The neuroprotective effect of cannabidiol is enhanced by resveratrol and alpha-lipoic acid in social isolation

Federica Ricciardi¹Andrea Maria Morace¹Rebecca Limongelli¹Monica Iannotta¹Serena Boccella¹ANTIMO FUSCO¹Roozbe Bonsale¹Michela Perrone¹Rosmara Infantino¹Emanuele Di Martino¹Consalvo Mattia²Francesca Gargano³Maria Consiglia Trotta¹Enza Palazzo¹Sabatino Maione¹Francesca Guida¹Livio Luongo¹Carmela Belardo^1,4*

• ¹Universita degli Studi della Campania Luigi Vanvitelli, Caserta, Italy
• ²Universita degli Studi di Roma La Sapienza, Rome, Italy
• ³Policlinico Universitario Campus Bio-Medico, Rome, Italy
• ⁴Link Campus University, Rome, Italy

Abstract Introduction: Post-traumatic stress disorder (PTSD) is a chronic psychiatric condition characterized by persistent cognitive and affective disturbances following exposure to severe trauma. In rodents, prolonged post-weaning social isolation is a well-established model of PTSD-like symptomatology. In this study, we investigated the behavioral effects of chronic cannabidiol (CBD) administration—either alone or in combination with two natural antioxidants, resveratrol (RES) and alpha-lipoic acid (ALA)in socially isolated mice. Methods: Male CD1 mice (n = 8) were isolated in individual cages from postnatal day 21 (PN21) and maintained in isolation for 30 days. They were then treated with CBD (2.5, 5, and 10 mg/kg), resveratrol (RES, 20 mg/kg), or alpha-lipoic acid (ALA, 10 mg/kg) for 15 days following social isolation. Results: While low-dose CBD (2.5 mg/kg) alone was ineffective, its combination with either RES or ALA restored the latency to the first attack and significantly reduced aggressive behavior, comparable to high-dose CBD (10 mg/kg). Similarly, combined treatments with RES or ALA markedly reduced immobility time in the tail suspension test, indicating antidepressant-like effects. In contrast, no significant anxiolytic effect was observed with the combinations in the hole-board test, suggesting a limited action on anxiety-like behavior. Discussion: These findings suggest that co-administration of CBD with RES or ALA exerts synergistic antidepressants and anti-aggressive effects in a PTSD-like model, potentially allowing for dose reduction of CBD. Further studies are warranted to explore the underlying molecular mechanisms.