Practitioner Review: Pharmacological treatment of attention-deficit/hyperactivity disorder symptoms in children and youth with autism spectrum disorder: a systematic review and meta-analysis
Abstract
BACKGROUND: Clinically significant attention-deficit/hyperactivity disorder (ADHD) symptoms are common and impairing in children and youth with autism spectrum disorder(ASD). The aim of this systematic review and meta-analysis was to (a) evaluate the efficacy and safety of pharmacotherapy for the treatment of ADHD symptoms in ASD and (b) distil findings for clinical translation. METHODS: We searched electronic databases and clinical trial registries (1992 onwards). We selected randomized controlled trials conducted in participants <25 years of age, diagnosed with ASD that evaluated ADHD outcomes (hyperactivity/impulsivity and inattention) following treatment with stimulants (methylphenidate or amphetamines), atomoxetine, alpha-2 adrenergic receptor agonists, antipsychotics, tricyclic antidepressants, bupropion, modafinil, venlafaxine, or a combination, in comparison with placebo, any of the listed medications, or behavioral therapies. Data were pooled using a random-effects model. RESULTS: Twenty-five studies (4 methylphenidate, 4 atomoxetine, 1 guanfacine, 14 antipsychotic, 1 venlafaxine, and 1 tianeptine) were included. Methylphenidate reduced hyperactivity (parent-rated: standardized mean difference [SMD] = -.63, 95%CI = -.95,-.30; teacher-rated: SMD = -.81, 95%CI = -1.43,-.19) and inattention (parent-rated: SMD = -.36, 95%CI = -.64,-.07; teacher-rated: SMD = -.30, 95%CI = -.49,-.11). Atomoxetine reduced inattention (parent-rated: SMD = -.54, 95%CI = -.98,-.09; teacher/investigator-rated: SMD = -0.38, 95%CI = -0.75, -0.01) and parent-rated hyperactivity (parent-rated: SMD = -.49, 95%CI = -.76,-.23; teacher-rated: SMD = -.43, 95%CI = -.92, .06). Indirect evidence for significant reductions in hyperactivity with second-generation antipsychotics was also found. Quality of evidence for all interventions was low/very low. Methylphenidate was associated with a nonsignificant elevated risk of dropout due to adverse events. CONCLUSIONS: Direct pooled evidence supports the efficacy and tolerability of methylphenidate or atomoxetine for treatment of ADHD symptoms in children and youth with ASD. The current review highlights the efficacy of standard ADHD pharmacotherapy for treatment of ADHD symptoms in children and youth with ASD. Consideration of the benefits weighed against the limitations of safety/efficacy data and lack of data evaluating long-term continuation is undertaken to help guide clinical decision-making regarding treatment of co-occurring ADHD symptoms in children and youth with ASD.
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In a recent review of nine controlled trials of 430 children with ASD comparing methylphenidate, atomoxetine, and guanfacine, methylphenidate and atomoxetine had superior effects than placebo in addressing ADHD symptoms; however, the response for hyperactivity symptoms was less than observed in neurotypical populations with both medications.
“In a recent review of nine controlled trials of 430 children with ASD comparing the response between methylphenidate, atomoxetine, and guanfacine, methylphenidate and atomoxetine had superior effects than placebo in addressing ADHD symptoms; however, the response for hyperactivity symptoms was less than observed in neurotypical populations with both medications [57].”
From An Update on Psychopharmacological Treatment of Autism Spectrum Disorder (2022) · cites this paper as [57]
Worse treatment outcomes were associated with individuals with lower cognitive functioning.
“Worse treatment outcomes were associated with individuals with lower cognitive functioning.”
From An Update on Psychopharmacological Treatment of Autism Spectrum Disorder (2022) · cites this paper as [57]
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Adverse Events of Atomoxetine in a Double-Blind Placebo-Controlled Study in Children with Autism
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Venlafaxine has modest effects in autistic children
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Common psychiatric comorbidities and their assessment
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The Lancet Commission on the future of care and clinical research in autism
Lord, C., Charman, T., Havdahl, A., Carbone, P., Anagnostou, E., Boyd, B., Carr, T., de Vries, P. J., Dissanayake, C., Divan, G., et al. (2022) · The Lancet · doi:10.1016/s0140-6736(21)01541-5 · Cited by 924 · see citing works
An Update on Psychopharmacological Treatment of Autism Spectrum Disorder
Aishworiya, R., Valica, T., Hagerman, R., & Restrepo, B. (2022) · Neurotherapeutics · doi:10.1007/s13311-022-01183-1 · Cited by 233 · see citing works
“In a recent review of nine controlled trials of 430 children with ASD comparing the response between methylphenidate, atomoxetine, and guanfacine, methylphenidate and atomoxetine had superior effects than placebo in addressing ADHD symptoms; however, the response for hyperactivity symptoms was less than observed in ne…”
BackgroundSiafis, S., Çıray, O., Wu, H., Schneider‐Thoma, J., Bighelli, I., Krause, M., Rodolico, A., Ceraso, A., Deste, G., Huhn, M., et al. (2022) · Molecular Autism · doi:10.1186/s13229-022-00488-4 · Cited by 138 · see citing works
Autism spectrum disorder: pathogenesis, biomarker, and intervention therapy
Zhuang, H., Liang, Z., Ma, G., Qureshi, A., Ran, X., Feng, C., Liu, X., Yan, X., & Shen, L. (2024) · MedComm · doi:10.1002/mco2.497 · Cited by 106 · see citing works
A systematic meta-review of systematic reviews on attention deficit hyperactivity disorder
Chaulagain, A., Lyhmann, I., Halmøy, A., Widding‐Havneraas, T., Nyttingnes, O., Bjelland, I., & Mykletun, A. (2023) · European Psychiatry · doi:10.1192/j.eurpsy.2023.2451 · Cited by 93 · see citing works
de Pablo, G. S., Jordá, C. P., Vaquerizo‐Serrano, J., Moreno, C., Cabras, A., Arango, C., Hernandez, P. A., Veenstra-VanderWeele, J. M., Simonoff, E. A., Fusar‐Poli, P., et al. (2022) · Journal of the American Academy of Child & Adolescent Psychiatry · doi:10.1016/j.jaac.2022.03.033 · Cited by 92 · see citing works
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Mental health challenges faced by autistic people
Lai, M. (2023) · Nature Human Behaviour · doi:10.1038/s41562-023-01718-2 · Cited by 80 · see citing works
Cortese, S., Bellgrove, M. A., Brikell, I., Franke, B., Goodman, D. W., Hartman, C. A., Larsson, H., LEVIN, F. R., Ostinelli, E. G., Parlatini, V., et al. (2025) · World Psychiatry · doi:10.1002/wps.21374 · Cited by 88 · see citing works
“While limited evidence exists for adults, a larger literature in children shows that stimulant and non-stimulant agents are eff ective in treating ADHD in individuals with autism spectrum disorder, particularly in the context of higher intellectual functioning 201 .”
Non-pharmacological interventions for autistic children: An umbrella review
Trembath, D. L., Varcin, K. J., Waddington, H. L., Sulek, R., Bent, C. A., Ashburner, J. K., Eapen, V., Goodall, E., Hudry, K., Roberts, J., et al. (2022) · Autism · doi:10.1177/13623613221119368 · Cited by 68 · see citing works
Prada, D., Ritz, B. R., Bauer, A. Z., & Baccarelli, A. (2025) · Environmental Health · doi:10.1186/s12940-025-01208-0 · Cited by 66 · see citing works
“Different NDDs often have shared/overlapping symptomology as well as shared biological pathways or causes, including toxic exposures during critical developmental windows [3] or genetic causes [4].”
Fu, D., Wu, D.-D., Guo, H.-L., Hu, Y.-H., Xia, Y., Ji, X., Fang, W.-R., Li, Y.-M., Xu, J., Chen, F., et al. (2022) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2021.780921 · Cited by 66 · see citing works
Bennett (2023) · doi:10.1097/yco.0000000000000775 · Cited by 51 · see citing works
“All rights rese irritability [7–10], psychostimulants or atomoxetine for ADHD symptoms [11,12], the alpha adrenergic agents, such as guanfacine for management of ADHD and/or disruptive behaviour (off-label for disruptive behaviour) [13,14], and N-acetyl cysteine for irritability (off-label) [15].”
BackgroundPharmacotherapy in autism spectrum disorders, including promising older drugs warranting trials
Hellings, J. A. (2023) · World Journal of Psychiatry · doi:10.5498/wjp.v13.i6.262 · Cited by 44 · see citing works
Maniram, J., Karrim, S. B., Oosthuizen, F., & Wiafe, E. (2022) · Neuropsychiatric Disease and Treatment · doi:10.2147/ndt.s371013 · Cited by 36 · see citing works
Roselló, R., Martı́nez-Raga, J., Mira, Á., Pastor, J. C., Solmi, M., & Cortese, S. (2021) · Autism · doi:10.1177/13623613211065545 · Cited by 33 · see citing works
“…and efficacy/effectiveness of ADHD pharmacotherapy in individuals with ASD+ are lower compared with those with ADHD−, there is support for its use in the treatment of inattentive and hyperactive/ impulsive symptoms in individuals with ASD+ (Cortese et al., 2012; Rodrigues et al., 2020).”
ResultChan, M. M. Y., Choi, C. X. T., Tsoi, T. C. W., Shea, C. K., Yiu, K. W. K., & Han, Y. M. Y. (2023) · Brain stimulation · doi:10.1016/j.brs.2023.10.012 · Cited by 34 · see citing works
“The use of ADHD medications, such as methylphenidate HCl and atom-oxetine, is common among these individuals [75].”
Unraveling the spectrum: overlap, distinctions, and nuances of ADHD and ASD in children
Martinez, S., Stoyanov, K., & Carcache, L. (2024) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2024.1387179 · Cited by 33 · see citing works
Pathways to adaptive functioning in autism from early childhood to adolescence
Chandler, S., Leno, V. C., White, P., Yorke, I., Hollocks, M. J., Baird, G., Pickles, A. R., Simonoff, E. A., & Charman, T. (2022) · Autism Research · doi:10.1002/aur.2785 · Cited by 30 · see citing works
Carnovale, C., Battini, V., Santoro, C., Riccio, M. P., Carucci, S., Nobile, M., Formisano, P., Bravaccio, C., Zuddas, A., Clementi, E., et al. (2023) · Journal of the American Academy of Child & Adolescent Psychiatry · doi:10.1016/j.jaac.2023.04.018 · Cited by 27 · see citing works
Diagnosis and treatment of children and adolescents with autism and ADHD
Hatch, B., Kadlaskar, G., & Miller, M. R. (2022) · Psychology in the schools (Print) · doi:10.1002/pits.22808 · Cited by 23 · see citing works
Han, Y. M. Y., Chan, M. M. Y., Shea, C. K., Mo, F. Y. M., Yiu, K. W. K., Chung, R. C. K., Cheung, M., & Chan, A. S.-Y. (2023) · Autism · doi:10.1177/13623613231169547 · Cited by 31 · see citing works
“, 2018) that are usually prescribed to ASD patients that have comorbid attentiondeficit/hyperactivity (ADHD) symptoms (Rodrigues et al., 2021), individuals on these medications were only included if they and their parents agreed to refrain from using these medications at least 96 h before the baseline assessment and u…”
Fecal Microbiota Transplantation in Children with Autism
Li, Y., Xiao, P. G., Ding, H., Wang, H., Xu, Q., Wang, R., Zheng, L., Song, X., Wang, Y., & Zhang, T. (2024) · Neuropsychiatric Disease and Treatment · doi:10.2147/ndt.s488001 · Cited by 24 · see citing works
Current and future directions of drug delivery for the treatment of mental illnesses
Brewster, P. R., Bari, S. M. I., Walker, G. M., & Werfel, T. A. (2023) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2023.114824 · Cited by 27 · see citing works
Huang, Z., Wang, F., Xue, L.-L., Zhu, H., & Zou, X. (2024) · Brain Sciences · doi:10.3390/brainsci14060566 · Cited by 25 · see citing works
“Yet, a notable proportion of individuals diagnosed with ASD+ADHD also show positive responses to stimulant medications [51].”
BackgroundAutism Spectrum Disorder in Children: Early Signs and Therapeutic Interventions
Abualait, T., Alabbad, M., Kaleem, I., Imran, H., Khan, H. R., Kiyani, M. M., & Bashir, S. (2024) · Children · doi:10.3390/children11111311 · Cited by 22 · see citing works
Evidence-based prescribing of medications for ADHD: where are we in 2023?
Cortese, S. (2023) · Expert Opinion on Pharmacotherapy · doi:10.1080/14656566.2023.2169604 · Cited by 22 · see citing works
“, autism spectrum disorder ([31]), are associated with lower chances of response; (g) Is the diagnosis correct? Only after all these aspects have been assessed, the prescriber should consider (1) second-line medications (atomoxetine – which selectively inhibits the norepinephrine transporter, and guanfacine – that sel…”
BackgroundAmygdalar neurotransmission alterations in the BTBR mice model of idiopathic autism
Bové, M., Palmieri, M. A., Santoro, M., Agosti, L. P., Gaetani, S., Romano, A., Dimonte, S., Costantino, G., Sikora, V., Tucci, P., et al. (2024) · Translational Psychiatry · doi:10.1038/s41398-024-02905-z · Cited by 20 · see citing works
Petruzzelli, M. G., Matera, E., Margari, L., Marzulli, L., Gabellone, A., Cotugno, C., Annecchini, F., & Cortese, S. (2025) · Expert Review of Neurotherapeutics · doi:10.1080/14737175.2025.2599856 · Cited by 18 · see citing works
“…to age 25 years, diagnosed with pervasive developmental disorders or ASD, testing the efficacy of different medication classes on ADHD symptoms (hyperactivity/impulsivity and inattention) as the primary outcome, along with secondary outcomes related to general functioning and adverse events [64].”
Autism Spectrum Disorder and Epilepsy: Pathogenetic Mechanisms and Therapeutic Implications
Giliberti, A., Frisina, A. M., Giustiniano, S., Carbonaro, Y., Roccella, M., & Nardello, R. (2025) · Journal of Clinical Medicine · doi:10.3390/jcm14072431 · Cited by 18 · see citing works
Seok, J., Vaughan, B. S., Lew, B. J., Ahmad, A., Blair, J., & Hwang, S. (2023) · Scientific Reports · doi:10.1038/s41598-023-33979-2 · Cited by 17 · see citing works
Cannabinoid treatment for the symptoms of autism spectrum disorder
Aran, A. A., & Cayam-Rand, D. (2024) · Expert Opinion on Emerging Drugs · doi:10.1080/14728214.2024.2306290 · Cited by 14 · see citing works
“…risperidone and aripiprazole (and possibly N-Acetylcysteine) for emotional dysregulation and irritability [22,36], methylphenidate, atomoxetine, and extended-release guanfacine for managing comorbid ADHD [37,38] and prolonged-release melatonin for mitigating associated sleep disturbances [39].”
BackgroundRoselló, R., Martı́nez-Raga, J., Tomás, J. M., Mira, Á., & Cortese, S. (2022) · Child and Adolescent Mental Health · doi:10.1111/camh.12562 · Cited by 13 · see citing works
Zhang, Y., Yin, L., You, C., Liu, C., Dong, P., Xu, X., & Zhang, K. (2023) · Drugs in R&D · doi:10.1007/s40268-023-00445-3 · Cited by 13 · see citing works
An Update on Psychopharmacological Treatment of Autism Spectrum Disorder
Aishworiya, R., Valica, T., Hagerman, R. J., & Restrepo, B. (2024) · FOCUS The Journal of Lifelong Learning in Psychiatry · doi:10.1176/appi.focus.24022006 · Cited by 15 · see citing works
Harkness, K., Bray, S., & Murias, K. (2024) · Research in Developmental Disabilities · doi:10.1016/j.ridd.2024.104691 · Cited by 9 · see citing works
Ameringen, M. V., Fineberg, N. A., Ravindran, A. V., Arnold, P. D., Beaulieu, S., Brakoulias, V., Brietzke, E. M., Dowlati, Y., Drummond, L. M., Ferretti, C. J., et al. (2026) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2025.12.039 · Cited by 10 · see citing works
Emerging Treatments and Therapies for Autism Spectrum Disorder: A Narrative Review
Kaye, A. D., Allen, K. E., Smith, V. S., Tong, V. T., Mire, V. E., Huy, N. V., Lee, Z., Kouri, M., Baptiste, C. J., Mosieri, C. N., et al. (2024) · Cureus · doi:10.7759/cureus.63671 · Cited by 12 · see citing works
Masi, G., Pfanner, C., Liboni, F., Lenzi, F., Villafranca, A., D’Acunto, G., Fantozzi, P., Falcone, F., Simonelli, V., Muratori, P., et al. (2022) · Pediatric Drugs · doi:10.1007/s40272-022-00492-4 · Cited by 8 · see citing works
“Our data suggest that it is ID, as an index of severe neurodevelopmental disorder, and not ASD that is linked with a lower tolerability to MPH [18, 19].”
Backgroundla Cerna‐Luna, R. D., Fernandez‐Guzman, D., Baquerizo-Sedano, M., Cabala-Olazabal, S., & Taype-Rondán, Á. (2024) · Revista Peruana de Medicina Experimental y Salud Pública · doi:10.17843/rpmesp.2024.411.13285 · Cited by 9 · see citing works
“…children had not completed their psychological evaluation, which may be related to the shortage of psychologists in the Peruvian health system, particularly at the first level of care and outside the capital (Lima) (27) , and to the fact that the SRP-HNERM had only two female psychologists in 2022.”
BackgroundReview of Pharmacogenomics of Psychiatric Comorbidities in Autism Spectrum Disorder
Pedrero, A. Á., Bote, V., Lamborena, C., Medina, R., Serra-Llovich, A., Amaia Hervas, G., & Arranz, M. J. (2023) · Pharmacogenomics · doi:10.2217/pgs-2023-0134 · Cited by 6 · see citing works
Zahid, Z., Ali, S., Shariq, S., Ayaz, Y., Naseer, N., & Yaseen, I. (2024) · Journal of Computer Assisted Learning · doi:10.1111/jcal.12990 · Cited by 5 · see citing works
Zhong, W., Luo, J., Luo, L., & Lyu, Y. (2025) · Journal of Computer Assisted Learning · doi:10.1111/jcal.70154 · Cited by 4 · see citing works
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“For the comorbid attention de fi cit and hyperactivity symptoms in ASD, stimulant medications such as methylphenidate and atomoxetine are commonly used clinical treatment options [267, 268].”
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- Authors
- Rodrigues, R., Lai, M., Beswick, A., Gorman, D. A., Anagnostou, E., Szatmari, P., Anderson, K. K., & Ameis, S. H.
- Affiliations
- Western University (CA)
- Centre for Addiction and Mental Health (CA)
- University of Toronto (CA)
- The Margaret and Wallace McCain Centre for Child, Youth and Family Mental Health Campbell Family Mental Health Research Institute Centre for Addiction and Mental Health Toronto ON Canada
- Corresponding author
- Ameis, Stephanie H.
- Venue
- Journal of Child Psychology and Psychiatry
- Publisher
- Wiley
- Published
- 2020-08-26
- Volume
- 62
- Issue
- 6
- Pages
- 680-700
- ISSN
- 0021-9630 (ISSN-L)
- 1469-7610
- OpenAlex
- W3080202693
- Cited by
- 98
- References
- 126
- Citations by year
- 2026: 13 · 2025: 17 · 2024: 20 · 2023: 19 · 2022: 23 · 2021: 4 · 2020: 2
- FWCI
- 1.99
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Child Psychology and Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Canadian Institutes of Health Research
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Attention Deficit Hyperactivity Disorder
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Social Sciences › Psychology › Developmental and Educational Psychology › Behavioral and Psychological Studies
- Keywords
- attention deficit hyperactivity disorder, autism spectrum disorder, pharmacotherapy, methylphenidate, atomoxetine, antipsychotic drugs, stimulants, hyperactivity, inattention, treatment efficacy and safety, children and young people, guanfacine, venlafaxine, tianeptine, modafinil, bupropion, tricyclic antidepressants
- MeSH terms
- Autism Spectrum Disorder, Atomoxetine Hydrochloride, Adolescent, Central Nervous System Stimulants, Attention Deficit Disorder with Hyperactivity, Child, Humans, Methylphenidate, Guanfacine
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