Cannabinoid-related Agents in the Treatment of Anxiety Disorders: Current Knowledge and Future Perspectives

Abstract

Rich evidence has shown that cannabis products exert a broad gamut of effects on emotional regulation. The main psychoactive ingredient of hemp, Δ9-tetrahydrocannabinol (THC), and its synthetic cannabinoid analogs have been reported to either attenuate or exacerbate anxiety and fear-related behaviors in humans and experimental animals. The heterogeneity of cannabis-induced psychological outcomes reflects a complex network of molecular interactions between the key neurobiological substrates of anxiety and fear and the endogenous cannabinoid system, mainly consisting of the arachidonic acid derivatives anandamide and 2-arachidonoylglycerol (2-AG) and two receptors, respectively termed CB1 and CB2. The high degree of interindividual variability in the responses to cannabis is contributed by a wide spectrum of factors, including genetic and environmental determinants, as well as differences in the relative concentrations of THC and other alkaloids (such as cannabidiol) within the plant itself. The present article reviews the currently available knowledge on the herbal, synthetic and endogenous cannabinoids with respect to the modulation of anxiety responses, and highlights the challenges that should be overcome to harness the therapeutic potential of some of these compounds, all the while limiting the side effects associated with cannabis consumption.

2-AG promotes the expression of conditioned fear via cannabinoid receptor type 1 on GABAergic neurons

“…Similar opposing effects were reported for fear-related freezing behavior (Kamprath et al 2009;Lafenêtre et al 2009;Metna-Laurent et al 2012). Furthermore, TRPV1 and CB1 seem to exert opposite effects on fear and anxiety (Marsch et al 2007; for review, see Moreira et al, Neuroscience 2012;Aguiar et al 2014), and also CB2 receptors were reported to modulate anxiety-like behavior (Tambaro and Bortolato 2012).…”

From Phytocannabinoids to Cannabinoid Receptors and Endocannabinoids: Pleiotropic Physiological and Pathological Roles Through Complex Pharmacology

“…Chronic exposure to ⌬ 9 -THC in adolescent rats induces a depressive-like phenotype in adulthood (720,756). In humans, the interindividual variability in the responses to cannabis may depend on a wide spectrum of factors, such as the relative concentrations of ⌬ 9 -THC and other phytocannabinoids (846).…”

Interactions of Cannabis and Amphetamine-Type Stimulants

“…This possibility is supported by preclinical evidence in rodents subjected to both acute and chronic administration of METH [105]. However, cannabis has been shown to produce variable effects with respect to anxiety [106] and may even exacerbate some of the negative subjective sensations induced by ATSs, such as panic and paranoia.…”

“…This scenario suggests that METH neurotoxicity may result in altered responsiveness of CB 1 receptors, possibly due to selective damages of specific subpopulation of neurons and homeostatic imbalances of the endocannabinoid system in the brain areas that regulate the modality and intensity of environmental reactivity, such as amygdala, prefrontal cortex and hippocampus [106,310].…”