Project Summary. The prevalence of daily cannabis use and cannabis use disorder (CUD) has increased in
the United States over the past two decades. Unfortunately, psychosocial treatments produce minimal long-
term abstinence rates and no FDA-approved medications for CUD exist. Thus, identifying novel CUD treatment
targets is an increasingly urgent public health need. Stress-elicited cannabis use motivation has been
implicated in worse CUD outcomes, but a mechanistic understanding of how acute stress increases cannabis
use motivation in CUD is limited. The PI’s work has demonstrated that acute psychosocial stress enhancement
of subsequent cannabis cue incentive salience, as indexed by the late positive potential (neural measure of
approach-motivated attention recorded using electroencephalography [EEG]), was associated with worse CUD
severity and intervention response, independent of subjective craving. Moreover, hypothalamic pituitary
adrenal [HPA]-axis, rather than noradrenergic or subjective reactivity to the psychosocial stressor was
associated with subsequent potentiation of the cannabis cue-elicited late positive potential. These studies
suggest that non-genomic, rapid glucocorticoid effects may be a contributing mechanism in stress amplification
of neural drug-cue reactivity, but their correlational designs preclude causal inference. Further, psychosocial
stressors are unable to isolate HPA-axis vs. noradrenergic components of stress reactivity. To isolate HPA-
axis activation and test causality, pharmacological manipulations, common in animal models but rare in human
studies, will be used to produce separate and co-operative glucocorticoid (hydrocortisone) and noradrenergic
(yohimbine) activation. We will employ a 2x2 randomized, placebo-controlled double-blind crossover design in
36 cannabis users with severe CUD. Our primary aim is to test the causal potentiating effect of glucocorticoids
on neural drug-cue reactivity, and further determine if the effect depends on co-occurring noradrenergic
stimulation. Preclinical work indicates that glucocorticoids can potentiate reward motivation via mobilization of
endocannabinoid activity (primary target of cannabis). Thus, as an exploratory aim in line with NIDA priorities
(NOT-DA-22-048), we will obtain plasma samples to test the impact of pharmacological stress on circulating
endocannabinoids and their mediating role in glucocorticoid potentiation of neural drug-cue reactivity. This
project represents a highly novel integration of a rigorous pharmacological challenge design with biological
markers of drug-cue incentive salience and endocannabinoid system activity. If hypotheses are confirmed, one
causal mechanism through which stress increases neural cannabis cue reactivity will be known, which has
immediate implications for testing experimental therapeutics. The long-term goal is to understand how a stress-
related mechanism predictive of worse CUD phenotype is generated and can be blocked in CUD.
Development of this model will provide a valid, efficient and (relative to other neuroimaging methods) low-cost
approach to screen candidate medications and optimize psychosocial drug cue exposure therapies.
