Hyperammonemia is an adverse effect that poses clinical uncertainty regarding the prescription of valproic acid (VPA) use. The prevalence of symptomatic and asymptomatic hyperammonemia and its relationship to VPA concentration is not well established. In this podcast, clinical pharmacists Michelle Gnrya and Yiu-Ching Jennifer Wong of St. Paul’s Hospital in Vancouver discuss their systematic review that summarizes evidence available regarding VPA-associated hyperammonemia and its prevalence, clinical outcomes, and management. Their review is published in the May-June 2023 issue of the Journal of Clinical Psychopharmacology. The review found various risk factors for this common adverse effect, 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. Further studies are required to determine the benefit of routine ammonia level monitoring and to guide the management of VPA-associated hyperammonemia.