CoChat
Sign Up
Cited by 314Neuroendocrine regulation and behaviorAutism Spectrum Disorder ResearchGenetics and Neurodevelopmental Disorders

Intranasal Oxytocin in Children and Adolescents with Autism Spectrum Disorder

Open access
Sikich, Linmarie, Kolevzon, Alexander, King, Bryan H., McDougle, Christopher J., Sanders, Kevin B., Kim, Soo-Jeong, Spanos, Marina, Chandrasekhar, Tara +26 more·2021·New England Journal of Medicine
DOI 10.1056/nejmoa2103583PMC PMC9701092
Open this paper in CoChat — free accountOpen PDF

Abstract

BACKGROUND: Experimental studies and small clinical trials have suggested that treatment with intranasal oxytocin may reduce social impairment in persons with autism spectrum disorder. Oxytocin has been administered in clinical practice to many children with autism spectrum disorder. METHODS: We conducted a 24-week, placebo-controlled phase 2 trial of intranasal oxytocin therapy in children and adolescents 3 to 17 years of age with autism spectrum disorder. Participants were randomly assigned in a 1:1 ratio, with stratification according to age and verbal fluency, to receive oxytocin or placebo, administered intranasally, with a total target dose of 48 international units daily. The primary outcome was the least-squares mean change from baseline on the Aberrant Behavior Checklist modified Social Withdrawal subscale (ABC-mSW), which includes 13 items (scores range from 0 to 39, with higher scores indicating less social interaction). Secondary outcomes included two additional measures of social function and an abbreviated measure of IQ. RESULTS: Of the 355 children and adolescents who underwent screening, 290 were enrolled. A total of 146 participants were assigned to the oxytocin group and 144 to the placebo group; 139 and 138 participants, respectively, completed both the baseline and at least one postbaseline ABC-mSW assessments and were included in the modified intention-to-treat analyses. The least-squares mean change from baseline in the ABC-mSW score (primary outcome) was -3.7 in the oxytocin group and -3.5 in the placebo group (least-squares mean difference, -0.2; 95% confidence interval, -1.5 to 1.0; P = 0.61). Secondary outcomes generally did not differ between the trial groups. The incidence and severity of adverse events were similar in the two groups. CONCLUSIONS: This placebo-controlled trial of intranasal oxytocin therapy in children and adolescents with autism spectrum disorder showed no significant between-group differences in the least-squares mean change from baseline on measures of social or cognitive functioning over a period of 24 weeks. (Funded by the National Institute of Child Health and Human Development; SOARS-B ClinicalTrials.gov number, NCT01944046.).

AI snapshot

Written from the paper’s full text.

TL;DR

In a 24-week, placebo-controlled phase 2 trial in children and adolescents with autism spectrum disorder, daily intranasal oxytocin did not improve social withdrawal or other social/cognitive outcomes compared with placebo. Adverse-event incidence and severity were similar between groups.

Key findings

  • Primary outcome: least-squares mean change from baseline on the ABC modified Social Withdrawal subscale was −3.7 with oxytocin and −3.5 with placebo (difference, −0.2; 95% CI, −1.5 to 1.0; P=0.61).
  • Secondary outcomes generally did not differ: SRS-2 Social Motivation T-score difference 0.9 (95% CI, −1.0 to 2.9); Sociability Factor difference 0.6 (95% CI, −1.8 to 3.1); SB5 Abbreviated IQ difference 0.1 (95% CI, −2.9 to 3.0).
  • Subgroup differences were also nonsignificant: fluent verbal speech difference 0.3 (95% CI, −1.4 to 2.1); minimal verbal fluency difference −0.9 (95% CI, −2.7 to 1.0).
  • Adverse events occurred in 82% of oxytocin participants and 83% of placebo participants; one serious adverse event was considered related to oxytocin (sedation while driving leading to a motor vehicle accident at 48 IU daily).

Methods

  • Investigator-initiated, randomized, double-blind, parallel-group, placebo-controlled phase 2 trial conducted at seven academic sites from August 2014 through June 2017; participants were children and adolescents 3 to 17 years of age meeting DSM-5 criteria for autism spectrum disorder.
  • Of 355 screened, 290 were enrolled and randomly assigned 1:1, stratified by age group and verbal fluency, to intranasal oxytocin or placebo; target total daily dose was 48 IU, with flexible dosing from 8 to 80 IU over 24 weeks.
  • Primary outcome was the ABC-mSW; secondary outcomes were SRS-2-SM, Sociability Factor, and SB5 Abbreviated IQ. Efficacy used a modified intention-to-treat population (277 participants) and mixed-effect repeated-measures models; no prespecified adjustment for multiple comparisons for secondary, exploratory, or sensitivity outcomes.

Limitations

  • The paper states that the ABC-mSW has not been validated, no minimum baseline score was required for enrollment, and the flexible-dose strategy differed from previous trials.
  • The paper notes uncertainty about intranasal oxytocin absorption, brain penetration, and time course, and that the formulation differed from the Novartis Syntocinon product used in some prior trials.
  • The paper states that the 24-week treatment period might attenuate an initial early response to oxytocin; it also reports no prespecified adjustment for multiple comparisons for secondary, exploratory, or sensitivity outcomes.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1056/nejmoa2103583

Cites

36 of 36 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

16 of 30 cited sources checked · 10 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    Several trials have shown that a single dose of intranasal oxytocin enhanced performance on measures of social cognition or motivation, compared with placebo, in persons with autism spectrum disorder.

    “Several trials have shown that a single dose of intranasal oxytocin enhanced performance on measures of social cognition10,11 or motivation,12–14 as compared with placebo, in persons with autism spectrum disorder.”
    Quote in the paperSubstantial claim2 of 5 sources checked
    • cites [10] Guastella AJ, Einfeld SL, Gray KM, Intranasal oxytocin improves emotion recognition for youth with autism spectrum disorders. Biol Psychiatry 2010; 67: 692– 4. 19897177 source
    • cites [11] Watanabe T, Abe O, Kuwabara H, Mitigation of sociocommunicational deficits of autism through oxytocin-induced recovery of medial prefrontal activity: a randomized trial. JAMA Psychiatry 2014; 71: 166– 75. 24352377 source
    • cites [12] Kanat M, Spenthof I, Riedel A, van Elst LT, Heinrichs M, Domes G. Restoring effects of oxytocin on the attentional preference for faces in autism. Transl Psychiatry 2017; 7(4): e1097. 28418399 PMC5416705 source
    • cites [13] Andari E, Duhamel J-R, Zalla T, Herbrecht E, Leboyer M, Sirigu A. Promoting social behavior with oxytocin in high-functioning autism spectrum disorders. Proc Natl Acad Sci U S A 2010; 107: 4389– 94. 20160081 PMC2840168 source
    • cites [14] Althaus M, Groen Y, Wijers AA, Noltes H, Tucha O, Hoekstra PJ. Oxytocin enhances orienting to social information in a selective group of high-functioning male adults with autism spectrum disorder. Neuropsychologia 2015; 79: Pt A: 53– 69. 26498227 source
  • Premisecitation

    Small randomized controlled trials of intranasal oxytocin administered for 4 to 24 weeks in persons with autism spectrum disorder have had equivocal results regarding improvements in social functioning, social cognition, or social attention.

    “Small, randomized, controlled trials of intranasal oxytocin administered for 4 to 24 weeks in persons with autism spectrum disorder have had equivocal results with regard to oxytocin-associated improvements in social functioning, social cognition, or social attention.18–21”
    Quote in the paperSubstantial claim3 of 4 sources checked
    • cites [18] Parker KJ, Oztan O, Libove RA, Intranasal oxytocin treatment for social deficits and biomarkers of response in children with autism. Proc Natl Acad Sci U S A 2017; 114: 8119– 24. 28696286 PMC5544319 source

      Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
    • cites [19] Watanabe T, Kuroda M, Kuwabara H, Clinical and neural effects of six-week administration of oxytocin on core symptoms of autism. Brain 2015; 138: 3400– 12. 26336909 source
    • cites [20] Yamasue H, Okada T, Munesue T, Effect of intranasal oxytocin on the core social symptoms of autism spectrum disorder: a randomized clinical trial. Mol Psychiatry 2020; 25: 1849– 58. 29955161 source
    • cites [21] Anagnostou E, Soorya L, Chaplin W, Intranasal oxytocin versus placebo in the treatment of adults with autism spectrum disorders: a randomized controlled trial. Mol Autism 2012; 3: 16. 23216716 PMC3539865 source
  • Premisecitation

    There is uncertainty regarding absorption, brain penetration, and time course of effects with intranasal oxytocin.

    “There is uncertainty regarding absorption, brain penetration, and time course of effects with intranasal oxytocin35,36 that may be amplified by differences among specific preparations of intranasal oxytocin.”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [35] Lee MR, Shnitko TA, Blue SW, Labeled oxytocin administered via the intranasal route reaches the brain in rhesus macaques. Nat Commun 2020; 11: 2783. 32494001 PMC7270110 source

      The Discussion (page not provided) says the extent and regional distribution of brain penetration need further study and that the two-hour sampling interval limits what can be inferred about timing. But the paper demonstrates brain penetration in rhesus macaques; it does not directly assess the time course of oxytocin’s effects or establish uncertainty about absorption. The claim is therefore supported only in part. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [36] Benner S, Aoki Y, Watanabe T, Neurochemical evidence for differential effects of acute and repeated oxytocin administration. Mol Psychiatry 2021; 26: 710– 20. 30262887 source
  • Premisecitation

    Functional neuroimaging studies in persons with autism spectrum disorder have shown differences in regional brain activation in response to social stimuli after intranasal oxytocin, compared with placebo.

    “These results have been supported by functional neuroimaging studies involving persons with autism spectrum disorder, which have shown differences in regional brain activation in response to social stimuli after the administration of intranasal oxytocin, as compared with placebo.11,15–17”
    Quote in the paperSubstantial claim3 of 4 sources checked
    • cites [11] Watanabe T, Abe O, Kuwabara H, Mitigation of sociocommunicational deficits of autism through oxytocin-induced recovery of medial prefrontal activity: a randomized trial. JAMA Psychiatry 2014; 71: 166– 75. 24352377 source
    • cites [15] Gordon I, Vander Wyk BC, Bennett RH, Oxytocin enhances brain function in children with autism. Proc Natl Acad Sci U S A 2013; 110: 20953– 8. 24297883 PMC3876263 source
    • cites [16] Kruppa JA, Gossen A, Oberwelland Weiß E, Neural modulation of social reinforcement learning by intranasal oxytocin in male adults with high-functioning autism spectrum disorder: a randomized trial. Neuropsychopharmacology 2019; 44: 749– 56. 30390065 PMC6372686 source
    • cites [17] Greene RK, Spanos M, Alderman C, The effects of intranasal oxytocin on reward circuitry responses in children with autism spectrum disorder. J Neurodev Disord 2018; 10: 12. 29587625 PMC5870086 source
  • Premisecitation

    One previous trial showed a significant benefit of intranasal oxytocin on the SRS-2 total score only when the baseline plasma oxytocin level was incorporated into the analysis.

    “One previous trial showed a significant benefit of intranasal oxytocin therapy on the SRS-2 total score only when the baseline plasma oxytocin level was incorporated into the analysis.18”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [18] Parker KJ, Oztan O, Libove RA, Intranasal oxytocin treatment for social deficits and biomarkers of response in children with autism. Proc Natl Acad Sci U S A 2017; 114: 8119– 24. 28696286 PMC5544319 source

      In “Evaluation of Biomarker Inclusion in the Statistical Model” (page not available), the SRS Total Raw Score treatment effect was nonsignificant without pretreatment biomarkers; “Effects of OXT Treatment on Social Abilities” reports a significant effect with them included. But the comparison added both pretreatment blood oxytocin and a receptor gene-expression measure, so it does not establish that incorporating oxytocin alone produced the significant result. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
  • Classified as probably not a substantial claim. 16
  • May combine two claims. 21
  • The quote only partly states this claim. 1

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Some, but not all, studies have shown reduced plasma oxytocin levels in children with autism spectrum disorder.

    “Some, but not all, studies have shown reduced plasma oxytocin levels in children with autism spectrum disorder.6”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [6] Rutigliano G, Rocchetti M, Paloyelis Y, Peripheral oxytocin and vasopressin: biomarkers of psychiatric disorders? A comprehensive systematic review and preliminary meta-analysis. Psychiatry Res 2016; 241: 207– 20. 27183106 source

      Section 3.2.2 (p. not available) reports a negative pooled estimate for plasma oxytocin in ASD, substantial variation between studies, and no statistically significant overall difference. Table 1 (p. not available) identifies plasma studies involving children with ASD, but the available passages do not state which individual studies found reduced levels and which did not. (LLM, conf=0.74)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Decreased oxytocin-receptor density has been found in the ventral pallidum of postmortem brain tissue from a few persons with autism spectrum disorder.

    “Decreased oxytocin-receptor density has been found in the ventral pallidum of postmortem brain tissue obtained from a few persons with autism spectrum disorder.9”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [9] Freeman SM, Palumbo MC, Lawrence RH, Smith AL, Goodman MM, Bales KL. Effect of age and autism spectrum disorder on oxytocin receptor density in the human basal forebrain and midbrain. Transl Psychiatry 2018; 8: 257. 30514927 PMC6279786 source

  • May combine two claims.

    Premisecitation

    In persons without known developmental or psychiatric disorders, intranasal oxytocin increases social affiliation, social memory, and empathy.

    “In persons without known developmental or psychiatric disorders, the use of intranasal oxytocin increases social affiliation, social memory, and empathy.2–5”
    Quote in the paperNot a substantial claim2 of 4 sources checked
    • cites [2] Kosfeld M, Heinrichs M, Zak PJ, Fischbacher U, Fehr E. Oxytocin increases trust in humans. Nature 2005; 435: 673– 6. 15931222 source

      The Subjects section describes healthy male students who received intranasal oxytocin or placebo; significant psychiatric illness was an exclusion criterion. The Abstract and LETTERS report increased trust in social interactions, which supports the social-affiliation aspect, but the paper does not report increases in social memory or empathy. (LLM, conf=0.90)

      Experimental — accuracy not yet measured
    • cites [3] Domes G, Heinrichs M, Michel A, Berger C, Herpertz SC. Oxytocin improves “mind-reading” in humans. Biol Psychiatry 2007; 61: 731– 3. 17137561 source
    • cites [4] De Dreu CKW, Greer LL, Handgraaf MJJ, The neuropeptide oxytocin regulates parochial altruism in intergroup conflict among humans. Science 2010; 328: 1408– 11. 20538951 source
    • cites [5] Bartz JA, Zaki J, Bolger N, Oxytocin selectively improves empathic accuracy. Psychol Sci 2010; 21: 1426– 8. 20855907 PMC6634294 source

      The Method and Results (page unavailable) describe healthy men given intranasal oxytocin and show improved empathic accuracy only among those with lower baseline social proficiency. The paper does not report increases in social affiliation or social memory, and its Discussion explicitly cautions against treating oxytocin as a universal social enhancer. (LLM, conf=0.90)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    In animals, oxytocin increases social approach and social memory, both of which are impaired in persons with autism.

    “In animals, oxytocin increases social approach and social memory,1 both of which are impaired in persons with autism.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [1] Insel TR. The challenge of translation in social neuroscience: a review of oxytocin, vasopressin, and affiliative behavior. Neuron 2010; 65: 768– 79. 20346754 PMC2847497 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Elevated promoter methylation in OXTR has been reported in persons with autism spectrum disorder compared with controls.

    “Elevated promoter methylation in OXTR has also been reported in persons with autism spectrum disorder, as compared with controls.8”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [8] Gregory SG, Connelly JJ, Towers AJ, Genomic and epigenetic evidence for oxytocin receptor deficiency in autism. BMC Med 2009; 7: 62. 19845972 PMC2774338 source

  • May combine two claims.

    Findingown data

    There were no other clinically meaningful changes in vital signs, height, clinical laboratory assessments, or electrocardiographic findings in either group.

    “There were no other clinically meaningful changes in vital signs, height, clinical laboratory assessments, or electrocardiographic findings in either group.”
    Quote in the paperNot a substantial claim

  • May combine two claims. The quote only partly states this claim.

    Findingown data

    The between-group difference in least-squares mean change from baseline on the ABC-mSW was 0.3 points (95% CI, −1.4 to 2.1) among fluent verbal participants and −0.9 points (95% CI, −2.7 to 1.0) among minimally verbal participants, indicating no significant difference in either subgroup.

    “Among participants with fluent verbal speech, the between-group difference in the least-squares mean change from baseline was 0.3 (95% CI, −1.4 to 2.1); among participants with minimal verbal fluency, the between-group difference in the least-squares mean change from baseline was −0.9 (95% CI, −2.7 to 1.0).”
    • Also stated in: § DISCUSSION · plain
      “The absence of between-group differences in outcomes was similar among participants with fluent verbal communication and among those with minimal verbal communication”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The modified ABC Social Withdrawal subscale (ABC-mSW) is a valid measure of social interaction in children and adolescents with autism spectrum disorder for the purpose of this trial.

  • May combine two claims.

    Findingown data

    Three serious adverse events occurred; one was considered related to oxytocin and involved sedation while driving that led to a motor vehicle accident at a total daily dose of 48 IU.

    “Three serious adverse events occurred during the trial. One serious adverse event was considered by the investigators to be related to oxytocin: sedation while driving that led to a motor vehicle accident while the participant was taking a total daily dose of 48 IU.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The oxytocin group had higher incidences than placebo of increased appetite, increased energy, restlessness, subjective weight loss, increased thirst, inattention, and myalgia.

    “The oxytocin group had higher incidences of increased appetite (16%, vs. 10% in the placebo group), increased energy (10% vs. 3%), restlessness (8% vs. 2%), subjective weight loss (7% vs. 3%), increased thirst (6% vs. 3%), inattention (6% vs. 3%), and myalgia (3% vs. 1%) (Table S7).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The incidence and severity of adverse events were similar in the oxytocin and placebo groups.

    “The incidence and severity of adverse events were similar in the two groups.”
    • Also stated in: § SAFETY · plain
      “Adverse events occurred in 82% of the participants in the oxytocin group and in 83% of those in the placebo group (Table 3).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Four participants in the oxytocin group and three in the placebo group discontinued the trial regimen because of adverse events; most oxytocin discontinuations were related to irritability or aggression, whereas only one placebo discontinuation was due to behavioral causes.

    “In the safety population, four participants in the oxytocin group and three in the placebo group discontinued the trial regimen owing to adverse events. Most of the discontinuations in the oxytocin group were related to irritability or aggression; only one of the discontinuations in the placebo group was due to behavioral causes (increased libido with impulsivity).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The oxytocin and placebo groups did not differ significantly in least-squares mean change from baseline on the Sociability Factor; the difference was 0.6 points (95% CI, −1.8 to 3.1).

    “The point estimate of the least-squares mean change from baseline in the Sociability Factor score was −7.7 in the oxytocin group and −8.3 in the placebo group (difference, 0.6 points; 95% CI, −1.8 to 3.1).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Mean weight gain was 1.6±2.2 kg in the oxytocin group and 2.3±2.8 kg in the placebo group.

    “The mean weight gain was 1.6±2.2 kg in the oxytocin group and 2.3±2.8 kg in the placebo group.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Efficacy analyses used a modified intention-to-treat approach that included randomized participants who received at least one day of oxytocin or placebo and had both a baseline and at least one postbaseline ABC-mSW score.

    “All the efficacy analyses were performed with the use of a modified intention-to-treat approach that included all the participants who had undergone randomization, received oxytocin or placebo for at least 1 day, and had both a baseline and at least one postbaseline ABC-mSW score.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductown data

    The trial was double-blind; the trial physician assessing participants was unaware of the trial-group assignment.

    “We conducted an investigator-initiated, randomized, double-blind, parallel-group, placebo-controlled trial of daily, flexible-dose intranasal oxytocin treatment in children and adolescents with autism spectrum disorder.”
    • Also stated in: § PARTICIPANTS · plain
      “At each visit, the trial physician, who was unaware of the participant’s trial-group assignment, completed a physical examination, systematically elicited a history of adverse events, verified concomitant treatments, and, at visits after the baseline visit, assessed current symptoms of autism spectrum disorder using the Clinical Global Impressions Scale of Improvement.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductown data

    Participants were randomly assigned in a 1:1 ratio using a centralized randomization table, with stratification by verbal fluency and age group.

    “Participants were randomly assigned in a 1:1 ratio, by means of a centralized randomization table, to receive intranasal oxytocin or matching intranasal placebo, with stratification according to verbal fluency (minimally verbal or fluently verbal, with the ability to perform ADOS-2 module 3 or 4 as an indication of fluent speech) and age group (3 to 6 years, 7 to 11 years, and 12 to 17 years).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductown data

    Participants' demographic characteristics, symptom severity, and use of concomitant medications were similar at baseline between the oxytocin and placebo groups.

    “The participants’ demographic characteristics, symptom severity, and use of concomitant medications were similar at baseline in the two trial groups (Tables 1 and S3).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    In the modified intention-to-treat population, 90% of participants (125 in each group) completed the trial.

    “In the modified intention-to-treat population, 14 participants in the oxytocin group and 13 in the placebo group withdrew before week 24; thus, 90% of the participants in the modified intention-to-treat population (125 in each group) completed the trial (Fig. 1).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductnone given

    The placebo contained no oxytocin but was otherwise identical to the active intranasal oxytocin product in ingredients, volume, labeling, container system, and other features.

    “The placebo contained no oxytocin but was otherwise identical to the intranasal oxytocin product with respect to the other ingredients, volume, labeling, container system, and other features.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductown data

    Of 1939 expected ABC-mSW assessments in the modified intention-to-treat population, 128 (6.6%) were missing, and the data were considered missing at random.

    “Of the 1939 ABC-mSW assessments that were expected if every participant in the modified intention-to-treat population completed all scheduled assessments, 128 (6.6%) were missing; the data were considered to be missing at random (Table S4).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    At the end of the trial, 52% of trial physicians, 49% of primary caregivers, and 50% of participants who answered guessed the trial-group assignment correctly.

    “A total of 52% of the trial physicians, 49% of the primary caregivers, and 22 of the 44 participants who answered (50%) guessed the trial-group assignment correctly at the end of the trial.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premiseown data

    The highest concentration of the formulation used in this trial was 24 IU per 0.1 ml.

    “The highest concentration of the formulation used in our trial was 24 IU per 0.1 ml.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The data and safety monitoring board reviewed unblinded safety data twice yearly.

    “The data and safety monitoring board reviewed unblinded safety data twice yearly.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    There was no prespecified plan to adjust confidence intervals for multiple comparisons for secondary, exploratory, or sensitivity outcomes, so those results are reported as point estimates with 95% confidence intervals and cannot be used to infer definitive treatment effects.

    “There was no prespecified plan for adjustment of confidence intervals to account for multiple comparisons for secondary, exploratory, or sensitivity outcomes. Results of these analyses are therefore reported as point estimates with 95% confidence intervals and cannot be used to infer definitive treatment effects.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Many children with autism spectrum disorder are thought to have tried intranasal oxytocin therapy on the basis of putatively promising data.

    “Many children with autism spectrum disorder are thought to have tried intranasal oxytocin therapy33 on the basis of putatively promising data.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [33] Hopf KP, Madren E, Santianni KA. Use and perceived effectiveness of complementary and alternative medicine to treat and manage the symptoms of autism in children: a survey of parents in a community population. J Altern Complement Med 2016; 22: 25– 32. 26654976 PMC4739350 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    There was no commercial involvement in the trial.

    “There was no commercial involvement in the trial.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisenone given

    Previous trials used 12 IU of oxytocin in children younger than 13 years and 24 IU once or twice daily in participants 13 years or older.

    “Previous trials used 12 IU of oxytocin in children younger than 13 years of age and 24 IU once or twice daily in participants 13 years of age or older.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A meta-analysis has tentatively supported an association between autism spectrum disorder and polymorphisms in the oxytocin receptor gene OXTR, but not at genomewide significance.

    “A meta-analysis has tentatively supported an association between autism spectrum disorder and polymorphisms in the oxytocin receptor gene, OXTR, but not at the level of genomewide significance.7”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [7] LoParo D, Waldman ID. The oxytocin receptor gene (OXTR) is associated with autism spectrum disorder: a meta-analysis. Mol Psychiatry 2015; 20: 640– 6. 25092245 source

  • May combine two claims.

    Premiseown data

    In this trial, total daily oxytocin doses ranged from 8 to 80 IU and depended on adverse effects rather than participant age or weight.

    “In contrast, the total daily doses of oxytocin in our trial ranged from 8 to 80 IU, depending on adverse effects in the participants rather than on participant age or weight.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisereasoning

    The Novartis product has a concentration of 4 IU of oxytocin per 0.1 ml, so a 24 IU dose requires 0.6 ml of solution at one time, which may influence absorption.

    “The concentration of the Novartis product is 4 IU of oxytocin per 0.1 ml of solution; a dose of 24 IU requires that 0.6 ml of solution be delivered at one time, which may influence absorption.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductreasoning

    A minimum ABC-mSW score was not required for enrollment, which potentially limited the ability to detect improvements in children with low baseline scores.

    “A minimum score on this scale was not required for enrollment, which potentially limited our ability to detect improvements in children who had low ABC-mSW scores at baseline.”
    Quote in the paperNot a substantial claim
31 of 31

  • The paper relies on this without support.

    The modified ABC Social Withdrawal subscale (ABC-mSW) is a valid measure of social interaction in children and adolescents with autism spectrum disorder for the purpose of this trial.

    “The ABC-mSW that was used to determine the primary outcome was a modification of the ABC Lethargy–Social Withdrawal subscale that omitted three questions (3, 32, and 53) pertaining to reduced physical movement in order to increase specificity for social function.”
    “our primary outcome was based on the use of the ABC-mSW, which has not been validated.”
1 of 1

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • The Sikich et al. study was rigorous, robust, and thorough in both design and execution.

    “the randomized, double-blind, parallel-group, placebo-controlled study by Sikich et al. was rigorous, robust, and thorough in both design and execution1”

    From Refining oxytocin therapy for autism: context is key (2022) · cites this paper as [1]

  • The Sikich et al. randomized controlled trial found no effect of chronic intranasal oxytocin on social behaviour or other clinical outcomes in children and adolescents with autism spectrum disorder.

    “A recent clinical trial found no effect of chronic intranasal oxytocin on social behaviour in children with autism spectrum disorders.”

    From Refining oxytocin therapy for autism: context is key (2022) · cites this paper as [1]

  • There is now compelling evidence that chronic administration of oxytocin is not beneficial.

    “now we have compelling evidence that chronic administration of oxytocin is not beneficial”

    From Refining oxytocin therapy for autism: context is key (2022) · cites this paper as [1]

  • The sample size of the Sikich et al. trial was more than adequate to detect an effect of clinically meaningful size.

    “a sample size more than adequate to detect an effect of clinically meaningful size”

    From Refining oxytocin therapy for autism: context is key (2022) · cites this paper as [1]

  • The Sikich et al. trial collected data from 277 of the 290 participants enrolled across seven academic sites.

    “Data were collected from 277 of the 290 participants enrolled across seven academic sites”

    From Refining oxytocin therapy for autism: context is key (2022) · cites this paper as [1]

Cites

Flagged first, then by citations

Cited by

Sorted by citations

Related

Authors
Sikich, L., Kolevzon, A., King, B. H., McDougle, C. J., Sanders, K. B., Kim, S.-J., Spanos, M., Chandrasekhar, T., Trelles, M. D. P., Rockhill, C. M., Palumbo, M. L., Witters Cundiff, A., Montgomery, A., Siper, P., Minjarez, M., Nowinski, L. A., Marler, S., Shuffrey, L. C., Alderman, C., Weissman, J., Zappone, B., Mullett, J. E., Crosson, H., Hong, N., Siecinski, S. K., Giamberardino, S. N., Luo, S., She, L., Bhapkar, M., Dean, R., Scheer, A., Johnson, J. L., Gregory, S. G., & Veenstra-VanderWeele, J.
Affiliations
  • University of North Carolina at Chapel Hill (US)
  • From the Department of Psychiatry and Behavioral Sciences (L. Sikich, M.S., T.C., C.A., A.S.), the Duke Clinical Research Institute (L. Sikich, C.A., S.L., L. She, M.B.), the Duke Molecular Physiology Institute (S.K.S., S.N.G., S.G.G.), and the Departments of Biostatistics and Bioinformatics (S.L.) and Neurology (S.G.G.), Duke University, Durham, the Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill (L. Sikich, M.S., T.C., C.A., R.D., A.S., J.L.J.), and SAS Institute, Cary (J.L.J.) — all in North Carolina; the Department of Psychiatry, Icahn School of Medicine at Mount Sinai (A.K., M.D.P.T., P.S., J.W.), the Department of Psychiatry, Columbia University (A.M., L.C.S., N.H., J.V.-V.), and New York State Psychiatric Institute (J.V.-V.), New York, and the Center for Autism and the Developing Brain, Weill Cornell Medicine, White Plains (J.V.-V.) — all in New York; the Department of Psychiatry, University of California San Francisco, San Francisco (B.H.K.); the Department of Psy...
ORCID
Venue
New England Journal of Medicine
Publisher
Massachusetts Medical Society
Published
2021-10-14
Volume
385
Issue
16
Pages
1462-1473
ISSN
  • 0028-4793 (ISSN-L)
  • 1533-4406
DOI
10.1056/nejmoa2103583
PMC
PMC9701092
OpenAlex
W3206744275
Cited by
314
References
36
Citations by year
2026: 45 · 2025: 52 · 2024: 47 · 2023: 72 · 2022: 65 · 2021: 5
FWCI
51.21
Type
journal article
Language
en
Open access
Licence
www.nejmgroup.org/legal/terms-of-use.htm (vor)
Locations
  • New England Journal of Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • Florida International University Digital Commons (Florida International University) (submittedVersion)
  • PubMed Central (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD073984)
Topics
  • Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
Keywords
intranasal oxytocin, autism spectrum disorder, children and adolescents, social withdrawal, social functioning, Aberrant Behavior Checklist, adverse events, cognitive function
MeSH terms
Autism Spectrum Disorder, Administration, Intranasal, Adolescent, Child, Child, Preschool, Double-Blind Method, Female, Humans

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-08.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-08.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review