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Experimental evaluation of the mechanisms driving acute stress potentiation of drug cue reactivity in Cannabis Use Disorder

Award Number: R21DA058780
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 10/01/2025
PERIOD OF PERFORMANCE END DATE: 04/30/2027

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Experimental evaluation of the mechanisms driving acute stress potentiation of drug cue reactivity in Cannabis Use Disorder - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = -$4,333 )
2026	2025	AUBURN UNIVERSITY	321-A INGRAM HALL	AUBURN	AL	36849	LEE	USA	Drug Use and Addiction Research Programs	000	2	2/10/2026	NON-COMPETING CONTINUATION	-$154,838
2026	2025	FLORIDA STATE UNIVERSITY	874 TRADITIONS WAY	TALLAHASSEE	FL	32306	LEON	USA	Drug Use and Addiction Research Programs	002	3	2/20/2026	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2026	2025	FLORIDA STATE UNIVERSITY	874 TRADITIONS WAY	TALLAHASSEE	FL	32306	LEON	USA	Drug Use and Addiction Research Programs	001	3	2/10/2026	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$150,505
														Subtotal = -$4,333

Issue Date FY: 2025 ( Subtotal = $230,242 )
2025	2025	AUBURN UNIVERSITY	321-A INGRAM HALL	AUBURN	AL	36849	LEE	USA	Drug Use and Addiction Research Programs	000	2	4/14/2025	NON-COMPETING CONTINUATION	$230,242
														Subtotal = $230,242

Issue Date FY: 2024 ( Subtotal = $194,670 )
2024	2024	AUBURN UNIVERSITY	321-A INGRAM HALL	AUBURN	AL	36849	LEE	USA	Drug Use and Addiction Research Programs	001	1	7/25/2024	NEW	$0
2024	2024	AUBURN UNIVERSITY	321-A INGRAM HALL	AUBURN	AL	36849	LEE	USA	Drug Use and Addiction Research Programs	000	1	4/29/2024	NEW	$194,670
														Subtotal = $194,670

Grand Total All Awards = $420,579

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Experimental evaluation of the mechanisms driving acute stress potentiation of drug cue reactivity in Cannabis Use Disorder

Award Number: R21DA058780

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 10/01/2025

PERIOD OF PERFORMANCE END DATE: 04/30/2027

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