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A systematic review and meta-analysis of pharmacological and nonpharmacological interventions for autism spectrum disorder

Nature Mental Health (2026) Cite this article

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Abstract

Autism spectrum disorder (ASD) is characterized by persistent deficits in social communication and restricted, repetitive behaviors, yet the comparative effectiveness of pharmacological and nonpharmacological interventions remains unclear. Here we conducted a systematic review and meta-analysis of randomized controlled trials to evaluate interventions targeting core ASD symptoms. PubMed, Embase, PsycINFO and Cochrane databases were searched through April 2025. Eligible studies included randomized trials with active or inactive controls assessing social communication, restricted or repetitive behaviors, or overall symptom severity. Data from 149 trials (N = 9,011), including 69 nonpharmacological studies (n = 2,889) and 217 pharmacological or dietary-supplement studies (n = 6,122), were pooled using random-effects models. The primary outcome was standardized improvement in core symptoms (Hedges’ g). Nonpharmacological interventions showed a significantly larger pooled effect size (g = 0.70; s.e. = 0.071; I2 = 75.6%) compared with pharmacological approaches (g = 0.20; s.e. = 0.025; I2 = 44.1%), with a significant between-group difference (Δ = 0.43; s.e. = 0.058; P < 0.0001). Moderator analyses indicated that smaller sample size, shorter duration, non-Western settings, clinician-rated outcomes and earlier publication were associated with larger effect sizes; meta-regression identified sample size and publication year as significant predictors. These findings suggest that behavioral and psychosocial interventions demonstrate greater efficacy for core ASD symptoms, while study design and contextual factors substantially influence reported outcomes, highlighting the need for rigorous, well-controlled clinical trials.

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Fig. 1: Preferred reporting items for systematic reviews and meta-analyses (PRISMA) flow diagram.
The alternative text for this image may have been generated using AI.
Fig. 2: Forest plot of pharmacological and nonpharmacological interventions for overall core ASD symptoms.
The alternative text for this image may have been generated using AI.
Fig. 3: Forest plots of pharmacological and nonpharmacological interventions for social communication and repetitive behaviors.
The alternative text for this image may have been generated using AI.
Fig. 4: Forest plots of moderator analyses of intervention effectiveness.
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Data availability

Data were extracted from the included studies as reported in the primary articles and their supplementary information. The study protocol was prospectively registered in PROSPERO (CRD420250653274). The registration record is available at https://www.crd.york.ac.uk/PROSPERO/view/CRD420250653274. The datasets generated and analyzed during this study are available via Zenodo at https://doi.org/10.5281/zenodo.19369463 (ref. 61).

Code availability

All analysis code used to conduct the analyses is available via Zenodo at https://doi.org/10.5281/zenodo.19369463 (ref. 61). Analyses were performed using the metafor and meta packages in R.

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Acknowledgements

This study was supported by the National Science and Technology Innovation 2030 Major Project of China (2021ZD0203900 to D.Z.), NSFC grant (82422029 to D.Z.), the Fundamental Research Funds for the Central Universities (YG2025ZD07 to D.Z.), the Science and Technology Commission of Shanghai Municipality (24Y22800200 to D.Z.), NSFC grant (82271530 to D.Z.), Innovation teams of high-level universities in Shanghai, and the Scientific Research and Innovation Team of Liaoning Normal University (24TD004 to D.Z.). This work was also supported by the China Scholarship Council (CSC) (202506230324 to D.Z.). The funder had no role in the design and conduct of the study; collection, management, analysis and interpretation of the data; preparation, review or approval of the manuscript; and decision to submit the manuscript for publication.

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Authors and Affiliations

  1. School of Nursing, Shanghai Jiao Tong University, Shanghai, China

    Yunhao Gu & Di Zhao

  2. Department of Applied Psychology in Education and Research Methodology, Indiana University Bloomington, Bloomington, IN, USA

    Yunhao Gu & Mia Fox

  3. Indiana Resource Center for Autism, Indiana University Bloomington, Bloomington, IN, USA

    Yunhao Gu & Mia Fox

  4. Shanghai Key Laboratory of Psychotic Disorders, Brain Health Institute, National Center for Mental Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Di Zhao

  5. School of Psychology, Shanghai Jiao Tong University, Shanghai, China

    Di Zhao

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  1. Yunhao Gu
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  2. Mia Fox
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Contributions

Y.G.: writing (original draft), visualization, methodology, investigation, formal analysis and data curation. M.F.: writing (review and editing) and data curation. D.Z.: supervision, writing (review and editing), methodology, investigation, funding acquisition and conceptualization.

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Correspondence to Di Zhao.

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Nature Mental Health thanks Samuel L. Odom and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Peer reviewer reports are available.

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Gu, Y., Fox, M. & Zhao, D. A systematic review and meta-analysis of pharmacological and nonpharmacological interventions for autism spectrum disorder. Nat. Mental Health (2026). https://doi.org/10.1038/s44220-026-00652-2

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