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The modes of action of pharmacological treatments for ADHD are not fully understood; however, agents such as methylphenidate, amfetamine, atomoxetine and guanfacine all appear to have distinct effects on dopamine (DA) and noradrenaline (NA) signalling pathways in the brain.1-34

There are numerous mode-of-action theories and hypotheses; some with stronger evidence than others, and some that are more widely accepted than others.

Childhood/adolescent ADHD and treatment effects in the brain by Dr Mitul Mehta

Note: please use Chrome to view this interactive guide

An interactive guide to the MOA of selected medications used in the treatment of ADHD

This is an MOA of pharmacological treatments only. Pharmacological treatment is not indicated for all patients and it must be used as part of a multimodal treatment approach


Although the precise mode of action of methylphenidate in humans with ADHD is not fully understood, current understanding is that methylphenidate targets the dopamine transporter (DAT) and the noradrenaline transporter (NET), inhibiting DA and NA reuptake, and therefore increasing DA and NA levels in the synaptic cleft.1,2,4,5,7,20,30,31

Figure: Hypothesised mode of action – methylphenidate2,5,7,20,30,31

Hypothesised mode of action – methylphenidate

It should be noted that studies in animals19,23 and in vitro studies13 have been inconclusive regarding the effect of methylphenidate on the release of DA and NA into the synapse.


Although the precise mode of action of amfetamine in humans with ADHD is not fully understood, amfetamine is thought to have a dual mode of action on DA and NA.

Hypothesised mode of action:

  • Targets DAT and NET, inhibiting DA and NA reuptake, and therefore increasing DA and NA levels in the synaptic cleft.15,20,31-33
  • Amfetamine also enters the presynaptic neuron, preventing DA/NA from storing in the vesicles, and promotes the release of catecholamines from vesicles into the cytosol and ultimately from the cytosol into the synaptic cleft.21,23,28,35,36
Figure: Hypothesised mode of action – amfetamine15,17,18,20,23,28,31-34

Hypothesised mode of action – amfetamine

Different mechanisms have been proposed to explain how amfetamine enhances the release of DA and NA into the synaptic cleft.

Competitive effects at vesicular monoamine transporter type 2 (VMAT2)

  • Amfetamine is known to bind to VMAT2, which mediates uptake of the neurotransmitter from the cytoplasm into presynaptic vesicles.21
  • Data suggest that amfetamine competes with neurotransmitter for uptake into the vesicles, where it displaces neurotransmitter into the cytoplasm.21
  • An in vitro study has supported the hypothesis that amfetamine inhibits the uptake of neurotransmitter into presynaptic vesicles through binding to VMAT2, and also promotes the release of DA into the synapse.37
  • A computer simulation model has described how amfetamine competes with DA for binding to VMAT.38

Reverse transport actions at DAT/NET

Amfetamine is hypothesised to reverse neurotransmitter uptake at transporter molecules, and studies in rat brain tissue have suggested that this process is dependent on protein kinase C activity.17

  • In a DAT-expressing cell line, application of amfetamine has been shown to lead to DAT-mediated efflux of DA via a reverse transport action, and possibly by a process resulting in rapid bursts of DA efflux through a channel-like mode of DAT.18
  • A study in an invertebrate cell line has indicated that amfetamine redistributes DA from vesicles into the cytosol, promoting release into the synapse through reverse transport.34
  • A study using striatal tissue from mice with and without DAT has supported a role for DAT in mediating the release of DA from neurons following application of amfetamine.39

These two principal modes of action lead to increased levels of DA and NA in the synaptic cleft.

  • Amfetamine increased extracellular and synaptic DA levels in the striatum of rats and primates.28,33


Although the precise mode of action of atomoxetine in humans with ADHD is not fully understood, atomoxetine is thought to target the NET.

Hypothesised mode of action: targets the NET, inhibiting the reuptake of NA, therefore increasing NA levels in the synaptic cleft.16,22

Atomoxetine demonstrated selective inhibition of NET, and not DAT, in cell lines expressing human transporter molecules.16

Figure: Hypothesised mode of action – atomoxetine16,22

Hypothesised mode of action – atomoxetine

This inhibition leads to increased levels of NA in the synaptic cleft:

  • Atomoxetine increased extracellular levels of DA and NA in the prefrontal cortex (PFC) of rats (NET is more abundant than DAT in the PFC and is known to take up DA as well as NA); however, atomoxetine did not increase extracellular DA levels in the striatum or nucleus accumbens, which was observed with methylphenidate.16
  • In another study, atomoxetine was again shown to increase extracellular levels of DA and NA in the PFC of rats; atomoxetine also increased extracellular levels of NA in the lateral hypothalamus, occipital cortex, dorsal hippocampus and cerebellum, but had no effect on extracellular DA levels in the hypothalamus or occipital cortex (regions where DA was quantifiable).22


Although the precise mode of action of guanfacine in humans with ADHD is not fully understood, guanfacine is thought to selectively target postsynaptic α2A-adrenergic receptors.

Hypothesised mode of action: guanfacine binds to postsynaptic α2A-adrenergic receptors, mimicking NA.24

Preclinical evidence suggests that guanfacine can modulate synaptic transmission in the PFC according to the following postsynaptic effects:

  • Stimulation of α2A-adrenergic receptors by guanfacine reduces cAMP production, closing hyperpolarisation-activated cyclic nucleotide (HCN)-gated ion channels and improving the efficacy of synaptic transmission in the PFC of rats.24
  • However, evidence from in vitro studies suggests that HCN-gated channels may have either a depolarising or hyperpolarising effect on excitatory postsynaptic potential (EPSPs), depending on the strength of the excitatory inward current generated by them.40
  • In vitro and animal studies have also indicated that stimulation of postsynaptic α2A-adrenoceptors by guanfacine may suppress EPSPs in the PFC, although the mechanism does not appear to involve HCN-gated channels.26,29
  • Such mechanisms are hypothesised to fine tune neurotransmission in the PFC, as appropriate and according to the context.26,29
  • Note that some brain networks may be over-activated in ADHD, whereas others may be under-activated.41
  • Limited evidence from in vitro studies suggests that guanfacine may also promote the maturation, and increase the number and density, of dendritic spines, a type of postsynaptic structure, in cultured rodent PFC neurons.25,27,42
Figure: Hypothesised mode of action – guanfacine24

Hypothesised mode of action – guanfacine

Guanfacine is a selective agonist of α2A-adrenergic receptors,40 the predominant subtype in the frontal cortex, cerebellum and hippocampus of the human brain.43

  • A study in a rat model of ADHD has indicated that it is binding to postsynaptic α2A-adrenergic receptors, rather than presynaptic α2A-adrenergic receptors, that may be responsible for the effects of guanfacine on attention/cognition.44
  • While guanfacine has high selectivity for the α2A-adrenoceptor, in vitro studies suggest that clonidine is a non-selective α2A agonist that binds to other α2-adrenoceptor subtypes, as well as imidazoline receptors, with a greater affinity than guanfacine.45,46
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