Anxiety Modulation by Cannabinoids—The Role of Stress Responses and Coping

Abstract

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.

The interaction of Suk-Saiyasna remedy with GABAA and CB1 receptor-targeting drugs: Enhancing hypnotic and sedative effects in in vivo models

“…In the EPM test, animals spent more time in the closed arm compared to the open arm, consistent with previous findings on cannabinoids inducing anxiety-like responses. [ 21 ] Our study concurs with prior research on cannabinoids in the Suk-Saiyasna remedy, which may produce pronounced anxiety-like symptoms. In addition, it aligns with findings on cannabidiol and Δ-9-THC inducing hypo-locomotive effects and behavior interactions.…”

The Use of Compounds Derived from Cannabis sativa in the Treatment of Epilepsy, Painful Conditions, and Neuropsychiatric and Neurodegenerative Disorders

“…Recent research shows three hypotheses surrounding the endocannabinoid system’s role in emotional and behavioral control [ 253 ]. The first is interaction with the stress response mechanism, notably the HPA-axis, which moderates behavioral reactions and maintains equilibrium [ 254 ].…”

Herbal Cannabis and Depression: A Review of Findings Published over the Last Three Years

“…It is widely believed that THC, the most important psychotropic component of cannabis mimics the effects of neural signaling molecules called endocannabinoids, particularly anandamide, and 2arachidonoylglycerol (2-AG) as well as of other lipid messengers called N-acylethanolamines [196][197][198]. We recently described endocannabinoid mechanisms in detail, together with a brief overview of the history of discoveries [199]. Briefly, the effects of cannabinoids are exerted through two Gprotein coupled receptors, the CB1 and the CB2 [200,201], both being present in the central nervous system [202,203].…”

“…", whereas gene disruption allows answering the question "What happens if part of the mechanisms are eliminated?" [199].…”