Polysubstance use disorder (PSUD) is more common among treatment seekers today than monosubstance use disorders. Chronic cigarette smoking is more prevalent among treated substance users than in the general population, and it is more prevalent in polysubstance users (PSU) than monosubstance users. Yet, very little is known about the neurobiological effects of PSUD and comorbid smoking, their potential relationships to neuro- cognition and related substance use behavior, or about effective treatment of PSUD. Extensive brain imaging and cognitive research indicate that monosubstance use is associated with abnormal brain biology and function that facilitate continued misuse; some of these brain abnormalities partially recover with abstinence. Further, smoking has clear detrimental effects on brain biology and function in monosubstance users (alcohol, methamphetamines), even in otherwise healthy controls. Notably, our preliminary studies show that brain abnormalities in PSU are different in extent, nature, and impact on cognition and behavior than in `pure' alcohol dependent samples with similar alcohol and tobacco use histories, and that both neurobiology and cognition improve in PSU over 3 months of abstinence. The ethnic and sociodemographic composition of PSU treatment cohorts is also distinctly different from that of `pure' alcohol dependent cohorts, altogether suggesting that they constitute different populations. We propose to study a well-defined and well-characterized group of PSU at 1- 3 weeks of abstinence with select brain magnetic resonance (MR), cognition, and self-regulation measures, to re-study abstinent PSU 3 months later, and to relate cross-sectional and longitudinal change measures to relapse and substance use assessed 6-9 months after baseline. Our regional focus is on fronto-striatal brain critical for achieving and maintaining long-term abstinence in addictive disorders. Our neuro-psychological focus is on traditional cognitive domains and measures of impulsive behavior and cognitive control. Our main neurobiological focus is on oxidative stress (OxS), hypothesized to underlie both PSUD and chronic smoking, and the neurobiological and systemic correlates of OxS. We further hypothesize that specific cognitive and regional MR abnormalities improve with abstinence and that longitudinal change measures during early remission predict subsequent relapse better than the corresponding cross-sectional measures. Additional MR measures will probe fronto-striatal neuronal injury, gliosis, glutamatergic and GABA-ergic effects, and perfusion deficits as they relate to cognition, self-regulation, and substance and tobacco use pre- and post-treatment. Studies will be conducted in treatment seekers with comorbid alcohol and cocaine use disorders (moderate to severe), with or without tobacco and mild cannabis use disorder. This hypotheses-driven proposal is aimed at identifying multifaceted determinants of continued substance misuse or abstinence as potential new targets for pharmacological and behavioral treatment of PSU. Showing neurobiological and functional improvements with abstinence will also help move public opinion to a mindset more helpfully described as `your brain in recovery'.

Public Health Relevance

Although the concurrent abuse of alcohol and illicit drugs is the most common form of substance abuse in the United States today and is often accompanied by chronic cigarette smoking, the effects of polysubstance abuse on brain biology and function are not well understood. The primary goal of this proposal is to identify new neuroimaging and neuropsychological factors that relate to increased risk for relapse in individuals seeking treatment for polysubstance abuse. These factors will then be evaluated as to their ability to serve as practical clinical predictors of relapse after treatment, in an effortto focus limited treatment resources on those at greatest risk for relapse after substance abuse treatment.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
Project #
Application #
Study Section
Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section (NPAS)
Program Officer
Grant, Steven J
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Northern California Institute Research & Education
San Francisco
United States
Zip Code
Zou, Yukai; Murray, Donna E; Durazzo, Timothy C et al. (2018) White matter microstructural correlates of relapse in alcohol dependence. Psychiatry Res Neuroimaging 281:92-100
Meyerhoff, Dieter J (2017) Structural Neuroimaging in Polysubstance Users. Curr Opin Behav Sci 13:13-18