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You can strike intranasal oxytocin off the list of potential treatments for autism spectrum disorder (ASD), results from the largest prospective trial to date indicated -- though not everyone agrees.

ASD symptom scores were no different in children and teens receiving the hormone as a nasal spray for 24 weeks than in a comparable placebo group, according to Linmarie Sikich, MD, of Duke University in Durham, North Carolina, and colleagues.

Most secondary outcomes in the 290-patient trial, known as , also failed to show any benefit for oxytocin, the researchers . The treatment, in common use for inducing labor and easily obtained from compounding pharmacies, has gained popularity with parents of children with ASD.

"There was a great deal of hope this drug would be effective," Sikich said in a Duke press release. "All of us on the study team were hugely disappointed, but oxytocin does not appear to change social function of people with autism."

Some earlier, smaller studies had pointed to a benefit in social functioning with oxytocin. For example, a 4-week randomized trial in 32 ASD children, , showed markedly greater improvement in Social Responsiveness Scale (SRS) scores with oxytocin versus placebo. This seemed to confirm results from a of 20 Japanese adults with ASD treated with oxytocin for 6 weeks in a cross-over design.

On the other hand, a more recent and bigger , also conducted in Japan, failed to find a benefit for oxytocin.

Said Sikich in the press release, "Our consensus as investigators is that there is no evidence in [SOARS-B] that is strong enough to justify more investigation of oxytocin as a treatment for autism spectrum disorders."

But an argued that such a conclusion was premature given the trial's limitations.

Daniel H. Geschwind, MD, PhD, of the University of California Los Angeles, pointed to several "potential mitigating factors" that render the trial less than fully definitive. He suggested that dosing might have been inadequate, the participants' age range too broad, and the outcome measures too insensitive "to capture social motivation." He also noted that autism is "genetically heterogeneous," such that oxytocin may benefit some genotypes more than others.

In addition, "the drug was administered without concomitant standardized behavioral intervention for social skills. Should we expect that increasing motivation alone, without contemporaneous behavioral intervention, would lead to ongoing improvements in social function? Motivation is just one component of the social behavior equation," Geschwind wrote.

"An analogy would be an attempt to build athletic prowess by the administration of anabolic steroids without simultaneous rigorous physical training," he added.

Study Details

SOARS-B was conceived in 2013, when the available data from small trials and research into oxytocin's functions in humans suggested that a treatment benefit in ASD was both likely and plausible. Numerous lines of research indicated that the hormone is a key mediator of socialization and empathy. Sikich and colleagues noted in their paper, for example, that "neuroimaging studies involving persons with autism spectrum disorder [showed] differences in regional brain activation in response to social stimuli after the administration of intranasal oxytocin, as compared with placebo."

Already by then the early studies and speculations had fueled demand from parents for oxytocin treatment for their ASD children.

Designated as phase II, SOARS-B enrolled patients ages 3 to 17 who met , without other diagnoses that overlap with ASD or make oxytocin treatment risky. Those who had previously received intranasal oxytocin for more than 30 days were also excluded.

About 85% of the participants were boys. Mean age was about 10 for those considered minimally verbal and 11 in those rated as verbally fluent. The age distribution was roughly equal in the ranges of 3-6, 7-11, and 12-17.

Oxytocin dosing was "flexible," the researchers explained. Patients started at 8 IU each morning, which was then raised to a target daily dose of 48 IU, typically as 24 IU twice daily, at week 8.

"Once the target dose was maintained for 7 weeks, the dose could be escalated further by 16 IU every 4 weeks to reach a maximal total daily dose of 80 IU," the group wrote, but doses could also be maintained at the 48-IU level or reduced by 8-16 IU, "if requested by the trial physician, caregiver, or participant." There was no specific dose adjustment for age or weight.

In all, 250 of the 290 individuals who began treatment completed the full 24 weeks.

Scores on the 13-item Aberrant Behavior Checklist modified Social Withdrawal subscale (ABC-mSW) served as the trial's primary outcome.

Mean scores on this measure at baseline were 11.6 in the placebo group and 11.0 in those assigned to oxytocin. By week 24, both groups showed some improvements, to 8.0 and 7.5 on average, respectively, for a mean least-squares difference in change from baseline of -0.2 points (95% CI -1.5 to 1.0, P=0.61).

Secondary outcomes included change from baseline in scores from the SRS, Sociability Factor index, and the Stanford-Binet IQ test. Oxytocin did not come close to making a difference in any of these, either.

The trial provided some safety data as well, which at least were relatively reassuring about oxytocin. Most participants in each group experienced some sort of adverse event, and 38 of these were rated as severe. However, more of these occurred in the placebo group (including those deemed treatment-related). The event types more common with oxytocin included increased appetite, thirst, and energy; subjective weight loss; inattention; and muscle pain. None of these occurred in more than 10% of participants.

Sikich and colleagues noted a number of limitations, including some highlighted by Geschwind as well as the potential that the particular oxytocin product they used might have problems with absorption at high doses. Also, the team acknowledged that the ABC-mSW scale is not a validated outcome measure for ASD research.

One point the researchers mentioned only briefly in their main article was whether baseline oxytocin levels made a difference in outcomes. The 2017 study that showed an overall benefit for oxytocin also found that the effect appeared magnified in those with low pretreatment levels. But in SOARS-B, neither ABC-mSW nor SRS scores differed "appreciably" when participants were stratified according to baseline levels, Sikich and colleagues wrote.

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