“Endocannabinoids were implicated in a variety of pathological conditions including anxiety and are considered promising new targets for anxiolytic drug development. The optimism concerning the potentials of this system for anxiolysis is probably justified. However, the complexity of the mechanisms affected by endocannabinoids, and discrepant findings obtained with various experimental approaches makes the interpretation of research results difficult. Here, we review the anxiety-related effects of the three main interventions used to study the endocannabinoid system: pharmacological agents active at endocannabinoid-binding sites present on both the cell membrane and in the cytoplasm, genetic manipulations targeting cannabinoid receptors, and function-enhancers represented by inhibitors of endocannabinoid degradation and transport. Binding-site ligands provide inconsistent findings probably because they activate a multitude of mechanisms concomitantly. More robust findings were obtained with genetic manipulations and particularly with function enhancers, which heighten ongoing endocannabinoid activation rather than affecting all mechanisms indiscriminately. The enhancement of ongoing activity appears to ameliorate stress-induced anxiety without consistent effects on anxiety in general. Limited evidence suggests that this effect is achieved by promoting active coping styles in critical situations. These findings suggest that the functional enhancement of endocannabinoid signaling is a promising drug development target for stress-related anxiety disorders.”

https://pubmed.ncbi.nlm.nih.gov/37958761/

“Three hypotheses have been put forward so far on the role of endocannabinoids in emotional and behavioral control.

• The endocannabinoid system controls behavior by its interactions with the stress system (HPA-axis) and ensures normal functioning by eliminating excessive stress responses at all three levels: the hormonal, neural, and behavioral.
• The endocannabinoid system contributes to the integration of perception and execution, by allowing this adaptation to the environment. It buffers maladaptive responses and protects against psychiatric symptoms.
• The endocannabinoid system promotes an active coping with challenges, which confers the organism advantages in critical situations. This may be the common denominator of its anxiolytic- and antidepression-like effects.

These three hypotheses appear complementary rather than contradictory. All three suggest that the endocannabinoid system is a valid target for the treatment of psychiatric conditions associated with dysregulated affect. The task is to find the agent that achieves the goal with minimal risks.”

https://www.mdpi.com/1422-0067/24/21/15777