Sex differences in the interactive effects of early life stress and the endocannabinoid system

Sex differences in both the endocannabinoid system and stress responses have been established for decades. While there is ample evidence that the sexes respond differently to stress and that the endocannabinoid system is involved in this response, what is less clear is whether the endocannabinoid system mediates this response to stress differently in both sexes. Also, do the sexes respond similarly to exogenous cannabinoids (CBs) following stress? Can the administration of exogenous CBs normalize the effects of stress and if so, does this happen similarly in male and female subjects? This review will attempt to delineate the stress induced neurochemical alterations in the endocannabinoid system and the resulting behavioral changes across periods of development: prenatal, early neonatal or adolescent in males and females. Within this frame work, we will then examine the neurochemical and behavioral effects of exogenous CBs and illustrate that the response to CBs is determined by the stress history of the animal. The theoretical framework for this endeavor relates to the established effects of adverse childhood experiences (ACE) in increasing substance abuse, depression and anxiety and the possibility that individuals with high ACE scores may consume cannabinoids to "self-medicate". Overall, we see that while there are instances where exogenous cannabinoids "normalize" the adverse effects produced by early stress, this normalization does not occur in all animal models with any sort of consistency. The most compelling report where CB administration appears to normalize behaviors altered by early stress, shows minimal differences between the sexes (Alteba et al., 2016). This is in stark contrast to the majority of studies on early stress and the endocannabinoid system where both sexes are included and show quite divergent, in fact opposite, effects in males and females. Frequently there is a disconnect between neurochemical changes and behavioral changes and often, exogenous CBs have greater effects in stressed animals compared to non-stressed controls. This report as well as others reviewed here do support the concept that the effects of exogenous CBs are different in individuals experiencing early stress and that these differences are not equal in males and females. However, due to the wide variety of stressors used and the range of ages when the stress is applied, additional careful studies are warranted to fully understand the interactive effects of stress and the endocannabinoid system in males and females. In general, the findings do not support the statement that CB self-administration is an effective treatment for the adverse behavioral effects of early maltreatment in either males or females. Certainly this review should draw the attention of clinicians working with children, adolescents and adults exposed to early trauma and provide some perspective on the dysregulation of the endocannabinoid system in the response to trauma, the complex actions of exogenous CBs based on stress history and the unique effects of these factors in men and women.