Oxytocin increases anxiety to unpredictable threat
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Written from the paper’s full text.
TL;DR
In a double-blind within-subjects startle study, oxytocin increased defensive responding to unpredictable but not predictable shocks in humans. The authors report this as the first evidence that oxytocin can be anxiogenic, suggesting it enhances anxiety under uncertainty.
Key findings
- Oxytocin significantly increased defensive responses to unpredictable shocks compared with placebo (F(1,42) = 5.1, P < 0.03) and with arginine vasopressin (F(1,42) = 6.6, P < 0.01).
- Defensive responses to predictable shocks were not affected by treatment (F(2,84) = 0.02, NS).
- The authors conclude that oxytocin selectively enhances anxiety to unpredictable threat, possibly via BNST/CRF signaling, and suggest this may help explain context-dependent social effects toward in-group versus out-group members.
Methods
- Double-blind randomized within-subjects design; 43 subjects were tested across three sessions with placebo, oxytocin, arginine vasopressin, and placebo (PLC).
- Startle reactivity was assayed in three conditions: no shock, predictable shocks administered only during threat cues, and unpredictable shocks administered randomly.
- Main analysis compared treatment effects on startle potentiation using F tests; methods are said to be fully described in Supplementary Information.
Limitations
- Stated: the failure to detect an AVP effect might reflect too low an AVP dose, oxytocin acting via oxytocin receptors rather than AVP receptors, or differential OT/AVP effects on brainstem pathways mediating anxiety components.
- Stated: the findings do not directly inform oxytocin’s pro-social effects, and the authors caution it is too early to speculate about therapeutic use for socio-emotional disorders.
- Evident: the main text gives only a brief methods summary and refers to Supplementary Information; no effect sizes or confidence intervals are reported in the main text.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
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Cites
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Claims the paper makes
0 of 20 cited sources checked · 0 supported · 0 flagged
- Findingown data§ Oxytocin increases anxiety to unpredictable threat
Treatment did not alter defensive responses to predictable shocks in humans.
“Defensive responses to predictable shocks were not affected by treatment (F(2,84) = 0.02, NS), suggesting that threat unpredictability is a critical factor underlying OT’s effects.”
Quote in the paperSubstantial claim - Findingown data§ Oxytocin increases anxiety to unpredictable threat
In humans, oxytocin administration increased defensive responses to unpredictable shocks relative to both placebo and arginine vasopressin.
“Defensive responses to unpredictable shocks were significantly increased by OT compared with both PLC (F(1,42) = 5.1, P<0.03) and AVP (F(1,42) = 6.6, P<0.01), demonstrating selectivity in OT effects on anxiety.”
Quote in the paperSubstantial claim - Interpretationown data§ Oxytocin increases anxiety to unpredictable threat
The unpredictability of a threat is a key factor behind oxytocin's effects on defensive responding.
“suggesting that threat unpredictability is a critical factor underlying OT’s effects.”
Quote in the paperSubstantial claim - Interpretationcitation§ Oxytocin increases anxiety to unpredictable threat
Rodent evidence that oxytocin directly activates corticotrophin releasing factor neurons and facilitates excitatory signaling in the BNST can account for the partial dissociation in oxytocin's effects on responses to predictable versus unpredictable shocks.
“The partial dissociation in the effect of OT on defensive responses to predictable and unpredictable shocks can be explained by evidence in rodents that OT facilitates excitatory signaling in a structure that underlies sustained anxiety-like behavior to uncertainty, the BNST,7,8 by directly activating corticotrophin releasing factor neurons.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [7] Dabrowska J, Hazra R, Ahern TH, Guo J-D, McDonald AJ, Mascagni F et al. Psychoneuroendocrinol 2011; 36: 1312–1326. source
Not checked in the free run.
- cites [8] Knobloch HS, Charlet A, Hofmann L, Eliava M, Khrulev S, Cetin AH et al. Neuron 2012; 73: 553–566. source
Not checked in the free run.
- Interpretationown data§ Oxytocin increases anxiety to unpredictable threat
Oxytocin makes defensive responses more sensitive under conditions of ambiguity or uncertainty.
“Our data suggest that OT sensitizes such responses in the face of ambiguity/uncertainty”
Quote in the paperSubstantial claim
- Premisecitation§ Oxytocin increases anxiety to unpredictable threat
Oxytocin originating in the hypothalamic paraventricular nucleus promotes excitatory signaling in the BNST.
“OT released from the paraventricular nucleus of the hypothalamus facilitates excitatory signaling in the bed nucleus of the stria terminalis (BNST),7,8”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [7] Dabrowska J, Hazra R, Ahern TH, Guo J-D, McDonald AJ, Mascagni F et al. Psychoneuroendocrinol 2011; 36: 1312–1326. source
Not checked in the free run.
- cites [8] Knobloch HS, Charlet A, Hofmann L, Eliava M, Khrulev S, Cetin AH et al. Neuron 2012; 73: 553–566. source
Not checked in the free run.
- Premisecitation§ Oxytocin increases anxiety to unpredictable threat
Administering oxytocin systemically leaves fear-potentiated startle to a threat cue unchanged.
“systemic OT administration does not affect fear-potentiated startle to a threat cue.9”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [9] Missig G, Ayer LW, Schulkin J, Rosen JB . Neuropsychopharmacol 2010; 35: 2607–2616. source
Not checked in the free run.
- Premisecitation§ Oxytocin increases anxiety to unpredictable threat
Within the rodent central amygdala, oxytocin receptor density differs across subdivisions.
“OT receptor density varies by subdivision within the central nucleus of the rodent amygdala (CeA)4,6”
Quote in the paperSubstantial claim0 of 2 sources checked - Interpretationreasoning§ Oxytocin increases anxiety to unpredictable threat
In humans, oxytocin does not create social bonds de novo.
“it does not create bonds de novo (for example, between strangers)”
Quote in the paperSubstantial claim - Interpretationreasoning§ Oxytocin increases anxiety to unpredictable threat
Oxytocin is better characterized as an 'us and them' molecule than as a 'love' or 'moral' molecule.
“implying that it is less of a ‘love’ or ‘moral’ molecule than an ‘us and them’ molecule2”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [2] De Dreu CKW, Greer LL, Handgraaf MJJ, Shalvi S, Van Kleef GA, Baas M et al. Science 2010; 328: 1408–1411. source
Not checked in the free run.
- Premisecitation§ Oxytocin increases anxiety to unpredictable threat
Endogenous oxytocin in rodents decreases freezing in response to a fear-conditioned cue.
“while in rodents endogenous OT reduces freezing to a fear conditioned cue,8”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [8] Knobloch HS, Charlet A, Hofmann L, Eliava M, Khrulev S, Cetin AH et al. Neuron 2012; 73: 553–566. source
Not checked in the free run.
- Premisecitation§ Oxytocin increases anxiety to unpredictable threat
The BNST plays a key role in defensive reactions to threats that are unpredictable.
“a critical structure mediating defensive responses to unpredictable threats.5”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [5] Davis M, Walker DL, Miles L, Grillon C . Neuropsychopharmacol 2010; 35: 105–135. source
Not checked in the free run.
- Premisecitation§ Oxytocin increases anxiety to unpredictable threat
Oxytocin boosts anti-social behaviors towards unfamiliar individuals.
“OT boosts anti-social behaviors towards unfamiliar individuals.2,3”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation§ Oxytocin increases anxiety to unpredictable threat
Different subdivisions of the rodent central amygdala contribute differently to defensive reactions to predictable fear versus unpredictable anxiety threats.
“these subdivisions are differentially involved in defensive responses to predictable (fear) and unpredictable threats (anxiety).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [5] Davis M, Walker DL, Miles L, Grillon C . Neuropsychopharmacol 2010; 35: 105–135. source
Not checked in the free run.
- Classified as probably not a substantial claim. 7
- The quote only partly states this claim. 1
- May combine two claims. 3
Classified as probably not a substantial claim.
Interpretationreasoning§ Oxytocin increases anxiety to unpredictable threatAnxiety caused by oxytocin could account for the different ways oxytocin influences reactions to familiar in-group versus unfamiliar out-group members.
“Although the finding of increased anxiety following OT administration does not directly inform on OT’s pro-social effects, it may explain why OT affects responses to in-group (familiar) and out-group (unfamiliar) members differently.2,3”
Quote in the paperSubstantial claim0 of 2 sources checkedClassified as probably not a substantial claim.
Interpretationreasoning§ Oxytocin increases anxiety to unpredictable threatIf this sensitization is applied to social situations, it would encompass people who are unfamiliar.
“which, when extended to the social domain, would include unfamiliar individuals whose behavior is inherently unpredictable.”
Quote in the paperSubstantial claim- Rests on an assumption: Unfamiliar individuals' behavior is inherently unpredictable.
The quote only partly states this claim.
Interpretationown data§ Oxytocin increases anxiety to unpredictable threatOxytocin enhances anxiety in humans.
“suggesting that OT enhances anxiety.”
- Also stated in: § Oxytocin increases anxiety to unpredictable threat · plain
“This is the first evidence that OT can be anxiogenic in humans.”
Quote in the paperSubstantial claim- Also stated in: § Oxytocin increases anxiety to unpredictable threat · plain
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Interpretationnone given§ Oxytocin increases anxiety to unpredictable threatOxytocin might reinforce already established human relationships, possibly lowering anxiety as a secondary effect.
“Although in humans OT may strengthen existing social bonds (for example, between relatives/friends), perhaps reducing anxiety secondarily”
Quote in the paperNot a substantial claimMay combine two claims.
Premisecitation§ Oxytocin increases anxiety to unpredictable threatIn the central amygdala, the medial part relates to fear and the lateral part to anxiety, and only the lateral part has abundant oxytocin receptors.
“The medial CeA (mCeA) and lateral CeA (lCeA) are involved in fear and anxiety,5 respectively, but only the lCeA is rich in OT receptors.6”
Quote in the paperSubstantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ Oxytocin increases anxiety to unpredictable threatIn animals, oxytocin can lessen anxiety-like behavior through its modulatory action on the amygdala.
“Indeed, OT can reduce anxiety-like behavior in animals, via its neuromodulatory influence on the amygdala, a core hub mediating fear and anxiety.4”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [4] Viviani et al. Science 2011; 333: 104–107. source
Not checked in the free run.
Classified as probably not a substantial claim.
Study design and conductcitation§ Oxytocin increases anxiety to unpredictable threatStartle reactivity is an established measure of aversive state.
“We assayed startle reactivity, a well-established index of aversive state,5”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [5] Davis M, Walker DL, Miles L, Grillon C . Neuropsychopharmacol 2010; 35: 105–135. source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation§ Oxytocin increases anxiety to unpredictable threatOxytocin encourages territoriality, aggression, and other defensive actions directed at out-group members.
“OT also promotes territoriality, aggression and other defensive behaviors toward out-group members,2”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [2] De Dreu CKW, Greer LL, Handgraaf MJJ, Shalvi S, Van Kleef GA, Baas M et al. Science 2010; 328: 1408–1411. source
Not checked in the free run.
Classified as probably not a substantial claim.
Study design and conductown data§ Oxytocin increases anxiety to unpredictable threatThe study used a double-blind randomized within-subjects design.
“Using a double-blind randomized within-subjects design, we administered placebo, OT, the structurally-related neuropeptide arginine vasopressin (AVP), and placebo (PLC) to 43 subjects in three sessions.”
Quote in the paperSubstantial claim
The paper relies on this without support.
Unfamiliar individuals' behavior is inherently unpredictable.
“unfamiliar individuals whose behavior is inherently unpredictable.”
The paper relies on this without support.
Anxiety serves as an adaptive defense against unpredictable threats.
“Anxiety is an adaptive defensive response to unpredictable threat.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
There is mounting evidence that oxytocin has anxiogenic and fear-enhancing effects.
“However, against the background of mounting evidence for anxiogenic and fearenhancing OXT effects (33,43,44), it is necessary that the mechanisms determining the outcome of an OXT treatment are completely identified.”
From Oxytocin enhances brain reward system responses in men viewing the face of their female partner (2013) · cites this paper as [44]
In “Oxytocin increases anxiety to unpredictable threat” (page not provided), the authors report increased defensive responses to unpredictable shocks and describe this as evidence that oxytocin can be anxiogenic in humans. The same results say responses to predictable shocks were not affected, so this paper does not support the fear-enhancing part of the claim. (LLM, conf=0.88)
Experimental — accuracy not yet measuredExogenous OXT can have anxiogenic effects in humans exposed to social stimuli.
“Likewise, exogenous OXT can have anxiogenic effects in humans exposed to social stimuli (Bartz et al., 2010; Striepens et al., 2012; Grillon et al., 2013; MacDonald et al., 2013).”
From Sex-specific modulation of juvenile social play behavior by vasopressin and oxytocin depends on social context (2014) · cites this paper as Grillon et al., 2013
In “Oxytocin increases anxiety to unpredictable threat” (page not supplied), the authors report increased defensive responses after oxytocin administration in humans. The experiment used unpredictable electric shocks, not social stimuli; the paper discusses social contexts only as a possible extension of its findings. (LLM, conf=0.88)
Experimental — accuracy not yet measuredIndividual differences in anxiety psychopathology influencing oxytocin have likely contributed to some of the mixed findings in the oxytocin literature.
“It is likely that this phenomenon has contributed to some of the mixed findings in the OXT literature (see Meyer-Lindenberg et al, 2011;but also Grillon et al, 2013).”
From Oxytocin modulation of amygdala functional connectivity to fearful faces in generalized social anxiety disorder (2015) · cites this paper as Grillon et al, 2013
Intranasal oxytocin may increase startle responses to stressful stimuli in humans.
“intranasal oxytocin may increase startle responses to stressful stimuli in humans (Grillon et al., 2013; Striepens et al., 2012)”
From Approaching the biology of human parental attachment: Brain imaging, oxytocin and coordinated assessments of mothers and fathers (2014) · cites this paper as Grillon et al., 2013
Four studies investigated the effects of intranasal oxytocin on the physiological response to generally threatening stimuli, including angry faces, images of threatening scenes, and predictable and unpredictable electric shocks.
“Four studies investigated the effects of intranasal oxytocin on the physiological response to generally threatening stimuli, including angry faces, images of threatening scenes, and predictable and unpredictable electric shocks (Grillon et al., 2013;Leknes et al., 2013;Prehn et al., 2013;Striepens et al., 2012).”
From Meta-analytic review of the effects of a single dose of intranasal oxytocin on threat processing in humans (2018) · cites this paper as Grillon et al., 2013
Statistics that don’t add up
Each reported p-value recomputed from its test statistic and degrees of freedom.
p-value fits an unstated one-tailed test: F(1,42) = 6.6, p < .01
MinorThe paper reports p < .01 here; recomputing from the test statistic and its degrees of freedom gives p = .014. The reported value is what a one-tailed test gives, but the paper does not say near this result that a one-tailed test was used.
Reported p < .01 · recomputed p = .014
“F(1,42) = 6.6, P<0.01”
Statistics recomputed
Every reported test result, recomputed from its test statistic and degrees of freedom. A result shows as not adding up only once an independent check has confirmed it.
- Doesn’t add upF(1, 42) = 6.6reported p < .01 · recomputed p = .014
“F(1,42) = 6.6, p < .01”
- ConsistentF(1, 42) = 5.1reported p < .03 · recomputed p = .029
“F(1,42) = 5.1, p < .03”
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Self-check results appear here once an independent check has confirmed them.
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Self-citationThe Neuropeptide Oxytocin Regulates Parochial Altruism in Intergroup Conflict Among Humans
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Evoked axonal oxytocin release in the central amygdala attenuates fear response
Knobloch, H. S., Charlet, A., Hoffmann, L. C., Eliava, M., Khrulev, S., Cetin, A. H., Osten, P., Schwarz, M. K., Seeburg, P. H., Stoop, R., et al. (2012) · Neuron · doi:10.1016/j.neuron.2011.11.030 · Cited by 1,049 · see citing works
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Self-citationOxytocin Selectively Gates Fear Responses Through Distinct Outputs from the Central Amygdala
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Oxytocin Reduces Background Anxiety in a Fear-Potentiated Startle Paradigm
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The oxytocin receptor: from intracellular signaling to behavior
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“For example, inOT increased the probability of aggression among high trait aggression people towards an intimate partner, as self-disclosed by participants, following a provocation task (16), and that OT increases anxiety to unpredictable threat (56).”
Oxytocin in general anxiety and social fear: a translational approach
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Oxytocin enhances brain reward system responses in men viewing the face of their female partner
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“Proc Natl Acad Sci USA 109(44):18144–18149.”
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“Second, oxytocin-biased biobehavioral approach avoidance fits evidence that intranasal oxytocin potentiates startle reactivity to threat stimuli, especially when these are unpredictable (35,56,64) and the growing evidence that oxytocin prepares for and enables aggressive responding to threat, especially threat to offs…”
BackgroundSwain, J. E., Kim, P., Spicer, J., Ho, S. S., Dayton, C. J., Elmadih, A., & Abel, K. M. (2014) · Brain Research · doi:10.1016/j.brainres.2014.03.007 · Cited by 290 · see citing works
“For example, we observe that intranasal oxytocin may increase startle responses to stressful stimuli in humans (Grillon et al., 2013; Striepens et al., 2012) and that less anxiously attached, healthy men remember their mother as more caring and close after OT (vs.”
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“However, there also has been evidence that the effects of oxytocin are context-dependent, and under some conditions, oxytocin can lead to negative relational behaviors such as gloating (e.g., Bartz et al., 2011; Grillon et al., 2013; Olff et al., 2013; Shamay-Tsoory et al., 2009).”
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“Some negative effects of OT on social behaviors may be due to the peptide’s ability to produce anxiogenic effects, such as increasing startle response and memory of negative stimuli (Striepens et al., 2012; Grillon et al., 2013).”
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“This hypothesis is concordant with recent findings that oxytocin administration increases anxiety in the context of unpredictable threats (Grillon et al., 2013), and with the associations between oxytocin and relationship distress that are discussed in more detail in Section VI.”
BackgroundResultBrown, S. L., & Brown, R. M. (2015) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2015.04.004 · Cited by 190 · see citing works
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Advances in human oxytocin measurement: challenges and proposed solutions
Tabak, B. A., Leng, G., Szeto, A., Parker, K. J., Verbalis, J. G., Ziegler, T. E., Lee, M. R., Neumann, I. D., & Mendez, A. J. (2023) · Molecular Psychiatry · doi:10.1038/s41380-022-01719-z · Cited by 170 · see citing works
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“Likewise, exogenous OXT can have anxiogenic effects in humans exposed to social stimuli (Bartz et al., 2010; Striepens et al., 2012; Grillon et al., 2013; MacDonald et al., 2013).”
BackgroundRoles of Oxytocin in Stress Responses, Allostasis and Resilience
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“Moreover, intranasal oxytocin increases anxiety to unpredictable threat in healthy humans, which, when extended to the social domain, would include unfamiliar individuals whose behavior is inherently unpredictable (Grillon et al., 2013).”
Oxytocin׳s role in anxiety: A critical appraisal
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“In the current study, the beginning of a new Fear Potentiated Startle (FPS) session (extinction training) may have elicited a sense of uncertainty regarding the CS-US contingency, resulting in increased potentiated startle responses in the OT group as shown by Grillon et al. (2012).”
InfluentialSex differences in fear extinction
Velasco, E. R., Florido, A., Milad, M. R., & Andero, R. (2019) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2019.05.020 · Cited by 125 · see citing works
“They regulate stress, social behavior and can shape defensive responses, especially to unpredictable threats (Dębiec, 2005; Grillon et al., 2013; Leppanen et al., 2018; MeyerLindenberg et al., 2011; Neumann, 2008).”
BackgroundOverview of human oxytocin research
Kendrick, K. M., Guastella, A. J., & Becker, B. (2017) · Current Topics in Behavioral Neurosciences · doi:10.1007/7854_2017_19 · Cited by 121 · see citing works
Sex-specific effects of stress on oxytocin neurons correspond with responses to intranasal oxytocin
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“All of the behavior tests described up to this point have used unfamiliar stimulus animals, and this may be an important factor because OT has more anxiogenic properties in ambiguous contexts (46).”
Gorka, S. M., Fitzgerald, D. A., Labuschagne, I., Hosanagar, A., Wood, A. G., Nathan, P. J., & Phan, K. L. (2015) · Neuropsychopharmacology · doi:10.1038/npp.2014.168 · Cited by 131 · see citing works
“It is likely that this phenomenon has contributed to some of the mixed findings in the OXT literature (see Meyer-Lindenberg et al, 2011; but also Grillon et al, 2013).”
ResultIntranasal oxytocin selectively attenuates rhesus monkeys’ attention to negative facial expressions
Parr, L. A., Modi, M., Siebert, E., & Young, L. J. (2013) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2013.02.011 · Cited by 124 · see citing works
“Therefore, it may be that IN-OT only affects the perception of the most arousing categories of stimuli, those being the most salient like aversive or threatening images, particularly if the threat is unexpected (Grillon et al., 2012).”
BackgroundOxytocin facilitates the sensation of social stress
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“This prosocial profile of OXT contrasts sharply with recent observations of anxiogenic effects of OXT treatment (Grillon et al., 2013; Guzman et al., 2013; Striepens et al., 2012).”
ResultKoch, S. B. J., van Zuiden, M., Nawijn, L., Frijling, J. L., Veltman, D. J., & Olff, M. (2014) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2013.11.018 · Cited by 123 · see citing works
“electric shocks) was increased after OTadministration compared to AVP and placebo administration (Grillon et al., 2012).”
BackgroundResultBethlehem, R. A. I., Baron-Cohen, S., van Honk, J., Auyeung, B., & Bos, P. A. (2014) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2014.00048 · Cited by 120 · see citing works
“In addition, direct empirical tests of the anxiolytic effects of OXT in humans has shown that oxytocin can increase anxiety toward an unpredictable threat (Grillon et al., 2012).”
BackgroundA Little Anthropomorphism Goes a Long Way
de Visser, E. J., Monfort, S. S., Goodyear, K., Lu, L., O’Hara, M., Lee, M. R., Parasuraman, R., & Krüeger, F. (2017) · Human Factors The Journal of the Human Factors and Ergonomics Society · doi:10.1177/0018720816687205 · Cited by 115 · see citing works
“Various mechanisms have been proposed to explain how oxytocin affects social bonding, including increased affiliative motivation, increased salience toward social stimuli, or a decrease in anxiety (Bartz et al., 2011; Bethlehem et al., 2014; Carter, 2014; Grillon et al., 2013; Kanat et al., 2014).”
BackgroundOxytocin facilitates social approach behavior in women
Preckel, K., Scheele, D., Kendrick, K. M., Maier, W., & Hurlemann, R. (2014) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2014.00191 · Cited by 111 · see citing works
“ORIGINAL RESEARCH ARTICLE published: 27 May 2014 doi: 10.3389/fnbeh.2014.00191 Oxytocin facilitates social approach behavior in women”
ResultInfluentialSteinman, M. Q., Duque-Wilckens, N., & Trainor, B. C. (2019) · Biological Psychiatry · doi:10.1016/j.biopsych.2018.10.008 · Cited by 105 · see citing works
“Indeed, intranasal OT increased anxiety responses in men and women 242 exposed to unpredictable shocks but had no effect when shocks were predictable (111).”
RDoC-based categorization of amygdala functions and its implications in autism
Hennessey, T., Andari, E., & Rainnie, D. G. (2018) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2018.04.007 · Cited by 105 · see citing works
“In healthy controls though, Grillon (2013) found that intranasal OT enhanced startle response after unpredictable shock stress, which suggests that care should be taken in translating OT, it may be most efficacious specifically for anxiety related to social behaviors (Neumann and Slattery, 2016).”
Sabihi, S., Durosko, N. E., Dong, S. M., & Leuner, B. (2014) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2014.03.009 · Cited by 106 · see citing works
“However, OT has also been shown to be anxiogenic depending on certain contextual cues and interindividual factors (Bartz et al., 2011; Tabak et al., 2011; Grillon et al., 2012; Striepens et al., 2012; Kanat et al., 2013).”
BackgroundRole of oxytocin in the control of stress and food intake
Onaka, T., & Takayanagi, Y. (2019) · Journal of Neuroendocrinology · doi:10.1111/jne.12700 · Cited by 98 · see citing works
Oxytocin and stress-related disorders: neurobiological mechanisms and treatment opportunities
Sippel, L. M., Allington, C. E., Pietrzak, R. H., Harpaz-Rotem, I., Mayes, L. C., & Olff, M. (2017) · Chronic Stress · doi:10.1177/2470547016687996 · Cited by 99 · see citing works
“Additional studies of the effects of IN OT on threat perception in PTSD samples are needed, given its role in the development and maintenance of PTSD,(144) OT-related increases in salience processing,(94) and evidence that IN OT increases anxiety to unpredictable threat.(145) IN OT may also have distinct effects at di…”
BackgroundStoop, R. (2014) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2014.09.012 · Cited by 84 · see citing works
Sabihi, S., Dong, S. M., Maurer, S., Goodpaster, C. M., & Leuner, B. (2017) · Neuropharmacology · doi:10.1016/j.neuropharm.2017.06.024 · Cited by 84 · see citing works
“It is also important to consider emerging evidence that OT is not solely involved in reducing fear and anxiety but can also have the opposite action and can increase fear and anxiety (Bartz et al., 2011; Grillon et al., 2013; Guzman et al., 2013; Lahoud and Maroun, 2013; Toth et al., 2012).”
BackgroundRole of oxytocin receptors in modulation of fear by social memory
Guzmán, Y. F., Tronson, N. C., Sato, K., Mesic, I., Guedea, A. L., Nishimori, K., & Radulović, J. (2013) · Psychopharmacology · doi:10.1007/s00213-013-3356-6 · Cited by 79 · see citing works
“Nevertheless, an increasing number of findings also report anxiogenic actions of Oxt (Grillon et al. 2012; Striepens et al. 2012; Tabak et al. 2011).”
BackgroundTheoretical frameworks for human behavioral endocrinology
Roney, J. R. (2016) · Hormones and Behavior · doi:10.1016/j.yhbeh.2016.06.004 · Cited by 80 · see citing works
“…activation of oxytocin neuron axons within the central amygdala likewise reduced fear-conditioned freezing responses (Knobloch et al., 2012; cf. Grillon et al., 2013), and the positive effect of oxytocin onmaternal aggression in rodent females has been interpreted as being secondary to…”
Antisocial oxytocin: Complex effects on social behavior
Beery, A. K. (2015) · Current Opinion in Behavioral Sciences · doi:10.1016/j.cobeha.2015.11.006 · Cited by 74 · see citing works
Oxytocin–Oxytocin Receptor Systems Facilitate Social Defeat Posture in Male Mice
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“In addition to personal factors such as relationship status (Scheele et al., 2012, 2013) and situational factors such as social threat (Grillon et al., 2012; Striepens et al., 2012), familiarity may thus represent another context-dependent variable that critically influences OXT effects (Bartz et…”
BackgroundInfluentialZebrafish oxytocin neurons drive nocifensive behavior via brainstem premotor targets
Wee, C. L., Nikitchenko, M., Wang, W., Luks-Morgan, S. J., Song, E. Y., Gagnon, J. A., Randlett, O., Bianco, I. H., Lacoste, A. M. B., Glushenkova, E., et al. (2019) · Nature Neuroscience · doi:10.1038/s41593-019-0452-x · Cited by 69 · see citing works
Oxytocin promotes intuitive rather than deliberated cooperation with the in-group
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“…Simpson et al., 2014), as well as research showing that oxytocin potentiates startle reactivity to unpredictable threat (Eckstein et al., 2014; Grillon et al., 2013; Striepens et al., 2012) and enables aggressive responding to danger, especially threat to off-spring (so-called maternal…”
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“In contrast to the above studies, Grillon et al. (2013) demonstrated that during fear conditioning, IN OT (24 IU) increased anxiety rather than fear responses in healthy males and females (data from both sexes was combined).”
Frijling, J. L., van Zuiden, M., Koch, S. B. J., Nawijn, L., Veltman, D. J., & Olff, M. (2016) · Social Cognitive and Affective Neuroscience · doi:10.1093/scan/nsv116 · Cited by 62 · see citing works
“A single intranasal OT administration increased startle responses to unexpected shocks (Grillon et al., 2013) and OT administration prior to psychotherapy in male patients with major depressive disorder increased anxiety during the session (MacDonald et al.”
Puglia, M. H., Connelly, J. J., & Morris, J. P. (2018) · Translational Psychiatry · doi:10.1038/s41398-018-0159-x · Cited by 63 · see citing works
Toward a radically embodied neuroscience of attachment and relationships
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“This dissociation between stress and predictability may be shown in oxytocin function: OT is usually associated with anxiolytic effects, but intranasal OT increased anxiety in response to an unpredictable stressor (Grillon et al., 2013).”
BackgroundCortisol and oxytocin show independent activity during chimpanzee intergroup conflict
Samuni, L., Preis, A., Deschner, T., Wittig, R. M., & Crockford, C. (2019) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2019.02.007 · Cited by 54 · see citing works
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Current findings on the role of oxytocin in the regulation of food intake
Spetter, M. S., & Hallschmid, M. (2017) · Physiology & Behavior · doi:10.1016/j.physbeh.2017.03.007 · Cited by 58 · see citing works
Grillon, C., & Monique Ernst, D. (2020) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2020.09.024 · Cited by 55 · see citing works
“…GSK561679 (Grillon et al., 2015), the group II metabotropic glutamate receptor (mGluR2/3) agonist LY354740 (Grillon et al., 2003), oxytocin (Grillon et al., 2013), the norepinephrine alpha-1 (NE-α1) antagonist prazosin (Kaye et al., 2019), and the vasopressin receptor (V1a) antagonist…”
BackgroundInfluentialSelf-citationAn overview of the oxytocin-oxytocin receptor signaling network
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Martial arts increase oxytocin production
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Complexity of oxytocin׳s effects in a chronic cocaine dependent population
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“Also, given recent reports on the pro-anxiety effect of OT in certain contexts (Grillon et al., 2013; Striepens et al., 2012; Macdonald et al., 2013), and the known relationship of anxiety and anger to drug use (Marlatt GA, 85 A.”
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Oxytocin Induces a Conditioned Social Preference in Female Mice
Kent, K., Arientyl, V., Khachatryan, M. M., & Wood, R. I. (2013) · Journal of Neuroendocrinology · doi:10.1111/jne.12075 · Cited by 48 · see citing works
The CRH1 Antagonist GSK561679 Increases Human Fear But Not Anxiety as Assessed by Startle
Grillon, C., Hale, E., Lieberman, L., Davis, A., Pine, D. S., & Ernst, M. (2014) · Neuropsychopharmacology · doi:10.1038/npp.2014.316 · Cited by 47 · see citing works
Self-citationOn the role of oxytocin in borderline personality disorder
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Sexual dimorphism of oxytocin and vasopressin in social cognition and behavior
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“Social context has repeatedly been shown to be an important moderating influence on the effects of OT administration (Declerck et al. 2010; Bartz et al. 2011; Grillon et al. 2013), and future studies of substance use disorder populations should factor this into their design.”
BackgroundLeppanen, J., Ng, K. W., Kim, Y.-R., Tchanturia, K., & Treasure, J. (2018) · Journal of Affective Disorders · doi:10.1016/j.jad.2017.08.041 · Cited by 45 · see citing works
“…ion with 1850- 2500ms ITI) - 0.31 [- 0.83 , 0.21 ] SCT: Avoidanc e (750ms stimulus presentat ion with 1850- 2500ms ITI) 0.03 [- 0.48 , 0.55 ] Grillon et al. 2013 Withi n subje cts (N of days betw een sessi ons NR) 24 IU 55 min Healthy Male = 24 NR Electric shock induced startle during cue…”
BackgroundInfluentialAcheson, D. T., Feifel, D., Kamenski, M., Mckinney, R., & Risbrough, V. B. (2015) · Depression and Anxiety · doi:10.1002/da.22362 · Cited by 44 · see citing works
“OT-induced increases in fear-potentiated startle have also been shown in response to unpredictable threat and negatively valenced social stimuli.[19, 20] In certain contexts OT can also increase social anxiety and perceptions of interpersonal conflict[43–45] and facilitate memory for aversive social events.”
BackgroundXin, F., Zhou, X., Dong, D., Zhao, Z., Yang, X., Wang, Q., Gu, Y., Kendrick, K. M., Chen, A., & Becker, B. (2020) · Advanced Science · doi:10.1002/advs.202001077 · Cited by 46 · see citing works
“some contexts (Grillon et al., 2013; Guzmán et al., 2013; Striepens et al., 2012), suggesting that OXT may produce anxiolytic versus anxiogenic effects depending on the specific context as well as”
Chronic oxytocin-driven alternative splicing of Crfr2α induces anxiety
Winter, J. J., Meyer, M., Berger, I., Royer, M., Bianchi, M., Kuffner, K., Peters, S., Stang, S., Langgartner, D., Hartmann, F., et al. (2021) · Molecular Psychiatry · doi:10.1038/s41380-021-01141-x · Cited by 45 · see citing works
“Consequently, they challenge the concept of treating emotional or social dysfunctions with repetitive or chronic OXT application [40, 49 – 51], and forward sCRFR2 α as a novel target for the development of anxiolytics.”
BackgroundOxytocin and Anxiety Disorders: Translational and Therapeutic Aspects
Naja, W., & Aoun, M. P. (2017) · Current Psychiatry Reports · doi:10.1007/s11920-017-0819-1 · Cited by 40 · see citing works
Oxytocin prevents the increase of cocaine-related responses produced by social defeat
Perez, C. F., Castro‐Zavala, A., Luján, M. Á., Filarowska, J., Ballestín, R., Miñarro, J., Valverde, O., & Rodríguez‐Arias, M. (2018) · Neuropharmacology · doi:10.1016/j.neuropharm.2018.11.011 · Cited by 40 · see citing works
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Williams Syndrome, Human Self-Domestication, and Language Evolution
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“, Cornish, H., and Smith, K. (2015). Compression and communication in the cultural evolution of linguistic structure.”
BackgroundLarval Zebrafish as a Model for Mechanistic Discovery in Mental Health
Tan, J. X. M., Ang, R. J. W., & Wee, C. L. (2022) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2022.900213 · Cited by 35 · see citing works
Oxytocin tempers calculated greed but not impulsive defense in predator–prey contests
Dreu, C. K. W. D., Scholte, H. S., van Winden, F. A. A. M., & Ridderinkhof, K. R. (2014) · Social Cognitive and Affective Neuroscience · doi:10.1093/scan/nsu109 · Cited by 38 · see citing works
“, 2010), potentiates startle reactivity to threat and facilitates protective (neural) responses to aversive stimuli, especially when unpredictable (Striepens et al., 2012; Grillon et al., 2013).”
BackgroundOxytocin and emotion processing
Simplicio, M. C. D., & Harmer, C. J. (2016) · Journal of Psychopharmacology · doi:10.1177/0269881116641872 · Cited by 38 · see citing works
“, 2014) and other measures of stress reactivity unrelated to social stimuli (for a review see Neumann and Slattery, 2016); however, there are also accounts of oxytocin-induced increases in anxiety (Grillon et al., 2013).”
BackgroundThe influence of Oxytocin on automatic motor simulation
Coster, L. D., Mueller, S. C., T'Sjoen, G. G., Saedeleer, L. D., & Braß, M. (2014) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2014.08.021 · Cited by 37 · see citing works
The Role of Intranasal Oxytocin in the Treatment of Patients with Schizophrenia: A Systematic Review
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“…responses to fear-evoking stimuli 22–24 , consistent with it facilitating either tolerance or avoidance of negative emotional situations, it can in some circumstances enhance reactivity towards and memory for them and therefore potentially trigger greater approach and conciliatory behavior 25,26 .”
Social Behavior of Pet Dogs Is Associated with Peripheral OXTR Methylation
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“…that the pyrosequencing technique used for DNA methylation assessment is not suitable for differentiating between 5-methylcytosines and 5-hydroxymethylcytosines (Guibert and Weber, 2013), so it cannot be ascertained yet if (some of) the observed relationships are not linked to hydroxymethylation.”
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From Oxytocin to Compassion: The Saliency of Distress
Kucerova, B., Levit‐Binnun, N., Gordon, I., & Golland, Y. (2023) · Biology · doi:10.3390/biology12020183 · Cited by 35 · see citing works
“Accordingly, oxytocin administration increased anxiety regarding unpredictable threats [52] and potentiated stress”
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“Those studies found increased aggression toward game partners in the “social orientation paradigm” (38), increased envy and schadenfreude or gloating in a game of chance (39), and even increased anxiety, indicated by an enhanced startle response after unpredictable threats (40).”
BackgroundKrimberg, J. S., Lumertz, F. S., Orso, R., Viola, T. W., & de Almeida, R. M. M. (2022) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2022.104549 · Cited by 33 · see citing works
Oxytocin and Facial Emotion Recognition
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“Acoustic startle response Higher with higher oxytocin (Striepens et al., 2012; Grillon et al., 2013) Higher in WS (Gallo et al.”
Oxytocin and vasopressin modulate risk-taking
Patel, N., Grillon, C., Pavletic, N., Rosen, D., Pine, D. S., & Ernst, M. (2015) · Physiology & Behavior · doi:10.1016/j.physbeh.2014.11.018 · Cited by 29 · see citing works
“P A A uthor M anuscript participants completed another independent study (Grillon et al., 2013).”
BackgroundInfluentialRazo, R. A., Berger, T., Conley, A. J., Freeman, S. M., Goetze, L. R., Jacob, S., Lawrence, R. H., Mendoza, S. P., Rothwell, E. S., Savidge, L. E., et al. (2019) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2019.104494 · Cited by 28 · see citing works
“Anxiogenic effects have also been reported in humans after IN OXT exposure (Bartz et al., 2010; Grillon, 2013; MacDonald et al., 2013) Psychoneuroendocrinology.”
BackgroundActivation of septal OXTr neurons induces anxiety- but not depressive-like behaviors
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Oxytocin for learning calm and safety
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Oxytozin: Evidenz für ein therapeutisches Potenzial des sozialen Neuromodulators
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Oxytocin Ameliorates Impaired Behaviors of High Fat Diet-Induced Obese Mice
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Therapeutic uses of oxytocin in stress-related neuropsychiatric disorders
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“But there are growing evidences presented that OXT some-times cannot attenuate the anxiety behavior and even led to an increase in social anxiety and aggressive behaviors [94, 95].”
BackgroundThe effects of adjunctive intranasal oxytocin in patients with schizophrenia
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“[55], there are also numerous reports of negative social effects, such as abhorrence [42], envy [56], and anxiety to unpredictable threat [57].”
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Intimate Relationships across Cultures: A Comparative Study
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Plasma oxytocin and personality traits in psychiatric outpatients
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- Authors
- Grillon, C., Krimsky, M., Charney, D. R., Vytal, K., Ernst, M., & Cornwell, B.
- Affiliations
- National Institute of Mental Health (US)
- Corresponding author
- Grillon, C
- ORCID
- Venue
- Molecular Psychiatry
- Published
- 2012-11-13
- Volume
- 18
- Issue
- 9
- Pages
- 958-960
- ISSN
- 1359-4184 (ISSN-L)
- 1476-5578
- PMC
- PMC3930442
- OpenAlex
- W2093394479
- Cited by
- 192
- References
- 10
- Citations by year
- 2026: 8 · 2025: 9 · 2024: 2 · 2023: 4 · 2022: 8 · 2021: 12 · 2020: 12 · 2019: 35 · 2018: 17 · 2017: 18 · 2016: 12 · 2015: 17 · 2014: 19 · 2013: 18
- FWCI
- 26.06
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute of Mental Health (ZIAMH002798, Z01MH002798)
- Topics
- Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Keywords
- oxytocin, anxiety, unpredictable threat, threat appraisal, fear conditioning, social stress
- MeSH terms
- Acoustic Stimulation, Animals, Antidepressive Agents, Anxiety, Arginine Vasopressin, Cross-Sectional Studies, Disease Models, Animal, Double-Blind Method, Electroshock, Female, Humans, Male, Oxytocin, Predictive Value of Tests, Septal Nuclei
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-08.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-08.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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