Chronic stress affects millions of people and has long been linked with changes in mood, motivation, and overall mental health. A new laboratory study now suggests that cannabidiol may reduce some of the biological effects of prolonged stress, with the clearest benefits seen in males. The findings, published in Cell, offer early insight into how the brain responds to stress and why some individuals may be more vulnerable than others.
Researchers exposed male and female rats to a widely used model of long-term stress to observe changes linked with low mood and altered behaviour. The team then administered cannabidiol during the final two weeks of the stress period. The study monitored behaviour as well as gene activity in brain regions involved in mood regulation, memory, and emotional processing. These included the ventromedial prefrontal cortex, the CA1 region of the hippocampus, and the ventral subiculum, which are known to play key roles in anxiety, depression, and responses to chronic stress.
The animals showed clear behavioural differences. Stressed males became more immobile in the forced swim test, a measure often used to identify depression-like responses, while stressed females became less immobile. Cannabidiol reversed these changes in both sexes. Males also displayed reduced swimming activity under stress, which was restored with treatment. The open field test showed that stress increased overall movement in both males and females, although cannabidiol did not alter this pattern. These behavioural findings indicate that stress affects males and females differently, yet cannabidiol appeared to normalise the mood-related aspects of behaviour in both groups.
At the biological level, the clearest effects involved genes linked with inflammation. Stressed males showed higher expression of tumour necrosis factor alpha in key hippocampal regions, which is a marker often associated with low mood. Cannabidiol prevented this increase. Stressed males also showed changes in the nuclear factor kappa B pathway, which is known to influence inflammation and stress responses. In females, inflammatory gene patterns differed and were less responsive to treatment. These sex-specific findings suggest that inflammation may be a more prominent factor in stress-related mood changes in males.
Cannabidiol also influenced the brain’s cannabinoid system. In males exposed to stress, the gene responsible for CB1 receptors was reduced in part of the hippocampus, but cannabidiol restored its activity. The same treatment did not produce comparable effects in females. The study also tracked genes linked with oestrogen signalling, given the known role of hormones in mood and stress. In stressed males, cannabidiol prevented the reduction of key oestrogen receptor genes in the ventral subiculum. These receptors are involved in modulating emotional responses and may help explain why males appeared more sensitive to the biological effects of cannabidiol in this study.
The findings highlight complex differences in how male and female brains respond to prolonged stress. They also show that cannabidiol may influence inflammation, hormone-related pathways, and cannabinoid receptors, particularly in males. While the research was carried out in animals and cannot be applied directly to humans, it adds to a growing set of findings on how stress, mood, and brain biology interact.
