Oro-mucosal administration of oxytocin using medicated lollipops alters social attention, similar to intranasal and lingual routes: Implications for therapeutic use

Abstract

A key functional effect of intranasal administration of the neuropeptide oxytocin is on top-down control of social attention. However, an oro-mucosal administration route may be better tolerated for chronic therapeutic use and evidence suggests that some functional effects of oxytocin can be mediated via peripheral routes. The current study investigated if oxytocin administered orally using medicated lollipops can both increase blood oxytocin concentrations and influence social attention and state anxiety. In a randomized, double-blind, clinical trial adult male participants received oral oxytocin (24IU) or placebo 30-min before completing a well-established anti-saccade paradigm which can assess treatment effects on both top-down and bottom-up attention. Oxytocin administration modulated top-down social attentional processing by increasing anti-saccade error rates on both social and non-social stimuli although it only increased response latencies for social cues. Anti-saccade errors were also positively associated with the proportionate increase in plasma oxytocin concentrations. A comparison analysis showed that oral oxytocin administration increased blood concentrations to a similar degree as given by lingual spray, although less than when given intranasally. Importantly, attentional and anxiolytic effects of oxytocin in the anti-saccade task were similar across intranasal, lingual, and oral administration routes. These findings demonstrate that oral administration of oxytocin, similar to via intranasal and lingual routes, can modulate top-down social attention and state anxiety and support its potential for therapeutic use. They also provide further evidence that functional effects of exogenously administered oxytocin can be mediated indirectly either by crossing the blood brain barrier or producing receptor mediated vagal stimulation, as opposed to via direct entry into the brain.

Oxytocin administration enhances pleasantness and neural responses to gentle stroking but not moderate pressure social touch by increasing peripheral concentrations

“…intravenous, intraperitoneal, subcutaneous and oral). Although, the intranasal administration route for OT produced significantly greater initial increases in plasma OT concentrations compared to an oral route in both the present study, and in two previous ones (Kou et al, 2021;Xu et al, 2022), this did not result in significant route-dependent differences, possibly due to the high doses involved. The broadly similar functional effects of intranasal and oral OT in the context of behavioral and neural responses to gentle stroking touch are also consistent with our previous findings for visual attention towards social and non-social stimuli (Zhuang et al, 2022;Xu et al, 2022), although there is also evidence for route-dependent effects of OT on neural and behavioral effects on responses to emotional faces (Kou et al, 2021).…”

“…We hypothesized firstly that intranasal OT would particularly enhance behavioral and brain reward (OFC) responses to gentle stroking touch targeting the CT-fiber system in line with previous studies (Chen et al, 2020a; Scheele et al, 2014). Secondly, based on recent studies comparing effects of intranasal and oral OT (Xu et al, 2022; Zhuang et al, 2022), we hypothesized that oral OT would have a similar effect to intranasal OT. Thirdly, we hypothesized that behavioral and neural effects of OT on social touch would be associated with treatment effects on peripheral plasma concentrations of the peptide, in line with observations in some previous studies (Martins et al, 2020; Kou et al, 2021).…”

Oral Oxytocin Facilitates Responses to Emotional Faces in Reward and Emotional-Processing Networks in Females

“…Recently, we have used an oral route of administration to demonstrate both neural and behavioral responses to OXT. An oral route precludes any possibility of direct entry into the brain, and using a lingual spray or medicated lollipop, we have shown increased blood concentrations of OXT [24, 25] which we assume are due primarily to absorption via blood vessels in the mouth and tongue since peptidases in the stomach rapidly metabolize OXT without pre-treatment with a gastric acid inhibitor [26]. In an initial study where OXT was administered as a lingual spray to male subjects, increased responses to emotional faces were found in both brain reward (putamen) and emotional-processing (amygdala) regions, with putamen responses to happy faces being associated with increased arousal and mediated by increased plasma OXT concentrations.…”

“…By contrast, intranasal OXT produced reduced amygdala responses to emotional faces and no effect on the putamen at all [24]. Other studies in male subjects have shown that oral OXT administered lingually [27], or using medicated lollipops [25], has an identical effect to intranasal OXT in modulating attention toward social stimuli in an anti-saccade eye-tracking task as well as reduced state anxiety. The effects of oral OXT on attention were also associated with altered plasma OXT concentrations [25].…”

“…Other studies in male subjects have shown that oral OXT administered lingually [27], or using medicated lollipops [25], has an identical effect to intranasal OXT in modulating attention toward social stimuli in an anti-saccade eye-tracking task as well as reduced state anxiety. The effects of oral OXT on attention were also associated with altered plasma OXT concentrations [25]. Thus, there is evidence that both intranasal and oral administration of OXT produce functional effects, although the oral route may be more potent in influencing the brain reward system.…”