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Research suggests that cannabis may cause anxiety when it is strong enough or taken in large enough quantity to produce an immediate effect

Cannabis is an increasingly common drug, with�� in 2024 in the United States alone, according to Statista—more than double the amount in 2010. Despite this, its effects are not well understood. For example, some people use cannabis for relief from anxiety, but there is also evidence that it can cause or worsen anxiety depending on the individual, how much is taken and other factors.

Determining what effect cannabis has on anxiety requires a better understanding of how it affects the endocannabinoid system. To this end, researchers from CUChange (Center for Health and Neuroscience, Genes and Environment), including��Renée Martin-Willett,��Carillon Skrzynski,��Ethan Taylor ���Ի���Cinnamon Bidwell, with assistance from Jost Klawitter and Cristina Sempio of the University of Colorado Anschutz, that occurred when people with anxiety took different cannabis products.

Endocannabinoids

The endocannabinoid system is a biological system that extends throughout the whole body. “It’s not just in our brains,” Martin-Willett says; “it’s also in the peripheral nervous system, which is just a fancy way of saying it’s all over the body.”

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Renée Martin-Willett (left) and Carillon Skrzynski (right), along with their CUChange research colleagues, assessed the biochemical changes that occurred when people with anxiety took different cannabis products.

The system uses two receptors: CB1 and CB2. In biology, receptors are chemical structures that contribute to a biological effect when they bind with compatible chemical messengers. Whether a receptor and messenger will be able to bind depends on their structure, similar to a lock and key, except that the structure is chemical. When a messenger binds to a receptor and the receptor uses the signal (by relaying or amplifying it, for example), the messenger is considered an agonist—as opposed to an antagonist, which is like a key that fits in a lock but, instead of opening that lock, prevents the correct key from being inserted.

Unlike keys, which either work or do not, chemical messengers can have effects of different strength. For example, THC (delta 9-tetrahydrocannabinol), the main psychoactive component of cannabis, is only a partial agonist of CB1. According to Martin-Willett, CB1 is mostly concentrated in the brain, whereas CB2 is mostly in the gut. The other main component of cannabis is CBD (cannabidiol), which modulates CB1 and CB2, making the effects they produce when activated by agonists weaker without preventing agonists from binding to the receptors.

These chemicals act on the endocannabinoid system because they have chemical structures like endocannabinoids, which are neurotransmitters that are produced by the human body. The two most-studied endocannabinoids are AEA (N-arachidonoyl ethanolamide) and 2-AG (2-arachidonoylglycerol), and they are the focus of this study for that reason.

“2-AG has a really high concentration, and it’s mostly in the brain,” Martin-Willett explains. “It binds with CB1. Then AEA, which has much lower concentrations, is more in the periphery. It’s implicated in implantation and the hormonal cycle for women and is increasingly being linked to anxiety and other kinds of mood disorders.” AEA is associated with positive feelings, and the receptors it binds with, CB1 and CB2, are thought to play a role in whether people view their environment in a positive or negative way. Therefore, AEA may ameliorate feelings of anxiety.

Although some simple facts about the endocannabinoid system are understood, many details remain unexplained. In particular, there is a question as to the effect of cannabis on the endocannabinoid system. This includes how THC and CBD may affect the concentration of AEA and 2-AG in the body, which has implications for what effect cannabis has on anxiety and other aspects of people’s mental state. “Sometimes I tell people the endocannabinoid system is like the Mariana Trench of biomedicine,” Martin-Willett says, “because it was only really discovered in the mid-‘90s. How did we not know about this entire, full-body system until the ‘90s?”

The study

Because this study was intended to determine the effect of cannabis use on anxiety, the participants all had scores on the GAD-7 (generalized anxiety disorder) screener that indicated at least mild anxiety. The participants were split up into four groups: one-fourth of the participants were in the control group (meaning they did not use any cannabis), one-fourth used THC-dominant products, one-fourth used CBD-dominant products and one-fourth used products that combined THC and CBD in a 1:1 ratio.

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Some people use cannabis for relief from anxiety, but there is also evidence that it can cause or worsen anxiety depending on the individual, how much is taken and other factors. (Photo: Unsplash)

The study found that the people in the THC-dominant and 1:1 groups had higher AEA levels than those in the control group when cannabis was taken during an acute administration session (meaning in a single dose that is strong enough to produce an immediate effect as opposed to administration over the course of weeks). These results are consistent with the hypothesis that the effects of THC on AEA are caused by competitive binding between the two chemicals at CB1.

“THC might affect AEA in a couple of different ways,” Martin-Willett explains. “THC will bind to CB1 in a ‘normal’ way at the synapse, but it will also permeate the lipid bilayer of the cell itself. The results from our paper support that first idea that THC is competitively binding with AEA at CB1. It is kind of fighting AEA to bind and winning more often than AEA is.”

The basic idea is that whenever THC binds to a receptor, it takes away an opportunity for AEA to bind, causing fewer receptors to be activated by AEA. Even though THC and AEA are both partial agonists of CB1, it is possible that the effects they create upon binding are different. “One idea,” Martin-Willett continues, “is if more AEA makes you less anxious, and in the moment, THC binds competitively with CB1 and keeps AEA from interacting, maybe that is contributing to the paranoia or anxiety after acute use of THC. That is speculative, though. We do not have good human studies on that yet.”

2-AG levels did not change when administered acutely. This could be because 2-AG has higher concentrations in the human body than AEA, making the consequences of introducing THC less significant in the short term. However, in the THC-dominant group, it increased from baseline after two weeks before decreasing to reach a near-baseline level by week four. While AEA is thought to be associated with positive feelings, the association between 2-AG is mostly unknown.

Catching up with the market

Since the Controlled Substances Act of 1971, cannabis has been classified as a Schedule I drug in the United States, which means that it faces special restrictions on the federal level. That may change soon because of the Department of Health and Human Services’ 2023 recommendation that cannabis be reclassified as a Schedule III drug and because of President Trump’s 2025 executive order on the subject. Despite this, and even in states where cannabis has been legalized, the current classification puts limits on studies like this one.

For example, second author Carillon Skrzynski says, “In a lot of our studies, we are not allowed to tell people how much to use, or what to use in some circumstances. That really puts a damper on any kind of causal conclusion.” Ordinarily, scientists keep all variables that could affect the phenomenon they want to understand constant except for one, called the independent variable, which they vary in a controlled manner. This makes the relationship between the independent variable and the phenomenon clear. If multiple variables change at the same time, it becomes almost impossible to say how much each variable contributes to the phenomenon, or even if they would have an effect individually.

“I think there are two really exciting areas that the field needs to move towards,” Martin-Willett adds. “Number one, we need to account for age. We know that the endocannabinoid system changes a lot when we get older. People talk about reduced tone, which just means you have fewer receptors, but we do not really know what that means—if it has a greater effect or a lower effect. And I think the other piece of it is sex assigned at birth. Like I mentioned, more and more the endocannabinoid system is being viewed like the endocrine system, or like the hormonal system, and these things are intertwined, especially AEA and the reproductive system.”

Martin-Willett and Skrzynski both plan to look into these areas. Additionally, their center, CUChange, has multiple studies running and is actively looking for research participants. That is important not only because the different effects of cannabis are unknown, but because it is already being used on a large scale. “A lot of this is really unregulated right now,” Martin-Willett says, “and I think the market is way ahead of the science. People are already using cannabinoids for anxiety, for sleep, for pain, for other kinds of mood problems, and so they can make their voices heard to the government, that this is someplace they want research money to go.”

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