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Background: Concurrent mental health problems is a major issue in opioid use disorder. As the first step in developing effective interventions, a clear understanding of factors that potentially contribute to the improvement of mental health in this population, most prominently the role of opioid medications, is required. Previous reviews did not isolate the impact of opioid agonists on mental health from those of psychosocial interventions in substitution treatment of opioid use disorder. We compared mental health outcomes between opioid medications and control conditions, i.e. placebo or waitlist, to isolate these effects.Methods: Embase, MEDLINE, PsychInfo, CINAHL Complete, Web of Science Core Collection and RCT registries were among the systematically searched databases. RCTs were included if they com- pared any opioids with each other or with a placebo/waitlist in substitution treatment of patients with opioid use disorder and reported mental health outcomes using a validated measure. Individual study-level data were extracted from all available sources. Primary outcomes included difference in standardized mean score changes (SMD) for depressive symptoms and overall mental health symptomatol- ogy between opioid agonists and placebo/waitlist. Random effects model was used for both the direct pairwise meta-analysis and network meta-analysis. (Registered at https://www.crd.york.ac.uk/pros- pero/, CRD42018109375)Results: Out of 6034 citations, 19 studies were included in the qualitative synthesis and 16 in the quantitative synthesis. Out of 19 studies, 18 had high overall risk of bias. Direct pairwise meta-analysis indicated that diacetylmorphine (DAM) outperformed methadone on overall mental health (SMD (CI95%)= -0.23 (-0.34, -0.13)). Buprenorphine outperformed waitlist or placebo on improvement of depressive symptoms (SMD (CI95%)= -0.95 (-1.53, -0.36)) and overall mental health (SMD (CI95%)= -0.68 (-1.33, -0.03)). Based on network meta-analysis for primary outcomes, buprenorphine (SMD (CI95%)= -0.61 (-1.20, -0.11)), DAM (SMD (CI95%)= -1.40 (-2.70, -0.23)), and methadone (SMD (CI95%)= -1.20 (-2.30, -0.11)) were superior to waitlist/placebo on overall mental health symp- tomatology, but none of the medications were superior to waitlist in improving depressive symptoms.Conclusions: Opioid agonists used in substitution treatment improve overall mental health, and DAM outperforms methadone in this regard which has implications for treatment guidelines. Future trials will benefit from stricter control for sources of bias.