Placebo Effect in Clinical Trials in Autism: Experience from a Pregnenolone Treatment Study

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McGrath, J. C., Gong, X., Hegarty, J. P., Fung, L. K., Uljarević, M., & Hardan, A. Y. (2025). Placebo Effect in Clinical Trials in Autism: Experience from a Pregnenolone Treatment Study. Journal of Autism and Developmental Disorders. https://doi.org/10.1007/s10803-025-06951-4

Publication date: 18 Jul 2025 Added to AutiHub: 5 Oct 2026 Type: Article Article language: English
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Authors

Publication authors
6
Publication authors identified as autistic
1 / 6 (16.7%)
  1. Joseph C. McGrath
  2. Xinyi Gong
  3. John P. Hegarty *
  1. Lawrence K. Fung
  2. Mirko Uljarević
  3. Antonio Y. Hardan

Abstract

Abstract Purpose The placebo effect is a significant limitation in subjective report, particularly when using informant-based outcome measures. In autism spectrum disorder (ASD), this effect is particularly complex due to high expectations for positive treatment outcomes. Therefore, interventional research in ASD needs to account for and remediate the placebo response. Methods This preliminary pilot report examines placebo effect in a single-blind, two-week placebo lead-in that preceded the double-blind phase of a randomized controlled trial. The trial assessed pregnenolone, an endogenous neurosteroid, for reducing irritability in adolescents and young adults (ages 14–25) with ASD. The Aberrant Behaviors Checklist (ABC) irritability subscale (ABC-I) was the primary outcome measure used to identify correlates of the placebo effect (IQ, age, sex, and baseline symptom severity). Paired, 2-tailed t-tests compared outcome measures at baseline and following the lead-in. Results Twenty-five participants (23 males, 2 females; mean age 18.5 ± 3.1 years) have completed the trial to date. The two-week lead-in resulted in a 30.2% decrease in irritability symptoms (t(24) = 5.090(24), p < 0.001; Cohen’s d = 1.018) across all participants. The remaining ABC subscales also decreased significantly. The magnitude of change in ABC-I was correlated (r s =0.488, p = 0.013) with baseline ABC-I score, but not sex, IQ, or age. Conclusion Findings from this preliminary pilot trial provide evidence of a significant placebo effect in a clinical trial for ASD, further highlighting the challenges that this phenomenon presents for interventional research. A single-blind placebo lead-in within ASD clinical trials is a recommended approach to both account and mitigate for the placebo effect.

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Cited references
40
With a DOI
37
Without a DOI, from raw bibliography text
3
0 / 40 (0.0%) cited references include at least one author identified as autistic.
References with data to complete
3 / 40 (7.5%)
References with detected author names
37 / 40 (92.5%)
Without detected author names
3
Without a structured title
3
Without a stable identifier
3
References with raw author names still to review
3
References with external metadata lookup issues
1
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Author names detected in the cited bibliography
211
From DOI or external metadata
211
From validated raw bibliography text
0
Raw names already validated
0
Raw names still to review
4
41 / 211 (19.4%) names are linked to an author already present in AutiHub. 170 / 211 (80.6%) names are not yet linked.
Names linked to a person identified as autistic
0 / 211 (0.0%)
Calculated across all author names detected in the cited bibliography. Among names linked to an author already present in AutiHub: 0 / 41 (0.0%). Distinct people identified as autistic: 0 / 188 (0.0%).
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