The THC & Anxiety Connection
By Keera Lindenburg, Educational Director of Lightscale Labs
You know when you’re having a hard day, and there’s a global pandemic raging, and then you smoke... and it makes you EVEN MORE ANXIOUS?
Turns out, the regions of your brain that THC acts on to make you calm and euphoric are the same areas that can flip the switch and send you into freak-out mode. The emotional state your brain experiences is very much dependent on just how much THC is in your system.
THE FEAR CIRCUIT
Even when you’re not consuming THC, there are three parts of your brain that are constantly communicating to decide if you are in danger: the Amygdala, the Hippocampus, and the Prefrontal Cortex. Together, these cerebral sections are sometimes known as the ‘Fear Circuit.’ [1]
When your sensory organs detect something threatening, like the sound of a lion’s roar or the sight of an angry person coming towards you, that information is first sent to the Amygdala for assessment. The Amygdala determines how much danger is present, and therefore how much of a panic signal to send to the rest of the brain.
Then, the Hippocampus assigns logical context to the thing causing panic, as in: “that’s the roar of a lion, and it wants to eat me.” This message is then sent to the Prefrontal Cortex, which is responsible for decision-making and planning. This area of ‘Executive Control’ decides what action to take in response to the lion-trying-to-eat-you situation: maybe you run, maybe you fight, maybe you just lay on the ground and cry.
Together, the Amygdala, Hippocampus, and Prefrontal Cortex work together to decide if a threat exists, how big the threat really is, and how your body should respond.
Because all three of these fear-managing brain regions contain a ton of ‘CB1’ receptors, where THC loves to attach, researchers in Italy decided to test how cannabis affects them. When they injected isolated THC directly into the amygdala (in mice, people, it's always in mice) they found that even very low doses caused it to produce an anxiety signal. [2]
A British study then indicated that THC seems to work in a similar way in humans. (Male humans, at least — cannabis’ effects on women’s bodies are grossly understudied, but that’s a topic for another article.) Fourteen volunteers underwent PET scans of their brains to discover the density of CB1 receptors in their amygdalas. The participants then took oral doses of THC, and completed fear-processing tasks such as answering questions about people that looked angry or scared. Turns out, the more CB1 receptors they had for THC to attach to, the more anxiety they felt during these tasks, indicating that THC likely contributes to the amygdala’s fear response. [3]
These findings may not fit with the usual experience of a cannabis consumer — most smokers will attest that ingesting small amounts of THC rarely gives them anxiety. But there’s a reason for that: at those low doses, the Hippocampus and Prefrontal Cortex can suppress the Amygdala’s fear signals. These brain regions can rationally assess that there is no threat present, and that roar you heard was just part of a Ratatat song. On top of that, in the previous study, low concentrations of THC injected directly into the Hippocampus and PFC seemed to have a calming effect on those mice. [2]
But, here’s the kicker: when you ramp the dosage of THC up to a certain level the Hippocampus and Prefrontal Cortex also flip into anxiety mode. (And that threshold varies depending on the individual.) At that point, good luck quelling your paranoia when all three parts of the fear-circuit are in agreement that they have every reason to be afraid.
GABA VS. GLUTAMATE
To understand what causes the Hippocampus and Prefrontal Cortex to suddenly give in to cannabis anxiety, we have to zoom in, down to the microscopic level.
What we think of as “the brain” is really a big collection of long, gangly cells called neurons. They spend all day passing messages back and forth to each other, using molecules called ‘neurotransmitters,’ in much the same way that humans use postcards.
Different neurotransmitters are used to send different messages, but also, their density and the frequency at which they’re pumped out can tweak that message. In many parts of the brain, an excited neuron sending rapid clusters of neurotransmitters means “something big is happening, wake up and pay attention!” The feeling of certain neurons getting over-excited, or engaging very suddenly, is what we would call Anxiety. [4]
Each neuron receives a message from the cell(s) behind it, and that helps determine which neurotransmitters it will send to the cell(s) in front of it. Let’s say you have a neuron that communicates via Noradrenaline, the cousin of regular Adrenaline. While its “sending” side is spitting out various amounts of Noradrenaline, its “receiving” side is being fed by two different neurons: one that communicates with a molecule called Glutamate, and another that uses a molecule called GABA.
Glutamate and GABA (G+G) behave much like traffic signals: Glutamate is the green light that tells the neuron to release more Noradrenaline, while GABA acts as the red light, restraining neurotransmitter release. If the Noradrenaline-releasing neuron receives a GABA molecule, it means, “You can calm down.” However, if the neuron receives Glutamate, it means, “Okay, freak out now, dispense all the Noradrenaline.”
A brain cell delivers Neurotransmitters (either GABA or Glutamate) to another brain cell. When THC attaches to the Cannabinoid Receptor (CB1) it will alter the speed or amount of Neurotransmitters the cell releases. The receiving cell will then alter the amount of Noradrenaline it sends to the next cell in the line (not shown.)
Both the GABA and the Glutamate-releasing neurons possess CB1 receptors — those docking stations with an affinity for THC. When THC attaches to one of these neurons, it calms down their communication, by telling them NOT to send out their neurotransmitter molecules (whether that be GABA or Glutamate.) [5]
The current consensus among researchers is that, in all probability, CB1 receptors on Glutamate-delivering neurons are easier for THC to latch to. That would mean that, even at low doses, THC suppresses Glutamate, therefore suppressing Noradrenaline (or whatever neurotransmitter the cell uses) and therefore suppressing anxiety. However, when more THC is present in the body, it also starts to suppress GABA, which was the molecule keeping anxiety in check. So more THC means… welcome back, panic attack.
THE NERVOUS SYSTEM
Let’s examine THC’s relationship with Noradrenaline a little further. Just as its name suggests, Noradrenaline’s function in your body is similar to Adrenaline’s: it increases your heart rate, dilates your eyes, and sharpens your mind. In other words, it works on your sympathetic nervous system to ready you for fighting or flight-ing from the lion that was chasing you a few paragraphs ago. For most (lucky) people, the decreased production of Noradrenaline caused by THC (through the intermediary GABA) is one of the ways that cannabis makes them feel calm and serene. [8]
But for some (unlucky) people, the sudden drop in Noradrenaline can cause a backlash in the sympathetic nervous system, which feels like a big heap of anxiety. An area of your brain called the Locus Coeruleus is responsible for pumping out more Noradrenaline when the levels in your bloodstream get low.
Occasionally, when the Locus Coeruleus notices the sudden and unusual dip in Noradrenaline caused by cannabis, it can set off alarm bells that something is very wrong in your body. This kicks your sympathetic nervous system into overdrive, so you have the energy and focus to save yourself from whatever Noradrenaline-sucking monster the Locus Coeruleus thinks you’re battling.
This is why your heart starts beating faster, your eyes dilate, and your brain starts releasing Cortisol, the stress hormone. All those changes in your body combine to make you feel, well, the exact opposite of calm and serene.
THE REWARD PATHWAY
Another neurotransmitter that’s influenced by cannabis, and the reason why smoking makes you feel ‘high,’ is Dopamine. THC in the brain causes the release of extra Dopamine, which is responsible for motivation, sexual arousal, and the feeling of reward (among other things). Dopamine levels increase when you smoke for the same reason that Noradrenaline levels decrease: the ratio of GABA to Glutamate molecules has been changed.
Doctors have long known that the presence of Dopamine in certain sections of the brain, such as the Ventral Tegmental Area, makes us humans feel great — as if we just ate chocolate cake, or won the lottery, or fell in love. The theory is that when you do something that ends up being beneficial to your survival, like eating a lot of calories, your brain releases Dopamine to help you associate that action with positive feelings. That way you’re more likely to complete the same action again.
According to recent research, it seems that Dopamine also plays a role in another type of survival tactic: perceiving and responding to danger. [6] When processing fear, or scary stimuli like loud noises or threatening images, dopamine tends to show up in our old friend, the Prefrontal Cortex of the brain. One main function of the PFC is to route information to other parts of the brain, based on the situation: if the PFC is happy, neural signals follow one path, If it's scared, they follow another path. And Dopamine plays some part in flipping the track.
Researchers found that when they presented rats with two different stimuli simultaneously — one that would make them happy, and one that would make them scared — the rats had trouble deciding which response to have. When the scientists supplemented the rats’ brains with excess dopamine, the rats almost always chose the fear response. That indicates that Dopamine may heighten the frequency at which neural signals are sent down the “fear” path. The theory is that the PFC sends out a "reward" signal for being attentive and responsive in the face of danger.
Occasionally though, excess Dopamine can cause your brain to be too responsive to scary stimuli. Negative inputs are weighed too highly, and the “fear” path is too active. This can lead to anxiety or paranoia, as is common among people with schizophrenia… or those who have just smoked a whole boat-load of cannabis.
MOOD MODULATORS
But wait, there’s more.
You’ve probably heard that Serotonin plays an important role in your ability to feel happy and regulate emotions. That’s in part because it acts on both of those same neurotransmitters that THC regulates: Glutamate and GABA.
Within the ‘Fear Circuit,’ many of the neurons that communicate via G+G were found to possess both ‘CB1’ receptors for THC, and ‘5-HT’ receptors for Serotonin. That means each of those molecules is individually capable of suppressing Glutamate, and therefore anxiety. It ALSO means that the calming effects of THC and Serotonin can be compounded. [7]
What’s more, it was recently discovered that CB1 receptors and 5-HT receptors can pop up in the same place on the same neuron, to create a SUPER-RECEPTOR. Activation of this frankenstein attachment site has an entirely different effect on the release of GABA and Glutamate, separate from either THC or Serotonin working alone.
Recent research suggests that something about the THC+Serotonin tag team is responsible for the effects that cannabis can have on anxiety. Scientists found that when they treated mice with small amounts of THC, the rodents were less nervous and more inclined towards social interaction, as they expected. However, mice who were missing 5HT receptors in their brains, and therefore could not accept or register Serotonin, did not experience the same anxiety relief. Even though the THC was still binding to CB1 receptors, it seems that the suppression of Glutamate might require THC and Serotonin to act on the same neuron, at the same time.
Interestingly, the mice lacking 5-HT receptors didn’t seem to be any more anxious than they were before being given THC. We can take this to mean that, most likely, THC+Serotonin Super-Receptors play a role in alleviating anxiety, but (luckily) not in causing it.
THE PERFECT DOSE
So what is the magic amount of THC that will calm you down but not induce paranoia? Like most medicines, the appropriate dose is probably dependent on your physical traits, genetic makeup, and, in this case, the density of CB1 receptors in your body. It's also not inconceivable that cannabis-induced panic would be influenced by someone’s tendency towards general anxiety, or traumas and disorders that change the sensitivity of their ‘Fear Circuit.’
Like most of the effects smoking cannabis has on the body, we may not fully understand the connection between THC and anxiety until much more medical research is done — this time, on humans.
REFERENCES
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Bhattacharyya, S., Egerton, A., Kim, E. et al. Acute induction of anxiety in humans by delta-9-tetrahydrocannabinol related to amygdalar cannabinoid-1 (CB1) receptors. Sci Rep 7, 15025 (2017). https://doi.org/10.1038/s41598-017-14203-4 - link
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Trafton, Anne. “Dopamine Primes the Brain for Enhanced Vigilance.” MIT News, 7 Nov. 2018, news.mit.edu/2018/dopamine-brain-vigilance-anxiety-1107. - link
Viñals X, Moreno E, Lanfumey L, et al. Cognitive Impairment Induced by Delta9-tetrahydrocannabinol Occurs through Heteromers between Cannabinoid CB1 and Serotonin 5-HT2A Receptors. PLoS Biol. 2015;13(7):e1002194. Published 2015 Jul 9. - link
Weiss, Suzannah. “This Is Why Weed Makes Some People Anxious.” Vice, 6 Feb. 2018, www.vice.com/en_us/article/gy8pa9/weed-causes-anxiety-for-some-people. - link
“How THC Can Both Cause and Reduce Anxiety.” Prof of Pot, 21 Jan. 2018, profofpot.com/thc-anxiety. - link
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