Addictive Potential of Methylphenidate: A Systematic Review of Human and Preclinical Behavioral, Clinical and Neurobiological Evidence

Background/Objectives: Methylphenidate is one of the most widely prescribed psychostimulants for attention-deficit/hyperactivity disorder, with increasing global use. Its pharmacological action on dopaminergic pathways raises concerns regarding its addictive potential. This systematic review aims to synthesize current evidence on the addictive properties of methylphenidate, including misuse, abuse, tolerance, craving, and withdrawal symptoms. Methods: This systematic review was conducted in accordance with PRISMA guidelines and registered in the PROSPERO database under registration number CRD420261303803. Literature searches were performed in PubMed, Web of Science, and Google Scholar without time restrictions. Studies assessing behavioral, subjective, or neurobiological indicators of methylphenidate addiction were included. Eligible designs comprised randomized controlled trials, observational studies, neuroimaging studies, case reports, and relevant preclinical models. Study quality was assessed using the EPHPP tool. A total of 35 studies were included in the qualitative synthesis. Results: The evidence demonstrated that methylphenidate produced measurable reinforcing effects and subjective drug liking, which were found to be closely related to craving and to depend on dose, pharmacokinetics, and route of administration. Rapid increases in brain dopamine levels, particularly following non-oral or high-dose administration, were associated with higher abuse potential. Misuse was observed to be more common among individuals without ADHD and was often motivated by cognitive enhancement rather than euphoria. In contrast, appropriately monitored therapeutic use was associated with a low observed risk of substance use disorders. Pharmacodynamic tolerance was identified in a subset of patients, whereas a classical withdrawal syndrome was not consistently observed and was generally limited to symptom recurrence. Conclusions: Methylphenidate exhibits measurable addictive potential. However, its clinical significance is context-dependent. Under therapeutic conditions, the risk of addiction is low, whereas it increases substantially with non-medical use, high doses, and alternative routes of administration. These findings support careful patient selection, preference for extended-release formulations, and monitoring of misuse risk.