ADHD medicines influence catecholamine signalling through different transporters and receptors. Their mechanisms, timing and clinical evidence need separate comparison.
1 · Quick understanding
ADHD medicines can influence catecholamine signalling through different transporters and receptors. Methylphenidate slows clearing. Amphetamines (dexamfetamine, and lisdexamfetamine once converted) both force release and slow clearing. Atomoxetine slows noradrenaline clearing. Guanfacine acts on a receptor that strengthens prefrontal signalling.
From genes to everyday experience — a six-level teaching model
Teaching model, not a diagnosis. Real systems involve hundreds of genes, many cell types and feedback loops. Solid = established mechanism · dashed = association in groups · dotted = hypothesis.
Genes
Many common variants: Twin studies estimate heritability around 74%. Genome-wide studies find many common variants, each with a very small effect; 27 loci reached significance in the largest study, with 76 candidate genes enriched for expression in early brain development. R7, W5
Rare variants: Rare protein-truncating variants and copy-number changes add risk in some people. The 2023 study implicated SORCS3 through both common and rare variants. W5, R7
Shared with other conditions: An estimated 84–98% of ADHD-influencing variants are shared with other psychiatric conditions — one reason ADHD so often co-occurs with others, and why genes cannot diagnose an individual. W5
Components
Tyrosine hydroxylase: The enzyme that makes L-DOPA from tyrosine — the usual rate-limiting step in making dopamine and noradrenaline. R8
VMAT2 (vesicle loader): Pumps dopamine from the cell fluid into storage vesicles, ready for release. Amphetamines disturb this storage and redistribute dopamine into the cell fluid. R8
DAT (dopamine transporter): Recaptures released dopamine, ending its signal. Methylphenidate blocks it; amphetamines can reverse it so it pushes dopamine out. R8, R2
NET (noradrenaline transporter): Recaptures noradrenaline — and in the prefrontal cortex, where DAT is sparse, much of the dopamine too. Atomoxetine blocks it. R9, W6
MAO and COMT: Enzymes that break dopamine and noradrenaline down inside and outside cells. R8
D1 and D2 receptors: Receive the dopamine signal. D2 receptors on the releasing cell also act as a brake (autoreceptors), feeding back to reduce release. R5, R9
Alpha-2A receptors: Noradrenaline receptors in prefrontal cortex that strengthen task-relevant network signals. Guanfacine stimulates them. R9
Store: Dopamine is packed into vesicles; unpacked dopamine is vulnerable to breakdown. R8
Release: Vesicles release their contents when the cell fires. Amphetamines add a second, firing-independent release route. R8
Clear: Transporters pull the signal back in; enzymes break it down. Most medicines act by slowing clearance or forcing release. R8, R2
Self-tune: Autoreceptors and adaptation adjust the system over time. Transporter levels appear to shift after stimulant exposure — which complicates brain-scan comparisons. R6
Circuits
Prefrontal regulation: Prefrontal cortex regulates attention, behaviour and emotion; imaging shows these regions less active, with weaker connections, in ADHD on average. Its function depends on finely tuned dopamine and noradrenaline levels. R9
Cortical maturation timing: In 223 children with ADHD versus 223 controls, half of cortical points reached peak thickness by about 10.5 years versus 7.5 years — a delay most marked in prefrontal regions. R4
Subcortical volumes: Across 23 sites, accumbens, amygdala, caudate, hippocampus and putamen were slightly smaller on average (effect sizes d −0.11 to −0.19), mainly in children; differences in adults were not significant. Medication did not explain them. R3
Reward pathway markers: In 53 unmedicated adults, PET showed lower dopamine transporter and D2/D3 receptor binding in reward regions, correlating with inattention. But a meta-analysis found transporter levels lower in drug-naive and higher in previously medicated people — so findings depend on history. R5, R6
Functions
Executive control: Holding a goal, inhibiting distractions, switching and planning. Common-variant ADHD risk is associated with weaker performance on several executive measures. W5, R9
Reward and motivation: How strongly future or delayed outcomes drive effort now. R5
Arousal and state: Matching alertness to the task — too little or too much both degrade control. R9
Experience
Starting tasks: Knowing what to do and not being able to begin — one of the most commonly described ADHD difficulties. W6
Holding intentions: Losing track of a plan between deciding and doing; forgetting why you entered a room. W6
Time awareness: Under-estimating elapsed time and time needed; 'now' and 'not now' as the only two clocks. W6
Acting before deciding: Speech or action running ahead of evaluation. W6
Connections and evidence strength
Many common variants → Cortical maturation timing: association — Risk genes are enriched for early brain development expression; the route to cortical timing is not demonstrated.
Many common variants → Reward pathway markers: association — Common-variant risk is associated with midbrain dopaminergic neuron expression (Demontis 2023).
Many common variants → Executive control: association
NET (noradrenaline transporter) → Clear: established
MAO and COMT → Clear: established
D1 and D2 receptors → Self-tune: established
Store → Release: established
Make → Store: established
Release → Prefrontal regulation: established
Release → Reward pathway markers: established
Alpha-2A receptors → Prefrontal regulation: established
Self-tune → Reward pathway markers: contested — Whether transporter differences are a cause or an adaptation to past medication is unresolved (Fusar-Poli 2012).
Prefrontal regulation → Executive control: established
Cortical maturation timing → Executive control: association
Subcortical volumes → Reward and motivation: association
Reward pathway markers → Reward and motivation: association
Prefrontal regulation → Arousal and state: established
Executive control → Starting tasks: association
Executive control → Holding intentions: association
Executive control → Acting before deciding: association
Reward and motivation → Starting tasks: association
Executive control → Time awareness: association
VMAT2 (vesicle loader) → Reward pathway markers: hypothesis — Individual differences in vesicle storage capacity shaping stimulant response is a research question, not an established ADHD mechanism.
Medicine overlays
Methylphenidate: Blocks dopamine and noradrenaline transporters, so released transmitter stays active longer. First-line in children and one of two first-line options in adults (NICE). R2, W1
Amphetamines (dexamfetamine): Enter the terminal, disturb vesicle storage and run transporters in reverse, releasing dopamine and noradrenaline independent of firing; they also block reuptake. In adults' clinician-rated trials, amphetamines had the largest average symptom effect, with lower tolerability than placebo. R8, R2
Lisdexamfetamine (Elvanse): An inactive prodrug absorbed intact and converted to d-amphetamine, mainly by red blood cells. Same active drug as dexamfetamine, delivered more gradually — a different exposure profile, not an identical one. R10, R1
Atomoxetine: Non-stimulant that blocks the noradrenaline transporter, raising noradrenaline and prefrontal dopamine. W6, R2
Guanfacine: Non-stimulant that stimulates alpha-2A receptors in prefrontal cortex, strengthening network signalling. R9
2 · Possible explanations for different responses
The review included 133 double-blind trials across age groups. In adult trials, amphetamines showed a larger average effect against placebo (SMD −0.79) than methylphenidate (−0.49); amphetamines and methylphenidate were both less well tolerated than placebo in adults.
Averages hide individual variation. Two people on the same drug can differ because of dose, timing, how quickly the drug is absorbed and converted, other medicines, sleep, and individual biological variation.
Lisdexamfetamine is absorbed intact and converted to d-amphetamine mainly by red blood cells, giving a more gradual exposure than immediate-release dexamfetamine.
Different products containing the same active drug are licensed separately; for example, Amfexa's ADHD indication is for ages 6–17 after inadequate response to methylphenidate, so adult use is off-label and a specialist decision.
NICE: consider in adults responding to lisdexamfetamine who cannot tolerate its longer profile W1
Atomoxetine
Blocks NET
Weeks to full effect
Non-stimulant
Guanfacine
Alpha-2A agonist
Weeks
Non-stimulant
5 · Deeper explanation
Amphetamines are unusual: they release catecholamines by a non-exocytic route, redistributing them from vesicles into the cell fluid and running transporters in reverse, alongside reuptake blockade.
That is why "same active drug" does not mean "same experience": a prodrug released gradually and an immediate-release tablet produce different concentration curves, and the curve shapes the effect and the side effects.
Mechanisms are well described in cells and animals; how they combine in a particular person's brain is not measurable in routine care.
Sources cited
R2 Cortese S, et al. Comparative efficacy and tolerability of medications for ADHD in children, adolescents, and adults: a systematic review and network meta-analysis. Lancet Psychiatry 2018;5(9):727–738. 133 double-blind RCTs. (Abstract read (PubMed))
R10 Pennick M. Absorption of lisdexamfetamine dimesylate and its enzymatic conversion to d-amphetamine. Neuropsychiatr Dis Treat 2010;6:317–27. (Abstract read (PubMed))
W4 Amfexa 5 mg, 10 mg and 20 mg Tablets, Summary of Product Characteristics (Medice UK). Section 4.1: ADHD in children and adolescents aged 6–17 when response to previous methylphenidate is clinically inadequate. Section 6.1 excipients: 10 mg — isomalt, magnesium stearate, yellow iron oxide; 20 mg — isomalt, magnesium stearate, red iron oxide; 5 mg — isomalt, crospovidone, magnesium stearate. link(Sections 4.1 and 6.1 checked (emc products 5004, 7403, 7404))
W1 NICE. Attention deficit hyperactivity disorder: diagnosis and management (NG87). 2018, updated 2019. Recommendations 1.7.11–1.7.14 (adult medication choice) and section 1.10 (review and discontinuation). link(Official text via search snippets and NHS shared-care documents quoting it; main page fetch blocked)
R8 Sulzer D, et al. Mechanisms of neurotransmitter release by amphetamines: a review. Progress in Neurobiology 2005;75(6):406–33. (Abstract read (PubMed))