The THC Freakout: Understanding the Science Behind Marijuana-Induced Mood Blowups


Look, we're not here for the cannabis is medicine debate.  We stick to the research and anyone who's used cannabis longer term or knows someone who has can agree…

The ability to deal with stress can get blown out!

Freakouts.  Blow ups.  Meltdowns.  Emotional explosions.  However, you want to name it.

There are actually good explanations for this effect longer term and two suspects are in play:

One is the here and now (serotonin), while the other is long term structural (the hippocampus).

Understanding how THC's effects build over time at these two crucial junctions and more importantly, how to offset the effect or better yet, find tools that support our stress response is key to feeling better.

We'll also touch on why THC may have felt so right to begin with and ways to address that differently and don't worry, we'll finish on a positive note!

Here are the topics we'll cover:

  • Does THC affect mood changes longer term?
  • THC and serotonin for stress response
  • THC and hippocampus for stress response
  • How to support these pathways without tolerance
  • How to taper THC or find a healthy relationship with it
  • Good news with abstinence

Let's get started before someone cuts you off onthe  highway again (you know who you are!)

Does THC affect mood changes longer term?

We have lots of deep dives on THC such as CBD to protect against THC.

Many people are initially drawn to cannabis with THC because of stress so what flips?

First, we need to understand what THC is doing in the brain.

THC mimics a natural substance we have called anandamide which is named after the Hindu goddess of…Bliss.



Yes, bliss.  The opposite of stress.

Anandamide is our "natural" high.  Feeling pretty good and at peace for lack of a better word.

It works primarily at a receptor called CB1 in our endocannabinoid system which is tasked with balancing every other key system.

So…when we get stressed, this system brings things back to normal. We can't stay in that state long term without adversely affecting our health.

In fact, we looked at whether exhausted or poorly functioning endocannabinoid systems is key to most modern diseases.  Answer…yes.  Or it's a part of it.

So…this should all be good with THC right?  In fact, most people speak to a relaxing effect from cannabis unless you're one of the 30ish% that has a histamine response to it (panic attacks, anxiety, paranoia, etc).

Here's the problem with THC.

It's a full blown agonist for CB1 activity. It pushes in one direction and it hits harder and lasts longer than the natural anandamide.

That's the "high" and other symptoms of cannabis use (foggy thinking, slowed reactions, etc).

The brain doesn't like meddling in such a key pathway so it will slowly start to downregulate CB1 receptors and sensitivity over time.

We see this with most drugs in fact (see tolerance review).



This means our natural production of anandamide is slowly getting whittled down.

A big problem!  Anandamide works like a big wet blanket in the brain on:

  • Inflammation - can disrupt proper brain function; tied to every mental health issue
  • Cortisol (stress messenger)
  • Glutamate (brain's gas pedal)
  • Adrenaline - fight or flight player
  • Histamine - the "wake" signal but also anxiety, OCD, insomnia when revved high

We looked at whether people used THC chronically to slow things down in the brain initially.

So…why bring up serotonin?  

Serotonin is the manager of ALL human behavior.  Seriously.

  • Libido
  • Learning
  • Aggression
  • Self-esteem
  • Stress response


Think of waves of stress response buffers:

  • GABA - the brain's "brake" pedal; target of benzos
  • Serotonin - main stress manager; target of SSRIs
  • Anandamide - backup stress cavalry; target of….THC!


All those medication classes build tolerance (benzos add in addiction) which means your natural levels will just keep dropping.

Let's focus on serotonin since it's the ringleader for mood.

THC and serotonin for stress response

First, we know there are issues with THC exposure during brain development (sorry…up to age 25):

Altogether, these findings suggest that chronic low-dose THC exposure during the critical developmental period of adolescence and during adulthood could result in increased vulnerability of the serotonin system accompanied by anxiety symptoms.

At high levels, it can actually look like serotonin syndrome (too much serotonin -very dangerous):

Therefore, marijuana toxicity should be considered in ED patients who present with signs and symptoms similar to that of serotonin syndrome.

Serotonin syndrome may speak to a freakout caused not so much by long term use (slow whittling) but to taking in too much THC in one setting (greening out).

They're seeing lots of that in ERs these days where cannabis is legal and/or much more potent.

Edibles are a big driver of this trend.

The main driver:

THC may activate serotonin receptors and inhibit serotonin reuptake, its abuse in high concentrations may mimic serotonin syndrome

So…short term, it's like a giant SSRI with the rebound expected when serotonin is exhausted.

Longer term though….watch what happens.

First, the mechanism:

THC can thereby mediate dopaminergic and serotonergic neurotransmission


Okay…so THC drives dopamine and serotonin activity.

But chronic use?

THC‐induced striatal dopamine release appears blunted in dependent users

Blunted.  The brain doesn't like the firehose of CB1 activity and will actually ratchet it down just like the volume (or better yet…equalizer) on a stereo (I date myself).


People...dopamine is your "verve" pathway.


This means your natural feel-good pathway (anandamide) and mood manager and drive manager are slowly losing volume in the brain.

People…this is your main line of defense against stress!  

At some point, you're just using cannabis to not feel terrible (as opposed to feeling high or really good).

Roughly 9% of people who use THC get addicted but probably 100% will feel the tolerance with longer term use.

Two different types of suffering really with pure addiction leaning heavily on the dopamine system.


Later, we'll look at ways to naturally support serotonin, dopamine, and anandamide.


Let's turn to actual brain areas now.  We'll zero in on tied to mood freakouts.

THC and hippocampus for stress response

Mood's a complicated thing but if there's one brain area with direct control, it's the hippocampus.

Part of our older "reptilian" brain, this area is in charge of both memory (THC impairs) and…mood control.

Analyzing the situation and deciding on how to respond.  

"Everything's going to be okay or….Freak the #%)& out!"

We're going to hit just fascinating highlights (of many).

The hippocampus, located in the medial temporal lobe and connected with the amygdala that controls emotional memory recalling and regulation

Okay…emotional regulation.  The opposite of losing your shit.

Here's the problem…the hippocampus is one of the most vulnerable areas to many assaults in the brain:

  • Inflammation
  • Stress
  • Infection
  • Trauma
  • Chemicals
  • THC!

The memory side of its job description makes it very malleable…able to change all day long.  This same flexibility makes it subject to damage from the list above.

THC specifically (but with a silver lining):

We confirmed that hippocampal volume is reduced in long-term cannabis users, and found that this atrophy can be restored following prolonged abstinence.

Lower volume = poorer mood control:

Difficulties with emotion regulation, increased amygdala reactivity to threat, and smaller hippocampal and amygdala volume are among the psychological and neural mechanisms that may increase vulnerability for internalizing problems in children and adolescents in response to stressful life events

"In response to stressful life events."

People…THC is not the way longer term for mental health.  

We're not even looking at the prefrontal cortex which keeps our fears and impulses at bay:

Frequent cannabis use was associated with reduced gyrification in prefrontal subregions.

Or…the white matter tracts that link all brain areas so we can think cohesively:

This white matter damage was significantly greater among heavy users of high potency cannabis than in occasional or low potency users, and was also independent of the presence of a psychotic disorder

Longer term, tolerance is the enemy of most medications and THC.

So…what to do?

How to support these pathways without tolerance

Some people are just drawn to THC.  From the get-go…it hits "the spot".

That "spot" is what we want to focus on.

There can be chemical and genetic differences surrounding the endocannabinoid system but our money is on the past.

Past trauma, stress, and infection.


Here's the secret code that we're all walking around with inside of us.

Early stress, trauma, and or infection (even in utero or past generations) can directly affect all these pathways and how we respond to…stress!


Early life stress has been associated with emotional dysregulations and altered architecture of limbic-prefrontal brain systems engaged in emotional processing. Serotonin regulates both, developmental and experience-dependent neuroplasticity in these circuits.

And anandamide (probably exhausted from serotonin running low):

Specifically, exposure to early stress results in bidirectional changes in anandamide and 2-AG tissue levels within the amygdala and hippocampus and reduces hippocampal endocannabinoid function at puberty.

Goodness.  We have deep dives into how much of this resides in the immune system and how to edit it out here


The brain's a prediction machine and it doesn't like being surprised…again, so vigilance gets built into the system.

We looked at this process in detail in our Is THC use tied to excess glutamate?

The best set of tools we can find that don't build tolerance can be found at our Tapering THC Tips guide.


A quick primer.

How to taper THC or find a healthy relationship with it



First, you have to address the original sin above (the priming).

This means focusing on the immune system where past misdeeds are recorded.

When they looked at the long term effects of psilocybin, it was due to changes in the epigenome (genetic recorder) in…the immune system!

If psilocybin is not ready for prime-time (it's coming!!) the medicinal mushrooms are interesting there.

Interestingly, there's a lot of overlap between our Tapering SSRIs and Tapering THC (go figure…hello Serotonin).

Most importantly, these don't build tolerance which is what got us into the freakout mess with THC to begin with.

Of course, we found all this due to the relationship of CBD and THC.

The original meaning of "the entourage effect" was how CBD would counter many of the negatives of THC.

You see it all over the research such as:

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.

People…that's the hippocampus!

Acutely administered, CBD exerts opposing effects to THC upon activation of specific brain regions, including the hippocampus,26 and ameliorates the induction of hippocampal-dependent cognitive impairment and psychotic-like symptoms by THC in healthy volunteers


Remember, this is where structural damage (loss of volume) occurs in the brain from THC longer term. 


And serotonin:

Overall, repeated treatment with low-dose CBD induces analgesia predominantly through TRPV1 activation, reduces anxiety through 5-HT1A receptor activation, and rescues impaired 5-HT neurotransmission under neuropathic pain conditions.

The key word there?   "Rescues impaired 5-HT"

5-HT is code for serotonin. We have a big review on CBD and serotonin here or how CBD protects the brain from THC.

It's definitely in the toolkit you can find at our Tapering THC Guide.

Again…sorry.  We want it to work longer term as well but we get emails all the time from people who find themselves blowing up on our significant others, coworkers, kids, or parents.  

Now you know why.

Lots of bad news above.  Brain structure?

Let's wrap on a positive note.

Good news with abstinence

Did you catch that last note in one of the dire study results?

We confirmed that hippocampal volume is reduced in long-term cannabis users, and found that this atrophy can be restored following prolonged abstinence.

Long-term cannabis users.  And then…

"Atrophy can be restored following prolonged abstinence"

Atrophy literally means brain shrinkage.  Structural volume reduction!  Of the brain!

We see this across many studies and here's the net net.

After about 30 days of abstinence, the CB1 receptors will start to come back online.  In fact, many of the deficits from long term THC use can revert.  

This is amazing.  And very hopeful.  Check out the tapering article!

Just a side note…starting as an adolescent and/or consuming massive amounts of cannabis may make this repair piece harder.  Longer.   

The key to support neurogenesis and we have a whole review on that here.


Related Research

CBD and performance anxiety

The ridiculous guide to CBD and anxiety

CBD and stress response


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