Why does weed cause anxiety? A new brain study investigates cannabis paranoia

Whether you are smoking or eating it, marijuana can be relaxing—or it can cause feelings of anxiety, panic and paranoia. But despite the prevalence of these unnerving experiences—studies suggest frequent cannabis use is associated with higher odds of anxiety—scientists have little understanding as to why they occur.

“From a biological perspective, we really know almost nothing,” says Sachin Patel, a neuroscientist at Northwestern University.

In a bid to understand why one of the world’s most popular drugs summons such negative emotions, Patel and his colleagues investigated its effect on mice. The team’s findings, published last week in Nature Communications, reveal that, when given such a drug, rodents suffer adverse reactions similar to the paranoia human cannabis users feel. The effect is driven by a specific group of neurons in the central amygdala, a brain region that processes fear and anxiety.

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The researchers injected mice with varying doses of CP55940, a synthetic cannabinoid that mimics the effects of tetrahydrocannabinol, or TCH, the main psychoactive compound in weed. Then they placed the mice in a cage with a petri dish full of fox urine. As expected, the animals became anxious, either fleeing the threatening odor or freezing in place. These responses were more extreme in mice who received larger doses—a relatable result if you’ve ever found yourself peering suspiciously through the living room blinds after one toke too many.

To tease out a connection between the animals’ behavior and their brain activity, the researchers turned to the central amygdala, which past research has shown to play a role in threat responses. Looking through small microscopes implanted in the mice’s heads, Patel’s team zoomed in on a particular subset of brain cells, called somatostatin neurons, as the animals reacted to the fox urine scent. “The take-home,” Patel says, “was that those cells were hyperactive when combining cannabinoids with the stress exposure.”

The researchers found that cannabinoids suppress the release of a neurotransmitter called gamma-aminobutyric acid, or GABA, which tamps down brain activity. In other words, the drug essentially weakens the central amygdala’s “brake,” Patel says, allowing fear and anxiety to run wild. When the researchers silenced the somatostatin neurons, the mice stopped trying so hard to avoid the threatening odor in their midst.

“This elegantly demonstrates a causal role,” says Ozge Gunduz-Cinar, a neuroscientist at the U.S. National Institute on Alcohol Abuse and Alcoholism, who was not involved in the study. She notes, however, that the researchers “examined only a single inhibitory cell type in a single brain region using an innate fear model,” suggesting there may be more to this story.

Humans are not mice, so it is unclear whether our own cannabis-induced anxiety arises in the exact same way. But Patel suspects a similar mechanism, given that stoned mice exhibit a pattern of behavior that might feel familiar to anyone who’s overdone it on edibles. “The fact that we can mimic that behavioral response in animals quite nicely makes me think that the neural data we have has some relevance to what’s probably going on in humans,” he says.

Human relevance might be difficult to prove, though. You could hypothetically get someone high, put them in a brain scanner, make them stare at pictures of scary faces and then look to see how their brain activity changes as dread wells up inside them—but that wouldn’t be very kind. “It’s a little difficult from an ethical perspective,” Patel acknowledges. Still, he believes that a deeper understanding of how marijuana affects the brain could produce new ways to counteract a bad trip.