CB₁ receptor signaling: Linking neuroplasticity, neuronal types, and mental health outcomes

The endocannabinoid system (ECS) is crucial in the pathophysiology of mental disorders. Historically, cannabis has been utilized for centuries to mitigate symptoms of anxiety and depression; however, the precise role of cannabinoids in these conditions has only recently garnered extensive research attention. Despite the growing body of literature on the ECS and its association with mental health, several critical questions remain unresolved. This review primarily focuses on cannabinoid CB₁ receptors (CB₁R), providing an examination of their regulatory roles in states related to mental disorders. Evidence suggests that CB₁R distribution occurs among various neuronal types, astrocytes, and subcellular membranes across multiple brain regions, potentially exhibiting both analogous and antagonistic effects. Additionally, various forms of stress have been shown to produce divergent impacts on CB₁R signaling pathways. Furthermore, numerous CB₁R agonists demonstrate biphasic, dose-dependent effects on anxiety and depression; specifically, low doses may exert anxiolytic effects, while higher doses can induce anxiogenic responses, a phenomenon observed in both rodent models and human studies. We also discuss the diverse underlying mechanisms that mediate these effects. We anticipate that this review will yield valuable insights into the role of CB₁R in mental disorders and provide a framework for future research endeavors on CB₁R and the ECS. This knowledge may ultimately inform therapeutic strategies aimed at alleviating symptoms associated with mental health conditions.