Attention-deficit hyperactivity disorder (ADHD) is among the most common neurodevelopmental conditions, affecting children, adolescents, and adults. The hallmark symptoms—inattention, hyperactivity, and impulsivity—are linked to differences in how dopamine and norepinephrine regulate the prefrontal cortex, the brain’s control center for focus and self-regulation.

Stimulant medications remain the gold standard treatment, with success rates of 70–80%. Among these, methylphenidate, amphetamines, and lisdexamfetamine are the most widely prescribed. Although they belong to the same therapeutic family, their mechanisms, benefits, and side-effect profiles differ in ways that matter for clinical practice.

Methylphenidate: The First-Line Choice

Methylphenidate works primarily as a dopamine and norepinephrine reuptake inhibitor (DNRI). It blocks the transporters (DAT, NET) that recycle these neurotransmitters, increasing their availability in the prefrontal cortex. Unlike amphetamines, it does not strongly trigger dopamine release, making its action somewhat “cleaner.”

Clinical highlights:

• Considered the first-line treatment for children and adolescents in most international guidelines.

• Often preferred where misuse potential is a concern.

• Formulations range from short-acting (2–4 hours) to extended-release (up to 12 hours), giving flexibility for school, work, or daily life schedules.

Common side effects: appetite suppression, weight loss, insomnia, irritability, and slowed growth in children (requiring regular monitoring). Rarely, it may trigger tics or psychotic symptoms.

Amphetamines: Potent and Long-Lasting

Amphetamines go one step further than methylphenidate: they not only block DAT/NET but also stimulate presynaptic release of dopamine and norepinephrine. This “double action” makes them more potent, especially for motivation and reward processing.

• Dexamphetamine (d-amphetamine): stronger central effects.

• Mixed amphetamine salts (MAS): combine d- and l-isomers, balancing potency and duration.

Clinical highlights:

• Often used when methylphenidate fails or is poorly tolerated.

• Particularly effective in adolescents and adults.

• Available in immediate- and extended-release forms (lasting up to 12 hours).

Downsides: appetite loss, insomnia, and higher risks of misuse/diversion compared with methylphenidate. Amphetamines can also raise blood pressure and heart rate, so caution is needed in patients with cardiac risk factors.

Lisdexamfetamine: The Prodrug Innovation

Lisdexamfetamine is a prodrug of dexamphetamine. It is inactive until enzymes in the blood split off the attached amino acid (lysine). This design means:

• A gradual onset (1–2 hours) compared with other stimulants.

• A long duration (10–13 hours), covering most of the day.

• Reduced potential for misuse—snorting or injecting has no immediate effect.

Clinical highlights:

• Recommended as a first-line option alongside methylphenidate in NICE guidelines.

• Also approved for binge eating disorder in some regions.

• Once-daily dosing supports adherence and reduces rebound crashes.

Side effects: similar to other amphetamines (appetite loss, insomnia, irritability), but smoother pharmacokinetics make it more tolerable for many.

How They Compare

Practical Guideline Takeaways

• Start with methylphenidate in children and adolescents.

• If ineffective at optimal dosing, switch to lisdexamfetamine.

• If lisdexamfetamine works but is too long-acting, consider shorter-acting dexamphetamine.

• If stimulants are contraindicated, non-stimulants (atomoxetine, guanfacine) are alternatives.

• Always monitor weight, height, blood pressure, and heart rate; ECG only if cardiac risk factors are present.

Final Thoughts

While methylphenidate, amphetamines, and lisdexamfetamine all share the same therapeutic goal, their profiles differ in ways that can make one a better fit than another. Methylphenidate offers a tried-and-tested first step, amphetamines provide stronger dopaminergic action for non-responders, and lisdexamfetamine adds safety and convenience through its prodrug design.

In practice, the art lies in personalizing treatment—balancing efficacy, tolerability, lifestyle fit, and safety for each individual living with ADHD.

✦ About the Author

I’m Dr. Srinivas Rajkumar T, MD (AIIMS, New Delhi), Consultant Psychiatrist in Chennai. At my clinic, we focus on a holistic approach to mental health, combining pharmacotherapy, psychotherapy, ketamine therapy, and evidence-based neuromodulation techniques such as rTMS and tDCS.

 Mind and Memory Clinic, Apollo Clinic, Velachery, Chennai (Opp. Phoenix Mall)
 +91 85951 55808