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The contribution of the endocannabinoid system to sex differences in THC-associated reward

Award Number: K01DA065775
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 08/01/2026
PERIOD OF PERFORMANCE END DATE: 07/31/2031

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The contribution of the endocannabinoid system to sex differences in THC-associated reward - PROJECT SUMMARY Women experience enhanced rewarding effects from delta-9-tetrahydrocannabinol (THC), the primary psychoactive constituent of cannabis, presenting a unique risk factor for the development of cannabis use disorder (CUD) and a potential target for individualized treatment. It has been hypothesized that sex differences in THC-associated reward may be mediated by sex differences in the endocannabinoid (eCB) system, including increased cannabinoid receptor expression in reward-related brain regions and estrogen-dependent expression of eCB synthetic and degradative enzymes. Yet, studies directly examining the relationship between sex differences in the eCB system and THC-associated reward are limited to-date and have not been conducted in individuals with CUD. The proposed project will examine sex differences in putative eCB expression and function in individuals with CUD using a multi-modal human laboratory paradigm. Adults with CUD (n=134) will first undergo pharmacogenetic screening. ECB-related genetic polymorphisms (i.e. in CNR1, FAAH), half of which have been shown to increase eCB expression, will be examined for associations with retrospective subjective ratings of cannabis-associated reward and differential prevalence across sexes in this sample. A sub-sample of participants (n=20/sex, matched by presence of eCB-related risk alleles) will be concurrently recruited for two human laboratory dosing sessions to assess the contributions of sex and genetics to acute THC-induced reward. At each session, participants will receive either 40 mg oral THC or placebo and will complete subjective assessments of acute drug reward; proton magnetic resonance spectroscopy (MRS) imaging of the nucleus accumbens, a brain region critical in reward processing; and repeated blood draws to assess peripheral eCB tone. By synthesizing pharmacological, genetic, and neuroimaging approaches, this study will clarify the role of central eCB signaling in sex differences in THC-associated reward, which can be applied to risk assessment for CUD and inform precision medicine approaches to substance use disorder treatment. This research aligns with NIDA’s goal of understanding intersections between drugs, the brain, and behavior and with the posted notice of special interest examining the role of the eCB system in chronic disease. Additionally, this research provides an essential, hands-on component to a comprehensive career development plan with the following aims: (1) develop expertise in the development and oversight of trials implementing pharmacological probes; (2) attain proficiency in the collection, analysis, and interpretation of MRS data; (3) gain experience pharmacogenetic data analysis and interpretation; and (4) enhance skills in scientific writing, grant writing, and scientific communication. Through a combination of personalized mentorship, didactics, and hands-on research experience, this training program will equip Dr. Martin with the skills necessary to achieve her long-term goal of becoming an independent investigator in cannabinoid neuropsychopharmacology.


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 = $207,792 )
2026	2026	THE MEDICAL UNIVERSITY OF SOUTH CAROLINA	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	Drug Use and Addiction Research Programs	000	1	7/22/2026	NEW	$207,792
														Subtotal = $207,792

Grand Total All Awards = $207,792

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The contribution of the endocannabinoid system to sex differences in THC-associated reward

Award Number: K01DA065775

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 08/01/2026

PERIOD OF PERFORMANCE END DATE: 07/31/2031

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