“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.”

https://pubmed.ncbi.nlm.nih.gov/41934896

“CBG has anxiolytic and antidepressant effects in healthy male CD-1 mice.”

https://www.sciencedirect.com/science/article/pii/S0753332226003318?via%3Dihub

“Background: Whilst preclinical evidence details the effects of cannabinoids on mood regulation, there is a paucity of clinical evidence on the use of cannabis-based medicinal products (CBMPs) in individuals with depression. This study aims to evaluate longitudinal changes in patient-reported outcome measures (PROMs) and the incidence of adverse events over 24 months in patients treated with CBMPs for depression.

Methods: Patient data from the UK Medical Cannabis Registry were used for analysis. PROMs, including the Patient Health Questionnaire-9 (PHQ-9), Generalised Anxiety Disorder-7 (GAD-7), Single-Item Sleep Quality Scale (SQS), EuroQol 5-Dimension 5-Level (EQ-5D-5L), and Patient Global Impression of Change (PGIC), were measured at baseline, 1, 3, 6, 12, 18, and 24 months. Adverse events (AEs) were also recorded. P < 0.050 was considered statistically significant.

Results: Of the 34,563 patients in the UK Medical Cannabis Registry on January 6th 2025, 698 (2.02 %) patients were included in the analysis. Improvements were observed across the PHQ-9. GAD-7, SQS, and EQ-5D-5L index value at all time points compared to baseline (p < 0.001). At baseline, half of the patients reported severe anxiety (GAD-7 ≥ 15: 50.86 %, n = 355), which was correlated with depression severity (PHQ-9; r = 0.67, p < 0.001). Sixty-three patients (9.03 %) reported at least one AE during treatment, of which 85 % (n = 411) were mild or moderate.

Discussion: Initiation of CBMPs was associated with statistically and clinically significant improvements in depression, anxiety, sleep quality, and health-related quality of life among patients. Improvements were most prominent in the first 3 months. Limitations of the study mean that no causal relationship can be ascertained.

Conclusion: The positive findings from this and other observational data support future evaluation of CBMPs for the treatment of depression to establish their efficacy.”

https://pubmed.ncbi.nlm.nih.gov/41506388

“This UK Medical Cannabis Registry study of patients with treatment-resistant depression prescribed CBMPs demonstrated sustained and clinically meaningful improvements in depression, anxiety, health-related quality of life, and sleep quality over 24 months. Improvements were most pronounced within the first three months and were sustained thereafter. Adverse events were infrequent and predominantly mild to moderate.”

https://www.sciencedirect.com/science/article/pii/S0165032725025728?via%3Dihub

“Mitochondrial autophagy has been regarded as a new signaling pathway for the action of antidepressant drugs.

The neuroprotective properties of the non-psychoactive cannabinoid cannabidiol (CBD) have been demonstrated in different animal models of neurological disorders. However, the therapeutic effect of cannabidiol on neuroinflammation-induced depression and its underlying molecular mechanisms involved has not been comprehensively studied.

In this study, depressive-like behaviors were induced in male C57BL/6 mice by LPS injection, with intragastric administration of CBD (70 or 140 mg/kg/day) for 6 days.

Our results demonstrated that CBD treatment significantly attenuated lipopolysaccharide (LPS)-induced depressive-like behaviors, accompanied by a marked amelioration of synaptic healthiness in the hippocampal region.

CBD effectively inhibited reactive oxygen species production, normalized the levels of oxidative stress markers, and restored superoxide dismutase activity, involving a mechanism that promotes mitochondrial biogenesis and mitophagy. In addition, LPS-induced neuroinflammation was reduced by CBD, as evidenced by a marked decrease in neuroinflammatory activation markers. CBD also inhibited LPS-activated inflammasome activation by targeting NLRP3/IL-1β/Caspase-1 signaling pathway.

These findings suggest that CBD may be a potential therapeutic drug for managing major depressive disorder.”

https://pubmed.ncbi.nlm.nih.gov/41484536

https://link.springer.com/article/10.1007/s12035-025-05614-w

“Background and aim: Major depressive disorder is a prevalent psychiatric condition associated with impaired neuroplasticity, particularly in the hippocampus. Although selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed, their delayed onset and adverse effects highlight the need for alternative therapies. Cannabidiol (CBD), a non-psychotomimetic cannabinoid, has shown antidepressant-like properties, but its mechanistic link to hippocampal synaptic plasticity remains unclear. This study aimed to evaluate the effects of CBD on depression-like behaviors and hippocampal neuroplasticity in rats subjected to chronic restraint stress (CRS).

Materials and methods: Sixty male Wistar rats were randomly divided into six groups: Non-stressed vehicle (NV), CRS vehicle (SV), escitalopram-treated CRS (SE, 10 mg/kg), and CBD-treated CRS at 10, 30, or 100 mg/kg (SC10, SC30, and SC100). Rats were subjected to CRS for 28 days and treated daily through intraperitoneal injection. Depression-like behaviors were assessed using the forced swim test (FST) and sucrose preference test (SPT). Locomotor activity was evaluated through the open-field test (OFT). Hippocampal dendritic spine density (Golgi-Cox staining) and long-term potentiation (LTP, electrophysiology) were measured on day 28.

Results: CRS induced behavioral despair (↑ immobility in FST) and anhedonia (↓ sucrose preference in SPT), accompanied by reduced hippocampal spine density. At all doses, CBD significantly reduced immobility, comparable to escitalopram. Notably, only CBD at 100 mg/kg and escitalopram reversed anhedonia. All CBD-treated groups showed an increase in dendritic spine density, with SC10 producing the greatest enhancement. Moreover, CBD at 100 mg/kg markedly improved hippocampal LTP at 1 h and 2 h post-stimulation, an effect not observed with escitalopram. Locomotor activity remained unaffected.

Conclusion: CBD demonstrated potent antidepressant-like effects in a CRS rat model, alleviating behavioral despair and anhedonia while enhancing hippocampal dendritic spine density and synaptic strength. These findings suggest CBD as a promising candidate for stress-related mood disorders, with mechanistic actions distinct from conventional SSRIs and potential utility in patients unresponsive to current therapies.”

https://pubmed.ncbi.nlm.nih.gov/41113223/

https://veterinaryworld.org/Vol.18/September-2025/22.php