A Novel Anti-Inflammatory Formulation Comprising Celecoxib and Cannabidiol Exerts Antidepressant and Anxiolytic Effects

Background: Ample research shows that anti-inflammatory drugs, particularly celecoxib, exert antidepressant effects, especially in patients with microglia activation. However, substantial cardiovascular adverse effects limit celecoxib's usefulness. Given that cannabidiol (CBD) exerts anti-inflammatory, microglia-suppressive, and antidepressant effects, we hypothesized that it may potentiate the therapeutic effects of celecoxib. Methods: The effects of celecoxib, CBD, and their combination were examined in murine models of antidepressant- and anxiolytic-like behavioral responsiveness, including the forced swim test (FST), elevated plus maze (EPM), lipopolysaccharide (LPS)-induced neuroinflammation, and chronic social defeat stress (CSDS), as well as in microglia cell cultures. Results: Acute administration of a combination of celecoxib plus CBD, at doses that had no effects by themselves (10 and 5 mg/kg, respectively), produced significant antidepressant- and anxiolytic-like effects in the FST and EPM, in male and female mice. In the LPS model, combinations of celecoxib (10 or 20 mg/kg) plus CBD (30 mg/kg) reversed the anxiety-like behavior in the open-field test (OFT) and anhedonia in the sucrose preference test (SPT), with minimal effects of celecoxib or CBD by themselves. In the CSDS paradigm, a combination of celecoxib plus CBD (each at 30 mg/kg) reversed the deficits in the OFT, EPM, social exploration, and SPT, whereas celecoxib or CBD by themselves had partial effects. In BV2 microglia cultures stimulated with LPS or α-synuclein, CBD markedly potentiated the suppressive effects of celecoxib over TNFα (tumor necrosis factor-α) and IL (interleukin)-1β secretion. Conclusions: Combinations of celecoxib plus CBD produce efficacious antidepressant- and anxiolytic-like effects, which may depend on their synergistic microglia-suppressive effects.