A team led by Professor Kaat Alaerts (KU Leuven) recruited 40 adult men with autism spectrum disorder to take part in their study.
“In a first stage, we examined the amount of oxytocin produced by the participants themselves. The subjects also filled out several questionnaires,” Professor Alaerts explains. “An analysis of the data revealed that the amount of oxytocin found in the subjects’ saliva was inversely related to their self-reported attachment issues.”
In a second stage of the research, the team examined the long-term effects of administering oxytocin through a nasal spray. This experiment produced remarkable results: the participants who had been given oxytocin for four weeks experienced positive effects until up to a year later.
Less repetition, more attachment
“We divided the 40 participants into an experimental group and a control group. The control group received a placebo for four weeks,” says doctoral student Sylvie Bernaerts, who is the first author of the study in Molecular Autism.
“Over the course of a full year, we also asked the participants to fill out questionnaires on four different occasions. These questionnaires were used to examine the impact of the oxytocin-containing nasal spray on the symptoms of autism.”
In terms of social interaction, the researchers found no difference between the experimental group and the control group.
But for repetitive behaviour (including the need for routines) and attachment, the results were significant: “The people in the experimental group reported far less repetitive behaviour and also reported fewer problems with forming close relationships.”
This study shows for the first time what the long-term effects are of repeatedly administering oxytocin to people with autism. Professor Alaerts:
“Participants who took oxytocin every day for four weeks experienced positive effects until up to a year later. That’s a remarkable result.”
Further research necessary
For this study, the scientists only selected male participants. This was partly because autism is more prevalent in men, and women’s hormonal cycle may influence the test results. Furthermore, oxytocin is already being used to induce labour or breastfeeding in pregnant women or women who have recently given birth, respectively. In other words, there are more factors to take into account in female test subjects.
This study shows for the first time what the long-term effects are of repeatedly administering oxytocin to people with autism. Image is in the public domain.
And what about using oxytocin as a treatment?
“As oxytocin is already being used in medicine, you might think that we can start using it quite soon to address attachment issues or to reduce repetitive behaviour in people with autism,” says Professor Alaerts.
But she is quick to temper expectations: “The findings we’re presenting today are the result of a first pilot study. A lot of further research needs to be done before oxytocin can be used to treat people with autism.”
This research was conducted in collaboration with Professor Jean Steyaert, head of the Leuven Autism Research Consortium, and was funded by the Branco Weiss Fellowship (ETH Zürich), the Marguerite-Marie Delacroix Foundation and Research Foundation – Flanders (FWO).
Autism spectrum disorder (ASD) is a neurodevelopmental condition with lifelong various phenotypes and a high prevalence, estimated at 0.62–2% [1,2,3]. The core symptoms of ASD have consisted of communication defects with social memory impairment and restrict interest and/or repetitive behavior [4,5,6].
A large number of studies investigating the theory of mind (ToM), which refers to the ability to attribute one’s own mind to others and oneself , have been conducted in individuals with ASD. As a result, impairment of ToM has been proven to be among the influential theories explaining social deficits in ASD [8,9,10].
Notably, considering that social deficits appear by 12 months of age in infants later diagnosed with ASD , these infants are not likely to be endowed with ToM, which is an essential requisite for participating in a human community.
Thus, the clinical domain of social deficits expressed symbolically as ‘autism’ results in serious maladjustment in individuals with ASD in their daily lives , and the societal domain of social deficits, conceptualized as ToM impairments, addresses critically interdisciplinary issues, including social psychology  and philosophy .
In clinical settings, there are no effective treatments for the various symptoms of ASD, except for irritability, which can be alleviated by risperidone or aripiprazole [15,16].
Regarding social deficits, no psychosocial interventions or pharmacological treatments have been effective [17,18,19], although recent researches suggest the effectiveness of risperidone or centanafadine for social disabilities based on the Aberrant Behavior Checklist (ABC) subscale of social withdrawal [16,18,20,21].
Since the pioneering study of maternal behavior induced by centrally administered oxytocin (OT) in virgin rats , studies have been conducted to investigate how the evolutionarily conserved OT modulates reciprocal interactions among individuals in each species of vertebrates [23,24,25].
In humans, many studies have focused on social cognition and prosociality promoted by OT in interpersonal relationships in typically developing individuals [26,27,28,29]. The results of these studies have suggested that OT could benefit individuals with ASD due to its favorable effects associated with sociality [30,31,32,33].
The endogenous OT systems are believed to be involved in the pathogenesis of ASD, based on results indicating low levels of plasma OT , alterations in OT peptide forms , sexually dimorphic patterns of OT associated with anxiety , dysregulation of OT signaling pathways  and common polymorphisms of the CD38 gene (CD38) [38,39,40,41] and OT receptor genes (OTR) [42,43] in individuals with ASD.
Exogenous OT is expected to be a promising candidate for the pharmacological treatment of ASD [26,29,31,44], and several clinical trials on short-term OT administration have been performed over the last decade [45,46,47,48].
A meta-analysis of this research suggested that OT has significant benefits compared with placebo in the treatment of ASD, with a moderate effect size (Cohen’s d = 0.57) . Notably, social deficits may be relieved by OT administration [46,47,48,50,51,52,53].
We must consider the important subclass (Kanner type) of ASD individuals with low intelligence quotient (IQ) and epilepsy for benefits of new drugs, because these subjects have not been considered as targets of clinical trials owing to doubt of no tolerance to such trials. Here, we reviewed and compared recent randomized controlled clinical trials (RCTs) of OT, and whether or not the primary, secondary and exploratory outcome measures were favourable, especially for improvement of social behavioral impairments.
It has been reported that levels of OT have a considerable variation in children, and that those with low levels of OT have fewer social skills, regardless of whether they suffer from ASD or not . Therefore, it is expected that the administration of OT to autistic patients could improve their condition.
The results of such studies have not always shown beneficial effects of OT (Table 1). We found that no conventional measurements could detect the possible effects of OT; however, an alternative means of describing interpersonal events observed in real-life situations  or doctors’ impressions (CGI; ) demonstrated favorable effects of OT, and baseline plasma OT levels predicted OT-induced behavioral improvements (Figure S3).
Future studies require a new design to clarify the efficacy of OT under circumstances similar to those faced by individuals with ASD in their daily lives as members of society.
It is important, especially after a recent request from the NIH in the USA, that new studies should be planned with a more significant sample of autistic individuals. Future RCTs have to ascertain whether the effects of OT are independent of the mode of administration of the substance, with intranasal or sublingual sprays being common options.
In this respect, very recently a report by Yamamoto et al.  showed that peripheral OT is transported into the brain by receptors for advanced glycation end-products in mice, suggesting that central OT has behavioral effects in humans after intranasal OT administration. This solves the long argument in this field of whether or not OT effects are mediated by OT binding to peripheral OT receptors that in turn influence brain activity, or directly by central OT receptors after recruitment of OT into the brain.