The dopamine hypothesis for ADHD: An evaluation of evidence accumulated from human studies and animal models
Hayley J. MacDonald, Rune Kleppe, Peter D. Szigetvari, Jan Haavik · 2024 · 98 citationsRead the paper
Multiple lines of evidence indicate that altered dopamine signaling may be involved in neuropsychiatric disorders and common behavioral traits. Here we critically review evidence collected during the past 40-plus years supporting the role of dopamine dysfunction in attention deficit hyperactivity disorder (ADHD). We recapitulate the basic components of dopaminergic signaling in the central nervous system, focusing on core enzymes, transporters and receptors involved in monoaminergic functions, particularly in striatal and cortical regions. We summarize key human brain imaging and genetic studies reporting associations between dopaminergic neurotransmission and behavioral traits, with an emphasis on ADHD. We also consider ADHD in the context of animal models and single gene, metabolic, and neurological disorders with established dysfunction of the dopaminergic system. Examining the evidence in this way leads us to conclude that there is evidence for the involvement of dopamine but limited evidence for a hypo-dopaminergic state per se as a key component of ADHD. We propose a path forward to increase our understanding of dopamine signaling in human behavioral traits and disorders that should particularly focus on its role in clinical subgroups, during brain development and how it interacts with other neurotransmitter systems.
What the full text shows
Theory or simulation- Limited evidence supports a general hypo-dopaminergic state (reduced DA levels) as a defining feature of ADHD. (Human clinical, genetic, imaging, and neurophysiological studies)
- Psychostimulants (methylphenidate, amphetamines) show greater effect sizes for ADHD symptom management than NE transporter inhibitors or alpha-2a agonists. (Meta-analysis of pharmacotherapies)
- Core DA-related genes are not among the major risk genes for ADHD in Genome-Wide Association (GWA) studies. (Human GWA studies)
- ADHD risk variants are enriched in genes expressed in midbrain dopaminergic neurons as well as excitatory and inhibitory neurons. (Genetic risk studies)
- Rare metabolic diseases with documented DA deficiency cause motor neurological symptoms but not typical ADHD symptoms. (Human metabolic disease models)
- Extracellular DA levels in ADHD relative to healthy controls are inconsistent, showing decreases, increases, or no change. (Neurophysiological studies)
- Setup
- Review of human clinical data, animal models (SHR, DAT KO, Coloboma mice), and genetic datasets.
- How
- Narrative multidisciplinary review of 40+ years of evidence, comparing ADHD data against animal models, GWA studies, brain imaging, and other neurological/metabolic disorders.
- Limitations
- Inconsistent results in candidate gene studies due to low power · Difficulty in isolating DA from other monoamines (NE, serotonin) · Lack of consistent neurophysiological support for frontostriatal DA deficiency
Summarized by Gemma 4 from the open-access full text · 3 Oct 2026. Read it