Sex-Dependent Synergism of an Edible THC: CBD Formulation in Reducing Anxiety and Depressive-like Symptoms Following Chronic Stress

Cannabis has shown therapeutic potential in mood and anxiety-related pathologies. However, the two primary constituents of cannabis, cannabidiol (CBD) and Δ-9-tetrahydrocannabinol (THC) produce distinct effects on molecular pathways in neural circuits associated with affective disorders. Moreover, it has been proposed that the combination of THC: and CBD may have unique synergistic properties. In the present study, the effects of a 1:100 THC: CBD ratio edible formulation were tested in behavioural, neuronal and molecular assays for anxiety and depressive-like endophenotypes. Adult male and female Sprague-Dawley rats were stressed for 14 days. Then, for three weeks, open field, elevated plus maze, light/dark box, social interaction, sucrose preference, and the forced swim test were performed 90 minutes after acute consumption of CBD (30 mg/kg), THC (0.3 mg/kg), or 1:100 combination of THC:CBD. After behavioural tests, in vivo, neuronal electrophysiological analyses were performed in the ventral tegmental area and prefrontal cortex (PFC). Furthermore, western-blot experiments examined the expression of biomarkers associated with mood and anxiety disorders, including protein kinase B (Akt), glycogen synthase kinase-3 (GSK-3), BDNF, mTOR, D1, and D2 receptor in nucleus accumbens (NAc) and PFC.Edible THC:CBD produces significant anxiolytic and antidepressant effects only in stressed male rats. In most cases, the combination of THC and CBD had stronger effects than either phytochemical alone. These synergistic effects are associated with alterations in Akt/GSK3 and D2-R expression in NAc and BDNF expression in PFC. Furthermore, THC:CBD reverses chronic stress-induced alterations in PFC neuronal activity. These findings demonstrate a novel synergistic potential for THC:CBD edible formulations in stress-related pathologies.