When both safety and efficacy are taken into account, the preferred first-choice medication for treating attention-deficit hyperactivity disorder (ADHD) should most often be amphetamines for adults and methylphenidate for children and adolescents, according to research published in Lancet Psychiatry.

Guidelines on which ADHD medications should be preferred across different age groups are unclear and the safety and benefits of these medications remain controversial. The present study sought to assess the comparative tolerability and efficacy of these medications for adults, adolescents, and children with ADHD via a systematic review and meta-analysis of published literature on randomized, double-blind, controlled drug trials comparing amphetamines, bupropion, atomoxetine, guanfacine, methylphenidate, clonidine, and modafinil, with one another or with placebo. 

Drug manufacturers and study investigators were contacted for additional information on the 133 trials that were ultimately included (51 for adults, 81 for adolescents and children, and 1 for all 3 groups). The efficacy analysis closest to 12 weeks was based on 8131 adults and 10,068 adolescents and children, and the tolerability analysis was based on 5362 adults and 11,018 adolescents and children. There were insufficient data to assess efficacy and tolerability at 26 and 52 weeks.

For ADHD core symptoms rated by clinicians in adults, all drugs except modafinil were superior to placebo (0.16, -0.28 to 0.59), with amphetamines rating the most effective (SMD -0.79, 95% CI, -0.99 to -0.58), followed by methylphenidate (-0.49, -0.64 to -0.35), and bupropion (-0.46, -0.85 to -0.07). For symptoms rated by clinicians in adolescents and children, all drugs were better than placebo (amphetamines SMD -1.02, 95% CI, -1.19 to -.85, methylphenidate -0.78, -0.93 to -0.62, and atomoxetine -0.56, -0.66 to -0.45), but only methylphenidate and modafinil were superior based on teacher’s ratings (SMD -0.82, 95% CI, -1.16 to -0.48 and -0.76, -1.15 to -0.37, respectively).

Related Articles

Methylphenidate, atomoxetine, and modafinil were less well-tolerated than placebo for adults only (OR 2.39, 95% CI, 1.40-4.08; 2.33, 1.28-4.25; and 4.01, 1.42-11.33, respectively) and guanfacine was less well-tolerated than placebo for adolescents and children only (2.64, 1.20-5.81). Amphetamines were less well-tolerated than placebo for adults as well as adolescents and children (3.26, 1.54-6.92; and 2.30, 1.36-3.89, respectively).

Study investigators conclude, “Our findings represent the best currently available evidence base…to inform future guidelines internationally and shared decision-making between patients, carers, and clinicians, when a balance has to be made between efficacy and tolerability of ADHD medications.”

Disclosures: Some of the researchers disclosed ties to the pharmaceutical industry. Please see reference for a full list of disclosures.


Cortese S, Adamo N, Del Giovane C, et al. Comparative efficacy and tolerability of medications for attention-deficit hyperactivity disorder in children, adolescents, and adults: a systematic review and network meta-analysis [published online August 7, 2018]. Lancet Psychiatry. doi:10.1016/S2215-0366(18)30269-4