost glutathione for anxiety

Let's get started. Clean up on aisle 5!

A quick introduction to glutathione

Before we look at glutathione, let's talk about the tremendous mess it's designed to clean up.

Oxidative stress. Also called ROS (short for reactive oxidative species).

See our articles on:

Basically, it's the waste material of energy production by our cells.

Little Tasmanian devils of oxygens in various forms that pretty much destroy whatever they touch.

It's just the downside of evolving on a planet rich in oxygen.

Our cells make energy solely in mitochondria which are basically ancient bacteria we took hostage to make our energy 100's of millions of years ago.

They even have their own DNA! Bacteria DNA that is. It's called mtDNA.

While they're churning out energy, occasionally oxygen escapes the process and runs amok.

Oxygen is incredibly reactive. That's why we use it in detergents and bleach.

It shreds organic molecules apart!

If that "organic molecule" happens to be a piece of our cellular machinery or worse yet, our DNA, there can be considerable damage.

Luckily, our body has developed robust systems to neutralize this threat.

It's called the redox system.

We need enough oxygen to carry out its energy functions but not too much that it does damage.

What's the most powerful antioxidant in the body?

Glutathione!

To understand just how powerful this job is, keep in mind that the level of glutathione in cells rivals the key ingredients of life:

As can be seen in Figure 1, this is the same concentration in cells as glucose, potassium, and cholesterol!

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4684116/

When they block the enzyme needed for glutathione in mouse liver cells, they died within 1 month:

Hepatocyte‐specific Gclc deletion leads to a rapid onset of steatosis with mitochondrial injury and liver failure

https://aasldpubs.onlinelibrary.wiley.com/doi/full/10.1002/hep.21635

The liver is a key site for glutathione production and activity.

That's why glutathione is typically used for liver toxicity due to acetaminophen (Tylenol) overdose.

Check out the connection between CBD and Tylenol by the way...it's fascinating.

Many things can eat up glutathione in the body:

Poor sleep
Stress
Alcohol and drugs
Heavy metals

Basically, anything the body has to clear out or neutralize.

There are also some intriguing ways to increase glutathione naturally in the body (some of which are surprising).

This article has a pretty good review of these options:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4684116/

You'll see many of the substances and actions that support this pathway.

Sulfur-containing foods
Vitamin C and E
Selenium, NAC, and ALA
Alcohol-free beer?? Yes but watch out for histamine issues
Exercise and meditation

The last one is interesting as there's a crossover for anxiety (see our CBD, meditation, and exercise for brain repair and anxiety).

We always hear about Vitamin C and Vitamin E being powerful antioxidants.

Go figure... they figure into the recycling of glutathione availability in the body.

Wait till you see what CBD does as an anti-oxidant compared to those two.

One final note…glutathione function oxidative damage is one of those tell-tale biomarkers of aging.

Simply put...

The incidence and abundance of these mutant mtDNAs are increased with age, particularly in tissues with great demand for energy. On the other hand, recent studies have revealed that the ability of the human cell to cope with oxidative stress is compromised in aging.

https://www.ncbi.nlm.nih.gov/pubmed/11499335

What's causing this increased damage??

Furthermore, the mitochondrial pool of reduced glutathione declines and DNA damage is enhanced in aging tissues.

Look...research is pointing to the mitochondria as our "weak link" for aging.

The buck stops there as they do not have the robust safety controls our cells have for detecting and repairing oxidative damage.

If we can prevent the damage to begin with, there's a potentially huge impact on longevity not to mention the illnesses that increase as we get older.

Let's turn our focus to anxiety as almost any health issue can be tied to poor glutathione pathways.

Glutathione in the brain for anxiety

We've established the link between oxidation, ROS, and anxiety pretty clearly in our CBD for oxidative stress article but let's do a quick recap with a focus on glutathione.

The key word in that entire sentence is stress.

First, we've seen how chronic stress early in life, now, or even in the womb can affect brain wiring and the anxiety circuit.

Check out the following for more detail:

If you need one experiment that ties this all together for anxiety, let's start here.

A study looked at the rats following restraint (a known inducer of anxiety).

One half of them were given carnosol, a powerful chemical antioxidant that gives odors and colors to certain plants (think rosemary and sage).

The rats who did not get the carnosol displayed typical anxiety-like behavior in follow up exercises.

They also showed reduced levels of antioxidants including glutathione:

In the vehicle-treated rats that submitted to the stress, the level of MDA levels were significantly increased (P < 0.001), and the levels of GSH and antioxidant enzymes were significantly decreased versus the non-stressed animals (P < 0.001).

GSH is glutathione.

As for the rats who had the anti-oxidant?:

Carnosol treatment reduced the modifications in the stressed animals as compared with the control groups (P < 0.001).

And finally, the most interesting piece:

All of these carnosol effects were nearly similar to those observed with fluoxetine.

Fluoxetine is Prozac, the first SSRI.

SSRI's are a mainstay in treatment for anxiety but they build tolerance (see CBD versus SSRI for anxiety).

What's interesting is that the main pathway of SSRI's is in rebuilding damaged brain areas.

See our artile on CBD and neurotrophines like BDNF for anxiety.

What the experiment above showed is that rather than repair existing damage from chronic stress, we can prevent it with antioxidants to get the same effect!

What chemicals were later measured in the brains of the rats?:

reduced glutathione (GSH), as well as superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR)

https://www.ncbi.nlm.nih.gov/pubmed/17961308

I see a pattern there. Those are all anti-oxidants in the body.

Remember how we said that mitochondria damage might be the first switch in aging and age-related diseases?

Another study found that chronic stress causes an increase of NO (nitric oxide), a known oxidant which partially governs energy production in the mitochondria.

The knock-on effect of this spike of NO following chronic stress:

We have found that stress (S21) decreases brain GSH levels by 36.7% as compared with control rats

https://www.nature.com/articles/1395616.pdf?origin=ppub

GSH is short for Glutathione! Stress is the enemy of glutathione!

Maybe, more importantly, the effect on mitochondria function from this imbalance between oxidants and antioxidants in the brain:

As shown in Figure 1, mitochondrial complex I-III activity was significantly decreased as early as seven days of repeated exposure to restraint stress. Complex II-III activity decreased after two weeks of stress exposure (Figure 1).

Keep in mind that mitochondria power every aspect of cell activity.

Housekeeping. DNA monitoring. Repair/Removal.

See our artile on CBD and brain repair.

Drops in mitochondrial activity is a known biomarker for aging and age-related diseases.

A decline in mitochondrial quality and activity has been associated with normal aging and correlated with the development of a wide range of age-related diseases.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4779179/

The twin terrors of chronic neuroinflammation...depression and anxiety are also in play here.

What's interesting is what happens in the brain in terms of fats (lipids) and oxidation.

The brain is our biggest user of fats (see Pregnenolone and cholesterol here).

This makes it especially susceptible to oxidation of this fat which creates a poison in our brain called malondialdehyde.

As researchers put it:

Lipid peroxidation decreases the life span of neurons, affects neurotransmitter release, and was reported as a major contributor to the loss of cell function under oxidative stress conditions in depression

https://www.hindawi.com/journals/omcl/2017/7313090/

That's depression...what about anxiety?

Enter the wild world of CRISPR and gene editing!

Researchers can now "knock-out" one gene and see the effects.

Scientists did such a thing to important glutathione genes:

Glyoxalase 1
Glutathione reductase 1

Their results:

Glyoxalase 1 and glutathione reductase 1 regulate anxiety in mice

research is here.

To be specific:

Local overexpression of these genes in the mouse brain resulted in increased anxiety-like behavior, while local inhibition of glyoxalase 1 expression by RNA interference decreased the anxiety-like behavior.

And what's the connection with stress?

Both of these genes are involved in oxidative stress metabolism, linking this pathway with anxiety-related behavior.

It points (partially) to a specific lever linking chronic stress and anxiety.

So the connection between ROS, glutathione, and anxiety has been shown in animal studies:

we found that anxiety in mice is accompanied by markedly elevated levels of ROS in neuronal and glial cells within the cerebellum and hippocampus, as well as in neurons of the cerebral cortex and in blood monocytes, granulocytes, and lymphocytes

http://downloads.hindawi.com/journals/omcl/2009/623654.pdf

Other studies increased oxidative stress via an oxidation boosting chemical which induced anxiety across a range of different genetic types:

The anxiogenic behavior due to BSO treatment was observed in several mouse models of anxiety, including elevated plus maze, hole-board, and open field tests.

http://downloads.hindawi.com/journals/omcl/2009/623654.pdf

Angiogenic means...anxiety creating.

How did they do this??

Masood et al.29 induced oxidative stress in mice by depleting glutathione with BSO inhibition of gamma-glutamylcysteine synthetase. Glutathione depletion causes a myriad of cellular stresses, including oxidative, nitrosative and carbonyl stresses, as glutathione is an important determinant of the oxygen, nitrogen and dicarbonyl metabolisms.1

They depleted glutathione.

Look at the last string of results from that depletion!

As for people, we all have the same pathways as those discussed above.

In fact, a study found that the severity of anxiety (but not depression) depended on oxidation:

Subjects scoring high on "psychic anxiety" had elevated F2-isoprostanes (p=.030) and GSSG (p=.020).

https://www.ncbi.nlm.nih.gov/pubmed/28564628

GSSG is the "used up" version of glutathione. It's a sign of high oxidative stress.

Again, check out CBD, neuroinflammation, and anxiety for more detail.

One more stop before we look at CBD.

Glutathione and GABA

We've covered GABA in detail due to its powerful influence on anxiety.

In fact, GABA is the main lever that benzos (Ativan, Xanax, valium, and others) trigger for anxiety (albeit with nasty side effects).

Check out CBD versus Benzos for GABA and anxiety.

What's the relationship between glutathione and GABA?

See our article CBD and GABA the complete guide.

There's intriguing new research tying the two.

First, they found that glutathione directly stimulated GABA release in a certain type of glial cell (cells found in the nervous system):

Despite its antioxidant role, data also point to GSH as a signaling agent, suggesting that GABA release and P2X7R-mediated calcium inwards occur in Müller cells in a GSH-enriched environment.

https://www.ncbi.nlm.nih.gov/pubmed/28564628

We need more research on this but the relationship is not surprising.

GABA is used to offset excitatory neurotransmitters (glutamate, histamine, NDMA, etc).

Glutathione is used to clean up the mess from all that excitement in the brain!

Let's move on to our main question.

What can CBD do for glutathione?

Does CBD boost glutathione for anxiety

First, CBD is a powerful antioxidant in its own right.

In fact, it's more powerful than either Vitamin E or C!

cannabidiol was demonstrated to reduce hydroperoxide toxicity in neurons. In a head to head trial of the abilities of various antioxidants to prevent glutamate toxicity, cannabidiol was superior to both alpha-tocopherol and ascorbate in a protective capacity.

https://www.ncbi.nlm.nih.gov/pubmed/10863546

Check out the effects of CBD on sepsis which is the most extreme form of oxidation.

As for CBD and glutathione directly:

Cannabidiol (CBD) has been shown to exhibit anti-inflammatory, antioxidant and neuroprotective properties.

https://www.ncbi.nlm.nih.gov/pubmed/22178458

How does it do this?:

Moreover, CBD treatment of BV-2 cells was found to induce a robust change in the expression of genes related to oxidative stress, glutathione deprivation, and inflammation.

This is important because of the type of the cell...microglia….brain immune cells!

Let's look at a specific use of CBD.

There's a chemotherapy agent called Doxorubicin (DOX).

Unfortunately, one of its side effects is a spike in heart tissue damage as the result of increases oxidation.

DOX’s cardiotoxicity involves increased oxidative/nitrative stress, impaired mitochondrial function in cardiomyocytes/endothelial cells and cell death.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4461586/

What happened when they supplemented CBD?

Treatment with CBD markedly improved DOX-induced cardiac dysfunction, oxidative/nitrative stress and cell death. CBD also enhanced the DOX-induced impaired cardiac mitochondrial function and biogenesis.

Take a look at the study.

It's pretty incredible...especially the NO (nitrous oxide) stress effects and mitochondrial activity.

This is a state of incredible oxidative stress.

To the point of cell death.

Which brings us to the most fascinating aspect of CBD and glutathione.

Keep in mind that CBD directly supports the endocannabinoid system.

This system is tasked with balance or "homeostasis".

We've only talked about the negatives of oxidative stress.

It also has some key roles in the body.

For example, our natural systems to detect and destroy cancer use oxidation to kill cancer!

We don't want to upset that apple cart with antioxidants, right?

Get ready to geek out.

Remember...it's about balance.

Researchers found that when cells are at a low oxidative level, CBD doesn't affect them.

When a cell is in high stress, it's anti-inflammatory.

When a cell is faulty or precancerous???

It boosts oxidation!!

It actually reduces glutathione to help kill the cell!

The exposure to CBD caused in glioma cells an early production of ROS, depletion of intracellular glutathione and increase activity of glutathione reductase and glutathione peroxidase enzymes.

https://www.ncbi.nlm.nih.gov/pubmed/16909207

What did it do to surrounding healthy cells?:

CBD did not impair primary glia.

In fact, CBD is one of the few antioxidants you can take with chemotherapy (check with your doctor of course).

We have a major review of CBD and Turkey Tail for cancer.

This "triphasic" effect of CBD and the endocannabinoid system speaks to why we don't see overdoses.

Again, the role of this system is to balance other key systems.

Check out CBD's, oxidative stress, and anxiety for much more detail.

Glutathione is just a player in that whole system (albeit, the biggest one).

Let's look at practical questions.

How much CBD to take to boost glutathione for anxiety.

The studies on CBD for extreme oxidative situations (heart oxidation from chemo or the ruptured intestine and sepsis study) use very high levels of CBD.

Research for serious issues typically are at about 600 - 800 mg of CBD.

Those are life and death situations so we obviously don't need to go that high.

Research on neurogenesis and anxiety put the max level at 300 mg where that aspect peaks.

This is about repairing the damage from oxidative stress and reduced glutathione. Most people actually see effects on anxiety and stress response at much lower levels.

The typical range we see for customers is between 40 -100 mg.

Sleep studies were pinned at 160 mg.

It's advisable to start at 25-30 mg and test how your body responds.

Since we only work with CBD isolate, many of the side effects from full-spectrum will not be there.

That brings up our next section.

The best type of CBD to boost glutathione for anxiety

The goal here is to reduce the load off of glutathione.

That means first, do no harm!

For this reason, we want very clean CBD in the simplest of ingredients.

The mandatory requirements:

Organically grown in the US
CO2 processed (cleanest option)
3rd party tested free of:
NO THC (see CBD versus THC for anxiety)
No pesticides
No heavy metals
No mold
No bacteria

At IndigoNaturals, we actually test twice:

Once for the biomass
Once for the finished product

After all, our entire families use the product so we're not messing around.

Hopefully, our research focus backs that up.

For glutathione, there's another important consideration.

Remember how glutathione is the cleanup crew for excitatory neurotransmitters (hence the relationship with GABA)?

Histamine is a powerful excitatory neurotransmitter in the brain.

See our article on full spectrum CBD versus CBD isolate for anxiety

In fact, it counters GABA for the wake-sleep cycle.

Guess which one is "wake"?

Histamine!

That's why antihistamines can make you feel drowsy (and reduce anxiety!).

Many people try full-spectrum CBD and they have side effects from it.

It's all that plant material!

Roughly 40-60% of the population has histamine issues (increases as we get older and for women).

We want clean CBD isolate (based on research above) and a base oil.

We use MCT (extract from coconut to avoid further histamine responses to either hemp or olive oil.

Let's not create more mess for glutathione to clean up!