# Establishing Behavioral and Biological Predictors of Problematic Cannabis Use

> **NIH NIH R21** · WASHINGTON STATE UNIVERSITY · 2021 · $230,028

## Abstract

PROJECT SUMMARY
The recent wave of recreational cannabis legalization in the US has left many concerned that rates of cannabis
dependence and cannabis use disorder (CUD) will rise dramatically in the coming years. Approximately 9% of
first-time users will become dependent on cannabis, yet there are no FDA-approved pharmacotherapies for
managing CUD. This is in part due to flawed diagnostic nosology resulting in a lack of understanding of the
mechanisms that give rise to CUD, as well as a conspicuous lack of translationally relevant animal models of
cannabis use. To address these gaps in knowledge, we have developed and validated a novel model of cannabis
self-administration that delivers vaporized cannabis extracts in a response-contingent manner via the pulmonary
route of administration that is most common among human users. Our data indicate that rats exhibit stable rates
of responding for cannabis vapor that produce dose-dependent elevations in plasma Δ9-tetrahydocannabinol
(THC) concentrations and metabolic alterations that are consistent with observations in human cannabis users.
We will use this model in the proposed studies to identify behavioral and biological factors that predict high vs.
low rates cannabis-seeking behavior and subsequently determine region-specific alterations in the
endocannabinoid (ECB) system following vapor self-administration. To accomplish this goal, we will conduct a
battery of behavioral assays in male and female rats prior to vapor self-administration training. In Aim 1, we will
rigorously characterize the phenotype of rats using the National Institute of Mental Health Research Domain
Criteria (RDoC) and then determine which behavioral dimensions are most strongly associated with high vs. low
responding for cannabis vapor in our model. Given that the endocannabinoid (ECB) system is the primary target
for cannabis and is fundamentally involved in the reinforcing effects of THC, in Aim 2 we will test whether
circulating endocannabinoid (ECB) tone is a biomarker of a high-responding phenotype. Finally, given that
alterations in ECB degradation have been associated with an exaggerated subjective response to the acute
effects of cannabis and increased problematic drug use, we will next examine whether cannabis self-
administration causes alterations in ECB hydrolysis and CB1 receptor binding in reward-relevant brain regions.
We predict that measures of positive valence and arousal/regulatory systems will be the best predictors of
individual rates of cannabis self-administration, and that circulating anandamide concentration will be positively
associated with cannabis-seeking behavior. We further predict that anandamide degradation and CB1 receptor
binding will be decreased in the mesolimbic pathway of high-responding rats following cannabis self-
administration. Together, these studies will establish behavioral and biological predictors of problematic cannabis
use, which can be leveraged to improve early diagnosis o...

## Key facts

- **NIH application ID:** 10128870
- **Project number:** 1R21DA051689-01A1
- **Recipient organization:** WASHINGTON STATE UNIVERSITY
- **Principal Investigator:** Ryan Joseph McLaughlin
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $230,028
- **Award type:** 1
- **Project period:** 2021-04-15 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10128870

## Citation

> US National Institutes of Health, RePORTER application 10128870, Establishing Behavioral and Biological Predictors of Problematic Cannabis Use (1R21DA051689-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10128870. Licensed CC0.

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