Scientists Identify Brain Cells That May Explain Why Cannabis Triggers Anxiety

Cannabis is famous for making people feel relaxed, amused, and even elated, but sometimes it can have almost the opposite effect.

In some cases, cannabis use can trigger feelings of anxiety, panic, and paranoia, and there’s evidence to suggest that ongoing use could lead to mood and anxiety disorders.

Now, a new study published in Nature Communications may have identified why the drug fuels such negative and intense reactions.

“The results of this study could explain why a good trip can turn bad pretty quickly if people consume too much cannabis,” says psychiatric neuroscientist and senior author Sachin Patel from Northwestern University, “or the situation they are in turns stressful or scary.”

Before now, scientists knew that cannabinoids, including tetrahydrocannabinol (THC), strongly affect the central amygdala (CeA), which helps to control anxiety, stress responses, and emotional behaviors.

One of the ways cannabinoids might affect the amygdala is by activating neurons in the CeA that produce a neuropeptide called somatostatin (SOM), which helps regulate stress responses.

In the context of rodent experiments, this can be seen in various threat-reactivity behaviors, including avoidance of threats and freezing in response to threats.

The activation of CeA SOM neurons may also explain why cannabis can trigger feelings of anxiety, but there’s still a lot we don’t know about how cannabinoids interact with CeA SOM neurons.

To explore the relationship further, Patel’s team conducted an experiment with mice, giving the animals a potent synthetic cannabinoid called CP 55,940, and then exposing them to a synthetic predator odor similar to a compound found in fox poop.

Upon exposure to the predator odor, the mice displayed defensive behaviors, including slowing down and freezing.

But compared to mice that received only a placebo, animals given the cannabinoid froze more and spent less time near the source of the smell, with the effects increasing at higher doses.

Small microscopes implanted in the mice’s brains during the experiment revealed higher activation of CeA SOM neurons in mice given the cannabinoid, and the effect was dose-dependent, with a higher dose of CP 55,940 leading to more SOM neuron activity.

In a separate experiment, the researchers blocked the usual behavior of SOM neurons by injecting genetically engineered mice with a virus carrying a toxin that inhibits their synaptic output. This prevented the release of neurotransmitters when the neurons were activated.

When these engineered mice were given the cannabinoid and were exposed to the predator odor, they no longer avoided the predator scent to the same extent, suggesting their heightened anxiety-like response to the threat had been partially quelled.

The researchers liken the situation to a car’s brake. In its natural state, the brain regulates the activity of SOM neurons, but when cannabinoids enter the equation, the brake loosens, and its ability to control anxiety gets away from us.

“Higher doses of cannabinoids and environmental stress worked together to synergistically release the ‘brake’ on the central amygdala, which in turn drove excessive anxiety,” Patel says.

It’s worth noting that so far we’ve only seen this brain circuit operating like this in mice, but if future research can demonstrate the same mechanism takes place in human brains – and we can find a way to mitigate the stress responses activated – it could point to new ways to manage people’s anxiety, whether arising from drug use or in other scenarios too.

“Understanding how cannabis affects brain function to generate its psychoactive effects could ultimately reveal new ways to counteract negative consequences should they arise in some people,” Patel says.

“Suppressing the activity of somatostatin neurons in the central amygdala could represent a final pathway for reducing anxiety symptoms, not just in the context of cannabis side effects.”

The findings are reported in Nature Communications.