THC’s effect on anxiety completely depends on the dose. Here is how low-dose THC reduces anxiety but too much can increase it.

The main receptor for THC, the cannabinoid CB1 receptor, is very important for emotions. It is highly expressed in various brain regions that regulate emotional response (stress, anxiety, depression, etc.)  Chronic blockade of CB1 receptors with rimonabant caused anxiety in many people. These results suggest that the CB1 receptor has a role in reducing anxiety.

But wait, things are about to get complicated.  There is extensive evidence that although low-dose THC is anxiolytic (reduces anxiety), high-dose THC is anxiogenic (increases anxiety). Just one recent example is a 2017 study showing that 7.5 mg of oral THC could reduce anxiety in a stressful situation, but 12.5 mg increased it.

But how can the same drug have completely opposite effects at different doses? Below, I will explain how the unique actions of THC in different brain regions make this possible.

 

Brain Areas Involved in THC Anxiety

The first thing to understand: the anxiolytic and anxiogenic effects of THC can arise from different areas of the brain. In fact, there are at least 3 distinct brain areas where THC activation of the CB1 receptor can affect anxiety:

  • Amygdala: An evolutionarily old part of the brain which processes sensory information and senses danger. These signals are sent to other parts of the brain for further processing.
  • Hippocampus: The hippocampus gives context to fear and anxiety signals (e.g. “am I in a safe place or a place where I am exposed to danger?”)
  • Prefrontal cortex (PFC): The PFC is a newer area of the brain which exerts “executive control” over emotions and behavior. When functioning properly, it can dampen anxiety signals sent by the amygdala.

These 3 brain areas are highly connected. Think of them like a circuit which integrates all available information to decide on a final response. However, different parts of your brain can literally be sending conflicting messages.

Imagine the level of anxiety and panic you would feel with a grizzly bear 5 feet in front of you in the wilderness. Now imagine the level of anxiety you would feel with that grizzly bear 5 feet in front of you, but inside a cage at a zoo. Your amygdala (which is a bit stupid on its own) doesn’t know the difference, but luckily the other parts of your brain do.

So how did scientists determine the role of various brain areas in THC modulation of anxiety? They microinjected THC into each of these brain areas in mice and measured their anxiety-like behavior:

Not surprisingly, THC in the amygdala generated an anxiety signal. This occurred even at very low doses. On the other hand, THC generated a biphasic response in the hippocampus and PFC – lower doses generated an anti-anxiety signal but higher doses increased anxiety.

So now that we understand the individual pieces, what is happening at the level of the whole circuit?

  • Low-dose THC: Although low-dose THC may generate an anxiety signal in the amygdala, this is probably suppressed by the anxiolytic effects in the hippocampus and PFC. In fact, an fMRI study showed that an anxiolytic dose of THC increased connectivity between the amygdala and cortex during signs of threat.
  • High-dose THC: At higher doses, all 3 brain regions are generating an anxiety signal. This explains why almost everyone will experience anxiety at a high enough THC dose.

But what THC dose will cause anxiety versus suppress anxiety in humans? This will be different for everyone. It can depend on your level of THC tolerance, current and past stress, sex, and (as I will describe below) your unique biology.  There is probably a strong genetic component, although it has not yet been elucidated.

 

How THC Generates an Anxiogenic Signal in the Amygdala

The anxiogenic response after delivering THC to the amygdala was blocked by a CB1 antagonist, indicating that it is not mediated through other THC receptors besides CB1.

But what exactly happens when THC activates the CB1 receptor in the amygdala? This initiates an intracellular signaling cascade leading to activation of a protein called mTORBlocking mTOR activation (with a drug called temsirolimus) was able to block the anxiogenic effects of THC. So mTOR is crucial to amygdala activation by THC and subsequent anxiety. In fact, the use of temsirolimus to block the anxiety of THC has even been patented.

Everyone responds to THC differently and some people are sensitive to THC-induced anxiety even at low doses. A recent 2017 study shed some light on this. Subjects with greater CB1 receptor availability in the right amygdala had greater amygdala activation and greater anxiety after a 10 mg oral dose of THC.  A strong enough THC-generated anxiety signal from the amygdala appears capable of overcoming moderation by other brain regions.

 

Different Doses of THC Change the Balance of GABA & Glutamate in the PFC

Mechanisms of THC reducing and increasing anxiety through GABA and glutamate

I still haven’t explained how different doses of THC can produce either an anxiolytic or an anxiogenic effect in brain regions such as the PFC and hippocampus. The answer may lie in the fact that THC can increase activation of the CB1 receptor  at lower concentrations in certain types of neurons.

Many of the anxiety-modulating signals in the brain converge onto two neurotransmitters: glutamate (excitatory, anxiety-generating) and GABA (inhibitory, anxiety-blocking).

THC can regulate glutamate and GABA release through activation of the CB1 receptor, which is present on both glutamatergic neurons and GABAergic neurons in the PFC.

It is hypothesized that CB1 receptors are more easily activated on glutamatergic neurons than on GABAergic neurons. So low doses of THC may only activate the CB1 receptors on glutamatergic neurons, which reduces glutamate and anxiety. At higher doses of THC, CB1 receptors on GABAergic neurons are activated. This reduces GABA release and ultimately increases glutamate levels and anxiety.

The next two sections will explain how this works in a little more depth.

 

THC Reduces Anxiety by Working With Serotonin Receptors

The serotonin system

Now let’s focus more on how THC can reduce glutamate levels (and thus anxiety).

Serotonin (5-HT) is an important regulator of emotions, including anxiety. Like endocannabinoids, serotonin can regulate both GABA and glutamate neurotransmission.

The 5-HT2A receptor is famous for being the target of hallucinogens, such as LSD and psilocybin, which themselves show an anxiolytic effect in low doses. The 5-HT2A receptor is expressed in most glutamatergic neurons in the PFC, but few GABAergic neurons. It is also found in the hippocampus.

A 2015 study showed that the anxiolytic effects of THC are mediated through this 5-HT2A receptor. In fact, the CB1 and 5-HT2A receptors bind together to form a “heterodimer“. Signaling from this CB1/5-HT2A heterodimer reduced anxiety and facilitated social interaction in mice. Unfortunately, some of the memory deficits from THC were also mediated through this heterodimer.

This heterodimer appears to be responsible for the reduction of glutamate levels in the PFC that is the basis for the anxiety-reducing effect of THC.

 

THC Increases Anxiety Via Decreased GABA 

Label of GABA(B) agonist baclofen

THC’s anxiogenic effect in the PFC ultimately comes down to a balance of GABA and glutamate. An anxiety-causing dose of THC to rats reduced GABA levels and boosted glutamate levels in the PFC.

Further studies revealed exactly how this happens. Glutamatergic neurons express the GABAB receptor presynaptically. Activation of the GABAB receptor inhibits glutamate release. Without sufficient GABA levels, glutamate release can be enhanced, resulting in anxiety.

A high enough dose of THC will increase CB1 receptor activation on GABAergic neurons, reducing GABA release. The reduced GABA levels can lead to higher glutamate release and anxiety.

In fact, an experimental GABAB positive allosteric modulator was able to reduce the anxiogenic effects of a CB1 agonist. Baclofen is an FDA-approved GABAB agonist (used as a muscle relaxant) that may similarly block THC-induced anxiety. Although these effects on anxiety have not been tested directly, baclofen boosted several positive effects of THC.

 

Summary of Why THC Both Causes and Reduces Anxiety

  • THC has different effects in different brain regions. In the amygdala, it causes anxiety at any dose. In the PFC and hippocampus, THC reduces anxiety at low doses, but increases anxiety at higher doses.
  • Effects of THC are linked to glutamate levels. THC reduces glutamate levels in the PFC at low doses and raises glutamate levels at high doses.
  • These opposite effects on glutamate may be due to THC inhibiting glutamate-releasing neurons at low doses, but inhibiting GABA-releasing neurons at higher doses.

 

[Featured image: Pixabay]

Last modified: January 21, 2018

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