Clinically Relevant Doses of Methylphenidate Significantly Occupy Norepinephrine Transporters in Humans In Vivo
Open accessAbstract
Background Attention-deficit/hyperactivity disorder is a psychiatric disorder that starts in childhood. The mechanism of action of methylphenidate, the most common treatment for attention deficit hyperactivity disorder, is unclear. In vitro, the affinity of methylphenidate for the norepinephrine transporter (NET) is higher than that for the dopamine transporter (DAT). The goal of this study was to use positron emission tomography to measure the occupancy of brain norepinephrine transporter by methylphenidate in vivo in humans. Methods We used (S,S)-[¹¹C] methylreboxetine ([¹¹C]MRB) to determine the effective dose 50 (ED₅₀) of methylphenidate for NET. In a within-subject design, healthy subjects (n = 11) received oral, single-blind placebo and 2.5, 10, and 40 mg of methylphenidate 75 min before [¹¹C]MRB injection. Dynamic positron emission tomography imaging was performed for 2 hours with the High Resolution Research Tomograph. The multilinear reference tissue model with occipital cortex as the reference region was used to estimate binding potential non-displaceable (BP(ND)) in the thalamus and other NET-rich regions. Results BP(ND) was reduced by methylphenidate in a dose-dependent manner in thalamus and other NET-rich regions. The global ED₅₀ was estimated to be .14 mg/kg; therefore, the average clinical maintenance dose of methylphenidate (.35-.55 mg/kg) produces 70% to 80% occupancy of NET. Conclusions For the first time in humans, we demonstrate that oral methylphenidate significantly occupies NET at clinically relevant doses. The ED₅₀ is lower than that for DAT (.25 mg/kg), suggesting the potential relevance of NET inhibition in the therapeutic effects of methylphenidate in attention-deficit/hyperactivity disorder.
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In frontal lobes, methylphenidate blocks 70% to 80% of norepinephrine transporters, which reuptake both dopamine and norepinephrine, leading to increased extracellular catecholamine levels.
“in other regions, such as frontal lobes, methylphenidate blocks 70% to 80% of norepinephrine transporters (15), which reuptake both dopamine and norepinephrine, leading to increased extracellular catecholamine levels (15).”
From Effects of stimulants on brain function in attention-deficit/hyperactivity disorder: a systematic review and meta-analysis (2014) · cites this paper as [15]
The Discussion’s Summary reports that clinically relevant methylphenidate doses block 70–80% of norepinephrine transporters, and “NET and DAT, NE and DA” explains that NET can clear dopamine as well as norepinephrine. But “Role of Prefrontal Cortex and Other Regions in ADHD” says occupancy could not be measured directly in the prefrontal cortex; similar occupancy there was an assumption. The paper also does not establish an increase in extracellular catecholamine levels from that blockade. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThe increase of IFG/insula activation with methylphenidate is likely mediated by both noradrenergic and dopaminergic mechanisms.
“The increase of IFG/insula activation with methylphenidate is likely mediated by both noradrenergic and dopaminergic mechanisms, given that in frontal regions both in humans 15, 69, 70 and in animals 69, 70 methylphenidate increases noradrenaline equally or more than dopamine via reuptake inhibition of noradrenaline transporters, which clear both catecholamines.”
From Effects of stimulants on brain function in attention-deficit/hyperactivity disorder: a systematic review and meta-analysis (2014) · cites this paper as [15]
The Introduction and Discussion (NET and DAT, NE and DA; pages unavailable) support a plausible role for both catecholamine systems: methylphenidate occupies NET and DAT, and NET can clear dopamine. The paper does not measure IFG/insula activation or show that methylphenidate raises frontal noradrenaline as much as, or more than, dopamine in humans. Its Discussion also notes a mouse finding of increased frontal dopamine without a significant noradrenaline change. (LLM, conf=0.87)
Experimental — accuracy not yet measuredMethylphenidate dose-dependently blocks the norepinephrine transporter in the thalamus and other NET-rich regions, with estimated NET occupancy of 70% to 80% at therapeutic doses of 0.35 to 0.55 mg/kg.
“NE systems have been implicated as key targets for MPH, with MPH dose-dependently blocking the NET in the thalamus and other NET-rich regions; the estimated occupancy of the NET at therapeutic doses of 0.35 to 0.55 mg/kg MPH is 70% to 80% (168).”
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- Authors
- Hannestad, J., Gallezot, J.-D., Planeta-Wilson, B., Lin, S.-F., Williams, W. A., van Dyck, C. H., Malison, R. T., Carson, R. E., & Ding, Y.-S.
- Affiliations
- Yale University (US)
- Corresponding author
- Ding, Yu-Shin
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2010-11
- Volume
- 68
- Issue
- 9
- Pages
- 854-860
- ISSN
- 0006-3223 (ISSN-L)
- PMC
- PMC3742016
- OpenAlex
- W2110412456
- Cited by
- 236
- References
- 41
- Citations by year
- 2026: 6 · 2025: 10 · 2024: 9 · 2023: 13 · 2022: 12 · 2021: 8 · 2020: 12 · 2019: 18 · 2018: 16 · 2017: 19 · 2016: 18 · 2015: 20 · 2014: 20 · 2013: 26 · 2012: 18
- FWCI
- 12.03
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biological Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Drug Abuse (DA019062, R56DA19062)
- National Center for Research Resources (UL1 RR024139)
- National Institutes of Health, and National Institutes of Health roadmap for Medical Research (K12 DA000167)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Attention Deficit Hyperactivity Disorder
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Keywords
- methylphenidate, norepinephrine transporter, attention deficit hyperactivity disorder, dose-response relationship, thalamus, binding potential, dopamine transporter, mechanism of action
- MeSH terms
- Reboxetine, Adult, Central Nervous System Stimulants, Brain, Dose-Response Relationship, Drug, Female, Humans, Magnetic Resonance Imaging, Male, Methylphenidate, Morpholines, Radioligand Assay, Positron-Emission Tomography, Norepinephrine Plasma Membrane Transport Proteins
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