Abstract
Centanafadine (EB-1020, CTN), also known as (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, is a norepinephrine-preferring triple (norepinephrine–dopamine–serotonin) reuptake inhibitor. The free base has a molecular formula C15H15N and a molecular weight of 209.3 g/mol; the drug is formulated as the hydrochloride salt (C15H15N·HCl, 245.7 g/mol). The molecule consists of a 3-azabicyclo[3.1.0]hexane core bearing a naphthalen-2-yl group at position 1, with (1R,5S) stereochemistry. Centanafadine is highly bound to plasma proteins, with an unbound fraction of less than 0.01, and it distributes extensively into extravascular tissues. The compound has a mean elimination half-life of 5.2 h and readily crosses the blood–brain barrier. Centanafadine is metabolized primarily by monoamine oxidase A to a lactam metabolite that lacks pharmacological activity. Clearance occurs predominantly through metabolism followed by renal excretion, with a minor contribution from fecal elimination.
MECHANISM OF ACTION:
Attention-Deficit/Hyperactivity Disorder (ADHD) is one of the most prevalent neurodevelopmental disorders worldwide, affecting approximately 5–7% of children and 2% of adults. Characterized by persistent inattention, hyperactivity, and impulsivity, ADHD inflicts substantial impairment across physical health, academic performance, social interaction, and professional functioning. It is also commonly associated with comorbid psychiatric conditions such as depression, anxiety, and bipolar disorder. Its neurobiological basis involves dysregulation of three monoaminergic systems, including norepinephrine (NE), dopamine (DA), and serotonin (5-HT). NE is primarily synthesized by neurons in the locus coeruleus (LC), which project extensively to the prefrontal cortex (PFC) to regulate attention and working memory. DA is mainly synthesized by neurons in the ventral tegmental area (VTA) and substantia nigra (SN), where it mediates reward processing, motor activity, and impulse control. In contrast, serotonin is primarily produced by neurons in the dorsal and median raphe nuclei. Serotonergic neurons innervate the prefrontal cortex and striatum, and abnormalities in the serotonin pathway are linked to mental illness. Converging neuroimaging, genetic, and pharmacological evidence demonstrates impairment in all three monoaminergic pathways in ADHD. NE, DA, and 5-HT are cleared from the synaptic cleft via reuptake by their respective presynaptic transporters, namely the norepinephrine transporter (NET), dopamine transporter (DAT), and serotonin transporter (SERT), primarily within the PFC/cortex, striatum, and forebrain serotonergic projection areas, respectively. Centanafadine is the first-in-class norepinephrine, dopamine, and serotonin reuptake inhibitor (NDSRI) and central nervous system (CNS) stimulant. Centanafadine inhibits NET, DAT, and SERT at ratios of 1:6:14 with half-maximal inhibitory concentration (IC50) values of 6 nM, 38 nM, and 83 nM in vitro, respectively. Centanafadine increases the extracellular concentrations of NE and DA in the prefrontal cortex, as well as the extracellular concentration of DA in the striatum, thereby improving working memory, sustained attention, and impulse control. In addition, SERT inhibition increases 5-HT availability in the PFC, amygdala, and orbitofrontal cortex, contributing to improved emotional regulation while reducing impulsivity and common comorbid symptoms such as anxiety and depression. Notably, centanafadine has abuse and misuse potential, but it does not produce physical dependence. Together, these complementary mechanisms target the core cognitive, behavioral, and emotional dysfunctions associated with ADHD. The illustration was created using BioRender (https://www.biorender.com).
NAME:
Centanafadine (also known as EB-1020 and CTN); FDA-approved under the brand name SIMTRIYO® (extended-release capsules, for oral use).
DRUG CLASS:
Centanafadine is a first-in-class, small-molecule norepinephrine–dopamine–serotonin reuptake inhibitor (NDSRI) and central nervous system stimulant, developed to treat ADHD.
CLINICAL USE:
Centanafadine is indicated for ADHD in adults and in pediatric patients aged 6 years and older who weigh at least 20 kg. The FDA-recommended dosages, taken orally once daily with or without food, are 210 mg in adults (maximum 280 mg), 280 mg in adolescents aged 13–17 years, and 140–280 mg by body weight in children aged 6–12 years.
DEVELOPED BY:
Otsuka Pharmaceutical Co., Ltd. (originally developed by Neurovance Inc., a Euthymics Bioscience spin-off, which was acquired by Otsuka in 2017)
ADVERSE EFFECTS:
Common side effects include headache, decreased appetite, insomnia, nausea, dry mouth, and diarrhea in adults; rash and decreased appetite in children aged 6 to 12 years; decreased appetite, nausea, rash, headache, and abdominal pain in adolescents. Centanafadine carries boxed warnings for suicidal ideation and behaviors in pediatric patients aged 6 years and older, as well as for abuse, misuse, and addiction.
TIMELINE:
2013–2014: completed Phase 2 trial, NCT01939353.
2015–2016: completed Phase 2 trial, NCT02547428.
2019–2020: completed Phase 3 trial, NCT03605680; NCT03605836.
2019–2021: completed Phase 3 long-term safety trial, NCT03605849.
2022–2023: completed Phase 3 trial in adolescents, NCT05257265.
2022–2025: completed Phase 3 trial in children, NCT05428033.
2022–2026: completed Phase 3 long-term safety trial in children and adolescents, NCT05279313.
2025–2026: completed Phase 3b trial, NCT06973577.
November 2025: NDA 218145, New drug application by Otsuka Pharmaceutical Co., Ltd.
January 27, 2026: FDA accepted the New Drug Application (NDA) for priority review.
July 24, 2026: FDA approval for centanafadine (SIMTRIYO®).
Acknowledgments
J.J. is supported by the National Institutes of Health (NIH)/National Institute of Neurological Disorders and Stroke (Grant numbers: R01NS100947, R21NS136070, and R61/R33NS130199). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
Footnotes
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