A different kind of high: How endocannabinoids provide a novel and exciting approach in anxiety disorder treatment
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With the Canadian legalization of cannabis in 2018, cannabis use has increased in recent years with an estimated 26% of the Canadian population (> 16 years old) reporting use of cannabis products in 2023. You have likely heard of, or possibly experienced, the association between cannabis and anxiety. It is a well-established connection, that funnily enough, is often one of two extremes – either cannabis induces sensations of relaxation and reduces anxiety, or cannabis puts you on high alert (no pun intended) and sends your anxiety levels through the roof. Regardless, there is no denying the connection between cannabis and anxiety.
Anxiety is an emotion known to all and has much value in everyday life. However, when anxiety becomes excessive, dysregulated, and disruptive, such as in the case of anxiety disorders, it’s a different story. Anxiety disorders are a common class of mental illnesses that share symptoms of disproportionate worrying, fear, and uneasiness that significantly impede occupational and social functioning. Despite about 1 in 3 people meeting the criteria for diagnosis of an anxiety disorder at some point in their lifetime, the drug options for treatment are not ideal. Currently prescribed anxiety medications possess a host of potential side-effects, including nausea, low sex drive, sleepiness, agitation, and weight changes. Evidently, the development of more effective, safer drug options is of upmost importance. In this article, we will focus on a promising area of research development for this purpose.
Cannabis, or more specifically the phytocannabinoid compounds within the Cannabis sativa plant such as ∆9-tetrahydrocannabinol (THC) and cannabidiol (CBD), impact brain functions such as emotions, cognition, appetite, and so on. When consumed, these phytocannabinoids enter the brain and activate the endocannabinoid system – a modulatory network expressed throughout the brain that is important in maintaining states of balance in various emotions, notably anxiety. Anandamide is a compound naturally produced in the brain and body that is used by the endocannabinoid system to relay signals. Anandamide is well-characterized for its uplifting and stress-reducing effect, with the nomenclature itself even being named after the Sanskrit word Ananda, which means bliss and joy. In addition, anandamide is well known for its anxiety-reducing properties. As a result, recent drug developments have investigated how modulating anandamide availability in the brain might impact anxiety processing and other behaviours, for use as a potential anxiety medication. One such method of interest involves mediating the transport of anandamide to increase anandamide signaling.
Anandamide requires carrier proteins for transport through the cell, and one prominent example of these carriers are fatty acid binding proteins (FABP). Without FABPs, the ability for anandamide to be inactivated is disturbed, resulting in increased anandamide activity. Thus, FABPs are pivotal in the regulation of anandamide and significantly impact anandamide levels. Of the different FABP subtypes, FABP5 shows one of the highest affinities for anandamide, is crucial in anandamide transportation, and is not widely expressed outside of the brain, making it an intriguing target for manipulating anandamide activity to reduce anxiety.
Recently, Dr. Taygun Uzuneser and colleagues at the University of Western Ontario examined a newly-developed FABP5 inhibitor drug, namely SBFI-103, to evaluate the potential of FABP5 inhibition as a novel mechanism for reducing anxiety. Researchers administered infusions of the FABP5 inhibitor directly to the brain of rats and found this drug induced significant reductions in anxiety and fear expression. Importantly, no side effects were identified in locomotor activity, memory performance, or sensory processing of these animals. Therefore, this novel FABP5 inhibitor was able to selectively reduce anxiety and fear processing without impacting various off-target behavioural facets. In the next part of the study, researchers wanted to evaluate the addictive potential of this drug. To do so, they administered the FABP5 inhibitor and measured neuronal activity along the dopamine circuit in the brain, which is important for mediating reward learning and motivational behaviour. Interestingly, neuronal activity was not altered along the dopamine circuit, suggesting that FABP5 inhibition poses a low risk for addiction and abuse.
In the study by Uzuneser et al. (2022), researchers were able to demonstrate reductions in anxiety without impacting motor behaviour, memory, or reward pathways. This seemingly benign side-effect profile of FABP5 inhibition can be attributed to multiple factors. First, there is limited FABP5 in the brain and body suggesting this drug will not induce widespread effects. Second, FABP5 inhibition indirectly modulates the endocannabinoid system by mediating anandamide availability, rather than directly activating a receptor system. As a result, only cells producing significant levels of anandamide will be impacted by FABP5 inhibition. Altogether, these create strict criteria required for a cell to be impacted by FABP5 inhibition. Following these criteria, it is evident why FABP5 inhibition can have such a targeted effect.
This study supports FABP5 inhibition as an enticing mechanism for anxiety regulation that is worthy of further investigation. This work provides a great example of how the endocannabinoid system plays an influential part in anxiety processing. Collectively, as we learn more about the endocannabinoid system through studies like these, it will provide more opportunities for drug development. Given the many prominent roles that endocannabinoid signaling plays in regulating anxiety, there are many ways that it could be the key to helping us design safer, more effective drug options for anxiety disorders. This is of upmost importance given the increasingly common prevalence of anxiety disorders.
Original Article:
Uzuneser, T. C. et al. Identification of a novel fatty acid binding protein-5-CB2 receptor-dependent mechanism regulating anxiety behaviors in the prefrontal cortex. Cerebral Cortex (2022) doi:10.1093/cercor/bhac220.