Winter 2022

Research: The Endocannabinoid System and Fear/Anxiety

Researchers are looking to determine how CBD and THC influence anxiety.

Anxiety disorders are the most prevalent type of psychiatric disorder and are a leading cause of disability. Characterized by persistent feelings of excessive or unreasonable worry or fear, an anxiety disorder interferes with daily life enough to often require prescribed medications. However, pharmaceuticals may not be effective or may have adverse side effects in 40% to 60% of those prescribed them for anxiety treatment.1 For that reason, the phytocannabinoids CBD and THC are commonly used as self-medication to alleviate anxiety. Recent and ongoing scientific research is focused on determining the mechanism by which CBD and THC may act on anxiety in the endocannabinoid system.

“The endogenous cannabinoid—or endocannabinoid—system was only discovered about 30 years ago. We have known for thousands of years that exogenous cannabinoids, such as THC, can affect the brain and body. But it wasn’t until the 1990s that we discovered that the body makes its own cannabinoids,” says Hilary Marusak, PhD, an assistant professor of psychiatry and behavioral sciences at Wayne State University.

The endocannabinoid system is a complex cell signaling system consisting of endocannabinoids, receptors, and enzymes. Researchers have identified the following components2:

  • Two primary endocannabinoids that act as neuromodulators—anandamide and 2-arachidonoylglycerol (2-AG)—are located in the brain and the body’s nerve tissue. Several other endocannabinoids have been identified, but their functions are not yet fully understood.
  • Two primary receptors (CB1-R, CB2-R), which are cell proteins that bind and react with endocannabinoids, work to inhibit or promote nerve activity. CB1-R is located in the central nervous system, and CB2-R is located in the peripheral nervous system and immune cells.
  • Two nerve-cell enzymes that break down and recycle the endocannabinoids for nerve signal transmissions. Fatty acid amide hydrolase (FAAH) acts on anandamide and monoacylglycerol lipase (MAGL) acts on 2-AG.

The functioning of the endocannabinoid system isn’t yet fully understood, but research suggests that it’s involved in several of the body’s critical functions or reactions, including metabolism and digestion, pain sensation, inflammation, sleep, mood, memory, cardiovascular and musculoskeletal functioning, and stress.2

With regard to fear and anxiety, the endocannabinoid system can help regulate the part of the brain that responds to danger and fear—the amygdala. Consisting of pair of small oval areas located deep in each brain hemisphere, the amygdala can trigger the “fight or flight” response to fear and also links fear to memories. Research has shown that complex interactions between anandamide, 2-AG, MAGL, FAAH, and CB1-R modulate fear responses and fear extinction, and when certain components are enhanced or impaired, fear and anxiety may result, depending on endocannabinoid, enzyme, and receptor levels and activation.3

“The endocannabinoid system acts as a stress buffer,” Marusak says. “Disruption of the body’s endocannabinoid system, for example, by chronic stress or trauma, may inhibit its natural ability to respond to stress. Exogenous cannabinoids—those not produced naturally by the body—such as THC and CBD, are being investigated to help reduce fear and anxiety when the body’s endocannabinoid system is deficient or disrupted being explored,” she explains.

Patricia Di Ciano, PhD, CCRP, an independent scientist at the Centre for Addiction and Mental Health and an assistant professor in the department of pharmacology and toxicology at the University of Toronto, notes, “CBD and THC interact with many of the receptor systems that are known to be important in fear and anxiety. Studies in animals have shown that CBD can be anxiolytic, or anxiety-reducing.” Research has demonstrated that CBD can indirectly inhibit FAAH enzymes, which metabolize anandamide; increased levels of anandamide then increase CB1-R activation. The fear response is then reduced with CB1-R activation.3,4

“There is preliminary evidence that CBD may help reduce fear and anxiety by boosting levels of endocannabinoids, such as anandamide,” Marusak observes. CBD also seems to interact with serotonin, a neurotransmitter important in controlling anxiety, according to Di Ciano and Marusak.

However, THC is able to bind directly with both CB1-R and CB2-R. “THC may work to reduce anxiety and fear by mimicking some of the effects of the endocannabinoid system and buffering the stress response,” Marusak says. But, as a psychoactive compound, THC can have more impact on the endocannabinoid system and the fear/anxiety response. Low doses of THC have been found to be therapeutic for anxiety, but higher doses induce anxiety. “It is important to note that too much THC can actually increase anxiety, so the effects of THC on fear and anxiety are complex,” Marusak says. CBD, which isn’t intoxicating, is more a focus in anxiety research. Di Ciano adds, “CBD is of therapeutic interest because, unlike THC, it has little or no abuse potential and has fewer side effects.”

Di Ciano and Marusak are two of the many researchers studying how derivatives of the cannabis plant can interact with the endocannabinoid system to help reduce fear and anxiety. Di Ciano has published a synthesis of preclinical and clinical evidence on the use of CBD for anxiety treatment.4 Marusak and her colleagues are studying whether CBD can affect the endocannabinoid system and lower stress and anxiety in children with epilepsy, and also whether variation in the endocannabinoid system is associated with risk of anxiety in children and adolescents. Results presented at professional meetings indicated that genetic differences in the endocannabinoid system may contribute to reduced ability to extinguish learned fear after trauma, thereby increasing risk for developing anxiety.5,6 Research is focusing on children and adolescents because anxiety disorders commonly begin at those stages, Marusak notes.

“The endocannabinoid system is a novel target for identifying who will be at risk for developing anxiety-related disorders, as well as for identifying new ways to prevent and treat them,” Marusak says. “Most anxiety treatments were developed for adults and not tailored to the unique neurobiology of children and adolescents. Research into the endocannabinoid system and CBD will help us develop more age-appropriate therapies for anxiety,” she adds.

Research into the anxiolytic properties of CBD will continue to be vigorous, given the high societal level of interest in CBD, advertising of numerous products, and its low rate of side effects relative to THC. “The evidence is still very preliminary, though. There have been some clinical trials on the anxiolytic effects of CBD, but more studies are definitely needed. We need studies with larger sample sizes, more controls, and the full range of potentially therapeutic doses,” Di Ciano emphasizes. “Because the endocannabinoid system is relatively new to modern medicine, there is still so much that researchers and doctors need to learn,” Marusak adds.

— Jennifer Van Pelt, MA, is a health care researcher and freelance writer in the Lancaster, Pennsylvania, area.


1. Craske MG, Stein MB, Eley TC, et al. Anxiety disorders. Nat Rev Dis Primers. 2017;3:17024.   

2. Cunha JP. What is the function of endocannabinoids? MedicineNet website. Updated July 31, 2020.

3. Maldonado R, Cabañero D, Martín-García E. The endocannabinoid system in modulating fear, anxiety, and stress. Dialogues Clin Neurosci. 2020;22(3):229-239.

4. Wright M, Di Ciano P, Brands B. Use of cannabidiol for the treatment of anxiety: a short synthesis of pre-clinical and clinical evidence. Cannabis Cannabinoid Res. 2020;5(3):191-196.

5. Paulisin S, Marusak HA, Iadipaolo AS, Peters C, Elrahal F, Rabinak CA. F17. Failure to extinguish fear in trauma-exposed children with a common variant in the cannabinoid receptor 1 gene. Biol Psychiatry. 2019;85(10):S219.

6. Marusak H, Peters C, Iadipaolo A, Elrahal F, Burghardt K, Rabinak C. T4. Endocannabinoid regulation of fear-extinction neural circuitry in youth: effects of FAAH genotype. Neuropsychopharmacology. 2019;44(Suppl 1):232.


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