Dysregulation in stress responsivity is a growing psychiatry-transdiagnostic fundamental phenomenon, with limited therapeutic strategies. With the legalization of medical and recreational cannabis, many people consume cannabidiol (CBD; a nonintoxicating cannabinoid) to alleviate stress response, without the benefit of scientific guidance. To address this gap, the investigators propose a rigorous translational neuroscience study in a clinical high-risk population to define the roles of CBD in stress response with mechanisms of mesocorticolimbic-network function and hierarchy, neurometabolic, endocrine, and behavior, building upon convergent evidence from animal models and human evidence from our laboratories.
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, the investigators 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 the investigators clinical and research expertise with high-risk populations with ELA and other investigators established experience with CBD clinical trials. Specifically, the researchers neuroimaging study demonstrated prefrontal neuroanatomical impairments associated with enhanced clinical symptomatology in individuals with ELA. In relation to CBD, the researchers have shown in healthy individuals that oral CBD is safe and well tolerated. The researchers 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 the randomized, double-blind placebo-controlled trial the researchers 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, the researchers pharmacokinetic trial replicated the previous findings showing rapid bioavailability in oral CBD dose (400mg) known to have behavioral efficacy. The investigators 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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
BASIC_SCIENCE
Masking
QUADRUPLE
Enrollment
160
400mg cannabidiol
Inactive oral solution
Ichan School of Medicine at Mount Sinai
New York, New York, United States
RECRUITINGNeural (BOLD) functional response
Measurement of brain activity using the Blood Oxygenation Level Dependent (BOLD) signal Neural (BOLD) functional response to acute stress and network hierarchy in resting state functional connectivity. BOLD response will measure neural activity during stress conditions as compared to rest and control conditions
Time frame: Day 2
Neuronal viability indexed by GLX (combined glutamate/glutamine levels) and N-acetylaspartate (NAA) using 1H-MRS.
Concentration of brain chemicals (N-acetylaspartate, Glutamate/Glutamine Levels) as an indicator of brain health measured using non-invasive imaging of magnetic resonance spectroscopy.
Time frame: at day 2
Serum Cortisol level
The cortisol blood test measures the level of cortisol in the blood. Cortisol is a steroid (glucocorticoid or corticosteroid) hormone produced by the adrenal gland.
Time frame: Day 2, Day 3
Salivary Cortisol level
The cortisol saliva test measures the level of cortisol in the saliva. Cortisol is a steroid (glucocorticoid or corticosteroid) hormone produced by the adrenal gland.
Time frame: Day 2, Day 3
Visual analog scale for stress (VASStress)
The VASStress consists of a continuous line, usually 10 centimeters long which is converted to a score. Full scale is scored from 0-10, with higher score indicating higher level of stress.
Time frame: Day 2, Day 3
Visual analog scale for anxiety (VASAnxiety)
The VASAnxiety consists of a continuous line, usually 10 centimeters long which is converted to a score. Full scale is scored from 0-10, with higher score indicating higher level of anxiety.
Time frame: Day 2, Day 3
Adrenocorticotropic hormone (ACTH) level
The ACTH test measures the level of adrenocorticotropic hormone (ACTH) in the blood. ACTH is a hormone released from the pituitary gland at the base of the brain.
Time frame: Day 2, Day 3
Serum noradrenaline level
Serum noradrenaline assesses adrenal gland function and the body's response to stress.
Time frame: Day 2, Day 3
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