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Background: The comorbidity of substance use disorders (SUDs) in bipolar disorder is among the highest in psychiatric disorders. Evidence-based controlled psychosocial or pharmacological interventions trials, which may guide treatment decisions, have not been systematically reviewed., Objective: To present a narrative review of the public health and clinical significance of this condition, including diagnostic and treatment implications, and to evaluate controlled trials conducted to date., Methods: Controlled trials reports in the English language were identified from multiple electronic databases and hand-searching bibliographies. We searched for treatment studies of bipolar disorder and comorbid SUDs (alcohol, cocaine, stimulants, opioid, tobacco, cannabis). Search period included all reports through September of 2016. We selected only randomized psychosocial studies or double-blind, placebo-controlled pharmacotherapy trials. We also reviewed reports of the public health and clinical significance and principle of managements of this condition., Results: We identified 16 treatment studies: 3 psychotherapy, and 13 pharmacotherapy trials. The following medications were evaluated: lithium carbonate, valproate, lamotrigine, topiramate, naltrexone, acamprosate, disulfiram, quetiapine, and citicoline. SUDs have substantial impact on the recognition and management of bipolar disorder. Integrated psychosocial interventions are helpful in decreasing substance abuse. Valproate and naltrexone may decrease alcohol use and citicoline may decrease cocaine use and enhance cognition., Conclusions: There is a very limited number of pharmacotherapy and an even smaller number of psychosocial interventions. Our review highlights the need for more research in this area and for larger, multisite studies with generalizable samples to provide more definite guidance for clinical practice.