Susceptibility to THC-Induced Anxiety is Affected by CB1 Receptors in the Brain

Anxiety disorders are among the most common mental health conditions in the United States. According to the Anxiety and Depression Association of America, 40 million adults suffer from some form of anxiety disorder. Increasingly, medical cannabis is being prescribed to treat these conditions. Different strains can have different palliative effects, based on the balance of THC and CBD. However, not everyone will react to the same strain in the same way; where one person may find great relief, another may actually experience more intense symptoms. This is due to differences in individual brain structure and function, though it isn’t clear which differences have the most impact. Recent research from King’s College London has shed some light on this question, using the tools of neuroimaging to understand what’s happening in the brain of someone undergoing THC-induced anxiety.

This work was motivated by two previous studies with partially contradictory results. In one study, it was shown that low-to-moderate doses of Δ9-THC, the main psychoactive ingredient in cannabis, had the ability to reduce anxiety in rats who were in a threatening environment. In another study, it was shown that high doses were able to prompt episodes of acute anxiety in humans. Both groups showed that these effects, while opposite in nature, were due to the action of THC in the amygdala, the part of the brain that processes anxiety and fear. The cannabidiol receptor CB1 is found throughout the brain, including the amygdala, and is activated by THC. Therefore, this group set out to determine how high-dose THC affects anxiety in humans, and how CB1 receptor density in the amygdala alters that effect.


The research group found a group of fourteen healthy, male volunteers for this study. All participants were in their mid- to late-twenties, had no history of psychiatric illness, and limited illicit drug use. All of the volunteers had at least one experience with recreational cannabis, but none of them were habitual cannabis users. Half of the subjects were given 10mg of pure THC in pill form, while the others were given a placebo. This was a double-blind study, so neither the subject nor the researchers knew which dose each subject had received. A clinician used two different questionnaires to determine the anxiety levels of each subject, and also drew blood to test for the presence of THC and its metabolites; this was repeated once an hour for four hours. Two hours into the test, the THC group experienced significantly increased levels of anxiety, demonstrating the detrimental effects of high-dose THC.

why marijuana makes you paranoidOne hour after dosing, the volunteers were placed in an fMRI, a neuroimaging device that detects local changes in brain activity, and given a task to perform. Subjects were shown various faces for two seconds at a time, and asked to determine the person’s gender, pressing one button for male, another for female. To simulate a threatening environment, and thus measure the response to anxiety, half of the faces shown were of people being scared, while the other half had neutral expressions. The fMRI results showed increased amygdala activity in the THC group while processing fear compared to the placebo group. Using a device similar to a lie detector, the researchers measured emotional responses to each face, and found that the THC group reacted more strongly to neutral faces than scared ones. This suggests that, even though high-doses of THC can cause anxiety, it may still be helpful in combating further stress.

The results of the above tests varied widely from person to person. In order to assess the cause of these differences, the researchers used a second neuroimaging technique, a PET scan, to assess CB1 density in the volunteer’s brains. Each subject was fed a mildly radioactive tracer that interacts with CB1. When CB1 processes the tracer, radioactivity is released and detected by the scanner, revealing regions of high and low CB1 density. The researchers found that, in general, the subjects that had the strongest reactions to THC had higher CB1 density in the amygdala.


This paper presents the first evidence that the number of CB1 receptors in the amygdala affects THC-induced anxiety. The number of CB1 receptors is determined primarily by a person’s genetic makeup; therefore, this is one potential mechanism to explain why different people have different experiences with cannabis. As we learn more about the genes that regulate the endocannabinoid system in humans, we may be able to predict how a person will react to cannabis based on their genetics.

The authors note that while this is one determinant of a person’s response to THC, there are many other factors to consider, such as route of administration, strength of dose, and the presence of mitigating factors like CBD. Also, these results may not be applicable to women or long-term cannabis users, as only males with limited cannabis experience took part in the study. Finally, there were only seven volunteers per group, which means that some of their results were not statistically significant. While this study does point to interesting trends, more research must be done to make definitive statements about CB1 receptor density in the amygdala and its relationship to anxiety.

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