Low-dose oxytocin delivered intranasally with Breath Powered device affects social-cognitive behavior: a randomized four-way crossover trial with nasal cavity dimension assessment

D S Quintana, L T Westlye, Ø G Rustan, N Tesli, C L Poppy, H Smevik, M Tesli, M Røine, R A Mahmoud, K T Smerud, P G Djupesland, O A Andreassen, D S Quintana, L T Westlye, Ø G Rustan, N Tesli, C L Poppy, H Smevik, M Tesli, M Røine, R A Mahmoud, K T Smerud, P G Djupesland, O A Andreassen

Abstract

Despite the promise of intranasal oxytocin (OT) for modulating social behavior, recent work has provided mixed results. This may relate to suboptimal drug deposition achieved with conventional nasal sprays, inter-individual differences in nasal physiology and a poor understanding of how intranasal OT is delivered to the brain in humans. Delivering OT using a novel 'Breath Powered' nasal device previously shown to enhance deposition in intranasal sites targeted for nose-to-brain transport, we evaluated dose-dependent effects on social cognition, compared response with intravenous (IV) administration of OT, and assessed nasal cavity dimensions using acoustic rhinometry. We adopted a randomized, double-blind, double-dummy, crossover design, with 16 healthy male adults completing four single-dose treatments (intranasal 8 IU (international units) or 24 IU OT, 1 IU OT IV and placebo). The primary outcome was social cognition measured by emotional ratings of facial images. Secondary outcomes included the pharmacokinetics of OT, vasopressin and cortisol in blood and the association between nasal cavity dimensions and emotional ratings. Despite the fact that all the treatments produced similar plasma OT increases compared with placebo, there was a main effect of treatment on anger ratings of emotionally ambiguous faces. Pairwise comparisons revealed decreased ratings after 8 IU OT in comparison to both placebo and 24 IU OT. In addition, there was an inverse relationship between nasal valve dimensions and anger ratings of ambiguous faces after 8-IU OT treatment. These findings provide support for a direct nose-to-brain effect, independent of blood absorption, of low-dose OT delivered from a Breath Powered device.

Trial registration: ClinicalTrials.gov NCT01983514.

Figures

Figure 1
Figure 1
Mean emotional ratings by stimulus and treatment. Angry ratings of emotionally ambiguous faces were reduced after the administration of 8 IU OPN-OT in comparison with placebo and 24 IU OPN-OT (a; FDR correction applied, q=0.05, revised critical value of P<0.017 for post hoc comparisons). There were no main effects for any of the other evaluation categories (b–f). Emotion ratings can theoretically range from 1 to 5 and error bars represent standard error of the mean. *P<0.05. **P<0.01. FDR, false discovery rate; IU, international unit; IV, intravenous; OPN-OT, OT delivered with the Breath Powered OptiNose device; OT, oxytocin.
Figure 2
Figure 2
Percentage reduction in anger ratings was greater when presented with ambiguous faces compared with non-ambiguous faces (with corresponding or conflicting cues) after 8 IU OPN-OT compared with both placebo (a) and 24 IU OPN-OT (b) treatments (FDR correction applied, q=0.05, revised critical value of P<0.025 for post hoc comparisons). Ambiguous indicates anger ratings of ambiguous faces; NA-corresponding indicates anger ratings of non-ambiguous faces with corresponding cues; NA-conflicting indicates anger ratings of non-ambiguous faces with conflicting cues. Error bars represent s.e.m. *P<0.05. FDR, false discovery rate; IU, international unit; IV, intravenous; OPN-OT, OT delivered with the Breath Powered OptiNose device; OT, oxytocin.
Figure 3
Figure 3
Pharmacokinetics of plasma OT (a) and AVP (b) after the administration of 8 IU OPN-OT, 24 IU OPN-OT, IV OT and placebo. Error bars represent s.e.m. IU, international unit; IV, intravenous; OPN-OT, OT delivered with the Breath Powered OptiNose device; OT, oxytocin.
Figure 4
Figure 4
The relationship between angry ratings of ambiguous faces after 8 IU OT treatment and bilaterally summed mean cross-sectional areas in cm2 of the nasal valves with best-fit line and 95% confidence band. The significant inverse relationship indicates that individuals with wider nasal valves rate ambiguous faces as less angry after 8 IU OPN-OT administration.

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