In a mouse PTSD-like model, β-caryophyllene’s effects depended on CB2

Post-traumatic stress disorder (PTSD) is characterized by excessive fear, hypervigilance, and dysregulation of stress-response systems, notably the hypothalamic-pituitary-adrenal (HPA) and sympathetic-adrenal-medullary (SAM) axes. Although benzodiazepines remain the most prescribed pharmacological treatment, their long-term use is associated with cognitive decline and fatigue, prompting the search for alternative therapeutic strategies. The endocannabinoid system (ECS) is a lipid-based neuro-immunomodulatory signaling network implicated in stress regulation. While the anxiolytic effects of cannabinoid type 1 (CB1) receptor agonism have been extensively examined, the potential role of cannabinoid type 2 (CB2) receptor activation remains largely unexplored. β-Caryophyllene is a naturally occurring dietary sesquiterpene and selective CB2 agonist. This study evaluated the effect of β-Caryophyllene on a murine PTSD-like model induced by a dual model of electric shock and acoustic stress in male C57BL/6 mice. β-Caryophyllene (10mg / kg, oral) was administered either during or after stress exposure. The CB2 antagonist AM630 (2mg / kg, intraperitoneal) was used to determine receptor involvement. Behavioral parameters were assessed using the light-dark box, open field, and elevated plus maze tests. Serum adrenaline, and serotonin were determined as part of the Sympathetic-Adrenal-Medullary axis activation, as well as corticosterone and central levels of glutamate as part of the Hypothalamic-Pituitary-Adrenal axis activation. β-Caryophyllene improved anxiety- and compulsive-like behaviors, reduced amygdalar and hypothalamic glutamate concentrations and mitigated plasma corticosterone, and serotonin levels. These effects were reversed by AM630. Collectively, these findings suggest that the anxiolytic effect of β-Caryophyllene involves CB2, highlighting its therapeutic potential for PTSD.