Statistical and Methodological Considerations for the Interpretation of Intranasal Oxytocin Studies

  • Hasse Walum
    Address correspondence to Hasse Walum, Emory University, Silvio O. Conte Center for Oxytocin and Social Cognition, Yerkes National Primate Research Center, 954 Gatewood Rd, Atlanta GA 30329
    Silvio O. Conte Center for Oxytocin and Social Cognition, Emory University, Atlanta, Georgia

    Center for Translational Social Neuroscience, Emory University, Atlanta, Georgia

    Yerkes National Primate Research Center, Department of Psychiatry and Behavioral Sciences , Emory University, Atlanta, Georgia

    Department of Psychology, Emory University, Atlanta, Georgia
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  • Irwin D. Waldman
    Center for Translational Social Neuroscience, Emory University, Atlanta, Georgia

    Department of Psychology, Emory University, Atlanta, Georgia
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  • Larry J. Young
    Silvio O. Conte Center for Oxytocin and Social Cognition, Emory University, Atlanta, Georgia

    Center for Translational Social Neuroscience, Emory University, Atlanta, Georgia

    Yerkes National Primate Research Center, Department of Psychiatry and Behavioral Sciences , Emory University, Atlanta, Georgia
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      Over the last decade, oxytocin (OT) has received focus in numerous studies associating intranasal administration of this peptide with various aspects of human social behavior. These studies in humans are inspired by animal research, especially in rodents, showing that central manipulations of the OT system affect behavioral phenotypes related to social cognition, including parental behavior, social bonding, and individual recognition. Taken together, these studies in humans appear to provide compelling, but sometimes bewildering, evidence for the role of OT in influencing a vast array of complex social cognitive processes in humans. In this article, we investigate to what extent the human intranasal OT literature lends support to the hypothesis that intranasal OT consistently influences a wide spectrum of social behavior in humans. We do this by considering statistical features of studies within this field, including factors like statistical power, prestudy odds, and bias. Our conclusion is that intranasal OT studies are generally underpowered and that there is a high probability that most of the published intranasal OT findings do not represent true effects. Thus, the remarkable reports that intranasal OT influences a large number of human social behaviors should be viewed with healthy skepticism, and we make recommendations to improve the reliability of human OT studies in the future.


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        • Bartz J.A.
        • Zaki J.
        • Bolger N.
        • Ochsner K.N.
        Social effects of oxytocin in humans: Context and person matter.
        Trends Cogn Sci. 2011; 15: 301-309
        • Churchland P.S.
        • Winkielman P.
        Modulating social behavior with oxytocin: How does it work? What does it mean?.
        Horm Behav. 2012; 61: 392-399
        • Evans S.L.
        • Monte O.D.
        • Noble P.
        • Averbeck B.B.
        Intranasal oxytocin effects on social cognition: A critique.
        Brain Res. 2014; 1580: 69-77
        • Guastella A.J.
        • Hickie I.B.
        • McGuinness M.M.
        • Otis M.
        • Woods E.A.
        • Disinger H.M.
        • et al.
        Recommendations for the standardisation of oxytocin nasal administration and guidelines for its reporting in human research.
        Psychoneuroendocrinology. 2013; 38: 612-625
        • Ross H.E.
        • Young L.J.
        Oxytocin and the neural mechanisms regulating social cognition and affiliative behavior.
        Front Neuroendocrin. 2009; 30: 534-547
        • Young L.J.
        Oxytocin, social cognition and psychiatry.
        Neuropsychopharmacology. 2015; 40: 243-244
        • Young L.J.
        • Flanagan-Cato L.M.
        Editorial comment: Oxytocin, vasopressin and social behavior.
        Horm Behav. 2012; 61: 227-229
        • Pereira T.V.
        • Ioannidis J.P.
        Statistically significant meta-analyses of clinical trials have modest credibility and inflated effects.
        J Clin Epidemiol. 2011; 64: 1060-1069
        • Van IJzendoorn M.H.
        • Bakermans-Kranenburg M.J.
        A sniff of trust: Meta-analysis of the effects of intranasal oxytocin administration on face recognition, trust to in-group, and trust to out-group.
        Psychoneuroendocrinology. 2012; 37: 438-443
        • Shahrestani S.
        • Kemp A.H.
        • Guastella A.J.
        The impact of a single administration of intranasal oxytocin on the recognition of basic emotions in humans: A meta-analysis.
        Neuropsychopharmacology. 2013; 38: 1929-1936
        • Bakermans-Kranenburg M.J.
        • Van IJzendoorn M.H.
        Sniffing around oxytocin: Review and meta-analyses of trials in healthy and clinical groups with implications for pharmacotherapy.
        Transl Psychiatry. 2013; 3: e258
        • 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. 2007; 39: 175-191
        • Core Team R.
        R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing, Vienna2014
        • Button K.S.
        • Ioannidis J.P.
        • Mokrysz C.
        • Nosek B.A.
        • Flint J.
        • Robinson E.S.
        • Munafò M.R.
        Power failure: Why small sample size undermines the reliability of neuroscience.
        Nat Rev Neurosci. 2013; 14: 365-376
        • Ioannidis J.P.
        Why most discovered true associations are inflated.
        Epidemiology. 2008; 19: 640-648
        • Ioannidis J.P.A.
        Why most published research findings are false.
        PLoS Med. 2005; 2: e124
        • Button K.S.
        • Ioannidis J.P.
        • Mokrysz C.
        • Nosek B.A.
        • Flint J.
        • Robinson E.S.
        • Munafò M.R.
        Empirical evidence for low reproducibility indicates low pre-study odds.
        Nat Rev Neurosci. 2013; 14: 877
        • Djulbegovic B.
        • Kumar A.
        • Glasziou P.
        • Miladinovic B.
        • Chalmers I.
        Medical research: Trial unpredictability yields predictable therapy gains.
        Nature. 2013; 500: 395-396
        • Leng G.
        • Ludwig M.
        Intranasal oxytocin: Myths and delusions.
        Biol Psychiatry. 2016; 79: 243-250
        • Bakker M.
        • van Dijk A.
        • Wicherts J.M.
        The rules of the game called psychological science.
        Perspect Psychol Sci. 2012; 7: 543-554
        • Pashler H.
        • Harris C.R.
        Is the replicability crisis overblown? Three arguments examined.
        Perspect Psychol Sci. 2012; 7: 531-536
        • Fanelli D.
        “Positive” results increase down the Hierarchy of the Sciences.
        PloS One. 2010; 5: e10068
        • Rosenthal R.
        The file drawer problem and tolerance for null results.
        Psychol Bull. 1979; 86: 638
        • Prinz F.
        • Schlange T.
        • Asadullah K.
        Believe it or not: How much can we rely on published data on potential drug targets?.
        Nat Rev Drug Discov. 2011; 10: 712
        • Dwan K.
        • Altman D.G.
        • Arnaiz J.A.
        • Bloom J.
        • Chan A.W.
        • Cronin E.
        • et al.
        Systematic review of the empirical evidence of study publication bias and outcome reporting bias.
        PloS One. 2008; 3: e3081
        • Ioannidis J.P.
        • Trikalinos T.A.
        The appropriateness of asymmetry tests for publication bias in meta-analyses: A large survey.
        CMAJ. 2007; 176: 1091-1096
        • Simmons J.P.
        • Nelson L.D.
        • Simonsohn U.
        False-positive psychology: Undisclosed flexibility in data collection and analysis allows presenting anything as significant.
        Psychol Sci. 2011; 22: 1359-1366
        • John L.K.
        • Loewenstein G.
        • Prelec D.
        Measuring the prevalence of questionable research practices with incentives for truth telling.
        Psychol Sci. 2012; 23: 524-532
        • Nieuwenhuis S.
        • Forstmann B.U.
        • Wagenmakers E.J.
        Erroneous analyses of interactions in neuroscience: A problem of significance.
        Nat Neurosci. 2011; 14: 1105-1107
        • Munafo M.R.
        • Stothart G.
        • Flint J.
        Bias in genetic association studies and impact factor.
        Mol Psychiatry. 2009; 14: 119-120
        • Bertamini M.
        • Munafò M.R.
        Bite-size science and its undesired side effects.
        Perspect Psychol Sci. 2012; 7: 67-71
        • Insel T.R.
        • Young L.J.
        Neuropeptides and the evolution of social behavior.
        Curr Opin Neurobiol. 2000; 10: 784-789
        • Visscher P.M.
        • Brown M.A.
        • McCarthy M.I.
        • Yang J.
        Five years of GWAS discovery.
        Am J Hum Genet. 2012; 90: 7-24
        • Open Science Collaboration
        An open, large-scale, collaborative effort to estimate the reproducibility of psychological science.
        Perspect Psychol Sci. 2012; 7: 657-660
        • Modi M.E.
        • Young L.J.
        The oxytocin system in drug discovery for autism: Animal models and novel therapeutic strategies.
        Horm Behav. 2012; 61: 340-350
        • Young L.J.
        • Barrett C.E.
        Can oxytocin treat autism?.
        Science. 2015; 347: 825-826
        • Modi M.E.
        • Inoue K.
        • Barrett C.E.
        • Kittelberger K.A.
        • Smith D.G.
        • Landgraf R.
        • Young L.J.
        Melanocortin receptor agonists facilitate oxytocin-dependent partner preference formation in the Prairie Vole.
        Neuropsychopharmacology. 2015; 40: 1856-1865
        • Sabatier N.
        • Caquineau C.
        • Dayanithi G.
        • Bull P.
        • Douglas A.J.
        • Guan X.M.
        • et al.
        Alpha-melanocyte-stimulating hormone stimulates oxytocin release from the dendrites of hypothalamic neurons while inhibiting oxytocin release from their terminals in the neurohypophysis.
        J Neurosci. 2003; 23: 10351-10358
        • Barrett C.E.
        • Arambula S.E.
        • Young L.J.
        The oxytocin system promotes resilience to the effects of neonatal isolation on adult social attachment in female prairie voles.
        Transl Psychiatry. 2015; 21 (e606): 5
        • Barrett C.E.
        • Modi M.E.
        • Zhang B.C.
        • Walum H.
        • Inoue K.
        • Young L.J.
        Neonatal melanocortin receptor agonist treatment reduces play fighting and promotes adult attachment in prairie voles in a sex-dependent manner.
        Neuropharmacology. 2014; 85: 357-366
        • Penagarikano O.
        • Lazaro M.T.
        • Lu X.H.
        • Gordon A.
        • Dong H.
        • Lam H.A.
        • et al.
        Exogenous and evoked oxytocin restores social behavior in the Cntnap2 mouse model of autism.
        Sci Transl Med. 2015; 7: 271ra278
        • Freeman S.M.
        • Inoue K.
        • Smith A.L.
        • Goodman M.M.
        • Young L.J.
        The neuroanatomical distribution of oxytocin receptor binding and mRNA in the male rhesus macaque (Macaca mulatta).
        Psychoneuroendocrinology. 2014; 45: 128-141
        • Freeman S.M.
        • Walum H.
        • Inoue K.
        • Smith A.L.
        • Goodman M.M.
        • Bales K.L.
        • Young L.J.
        Neuroanatomical distribution of oxytocin and vasopressin 1a receptors in the socially monogamous coppery titi monkey (Callicebus cupreus).
        Neuroscience. 2014; 273: 12-23
        • 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. 1991; 555: 220-232
        • Andari E.
        • Duhamel J.R.
        • Zalla T.
        • Herbrecht E.
        • Leboyer M.
        • Sirigu A.
        Promoting social behavior with oxytocin in high-functioning autism spectrum disorders.
        Proc Natl Acad Sci U S A. 2010; 107: 4389-4394
        • Auyeung B.
        • Lombardo M.V.
        • Heinrichs M.
        • Chakrabarti B.
        • Sule A.
        • Deakin J.B.
        • et al.
        Oxytocin increases eye contact during a real-time, naturalistic social interaction in males with and without autism.
        Transl Psychiatry. 2015; 5: e507
        • Guastella A.J.
        • Mitchell P.B.
        • Dadds M.R.
        Oxytocin increases gaze to the eye region of human faces.
        Biol Psychiatry. 2008; 63: 3-5
        • Skuse D.H.
        • Lori A.
        • Cubells J.F.
        • Lee I.
        • Conneely K.N.
        • Puura K.
        • et al.
        Common polymorphism in the oxytocin receptor gene (OXTR) is associated with human social recognition skills.
        Proc Natl Acad Sci U S A. 2014; 111: 1987-1992