Full-text articles were screened and reviewed to provide an update on pitolisant and other histamine-3 receptor antagonists. Methods: A database search of PubMed, Google Scholar, and was performed in June 2020. These central effects are mediated by the histamine-3 auto receptors, the modulation of which is thought to be beneficial for the treatment of disorders that impair cognition or manifest with excessive daytime sleepiness. Background: Besides its well-known role as a peripheral chemical mediator of immune, vascular, and cellular responses, histamine plays major roles in the central nervous system, particularly in the mediation of arousal and cognition-enhancement.