“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

“Background: Recent preclinical studies have shown sex-dependent antidepressant-like responses of cannabidiol in adolescence, which were dependent on biological sex, early-life stress, and dose. In particular, cannabidiol (10 mg/kg) induced acute and sustained antidepressant-like responses in adolescent male rats, while it lacked efficacy in females. This follow-up study aimed at further characterizing cannabidiol’s effects in adolescence, in an attempt to overcome female unresponsiveness, while also evaluating its long-term safety profile in adulthood.

Methods: Groups of adolescent rats of both sexes were treated (ip) with cannabidiol (10, 30, 60 mg/kg) or vehicle (1 ml/kg) for 7 days. Acute (30 min post-injection) and repeated (24 h post-treatment) antidepressant-like responses were measured in the forced-swim test. Brains were collected to evaluate several neurochemical correlates in the hippocampus (CBR1, CBR2, BDNF, and cell proliferation) after adolescent cannabidiol exposure (acute and repeated). Some rats were left undisturbed until adulthood, when long-term effects on cognition were measured in the Barnes maze (short- and long-term memory) or affective-like responses in the forced-swim test. Data was analyzed with two-way ANOVAs (independent variables: sex and treatment).

Results: While the dose of 10 mg/kg of cannabidiol induced antidepressant-like effects in adolescent rats, higher doses had no effect in adolescent rats of both sexes. No changes were observed in any of the hippocampal neuroplasticity markers evaluated. Adolescent cannabidiol exposure did not induce long-term changes in cognitive performance or affective-like behavior.

Conclusions: Overall, our data suggest that adolescent cannabidiol treatment produces dose-dependent antidepressant-like effects of moderate magnitude without compromising long-term cognition in rats.”

https://pubmed.ncbi.nlm.nih.gov/40522606/

“To conclude, our data suggest that adolescent cannabidiol treatment produces dose-dependent antidepressant-like effects without compromising long-term cognition in rats. In particular, it reinforces prior studies by including more doses of cannabidiol tested during adolescence, while demonstrating efficacy mainly in male rats. Based on the literature, the combination of another antidepressant with cannabidiol might be a good strategy for attempting to induce efficacy in adolescent female rats, and should be further explored. Since no molecular print could be found to parallel the antidepressant-like potential of cannabidiol in adolescence, future studies should explore other avenues while searching for the specific role of sex hormones in the lack of response in females. Finally, and in line with the results that demonstrate that cannabidiol improves cognitive performance, this study adds to this existing literature by providing long-term results on this topic following adolescent cannabidiol exposure in rats of both sexes.”

https://link.springer.com/article/10.1007/s43440-025-00750-5

“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.”

https://pubmed.ncbi.nlm.nih.gov/40358684/

https://link.springer.com/article/10.1007/s00210-025-04236-2