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Abstract Objective Summarize the evidence on drug therapies for obstructive sleep apnea. Methods The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. PubMed, Embase, Scopus, Web of Science, SciELO, LILACS, Scopus, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov were searched on February 17th, 2023. A search strategy retrieved randomized clinical trials comparing the Apnea-Hypopnea Index (AHI) in pharmacotherapies. Studies were selected and data was extracted by two authors independently. The risk of bias was assessed using the Cochrane Risk of Bias tool. RevMan 5.4. was used for data synthesis. Results 4930 articles were obtained, 68 met inclusion criteria, and 29 studies (involving 11 drugs) were combined in a meta-analysis. Atomoxetine plus oxybutynin vs placebo in AHI mean difference of -7.71 (-10.59, -4.83) [Fixed, 95 % CI, I2 = 50 %, overall effect: Z = 5.25, p < 0.001]. Donepezil vs placebo in AHI mean difference of -8.56 (-15.78, -1.33) [Fixed, 95 % CI, I2 = 21 %, overall effect: Z = 2.32, p = 0.02]. Sodium oxybate vs placebo in AHI mean difference of -5.50 (-9.28, -1.73) [Fixed, 95 % CI, I2 = 32 %, overall effect: Z = 2.86, p = 0.004]. Trazodone vs placebo in AHI mean difference of -12.75 (-21.30, -4.19) [Fixed, 95 % CI, I2 = 0 %, overall effect: Z = 2.92, p = 0.003]. Conclusion The combination of noradrenergic and antimuscarinic drugs shows promising results. Identifying endotypes may be the key to future drug therapies for obstructive sleep apnea. Moreover, studies with longer follow-up assessing the safety and sustained effects of these treatments are needed. PROSPERO registration number CRD42022362639. apnea MetaAnalyses Meta Analyses PRISMA (PRISMA followed PubMed Embase Scopus Science SciELO LILACS Trials ClinicalTrialsgov ClinicalTrials gov 17th th 2023 ApneaHypopnea Apnea Hypopnea (AHI pharmacotherapies independently tool 54 5 4 5.4 synthesis 493 obtained 6 criteria 2 involving 1 metaanalysis. metaanalysis meta analysis. analysis meta-analysis 7.71 771 7 71 -7.7 10.59, 1059 10 59 (-10.59 4.83 483 83 -4.83 Fixed, Fixed [Fixed 9 CI I effect 525 25 5.25 0.001. 0001 0.001 . 001 0.001] 8.56 856 8 56 -8.5 15.78, 1578 15 78 (-15.78 1.33 133 33 -1.33 232 2.32 0.02. 002 0.02 02 0.02] 5.50 550 -5.5 9.28, 928 28 (-9.28 1.73 173 73 -1.73 3 286 86 2.86 0.004. 0004 0.004 004 0.004] 12.75 1275 12 75 -12.7 21.30, 2130 30 (-21.30 4.19 419 19 -4.19 292 92 2.92 0.003. 0003 0.003 003 0.003] results Moreover followup follow up needed CRD42022362639 CRD 202 5. 49 7.7 77 -7. 10.59 105 (-10.5 4.8 48 -4.8 52 5.2 000 0.00 00 8.5 85 -8. 15.78 157 (-15.7 1.3 13 -1.3 23 2.3 0.0 5.5 55 -5. 9.28 (-9.2 1.7 17 -1.7 2.8 12.7 127 -12. 21.30 213 (-21.3 4.1 41 -4.1 2.9 CRD4202236263 20 7. -7 10.5 (-10. 4. -4. 8. -8 15.7 (-15. 1. -1. 2. 0. -5 9.2 (-9. 12. -12 21.3 (-21. CRD420223626 - 10. (-10 -4 15. (-15 -1 9. (-9 21. (-21 CRD42022362 (-1 (- (-2 CRD4202236 ( CRD420223 CRD42022 CRD4202 CRD420 CRD42 CRD4