Attention-Deficit/Hyperactivity Disorder Medication Use: Stimulant Medication and Non-stimulant Medication

Research Article
Open access

Attention-Deficit/Hyperactivity Disorder Medication Use: Stimulant Medication and Non-stimulant Medication

Yarto Lai 1*
  • 1 Elegantia College (Sponsored by Education Convergence), HKSAR, China    
  • *corresponding author yartolai07@gmail.com
Published on 20 June 2025 | https://doi.org/10.54254/2753-8818/2025.24228
TNS Vol.116
ISSN (Print): 2753-8826
ISSN (Online): 2753-8818
ISBN (Print): 978-1-80590-197-6
ISBN (Online): 978-1-80590-198-3

Abstract

This paper aims to compare the effectiveness and indications of stimulant vs non-stimulating medications for treating Attention Deficit/ Hyperactivity Disorder (ADHD). The literature review was systematic and included comparative (data on both types of drug) data from observational studies. The results indicate that stimulant medications, including methylphenidate (MPH), dexmethylphenidate (d-MPH), and lisdexamfetamine (LDX), are superior to non-stimulant medications in alleviating key symptoms of ADHD. Specifically, d-MPH has shown to have similar efficacy to racemic MPH but also has potential with longer-lasting benefit; and LDX has demonstrated slightly superior efficacy to osmotic-release oral system-MPH (OROS-MPH) in certain dose-escalation conditions. Nonetheless, a number of side effects have also been noted following the use of these medications. In contrast, the non-stimulant medication atomoxetine (ATX) has efficacy in reducing ADHD symptoms but this effect is weaker than stimulants like MPH and it does not have classical side effects such as drowsiness, nausea or emesis. Treatment decisions should be based on efficacy of drugs, and their side effects must satisfy the personalized approaches to increase its effectiveness. Further studies are needed to examine the possible long-term effects and patient preferences in those with ADHD.

Keywords:

Attention Deficit/Hyperactivity Disorder, methylphenidate, dexmethylphenidate, lisdexamfetamine, atomoxetine, stimulant medication, non-stimulant medication

Lai,Y. (2025). Attention-Deficit/Hyperactivity Disorder Medication Use: Stimulant Medication and Non-stimulant Medication. Theoretical and Natural Science,116,96-105.
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References

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[11]. Gamo, N. J., Wang, M., & Arnsten, A. F. (2010). Methylphenidate and atomoxetine enhance prefrontal function through Α2-Adrenergic and dopamine D1 receptors. Journal of the American Academy of Child & Adolescent Psychiatry, 49(10), 1011–1023. https://doi.org/10.1016/j.jaac.2010.06.015

[12]. Federici, M., Geracitano, R., Bernardi, G., & Mercuri, N. B. (2005). Actions of methylphenidate on dopaminergic neurons of the ventral midbrain. Biological Psychiatry, 57(4), 361–365. https://doi.org/10.1016/j.biopsych.2004.11.030

[13]. Jaeschke, R. R., Sujkowska, E., & Sowa-Kućma, M. (2021). Methylphenidate for attention-deficit/hyperactivity disorder in adults: a narrative review. Psychopharmacology, 238(10), 2667–2691. https://doi.org/10.1007/s00213-021-05946-0

[14]. Economidou, D., Theobald, D. E. H., Robbins, T. W., Everitt, B. J., & Dalley, J. W. (2012). Norepinephrine and dopamine modulate impulsivity on the Five-Choice serial reaction time task through opponent actions in the shell and core Sub-Regions of the nucleus accumbens. Neuropsychopharmacology, 37(9), 2057–2066. https://doi.org/10.1038/npp.2012.53

[15]. Chiara, C., Bernanda, P. M., Claudia, M., Elisa, D., Tony, M. M., Valentina, R., Sandro, G., Paolo, C., Paola, S., Augusto, P., & Emanuela, B. (2018). The Decrease in Human Endogenous Retrovirus-H Activity Runs in Parallel with Improvement in ADHD Symptoms in Patients Undergoing Methylphenidate Therapy. International Journal of Molecular Sciences, 19(11), 3286. https://doi.org/10.3390/ijms19113286

[16]. Steingard, R., Taskiran, S., Connor, D. F., Markowitz, J. S., & Stein, M. A. (2019). New formulations of stimulants: an update for clinicians. Journal of Child and Adolescent Psychopharmacology, 29(5), 324–339. https://doi.org/10.1089/cap.2019.0043

[17]. Ermer, J. C., Pennick, M., & Frick, G. (2016). Lisdexamfetamine dimesylate: prodrug delivery, amphetamine exposure and duration of efficacy. Clinical Drug Investigation, 36(5), 341–356. https://doi.org/10.1007/s40261-015-0354-y

[18]. Quintero, J., Gutiérrez-Casares, J. R., & Álamo, C. (2022). Molecular Characterisation of the mechanism of action of stimulant drugs lisdexamfetamine and methylphenidate on ADHD Neurobiology: a review. Neurology and Therapy, 11(4), 1489–1517. https://doi.org/10.1007/s40120-022-00392-2

[19]. Corona, J. C., Carreón-Trujillo, S., González-Pérez, R., Gómez-Bautista, D., Vázquez-González, D., & Salazar-García, M. (2019). Atomoxetine produces oxidative stress and alters mitochondrial function in human neuron-like cells. Scientific Reports, 9(1). https://doi.org/10.1038/s41598-019-49609-9

[20]. Logan, J., Wang, G., Telang, F., Fowler, J. S., Alexoff, D., Zabroski, J., Jayne, M., Hubbard, B., King, P., Carter, P., Shea, C., Xu, Y., Muench, L., Schlyer, D., Learned-Coughlin, S., Cosson, V., Volkow, N. D., & Ding, Y. (2007). Imaging the norepinephrine transporter in humans with (S,S)-[11C]O-methyl reboxetine and PET: problems and progress. Nuclear Medicine and Biology, 34(6), 667–679. https://doi.org/10.1016/j.nucmedbio.2007.03.013

[21]. Hussain, L. S., Reddy, V., & Maani, C. V. (2023, May 1). Physiology, noradrenergic synapse. StatPearls - NCBI Bookshelf. https://www.ncbi.nlm.nih.gov/books/NBK540977/

[22]. Sugimoto, A., Suzuki, Y., Yoshinaga, K., Orime, N., Hayashi, T., Egawa, J., Ono, S., Sugai, T., & Someya, T. (2021). Influence of atomoxetine on relationship between ADHD symptoms and prefrontal cortex activity during task execution in adult patients. Frontiers in Human Neuroscience, 15. https://doi.org/10.3389/fnhum.2021.755025

[23]. Arnsten, A. F. T. (2009). Stress signalling pathways that impair prefrontal cortex structure and function. Nature Reviews. Neuroscience, 10(6), 410–422. https://doi.org/10.1038/nrn2648

[24]. Atomoxetine: MedlinePlus drug information. (n.d.). https://medlineplus.gov/druginfo/meds/a603013.html

[25]. Clemow, D. B., Nyhuis, A. W., & Robinson, R. L. (2016). Clinical Impact of Not Achieving Recommended Dose on Duration of Atomoxetine Treatment in Adults with Attention‐Deficit/Hyperactivity Disorder. CNS Neuroscience & Therapeutics, 22(12), 970–978. https://doi.org/10.1111/cns.12595

[26]. Brown, J., Abdel‐Rahman, S., Van Haandel, L., Gaedigk, A., Lin, Y., & Leeder, J. (2015). Single dose, CYP2D6 genotype‐stratified pharmacokinetic study of atomoxetine in children with ADHD. Clinical Pharmacology & Therapeutics, 99(6), 642–650. https://doi.org/10.1002/cpt.319

[27]. Sauer, J., Ring, B. J., & Witcher, J. W. (2005). Clinical pharmacokinetics of atomoxetine. Clinical Pharmacokinetics, 44(6), 571–590. https://doi.org/10.2165/00003088-200544060-00002

[28]. Perugi, G., & Vannucchi, G. (2015). The use of stimulants and atomoxetine in adults with comorbid ADHD and bipolar disorder. Expert Opinion on Pharmacotherapy, 16(14), 2193–2204. https://doi.org/10.1517/14656566.2015.1079620

[29]. Quinn, D., Wigal, S., Swanson, J., Hirsch, S., Ottolini, Y., Dariani, M., Roffman, M., Zeldis, J., & Cooper, T. (n.d.). Comparative Pharmacodynamics and Plasma Concentrations of d-threo-Methylphenidate Hydrochloride After Single Doses of d-threo-Methylphenidate Hydrochloride and d,l-threo-Methylphenidate Hydrochloride in a Double-Blind, Placebo-Controlled, Crossover Laboratory School Study in Children With Attention-Deficit/Hyperactivity Disorder. Journal of the American Academy of Child & Adolescent Psychiatry, 43(11), 1422–1429. https://doi.org/10.1097/01.chi.0000140455.96946.2b

[30]. Quinn, D., Wigal, S., Swanson, J., Hirsch, S., Ottolini, Y., Dariani, M., Roffman, M., Zeldis, J., & Cooper, T. (n.d.). Comparative Pharmacodynamics and Plasma Concentrations of d-threo-Methylphenidate Hydrochloride After Single Doses of d-threo-Methylphenidate Hydrochloride and d,l-threo-Methylphenidate Hydrochloride in a Double-Blind, Placebo-Controlled, Crossover Laboratory School Study in Children With Attention-Deficit/Hyperactivity Disorder. Journal of the American Academy of Child & Adolescent Psychiatry, 43(11), 1422–1429. https://doi.org/10.1097/01.chi.0000140455.96946.2b

[31]. Liu, Q., Zhang, H., Fang, Q., & Qin, L. (2017). Comparative efficacy and safety of methylphenidate and atomoxetine for attention-deficit hyperactivity disorder in children and adolescents: Meta-analysis based on head-to-head trials. Journal of Clinical and Experimental Neuropsychology, 39(9), 854–865. https://doi.org/10.1080/13803395.2016.1273320

Cite this article

Lai,Y. (2025). Attention-Deficit/Hyperactivity Disorder Medication Use: Stimulant Medication and Non-stimulant Medication. Theoretical and Natural Science,116,96-105.

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The datasets used and/or analyzed during the current study will be available from the authors upon reasonable request.

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Volume title: Proceedings of the 3rd International Conference on Modern Medicine and Global Health

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Volume number: Vol.116
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References

[1]. Arnsten, A. F. (2009). ADHD and the prefrontal cortex. The Journal of Pediatrics, 154(5), I-S43. https://doi.org/10.1016/j.jpeds.2009.01.018

[2]. Polanczyk, G. V., Willcutt, E. G., Salum, G. A., Kieling, C., & Rohde, L. A. (2014). ADHD prevalence estimates across three decades: an updated systematic review and meta-regression analysis. International Journal of Epidemiology, 43(2), 434–442. https://doi.org/10.1093/ije/dyt261

[3]. Nazarova, V. A., Sokolov, A. V., Chubarev, V. N., Tarasov, V. V., & Schiöth, H. B. (2022). Treatment of ADHD: Drugs, psychological therapies, devices, complementary and alternative methods as well as the trends in clinical trials. Frontiers in Pharmacology, 13. https://doi.org/10.3389/fphar.2022.1066988

[4]. Team, E. W. (n.d.). methyl phenyl(piperidin-2-yl)acetate (CHEBI:84276). https://www.ebi.ac.uk/chebi/searchId.do?chebiId=84276

[5]. Team, E. W. (n.d.-a). dexmethylphenidate (CHEBI:51860). https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:51860

[6]. Blick, S. K. A., & Keating, G. M. (2007). Lisdexamfetamine. Pediatric Drugs, 9(2), 129–135. https://doi.org/10.2165/00148581-200709020-00007

[7]. Team, E. W. (n.d.). lisdexamfetamine (CHEBI:135925). https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:135925

[8]. Team, E. W. (n.d.-a). atomoxetine (CHEBI:127342). https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:127342

[9]. PubChem. (n.d.). Atomoxetine. PubChem. https://pubchem.ncbi.nlm.nih.gov/compound/Atomoxetine

[10]. Dresel, S. H. J., Kung, M. T., Huang, X., Plössl, K., Hou, C., Shiue, C. Y., Karp, J., & Kung, H. F. (1999). In vivo imaging of serotonin transporters with [ 99m Tc]TRODAT-1 in nonhuman primates. European Journal of Nuclear Medicine and Molecular Imaging, 26(4), 342–347. https://doi.org/10.1007/s002590050396

[11]. Gamo, N. J., Wang, M., & Arnsten, A. F. (2010). Methylphenidate and atomoxetine enhance prefrontal function through Α2-Adrenergic and dopamine D1 receptors. Journal of the American Academy of Child & Adolescent Psychiatry, 49(10), 1011–1023. https://doi.org/10.1016/j.jaac.2010.06.015

[12]. Federici, M., Geracitano, R., Bernardi, G., & Mercuri, N. B. (2005). Actions of methylphenidate on dopaminergic neurons of the ventral midbrain. Biological Psychiatry, 57(4), 361–365. https://doi.org/10.1016/j.biopsych.2004.11.030

[13]. Jaeschke, R. R., Sujkowska, E., & Sowa-Kućma, M. (2021). Methylphenidate for attention-deficit/hyperactivity disorder in adults: a narrative review. Psychopharmacology, 238(10), 2667–2691. https://doi.org/10.1007/s00213-021-05946-0

[14]. Economidou, D., Theobald, D. E. H., Robbins, T. W., Everitt, B. J., & Dalley, J. W. (2012). Norepinephrine and dopamine modulate impulsivity on the Five-Choice serial reaction time task through opponent actions in the shell and core Sub-Regions of the nucleus accumbens. Neuropsychopharmacology, 37(9), 2057–2066. https://doi.org/10.1038/npp.2012.53

[15]. Chiara, C., Bernanda, P. M., Claudia, M., Elisa, D., Tony, M. M., Valentina, R., Sandro, G., Paolo, C., Paola, S., Augusto, P., & Emanuela, B. (2018). The Decrease in Human Endogenous Retrovirus-H Activity Runs in Parallel with Improvement in ADHD Symptoms in Patients Undergoing Methylphenidate Therapy. International Journal of Molecular Sciences, 19(11), 3286. https://doi.org/10.3390/ijms19113286

[16]. Steingard, R., Taskiran, S., Connor, D. F., Markowitz, J. S., & Stein, M. A. (2019). New formulations of stimulants: an update for clinicians. Journal of Child and Adolescent Psychopharmacology, 29(5), 324–339. https://doi.org/10.1089/cap.2019.0043

[17]. Ermer, J. C., Pennick, M., & Frick, G. (2016). Lisdexamfetamine dimesylate: prodrug delivery, amphetamine exposure and duration of efficacy. Clinical Drug Investigation, 36(5), 341–356. https://doi.org/10.1007/s40261-015-0354-y

[18]. Quintero, J., Gutiérrez-Casares, J. R., & Álamo, C. (2022). Molecular Characterisation of the mechanism of action of stimulant drugs lisdexamfetamine and methylphenidate on ADHD Neurobiology: a review. Neurology and Therapy, 11(4), 1489–1517. https://doi.org/10.1007/s40120-022-00392-2

[19]. Corona, J. C., Carreón-Trujillo, S., González-Pérez, R., Gómez-Bautista, D., Vázquez-González, D., & Salazar-García, M. (2019). Atomoxetine produces oxidative stress and alters mitochondrial function in human neuron-like cells. Scientific Reports, 9(1). https://doi.org/10.1038/s41598-019-49609-9

[20]. Logan, J., Wang, G., Telang, F., Fowler, J. S., Alexoff, D., Zabroski, J., Jayne, M., Hubbard, B., King, P., Carter, P., Shea, C., Xu, Y., Muench, L., Schlyer, D., Learned-Coughlin, S., Cosson, V., Volkow, N. D., & Ding, Y. (2007). Imaging the norepinephrine transporter in humans with (S,S)-[11C]O-methyl reboxetine and PET: problems and progress. Nuclear Medicine and Biology, 34(6), 667–679. https://doi.org/10.1016/j.nucmedbio.2007.03.013

[21]. Hussain, L. S., Reddy, V., & Maani, C. V. (2023, May 1). Physiology, noradrenergic synapse. StatPearls - NCBI Bookshelf. https://www.ncbi.nlm.nih.gov/books/NBK540977/

[22]. Sugimoto, A., Suzuki, Y., Yoshinaga, K., Orime, N., Hayashi, T., Egawa, J., Ono, S., Sugai, T., & Someya, T. (2021). Influence of atomoxetine on relationship between ADHD symptoms and prefrontal cortex activity during task execution in adult patients. Frontiers in Human Neuroscience, 15. https://doi.org/10.3389/fnhum.2021.755025

[23]. Arnsten, A. F. T. (2009). Stress signalling pathways that impair prefrontal cortex structure and function. Nature Reviews. Neuroscience, 10(6), 410–422. https://doi.org/10.1038/nrn2648

[24]. Atomoxetine: MedlinePlus drug information. (n.d.). https://medlineplus.gov/druginfo/meds/a603013.html

[25]. Clemow, D. B., Nyhuis, A. W., & Robinson, R. L. (2016). Clinical Impact of Not Achieving Recommended Dose on Duration of Atomoxetine Treatment in Adults with Attention‐Deficit/Hyperactivity Disorder. CNS Neuroscience & Therapeutics, 22(12), 970–978. https://doi.org/10.1111/cns.12595

[26]. Brown, J., Abdel‐Rahman, S., Van Haandel, L., Gaedigk, A., Lin, Y., & Leeder, J. (2015). Single dose, CYP2D6 genotype‐stratified pharmacokinetic study of atomoxetine in children with ADHD. Clinical Pharmacology & Therapeutics, 99(6), 642–650. https://doi.org/10.1002/cpt.319

[27]. Sauer, J., Ring, B. J., & Witcher, J. W. (2005). Clinical pharmacokinetics of atomoxetine. Clinical Pharmacokinetics, 44(6), 571–590. https://doi.org/10.2165/00003088-200544060-00002

[28]. Perugi, G., & Vannucchi, G. (2015). The use of stimulants and atomoxetine in adults with comorbid ADHD and bipolar disorder. Expert Opinion on Pharmacotherapy, 16(14), 2193–2204. https://doi.org/10.1517/14656566.2015.1079620

[29]. Quinn, D., Wigal, S., Swanson, J., Hirsch, S., Ottolini, Y., Dariani, M., Roffman, M., Zeldis, J., & Cooper, T. (n.d.). Comparative Pharmacodynamics and Plasma Concentrations of d-threo-Methylphenidate Hydrochloride After Single Doses of d-threo-Methylphenidate Hydrochloride and d,l-threo-Methylphenidate Hydrochloride in a Double-Blind, Placebo-Controlled, Crossover Laboratory School Study in Children With Attention-Deficit/Hyperactivity Disorder. Journal of the American Academy of Child & Adolescent Psychiatry, 43(11), 1422–1429. https://doi.org/10.1097/01.chi.0000140455.96946.2b

[30]. Quinn, D., Wigal, S., Swanson, J., Hirsch, S., Ottolini, Y., Dariani, M., Roffman, M., Zeldis, J., & Cooper, T. (n.d.). Comparative Pharmacodynamics and Plasma Concentrations of d-threo-Methylphenidate Hydrochloride After Single Doses of d-threo-Methylphenidate Hydrochloride and d,l-threo-Methylphenidate Hydrochloride in a Double-Blind, Placebo-Controlled, Crossover Laboratory School Study in Children With Attention-Deficit/Hyperactivity Disorder. Journal of the American Academy of Child & Adolescent Psychiatry, 43(11), 1422–1429. https://doi.org/10.1097/01.chi.0000140455.96946.2b

[31]. Liu, Q., Zhang, H., Fang, Q., & Qin, L. (2017). Comparative efficacy and safety of methylphenidate and atomoxetine for attention-deficit hyperactivity disorder in children and adolescents: Meta-analysis based on head-to-head trials. Journal of Clinical and Experimental Neuropsychology, 39(9), 854–865. https://doi.org/10.1080/13803395.2016.1273320

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