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Sex differences in the neural and behavioral response to intranasal oxytocin and vasopressin during human social interaction
Open accessAbstract
Both oxytocin (OT) and vasopressin (AVP) are known to modulate social behavior, and dysfunction in both systems has been postulated as a potential cause of certain psychiatric disorders that involve social behavioral deficits. In particular, there is growing interest in intranasal OT as a potential treatment for certain psychiatric disorders, and preliminary pre-clinical and clinical studies suggest efficacy in alleviating some of the associated symptoms. However, the vast majority of research participants in these studies have been male, and there is evidence for sexually differentiated effects of nonapeptides in both humans and non-human animals. To date, no study has investigated the effect of intranasal OT on brain function in human males and females within the same paradigm. Previously, in a randomized, placebo-controlled, double-blind fMRI study, we reported effects of intranasal OT and AVP on behavior and brain activity of human males as they played an interactive social game known as the Prisoner's Dilemma Game. Here, we present findings from an identical study in human females, and compare these with our findings from males. Overall, we find that both behavioral and neural responses to intranasal OT and AVP are highly sexually differentiated. In women, AVP increased conciliatory behavior, and both OT and AVP caused women to treat computer partners more like humans. In men, AVP increased reciprocation of cooperation from both human and computer partners. However, no specific drug effects on behavior were shared between men and women. During cooperative interactions, both OT and AVP increased brain activity in men within areas rich in OT and AVP receptors and in areas playing a key role in reward, social bonding, arousal and memory (e.g., the striatum, basal forebrain, insula, amygdala and hippocampus), whereas OT and AVP either had no effect or in some cases actually decreased brain activity in these regions in women. OT treatment rendered neural responses of males more similar to responses of females in the placebo group and vice versa, raising the prospect of an inverted u-shaped dose response to central OT levels. These findings emphasize the need to fully characterize the effects of intranasal OT and AVP in both males and females and at multiple doses before widespread clinical application will be warranted.
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In the citing paper
“This bias can be observed in much of the prior work on oxytocin in humans as well, with some neuroimaging studies indicating potential differences in the oxytocin system between sexes.13, 14, 47, 48, 49”
From Intranasal oxytocin enhances intrinsic corticostriatal functional connectivity in women (2017) · cites this paper as [48]
In the citing paper
“This bias can be observed in much of the prior work on oxytocin in humans as well, with some neuroimaging studies indicating potential differences in the oxytocin system between sexes.13, 14, 47, 48, 49”
From Intranasal oxytocin enhances intrinsic corticostriatal functional connectivity in women (2017) · cites this paper as [48]
In the citing paper
“These data have, however, found OT and AVP can have differential effects on neural activity (i.e., BOLD fMRI responses) and cognition, at least in some cases although the effects of OT are more robust [84; 86; 87; 88; 89; 90].”
From Cross-talk among oxytocin and arginine-vasopressin receptors: Relevance for basic and clinical studies of the brain and periphery (2018) · cites this paper as [88]
In the citing paper
“The few studies that have compared the effects of intranasally administered OT and AVP in humans have reported that these peptides do not have opposing roles.”
From Cross-talk among oxytocin and arginine-vasopressin receptors: Relevance for basic and clinical studies of the brain and periphery (2018) · cites this paper as [88]
In the citing paper
“In humans, intranasal VP had sex-specific effects during social communication and cooperation interactions”
From Vasopressin and oxytocin receptor systems in the brain: Sex differences and sex-specific regulation of social behavior (2016) · cites this paper as Rilling et al., 2014
In the citing paper
“Intranasal OT increased the caudate/putamen response in males, whereas it decreased this response in females (Rilling et al., 2014).”
From Vasopressin and oxytocin receptor systems in the brain: Sex differences and sex-specific regulation of social behavior (2016) · cites this paper as Rilling et al., 2014
In the citing paper
“Sex differences were also found for the effect of OT on brain activation during reciprocated cooperation.”
From Vasopressin and oxytocin receptor systems in the brain: Sex differences and sex-specific regulation of social behavior (2016) · cites this paper as Rilling et al., 2014
In the citing paper
“previous research has shown that oxytocin effects can vary as a function of emotion regulation skills (Quirin et al., 2011), social context history of childhood maltreatment (Ebert et al., 2013; Flanagan et al., 2015), and sex (Ditzen et al., 2012; Rilling et al., 2014).”
From Augmenting Prolonged Exposure therapy for PTSD with intranasal oxytocin: a randomized, placebo-controlled pilot trial (2018) · cites this paper as Rilling et al., 2014
In the citing paper
“In healthy individuals, OT effects seem to follow an inverted u-shape (Rilling et al, 2014), with doses ~24 IU, resulting in more anxiolytic effects than higher doses of OT (Cardoso et al, 2013).”
From Intranasal oxytocin administration dampens amygdala reactivity towards emotional faces in male and female PTSD patients (2016) · cites this paper as Rilling et al, 2014
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“More generally stating, OXT may improve neural functioning in subjects with sub-optimal performance, whereas it may have no effect or even deteriorate neural functioning in subjects with already optimal performance [50, 51].”
Non-Invasive Brain Delivery of G4 70/30 PAMAM Dendrimers via the Intranasal Route
Khiabani, N. A., Elmhirst, A. R.-J., Dubey, O., Poudel, A., Singh, M., Monville, H., Sahouri, A., Alani, Y., Swanson, D. R., Dunbar, G. L., et al. (2026) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.5c00787 · Cited by 3
Esmaili‐Shahzade‐Ali‐Akbari, P., Bozorgnia, A., Shaterian, M., Jandaghian, S., & Shahri, S. M. (2025) · European Journal of Neuroscience · doi:10.1111/ejn.70197 · Cited by 3
“On the other hand, Rilling et al. reported that intranasal OXT increased left amygdala response in men and decreased it in women (Rilling et al. 2014).”
Wang, J., Gan, X., Han, M., Dong, W., He, J., Fu, K., Bore, M. C., Xu, T., Klugah‐Brown, B., Ferraro, S., et al. (2025) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2025.106478 · Cited by 3
“The two voices,” or more? Music and gender from myth and conquests to the neurosciences
Majno, M. (2023) · Journal of Neuroscience Research · doi:10.1002/jnr.25175 · Cited by 3
“In more rhythmically dominated activities such as dance, AVP and oxytocin have been shown to interact in influencing prosocial versus antisocial behaviors, exhibiting some dimorphic characteristics (Bredewold & Veenema, 2018; Feng et al., 2015; Rilling et al., 2014).”
BackgroundGully, B. J., Brown, Z. E., Hornbacher, R., Brown, J. C., Back, S. E., McCance‐Katz, E. F., Swift, R. M., & Haass‐Koffler, C. L. (2024) · Biological Psychiatry Global Open Science · doi:10.1016/j.bpsgos.2024.100395 · Cited by 3
“Neural and behavioral responses have been shown to differ between sexes due in part to hormonal differences, and future research should take this into consideration through hormone testing (67).”
Human, L. J., Thorson, K. R., Woolley, J. D., & Mendes, W. B. (2017) · Hormones and Behavior · doi:10.1016/j.yhbeh.2017.03.002 · Cited by 3
“placebo) in women has been shown to decrease neural activity in regions associated with social bonding and reward (Rilling et al., 2014) and enhance anger following social evaluation (Kubzansky et al.”
BackgroundThe Creative Mind: Blending Oxytocinergic, Dopaminergic and PersonalityPreprint
Chong, A., Becker, B., Angeles, D. C., Matos, M. G., Yue, X., Lai, P. S., Cheung, M. W. ‐., Lei, Z., Malavasi, F., Chew, S. H., et al. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/700807 · Cited by 3
Nasal dominance potentiates intranasal oxytocin’s anxiolytic effects
Julius, N., Nicholls, D., Nowell, J., & Burmester, V. (2025) · Scientific Reports · doi:10.1038/s41598-025-95148-x · Cited by 2
Intranasal oxytocin increases cooperation of heterosexual men with women
Cosme, G., Patrocínio, M., Cogoni, C., Kosilo, M., & Prata, D. P. (2025) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2025.107519 · Cited by 2
Intranasal vasopressin, but not oxytocin, decreases ethanol intake in socially housed mice
Nipper, M. A., Zweig, J. A., Johnson, M., Abshire, K. M., & Ryabinin, A. E. (2025) · Psychopharmacology · doi:10.1007/s00213-025-06962-0 · Cited by 2
“The most frequently observed effects of this treatment are increases in altruistic or cooperative behaviors (Brunnlieb et al. 2016; Deng et al. 2023; Rilling et al. 2012, 2014; Tabak et al. 2015), sex-dependent effects on social approach (Thompson et al. 2006; Wu et al. 2018, 2019) and improved…”
Shehadeh, E., Narattil, N. R., Kritman, M., & Maroun, M. (2025) · Behavioral and Brain Functions · doi:10.1186/s12993-025-00307-9 · Cited by 2
“Sex-specific differences have also been observed in both neural and behavioral responses to OXT during social interactions [85].”
Neuropeptidergic systems in psychiatric disorders
Hodzic, S., & Riedemann, T. (2026) · Frontiers in Endocrinology · doi:10.3389/fendo.2025.1654292 · Cited by 2
Oxytocin and autism – A precision medicine framework to unpack mechanisms and evidence
Boulton, K., & Guastella, A. J. (2026) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2026.106746 · Cited by 2
Shiga, T., Furui, T., & Morishige, K. (2024) · Maternal Health Neonatology and Perinatology · doi:10.1186/s40748-024-00176-6 · Cited by 3
Neurochemistry of Prosocial Decision Making
Declerck, C. H., & Boone, C. (2016) · Elsevier eBooks · doi:10.1016/b978-0-12-801303-8.00003-3 · Cited by 2
Videla, M. D., & López, P. A. (2017) · Interdisciplinaria Revista de Psicología y Ciencias Afines · doi:10.16888/interd.2017.34.1.5 · Cited by 2
Editorial: The Vasopressin System and Behavior
Caldwell, H. K., & Petrulis, A. (2018) · Frontiers in Endocrinology · doi:10.3389/fendo.2018.00438 · Cited by 2
Coenjaerts, M., Trimborn, I., Adrovic, B., Stoffel‐Wagner, B., Cahill, L. F., Philipsen, A., Hurlemann, R., & Scheele, D. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.11.22.469500 · Cited by 2
“Selective OXTint effects in men, but not in women, have been previously observed for hippocampal responses to cooperative interactions([29]) and chemosensory stress signals.”
BackgroundSnowden, A. W., Schwartz, S., Smith, A. L., Goodman, M. M., & Freeman, S. M. (2025) · Social Neuroscience · doi:10.1080/17470919.2025.2536570 · Cited by 1
“In men, but not women, IN-AVP increases cooperation and activates regions including the nucleus accumbens and amygdala (Rilling et al., 2014).”
The neurophysiological correlates of altruism: A scoping review of fMRI, EEG, and autonomic studies
Orui, J., Inoue, T., Shiraiwa, K., Ueda, M., Naito, Y., & Ishii, R. (2025) · Cognitive Affective & Behavioral Neuroscience · doi:10.3758/s13415-025-01380-3 · Cited by 3
“Activation in reward-related regions, such as the striatum and nucleus accumbens (NAcc), was consistently linked to altruistic acts (Harbaugh et al., 2007; Hu et al., 2015; Hubbard et al., 2016; Karns et al., 2017; Moll et al., 2006; Rilling et al., 2002, 2014; Tamir et al., 2015).”
A narrative review on oxytocin at the intersection of sleep, stress, and social behavior
Boccalaro, I. L., Rillosi, E., Ramírez‐Plascencia, O. D., Luca, R. D., & Mahoney, C. E. (2026) · Frontiers in Neuroscience · doi:10.3389/fnins.2026.1745281 · Cited by 2
“The most robust attenuation of fear-related amygdala activity has been observed following administration of 24 IU intranasal OT approximately 45–70 min post-dose (Kirsch et al., 2005; Domes et al., 2007; Rilling et al., 2014).”
Us against them: oxytocin response to competition in a small-scale human society
Debras, C. C., Colby, A. E., Martin, J. S., Baettig, V., Jud, D. C., Ista, A. C., Tayo, L. C., Trumble, B., Scaff, C., & Jaeggi, A. V. (2026) · Proceedings of the Royal Society B Biological Sciences · doi:10.1098/rspb.2026.0242 · Cited by 1
Symptômes négatifs de la schizophrénie : nouvelles approches pharmacologiques
Lodovighi, M.-A., Palomba, A., Belzeaux-R, R., Adida, M., & Azorin, J. (2015) · L Encéphale · doi:10.1016/s0013-7006(16)30010-0 · Cited by 1
The Neuroscientific Validation of the Leadership Competency Model Drenica
Çitaku, F., & Ramadani, H. (2024) · Journal of Human Resource Management · doi:10.11648/j.jhrm.20241202.13 · Cited by 1
Sosnowski, M. J., & Brosnan, S. F. (2024) · Frontiers in Endocrinology · doi:10.3389/fendo.2024.1418089 · Cited by 2
The Effects of vasopressin on human social behaviors
Wu, X., Feng, C., Xu, J., He, Z., Luo, Y., & Luo, Y. (2019) · Advances in Psychological Science · doi:10.3724/sp.j.1042.2019.00811 · Cited by 1
Balovaptan and Autism Spectrum Disorder
da, S. D. L., Ventura, D. L. L., Félix, S. E., Maciel, R. L. K., de, C. M. B. N., de Oliveira, R. T. M., Teixeira, A. M. L., da, S. J. N. R., & Aragão, G. F. (2020) · Insights of Biomedical Research · doi:10.36959/584/458 · Cited by 1
Levin, S. B. (2021) · Oxford University Press eBooks · doi:10.1093/oso/9780190051495.003.0006 · Cited by 1
How Is God “Like a Drug”? Exploring the Evolution of Social Affects and Oxytocin
Stockly, K. J. (2020) · Oxford University Press eBooks · doi:10.1093/oso/9780199827718.005.0002 · Cited by 1
The Influence of Oxytocin on Older Adults’ Emotion Processing
Campbell, A. (2015) · Otago University Research Archive (University of Otago)
The effects of oxytocin on social behaviour: the influence of context and individual differences
Daughters, K. (2016) · ORCA Online Research @Cardiff (Cardiff University)
The relationship between oxytocin pathway genes and personality traits and psychosis characteristics
Haram, M. (2017) · NORA - Norwegian Open Research Archives
Implications of placebos and nocebos in clinical research
Colloca, L., & Haycock, N. R. (2018) · PNEI REVIEW · doi:10.3280/pnei2018-001009
Interaction Rituals and Embodied Choice Theory
Wellman, J. K., Corcoran, K. E., & Stockly, K. J. (2019) · Oxford University Press eBooks · doi:10.1093/oso/9780199827718.003.0003
Megachurch: An American Original (Almost)
Wellman, J. K., Corcoran, K. E., & Stockly, K. J. (2019) · Oxford University Press eBooks · doi:10.1093/oso/9780199827718.003.0005 · Cited by 1
Dissecting Megachurch Scandals
Wellman, J. K., Corcoran, K. E., & Stockly, K. J. (2019) · Oxford University Press eBooks · doi:10.1093/oso/9780199827718.003.0014
Conclusion: Havens of Health or Habitats for the Prosperity Gospel?
Wellman, J. K., Corcoran, K. E., & Stockly, K. J. (2019) · Oxford University Press eBooks · doi:10.1093/oso/9780199827718.003.0015
Desire for Wow, or Hacking the Happy
Wellman, J. K., Corcoran, K. E., & Stockly, K. J. (2019) · Oxford University Press eBooks · doi:10.1093/oso/9780199827718.003.0009 · Cited by 1
Wellman, J. K., Corcoran, K. E., & Stockly, K. J. (2019) · Oxford University Press eBooks · doi:10.1093/oso/9780199827718.003.0010
Megachurch: The Drug That Works
Wellman, J. K., Corcoran, K. E., & Stockly, K. J. (2019) · Oxford University Press eBooks · doi:10.1093/oso/9780199827718.003.0001
Wellman, J. K., Corcoran, K. E., & Stockly, K. J. (2019) · Oxford University Press eBooks · doi:10.1093/oso/9780199827718.003.0011
Metadata
- Authors
- Rilling, J. K., DeMarco, A. C., Hackett, P. D., Chen, X., Gautam, P., Stair, S., Haroon, E., Thompson, R., Ditzen, B., Patel, R., & Pagnoni, G.
- Affiliations
- Emory University (US)
- University of Kansas (US)
- Bowdoin College (US)
- University of Modena and Reggio Emilia (IT)
- Corresponding author
- Rilling, James K.
- ORCID
- Venue
- Psychoneuroendocrinology
- Publisher
- Elsevier BV
- Published
- 2014-01
- Volume
- 39
- Pages
- 237-248
- ISSN
- 0306-4530 (ISSN-L)
- PMC
- PMC3842401
- OpenAlex
- W2129575907
- Cited by
- 343
- References
- 54
- Citations by year
- 2026: 11 · 2025: 14 · 2024: 13 · 2023: 16 · 2022: 19 · 2021: 38 · 2020: 35 · 2019: 50 · 2018: 35 · 2017: 35 · 2016: 32 · 2015: 28 · 2014: 17
- FWCI
- 38.53
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Psychoneuroendocrinology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- IRIS UNIMORE (University of Modena and Reggio Emilia) (submittedVersion, cc-by)
- Funders
- National Institute of Mental Health (R01 MH084068-01A1)
- National Center for Research Resources
- Yerkes Regional Primate Research Center (2P51RR000165-51)
- National Institutes of Health
- Presbyterian Historical Society (UL1 RR025008)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Neuroendocrine regulation and behavior
- Life Sciences › Neuroscience › Sensory Systems › Olfactory and Sensory Function Studies
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- oxytocin, vasopressin, sex differences, intranasal administration, social interaction, prisoner's dilemma game, cooperation, conciliation, social bonding, reward processing, brain activity, nonapeptide, mental illness
- MeSH terms
- Administration, Intranasal, Adolescent, Arginine Vasopressin, Brain, Cooperative Behavior, Double-Blind Method, Female, Game Theory, Humans, Image Processing, Computer-Assisted, Interpersonal Relations, Magnetic Resonance Imaging, Male, Oxytocin, Sex Characteristics, Social Behavior, Young Adult, Functional Neuroimaging
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