Nasal Dominance Potentiates Intranasal Oxytocin’s Anxiolytic Effects

doi:10.21203/rs.3.rs-4168871/v1

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Nasal Dominance Potentiates Intranasal Oxytocin’s Anxiolytic Effects

https://doi.org/10.21203/rs.3.rs-4168871/v1

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The nasal cycle is a phenomenon whereby alterations in airflow alternate between left and right nostrils. During a nostril’s decongested – or dominant – state, the contralateral nostril is congested, or non-dominant. Intranasal oxytocin may elicit anxiolytic effects. To date, no study has investigated whether there is an optimal nasal pathway for oxytocin’s effects. Forty-four female adolescents aged 16 to 17 years were included in this exploratory study investigating effects of nasal dominance on intranasal oxytocin delivery. We show that intranasal oxytocin significantly reduces stress relative to placebo (p = 0.019, ηp² = 0.129) and greater stress reduction occurs when oxytocin is delivered to the dominant, rather than non-dominant, nostril (p = 0.045, ηp² = 0.102). We postulate that oxytocin administration may reduce stress and be most effective in the context of anxiolysis when administered to the dominant nostril. Further research investigating whether other intranasal psychotropic drugs have nostril-specific effects might benefit clinical practice.

Biological sciences/Neuroscience/Emotion

Biological sciences/Neuroscience/Social behaviour

Biological sciences/Neuroscience/Stress and resilience

Biological sciences/Psychology/Human behaviour

The nasal cycle is characterised by rhythmic alterations in airflow between the left and right nostrils, where congestion in one nostril is cyclically accompanied by decongestion in the other nostril¹. This phenomenon is seen in approximately 70–80% of healthy adults, switching states approximately every two hours in wake and 4.5 hours in sleep². Although significant variability in cycle length has been reported^{3 4 5}, the cycle frequency can be indirectly affected by factors such as body mass index (BMI)⁶.

In the decongested nostril, referred to as the dominant nostril, there is increased airflow. In the contralateral nostril, also known as the congested or non-dominant nostril, airflow is decreased, marking the ‘resting phase’ of the cycle⁷. It is currently thought that dominance is related to vasoconstriction in the decongested nasal cavity, while non-dominance is associated with vasodilation in the congested nasal cavity⁸.

Oxytocin is a nonapeptide, primarily synthesised in the hypothalamic supraoptic and paraventricular nuclei and released by exocytosis into the central nervous system⁹. Oxytocin receptors are the only described receptor expressed in neural tissue and other parts of the body in species-dependent patterns¹⁰. Owing to its molecular mass of 1007 Daltons¹¹, oxytocin was previously considered unable to penetrate the blood-brain barrier (BBB). However, recent findings have demonstrated that oxytocin may bind to the receptor for advanced glycation end-products (RAGE), facilitating its transport across the BBB¹²¹³.

Oxytocin has a wide role in the stress response, acting as an anxiolytic agent via the hypothalamic-pituitary-adrenal axis¹⁴. Pierrehumbert et al. induced laboratory stress in humans using the Trier Social Stress Test to investigate the presence of an oxytocin response and found a negative correlation between oxytocin and cortisol, suggesting an interaction between cortisol release and oxytocin¹⁵.

Intranasal oxytocin is widely used in psychological and psychiatric studies. The mechanism by which exogenously administered oxytocin elicits its effects on brain and behaviour is still unclear, in part due to the absence of a positron emission tomography radiotracer approved for human use. There are three main theories, although not necessarily competing, explaining how oxytocin is absorbed through the nostril to effect central change. The direct route theory assumes that oxytocin circumvents the BBB through an extracellular pathway involving the olfactory and trigeminal nerves and perineural clefts in the nasal epithelium¹⁶. Once intranasal oxytocin reaches the olfactory and respiratory epithelia, it is transported via the ensheathed channels surrounding the olfactory and trigeminal nerve fibres¹⁷. The olfactory nerve fibres then pass through clefts in the cribriform plate, leading to the olfactory bulbs. The BBB theory posits that oxytocin may be delivered to the brain by crossing the BBB in small but biologically relevant quantities¹⁸. Recent findings substantiate oxytocin’s transport across the BBB following exogenous administration via RAGE-mediated transport¹³. Thirdly, oxytocin administered intranasally may have the potential to influence afferent feedback to the brain from peripheral systems, specifically from organs abundant in oxytocin receptors, thereby influencing central oxytocin function¹⁹.

Although the transport of oxytocin from nose-to-brain is not fully articulated, understanding the influence of nasal dominance on oxytocin absorption may shed light on oxytocin’s pathway to the brain. We hypothesised that there would be a difference in stress scores following administration of a stressor depending on whether intranasal oxytocin was delivered via the dominant or non-dominant nostril.

Participant Characteristics

A convenience sample of 44 adolescent females aged 16–17 years (Table 1) with BMI from 15.61 to 29.75 kg/m² [M (SD) = 21.19 (3.91) kg/m²] were included in this study.

Table 1: Participant Sociodemographics

Total, n = 44

Ethnicity, n (%)

White

Black

Asian

Mixed

Other

16 (36.4)

11 (25)

9 (20.5)

6 (13.6)

2 (4.5)

Social support relationship, n (%)

Friend

Parent/guardian

Sibling

Romantic partner

Other

29 (65.9)

8 (18.2)

4 (9.1)

2 (4.5)

1 (2.3)

Parental education, n (%)

At least one with university degree

No university degree

Unsure

25 (56.8)

16 (36.4)

3 (6.8)

Effects of Oxytocin on Stress

A repeated-measures analysis of variance (RM-ANOVA) evaluated the effects of oxytocin on stress scores after the shortened Sing-a-Song Stress Test (SSSTs) between the oxytocin and placebo conditions. Baseline stress scores in the two conditions and RCADS social phobia scores were used as covariates in the model. Results indicated that that oxytocin significantly reduced stress [M (SD) = 4.68 (2.66)] relative to placebo [M (SD) = 4.75 (3.30)], with medium to large effect: F(1,40) = [5.928], p = 0.019, ηp² = 0.129 (Fig. 1).

Nostril Dominance

A one-way ANOVA evaluated the effects of nostril dominance on stress scores after the SSSTs in the oxytocin condition with baseline stress scores and RCADS social phobia scores as covariates. Results indicated that oxytocin elicited a significant difference in stress score by nostril after the SSSTs with medium-large effect: F(1,42) = [4.312], p = 0.045, ηp² = 0.102 (Fig. 2.)

Post hoc testing using Fisher’s Least Significant Difference (LSD) indicated that the stress score was significantly lower when oxytocin was delivered intranasally to the dominant nostril [M (SD) = 4.00 (2.65)] compared with the non-dominant nostril [M (SD) = 5.55 (2.52)], p = 0.045.

Nostril Dominance in Placebo Condition

A one-way ANOVA evaluated the effects of nostril dominance on stress scores after the SSSTs in the placebo condition with baseline stress scores and RCADS social phobia scores as covariates. The results indicated that there was no significant difference in stress score by nostril: F(1,42) = [2.404], p = 0.129, ηp² = 0.060.

To the best of our knowledge, this study is the first to explore whether intranasal oxytocin’s anxiolytic effects are affected by nostril dominance. Administration of 24IU of intranasal oxytocin significantly reduced stress when compared with placebo. Intranasal oxytocin showed a significant increase in effectiveness in reducing self-reported stress when applied to the dominant nostril compared to the non-dominant nostril.

Following induction of stress using the modified SSSTs, oxytocin significantly decreased self-reported stress relative to placebo, indicating its potential role in mitigating social-evaluative stress. This effect was seen when controlling for baseline stress scores and social phobia symptomatology. This finding aligns with the literature implicating oxytocin as an anxiolytic agent. Without accounting for social phobia symptoms, there was no significant reduction in social-evaluative stress, underscoring oxytocin’s interindividual-dependent properties, specifically social anxiety symptomatology. The extent of oxytocin’s social anxiolytic effects, therefore, may vary depending on the presence of social phobia symptoms, highlighting the importance of considering individual differences when assessing its utility as a therapeutic agent across different populations.

The dominant nostril elicited significantly lower stress scores compared to the non-dominant nostril in the oxytocin condition. This result suggests that, for the purpose of anxiolysis, oxytocin might be more efficacious when administered to the dominant than the non-dominant pathway. This is an important finding as it indicates that there may be a preferred nostril for optimal oxytocin administration in the context of stress reduction.

In our sample, the significant nostril-specific effect of oxytocin can be attributed to several factors. Firstly, we implemented a rigorous procedure to identify the dominant or non-dominant nostril for oxytocin administration and identified the presence of definitive nostril states in 98% of our sample. This procedure involved clearing the nasal passage by exhaling into a tissue and obtaining a self-report of the dominant nostril, which was objectively confirmed using the Glatzel mirror test²⁰. Additionally, participants received a demonstration of the self-administration procedure by a researcher and were provided with printed instructions. We excluded participants with hay fever and nasal congestion to maintain consistency in the sample. Our sample was homogenous, comprising only females aged 16–17. Participants with a BMI > 30 kg/m² were excluded from all analyses to mitigate any influence of BMI-related effects, such as increased airflow.

We postulate that the observed differences in stress scores between nostrils in the drug condition might be attributed to the effects of oxytocin as we found no nostril-specific response in the placebo condition. The interplay between oxytocin’s effects, placebo responses, and nostril-specific variations in stress scores present a complex interaction, warranting further research.

This exploratory work aligns with literature suggesting that the olfactory and trigeminal nerves might function as the optimal route for oxytocin delivery to the brain within the window of approximately 20–90 minutes²¹. In this timeframe, the dominant nostril, with constricted blood vessels, might provide a more direct pathway to the brain, while the non-dominant nostril, with dilated blood vessels, could lead to greater absorption into the peripheral system before being transported to the brain. Oxytocin’s delivery to the brain via these pathways is also influenced by its uptake speed. The significantly greater reduction in stress scores we observed when oxytocin was administered to the dominant nostril supports existing literature that suggest the olfactory and trigeminal nerve routes may play a more substantial role in oxytocin’s nose-to-brain delivery than the peripheral route during the putative peak effects of oxytocin^22,23.However, we acknowledge the possibility that the peripheral pathway might also contribute to its effects differentially. Further investigation, perhaps considering dose-response, uptake speed, and timeframe, is needed.

In addition to the conventional nasal spray, an alternative method of administering oxytocin via the nasal passage involves the use of a nebuliser. A nebuliser is purported to improve oxytocin deposition in specific nasal regions directly implicated in transportation to the brain²⁴. Employing this method of delivery could shed more light on the mechanisms involved in nose-to-brain transport, offering more evidence for the nostril-specific effect.

This study has its limitations. Although a significant increase in stress was observed from baseline readings to post-stressor in both the oxytocin and placebo conditions, our stressor primarily applies to social-evaluative stress and may not be applicable to general stress without further investigation. While our use of self-reported VAS stress scores yielded significant results as an outcome measure, future studies could employ objective measures, such as skin conductance, heart rate variability, salivary cortisol measures, or neuroimaging techniques to increase sensitivity and minimise subjectivity in capturing stress responses.

Further, there are various administration positions for intranasal drug delivery, each influencing deposition differently²⁵. While we opted for the basic head-tilt position as it required less movement, which could potentially serve to reduce external stressors, future research should explore alternative positions to enhance the deposition of the active drug in optimum regions of the nasal cavity. The Mygind and ‘praying-to-Mecca’ positions are suggested to deposit drugs closer to the olfactory nerves²⁵ and thus may offer improved efficacy for nose-to-brain delivery.

This preliminary work should be replicated in a larger, more diverse sample, including males^26,27 and exploring different doses, timeframes, and- other intranasal psychotropic drugs, such as esketamine²⁸. The potential clinical implications could be substantial. If the nasal cycle state indeed influences responses to intranasal delivery, determining the optimal nostril for administering drugs targeting the brain could have significant implications for effectiveness and efficiency. This theory could be extended to individuals with a clear nasal cycle, suggesting that adjusting drug volume based on the most effective nostril could have pharmaceutical implications. Additionally, future research could investigate intranasal drugs targeting sites aligned with the peripheral system and whether there is an optimal nostril for their effects.

This is the first study of its kind to examine nostril-specific effects of oxytocin. We show that 24 IU of intranasal oxytocin significantly reduces social-evaluative stress and is significantly more effective in this stress reduction when administered to the dominant nostril compared to the non-dominant nostril. Future work should aim to corroborate this in a larger sample, with objective methodologies, and utilise other psychotropic drugs.

Design

This exploratory study was part of a larger placebo-controlled, double-blinded, randomised crossover trial investigating a range of social functions in adolescent females with eating disorders (ED). Participants were tested twice, approximately seven days apart [M (SD) = 7.95 (6.24)].

Participants

Forty-eight adolescent females aged 16 and 17 years were recruited via social media campaigns. Four participants were excluded from the final analyses for this study due to their BMI exceeding 30kg/m^{2 6}.

To confirm eligibility, participants completed an online Qualtrics screening survey. The inclusion criteria required that participants were females aged 16 to 17 years, able to travel to the Children’s Clinical Research Facility at St. Mary’s Hospital, London. Exclusion criteria included insufficient English language skills and uncorrected hearing or sight impairment; regular or accomplished solo singers; pregnancy or breastfeeding; or recent experience of a significant life event. It was noted whether participants took an oral contraceptive pill due to the potential influence of menstrual cycle on endogenous oxytocin concentrations.

Materials

Intranasal sprays containing 24 international units (IU) of Syntocinon® or vehicle were supplied by Victoria Apotheke, Switzerland and over-the-counter urine pregnancy tests were provided.

Self-Report Questionnaires

A bespoke questionnaire via Qualtrics collected information on participant gender, age, ethnicity, parental education level, type of social support, date since last period, time since most recent meal, caffeine consumption, hours slept the previous night, and handedness.

A digital Visual Analog Scale (VAS) scale with a sliding marker from 0 to 10 anchored by “not at all” and “as much as I can imagine” asked how stressed the participant felt at baseline and post stressor. Other measures included in the parent study were not analysed here.

The 9-item Revised Children’s Anxiety and Depression scale – Social Phobia subscale²⁹ determined social phobia symptomatology. For each statement, participants selected one of four responses: ‘Never’, ‘Sometimes’, ‘Often’, and ‘Always’. Possible scores for the social phobia subscale range from 0 to 27, with scores between 0 and 15 considered a ‘normal range’ for this population. Other measures included in the parent study were not analysed here.

Shortened ‘Sing-a-Song' Stress Test

Singing to an audience is a reliable method for inducing social-evaluative threat in participants. A shortened Sing-a-Song Stress Test that required a 50 second singing performance, was used³⁰. After choosing a song, participants stood and performed it in front of the research team and the person accompanying them. As part of the sham story, and to increase stress, the researchers were seen to be scoring the participant’s performance. Nursery rhymes, humming and children’s songs were not allowed as these were considered less stressful to perform.

Procedures

The study was sponsored by Imperial College London and approvals were obtained from the Leicestershire South Research Ethics Committee (reference: 22/EM/0044; IRAS project ID: 297695). All methods were carried out in accordance with relevant guidelines/regulations. Testing was carried out in the Clinical Research Facility at St Mary’s Hospital, London.

Each visit lasted approximately one hour, and participants were instructed to bring a social support who remained present throughout the visit. This recommendation is based on evidence suggesting that the presence of a social support figure may enhance oxytocin’s effects³¹. Participants and their social support were compensated through a £50 and £20 online voucher, respectively, upon the completion of both visits.

Participants were told that the study was investigating whether oxytocin, an agent that may reduce anxiety and increase sociability, impacts social behaviour in adolescent females with and without ED. To minimise biases, both researchers and participants were blinded to whether subjects met the criteria for an ED.

At the start of the first visit, participants verbally confirmed eligibility and provided informed consent electronically. Experimenters recorded the blind weights and heights of participants and noted whether they had consumed alcohol in the last 12 hours, smoked or vaped, or had any conditions causing nasal congestion on the day. After participants cleared their nasal passages using a tissue, with a closed mouth, they forcefully exhaled through each nostril while keeping the other nostril closed, and self-reported which nostril felt more, and less, blocked. The decision on left or right nasal dominance was then confirmed using the Glatzel Mirror test²⁰. Participants proceeded to self-administer either placebo or 24IU oxytocin by closing one nostril with their finger, tilting their head ³² and inhaling once, with a 30 second interval to allow for maximum absorption in either the dominant or non-dominant nostril. The selection of the nostril was pre-determined using a pseudo-randomised alternating design.

Oxytocin’s peak effects typically manifest between 20 and 90 minutes following intranasal administration²¹. Following a series of additional tasks detailed in the parent study, participants underwent the SSSTs, approximately 50 minutes post oxytocin administration. Subsequently, the stress VAS was administered before concluding the testing session.

Data

Data were analysed using Statistical Package for the Social Sciences (SPSS) software version 29. A p-value < 0.05 was considered statistically significant. No missing data were observed in this study⁶. Two-tailed t-tests were employed to investigate whether there were differences in stress scores between baseline and post-stressor readings in both the oxytocin and placebo conditions. A RM-ANOVA was performed for stress scores in the oxytocin and placebo conditions with baseline stress scores and RCADS social phobia subscale as covariates. An ANOVA was performed for stress scores within the oxytocin condition, with nostril dominance as the independent factor and RCADS social phobia score and baseline stress scores as covariates.

ACKNOWLEDGEMENTS

This experimental work was funded by the National Institute for Health Research (NIHR) Imperial Biomedical Research Collaboration (BRC). We acknowledge the support received from the Children’s Research Facility, St Mary’s Hospital, Imperial College Healthcare NHS Trust.

AUTHOR CONTRIBUTIONS

Conceptualisation: DN, VB; Recruitment of study participants: NJ; Data collection: NJ, VB; Statistical analyses: NJ, JN; Writing – original draft: NJ; Writing – review and editing: all authors.

DATA AVAILABILITY
All data are available from the authors upon reasonable request

COMPETING INTERESTS

None of the authors reported conflicts of interest for the present work.

Funding
This report is independent research funded by the National Institute for Health Research (NIHR) Imperial Biomedical Research Collaboration (BRC). DN is also supported by the NIHR Applied Research Collaboration (ARC) Northwest London. The views expressed in this publication are those of the authors and not necessarily those of the National Institute for Health Research or the Department of Health and Social Care

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No competing interests reported.

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Nasal Dominance Potentiates Intranasal Oxytocin’s Anxiolytic Effects

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