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.
Comparable studies
Other preclinical and animal studies on depression, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psychedelics, but Not Ketamine, Produce Persistent Antidepressant-like Effects in a Rodent Experimental System for the Study of Depression Rats | 2020 | Preclinical study | |
| A Single Subanesthetic Dose of Ketamine Relieves Depression-like Behaviors Induced by Neuropathic Pain in Rats Rats with spared nerve injury (neuropathic pain model), sham-operated rats, and control... | 2011 | Animal experimental study | |
| Effects of N,N-Dimethyltryptamine on Rat Behaviors Relevant to Anxiety and Depression Adult male Sprague-Dawley rats | 2018 | Experimental study | |
| A non-hallucinogenic LSD analog with therapeutic potential for mood disorders. Mice and cultured rat cortical neurons | 2023 | Preclinical study | |
| Comparison of (R)-ketamine and lanicemine on depression-like phenotype and abnormal composition of gut microbiota in a social defeat stress model Susceptible mice after chronic social defeat stress | 2017 | Preclinical animal study |
Citations in the library
Cites 6
- (R)-Ketamine Rapidly Ameliorates the Decreased Spine Density in the Medial Prefrontal Cortex and Hippocampus of Susceptible Mice After Chronic Social Defeat Stress The International Journal of Neuropsychopharmacology August 28, 2019
- PPARα and PPARγ are expressed in midbrain dopamine neurons and modulate dopamine- and cannabinoid-mediated behavior in mice. Molecular Psychiatry October 2023
- Unveiling behavioral and molecular neuroadaptations related to the antidepressant action of cannabidiol in the unpredictable chronic mild stress model Frontiers in Pharmacology April 18, 2023
- In vitro and in vivo pharmacological activity of minor cannabinoids isolated from Cannabis sativa Scientific Reports November 23, 2020
- Cannabidiol induces rapid-acting antidepressant-like effects and enhances cortical 5-HT/glutamate neurotransmission: role of 5-HT1A receptors. Neuropharmacology April 1, 2016
and 1 more in the library