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Influence of Orexin Antagonism on Methamphentamine Demand

Award Number: R01DA055634
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2026
PERIOD OF PERFORMANCE END DATE: 12/31/2027

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Influence of Orexin Antagonism on Methamphentamine Demand - PROJECT SUMMARY ABSTRACT Deemed a “Twin Epidemic” or “Fourth Wave”, epidemiological evidence emphasizes rapidly increasing public health harms of methamphetamine use among people who use opioids. These data are particularly worrisome given there are no FDA approved pharmacotherapies for methamphetamine use or established treatments for methamphetamine/opioid co-use. A promising target for the regulation of stimulant and opioid motivation is the orexin system. Preclinical and early clinical findings suggest that orexin system antagonism is a clinically viable approach to selectively reduce motivation for both opioids and stimulants. Human laboratory data are needed to investigate this mechanism and extend it to a co-use setting. This project will address this gap by using a behavioral economic demand framework to evaluate motivation for use of opioids, methamphetamine, and their combination in people with opioid use disorder. Demand analyses will directly inform the direction of subsequent treatment studies by identifying motives for opioid-methamphetamine co-use and determining whether these drugs act as substitutes (i.e., as consumption of one decreases, consumption of the other increases), which would necessitate treatments that target both drugs to avoid breakthrough use, or as complements (i.e., as consumption of one decreases, consumption of the other decreases), which would support treatments that target one drug to concomitantly decrease use of the other. This is an optimal approach that will inform more expeditious development of treatment trials and reduce risk of inducing harm with identification of incorrect targets. We will conduct a residential human laboratory study with non-treatment seeking participants with opioid use disorder. Participants will complete sessions with blinded administration of oral methamphetamine, oxycodone, their combination, and placebo. Validated demand measures sensitive to pharmacological manipulation will determine own-price demand (commodity alone) and cross-commodity demand (concurrent commodities). Participants will be randomized to receive oral suvorexant or placebo throughout the residential stay. We hypothesize that orexin antagonism will result in higher demand elasticity (lower drug use motivation) for methamphetamine, oxycodone, and their combination. We also hypothesize that the majority of participants will show a demand response in which methamphetamine serves as a substitute for oxycodone use, suggesting that treatments will be needed to target both drugs to avoid breakthrough use. Secondary analyses will evaluate sleep disturbances on non-session days and days in which study drug (methamphetamine, oxycodone, or their combination) is administered and we hypothesize fewer sleep disturbances in the suvorexant condition. This work will use translational laboratory methods to evaluate pharmacological and behavioral mechanisms underlying opioid, stimulant, and co-use motivation, providing insight into and treatment directives for a co-use trend of increasing public health harm.


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 = $593,386 )
2026	2026	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Drug Use and Addiction Research Programs	002	4	3/16/2026	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2026	2026	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Drug Use and Addiction Research Programs	001	4	3/6/2026	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$593,386
2026	2025	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Drug Use and Addiction Research Programs	000	3	3/6/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $593,386

Issue Date FY: 2025 ( Subtotal = $667,818 )
2025	2025	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Drug Use and Addiction Research Programs	000	3	1/15/2025	NON-COMPETING CONTINUATION	$601,036
2025	2025	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Drug Use and Addiction Research Programs	001	3	4/9/2025	NON-COMPETING CONTINUATION	$66,782
														Subtotal = $667,818

Issue Date FY: 2024 ( Subtotal = $667,818 )
2024	2024	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Drug Use and Addiction Research Programs	000	2	1/5/2024	NON-COMPETING CONTINUATION	$601,036
2024	2024	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Drug Use and Addiction Research Programs	001	2	4/24/2024	NON-COMPETING CONTINUATION	$66,782
														Subtotal = $667,818

Issue Date FY: 2023 ( Subtotal = $711,752 )
2023	2023	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Drug Use and Addiction Research Programs	000	1	4/14/2023	NEW	$711,752
														Subtotal = $711,752

Grand Total All Awards = $2,640,774

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Influence of Orexin Antagonism on Methamphentamine Demand

Award Number: R01DA055634

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/2026

PERIOD OF PERFORMANCE END DATE: 12/31/2027

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