Substance use disorders are a major public health concern in the USA and cause more deaths, illness and disabilities than any other modifiable health problem in the USA. Chronic and excessive use of alcohol, methamphetamines, cocaine, cannabinoids, heroin, and tobacco products individually and in various combinations (i.e., polysubstance use disorder, PSUD), have been linked to numerous abnormalities in human brain biology and cognition. Nearly 50% of all individuals with substance abuse problems have PSUD and more than half are also nicotine dependent. Comorbid chronic cigarette smoking in PSUD may be of considerable clinical and functional relevance, as recent research provides converging lines of evidence that cigarette smoking adversely affects brain morphology, blood flow, biochemistry, and cognition. These smoking-related biological findings are similar in nature to those observed in substance abuse and involve major components of the mesocorticolimbic reward circuitry, which is implicated in the initiation and maintenance of all forms of addiction. Furthermore, chronic smoking hinders neurobiological and cognitive recovery in alcoholics, and smoking is related to higher levels of alcohol and substance use after treatment. Research on the neurobiological and cognitive consequences of PSUD is sparse and has not yet considered the potential modulating effects of chronic smoking on recovery. Additionally, although relapse is common in PSUD, the neurobiological and cognitive correlates of relapse in this population are poorly understood. Recent research increasingly implicates abnormalities of the reward circuitry as a major contributing factor to relapse in all substance use, but corresponding evidence in PSUD is lacking. We hypothesize that (i) chronic cigarette smoking has measurable adverse effects on neurobiology and cognition in PSUD, especially in major components of the mesocorticolimbic reward pathway, (ii) smoking is associated with diminished cognitive recovery in short-term abstinent PSUD, and (iii) the proposed neurobiological and cognitive measures distinguish individuals who abstain from those who resume substance use after treatment. We will combine state-of-the-art magnetic resonance methods with cognitive assessment to measure consequences of PSUD and chronic cigarette smoking in 20 smoking and 20 non-smoking polysubstance users at entry into treatment for substance use disorders. Baseline magnetic resonance studies will compare these groups on measures of regional brain volumes, blood flow and metabolites markers of neuronal and glial viability, as well as major neurotransmitter systems. Cognitive testing will assess brain function immediately after detoxification and after 4-6 weeks of monitored abstinence from substances. This innovative research investigates neurobiological and cognitive effects of chronic smoking in PSUD. Results from this exploratory and translational proposal will inform future research in PSUD and other substance use disorders, may help to predict treatment outcome, and will have major implications for public health education and policy making.