<p>The aim of this article is to review the neurobiological changes associated with methamphetamine use disorder (MUD) and consider what implications they have for the development of effective pharmacotherapies. Novel pharmacotherapies are urgently needed to address the complex neurobiological changes that occur both during and after MUD. Current approaches are modelled on maintenance therapies for opioid use, particularly with the use of prescription stimulant medications to substitute for illicit methamphetamine. Existing evidence suggests that these have limited effectiveness, and enthusiasm has been dampened by concerns about the risk of toxicity. We identify an opportunity to look beyond maintenance therapies and to consider alternative models of pharmacotherapy that support the initiation and maintenance of abstinence. In doing this, we highlight the complexity of the neurobiological changes that occur both during and after cessation of methamphetamine use. We identify a need for pharmacotherapies that can address the lasting neurobiological changes from long-term methamphetamine use to improve treatment engagement and retention as well as functional recovery and to reduce relapse risk.</p>