Chronic oxytocin administration stimulates the endogenous oxytocin system: an RCT in autistic children

Background: Clinical efficacy of chronic intranasal administration of oxytocin is increasingly explored in autism spectrum disorder (ASD), but to date, little is known regarding its biological effects and in particular how chronic administration regimes impact endogenous oxytocinergic function. Methods: To fill this gap, this double-blind, randomized, placebo-controlled study explored chronic oxytocin administration effects on endogenous salivary oxytocin levels and oxytocin receptor gene (OXTR) epigenetics (DNA methylation) in 8-to-12-year-old children with ASD (n = 79, 16 females). Biological sampling was performed at baseline (pre-treatment), immediately (24 hours) after the four-week oxytocin administration period (12 IU, twice daily) and at a follow-up session, four weeks after the last nasal spray administration. Results: Compared to placebo, children receiving the oxytocin nasal spray displayed significantly higher salivary oxytocin levels 24 hours after the last oxytocin nasal spray administration, but no longer at the four-week follow up session. Regarding epigenetics, oxytocin-induced reductions in OXTR methylation were observed, reflecting a facilitation of oxytocin receptor expression in the oxytocin, compared to the placebo group. Notably, heightened oxytocin levels post-treatment were significantly associated with reduced OXTR DNA methylation and improved feelings of secure attachment. Conclusion: Four weeks of chronic oxytocin administration stimulated the endogenous oxytocinergic system in children with ASD, as evidenced by increased salivary oxytocin levels and reduced OXTR DNA methylation (indicating increased receptor expression). ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial EudraCT 2018-000769-35 ### Funding Statement This work was supported by KU Leuven, Excellence of Science, Branco Weiss -Society in Science, the King Baudoin Foundation and the Flanders Fund for Scientific Research (FWO). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Consent forms and all study procedures (including human data sample collection) were approved by the Ethics Committee at the Katholic University Leuven, Belgium (S61358) in accordance with Declaration of Helsinki and were registered at the European Clinical Trial Registry (EudraCT 2018-000769-35) and the Belgian Federal Agency for Medicines and Health products. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors