Therapeutic potential of phytocannabinoids in depression and cognitive dysfunction: Evidence from preclinical models.
Carla Fonseca, F. Gouveia, Soraia Silva, Sara Castanheira, Leila Driouech, A. M. Matos, R. Barbosa, Antoni Camins, A. Falcão, M. Ettcheto, Ana Fortuna
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie May 1, 2026 DOI: 10.1016/j.biopha.2026.119298 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical study Peer reviewed |
|---|---|
| Population | BV-2 microglial cells and healthy male CD-1 mice |
| Interventions | Cannabichromene Cannabidiol Cannabidivarin Cannabigerol Cannabinol Ketamine |
| Dose | 55 µmol/kg, i.p. |
| Measures | forced swimming test |
| Topics | Depression |
| Key points | Cannabigerol showed the lowest cytotoxicity in microglial cells and was the only phytocannabinoid to produce consistent antidepressant-like effects in healthy mice, comparable to ketamine. In the chronic stress model, cannabigerol improved cognitive performance and increased hippocampal dendritic spine density, whereas cannabidivarin was anxiogenic and cannabidiol showed no benefit. |
Abstract
Depression is a highly prevalent and incident mental illness. Current pharmacological therapies fail in approximately 30-40% of patients, highlighting the urgent need for novel agents with pleiotropic effects. This preclinical study aimed to identify new antidepressants and cognitive modulators among five phytocannabinoids: cannabichromene, cannabidiol, cannabidivarin, cannabigerol and cannabinol. Phytocannabinoids were first evaluated in BV-2 microglial cells for cell viability and then, for anti-inflammatory activity, where BV-2 cells were previously stimulated with lipopolysaccharide (50 ng/mL). Based on these profiles, and comparing with ketamine, cannabidiol, cannabidivarin and cannabigerol were selected to be administered (55 µmol/kg, i.p.) once to healthy CD-1 male mice, and subsequently, administered six times to mice submitted to the unpredictable chronic mild stress (UCMS) protocol, which is a validated model of depression. Among the phytocannabinoids under investigation, cannabigerol exhibited the lowest cytotoxicity, whereas cannabidiol and cannabidivarin demonstrated the strongest anti-inflammatory effects, significantly reducing nitrite, iNOS and pro-IL1β levels. In healthy mice, only cannabigerol produced consistent antidepressant-like effects in the forced swimming test compared to ketamine. Under UCMS protocol, cannabidivarin was anxiogenic and impaired cognitive and hepatic functions. Cannabidiol, despite its favorable safety profile, failed to ameliorate depressive phenotype or cognitive deficits. Notably, cannabigerol significantly improved cognitive performance, associated with increased dendritic spine density in the hippocampus. Overall, our unprecedented findings demonstrated that a single administration of cannabigerol ameliorates depressive-like behavior in healthy animals, while multiple administrations improved cognitive function in mice exhibiting depressive-like phenotypes. Together, these results highlight the therapeutic potential of cannabigerol in mood and cognitive disorders.