Date of Award

Spring 4-11-2024

Embargo Period

4-11-2024

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Neuroscience

College

College of Graduate Studies

First Advisor

Aimee McRae-Clark

Second Advisor

Carmela M. Reichel

Third Advisor

Kevin M. Gray

Fourth Advisor

Jens H. Jensen

Fifth Advisor

Lindsay M. Squeglia

Sixth Advisor

Jane E. Joseph

Abstract

Cannabis use disorder (CUD) is increasingly prevalent in the United States, but there is no effective pharmacological means to treat it. The endocannabinoid (eCB) system has emerged as a candidate therapeutic target demonstrating some evidence of efficacy in treating CUD. However, clinical trials evaluating eCB-modulating therapeutics have historically undervalued individual differences that could contribute to variation in treatment outcome (e.g. sex, comorbid psychiatric illness). To address this gap in the literature, the present set of studies (a) compared plasma eCB tone in groups underrepresented in treatment trials for CUD (females, individuals with comorbid major depressive disorder; MDD/CUD) with males or otherwise healthy people with CUD, (b) examined group differences in behavioral predictors of relapse (withdrawal symptoms, stress response), and (c) related plasma eCB tone to these behavioral predictors. We found that, as hypothesized, women or individuals with MDD/CUD self-reported more severe cannabis withdrawal symptoms compared to men or individuals with CUD alone, respectively. Self-reported withdrawal was moderately positively associated with eCB tone across studies, with the strongest associations observed in women with CUD. In MDD/CUD, however, self-reported withdrawal appeared largely uncoupled from objective withdrawal measures and abstinence from cannabis. With respect to stress, MDD/CUD was associated with a prolonged stress response relative to CUD alone, suggesting individuals with MDD/CUD may be at a greater risk for stress-induced relapse. Individuals with MDD/CUD also presented differently from those with CUD alone in stress-associated eCB levels, raising questions as to the mechanistic role of peripheral eCBs in stress responding. Taken together, these studies demonstrate that exploration into individual differences in the eCB system, particularly in the periphery, is still in its infancy. The utility of eCB-modulating pharmacotherapeutics likely differs significantly across subpopulations of people with CUD. Greater mechanistic understanding of the eCB system across subpopulations is warranted.

Rights

Copyright is held by the author. All rights reserved.

Download

Share

COinS