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Unintentional drug overdose has increased markedly in the United States. Studies document an association between psychiatric disorder and unintentional overdose; we extend this research through a preliminary test of a causal model of recurrent injection drug use mediating this relationship. In a cross-sectional study of 241 adults in New York City with a possible current substance use disorder, we conducted conventional and Imai's mediation analyses to examine if psychiatric disorder is associated with increased prevalence of ever overdosing and if recurrent injection drug use mediates this association. Our cross-sectional data permit the first step of assessing causal models: testing if statistical associations are consistent with the model. Fifty-eight percent of the sample endorsed previous psychiatric disorder diagnosis and 35.7% reported ever overdosing. Imai's mediation analysis showed that, adjusting for covariates, the total association between psychiatric diagnosis and ever overdosing (adjusted prevalence difference [aPD] = 0.16, 95% CI 0.04–0.28) was composed of a direct effect (aPD = 0.09, 95% CI −0.03 − 0.21, p = 0.136) and an indirect effect (aPD = 0.07, 95% CI 0.02–0.13). Recurrent injecting drug use contributed to 42% (ratio of indirect effect to total effect; 95% CI 12 − 100%, p = 0.02) of the association between psychiatric diagnosis and ever overdosing. Conventional mediation analysis produced similar results. Our results provide a warrant for taking the necessary next step for assessing a causal model using longitudinal data, potentially providing a strong rationale for intervening on psychiatric disorders to stem overdose. [ABSTRACT FROM AUTHOR]