Pathophysiological mechanisms of cannabidiol in stress regulation - PROJECT SUMMARY Dysregulation in stress responsivity, encompassing mesocorticolimbic and hypothalamus-pituitary-adrenal-axis pathways, is a psychiatry-transdiagnostic fundamental phenomenon. Current anxiolytic pharmacotherapies are limited in their efficacy and could cause dependence, low tolerance, and sexual dysfunction. With the growing number of vulnerable individuals suffering from stress-related disorders in society, there is an urgent need for novel therapeutic modalities particularly for early intervention and to improve treatments of stress-related disorders. Convergent evidence from animal and human studies of cannabidiol (CBD), a nonintoxicating and well-tolerated cannabinoid, has shown to have anxiolytic effects on stress reactivity especially in responses to environmental stimuli (cue-sensitized states). CBD has multiple pharmacological targets acting as an allosteric modulator of cannabinoid receptors and a glutamate-modulating agent. Despite recent surges in the use of CBD to alleviate stress symptoms, its pathophysiological mechanisms in human stress-system pathways remain largely unknown. Understanding the mechanisms of action of CBD in stress responsivity may lead to novel therapeutic strategies for stress-related disorders. Based on its safety and the growing evidence of CBD to reduce cue-induced reactivity, we propose to evaluate the mechanisms underlying CBD’s roles in stress response in a clinical high-risk population of young adults with early life adversity (ELA), known to exhibit this phenotype. This proposal leverages our clinical and research expertise with high-risk populations with ELA and our established experience with CBD clinical trials. Specifically, our neuroimaging study demonstrated prefrontal neuroanatomical impairments associated with enhanced clinical symptomatology in individuals with ELA. In relation to CBD, we have shown in healthy individuals that oral CBD is safe and well tolerated. We have demonstrated that CBD reduced cue-induced anxiety in individuals with psychopathology and that the effects persisted even when the cannabinoid was no longer detectable in the body. Moreover, in our randomized, double-blind placebo-controlled trial we not only replicated the original findings that CBD decreased cue-induced anxiety but also showed that it concomitantly reduced physiological stress responsivity marks (cortisol and heart rate). Importantly, its protracted effects were again evident a week after the last administration. Notably, our pharmacokinetic trial replicated our previous findings showing rapid bioavailability in oral CBD dose (400mg) known to have behavioral efficacy. Our hypotheses are that during stress responsivity CBD will: 1) downregulate the neural reactivity in mesocorticolimbic regions; 2) reduce influence of limbic regions within the stress network dependency hierarchy; 3) reduce neuronal viability in mesocorticolimbic regions; and 4) decrease endocrine and behavioral hyperreactivity, in clinical high-risk individuals. This study of unmedicated young adult males and females (N=160) with ELA, will examine neurobiological mechanisms of stress as manipulated by acute CBD vs. placebo (400mg, oral; using a double-blind, randomized, placebo-control design), as well as determine the relationship between CBD-sustained (7-day) change and endocrine and behavioral acute stress responsivity.
