The role of polysubstance use in the development, maintenance, and treatment of stimulant use disorders.

Stimulant use disorders represent a significant public health challenge, with no U.S. Food and Drug Administration (FDA) pharmacotherapies currently available. A growing concern is that stimulant use rarely occurs in isolation. Instead, it often involves sequential or simultaneous use of multiple substances. This review explores the mechanistic, epidemiological, clinical, and preclinical dimensions of polysubstance use involving stimulants, particularly cocaine and methamphetamine. Key gaps in the existing literature are identified to underscore the critical need for polysubstance use research across epidemiological, clinical, and preclinical domains. Additionally, the review highlights the importance of fostering interdisciplinary collaborations across these domains to inform the development of more effective interventions for stimulant use disorders and to mitigate the widespread harm caused by substance use globally. SIGNIFICANCE STATEMENT: Stimulant use rarely occurs in isolation and is frequently accompanied by polysubstance use, which increases health risks and complicates prevention and treatment strategies. This review highlights critical gaps in research examining polysubstance use involving stimulants and emphasizes the urgent need for the study of the co-use of drugs and interdisciplinary collaboration. Addressing these gaps is essential to inform the development of effective interventions for stimulant use disorders.