Oxytocin and the social facilitation of placebo effects

Abstract

Significant clinical improvement is often observed in patients who receive placebo treatment in randomized double-blind placebo-controlled trials. While a proportion of this “improvement” reflects experimental design limitations (e.g., reliance on subjective outcomes, unbalanced groups, reporting biases), some of it reflects genuine improvement corroborated by physiological change. Converging evidence across diverse medical conditions suggests that clinically-relevant benefits from placebo treatment are associated with the activation of brain reward circuits. In parallel, evidence has accumulated showing that such benefits are facilitated by clinicians that demonstrate warmth and proficiency during interactions with patients. Here, we integrate research on these neural and social aspects of placebo effects with evidence linking oxytocin and social reward to advance a neurobiological account for the social facilitation of placebo effects. This account frames oxytocin as a key mediator of treatment success across a wide-spectrum of interventions that increase social connectedness, thereby providing a biological basis for assessing this fundamental non-specific element of medical care.

The effect of oxytocin nasal spray on social interaction in young children with autism: a randomized clinical trial

“…Previous studies have also highlighted the potential of placebobased responses to provide therapeutic outcomes across many clinical conditions [37][38][39] and also to moderate oxytocin based effects [19]. Meta-analyses in the autism field have further supported the existence of placebo responses of a moderate effect size [40].…”

“…These studies have, however, not been without controversy. Reviews of this evidence have highlighted the potential for placebo and expectancy effects to impact outcomes [14,18,19], a need for biological markers [13], a better understanding of drug delivery factors to inform use [20], and the role of early life development and social learning contexts [8], all of which might potentially moderate response [12]. To illustrate, the age of the child may play a part, with some evidence suggesting that younger children may show greater response to social interventions [21].…”

“…To illustrate, the age of the child may play a part, with some evidence suggesting that younger children may show greater response to social interventions [21]. Other research has highlighted that oxytocin responses may be partly moderated by placebo effects [14,18,19]. There is also a need to further establish evidence around oxytocin use in social development to inform ethical and scientific arguments about whether it remains a sound target for intervention to support outcomes for autistic people.…”

Effects of multiple-dose intranasal oxytocin treatment on social responsiveness in children with autism: A randomized, placebo-controlled trial

“…While not explicitly addressed in the current study, it is also noteworthy to stipulate that the oxytocinergic system itself has been suggested to form a key mediator for facilitating placebo-induced improvements. Indeed, as postulated in the recent oxytocin-placebo account of Itskovich et al (2022); OT is suggested to mediate social facilitation of placebo effects, an effect that is thought to be facilitated by increased social connectedness between patient and clinician during trial participation. In line with this notion, a prior OT administration trial showed that placebo-induced improvements in social functioning coincided with endogenous increases in oxytocin secretion (Parker et al, 2017)…”

“…While not explicitly addressed in the current study, it is also noteworthy to stipulate that the oxytocinergic system itself has been suggested to form a key mediator for facilitating placebo-induced improvements. Indeed, as postulated in the recent oxytocin-placebo account of Itskovich et al (2022); OT is suggested to mediate social facilitation of placebo effects, an effect that is thought to be facilitated by increased social connectedness between patient and clinician during trial participation. In line with this notion, a prior OT administration trial showed that placebo-induced improvements in social functioning coincided with endogenous increases in oxytocin secretion (Parker et al, 2017) Further, in our trial, children who received the actual OT treatment in the first phase and crossed over to a second phase of active treatment, showed only non-significant withinsubject improvements from phase I to phase II, particularly at the four-week follow-up session of phase II -supporting prior observations of a retention of OT's beneficial effects, also after cessation of the daily nasal spray administrations (Alaerts et al, 2020;.…”