Cannabidiol Combats Depression Through Isgs-Mediated Inflammation in Zebrafish Model
DOI:
https://doi.org/10.54097/8rz7q762Keywords:
Zebrafish; Cannabidiol (CBD); Depression; Immune response; Reward system.Abstract
Major depressive disorder (MDD) is chronic and disabling. Current monoaminergic drugs act slowly and fail to achieve remission in many patients. The endocannabinoid system (ECS), which regulates mood, reward processing, and synaptic plasticity, has emerged as a promising target, yet clinical results are inconsistent, and key determinants such as dose, cellular context, and individual variability remain unresolved. We addressed these gaps by coupling a systematic review of placebo-controlled trials of exogenous cannabinoids with an experimental zebrafish model of reserpine-induced depression. In zebrafish larvae, behavior was quantified in the light-dark box, and whole-organism RNA sequencing was used to map the mechanism. The result showed largely non-significant antidepressant outcomes, with efficacy appearing formulation-dependent. In zebrafish, cannabidiol (CBD) at the maximum tolerated concentration (0.312 μg/mL) partially rescued depression-like behavior. Transcriptomics analysis revealed selective upregulation of interferon-stimulated genes (ISGs), including IFIT15 and RSAD2, with enrichment of immune, synaptic, and metabolic pathways. These cross-species findings indicate that CBD can ameliorate depressive phenotypes through endocannabinoid-linked modulation of neuroimmune pathways. They highlight dose sensitivity and microglial state as likely drivers of heterogeneity and motivate species-appropriate dosing and stratification by inflammatory status. Interferon-stimulated gene networks emerge as tractable entry points for developing safer, more effective, and personalized antidepressant strategies targeting the ECS.
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