Is Glutamate Why People Chronically Use THC and Cannabis?

by Indigo Naturals May 14, 2020

We just wrapped up a massive review of glutamate and mental health.

It's going to be the new star for years to come (with psilocybin close on its heals - see that research here).

Our research was prompted from a discussion we had with someone who uses high THC cannabis daily.

When we asked them why they used it, their reply was unequivocal:

"It slows things down"

By things, this person meant negative thoughts, constant chatter, anxiety, and the like.

We looked at negative and repetitive thoughts in our CBD and ruminations here.

It's really a question of low GABA...similar to OCD.

There's a huge amount of focus on GABA since its the primary lever for benzos like Ativan and Xanax (see CBD versus Ativan and Xanax).

Newer research is saying that glutamate (GABA's main adversary in the brain) may be the key player, however.

What on earth would this have to do with THC and cannabis?

Oh, just you wait till we look at the research.

THC daily use may be nothing more than self-medicating for hyperactive glutamate activity!

We'll cover all the clues in these sections:

A quick introduction to glutamate
CB1 receptors and glutamate
THC activity on CB1 receptors and glutamate
The downside with long term daily use of THC on glutamate
Are people self-medicating with THC to reduce glutamate
Where the excess glutamate comes from
How CBD protects against daily THC use
Other tools to address glutamate levels
How much CBD and NAC for glutamate balancing
What's the best CBD for daily THC use

Let's get started. We may have had daily THC use all wrong!

A quick introduction to glutamate

Glutamate is the new rising start in mental health and pain.

We did a full review of glutamate in the nervous system.

Basically, it acts as the gas pedal for brain activity in EVERY pathway.

This is an interesting piece because you can actually apply glutamate (gas pedal) to GABA neurons and it can have the opposite effect!

GABA is glutamate's opposing force in the brain and acts as a brake pedal.

It's also the target of benzos which is why we know so much about it (see CBD versus benzos or CBD and GABA).

You can apply this to the other big pathways like serotonin (feel "right", human behavior) and dopamine (reward circuit) that big Pharma has been pounding for decades now.

Lying at the heart of all of these pathways is Glutamate.

That's why it's so integral to every mental health issue we've come across.

Addiction is front and center (see CBD and addiction).

It goes beyond that though.

There are multiple systems in place to keep glutamate in-check both on the high and low end.

It's incredibly toxic to brains if too high!

On the low end, things literally shut down without this fuel.

This has implications for a suite of issues from autism to schizophrenia with depression being front and center.

We went into how glutathione, our brain and body's main anti-oxidant player, is key to balancing glutamate by acting as a reservoir for it in our NAC article.

You can also check out CBD and glutathione here.

We'll talk about NAC specifically later with CBD.

So, that's glutamate in a nutshell...our main excitatory neurotransmitter with fingers in every pie (neurotransmitter pathway and brain area).

80% of the brain's energy consumption is for glutamate processing. More than half of all neurons are directly involved in glutamate processing.

No wonder it's showing up everywhere.

The sad piece is that we didn't think it was a neurotransmitter till relatively recently since it's so ubiquitous or commonplace in the brain.

You can get the unabbreviated (8000 plus words) full glutamate and mental health review here

Otherwise, let's keep making our way down to THC.

Next stop, our endocannabinoid system.

CB1 receptors and glutamate

We all have a system tasked with balancing other key systems:

Immune system - inflammatory pathways
Endocrine system - hormones
Nervous system - neurotransmitters including glutamate, GABA, Dopamine, and Serotonin

By all, I mean every animal out there! It's dated to about 600 million years old evolutionarily speaking so mother Nature seems to like it.

There are two primary receptors:

CB1 - found mainly in the nervous system
CB2 - found mainly in the immune system

We'll focus on CB1 since that's where THC operates.

CB1 is where our two main endocannabinoids operate:

Anandamide - named after Hindu goddess of bliss, Anand
2AG - abbreviation for a ridiculously long chemical name

We'll focus on anandamide for this article.

It's very fascinating and research is pinpointing its role as a stress response reserve.

When things get rough, anandamide is called into service to calm things down.

By definition, we would expect this to interact with glutamate since glutamate's role is to rev things up?

Too much glutamate can be tied to ADHD, seizures, anxiety, etc.

You can see the shared pattern there.

With enough prolonged glutamate, neurons and their cohorts (astrocytes, microglia) can actually wither and die.

It's like red-lining your engine for too long.

Anandamide is the emergency brake!

Look what happens when CB1 activity (which is driven by anandamide) is reduced:

Similarly, the results of animal studies show that pharmacological blockade or genetic deletion of CB1 receptors increases stress-related behaviors (Arevalo et al., 2001; Haller et al., 2004a) and impairs the extinction of conditioned fear-responses

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3110547/

Like we said, stress response back-up if not the cavalry itself!

So...what does anandamide have to do with glutamate specifically?

Anandamide, THC, and other anandamide-receptor agonists inhibit the presynaptic release of the excitatory neurotransmitter glutamate in the hippocampus

https://www.sciencedirect.com/topics/neuroscience/anandamide

Interesting.

Anandamide acts as a wet blanket on brain function. It slows things down!

Keep in mind that this can apply to specific neurons such as those involved in serotonin or dopamine function (hence the bad effects at very high levels of THC).

For example:

Consistent with this prediction, activation of CB1 receptors have been shown to inhibit the 5-HT release

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2766225/

5HT is short for serotonin. Anandamide, which pushes more CB1 activity, is actually depressing serotonin function as well.

So, what's the connection with THC?

THC activity on CB1 receptors and glutamate

Chemically, THC looks very similar to anandamide.

They're both cannabinoids (one made in our body and the other in the cannabis plant - the naming of the plant not being causal).

We didn't get the endocannabinoid system so we could smoke pot!

Those chemicals just happen to affect a pathway existing in our bodies.

You can say the same for anything we get out of plants and the food we eat.

It's all one varied tree of life!

Anyway, since THC looks so similar to anandamide, it's able to fit into the lock of CB1 receptors!

It's a substitute teacher for anandamide.

Technically, it's a partial agonist (booster) of CB1 activity.

The net effect is that THC slows down nervous system activity!

For decades now, researchers could (would) only see this effect in the major pathways such as dopamine.

In very recent years, they looked closer for cause and effect:

In fact, it is thought that cannabis or Δ9-THC may not act on dopamine firing directly but indirectly by altering glutamate neurotransmission.

https://www.ncbi.nlm.nih.gov/pubmed/26987641

Interesting. The plot thickens. And glutamate is a major suspect!

CB1 activity and by default, THC, is all over glutamate function:

Research in animals tends to consistently suggest that Δ9-THC depresses glutamate synaptic transmission via CB1 receptor activation, affecting glutamate release, inhibiting receptors and transporters function, reducing enzyme activity, and disrupting glutamate synaptic plasticity after prolonged exposure.

https://www.ncbi.nlm.nih.gov/pubmed/26987641

The downside with long term daily use of THC on glutamate

That last piece is important.

"Disrupting glutamate synaptic plasticity with prolonged exposure".

See...THC, when ingested or smoked, hits the CB1 receptor at a much higher rate than naturally occurring anandamide.

Do this once maybe no problem.

If you keep doing it, the brain tries to counteract this imbalance by reducing CB1 sensitivity and/or numbers.

The whole role of the endocannabinoid system is balance or homeostasis after all.

Long term, this is bad news as it's the very opposite of why a person is smoking cannabis, to begin with!

There is an implied risk for long term depression and anxiety as a result of long-term THC use as the brain essentially builds tolerance.

Check out CBD and tolerance to understand this powerful piece better.

At this point, it's closer to addiction (estimated at about 9% of cannabis users) but we're interested in the initial question.

This gives us a clue to how long it will take normalize these pathways and support perhaps, the original deficits. Let's go to that piece now (original deficits).

Why are some people drawn to THC on a daily basis?

Are people self-medicating with THC to reduce glutamate

This finally loops back to the start of the article.

The person who was using THC (essentially) to slow things down.

To slow down negative, repetitive thoughts and a racing mind.

We now understand how THC does since it boosts CB1 activity which suppresses brain activity via glutamate.

We were fascinated that maybe the reason people chronically use THC isn't to get high (although stress relief is a component of the anandamide pathway).

Perhaps, it's to address hyperactive glutamate activity.

At that point, it's self-medicating.

After all, we covered how most drugs are hitting specific pathways that people may have deficits in:

Nicotine - glutamate, and acetylcholine (hence the schizophrenia tie)
Alcohol - GABA and serotonin (almost every neurotransmitter for that matter)
Opioids - opioid system (more on that below)
Benzos - GABA (by default, a glutamate issue)
SSRI's - serotonin (see CBD versus SSRI's)
Sleeping meds - GABA
THC - Anandamide???

Before we jump into the THC clues, what about the opioid epidemic.

That's clearly just about the opioid system, right?

Among the neurotransmitters involved in pain transmission from the periphery to the brain, glutamate has a leading role.

https://www.frontiersin.org/articles/10.3389/fnmol.2018.00464/full

Furthermore...

Glutamate is also involved in central sensitization, which is associated with chronic pain.

Goodness folks. This is 2019 research and a whole slew of studies are showing that too much glutamate can damage neurons and lead to pain.

It's the basis for neuropathy and chronic pain.

In fact, topical ketamine's action is to block glutamate receptors and allow them to recover.

This is the future of pain by the way.

Sorry, we digress but it's too cool.

Back to THC.

Our first clue is when we did our big review of NAC (N-acetylcysteine).

Read it...along with CBD, it's a game-changer.

Cheap, safe, and available (although maybe in short supply now due to antiviral effect).

NAC sponges excess glutamate out of the system. Look at the effect on THC addiction:

Results from this preliminary open-label study indicate that treatment with NAC was well tolerated and associated with significant decreases in self-report measures of marijuana use and craving.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2826714/

What's so intriguing about this study is that it was done on adolescents (teens) with chronic use.

This is when people generally start and it speaks to self-medicating if it's daily use.

Again, the primary means of action for NAC is glutamate:

Within animal studies, the antioxidant N-acetylcysteine (NAC) has been shown to reverse drug-induced down-regulation of the cystine-glutamate exchanger (5), which presumably allows for regulation of glutamate release, reducing compulsive drug-seeking behaviors.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2826714/

Let's reword all this.

Some people may have imbalanced glutamate function (towards the high end) which feels horrible (anxiety, depression, OCD, and worse).

They try pot and it slows this system down which brings relief.

That's the difference between getting high for kicks versus to bring relief.

It may also be why some people use cannabis daily!

Unfortunately, there are other consequences as we mentioned above.

Check out this article - The downside to high THC products

Now, let's really get to the root of the problem.

Where the excess glutamate comes from

Why do some people have hyperactivated glutamate activity and feel horribly for it?

You can blame your parents.

Just kidding but not kinda.

Here's where it gets really interesting.

If our immune system is revved up, the little sentinels in the brain called microglia just spill out excess glutamate!

Brain inflammation may be at the heart of this barring genetic differences.

Why would the immune system be ramped up?

Turns out that early trauma, infection, and stress (even in utero) can drive these changes later in life!

Check out our review of why the immune system is the future of mental health to learn more.

Overwrite these edits to the immune system to calm glutamate and inflammation in the brain.

People...this is the future of actually feeling better!

Back to our regular program.

So...two questions come to mind:

Are there ways to protect against THC use
Are there other ways to address the glutamate imbalance

Let's look at the first one.

How CBD protects against daily THC use

Ideally, you don't use THC daily and let that system normalize (check out CBD and withdrawals) but CBD is a must if you use THC or cannabis.

Unfortunately, a lot of the products on the legal market are very high THC...all THC even. It's crazy!

That's what the market is demanding, however. Apparently lots of tolerance and inflammation out there!

There's tons of research on how CBD has opposing and protective effects against THC use.

We covered it in detail at our CBD is a must if you use THC or cannabis.

Some highlights.

First, let's look at the effects of CBD and THC on the hippocampus, key to mood balancing.

Our findings suggest a restorative effect of CBD on the subicular and CA1 subfields in current cannabis users, especially those with greater lifetime exposure to cannabis.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5908414/

This is pretty revolutionary. We're talking about neurogenesis (see CBD and neurogenesis) which is key to rewiring the brain.

Then there are the mood and risk for psychiatric issues:

A study by neuroscientists finds that a non-psychoactive compound in cannabis called cannabidiol, or CBD, appears to protect against the long-term negative psychiatric effects of THC, the primary psychoactive ingredient in cannabis.

https://www.sciencedaily.com/releases/2017/09/170906135554.htm

Again, check out our article.

What about the underlying glutamate issue.

Other tools to address glutamate levels

Let's focus on CBD and NAC.

CBD's primary lever appears to be serotonin, the linchpin for all human behavior.

This makes sense since stimulating activity in one area of the brain is needed to cause a certain behavior:

Modulation of glutamate transmission by 5-HT has been described in several CNS regions, especially in those controlling cognition, nociception, and motor functions.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2430669/

So...thinking, pain, and feeling, plus bodily control.

Interesting research is pointing to CBD's effects on issues directly tied to glutamate imbalance:

Seizures - too much glutamate, almost exclusively a glutamate issue
Anxiety - reduced GABA and too much glutamate (see CBD and anxiety)
Depression - too much glutamate causing damage or too little leading to atrophy (see CBD and depression)
Schizophrenia - glutamate is now widely implicated (see CBD and schizophrenia)

Check out the glutamate and mental health article for more details.

So...what does CBD do for glutamate/GABA balancing?

Let's look at the most complex and frustrating example of glutamate imbalance in mental health… schizophrenia:

Overall, these findings show that CBD can restore cannabinoid/GABAergic signaling deficits in regions of the brain implicated in schizophrenia

https://www.ncbi.nlm.nih.gov/pubmed/31202911

That study was interesting since the researchers induced glutamate imbalance with early infection (which is a key risk across a range of mental health issues).

Remember the early trauma/infection piece!!!

Check out CBD and neuroinflammation to understand why.

NAC is also a key player here.

As one powerful example, let's look at NAC's effect on glutamate imbalance following cocaine use (an explosion in glutamate by the way).

Disrupted glutamate homeostasis is thought to contribute to the cocaine-use disorder, in particular, by enhancing the incentive salience of cocaine stimuli. n-Acetylcysteine might be useful in cocaine-use disorder by normalizing glutamate function.

https://www.science.gov/topicpages/n/n-acetylcysteine+reverses+cocaine

What you have to understand is that addiction is a form of learning. Certain drugs such as cocaine can hijack this learning process and make it nearly impossible to "unlearn" the habit.

Glutamate is a primary instrument in new learning!

Check out the NAC and mental health review.

Also, CBD and addiction go through this whole re-learning process.

Ultimately, NAC and CBD may be powerful allies for glutamate balancing, THC addiction, and weaning off of cannabis.

We did a massive review of CBD for THC addiction and tolerance/withdrawal

Let's look at some practical questions.

How much CBD and NAC for glutamate balancing

The key to this whole process is neurogenesis...building new connections in the brain.

Research is pointing to 300 mg as the peak dosage of CBD for neurogenesis.

Larger amounts have been tested for more acute situational effects on anxiety, panic attacks, schizophrenia, etc at 600-800 mg.

Long term, the neurogenesis effect is key to normalizing brain activity and that's 300 mg.

As for NAC, the studies are generally 1800-2000 mg daily. The standard doses on the market are 600 mg or 1000 mg capsules.

The safety for both at these levels is pretty well established.

Make sure to work with your doctor or naturopath with any supplement.

In terms of the type of CBD and NAC.

What's the best CBD for daily THC use

Some basic requirements apply for CBD:

Organically grown in the US at an FDA registered farm
Co2 processed
3rd party tested
No THC (obviously but that's not the case for a lot of CBD on the market)
No pesticides
No solvents
No heavy metals
No pesticides
No mold

We test IndigoNaturals twice since our whole family uses it daily.

We also focus on CBD isolate (by itself) as opposed to full spectrum.

All the research (we reference 100's of NIH studies on this side) are on CBD isolate.

More importantly, many people have allergy or histamine responses to full spectrum.

We originally tried 3-4 of the biggest brands and had bad reactions which is why IndigoNaturals was born.

Histamine eats up GABA which means...more glutamate!

We look forward to new research but the recent movement has all been along these lines.

Now, we may finally understand why some people can smoke cannabis once and a while and others start the day with it.

CBD and NAC may prove to be powerful allies here and with stopping cannabis daily use.

If someone doesn't like their relationship with THC, check out our taper section: