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Effects of the Orexin Dual Receptor Antagonist Suvorexant on Cannabis Withdrawal and Self-Administration: a Controlled Inpatient Human Laboratory Study in People with Cannabis Use Disorder

Award Number: R01DA065557
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2026
PERIOD OF PERFORMANCE END DATE: 06/30/2031

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Effects of the Orexin Dual Receptor Antagonist Suvorexant on Cannabis Withdrawal and Self-Administration: a Controlled Inpatient Human Laboratory Study in People with Cannabis Use Disorder - ABSTRACT Cannabis use disorder (CanUD) is a growing public health concern with no approved treatments, so novel targets for intervention development are needed. Recently, the orexin system has gained considerable attention for its involvement in addiction. Endogenous orexin neuropeptides act on two receptors (OXR1 and OXR2) to control sleep, food intake and other adaptive behaviors. Orexin neurons are highly interconnected with brain reward regions and the orexin system is also involved in behavior maintained by maladaptive drug rewards. Encouragingly, a recent trial found that the dual orexin OXR1/OXR2 antagonist suvorexant improved withdrawal symptoms in people with opioid use disorder during a buprenorphine taper. Orexin and cannabinoid (CB) systems functionally interact, suggesting that suvorexant might also be effective for CanUD. The CB system also has two primary receptors (CBR1 and CBR2) as well as endogenous ligands (e.g., 2-AG and AEA). Receptors from these two systems are co-localized in several brain areas, they form heterodimers, their activation triggers common intracellular signaling cascades, and orexins suppress neuron activity through cannabinoid signaling. To date, limited research has investigated the orexin system as it relates to CanUD, though initial preclinical results are promising. Specifically, self-administration of a CB agonist was reduced by an OXR1 antagonist and in OXR1 knockout mice. In addition, elevation of dopamine in the nucleus accumbens was lower in OXR1 knockouts following CB agonist administration. The available literature supports the continued evaluation of orexin ligands such as suvorexant for CanUD, and the immediate need for CanUD interventions bolsters this strategy. To this end, we propose to conduct a rigorous 8-day inpatient experiment that will assess the initial efficacy of suvorexant for treating people with CanUD. Two groups of non-treatment- seeking subjects (N=31/group), matched on age, sex and cannabis use frequency, will be admitted to the inpatient research unit and maintained on placebo or active suvorexant (20 mg). Cannabis withdrawal will be assessed across the first six inpatient days, which will capture the peak response (typically 2-6 days after last use). After the 6-day withdrawal assessment, subjects will complete two smoked cannabis (5 mg THC) versus money ($0.50 and $5.00) choice sessions. The subjective effects of cannabis-suvorexant combinations will also be measured. The proposed research will fill a significant knowledge gap by providing much needed clinical data on the potential use of suvorexant to treat CanUD. These results will also reveal whether suvorexant might be an effective treatment by attenuating withdrawal and/or the reinforcing effects of cannabis. Positive findings from this experiment would provide the impetus for a subsequent large, multi-site clinical trial to test the efficacy of suvorexant in people seeking treatment for their cannabis use.


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: 2027 ( Subtotal = $0 )
2027	2026	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE	LEXINGTON	KY	40526	FAYETTE	USA	Drug Use and Addiction Research Programs	000	1	10/14/2026	NEW	$0
														Subtotal = $0

Issue Date FY: 2026 ( Subtotal = $611,927 )
2026	2026	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE	LEXINGTON	KY	40526	FAYETTE	USA	Drug Use and Addiction Research Programs	001	1	9/14/2026	NEW	$0
2026	2026	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE	LEXINGTON	KY	40526	FAYETTE	USA	Drug Use and Addiction Research Programs	000	1	9/11/2026	NEW	$611,927
														Subtotal = $611,927

Grand Total All Awards = $611,927

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Effects of the Orexin Dual Receptor Antagonist Suvorexant on Cannabis Withdrawal and Self-Administration: a Controlled Inpatient Human Laboratory Study in People with Cannabis Use Disorder

Award Number: R01DA065557

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/15/2026

PERIOD OF PERFORMANCE END DATE: 06/30/2031

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