Neurobiological and Molecular Mechanisms of Cannabidiol in Depressive Disorders: A Preclinical Systematic Review

Abstract

Purpose: This review aims evaluated preclinical studies published in the last five years investi gating the antidepressant-like effects of CBD and related cannabinoids. Methods: This work is a systematic review. The entire process of selecting and choosing the studies for the review was carried out according to the PRISMA protocol. The descriptors used were "Depressive Disorder", "Cannabidiol", and "Phytotherapy". Seven experimental studies met the inclusion criteria. Results: The reviewed evidence demonstrates that CBD reduces immobility in the forced swim test, increases sucrose preference, and modulates molecular pathways associated with neuroplasticity and inflammation. Key mechanisms include activation of AMPA receptors, modulation of serotonergic and noradrenergic transmission, reduction of NF-κB and IL-6 expression, and regulation of the kynurenine pathway. Additionally, CBD influences hippocampal neurogenesis and exhibits anti-inflammatory and anti-apoptotic effects through BDNF/TRPC6 signaling. Conclusion: Collectively, these findings highlight the multifactorial antidepressant potential of CBD and its analogs, suggesting a role as adjunctive or alternative therapies for mood disorders. However, further randomized controlled trials in humans are essential to confirm efficacy, safety, and optimal dosing parameters for clinical use.