Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Improving the precision of intranasal oxytocin research

Abstract

The neuropeptide oxytocin has been popularized for its role in social behaviour and nominated as a candidate treatment for several psychiatric illnesses due to promising preclinical results. However, these results so far have failed to reliably translate from animal models to human research. In response, there have been justified calls to improve intranasal oxytocin delivery methodology in terms of verifying that intranasal administration increases central levels of oxytocin. Nonetheless, improved methodology needs to be coupled with a robust theory of the role of oxytocin in behaviour and physiology to ask meaningful research questions. Moreover, stringent methodology based on robust theory may yield interesting results, but such findings will have limited utility if they are not reproducible. We outline how the precision of intranasal oxytocin research can be improved by the complementary consideration of methodology, theory and reproducibility.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Expression of the oxytocin receptor in the human brain.
Fig. 2: Oxytocin production and targets.

Similar content being viewed by others

References

  1. Guastella, A. J. & MacLeod, C. A critical review of the influence of oxytocin nasal spray on social cognition in humans: evidence and future directions. Horm. Behav. 61, 410–418 (2012).

    Article  PubMed  CAS  Google Scholar 

  2. Yatawara, C. J., Einfeld, S. L., Hickie, I. B., Davenport, T. A. & Guastella, A. J. The effect of oxytocin nasal spray on social interaction deficits observed in young children with autism: a randomized clinical crossover trial. Mol. Psychiatry 21, 1225–1231 (2016).

    Article  CAS  PubMed  Google Scholar 

  3. Peled-Avron, L., Abu-Akel, A. & Shamay-Tsoory, S. Exogenous effects of oxytocin in five psychiatric disorders: a systematic review, meta-analyses and a personalized approach through the lens of the social salience hypothesis. Neurosci. Biobehav. Rev. 114, 70–95 (2020).

    Article  CAS  PubMed  Google Scholar 

  4. Insel, T. R. & Shapiro, L. E. Oxytocin receptor distribution reflects social organization in monogamous and polygamous voles. Proc. Natl. Acad. Sci. USA 89, 5981–5985 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Olazábal, D. E. & Young, L. J. Oxytocin receptors in the nucleus accumbens facilitate “spontaneous” maternal behavior in adult female prairie voles. Neuroscience 141, 559–568 (2006).

    Article  PubMed  CAS  Google Scholar 

  6. Schafer, E. A. & Mackenzie, K. The action of animal extracts on milk secretion. Proc. R. Soc. Lond., B 84, 16–22 (1911).

    Article  CAS  Google Scholar 

  7. Dale, H. H. On some physiological actions of ergot. J. Physiol. (Lond.) 34, 163–206 (1906).

    Article  Google Scholar 

  8. Coghlan, A. ‘Cuddle chemical’ eases symptoms of schizophrenia. New Sci. 207, 10 (2010).

    Google Scholar 

  9. Shamay-Tsoory, S. G. et al. Intranasal administration of oxytocin increases envy and schadenfreude (gloating). Biol. Psychiatry 66, 864–870 (2009).

    Article  CAS  PubMed  Google Scholar 

  10. Dadds, M. R. et al. Nasal oxytocin for social deficits in childhood autism: a randomized controlled trial. J. Autism Dev. Disord. 44, 521–531 (2014).

    Article  PubMed  Google Scholar 

  11. O’Leary, D. E. Gartner’s hype cycle and information system research issues. Int. J. Account. Inf. Syst. 9, 240–252 (2008).

    Article  Google Scholar 

  12. Alvares, G. A., Quintana, D. S. & Whitehouse, A. J. O. Beyond the hype and hope: critical considerations for intranasal oxytocin research in autism spectrum disorder. Autism Res. 10, 25–41 (2017).

    Article  PubMed  Google Scholar 

  13. Leng, G. & Ludwig, M. Intranasal oxytocin: myths and delusions. Biol. Psychiatry 79, 243–250 (2016).

    Article  CAS  PubMed  Google Scholar 

  14. Gwee, P.-C., Tay, B.-H., Brenner, S. & Venkatesh, B. Characterization of the neurohypophysial hormone gene loci in elephant shark and the Japanese lamprey: origin of the vertebrate neurohypophysial hormone genes. BMC Evol. Biol. 9, 47 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Stafflinger, E. et al. Cloning and identification of an oxytocin/vasopressin-like receptor and its ligand from insects. Proc. Natl. Acad. Sci. USA 105, 3262–3267 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Auyeung, B. et al. Oxytocin increases eye contact during a real-time, naturalistic social interaction in males with and without autism. Transl. Psychiatry 5, e507 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Guastella, A. J. et al. The effects of a course of intranasal oxytocin on social behaviors in youth diagnosed with autism spectrum disorders: a randomized controlled trial. J. Child Psychol. Psychiatry 56, 444–452 (2015).

    Article  PubMed  Google Scholar 

  18. Buchanan, R. W. et al. A randomized clinical trial of oxytocin or galantamine for the treatment of negative symptoms and cognitive impairments in people with schizophrenia. J. Clin. Psychopharmacol. 37, 394–400 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Davis, M. C. et al. Oxytocin-augmented social cognitive skills training in schizophrenia. Neuropsychopharmacology 39, 2070–2077 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Walum, H., Waldman, I. D. & Young, L. J. Statistical and methodological considerations for the interpretation of intranasal oxytocin studies. Biol. Psychiatry 79, 251–257 (2016).

    Article  CAS  PubMed  Google Scholar 

  21. Muthukrishna, M. & Henrich, J. A problem in theory. Nat. Hum. Behav. 3, 221–229 (2019).

    Article  PubMed  Google Scholar 

  22. Klopfer, P. H. & Klopfer, M. S. Maternal “imprinting” in goats: fostering of alien young. Ethology 25, 862–866 (1968).

    Google Scholar 

  23. Kosfeld, M., Heinrichs, M., Zak, P. J., Fischbacher, U. & Fehr, E. Oxytocin increases trust in humans. Nature 435, 673–676 (2005).

    Article  CAS  PubMed  Google Scholar 

  24. Nave, G., Camerer, C. & McCullough, M. Does oxytocin increase trust in humans? A critical review of research. Perspect. Psychol. Sci. 10, 772–789 (2015).

    Article  PubMed  Google Scholar 

  25. Declerck, C. H., Boone, C., Pauwels, L., Vogt, B. & Fehr, E. A registered replication study on oxytocin and trust. Nat. Hum. Behav. 4, 646–655 (2020).

    Article  PubMed  Google Scholar 

  26. Shamay-Tsoory, S. G. & Abu-Akel, A. The social salience hypothesis of oxytocin. Biol. Psychiatry 79, 194–202 (2016).

    Article  CAS  PubMed  Google Scholar 

  27. Kemp, A. H. & Guastella, A. J. The role of oxytocin in human affect a novel hypothesis. Curr. Dir. Psychol. Sci. 20, 222–231 (2011).

    Article  Google Scholar 

  28. Quintana, D. S. & Guastella, A. J. An allostatic theory of oxytocin. Trends Cogn. Sci. 24, 515–528 (2020).

    Article  PubMed  Google Scholar 

  29. Harari-Dahan, O. & Bernstein, A. A general approach-avoidance hypothesis of oxytocin: accounting for social and non-social effects of oxytocin. Neurosci. Biobehav. Rev. 47, 506–519 (2014).

    Article  CAS  PubMed  Google Scholar 

  30. Quintana, D. S. et al. Low-dose intranasal oxytocin delivered with breath powered device modulates pupil diameter and amygdala activity: a randomized controlled pupillometry and fMRI study. Neuropsychopharmacology 44, 306–313 (2019).

    Article  CAS  PubMed  Google Scholar 

  31. Harari-Dahan, O. & Bernstein, A. Oxytocin attenuates social and non-social avoidance: re-thinking the social specificity of oxytocin. Psychoneuroendocrinology 81, 105–112 (2017).

    Article  CAS  PubMed  Google Scholar 

  32. Fam, J., Holmes, N., Delaney, A., Crane, J. & Westbrook, R. F. Oxytocin receptor activation in the basolateral complex of the amygdala enhances discrimination between discrete cues and promotes configural processing of cues. Psychoneuroendocrinology 96, 84–92 (2018).

    Article  CAS  PubMed  Google Scholar 

  33. Zhao, Z. et al. Oxytocin differentially modulates specific dorsal and ventral striatal functional connections with frontal and cerebellar regions. Neuroimage 184, 781–789 (2019).

    Article  CAS  PubMed  Google Scholar 

  34. Eliava, M. et al. A new population of parvocellular oxytocin neurons controlling magnocellular neuron activity and inflammatory pain processing. Neuron 89, 1291–1304 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Wang, Y.-L. et al. The interaction between the oxytocin and pain modulation in headache patients. Neuropeptides 47, 93–97 (2013).

    Article  CAS  PubMed  Google Scholar 

  36. Boll, S., Almeida de Minas, A. C., Raftogianni, A., Herpertz, S. C. & Grinevich, V. Oxytocin and pain perception: from animal models to human research. Neuroscience 387, 149–161 (2018).

    Article  CAS  PubMed  Google Scholar 

  37. Insel, T. R. Translating oxytocin neuroscience to the clinic: a national institute of mental health perspective. Biol. Psychiatry 79, 153–154 (2016).

    Article  PubMed  Google Scholar 

  38. King, L. B., Walum, H., Inoue, K., Eyrich, N. W. & Young, L. J. Variation in the oxytocin receptor gene predicts brain region–specific expression and social attachment. Biol. Psychiatry 80, 160–169 (2016).

    Article  CAS  PubMed  Google Scholar 

  39. Keebaugh, A. C. & Young, L. J. Increasing oxytocin receptor expression in the nucleus accumbens of pre-pubertal female prairie voles enhances alloparental responsiveness and partner preference formation as adults. Horm. Behav. 60, 498–504 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Loup, F., Tribollet, E., Dubois-Dauphin, M. & Dreifuss, J. J. Localization of high-affinity binding sites for oxytocin and vasopressin in the human brain. An autoradiographic study. Brain Res. 555, 220–232 (1991).

    Article  CAS  PubMed  Google Scholar 

  41. Uhrig, S. et al. Reduced oxytocin receptor gene expression and binding sites in different brain regions in schizophrenia: A post-mortem study. Schizophr. Res. 177, 59–66 (2016).

    Article  PubMed  Google Scholar 

  42. Yarkoni, T., Poldrack, R. A., Nichols, T. E., Van Essen, D. C. & Wager, T. D. Large-scale automated synthesis of human functional neuroimaging data. Nat. Methods 8, 665–670 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Quintana, D. S. et al. Oxytocin pathway gene networks in the human brain. Nat. Commun. 10, 668 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Paloyelis, Y. et al. A spatiotemporal profile of in vivo cerebral blood flow changes following intranasal oxytocin in humans. Biol. Psychiatry 79, 693–705 (2016).

    Article  CAS  PubMed  Google Scholar 

  45. Beard, R., Singh, N., Grundschober, C., Gee, A. D. & Tate, E. W. High-yielding 18F radiosynthesis of a novel oxytocin receptor tracer, a probe for nose-to-brain oxytocin uptake in vivo. Chem. Commun. (Camb.) 54, 8120–8123 (2018).

    Article  CAS  Google Scholar 

  46. Love, T. M. Oxytocin, motivation and the role of dopamine. Pharmacol. Biochem. Behav. 119, 49–60 (2014).

    Article  CAS  PubMed  Google Scholar 

  47. Feldman, R., Feldman, R., Monakhov, M., Pratt, M. & Ebstein, R. P. Oxytocin pathway genes: evolutionary ancient system impacting on human affiliation, sociality, and psychopathology. Biol. Psychiatry 79, 174–184 (2015).

    Article  PubMed  CAS  Google Scholar 

  48. Gimpl, G. & Fahrenholz, F. The oxytocin receptor system: structure, function, and regulation. Physiol. Rev. 81, 629–683 (2001).

    Article  CAS  PubMed  Google Scholar 

  49. Leng, G. & Sabatier, N. Oxytocin – the sweet hormone? Trends Endocrinol. Metab. 28, 365–376 (2017).

    Article  CAS  PubMed  Google Scholar 

  50. Stanley, S. A. et al. Bidirectional electromagnetic control of the hypothalamus regulates feeding and metabolism. Nature 531, 647–650 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Noble, E. E., Billington, C. J., Kotz, C. M. & Wang, C. Oxytocin in the ventromedial hypothalamic nucleus reduces feeding and acutely increases energy expenditure. Am. J. Physiol. Regul. Integr. Comp. Physiol. 307, R737–R745 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Geerling, J. C., Shin, J. W., Chimenti, P. C. & Loewy, A. D. Paraventricular hypothalamic nucleus: axonal projections to the brainstem. J. Comp. Neurol. 518, 1460–1499 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  53. Browning, K. N. & Travagli, R. A. Central nervous system control of gastrointestinal motility and secretion and modulation of gastrointestinal functions. Compr. Physiol. 4, 1339–1368 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  54. Maejima, Y. et al. Peripheral oxytocin treatment ameliorates obesity by reducing food intake and visceral fat mass. Aging (Albany NY) 3, 1169–1177 (2011).

    Article  CAS  Google Scholar 

  55. Sabatier, N., Leng, G. & Menzies, J. Oxytocin, feeding, and satiety. Front. Endocrinol. (Lausanne) 4, 35 (2013).

    Article  CAS  Google Scholar 

  56. Lawson, E. A. et al. Oxytocin reduces caloric intake in men. Obesity (Silver Spring) 23, 950–956 (2015).

    Article  CAS  Google Scholar 

  57. Ott, V. et al. Oxytocin reduces reward-driven food intake in humans. Diabetes 62, 3418–3425 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Zhang, H. et al. Treatment of obesity and diabetes using oxytocin or analogs in patients and mouse models. PLoS One 8, e61477 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Valentino, R. J., Foote, S. L. & Page, M. E. The locus coeruleus as a site for integrating corticotropin-releasing factor and noradrenergic mediation of stress responses. Ann. NY Acad. Sci. 697, 173–188 (1993).

    Article  CAS  PubMed  Google Scholar 

  60. Grewen, K. M. & Light, K. C. Plasma oxytocin is related to lower cardiovascular and sympathetic reactivity to stress. Biol. Psychol. 87, 340–349 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  61. Tops, M., van Peer, J. M., Korf, J., Wijers, A. A. & Tucker, D. M. Anxiety, cortisol, and attachment predict plasma oxytocin. Psychophysiology 44, 444–449 (2007).

    Article  PubMed  Google Scholar 

  62. Nicolson, N. A., Davis, M. C., Kruszewski, D. & Zautra, A. J. Childhood maltreatment and diurnal cortisol patterns in women with chronic pain. Psychosom. Med. 72, 471–480 (2010).

    Article  PubMed  Google Scholar 

  63. Norman, G. J. et al. Oxytocin increases autonomic cardiac control: moderation by loneliness. Biol. Psychol. 86, 174–180 (2011).

    Article  PubMed  Google Scholar 

  64. Gutkowska, J., Jankowski, M., Mukaddam-Daher, S. & McCann, S. M. Oxytocin is a cardiovascular hormone. Braz. J. Med. Biol. Res. 33, 625–633 (2000).

    Article  CAS  PubMed  Google Scholar 

  65. Porges, S.W. The Polyvagal Theory: Neurophysiological Foundations of Emotions, Attachment, Communication, and Self-regulation. (W. W. Norton & Co., 2011).

  66. Akselrod, S. et al. Power spectrum analysis of heart rate fluctuation: a quantitative probe of beat-to-beat cardiovascular control. Science 213, 220–222 (1981).

    Article  CAS  PubMed  Google Scholar 

  67. Quintana, D. S., Guastella, A. J., Outhred, T., Hickie, I. B. & Kemp, A. H. Heart rate variability is associated with emotion recognition: direct evidence for a relationship between the autonomic nervous system and social cognition. Int. J. Psychophysiol. 86, 168–172 (2012).

    Article  PubMed  Google Scholar 

  68. Butler, E. A., Wilhelm, F. H. & Gross, J. J. Respiratory sinus arrhythmia, emotion, and emotion regulation during social interaction. Psychophysiology 43, 612–622 (2006).

    Article  PubMed  Google Scholar 

  69. Berntson, G. G., Cacioppo, J. T. & Grossman, P. Whither vagal tone. Biol. Psychol. 74, 295–300 (2007).

    Article  PubMed  Google Scholar 

  70. Kemp, A. H. et al. Oxytocin increases heart rate variability in humans at rest: implications for social approach-related motivation and capacity for social engagement. PLoS One 7, e44014 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Kubzansky, L. D., Mendes, W. B., Appleton, A. A., Block, J. & Adler, G. K. A heartfelt response: Oxytocin effects on response to social stress in men and women. Biol. Psychol. 90, 1–9 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  72. Everett, N.A., Turner, A.J., Costa, P.A., Baracz, S.J. & Cornish, J.L. The vagus nerve mediates the suppressing effects of peripherally administered oxytocin on methamphetamine self-administration and seeking in rats. Neuropsychopharmacology https://doi.org/10.1038/s41386-020-0719-7 (2020).

  73. Neumann, I. D. & Landgraf, R. Balance of brain oxytocin and vasopressin: implications for anxiety, depression, and social behaviors. Trends Neurosci. 35, 649–659 (2012).

    Article  CAS  PubMed  Google Scholar 

  74. Quintana, D. S., Alvares, G. A., Hickie, I. B. & Guastella, A. J. Do delivery routes of intranasally administered oxytocin account for observed effects on social cognition and behavior? A two-level model. Neurosci. Biobehav. Rev. 49, 182–192 (2015).

    Article  CAS  PubMed  Google Scholar 

  75. Li, Y., Field, P. M. & Raisman, G. Olfactory ensheathing cells and olfactory nerve fibroblasts maintain continuous open channels for regrowth of olfactory nerve fibres. Glia 52, 245–251 (2005).

    Article  PubMed  Google Scholar 

  76. Thorne, R. G., Emory, C. R., Ala, T. A. & Frey, W. H. II Quantitative analysis of the olfactory pathway for drug delivery to the brain. Brain Res. 692, 278–282 (1995).

    Article  CAS  PubMed  Google Scholar 

  77. Guastella, A. J. et al. Recommendations for the standardisation of oxytocin nasal administration and guidelines for its reporting in human research. Psychoneuroendocrinology 38, 612–625 (2013).

    Article  CAS  PubMed  Google Scholar 

  78. Gizurarson, S. Anatomical and histological factors affecting intranasal drug and vaccine delivery. Curr. Drug Deliv. 9, 566–582 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Smith, A. S., Korgan, A. C. & Young, W. S. Oxytocin delivered nasally or intraperitoneally reaches the brain and plasma of normal and oxytocin knockout mice. Pharmacol. Res. 146, 104324 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Striepens, N. et al. Elevated cerebrospinal fluid and blood concentrations of oxytocin following its intranasal administration in humans. Sci. Rep. 3, 3440 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  81. Dal Monte, O., Noble, P. L., Turchi, J., Cummins, A. & Averbeck, B. B. CSF and blood oxytocin concentration changes following intranasal delivery in macaque. PLoS One 9, e103677 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  82. Lee, M. R. et al. Oxytocin by intranasal and intravenous routes reaches the cerebrospinal fluid in rhesus macaques: determination using a novel oxytocin assay. Mol. Psychiatry 23, 115–122 (2018).

    Article  CAS  PubMed  Google Scholar 

  83. Quintana, D. S. et al. Low-dose oxytocin delivered intranasally with breath powered device affects social-cognitive behavior: a randomized four-way crossover trial with nasal cavity dimension assessment. Transl. Psychiatry 5, e602 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Hollander, E. et al. Oxytocin increases retention of social cognition in autism. Biol. Psychiatry 61, 498–503 (2007).

    Article  CAS  PubMed  Google Scholar 

  85. Hollander, E. et al. Oxytocin infusion reduces repetitive behaviors in adults with autistic and Asperger’s disorders. Neuropsychopharmacology 28, 193–198 (2003).

    Article  CAS  PubMed  Google Scholar 

  86. Neumann, I. D., Maloumby, R., Beiderbeck, D. I., Lukas, M. & Landgraf, R. Increased brain and plasma oxytocin after nasal and peripheral administration in rats and mice. Psychoneuroendocrinology 38, 1985–1993 (2013).

    Article  CAS  PubMed  Google Scholar 

  87. Quintana, D. S. et al. Low dose intranasal oxytocin delivered with breath powered device dampens amygdala response to emotional stimuli: A peripheral effect-controlled within-subjects randomized dose-response fMRI trial. Psychoneuroendocrinology 69, 180–188 (2016).

    Article  CAS  PubMed  Google Scholar 

  88. Lee, M. R. et al. Labeled oxytocin administered via the intranasal route reaches the brain in rhesus macaques. Nat. Commun. 11, 2783 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. van der Aart, J. et al. First in human evaluation of [18F]PK-209, a PET ligand for the ion channel binding site of NMDA receptors. EJNMMI Res. 8, 69 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  90. MacLean, E. L. et al. Challenges for measuring oxytocin: The blind men and the elephant? Psychoneuroendocrinology 107, 225–231 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Quintana, D. S. et al. Saliva oxytocin measures do not reflect peripheral plasma concentrations after intranasal oxytocin administration in men. Horm. Behav. 102, 85–92 (2018).

    Article  CAS  PubMed  Google Scholar 

  92. Valstad, M. et al. The correlation between central and peripheral oxytocin concentrations: A systematic review and meta-analysis. Neurosci. Biobehav. Rev. 78, 117–124 (2017).

    Article  CAS  PubMed  Google Scholar 

  93. Brandtzaeg, O. K. et al. Proteomics tools reveal startlingly high amounts of oxytocin in plasma and serum. Sci. Rep. 6, 31693 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Leng, G. & Sabatier, N. Measuring oxytocin and vasopressin: bioassays, immunoassays and random numbers. J. Neuroendocrinol. https://doi.org/10.1111/jne.12413 (2016).

  95. Lefevre, A. et al. A comparison of methods to measure central and peripheral oxytocin concentrations in human and non-human primates. Sci. Rep. 7, 17222 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  96. Jurek, B. & Neumann, I. D. The oxytocin receptor: from intracellular signaling to behavior. Physiol. Rev. 98, 1805–1908 (2018).

    Article  CAS  PubMed  Google Scholar 

  97. Quintana, D. S., Guastella, A. J., Westlye, L. T. & Andreassen, O. A. The promise and pitfalls of intranasally administering psychopharmacological agents for the treatment of psychiatric disorders. Mol. Psychiatry 21, 29–38 (2016).

    Article  CAS  PubMed  Google Scholar 

  98. Baker, M. 1,500 scientists lift the lid on reproducibility. Nature 533, 452–454 (2016).

    Article  CAS  PubMed  Google Scholar 

  99. Quintana, D. Most oxytocin administration studies are statistically underpowered to reliably detect (or reject) a wide range of effect sizes. Preprint at PsyArXiv https://doi.org/10.31234/osf.io/kzp4n (2020).

  100. Mierop, A. et al. How can intranasal oxytocin research be trusted? A systematic review of the interactive effects of intranasal oxytocin on psychosocial outcomes. Perspect. Psychol. Sci. 15, 1228–1242 (2020).

    Article  CAS  PubMed  Google Scholar 

  101. Munafò, M. R. et al. A manifesto for reproducible science. Nat. Hum. Behav. 1, 0021 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  102. Morey, R. & Lakens, D. Why most of psychology is statistically unfalsifiable. Preprint at Zenodo https://doi.org/10.5281/zenodo.838684 (2016).

  103. Dienes, Z. Using Bayes to get the most out of non-significant results. Front. Psychol. 5, 781 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  104. Hauck, W. W. & Anderson, S. A new statistical procedure for testing equivalence in two-group comparative bioavailability trials. J. Pharmacokinet. Biopharm. 12, 83–91 (1984).

    Article  CAS  PubMed  Google Scholar 

  105. Lakens, D. Equivalence tests: a practical primer for t tests, correlations, and meta-analyses. Soc. Psychol. Personal. Sci. 8, 355–362 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  106. Wagenmakers, E.-J. et al. Bayesian inference for psychology. Part I: Theoretical advantages and practical ramifications. Psychon. Bull. Rev. 25, 35–57 (2018).

    Article  PubMed  Google Scholar 

  107. Quintana, D. S. & Williams, D. R. Bayesian alternatives for common null-hypothesis significance tests in psychiatry: a non-technical guide using JASP. BMC Psychiatry 18, 178 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  108. Quintana, D. S. Revisiting non-significant effects of intranasal oxytocin using equivalence testing. Psychoneuroendocrinology 87, 127–130 (2018).

    Article  CAS  PubMed  Google Scholar 

  109. Tabak, B. A. et al. Null results of oxytocin and vasopressin administration across a range of social cognitive and behavioral paradigms: Evidence from a randomized controlled trial. Psychoneuroendocrinology 107, 124–132 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Mello, M. M., Lieou, V. & Goodman, S. N. Clinical trial participants’ views of the risks and benefits of data sharing. N. Engl. J. Med. 378, 2202–2211 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  111. Reiter, J. P. Releasing multiply imputed, synthetic public use microdata: an illustration and empirical study. J. R. Stat. Soc. Ser. A Stat. Soc. 168, 185–205 (2005).

    Article  Google Scholar 

  112. Quintana, D. S. A synthetic dataset primer for the biobehavioural sciences to promote reproducibility and hypothesis generation. eLife 9, e53275 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  113. Lane, A., Luminet, O., Nave, G. & Mikolajczak, M. Is there a publication bias in behavioural intranasal oxytocin research on humans? Opening the file drawer of one laboratory. J. Neuroendocrinol. https://doi.org/10.1111/jne.12384 (2016).

  114. McCullough, M. E., Churchland, P. S. & Mendez, A. J. Problems with measuring peripheral oxytocin: can the data on oxytocin and human behavior be trusted? Neurosci. Biobehav. Rev. 37, 1485–1492 (2013).

    Article  CAS  PubMed  Google Scholar 

  115. Marín, O. Developmental timing and critical windows for the treatment of psychiatric disorders. Nat. Med. 22, 1229–1238 (2016).

    Article  PubMed  CAS  Google Scholar 

  116. Kamesh, N., Aradhyam, G. K. & Manoj, N. The repertoire of G protein-coupled receptors in the sea squirt Ciona intestinalis. BMC Evol. Biol. 8, 129 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Ding, C., Leow, M. K.-S. & Magkos, F. Oxytocin in metabolic homeostasis: implications for obesity and diabetes management. Obes. Rev. 20, 22–40 (2019).

    Article  CAS  PubMed  Google Scholar 

  118. Palkovits, M. Interconnections between the neuroendocrine hypothalamus and the central autonomic system. Geoffrey Harris Memorial Lecture, Kitakyushu, Japan, October 1998. Front. Neuroendocrinol. 20, 270–295 (1999).

    Article  CAS  PubMed  Google Scholar 

  119. Tamma, R. et al. Oxytocin is an anabolic bone hormone. Proc. Natl. Acad. Sci. USA 106, 7149–7154 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Colaianni, G. et al. Regulated production of the pituitary hormone oxytocin from murine and human osteoblasts. Biochem. Biophys. Res. Commun. 411, 512–515 (2011).

    Article  CAS  PubMed  Google Scholar 

  121. Nesse, R. M. Tinbergen’s four questions: two proximate, two evolutionary. Evol. Med. Public Health 2019, 2 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  122. Fujino, Y. et al. Possible functions of oxytocin/vasopressin-superfamily peptides in annelids with special reference to reproduction and osmoregulation. J. Exp. Zool. 284, 401–406 (1999).

    Article  CAS  PubMed  Google Scholar 

  123. Kawada, T., Sekiguchi, T., Itoh, Y., Ogasawara, M. & Satake, H. Characterization of a novel vasopressin/oxytocin superfamily peptide and its receptor from an ascidian, Ciona intestinalis. Peptides 29, 1672–1678 (2008).

    Article  CAS  PubMed  Google Scholar 

  124. Beets, I. et al. Vasopressin/oxytocin-related signaling regulates gustatory associative learning in C. elegans. Science 338, 543–545 (2012).

    Article  CAS  PubMed  Google Scholar 

  125. Chini, B., Leonzino, M., Braida, D. & Sala, M. Learning about oxytocin: pharmacologic and behavioral issues. Biol. Psychiatry 76, 360–366 (2014).

    Article  CAS  PubMed  Google Scholar 

  126. Wallis, M. Molecular evolution of the neurohypophysial hormone precursors in mammals: Comparative genomics reveals novel mammalian oxytocin and vasopressin analogues. Gen. Comp. Endocrinol. 179, 313–318 (2012).

    Article  CAS  PubMed  Google Scholar 

  127. Freeman, S.M. & Young, L.J. Comparative perspectives on oxytocin and vasopressin receptor research in rodents and primates: translational implications. J. Neuroendocrinol. https://doi.org/10.1111/jne.12382 (2016).

  128. Carter, C. S. Sex differences in oxytocin and vasopressin: implications for autism spectrum disorders? Behav. Brain Res. 176, 170–186 (2007).

    Article  CAS  PubMed  Google Scholar 

  129. Holt-Lunstad, J., Birmingham, W. & Light, K. C. The influence of depressive symptomatology and perceived stress on plasma and salivary oxytocin before, during and after a support enhancement intervention. Psychoneuroendocrinology 36, 1249–1256 (2011).

    Article  CAS  PubMed  Google Scholar 

  130. Weisman, O., Zagoory-Sharon, O., Schneiderman, I., Gordon, I. & Feldman, R. Plasma oxytocin distributions in a large cohort of women and men and their gender-specific associations with anxiety. Psychoneuroendocrinology 38, 694–701 (2013).

    Article  CAS  PubMed  Google Scholar 

  131. Zhong, S. et al. U-shaped relation between plasma oxytocin levels and behavior in the trust game. PLoS One 7, e51095 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Geng, Y. et al. Oxytocin enhancement of emotional empathy: generalization across cultures and effects on amygdala activity. Front. Neurosci. 12, 512 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  133. Feldman, R. et al. Sensitive parenting is associated with plasma oxytocin and polymorphisms in the OXTR and CD38 genes. Biol. Psychiatry 72, 175–181 (2012).

    Article  CAS  PubMed  Google Scholar 

  134. Rilling, J. K. et al. Sex differences in the neural and behavioral response to intranasal oxytocin and vasopressin during human social interaction. Psychoneuroendocrinology 39, 237–248 (2014).

    Article  CAS  PubMed  Google Scholar 

  135. Lieberz, J. et al. Kinetics of oxytocin effects on amygdala and striatal reactivity vary between women and men. Neuropsychopharmacology 45, 1134–1140 (2020).

    Article  CAS  PubMed  Google Scholar 

  136. Simonsohn, U., Nelson, L. D. & Simmons, J. P. P-curve and effect size: correcting for publication bias using only significant results. Perspect. Psychol. Sci. 9, 666–681 (2014).

    Article  PubMed  Google Scholar 

  137. Gilbert, C., Brown, M. C. J., Cappelleri, J. C., Carlsson, M. & McKenna, S. P. Estimating a minimally important difference in pulmonary arterial hypertension following treatment with sildenafil. Chest 135, 137–142 (2009).

    Article  CAS  PubMed  Google Scholar 

  138. Faul, F., Erdfelder, E., Lang, A.-G. & Buchner, A. G*Power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behav. Res. Methods 39, 175–191 (2007).

    Article  PubMed  Google Scholar 

  139. DeBruine, L. & Barr, D.J. Understanding mixed effects models through data simulation. Preprint at PsyArXiv https://doi.org/10.31234/osf.io/xp5cy (2019).

  140. Lakens, D., Scheel, A. M. & Isager, P. M. Equivalence testing for psychological research: a tutorial. Adv. Methods Practices Psychol. Sci. 1, 259–269 (2018).

    Article  Google Scholar 

  141. Grinevich, V., Desarménien, M. G., Chini, B., Tauber, M. & Muscatelli, F. Ontogenesis of oxytocin pathways in the mammalian brain: late maturation and psychosocial disorders. Front. Neuroanat. 8, 164 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  142. Goudsmit, E., Neijmeijer-Leloux, A. & Swaab, D. F. The human hypothalamo-neurohypophyseal system in relation to development, aging and Alzheimer’s disease. Prog. Brain Res. 93, 237–247 (1992). discussion 247–248.

    Article  CAS  PubMed  Google Scholar 

  143. Hammock, E. A. D. Developmental perspectives on oxytocin and vasopressin. Neuropsychopharmacology 40, 24–42 (2015).

    Article  CAS  PubMed  Google Scholar 

  144. Vaidyanathan, R. & Hammock, E. A. D. Oxytocin receptor dynamics in the brain across development and species. Dev. Neurobiol. 77, 143–157 (2017).

    Article  CAS  PubMed  Google Scholar 

  145. Zheng, J.-J. et al. Oxytocin mediates early experience-dependent cross-modal plasticity in the sensory cortices. Nat. Neurosci. 17, 391–399 (2014).

    Article  CAS  PubMed  Google Scholar 

  146. Winslow, J. T. et al. Infant vocalization, adult aggression, and fear behavior of an oxytocin null mutant mouse. Horm. Behav. 37, 145–155 (2000).

    Article  CAS  PubMed  Google Scholar 

  147. Alberts, J. R. Huddling by rat pups: ontogeny of individual and group behavior. Dev. Psychobiol. 49, 22–32 (2007).

    Article  PubMed  Google Scholar 

  148. Feldman, R. Oxytocin and social affiliation in humans. Horm. Behav. 61, 380–391 (2012).

    Article  CAS  PubMed  Google Scholar 

  149. Clark, C. L. et al. Neonatal CSF oxytocin levels are associated with parent report of infant soothability and sociability. Psychoneuroendocrinology 38, 1208–1212 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by an Excellence Grant from the Novo Nordisk Foundation (NNF16OC0019856), the Research Council of Norway (301767) and the European Research Council under the European Union’s Horizon 2020 research and Innovation program (ERC StG, Grant 802998).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Daniel S. Quintana.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information Primary Handling Editor: Marike Schiffer

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Winterton, A., Westlye, L.T., Steen, N.E. et al. Improving the precision of intranasal oxytocin research. Nat Hum Behav 5, 9–18 (2021). https://doi.org/10.1038/s41562-020-00996-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41562-020-00996-4

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing