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A new study published in Neuropharmacology provides evidence that cannabidiol, a non-psychoactive compound found in cannabis, may help buffer against the lasting psychological and neurobiological impacts of social stress. Researchers in Spain and Germany found that cannabidiol reduced social avoidance and sensitivity to cocaine in male mice previously exposed to repeated social defeat during adolescence. Cannabidiol also reversed several stress-induced changes in brain gene expression related to serotonin, the endocannabinoid system, and the hypothalamic-pituitary-adrenal axis.
Cannabidiol, commonly known as CBD, is one of the primary compounds found in the Cannabis sativa plant. Unlike delta-9-tetrahydrocannabinol (THC), cannabidiol does not produce intoxicating effects. Over the past decade, it has been widely studied for its potential therapeutic properties, including anti-anxiety, antidepressant, anti-inflammatory, and anti-addiction effects. Importantly, cannabidiol influences multiple biological systems, including those involved in stress regulation, mood, and reward processing.
Stress during adolescence is known to increase vulnerability to a wide range of mental health conditions, including anxiety, depression, and substance use disorders. One form of stress, social defeat, models repeated negative social interactions such as bullying or subordination and has been shown to induce lasting behavioral and neurobiological changes in rodents.
“Social stress (e.g., bullying) is one of the factors that contributes to the development of mental disorders and drug use. Given that cannabidiol, a compound found in the cannabis plant, has anxiolytic and antidepressant potential, we believe it could be effective in reversing the negative consequences of stress on mental health and cocaine use,” said study author Maria A. Aguilar, a professor of psychobiology and director of the Neurobehavioral Mechanisms and Endophenotypes of Addictive Behavior Lab at the University of Valencia.
Previous research by the study authors demonstrated that intermittent social defeat during adolescence leads to anxiety- and depression-like behaviors in mice and increases sensitivity to the rewarding effects of drugs like cocaine. However, the biological mechanisms underlying this vulnerability—and whether it can be prevented—remain unclear. The present study sought to test whether cannabidiol could mitigate these behavioral changes and normalize stress-related alterations in brain gene expression.
The new study was divided into two main experiments. In both, male mice were exposed to four episodes of social defeat during late adolescence. In each episode, a test mouse (the intruder) was placed in a cage with a larger, aggressive resident mouse, leading to repeated instances of defeat and submission. This procedure aimed to model intermittent social stress, known to mimic aspects of chronic psychosocial stress in humans.
Before each social defeat episode, mice were injected with either a low dose (30 mg/kg) or high dose (60 mg/kg) of cannabidiol. Control groups included mice that were not exposed to stress and mice that received no cannabidiol.
In the first experiment, the researchers assessed behavioral outcomes both shortly after the stress period and several weeks later. These included tests of anxiety-like behavior, social interaction, memory, and depression-like responses, as well as sensitivity to cocaine in a conditioned place preference paradigm—a method for assessing the rewarding effects of drugs.
In the second experiment, the researchers examined the expression of several genes in brain regions implicated in stress and reward, including the serotonin transporter, corticotrophin-releasing factor, and cannabinoid receptors.
Exposure to social defeat produced significant behavioral changes. Stressed mice showed increased anxiety in the elevated plus maze and reduced social interaction—two indicators commonly used to model human anxiety and social withdrawal. They also developed a stronger preference for environments associated with cocaine, suggesting enhanced vulnerability to drug reward.
Cannabidiol had mixed effects. It did not appear to alleviate anxiety-like behavior in the elevated plus maze. “Contrary to expectations, treatment with cannabidiol did not reverse the anxiogenic effects of social defeat,” Aguilar told PsyPost. “This could be due to the doses used in our study.”
But the researchers found that cannabidiol reversed the reduction in social interaction. It also blocked the enhanced preference for cocaine observed in stressed mice. This suggests that cannabidiol may reduce both social withdrawal and susceptibility to the rewarding effects of addictive drugs following stress.
The researchers also found that social defeat led to widespread changes in brain gene expression, many of which were normalized by cannabidiol. Specifically, social stress reduced the expression of genes involved in the serotonin system, endocannabinoid receptors, and components of the hypothalamic-pituitary-adrenal axis—the body’s central stress response system.
For instance, mice exposed to social defeat had lower levels of the serotonin transporter in the dorsal raphe nucleus, lower levels of CB1 and CB2 cannabinoid receptors in the hippocampus, and reduced expression of corticotrophin-releasing factor and proopiomelanocortin in the hypothalamus. These molecules are all involved in regulating mood, stress response, and emotional memory.
Cannabidiol tended to reverse these changes, although the effects varied depending on the dose. For example, the higher dose increased CB1 receptor expression in both stressed and non-stressed animals, while the lower dose selectively increased CB2 receptor expression in stressed mice. Similarly, cannabidiol restored serotonin transporter levels at the higher dose but not at the lower one, which paradoxically further reduced expression.
One exception was the glucocorticoid receptor (NR3C1), which was upregulated by stress but not altered by cannabidiol. This suggests that some components of the stress response may remain elevated even when others are normalized.
“Using an animal model of stress, defeat in a social encounter with a more aggressive animal, we have observed that stressed mice show depression- and anxiety-like symptoms, as well as greater sensitivity to the rewarding effects of cocaine,” Aguilar said. “The administration of cannabidiol before each social defeat reverses social avoidance, one of the main symptoms of depression in humans. Furthermore, stressed mice treated with cannabidiol are no more sensitive to cocaine, which would reduce their vulnerability to developing addiction.”
The findings indicate that cannabidiol may have protective effects against certain behavioral and neurobiological consequences of adolescent social stress. By reversing deficits in social interaction and preventing increased sensitivity to cocaine reward, cannabidiol shows promise as a potential intervention for stress-related risk factors in addiction and mood disorders.
Importantly, the study links these behavioral effects to measurable changes in the brain’s stress and reward systems. The involvement of the serotonin transporter, endocannabinoid receptors, and hypothalamic stress hormones suggests that cannabidiol interacts with multiple overlapping pathways. The fact that different doses had different effects on gene expression points to a need for careful dose optimization in future therapeutic studies.
“An important contribution of our study is the demonstration that exposure to social stress due to defeat induces brain alterations in the expression of genes related to the hypothalamic-pituitary-adrenal axis (the stress response system), serotonin, and receptors of the endocannabinoid system (receptors that bind both the cannabinoids produced by our brain and the cannabinoids present in the cannabis plant),” Aguilar said. “Increasing our knowledge of the neurobiological substrates of the effects of stress may contribute to the development of new drugs for its treatment.”
While the study provides important preclinical evidence, it also has some limitations. The behavioral and molecular analyses were conducted in separate groups of mice, making it impossible to directly link individual behavioral outcomes with specific gene expression profiles. Only male mice were used, leaving open questions about how these effects might differ in females. In addition, the researchers note that cannabidiol often produces dose-dependent and sometimes opposing effects, a finding that complicates clinical translation..
“As we mentioned earlier, our study only evaluated the effects of two doses of cannabidiol, so it is possible that different doses would have yielded different results,” Aguilar noted. “Another limitation is that the study was conducted on mice, so the results cannot be directly extrapolated to humans.”
The research team plans to test whether cannabidiol produces similar effects in female mice. They are also exploring other treatments to determine whether these can also reverse the negative consequences of adolescent social stress.
“The next step in our research will be to assess whether cannabidiol also reverses the effects of social stress in female mice,” Aguilar explained. “There are significant sex differences in the effects of stress as well as in the development of mental disorders and drug addiction. We also intend to evaluate the potential of other pharmacological treatments or environmental interventions, such as physical activity, to reverse the negative consequences of social stress.”
“Our work suggests that cannabidiol could be effective in treating stress-induced mental disorders, including drug use. However, this potential must be verified in clinical studies with humans.
The study, “Cannabidiol prevents social avoidance, potentiation of cocaine reward and gene expression alterations induced by exposure to intermittent social defeat in mice,” was authored by Maria Ángeles Martínez-Caballero, Daniela Navarro, Claudia Calpe-López, Abraham B. Torregrosa, Maria Pilar García-Pardo, Jorge Manzanares, and Maria Asunción Aguilar.
