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Oxytocin Attenuates Amygdala Reactivity to Fear in Generalized Social Anxiety Disorder
Open accessAbstract
Patients with generalized social anxiety disorder (GSAD) exhibit heightened activation of the amygdala in response to social cues conveying threat (eg, fearful/angry faces). The neuropeptide oxytocin (OXT) decreases anxiety and stress, facilitates social encounters, and attenuates amygdala reactivity to threatening faces in healthy subjects. The goal of this study was to examine the effects of OXT on fear-related amygdala reactivity in GSAD and matched healthy control (CON) subjects. In a functional magnetic resonance imaging study utilizing a double-blind placebo-controlled within-subjects design, we measured amygdala activation to an emotional face matching task of fearful, angry, and happy faces following acute intranasal administration of OXT (24 IU or 40.32 μg) and placebo in 18 GSAD and 18 CON subjects. Both the CON and GSAD groups activated bilateral amygdala to all emotional faces during placebo, with the GSAD group exhibiting hyperactivity specifically to fearful faces in bilateral amygdala compared with the CON group. OXT had no effect on amygdala activity to emotional faces in the CON group, but attenuated the heightened amygdala reactivity to fearful faces in the GSAD group, such that the hyperactivity observed during the placebo session was no longer evident following OXT (ie, normalization). These findings suggest that OXT has a specific effect on fear-related amygdala activity, particularly when the amygdala is hyperactive, such as in GSAD, thereby providing a brain-based mechanism of the impact of OXT in modulating the exaggerated processing of social signals of threat in patients with pathological anxiety.
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In the citing paper
“Heightened amygdala reactivity has been strongly linked to these social threat-related impairments and many have posited that the amygdala is an important therapeutic target for the management of GSAD (Labuschagne et al, 2010;Phan et al, 2006).”
From Oxytocin modulation of amygdala functional connectivity to fearful faces in generalized social anxiety disorder (2015) · cites this paper as Labuschagne et al, 2010
In the citing paper
“Heightened amygdala reactivity has been strongly linked to these social threat-related impairments and many have posited that the amygdala is an important therapeutic target for the management of GSAD (Labuschagne et al, 2010;Phan et al, 2006).”
From Oxytocin modulation of amygdala functional connectivity to fearful faces in generalized social anxiety disorder (2015) · cites this paper as Labuschagne et al, 2010
In the citing paper
“We have extended these studies to examine the effects of OXT on amygdala reactivity to social threat in GSAD (Labuschagne et al, 2010) and found that OXT attenuated (or normalized) the hyperactive amygdala reactivity to fearful faces in GSAD patients.”
From Oxytocin modulation of amygdala functional connectivity to fearful faces in generalized social anxiety disorder (2015) · cites this paper as Labuschagne et al, 2010
In the citing paper
“These effects were not observed in response to angry or happy faces.”
From Oxytocin modulation of amygdala functional connectivity to fearful faces in generalized social anxiety disorder (2015) · cites this paper as Labuschagne et al, 2010
In the citing paper
“We first confirmed using a whole-brain, 2 (session: PBO, OXT)  2 (group: HC, GSAD) analysis of variance (ANOVA) that consistent with Labuschagne et al (2010), there was a significant group  drug interaction on left amygdala reactivity to fearful faces (peak MNI coordinates: ( À 24, À 2, À 22), Z ¼ 2.77, k ¼ 81, po0.05, small volume corrected), such that OXT attenuated (or normalized) the hypera”
From Oxytocin modulation of amygdala functional connectivity to fearful faces in generalized social anxiety disorder (2015) · cites this paper as Labuschagne et al, 2010
In the citing paper
“The EFMT task has previously been described in detail elsewhere (Labuschagne et al, 2010), and has been used in previous pharmaco-fMRI studies to probe drug effects on amygdala activation (Kirsch et al, 2005;Paulus et al, 2005;Phan et al, 2008;Labuschagne et al, 2010) and amygdala functional connectivity (Gorka et al, 2013).”
From Oxytocin modulation of amygdala functional connectivity to fearful faces in generalized social anxiety disorder (2015) · cites this paper as Labuschagne et al, 2010
In the citing paper
“This finding of divergent effects is consistent with the two other OXT administration studies from our group (Dodhia et al, 2014;Labuschagne et al, 2010)”
From Oxytocin modulation of amygdala functional connectivity to fearful faces in generalized social anxiety disorder (2015) · cites this paper as Labuschagne et al, 2010
In the citing paper
“We had previously shown that acute OXT exerted effects on the amygdala and mPFC/ACC during the processing of threat and other negative emotions (Labuschagne et al, 2010(Labuschagne et al, , 2011)).”
From Modulation of Resting-State Amygdala-Frontal Functional Connectivity by Oxytocin in Generalized Social Anxiety Disorder (2014) · cites this paper as Labuschagne et al, 2010
In the citing paper
“In two recent task-based studies, we showed that OXT attenuates heightened activity in the amygdala of GSAD patients after viewing fearful faces (Labuschagne et al, 2010)”
From Modulation of Resting-State Amygdala-Frontal Functional Connectivity by Oxytocin in Generalized Social Anxiety Disorder (2014) · cites this paper as Labuschagne et al, 2010
In the citing paper
“This is also agreement with decreasing amygdala activation to fearful faces in healthy (45), as well as anxious (46), humans with OT administration.”
From Neuroendocrinology of Parental Response to Baby‐Cry (2011) · cites this paper as [46]
In the citing paper
“Importantly, IN-OT attenuates heightened amygdala reactivity to fearful faces in patients with generalized social anxiety disorder (GSAD) (Labuschagne et al. 2010).”
From A precision medicine approach to oxytocin trials (2017) · cites this paper as Labuschagne et al. 2010
In the citing paper
“there are increasing evidence for the role of OT in reducing anxiety, fear, and stress, in part by dampening amygdala activity”
From A precision medicine approach to oxytocin trials (2017) · cites this paper as Labuschagne et al. 2010
In the citing paper
“IN-OT restores functional connectivity between subcortical regions such as amygdala and frontal areas, including the ACC and mPFC”
From A precision medicine approach to oxytocin trials (2017) · cites this paper as Labuschagne et al. 2010
In the citing paper
“reduces the heightened amygdala reactivity to fearful faces in patients with generalized anxiety disorders”
From A precision medicine approach to oxytocin trials (2017) · cites this paper as Labuschagne et al. 2010
In the citing paper
“Results indicate that the tested type of intranasal OT delivery -but not peripherally delivered OT that produces similar blood levels -replicates prior findings of reduced right amygdala activation in response to emotional stimuli after OT treatment (Domes et al., 2007;Labuschagne et al., 2010;Petrovic et al., 2008).”
From 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 (2016) · cites this paper as Labuschagne et al., 2010
In the citing paper
“Of note, other studies have reported similar results after administration of 24 IU (Domes et al., 2007;Kanat et al., 2015;Labuschagne et al., 2010), however, the dosages are difficult to compare between experiments as these studies used traditional nasal spray devices to administer OT.”
From 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 (2016) · cites this paper as Labuschagne et al., 2010
In the citing paper
“normalized the abnormal neural responses to negative social stimuli in patients with social anxiety disorder (32, 33).”
From Placebo treatment facilitates social trust and approach behavior (2018) · cites this paper as [32]
In the citing paper
“Some research indicates that OXT could be influential in the treatment of established SAD (Labuschagne et al, 2010) and PTSD (Olff et al, 2014).”
From Oxytocin Facilitates Pavlovian Fear Learning in Males (2016) · cites this paper as Labuschagne et al, 2010
In the citing paper
“This fits with the hypothesis that OT administration effects may be especially beneficial in those who lack proficiency in fear regulation (Labuschagne et al, 2010) or social functioning (Olff et al, 2013;Weisman and Feldman, 2013).”
From Intranasal oxytocin administration dampens amygdala reactivity towards emotional faces in male and female PTSD patients (2016) · cites this paper as Labuschagne et al, 2010
In the citing paper
“In addition, functional MRI (fMRI) studies have shown that OT administration dampened amygdala reactivity toward emotional stimuli in healthy males (Kirsch et al, 2005), males with generalized social anxiety disorder (GSAD; Labuschagne et al, 2010) and females with borderline personality disorder (BPD; Bertsch et al, 2013), although findings for females have been mixed (Domes et al, 2010).”
From Intranasal oxytocin administration dampens amygdala reactivity towards emotional faces in male and female PTSD patients (2016) · cites this paper as Labuschagne et al, 2010
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“For example, it has been shown that intranasal oxytocin stimulates key brain regions associated with FER ability, such as the amygdala and the prefrontal (Labuschagne et al, 2010, 2012) and striatum cortices (Feng et al, 2015; Nawijn et al, 2017).”
BackgroundHe, F., Fan, M., Hui, Y.-N., Lai, R.-J., Chen, X., Yang, M.-J., Cheng, X., Wang, Z.-J., Yu, B., Yan, B.-J., et al. (2021) · IBRO Neuroscience Reports · doi:10.1016/j.ibneur.2021.10.001 · Cited by 9
Oral oxytocin delivery with proton pump inhibitor pretreatment decreases food intake
Maejima, Y., Horita, S., Otsuka, A., Hidema, S., Nishimori, K., & Shimomura, K. (2020) · Peptides · doi:10.1016/j.peptides.2020.170312 · Cited by 9
Intranasal oxytocin attenuates insula activity in response to dynamic angry faces
Ma, Y., Ran, G., Hu, N., Hu, Y., Long, W., & Chen, X. (2020) · Biological Psychology · doi:10.1016/j.biopsycho.2020.107976 · Cited by 9
Four-Week Intranasal Oxytocin Administration Reduces Attachment Avoidance in Older Women
Wright, K. A., Polk, R. J., Lin, T., Feifel, D., & Ebner, N. C. (2022) · Hormones and Behavior · doi:10.1016/j.yhbeh.2023.105413 · Cited by 7
Oxytocin and social learning in socially anxious men and women
Flechsenhar, A., Levine, S. M., Müller, L. E., Herpertz, S. C., & Bertsch, K. (2024) · Neuropharmacology · doi:10.1016/j.neuropharm.2024.109930 · Cited by 8
Oxytocin in the Treatment of Psychiatric Disorders
Kağızman, S. Ç., & Hocaoğlu, Ç. (2023) · Medeniyet Medical Journal · doi:10.4274/mmj.galenos.2023.13707 · Cited by 10
The Use of Oxytocin in Personality Disorders: Rationale and Current Status
Pérez-Rodríguez, M. M., Derish, N. E., & New, A. S. (2014) · Current Treatment Options in Psychiatry · doi:10.1007/s40501-014-0026-1 · Cited by 8
Neuroendocrinology and Neuroimaging Studies of Social Anxiety Disorder
Phan, K. L., & Klumpp, H. (2010) · Elsevier eBooks · doi:10.1016/b978-0-12-375096-9.00010-9 · Cited by 9
Self-citationPotential role of oxytocin in the regulation of memories and treatment of memory disorders
Walia, V., Wal, P., Mishra, S., Agrawal, A., Kosey, S., & Patil, A. D. (2024) · Peptides · doi:10.1016/j.peptides.2024.171222 · Cited by 9
Scotland-Coogan, D. (2019) · The Qualitative Report · doi:10.46743/2160-3715/2019.3573 · Cited by 10
“…the hormone oxytocin to moderate stress reduction (Neumann & Landgraf, 2012; Uvnäs-Moberg, 1998a), enhance sleep (Lipschitz et al., 2015), attenuate cortisol in the stress response (Ditzen et al., 2009), and promote fear response and extinction (Eckstein et al., 2015; Labuschagne et al., 2010).”
BackgroundIntranasal Oxytocin Increases Perceptual Salience of Faces in the Absence of Awareness
Xue, S., Wu, H.-B., Zhang, L., & Zhang, D.-X. (2020) · Psychiatry Investigation · doi:10.30773/pi.2019.0130 · Cited by 8
Guittard, C., Eutrope, J., Caillies, S., & Loron, G. (2024) · BMC Psychology · doi:10.1186/s40359-023-01510-x · Cited by 7
The Brain That Feels Into Others: Toward a Neuroscience of Empathy
Flasbeck, V., Gonzalez-Liencres, C., & Brüne, M. (2018) · Elsevier eBooks · doi:10.1016/b978-0-12-809837-0.00002-7 · Cited by 10
Oxytocin differentially modulates the early neural responses to faces and non-social stimuli
Moses, E., Nelson, N. L., Taubert, J., & Pegna, A. J. (2024) · Social Cognitive and Affective Neuroscience · doi:10.1093/scan/nsae010 · Cited by 6
“These OT-induced modulations occur as a function of clinical anxiety (Labuschagne et al. , 2010), yet it remains unclear whether the hormone uniquely impacts social processing or produces a blanket anxiolytic effect that impacts all visual stimuli.”
BackgroundResultInfluentialOral Oxytocin Blurs Sex Differences in Amygdala Responses to Emotional Scenes
Lan, C., Kou, J., Liu, Q., Qing, P., Zhang, X., Song, X., Xu, D., Zhang, Y., Chen, Y., Zhou, X., et al. (2024) · Biological Psychiatry Cognitive Neuroscience and Neuroimaging · doi:10.1016/j.bpsc.2024.05.010 · Cited by 7
Liu, Y. T., Wang, D., & Li, H. (2021) · Cerebral Cortex · doi:10.1093/cercor/bhab277 · Cited by 7
Recent Developments in Protein Lactylation in PTSD and CVD: Novel Strategies and Targets
Kozlakidis, Z., Shi, P., Abarbanel, G., Klein, C. A., & Sfera, A. (2023) · BioTech · doi:10.3390/biotech12020038 · Cited by 7
“OXT is an established inhibitor of stress-related amygdalar activation, thus a negative regulator of PTSD and CVD, while ANG II has the opposite effect [86,93,94].”
BackgroundThe Associations Between Endogenous Oxytocin Levels and Emotion Recognition in Bipolar Disorder
Taş, C., Brown, E. C., Onur, E., Aydemır, Ö., & Brüne, M. (2015) · Klinik Psikofarmakoloji Bülteni-Bulletin of Clinical Psychopharmacology · doi:10.5455/bcp.20140514043545 · Cited by 6
Socially anxious tendencies affect neural processing of gaze perception
Tsuji, Y., & Shimada, S. (2017) · Brain and Cognition · doi:10.1016/j.bandc.2017.08.002 · Cited by 7
Lu, P., Yin, Z., Fang, M., Yao, L., Zhang, S., Zhang, S., Guo, G., He, P., & qin, Y. (2024) · Physiology & Behavior · doi:10.1016/j.physbeh.2024.114534 · Cited by 5
Jenkins, K. C., Koning, K. M., Mehzad, A., LaRocco, J., Jimmy, J., Toleson, S., Reeves, K. C., Gorka, S. M., & Phan, K. L. (2025) · Frontiers in Neuroimaging · doi:10.3389/fnimg.2025.1580623 · Cited by 5
Self-citationTuman, T. C., YILDIRIM, O., & Tufan, A. E. (2021) · Journal of Surgery and Medicine · doi:10.28982/josam.922612 · Cited by 5
Neural Circuits Underlying Social Fear in Rodents: An Integrative Computational Model
Alfieri, V., Mattera, A., & Baldassarre, G. (2022) · Frontiers in Systems Neuroscience · doi:10.3389/fnsys.2022.841085 · Cited by 9
“Moreover, oxytocin (OXT), which has pro-social effects and has been proposed as a therapy for SAD (Guastella et al., 2009; Labuschagne et al., 2010), when directly administrated to the LS of mice facilitates social fear extinction (Zoicas et al., 2014; Menon et al., 2018).”
BackgroundInfluentialUtility of Downstream Biomarkers to Assess and Optimize Intranasal Delivery of Oxytocin
DuBois, M. C., Tseng, A., Francis, S. M., Haynos, A. F., Peterson, C. B., & Jacob, S. (2022) · Pharmaceutics · doi:10.3390/pharmaceutics14061178 · Cited by 5
Intranasal delivery of drugs to the central nervous system of adult zebrafish
Galstyan, D. S., Kolesnikova, T. O., Demin, K. A., Dubrovskii, Y. A., Murashko, E. A., Kessenikh, E. D., Ilyin, N. P., Ikrin, A. N., Moskalenko, A. M., de Abreu, M. S., et al. (2025) · Lab Animal · doi:10.1038/s41684-025-01545-0 · Cited by 5
Holmqvist-Jämsén, S., Johansson, A., Westberg, L., Santtila, P. O., von der Pahlen, B., & Simberg, S. (2017) · Journal of Speech Language and Hearing Research · doi:10.1044/2016_jslhr-s-16-0059 · Cited by 6
“OXT attenuates amygdala reactivity (Labuschagne et al., 2010), whereas AVP promotes increased amygdala activation (Herman & Cullinan, 1997; Herman, Ostrander, Mueller, & Figueiredo, 2005).”
BackgroundPharmacological Treatment of Social Anxiety Disorder
Masdrakis, V. G., Turic, D., & Baldwin, D. S. (2013) · Modern trends in psychiatry · doi:10.1159/000351960 · Cited by 5
Becker, B., & Montag, C. (2017) · Studies in neuroscience, psychology and behavioral economics · doi:10.1007/978-3-319-46276-9_18 · Cited by 5
Ledley, D. R., Erwin, B. A., Morrison, A. S., & Heimberg, R. G. (2017) · Psychopathology · doi:10.1002/9781394258949.ch2 · Cited by 5
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Association between salivary oxytocin levels and the amygdala and hippocampal volumes
Shou, Q., Yamada, J., Nishina, K., Matsunaga, M., Matsuda, T., & Takagishi, H. (2022) · Brain Structure and Function · doi:10.1007/s00429-022-02543-5 · Cited by 4
“Exogenous oxytocin studies have demonstrated that amygdala activity is involved in the effect of oxytocin on anxiety regulation (Gorka et al. 2015; Labuschagne et al. 2010; Tops et al. 2007), social cognition (Gamer et al.”
BackgroundBrain Oxytocin is a Main Regulator of Prosocial Behaviour - Link to Psychopathology
Lukas, M., & Inga, N. (2011) · InTech eBooks · doi:10.5772/18841 · Cited by 7
The roles of vasopressin and oxytocin in aggression
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Zhu, X., Zhou, H., Geng, F., Wang, J., Xu, H., & Hu, Y. (2022) · Neuroscience · doi:10.1016/j.neuroscience.2022.12.020 · Cited by 3
Heralding a new era of oxytocinergic research: New tools, new problems?
Althammer, F. (2023) · Journal of Neuroendocrinology · doi:10.1111/jne.13333 · Cited by 4
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Виноградова, Е. П., & Zhukov, D. A. (2018) · Neuroscience and Behavioral Physiology · doi:10.1007/s11055-018-0566-8 · Cited by 4
“Oxytocin weakens the infl uences of stress (novelty, jolting, restraint) on behavior in rodents [8, 10] and humans, for example, after presenting images of angry faces [19] and socially evaluative situations (the Trier test) [7].”
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Socially Anxious Tendencies Affect Autonomic Responses during Eye Gaze Perception
Tsuji, Y., & Shimada, S. (2015) · Psychology · doi:10.4236/psych.2015.613160 · Cited by 4
“However, whether HR is modulated by eye gaze perception in individuals with SAD has not been fully investigated (Wieser, Pauli, Alpers, & Mühlberger, 2009).”
BackgroundInfluentialTranslational Research in Social Anxiety: Summary of Newest Developments and Future Directions
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“These effects were accompanied by a dampening of amygdala activity (Labuschagne et al., 2010; Koch et al., 2016; Frijling, 2017).”
Metadata
- Authors
- Labuschagne, I., Phan, K. L., Wood, A., Angstadt, M., Chua, P., Heinrichs, M., Stout, J. C., & Nathan, P. J.
- Affiliations
- Monash University (AU)
- University of Michigan (US)
- Royal Children's Hospital (AU)
- University of Freiburg (DE)
- University of Cambridge (GB)
- Corresponding author
- Nathan, Pradeep J
- ORCID
- Venue
- Neuropsychopharmacology
- Published
- 2010-08-18
- Volume
- 35
- Issue
- 12
- Pages
- 2403-2413
- ISSN
- 0893-133X (ISSN-L)
- 1740-634X
- PMC
- PMC3055328
- OpenAlex
- W2116280488
- Cited by
- 549
- References
- 91
- Citations by year
- 2026: 14 · 2025: 13 · 2024: 20 · 2023: 62 · 2022: 22 · 2021: 22 · 2020: 47 · 2019: 27 · 2018: 35 · 2017: 48 · 2016: 37 · 2015: 54 · 2014: 44 · 2013: 43 · 2012: 28
- FWCI
- 45.04
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Neuropsychopharmacology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Research Bank (Australian Catholic University) (submittedVersion)
- Own your potential (DEAKIN) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- FreiDok plus (Universitätsbibliothek Freiburg) (submittedVersion)
- Aston Publications Explorer (Aston University) (submittedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
- Funders
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (114788)
- National Institute of Mental Health (MH076198, K23MH076198)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Neuroendocrine regulation and behavior
- Social Sciences › Psychology › Experimental and Cognitive Psychology › Anxiety, Depression, Psychometrics, Treatment, Cognitive Processes
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Keywords
- oxytocin, generalized social anxiety disorder, amygdala reactivity, fear, emotional face processing, amygdala hyperactivity, intranasal administration, social danger
- MeSH terms
- Administration, Intranasal, Adult, Amygdala, Anxiety Disorders, Brain Mapping, Double-Blind Method, Facial Expression, Fear, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Oxytocin, Placebos, Psychomotor Performance
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