The neuropharmacology of ADHD drugs in vivo: insights on efficacy and safety

Neuropharmacology. 2009 Dec;57(7-8):608-18. doi: 10.1016/j.neuropharm.2009.08.020. Epub 2009 Sep 15.


Results from in vivo techniques, especially intracerebral microdialysis in freely-moving rats, have provided insights into potential mechanisms responsible for the efficacy and safety of catecholaminergic drugs for ADHD treatment. The drugs reviewed come from distinct pharmacological classes: psychostimulant releasing agents, eg d-amphetamine; psychostimulant reuptake inhibitors, eg dl-threo-methylphenidate (dl-MPH), and non-stimulant reuptake inhibitors, eg atomoxetine. Psychostimulants, which currently deliver the best efficacy in treating ADHD, exhibit the following characteristics on extraneuronal catecholamine concentrations in rodent brain in vivo: 1) They enhance the efflux and function of both noradrenaline and dopamine in the central nervous system. 2) The increase of dopamine efflux that they produce is not limited to cortical regions. 3) They have a rapid onset of action with no ceiling on drug effect. d-Amphetamine has a mechanism independent of neuronal firing rate, displacing intraneuronal stores of catecholamines, delaying their reuptake and inhibiting catabolism by monoamine oxidase. dl-MPH has an enigmatic, extraneuronal action that is neuronal firing rate-dependent and reuptake transporter-mediated, yet paradoxically, almost as powerful as that of d-amphetamine. In safety terms, these powerful catecholaminergic effects also make the psychostimulants liable for abuse. Since efficacy and safety derive from the same pharmacological mechanisms, it has not yet been possible to separate these two components. However, the development of once-daily psychostimulant formulations and a prodrug, lisdexamfetamine, has improved patient compliance and markedly reduced scope for their diversion/abuse. This review will discuss the in vivo pharmacological profiles of approved catecholaminergic drugs for treatment of ADHD and implications for their clinical efficacy and abuse liability.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Adrenergic Uptake Inhibitors / adverse effects
  • Adrenergic Uptake Inhibitors / pharmacology
  • Adrenergic Uptake Inhibitors / therapeutic use
  • Amphetamine / adverse effects
  • Amphetamine / pharmacology
  • Amphetamine / therapeutic use
  • Animals
  • Atomoxetine Hydrochloride
  • Attention Deficit Disorder with Hyperactivity / drug therapy*
  • Attention Deficit Disorder with Hyperactivity / metabolism
  • Brain / drug effects
  • Brain / metabolism
  • Catecholamines / metabolism
  • Central Nervous System Stimulants / adverse effects
  • Central Nervous System Stimulants / pharmacology
  • Central Nervous System Stimulants / therapeutic use*
  • Dopamine Agents / adverse effects
  • Dopamine Agents / pharmacology
  • Dopamine Agents / therapeutic use
  • Humans
  • Methylphenidate / adverse effects
  • Methylphenidate / pharmacology
  • Methylphenidate / therapeutic use
  • Propylamines / adverse effects
  • Propylamines / pharmacology
  • Propylamines / therapeutic use
  • Stereoisomerism
  • Substance-Related Disorders / prevention & control


  • Adrenergic Uptake Inhibitors
  • Catecholamines
  • Central Nervous System Stimulants
  • Dopamine Agents
  • Propylamines
  • Methylphenidate
  • Atomoxetine Hydrochloride
  • Amphetamine