Purpose: Narcolepsy is a rare debilitating disorder for which multiple novel pharmacological options have been approved as treatment for the past few years. The current study systematically updates the comparative efficacy and detailed safety analysis of approved wake-promoting agents in narcolepsy.Methods: Randomized controlled trials (RCTs) were searched for diagnosed narcolepsy with approved interventions. Efficacy outcomes included the Maintenance of Wakefulness Test (MWT), Epworth Sleepiness Scale (ESS), Clinical Global Impression of Change (CGI-C), and Patient Global Impression of Change (PGI-C). Safety outcomes including overall adverse event (AE) risk were measured. The study was registered at PROSPERO (CRD 42022334915).Results: The final analysis included 17 RCTs with five drug treatments: modafinil/armodafinil, sodium oxybate, pitolisant, solriam- fetol, and lower-sodium oxybate (LXB). For efficacy measures, interventions included in each outcome were effective compared with placebo. Furthermore, the magnitude of solriamfetol effect on MWT (9.11 minutes; 95% CI=7.05-11.16), ESS (-4.79; 95% CI=-6.56 to -3.01), and PGI-C (9.39; 95% CI=2.37-37.19), and LXB effect on CGI-C (9.67; 95% CI=2.73-34.26) was greater than that of other treatments included in each outcome compared with placebo. For safety measures, all interventions had an acceptable safety profile with LXB having least risk for overall AEs (0.56; 95% CI=0.20-1.53), serious AEs (0.33; 95% CI=0.09-1.20), AEs leading to treatment discontinuation (0.11; 95% CI=0.01-2.04), and all-cause discontinuation (0.04; 95% CI=0.00-0.67) compared to placebo. Placebo had the lowest risk for exploratory AEs.Conclusion: All approved interventions were effective in controlling the symptoms of narcolepsy at varying degrees with an acceptable safety profile.