Cannabichromene, a key non-psychotropic phytocannabinoid in treatment of major depressive disorder: in silico and in vivo explorations

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Abstract
Cannabichromene, a non-psychotropic cannabinoid with antioxidant and neuroprotective properties, is hypothesized to possess antidepressant potential. This study aimed to evaluate cannabichromene’s depression-alleviating effects in mice exposed to chronic unpredictable mild stress and unstressed mice using a combination of in silico and in vivo approaches. Initially, gene targets associated with major depressive disorder were identified through GeneCards, while cannabichromene’s target genes were predicted using SwissTargetPrediction. Overlapping targets were visualized using Venny software, and protein–protein interaction networks were constructed with the STRING database. The cannabinoid receptor two genes, encoding the cannabinoid 2 receptor, emerged as a key shared target. Molecular docking studies revealed that cannabichromene exhibited a strong binding affinity to cannabinoid 2 receptors (docking score: − 9.4) compared to cannabidiol (CBD) (− 8.8) and Δ9-tetrahydrocannabinol (− 9.1). For in vivo analysis, male Swiss albino mice were subjected to chronic unpredictable mild stress for 3 weeks to induce depression-like behavior. Cannabichromene (10 and 20 mg/kg) and imipramine (15 mg/kg) were administered for 21 days. Cannabichromene at 20 mg/kg significantly reduced immobility in stressed mice, like imipramine, without affecting locomotor activity. Additionally, both cannabichromene and imipramine reduced elevated plasma nitrite and corticosterone levels and inhibited monoamine oxidase-A activity in the brain. Cannabichromene also reversed stress-induced catalase suppression. In conclusion, cannabichromene revealed a relatively substantial antidepressant character with chronic unpredictable mild stress model of depression in Swiss albino male mice, likely through interaction with cannabinoid 2 receptors encoded by the cannabinoid 2 gene, as ratified via in silico modeling and in vivo findings. This highlights cannabichromene’s potential as a novel therapeutic agent for depression after further in vitro and clinical assessments in other models. Graphical Abstract

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