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BackgroundReviews and meta-analyses suggest that substance use and suicidality (i.e., suicidal ideations and attempts) are associated in youth, but the direction of this association remains unclear. Theoretically, the secondary psychiatric disorder hypothesis (SPDH) posits that substance use leads to suicidality, while the secondary substance use disorder hypothesis (SSUDH) posits that suicidality leads to substance use. To clarify these associations, this meta-analysis systematically reviewed studies that examined the prospective associations between SUDs and suicidality in youth (age 25 and younger) and compared results according to the direction of the association.MethodsWeb of Science, Embase, PsycINFO, PubMed, Medline and ProQuest Dissertations & Theses Global were searched from inception to March 8, 2020, and 55 effect sizes from 23 samples were included and analyzed using a three-level meta-analysis.ResultsSUDs significantly predicted subsequent suicidality (OR = 2.16, 95%CI 1.57–2.97), suicidality significantly predicted subsequent SUDs (OR = 2.16, 95%CI 1.53–3.04), and these effect sizes did not differ (p = 0.49).ConclusionsConsidering that 65% of reviewed studies only examined the SPDH, this review highlights that more attention should be given to the SSUDH, and that studies should examine bidirectional associations between SUDs and suicidality across time. Clinically, because SUDs and suicidality were found to influence each other, results suggest that mental health and SUDs should ideally be detected and treated early, and that co-occurring disorders should be assessed and treated concomitantly.