Deciphering the role of the oxytocin system in mental traits and physical health

• Iversen, Ingebjørg A.; Alaerts, Kaat; Bakermans-Kranenburg, Marian; Becker, Benjamin; Blair, Robert James & Bartz, Jennifer A. [Show all 24 contributors for this article] (2025). The active monitoring of oxytocin research evidence (AMORE) platform. Psychoneuroendocrinology. ISSN 0306-4530. 185, p. 1–12. doi: 10.1016/j.psyneuen.2025.107713. Full text in Research Archive Show summary

  Oxytocin, an evolutionarily conserved neuropeptide, plays a crucial role in various physiological and behavioural processes, offering potential therapeutic benefits for several psychiatric and neurodevelopmental conditions. Despite its promise, oxytocin research has been marked by inconsistent results concerning its therapeutic applications and underlying mechanisms. Performing a systematic review and meta-analysis is a popular approach to shed light on mixed findings in a body of literature; however, they can become quickly outdated as new evidence becomes available. Given these challenges, research on the links between oxytocin and biobehavioural outcomes is ideally positioned for the adoption of ‘living’ meta-analyses, which allow for the continuous integration of new data and updated conclusions. Here we introduce the Active Monitoring of Oxytocin Research Evidence (AMORE) platform (https://amore-project.org), which is a hub that aggregates articles and materials associated with living meta-analyses for biobehavioural oxytocin research in humans. Developed through consensus among 24 expert researchers, a standardized framework was established that either requires or recommends practices ensuring transparency and rigor in living meta-analyses featured on the AMORE platform. Overall, AMORE has been designed to advance human oxytocin biobehavioural research by the timely integration of emerging evidence through transparent living meta-analyses. To date, two living meta-analysis projects at different stages of publication are hosted on AMORE, demonstrating the platform’s practical application.

• Kang, Heemin; Deilhaug, Elisabeth; Walle, Kjersti Mæhlum; Sartorius, Alina Marie & Quintana, Daniel S. (2025). A multiverse meta-analysis of oxytocin administration studies. Biological Psychology. ISSN 0301-0511. 201, p. 1–10. doi: 10.1016/j.biopsycho.2025.109112. Full text in Research Archive Show summary

  Oxytocin administration is a valuable approach for experimentally increasing central oxytocin levels to investigate its impact on brain function and behavior. Despite considerable research interest, results have shown considerable variability across studies. Several meta-analyses have been conducted to help address this inconsistency. However, conducting a meta-analysis requires researchers to make numerous decisions, such as defining inclusion criteria and analytical techniques. In response to this challenge, a ‘multiverse’ approach can be used to simultaneously explore a range of different potential and realistic scenarios by systematically varying these analytical decisions. In this study, we performed a multiverse meta-analysis to investigate how researcher decisions can influence outcomes in meta-analyses of oxytocin administration studies. We systematically varied inclusion criteria, data synthesis models, and methods for correcting publication bias across 530 effect sizes derived from 185 studies, conducting 256 distinct meta-analyses. Our results demonstrate that summary effect estimates can vary considerably depending on meta-analytic decisions (from d = −0.16 to d = 1.45). Notably, meta-analyses with neurotypical populations tended to yield larger effect sizes than non-neurotypical populations, and multiple administrations studies tended to yield larger effect sizes than single administration studies. Furthermore, summary effect estimates can substantially vary according to the applied publication bias correction method. Our findings also demonstrated that the current evidence mostly supports the presence of the effect of oxytocin across domains, regardless of meta-analytic choices, as over 90% of the observed meta-analyses exceeded the range of bootstrapped meta-analyses assuming a null effect. These results warrant future research on how different contexts may impact the robustness of the effects of oxytocin, while underscoring the value of meta-analysis pre-registration to facilitate the transparent evaluation of meta-analyst decision-making.

• Sartorius, Alina Marie; Rokicki, Jaroslav; Birkeland, Siri; Bettella, Francesco; Barth, Claudia & Lange, Ann-Marie Glasø de [Show all 17 contributors for this article] (2024). An evolutionary timeline of the oxytocin signaling pathway. Communications Biology. 7(1). doi: 10.1038/s42003-024-06094-9. Full text in Research Archive Show summary

  Oxytocin is a neuropeptide associated with both psychological and somatic processes like parturition and social bonding. Although oxytocin homologs have been identified in many species, the evolutionary timeline of the entire oxytocin signaling gene pathway has yet to be described. Using protein sequence similarity searches, microsynteny, and phylostratigraphy, we assigned the genes supporting the oxytocin pathway to different phylostrata based on when we found they likely arose in evolution. We show that the majority (64%) of genes in the pathway are ‘modern’. Most of the modern genes evolved around the emergence of vertebrates or jawed vertebrates (540 - 530 million years ago, ‘mya’), including OXTR, OXT and CD38. Of those, 45% were under positive selection at some point during vertebrate evolution. We also found that 18% of the genes in the oxytocin pathway are ‘ancient’, meaning their emergence dates back to cellular organisms and opisthokonta (3500–1100 mya). The remaining genes (18%) that evolved after ancient and before modern genes were classified as ‘medium-aged’. Functional analyses revealed that, in humans, medium-aged oxytocin pathway genes are highly expressed in contractile organs, while modern genes in the oxytocin pathway are primarily expressed in the brain and muscle tissue.

• Quintana, Daniel; Glaser, Bernt Damian; Kang, Heemin; Bull, Emilie Meyer; Audunsdottir, Kristin & Sartorius, Alina Marie [Show all 7 contributors for this article] (2024). The interplay of oxytocin and sex hormones. Neuroscience and Biobehavioral Reviews. ISSN 0149-7634. 163, p. 1–18. doi: 10.1016/j.neubiorev.2024.105765. Full text in Research Archive Show summary

  The neuropeptide oxytocin has historically been associated with reproduction and maternal behavior. However, more recent research has uncovered that oxytocin has a much wider range of roles in physiology and behavior. Despite the excitement surrounding potential therapeutical applications of intranasally administered oxytocin, the results of these intervention studies have been inconsistent. Various reasons for these mixed results have been proposed, which tend to focus on methodological issues, such as study design. While methodological issues are certainly important, emerging evidence suggests that the interaction between oxytocin and sex hormones may also account for these varied findings. To better understand the purpose and function of the interaction of oxytocin with sex hormones, with a focus on estrogens, progesterone, and testosterone, we conducted a comprehensive thematic review via four perspectives: evolutionary, developmental, mechanistic, and survival. Altogether, this synergistic approach highlights the critical function of sex hormone activity for accomplishing the diverse roles of oxytocin via the modulation of oxytocin release and oxytocin receptor activity, which is also likely to contribute to the heterogeneity of outcomes after oxytocin administration.

• Quintana, Daniel (2023). A Guide for Calculating Study-Level Statistical Power for Meta-Analyses. Advances in Methods and Practices in Psychological Science (AMPPS). ISSN 2515-2459. 6(1). doi: 10.1177/25152459221147260. Full text in Research Archive
• Jongerius, Chiara; Hillen, Marij A.; Smets, Ellen M. A.; Mol, Mathijs J.; Kooij, Eefje S. & Nood, Maria A. de [Show all 10 contributors for this article] (2023). Nasal oxytocin administration does not influence eye gaze or perceived relationship of male volunteers with physicians in a simulated online consultation: a randomized, placebo-controlled trial. Endocrine Connections. 12(8). doi: 10.1530/EC-22-0377. Full text in Research Archive Show summary

  The patient–physician relationship is a critical determinant of patient health outcomes. Verbal and non-verbal communication, such as eye gaze, are vital aspects of this bond. Neurobiological studies indicate that oxytocin may serve as a link between increased eye gaze and social bonding. Therefore, oxytocin signaling could serve as a key factor influencing eye gaze as well as the patient–physician relationship. We aimed to test the effects of oxytocin on gaze to the eyes of the physician and the patient–physician relationship by conducting a randomized placebo-controlled crossover trial in healthy volunteers with intranasally administered oxytocin (with a previously effective single dose of 24 IU, EudraCT number 2018-004081-34). The eye gaze of 68 male volunteers was studied using eye tracking during a simulated video call consultation with a physician, who provided information about vaccination against the human papillomavirus. Relationship outcomes, including trust, satisfaction, and perceived physician communication style, were measured using questionnaires and corrected for possible confounds (social anxiety and attachment orientation). Additional secondary outcome measures for the effect of oxytocin were recall of information and pupil diameter and exploratory outcomes included mood and anxiety measures. Oxytocin did not affect the eye-tracking parameters of volunteers’ gaze toward the eyes of the physician. Moreover, oxytocin did not affect the parameters of bonding between volunteers and the physician nor other secondary and exploratory outcomes in this setting. Bayesian hypothesis testing provided evidence for the absence of effects. These results contradict the notion that oxytocin affects eye gaze patterns or bonding.

• Montag, Christian & Quintana, Daniel (2022). Digital phenotyping in molecular psychiatry—a missed opportunity? Molecular Psychiatry. ISSN 1359-4184. 28, p. 6–9. doi: 10.1038/s41380-022-01795-1. Full text in Research Archive
• Rokicki, Jaroslav; Kaufmann, Tobias; Lange, Ann-Marie Glasø de; Meer, Dennis van der; Bahrami, Shahram & Sartorius, Alina [Show all 14 contributors for this article] (2022). Oxytocin receptor expression patterns in the human brain across development. Neuropsychopharmacology. ISSN 0893-133X. doi: 10.1038/s41386-022-01305-5. Full text in Research Archive
• Bøen, Rune; Quintana, Daniel; Ladouceur, Cecile D. & Tamnes, Christian Krog (2022). Age-related differences in the error-related negativity and error positivity in children and adolescents are moderated by sample and methodological characteristics: A meta-analysis. Psychophysiology. ISSN 0048-5772. 59(6). doi: 10.1111/psyp.14003. Full text in Research Archive Show summary

  The error- related negativity (ERN) and the error positivity (Pe) are electrophysi-ological components associated with error processing that are thought to exhibit distinctive developmental trajectories from childhood to adulthood. To investi-gate the age and age moderation effects on the ERN and the Pe strength during development, we conducted a preregistered three- level meta- analysis synthe-sizing 120 and 41 effect sizes across 18 group comparison studies and 19 cor-relational studies, respectively. The meta- analysis included studies with mean age between 3.6 and 28.7 (min- max age range: 3.5 and 49.8) years for age- group comparisons and 6.1 to 18.7 (min- max age range: 4.0– 35.7) years for age cor-relations. Results showed that age was associated with a more negative ERN (SMD = −.433, r = −.230). No statistically significant association between age and the Pe was found (SMD = .059, r = −.091), except for in a group comparison between younger and older adolescents. The age effects were not significantly moderated by whether a Flanker or a Go/No- Go task was used, whereas a proba-bilistic learning task moderated the age effect on the Pe. Moreover, the Fz and Cz electrode sites yielded stronger negative associations between age and the ERN and the Pe, respectively. The results confirm that the ERN and the Pe show differential development courses and suggest that sample and methodological characteristics influence the age effects, and lay the foundation for investigations of developmental patterns of the ERN and the Pe in relation to psychopathology and early genetic and environmental risk factors.

• Winterton, Adriano; Bettella, Francesco; Beck, Dani; Gurholt, Tiril Pedersen; Steen, Nils Eiel & Rødevand, Linn Nilsen [Show all 9 contributors for this article] (2022). The oxytocin signalling gene pathway contributes to the association between loneliness and cardiometabolic health. Psychoneuroendocrinology. ISSN 0306-4530. 144. doi: 10.1016/j.psyneuen.2022.105875. Full text in Research Archive Show summary

  Increasing evidence has shown adverse effects of loneliness on cardiometabolic health. The neuromodulator and hormone oxytocin has traditionally been linked with social cognition and behaviour. However, recent implications of the oxytocin system in energy metabolism and the overrepresentation of metabolic issues in psychiatric illness suggests that oxytocin may represent a mechanism bridging mental and somatic traits. To clarify the role of the oxytocin signalling system in the link between cardiometabolic risk factors and loneliness, we calculated the contribution of single nucleotide polymorphisms (SNPs) in the oxytocin signalling pathway gene-set (154 genes) to the polygenic architecture of loneliness and body mass index (BMI). We investigated the associations of these oxytocin signalling pathway polygenic scores with body composition measured using body magnetic resonance imaging (MRI), bone mineral density (BMD), haematological markers, and blood pressure in a sample of just under half a million adults from the UK Biobank (BMD subsample n = 274,457; body MRI subsample n = 9796). Our analysis revealed significant associations of the oxytocin signalling pathway polygenic score for BMI with abdominal subcutaneous fat tissue, HDL cholesterol, lipoprotein(a), triglycerides, and BMD. We also found an association between the oxytocin signalling pathway polygenic score for loneliness and apolipoprotein A1, the major protein component of HDL. Altogether, these results provide additional evidence for the oxytocin signalling pathway’s role in energy metabolism, lipid homoeostasis, and bone density, and support oxytocin’s complex pleiotropic effects.

• Audunsdottir, Kristin & Quintana, Daniel (2022). Oxytocin’s dynamic role across the lifespan. Aging Brain. 2. doi: 10.1016/j.nbas.2021.100028. Full text in Research Archive Show summary

  Older adults have been neglected in biobehavioral oxytocin research. Emerging research indicates that oxytocin signaling activity fluctuates over the lifespan, which suggests that results from studies investigating youth and young adults cannot be easily generalized to older adults. The recruitment of a wider age range of research participants using a variety of research tools is required to uncover the role of the oxytocin signaling system over the lifespan and may reveal novel treatment target candidates in older adults, beyond social cognition and behavior.

• Quintana, Daniel & Heathers, James A. J. (2021). How podcasts can benefit scientific communities. Trends in Cognitive Sciences. ISSN 1364-6613. 25(1), p. 3–5. doi: 10.1016/j.tics.2020.10.003. Full text in Research Archive
• Lange, Ann-Marie Glasø de; Kaufmann, Tobias; Quintana, Daniel; Winterton, Adriano; Andreassen, Ole Andreas & Westlye, Lars Tjelta [Show all 7 contributors for this article] (2021). Prominent health problems, socioeconomic deprivation, and higher brain age in lonely and isolated individuals: A population-based study. Behavioural Brain Research. ISSN 0166-4328. doi: 10.1016/j.bbr.2021.113510. Full text in Research Archive Show summary

  Loneliness is linked to increased risk for Alzheimer's disease, but little is known about factors potentially contributing to adverse brain health in lonely individuals. In this study, we used data from 24,867 UK Biobank participants to investigate risk factors related to loneliness and estimated brain age based on neuroimaging data. The results showed that on average, individuals who self-reported loneliness on a single yes/no item scored higher on neuroticism, depression, social isolation, and socioeconomic deprivation, performed less physical activity, and had higher BMI compared to individuals who did not report loneliness. In line with studies pointing to a genetic overlap of loneliness with neuroticism and depression, permutation feature importance ranked these factors as the most important for classifying lonely vs. not lonely individuals (ROC AUC = 0.83). While strongly linked to loneliness, neuroticism and depression were not associated with brain age estimates. Conversely, objective social isolation showed a main effect on brain age, and individuals reporting both loneliness and social isolation showed higher brain age relative to controls – as part of a prominent risk profile with elevated scores on socioeconomic deprivation and unhealthy lifestyle behaviours, in addition to neuroticism and depression. While longitudinal studies are required to determine causality, this finding may indicate that the combination of social isolation and a genetic predisposition for loneliness involves a risk for adverse brain health. Importantly, the results underline the complexity in associations between loneliness and adverse health outcomes, where observed risks likely depend on a combination of interlinked variables including genetic as well as social, behavioural, physical, and socioeconomic factors.

• Winterton, Adriano; Bettella, Francesco; Lange, Ann-Marie Glasø de; Haram, Marit; Steen, Nils Eiel & Westlye, Lars Tjelta [Show all 8 contributors for this article] (2021). Oxytocin-pathway polygenic scores for severe mental disorders and metabolic phenotypes in the UK Biobank. Translational Psychiatry. doi: 10.1038/s41398-021-01725-9. Full text in Research Archive Show summary

  Abstract Oxytocin is a neuromodulator and hormone that is typically associated with social cognition and behavior. In light of its purported effects on social cognition and behavior, research has investigated its potential as a treatment for psychiatric illnesses characterized by social dysfunction, such as schizophrenia and bipolar disorder. While the results of these trials have been mixed, more recent evidence suggests that the oxytocin system is also linked with cardiometabolic conditions for which individuals with severe mental disorders are at a higher risk for developing. To investigate whether the oxytocin system has a pleiotropic effect on the etiology of severe mental illness and cardiometabolic conditions, we explored oxytocin’s role in the shared genetic liability of schizophrenia, bipolar disorder, type-2 diabetes, and several phenotypes linked with cardiovascular disease and type 2 diabetes risk using a polygenic pathway-specific approach. Analysis of a large sample with about 480,000 individuals (UK Biobank) revealed statistically significant associations across the range of phenotypes analyzed. By comparing these effects to those of polygenic scores calculated from 100 random gene sets, we also demonstrated the specificity of many of these significant results. Altogether, our results suggest that the shared effect of oxytocin-system dysfunction could help partially explain the co-occurrence of social and cardiometabolic dysfunction in severe mental illnesses.

• Quintana, Daniel (2021). Towards better hypothesis tests in oxytocin research: Evaluating the validity of auxiliary assumptions. Psychoneuroendocrinology. ISSN 0306-4530. doi: 10.1016/j.psyneuen.2021.105642. Full text in Research Archive Show summary

  Various factors have been attributed to the inconsistent reproducibility of human oxytocin research in the cognitive and behavioral sciences. These factors include small sample sizes, a lack of pre-registered studies, and the absence of overarching theoretical frameworks that can account for oxytocin’s effects over a broad range of contexts. While there have been efforts to remedy these issues, there has been very little systematic scrutiny of the role of auxiliary assumptions, which are claims that are not central for testing a hypothesis but nonetheless critical for testing theories. For instance, the hypothesis that oxytocin increases the salience of social cues is predicated on the assumption that intranasally administered oxytocin increases oxytocin levels in the brain. Without robust auxiliary assumptions, it is unclear whether a hypothesis testing failure is due to an incorrect hypothesis or poorly supported auxiliary assumptions. Consequently, poorly supported auxiliary assumptions can be blamed for hypothesis failure, thereby safeguarding theories from falsification. In this article, I will evaluate the body of evidence for key auxiliary assumptions in human behavioral oxytocin research in terms of theory, experimental design, and statistical inference, and highlight assumptions that require stronger evidence. Strong auxiliary assumptions will leave hypotheses vulnerable for falsification, which will improve hypothesis testing and consequently advance our understanding of oxytocin’s role in cognition and behavior.

• Winterton, Adriano; Westlye, Lars Tjelta; Steen, Nils Eiel; Andreassen, Ole Andreas & Quintana, Daniel (2020). Improving the precision of intranasal oxytocin research. Nature Human Behaviour. p. 1–10. doi: 10.1038/s41562-020-00996-4. Full text in Research Archive

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• Quintana, Daniel (2022). Oxytocin’s role in health and wellbeing. Full text in Research Archive
• Quintana, Daniel (2022). Accelerating the translation of intranasal oxytocin research. Full text in Research Archive

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