Evaluation of abuse and addiction potential of methylphenidate by a systematic review and meta-analysis

This study aims to evaluate the misuse, abuse, and addiction potential of methylphenidate (MPH), a medication widely used in the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD). The rise in nonmedical use has necessitated a comprehensive assessment of MPH's neurobiological effects and its abuse risk. Studies published between 1980 and October 2023 were searched via Scopus, PubMed, and Web of Science and screened according to PRISMA guidelines. Ultimately, 65 studies—including clinical, epidemiological, preclinical, case-report, and cohort designs—were evaluated using systematic review and meta-analysis methods. Meta-analytic results indicated an overall MPH misuse/abuse prevalence of 5.82%, with subgroup rates of 7.57% among individuals with ADHD, 6.73% among university students, 5.47% among high school students, 4.46% among patients with substance use disorder, and 4.22% in the general population. Smaller-sample studies reported higher rates (11.44%). Clinical laboratory findings showed that high doses and rapid administration routes (intranasal, intravenous) increased "drug-liking" and reinforcing responses, and that immediate-release formulations carried higher misuse risk. Preclinical studies demonstrated consistent reinforcing, sensitizing, and cross-sensitizing effects of MPH, while reinstatement was significantly shaped by dose, pre-exposure, and strain. Case reports indicated that extremely high doses were associated with dependence, withdrawal, and medical complications. Cohort data suggested that therapeutic MPH use does not elevate long-term substance use disorder risk, although age at treatment initiation, nonmedical use or sociodemographic factors may increase vulnerability to misuse and addiction. Overall, MPH appears safe under therapeutic conditions, yet nonmedical, high-dose, and rapid-onset use poses substantial risks for misuse, abuse, and addiction.