BackgroundHyperammonemia is an adverse effect that poses clinical uncertainty around valproic acid (VPA) use. The prevalence of symptomatic and asymptomatic hyperammonemia and its relationship to VPA concentration is not well established. There is also no clear guidance regarding its management. This results in variability in the monitoring and treatment of VPA–induced hyperammonemia. To inform clinical practice, this systematic review aims to summarize evidence available around VPA-associated hyperammonemia and its prevalence, clinical outcomes, and management.MethodsAn electronic search was performed through Ovid MEDLINE, Ovid Embase, Web of Science, and PsycINFO using search terms that identified hyperammonemia in patients receiving VPA. Two reviewers independently performed primary title and abstract screening with a third reviewer resolving conflicting screening results. This process was repeated during the full-text review process.ResultsA total of 240 articles were included. Prevalence of asymptomatic hyperammonemia (5%–73%) was higher than symptomatic hyperammonemia (0.7%–22.2%) and occurred within the therapeutic range of VPA serum concentration. Various risk factors were identified, including concomitant medications, liver injury, and defects in carnitine metabolism. With VPA discontinued, most symptomatic patients returned to baseline mental status with normalized ammonia level. There was insufficient data to support routine monitoring of ammonia level for VPA-associated hyperammonemia.ConclusionsValproic acid–associated hyperammonemia is a common adverse effect that may occur within therapeutic range of VPA. Further studies are required to determine the benefit of routine ammonia level monitoring and to guide the management of VPA-associated hyperammonemia.