ADHD Beyond Dopamine: What Is the Science Actually Telling Us

The Society Journal | Research Insight

Abstract

Attention-deficit/hyperactivity disorder (ADHD) is frequently described in popular discourse as a condition caused by “low dopamine”. Dopamine is unquestionably relevant to ADHD: it participates in attention, motivation, reward processing and cognitive control, and several established ADHD medications influence catecholaminergic signalling. Yet contemporary research does not support the stronger proposition that ADHD can be explained as a uniform dopamine-deficiency disorder.

A critical review by MacDonald et al. (2024), examining more than four decades of human and animal research, concluded that there is evidence for dopaminergic involvement in ADHD but limited evidence for a general hypodopaminergic state as its defining mechanism. More recent research has further broadened the biological picture. Large genomic studies implicate thousands of common variants as well as rarer coding variants; neuroimaging studies identify subtle differences in distributed neural systems rather than a single diagnostic brain signature; and research increasingly points towards interactions among dopamine, noradrenaline, glutamate, GABA and other biological pathways.

This Research Insight examines what contemporary evidence actually supports, what remains uncertain, and why moving beyond a simplistic dopamine narrative may provide a more scientifically useful understanding of ADHD.

Keywords: ADHD, dopamine, genetics, neurodevelopment, neuroimaging, neurotransmission, genomics, biomarkers

Editorial approach

This article is a narrative research synthesis, not a systematic review or scoping review. It prioritises recent peer-reviewed reviews, large-scale genomic studies, mega-analyses and emerging longitudinal research relevant to the biological understanding of ADHD.

The purpose is not to provide an exhaustive review of every biological hypothesis associated with ADHD, but to evaluate one influential public explanation: that ADHD is fundamentally a disorder of “low dopamine”.

The appeal of the dopamine explanation

The dopamine explanation has intuitive appeal.

Dopamine contributes to reward processing, motivation, reinforcement learning, movement and aspects of attention and executive function. These are domains frequently discussed in relation to ADHD. Stimulant medications such as methylphenidate and amphetamine also affect catecholamine signalling, including dopamine, and can substantially reduce core ADHD symptoms in many individuals.

It therefore became tempting to convert two defensible observations—

dopamine is involved in ADHD, and
medications affecting dopaminergic systems can improve ADHD symptoms

—into a much stronger proposition:

people with ADHD have too little dopamine.

The scientific evidence does not justify that simple equivalence.

MacDonald, Kleppe, Szigetvari and Haavik conducted a critical review of more than 40 years of human and animal evidence on the dopamine hypothesis of ADHD. Their conclusion was carefully qualified: there is evidence that dopamine signalling is involved, but comparatively limited evidence that a generalised hypodopaminergic state is the key biological feature of ADHD. The authors instead emphasised the need to investigate developmental stage, clinical subgroups and interactions between dopamine and other neurotransmitter systems.

This is an important distinction.

Saying that dopamine participates in ADHD biology is very different from saying that ADHD is caused by a universal shortage of dopamine.

Dopamine remains important

Rejecting an overly simple dopamine-deficiency narrative does not mean that dopamine is irrelevant.

The opposite is true.

Dopamine remains one of the best-studied neurotransmitter systems in ADHD. Contemporary research continues to implicate dopaminergic pathways, particularly systems involving cortical and striatal function.

Large-scale genetics provides one example.

In 2023, Demontis et al. published a genome-wide association study involving 38,691 people with ADHD and 186,843 controls. The analysis identified 27 genome-wide significant loci and 76 potential risk genes. The genetic signal was enriched in genes expressed in several neuronal cell types, including midbrain dopaminergic neurons.

That is meaningful evidence connecting ADHD genetic liability with neuronal biology involving dopamine.

But it is not evidence for a simple brain-wide dopamine shortage.

The same study implicated numerous genes and biological processes, particularly those associated with early brain development. ADHD genetic architecture was highly polygenic rather than concentrated in a single dopamine-related pathway.

The more accurate conclusion is therefore:

dopamine is one important component of a much larger neurodevelopmental system.

Medication effectiveness does not establish cause

Pharmacology provides another reason to be careful with causal explanations.

Psychostimulants alter catecholamine availability and can improve ADHD symptoms. Atomoxetine acts primarily through inhibition of the norepinephrine transporter and is also effective for ADHD.

These observations tell us something important about biological systems that can be therapeutically modified.

They do not prove that ADHD was originally caused by a deficiency of the chemical affected by the treatment.

A medication's mechanism of therapeutic action and the original aetiology of a condition are not necessarily identical.

The comprehensive biological review published by Folego-Temoteo and colleagues in Bioscience Reports in 2026 describes contemporary ADHD neurochemical models as centred particularly on dopaminergic and noradrenergic systems, while also reviewing evidence involving serotonin, glutamate and gamma-aminobutyric acid (GABA).

The resulting picture is not one of a solitary neurotransmitter operating independently.

It is one of interacting neurochemical systems.

Beyond dopamine: noradrenaline and other neurotransmitters

Noradrenaline is especially relevant to ADHD biology.

Noradrenergic systems participate in arousal, attention, stress responses and cognitive regulation. The therapeutic effectiveness of atomoxetine further supports the clinical relevance of noradrenergic mechanisms.

Yet contemporary research also extends beyond the two catecholamines.

Glutamate

Glutamate is the major excitatory neurotransmitter in the central nervous system and contributes to synaptic plasticity, learning and neural development.

Evidence of altered glutamatergic function in ADHD comes from animal models, genetic research, biochemical studies and magnetic resonance spectroscopy.

The 2026 biological review discusses a meta-analysis of 33 magnetic resonance spectroscopy studies, comprising 874 participants with ADHD and 775 controls. In children, the pooled analysis found higher concentrations of a composite glutamate/glutamine measure in the right medial frontal region. Other studies, however, have reported different patterns depending on age and brain region.

This inconsistency is scientifically important.

It suggests that even where glutamatergic involvement exists, it cannot currently be reduced to another simple “too much” or “too little” neurotransmitter model.

GABA

Research has also examined GABA, the major inhibitory neurotransmitter in the mature central nervous system.

Some paediatric magnetic resonance spectroscopy studies have reported lower GABA concentrations in regions such as the sensorimotor cortex or striatum, while studies examining other regions, including the anterior cingulate cortex, have sometimes found no significant differences. Methodological differences in imaging technique and brain-region selection may partly account for the variability.

The current evidence therefore supports investigation of GABAergic mechanisms without establishing a universal GABA abnormality in ADHD.

Taken together, these findings reinforce a central point:

ADHD biology is increasingly being investigated as dysregulation across interacting systems rather than deficiency of one molecule.

Genetics changes the scale of the question

Some of the strongest evidence against any single-cause explanation comes from genetics.

Family and twin studies have consistently demonstrated a substantial genetic contribution to ADHD. Faraone and Larsson's major review reported an estimated heritability of approximately 74%, while the 2026 biological synthesis cites a weighted twin-study estimate of approximately 76%.

These figures require careful interpretation.

A heritability estimate does not mean that an individual's ADHD is “76% genetic”. Heritability refers to the proportion of variation in a trait within a particular population that is statistically associated with inherited genetic differences under the conditions studied.

It is a population-level concept.

More importantly, high heritability does not imply one gene or one biological pathway.

ADHD is highly polygenic.

Thousands of common genetic variants

The 2023 Demontis et al. genome-wide association study identified 27 significant loci, but its broader modelling suggested that thousands of variants collectively contribute to ADHD genetic liability.

Research published in Nature Genetics in 2025 expanded this picture further.

Van der Laan et al. analysed 290,134 ADHD symptom measurements from 70,953 unique individuals, drawn from different ages, raters and instruments, and subsequently combined those data with a large genome-wide study of clinical ADHD.

The combined analysis identified 39 independent loci, 17 of which were new, and prioritised 22 potential effector genes.

The study also supported the interpretation that clinical ADHD may represent the more impairing extreme of an underlying continuum of ADHD-related liability.

That finding should not be misinterpreted as meaning diagnosis is meaningless. Clinical ADHD involves persistent symptoms together with clinically significant impairment.

Rather, the genetic evidence suggests that biological liability is unlikely to fall neatly into two completely separate populations of “ADHD biology” and “non-ADHD biology”.

This is consistent with the wider move away from seeking a single defining biological abnormality.

Rare genetic variants add a different layer

Common variants generally contribute individually tiny increments of risk.

Rare variants can behave differently.

In an important study published online in Nature in November 2025 and appearing in volume 649 in 2026, Demontis and colleagues analysed exome-sequencing data from 8,895 individuals with ADHD and 53,780 controls.

Three genes reached exome-wide significance:

MAP1A
ANO8
ANK2

Rare deleterious variants in those genes were associated with substantially larger individual odds ratios than are normally seen for common ADHD-associated variants.

The biological interpretation was also broader than neurotransmission alone.

Protein-interaction networks associated with these genes were enriched for functions involving:

synaptic biology,
cytoskeletal organisation,
cell junctions,
RNA-related processes, and
other neurodevelopmental mechanisms.

The associated genes also showed expression across developmental stages and within several neuronal populations, including both dopaminergic and GABAergic neurons.

Yet the study contains an equally important limitation.

Rare variants do not explain ADHD in most individuals.

The authors estimated that rare class-I variant burden accounted for only a modest proportion of liability, and even the three statistically significant genes explained only part of that rare-variant component.

This therefore does not reveal “the ADHD genes”.

Instead, it adds another level to an increasingly complex genetic architecture involving both common and rare variation.

There is no single “ADHD brain”

Neuroimaging has undergone a similar conceptual transition.

Smaller studies historically produced inconsistent findings, sometimes creating the impression that ADHD might eventually be localised to one specific brain region.

Larger collaborative analyses suggest something subtler.

Norman et al. published a voxel-wise mega-analysis in the American Journal of Psychiatry in 2024 using six neuroimaging datasets.

The case-control analysis included:

1,696 young people with ADHD

and

6,737 unaffected controls.

The researchers also investigated dimensional ADHD traits across 9,890 participants.

They identified differences in resting-state connectivity involving striatal regions and cortical areas including inferior frontal, insular, supplementary motor and inferior parietal regions, together with differences involving amygdala connectivity.

But the effect sizes were small: peak Cohen's d values ranged approximately from 0.11 to 0.15.

That detail is crucial.

A statistically robust group difference does not automatically provide a clinically useful diagnostic marker.

People with and without ADHD substantially overlap biologically.

Development may matter as much as structure

A particularly interesting development appeared in Nature Biomedical Engineering on 31 August 2026.

Xu and colleagues investigated developmental trajectories of white-matter structural connectivity rather than looking only for fixed differences.

Their primary longitudinal dataset contained 6,687 typically developing scans and 1,114 ADHD scans. An independent cohort contained 355 typically developing participants and 477 participants with ADHD.

The researchers identified deviations in structural connectivity that were particularly enriched towards higher-order association networks.

Importantly, changes in these deviations over time tracked changes in ADHD symptoms.

Baseline measures also predicted 12-week treatment response to atomoxetine, but not methylphenidate, within the relevant treatment sample.

This is potentially important precision-medicine research.

It should not, however, be reported as evidence that researchers have discovered a clinically available ADHD brain scan.

They have not.

The study itself begins from the premise that validated biomarkers capable of monitoring ADHD trajectories or guiding treatment selection are currently lacking.

Independent replication, external validation and demonstration of real-world clinical utility remain necessary before findings of this kind could become routine diagnostic or treatment tools.

Biomarkers: promising science, not clinical diagnosis

This distinction is especially important because emerging ADHD research frequently attracts headlines about blood tests, brain scans or biological diagnosis.

At present, ADHD remains a clinical diagnosis.

The comprehensive 2026 review by Folego-Temoteo et al. concludes that, despite extensive investigation across neurochemistry, neuroimaging, genomics and other omics disciplines, validated biomarkers for routine clinical diagnosis and treatment guidance remain unavailable.

No single gene identifies ADHD.

No single brain-imaging feature identifies ADHD.

No measurement of dopamine establishes ADHD.

No currently validated blood test independently diagnoses ADHD.

Research biomarkers may eventually become clinically useful, particularly if multiple weak biological signals can be integrated with developmental and clinical information.

That remains an area of active investigation rather than present clinical reality.

Why heterogeneity may be the important finding

Perhaps the most consequential implication of contemporary research is that heterogeneity may not simply be an inconvenience that science has yet to eliminate.

It may be part of ADHD's biology.

Two people who both meet clinical diagnostic criteria can differ substantially in:

symptom presentation,
developmental history,
co-occurring conditions,
genetic profile,
cognitive characteristics,
medication response, and
long-term trajectory.

Genomics identifies thousands of common contributors alongside rarer variants.

Neuroimaging identifies distributed and generally small group-level effects.

Neurochemical research implicates interacting neurotransmitter systems.

Developmental research suggests that trajectories themselves may matter.

The 2026 biological review therefore characterises ADHD as highly polygenic and multifactorial, spanning multiple biological levels rather than one definitive mechanism.

This complexity does not make ADHD less biologically meaningful.

It means that biological reality is more complicated than the public shorthand used to explain it.

What the evidence currently supports

What we know

ADHD is a neurodevelopmental condition with a substantial genetic contribution.

Dopaminergic signalling is relevant to ADHD, but noradrenergic and other neurotransmitter systems are also implicated.

Large genomic studies demonstrate a highly polygenic architecture involving many common variants, while rare coding variants can confer substantially greater risk in a minority of individuals.

Large neuroimaging analyses identify differences in brain connectivity at a population level, although individual overlap between ADHD and non-ADHD populations remains extensive.

The strongest contemporary evidence therefore supports a multilevel neurodevelopmental model, not a single-neurotransmitter explanation.

What the research suggests

Different combinations of genetic, neurochemical and developmental mechanisms may contribute to clinically similar ADHD presentations.

Developmental trajectories may prove more informative than static biological snapshots.

Combining multiple forms of data—genomics, imaging, cognition, development and clinical characteristics—may eventually help identify meaningful ADHD subgroups or treatment-response profiles.

These remain research directions rather than established clinical applications.

What we do not yet know

We do not have one biological mechanism that explains ADHD in every individual.

We do not know whether reliable biological subtypes of ADHD will eventually be identified.

We do not currently possess a validated brain scan, genetic profile, neurotransmitter test or other biological marker capable of independently diagnosing ADHD.

And we cannot yet reliably predict an individual's most effective treatment from biological measurements alone.

What should research examine next?

Several priorities emerge from the evidence.

First, ADHD research needs longitudinal studies capable of following biological and behavioural development over time rather than relying predominantly on cross-sectional comparisons.

Second, genomic research needs more ancestrally and geographically diverse populations. Biological conclusions derived overwhelmingly from particular populations may not generalise globally.

Third, promising neuroimaging and molecular biomarkers require independent replication before they are translated into clinical claims.

Fourth, research needs to take heterogeneity seriously rather than automatically treating it as statistical noise.

Finally, the future may lie in integration.

Genetic susceptibility does not operate independently of brain development, developmental context, experience or other biological systems. Multi-omics, longitudinal imaging and sophisticated developmental datasets may eventually allow researchers to understand how these levels interact.

But complexity should not become an excuse for premature certainty.

The more detailed our measurements become, the greater the responsibility to distinguish an interesting association from a clinically validated mechanism.

Conclusion: dopamine is part of the story

The statement that ADHD is simply caused by “low dopamine” offers an appealing biological narrative.

The scientific literature supports something both more complicated and more interesting.

Dopamine matters.

But contemporary evidence does not establish ADHD as a universal dopamine-deficiency disorder.

Instead, ADHD appears to reflect a heterogeneous neurodevelopmental architecture involving widespread polygenic liability, rarer genetic variation, multiple neurotransmitter systems, neural-network development and biological processes that unfold across time.

Perhaps the most significant development in ADHD science is therefore not the discovery of a new molecule, gene or brain region.

It is the movement away from expecting one to explain the condition.

The central scientific question is changing.

It is no longer simply:

“Which chemical is deficient?”

Increasingly, it is:

“Which biological and developmental processes contribute to ADHD, in which individuals, at which stages of life, and with what clinical consequences?”

That question is considerably harder.

It is also much closer to where the evidence now leads.

The Society Research Position

WHAT WE KNOW

ADHD has substantial biological and genetic foundations. Dopamine is relevant, but it represents one component of a much broader neurodevelopmental picture.

WHAT THE RESEARCH SUGGESTS

ADHD may arise through multiple partially overlapping biological pathways rather than one universal mechanism.

WHAT WE DO NOT YET KNOW

There is currently no validated biological test capable of independently diagnosing ADHD or revealing its precise underlying mechanism in an individual.

WHAT SHOULD BE STUDIED NEXT

Longitudinal, diverse and multimodal research is needed to understand biological heterogeneity and determine whether emerging findings can eventually improve individual prediction and treatment.

References

1. MacDonald HJ, Kleppe R, Szigetvari PD, Haavik J. The dopamine hypothesis for ADHD: an evaluation of evidence accumulated from human studies and animal models. Frontiers in Psychiatry. 2024;15:1492126. doi: 10.3389/fpsyt.2024.1492126.

2. Folego-Temoteo I, Lima YC, Grevet EH, Vidor MV, Tavares MEA, da Silva BS, Bau CHD, Rovaris DL. A comprehensive overview of the biological foundations of ADHD. Bioscience Reports. 2026;46(6). doi: 10.1042/BSR20254061.

3. Faraone SV, Larsson H. Genetics of attention deficit hyperactivity disorder. Molecular Psychiatry. 2019;24:562–575. doi: 10.1038/s41380-018-0070-0.

4. Demontis D, Walters GB, Athanasiadis G, et al. Genome-wide analyses of ADHD identify 27 risk loci, refine the genetic architecture and implicate several cognitive domains. Nature Genetics. 2023;55:198–208. doi: 10.1038/s41588-022-01285-8.

5. van der Laan CM, Ip HF, Schipper M, et al. Genome-wide association meta-analysis of childhood ADHD symptoms and diagnosis identifies new loci and potential effector genes. Nature Genetics. 2025;57:2427–2435. doi: 10.1038/s41588-025-02295-y.

6. Demontis D, Duan J, Hsu Y-HH, et al. Rare genetic variants confer a high risk of ADHD and implicate neuronal biology. Nature. Published online 12 November 2025; volume 649:909–917 (2026). doi: 10.1038/s41586-025-09702-8.

7. Norman LJ, Sudre G, Price J, Shaw P. Subcortico-cortical dysconnectivity in ADHD: a voxel-wise mega-analysis across multiple cohorts. American Journal of Psychiatry. 2024;181(6):553–562. doi: 10.1176/appi.ajp.20230026.

8. Xu X, Fu Z, Xu H, et al. Developmental deviations of association-network structural connectivity in youths with ADHD predict symptom and treatment outcomes. Nature Biomedical Engineering. Published 31 August 2026. doi: 10.1038/s41551-026-01779-4.

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