Effects of adverse childhood experiences on the association between intranasal oxytocin and social stress reactivity among individuals with cocaine dependence
Open accessAbstract
Background Drug dependence and adverse childhood experiences (ACE) are commonly reflected by dysregulation of the hypothalamic-pituitary-adrenal axis (HPA). Accumulating research indicates that the neuropeptide oxytocin may regulate HPA function, resulting in reductions in neuroendocrine reactivity to social stress among individuals with drug dependence. However, emerging literature suggests that individual differences may differentially impact intranasal oxytocin's effects on human social behaviors.Methods This study employed a double-blind, placebo-controlled design to examine the extent to which ACE influenced the effects of intranasal oxytocin (40IU) on neuroendocrine reactivity to a laboratory social stress paradigm in a sample of 31 cocaine-dependent individuals.Results ACE scores modified the relationship between intranasal oxytocin and cortisol reactivity. While ACE modified the relationship between intranasal oxytocin and DHEA response in a similar direction to what was seen in cortisol, it did not reach statistical significance.Conclusions Findings are congruent with the emerging hypothesis that intranasal oxytocin may differentially attenuate social stress reactivity among individuals with specific vulnerabilities. Future research examining the nuances of intranasal oxytocin's therapeutic potential is necessary.
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TL;DR
This double-blind, placebo-controlled pilot study tested whether adverse childhood experiences (ACE) modify the effects of intranasal oxytocin (40 IU) on neuroendocrine reactivity to a laboratory social stress task in 31 cocaine-dependent individuals. ACE scores significantly modified the relationship between intranasal oxytocin and cortisol reactivity, with a similar but non-significant pattern for DHEA.
Key findings
- ACE scores significantly modified the relationship between intranasal oxytocin and cortisol response to the Trier Social Stress Test (β = 0.30 ± 0.12, t115 = 2.5, p = 0.013).
- In the placebo group, baseline ACE scores were positively associated with cortisol response (β = 0.24 ± 0.09, t115 = 2.5, p = 0.014); this association was attenuated in the oxytocin group (β = 0.09 ± 0.06, t115 = 1.6, p = 0.121). Area under the cortisol response curve was significantly increased in placebo participants (β = 2.7 ± 1.2, t13 = 2.3, p = 0.039) but not in those receiving oxytocin (β = −0.3 ± 0.9, t12 = −0.3, p = 0.748).
- Immediately after the stressor, baseline ACE scores correlated with cortisol in the placebo group (ρ = 0.60, p = 0.015) but not in the oxytocin group (ρ = −0.18, p = 0.515).
- The modifying effect of ACE on the relationship between intranasal oxytocin and DHEA response was similar in direction but did not reach significance (β = 0.19 ± 0.11, t115 = 1.8, p = 0.072). There was no significant overall effect of intranasal oxytocin on cortisol or DHEA response to the TSST (cortisol: Δ = 0.20 ± 0.15, t115 = 1.4, p = 0.166; DHEA: Δ = 0.10 ± 0.13, t115 = 0.8, p = 0.419).
Methods
- Double-blind, placebo-controlled design in 31 cocaine-dependent individuals (mean age 42.6 years, SD 9.2; 83.9% male; 16.1% Caucasian) who were randomized to intranasal oxytocin (40 IU) or placebo and completed the Trier Social Stress Test.
- Salivary cortisol and DHEA were measured at baseline, pre-medication, pre-TSST, immediately post-TSST, and at 5, 30, and 60 minutes post-task. ACE was assessed with the 10-item Adverse Childhood Experiences Survey (Cronbach’s α = .65).
- Linear mixed effects models included treatment assignment, ACE scores, time, pre-medication cortisol/DHEA levels, treatment × time, and treatment × ACE interactions; area under the response curve was calculated with the trapezoidal rule, and Spearman correlations examined ACE–neuroendocrine relationships. Significance was set at two-sided p < 0.05 with no correction for multiple testing.
Limitations
- The paper states the study was exploratory, used a small sample of cocaine-dependent individuals, and lacked healthy control or “no-stress” conditions, so it is unclear whether findings reflect altered HPA sensitivity to intranasal oxytocin in cocaine-dependent subjects with childhood adversity.
- The paper states ACE score distribution was limited: none in the placebo group reported ACE scores greater than three, and none reported ACE scores greater than five, limiting generalizability; ACE internal consistency fell slightly below the traditional cutoff; chronic powder cocaine use may affect rhinoanatomy and intranasal oxytocin absorption; and days abstinent can influence DHEA levels.
- Evident from the text: no correction for multiple testing was applied; the sample was predominantly male and only 16.1% Caucasian, limiting generalizability; and the TSST did not significantly increase cortisol or DHEA, which may have limited power to detect DHEA effects.
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- Findingown data
There is a significant positive association between baseline ACE scores and cortisol response levels in the untreated placebo group (β = 0.24±0.09, t115=2.5, p=0.014).
“Results indicate that there is a significant positive association between baseline ACE scores and cortisol response levels in the untreated placebo group (β = 0.24±0.09, t115=2.5, p=0.014) that were attenuated in those that received intranasal oxytocin (β = 0.09±0.06, t115=1.6, p=0.121).”
Quote in the paperSubstantial claim - Findingown data
Following the stressor (TSST), there was no significant increase in cortisol from the pre-TSST time point (Δ=−0.07±0.07, t115=−1.0, p=0.315).
“Following the stressor (TSST), there was no significant increase in either cortisol or DHEA from the pre-TSST time point (Cortisol: Δ =−0.07±0.07, t115=−1.0, p=0.315 and DHEA: Δ=−0.04±0.06, t115=−0.7, p=0.515; Figure 1).”
Quote in the paperNot a substantial claim - Findingown data
There was no modifying effect of intranasal oxytocin on cortisol response levels immediately following the TSST (Δ=0.20±0.15, t115=1.4, p=0.166).
“Additionally, there was no modifying effect of the administration of intranasal oxytocin on cortisol or DHEA response levels immediately following the TSST (Cortisol: Δ =0.20±0.15, t115=1.4, p=0.166 and DHEA: Δ=0.10±0.13, t115=0.8, p=0.419).”
Quote in the paperSubstantial claim - Findingown data
Following the stressor (TSST), there was no significant increase in DHEA from the pre-TSST time point (Δ=−0.04±0.06, t115=−0.7, p=0.515).
“Following the stressor (TSST), there was no significant increase in either cortisol or DHEA from the pre-TSST time point (Cortisol: Δ =−0.07±0.07, t115=−1.0, p=0.315 and DHEA: Δ=−0.04±0.06, t115=−0.7, p=0.515; Figure 1).”
Quote in the paperNot a substantial claim - Findingown data
Administration of intranasal oxytocin induced a significant decrease in DHEA levels (Δ=−0.40±0.13, t29=−3.2, p=0.004).
“whereas the administration of intranasal oxytocin induced a significant decrease in both cortisol and DHEA levels (Cortisol: Δ=−0.29±0.13, t29=−2.2, p=0.035 and DHEA: Δ=−0.40±0.13, t29=−3.2, p=0.004).”
Quote in the paperNot a substantial claim
- Findingown data
The decrease in cortisol levels was not significantly greater in the oxytocin group compared to the placebo group (Δ=−0.17±0.18, t29=−0.9, p=0.361).
“Although measured neuroendocrine level decreases were greater in the oxytocin group, the difference was not significantly reduced as compared to the placebo group (Cortisol: Δ=−0.17±0.18, t29=−0.9, p=0.361 and DHEA: Δ=−0.29±0.18, t29=−1.6, p=0.114).”
Quote in the paperSubstantial claim - Findingown data
The area under the cortisol response curve following administration of medication/placebo was significantly increased in placebo randomized participants (β = 2.7±1.2, t13=2.3, p=0.039).
“Similarly, the analysis of the area under the cortisol response curve (following administration of medication/placebo) was significantly increased in placebo randomized participants (β = 2.7±1.2, t13=2.3, p=0.039) and not in those receiving intranasal oxytocin (β = −0.3±0.9, t12=−0.3, p=0.748).”
Quote in the paperSubstantial claim - Findingown data
The positive association between baseline ACE scores and cortisol response levels was attenuated in those that received intranasal oxytocin (β = 0.09±0.06, t115=1.6, p=0.121).
“Results indicate that there is a significant positive association between baseline ACE scores and cortisol response levels in the untreated placebo group (β = 0.24±0.09, t115=2.5, p=0.014) that were attenuated in those that received intranasal oxytocin (β = 0.09±0.06, t115=1.6, p=0.121).”
Quote in the paperSubstantial claim - Findingown data
ACE scores had a significant modifying effect on the relationship between intranasal oxytocin administration and cortisol in response to the TSST (β = 0.30±0.12, t115=2.5, p=0.013).
“ACE scores modified the relationship between intranasal oxytocin and cortisol reactivity.”
- Also stated in: § 3.3 Effect of ACE on Neuroendocrine Response to the TSST · plain
“There was a significant modifying effect of ACE scores on the relationship between intranasal oxytocin administration and cortisol in response to the TSST (β = 0.30±0.12, t115=2.5, p=0.013).”
Quote in the paperSubstantial claim - Also stated in: § 3.3 Effect of ACE on Neuroendocrine Response to the TSST · plain
- Findingown data
The area under the cortisol response curve following administration of medication/placebo was not significantly changed in those receiving intranasal oxytocin (β = −0.3±0.9, t12=−0.3, p=0.748).
“Similarly, the analysis of the area under the cortisol response curve (following administration of medication/placebo) was significantly increased in placebo randomized participants (β = 2.7±1.2, t13=2.3, p=0.039) and not in those receiving intranasal oxytocin (β = −0.3±0.9, t12=−0.3, p=0.748).”
Quote in the paperNot a substantial claim - Findingown data
The decrease in DHEA levels was not significantly greater in the oxytocin group compared to the placebo group (Δ=−0.29±0.18, t29=−1.6, p=0.114).
“Although measured neuroendocrine level decreases were greater in the oxytocin group, the difference was not significantly reduced as compared to the placebo group (Cortisol: Δ=−0.17±0.18, t29=−0.9, p=0.361 and DHEA: Δ=−0.29±0.18, t29=−1.6, p=0.114).”
Quote in the paperNot a substantial claim - Findingown data
In response to the administration of the study drug (pre-TSST), there was a significant decrease in measured cortisol levels in the study cohort (Δ=−0.21±0.09, t29=−2.3, p=0.032).
“In response to the administration of the study drug (pre-TSST), there was a significant decrease in measured neuroendocrine levels in the study cohort (Cortisol: Δ=−0.21±0.09, t29=−2.3, p=0.032 and DHEA: Δ=−0.26±0.09, t29=−2.9, p=0.007).”
Quote in the paperNot a substantial claim - Findingown data
Administration of intranasal oxytocin induced a significant decrease in cortisol levels (Δ=−0.29±0.13, t29=−2.2, p=0.035).
“whereas the administration of intranasal oxytocin induced a significant decrease in both cortisol and DHEA levels (Cortisol: Δ=−0.29±0.13, t29=−2.2, p=0.035 and DHEA: Δ=−0.40±0.13, t29=−3.2, p=0.004).”
Quote in the paperSubstantial claim - Findingown data
There was no modifying effect of intranasal oxytocin on DHEA response levels immediately following the TSST (Δ=0.10±0.13, t115=0.8, p=0.419).
“Additionally, there was no modifying effect of the administration of intranasal oxytocin on cortisol or DHEA response levels immediately following the TSST (Cortisol: Δ =0.20±0.15, t115=1.4, p=0.166 and DHEA: Δ=0.10±0.13, t115=0.8, p=0.419).”
Quote in the paperNot a substantial claim - Findingown data
In response to the administration of the study drug (pre-TSST), there was a significant decrease in measured DHEA levels in the study cohort (Δ=−0.26±0.09, t29=−2.9, p=0.007).
“In response to the administration of the study drug (pre-TSST), there was a significant decrease in measured neuroendocrine levels in the study cohort (Cortisol: Δ=−0.21±0.09, t29=−2.3, p=0.032 and DHEA: Δ=−0.26±0.09, t29=−2.9, p=0.007).”
Quote in the paperNot a substantial claim - Findingown data
The less robust correlation between ACE scores and DHEA reactivity to the TSST was attenuated among participants in the oxytocin condition.
“Additionally, the less robust correlation between ACE scores and DHEA reactivity to the TSST was also attenuated among participants in the oxytocin condition.”
Quote in the paperSubstantial claim - Findingown data
There was no effect of the TSST on DHEA levels in the placebo group.
“There was no effect of the TSST on DHEA levels in the placebo group.”
Quote in the paperSubstantial claim - Findingown data
In the oxytocin group, the association between ACE scores and DHEA response was attenuated in a similar manner.
“However, the group receiving intranasal oxytocin was attenuated in a similar manner (β = 0.04±0.05, t115=0.8, p=0.419).”
Quote in the paperNot a substantial claim - Findingown data
The association between ACE scores and DHEA response was not as robust as the cortisol response.
“group was not as robust as was seen in the cortisol response (β = 0.14±0.09, t115=1.6, p=0.110).”
Quote in the paperNot a substantial claim - Findingown data
The positive association between baseline ACE scores and DHEA response to the TSST in the placebo group was not as robust as was seen in the cortisol response (β = 0.14±0.09, t115=1.6, p=0.110).
“The positive association between baseline ACE scores and DHEA response to the TSST in the placebo group was not as robust as was seen in the cortisol response (β = 0.14±0.09, t115=1.6, p=0.110).”
Quote in the paperNot a substantial claim - Findingown data
There was no modifying effect of ACE scores on DHEA levels in response to the TSST.
“In contrast to the cortisol findings there was no modifying effect of ACE scores on DHEA levels in response to the TSST.”
Quote in the paperSubstantial claim - Findingown data
In cocaine-dependent participants who received placebo, ACE scores were positively correlated with cortisol reactivity to the TSST.
“A significant and positive association between the cortisol responses to the TSST and the number of adverse childhood experiences was found in cocaine-dependent subjects that received placebo.”
- Also stated in: § 3.3 Effect of ACE on Neuroendocrine Response to the TSST · boosted
“there was a strong correlation between baseline ACE scores and cortisol in the group that received placebo (ρ=0.60; p=0.015)”
Quote in the paperSubstantial claim - Also stated in: § 3.3 Effect of ACE on Neuroendocrine Response to the TSST · boosted
- Findingown data
The positive association between ACE scores and cortisol reactivity to the TSST was attenuated in cocaine-dependent participants who received intranasal oxytocin.
“This association was attenuated among participants in the oxytocin condition.”
- Also stated in: § 3.3 Effect of ACE on Neuroendocrine Response to the TSST · plain
“that was attenuated in the group that received oxytocin (ρ=−0.18; p=0.515)”
- Also stated in: § 4.Discussion · plain
“This association was blunted in cocaine-dependent subjects that received intranasal oxytocin.”
Quote in the paperSubstantial claim - Also stated in: § 3.3 Effect of ACE on Neuroendocrine Response to the TSST · plain
- Findingown data
Correlations between baseline ACE scores and DHEA measured following TSST were insignificant in both treatment groups.
“the correlations between baseline ACE scores and DHEA measured following TSST were insignificant in both treatment groups.”
Quote in the paperNot a substantial claim - Findingown data
In the placebo group, the area under the DHEA response curve was not significantly associated with ACE scores.
“the area under the DHEA response curve was not significantly associated with ACE scores in either the placebo (β = 33.9±22.1, t13=1.5, p=0.149) or oxytocin groups (β = −7.2±10.1, t12=−0.7, p=0.492).”
Quote in the paperNot a substantial claim - Findingown data
The remaining time points show similar relationships between ACE scores and cortisol/DHEA levels across treatment groups.
“The remaining time points show similar relationships between ACE scores and cortisol/DHEA levels across treatment groups (Data not shown).”
Quote in the paperNot a substantial claim - Findingown data
In the oxytocin group, the area under the DHEA response curve was not significantly associated with ACE scores.
“the area under the DHEA response curve was not significantly associated with ACE scores in either the placebo (β = 33.9±22.1, t13=1.5, p=0.149) or oxytocin groups (β = −7.2±10.1, t12=−0.7, p=0.492).”
Quote in the paperNot a substantial claim - Findingown data
Intranasal oxytocin had no effect on cortisol levels in response to the TSST.
“We found no effect of intranasal oxytocin on cortisol levels in response to the TSST.”
Quote in the paperSubstantial claim - Premisecitation
Adverse childhood experiences affect drug dependence.
“The effects of adverse childhood experiences (ACE; e.g. physical, psychological, or environmental threats to stable and functional development) on drug dependence (Benjet et al., 2013; Enoch, 2011; Mersky et al., 2013) and HPA axis function are also salient (Carpenter et al., 2011; Heim et al., 2002; MacMillan et al., 2009).”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation
Substance dependence is associated with dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis.
“Abundant research has demonstrated an association between substance dependence and dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis (Clarke et al., 2008; Koob, 2008; Sinha, 2008).”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation
ACE and substance dependence have combined negative effects on stress reactivity in the HPA axis.
“Indeed, recent research illustrates the combined negative effects of ACE and substance dependence on stress reactivity in the HPA axis (Doan et al., in press; Gerra et al., 2014; Schäfer et al., 2010).”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation
Adverse childhood experiences affect HPA axis function.
“The effects of adverse childhood experiences (ACE; e.g. physical, psychological, or environmental threats to stable and functional development) on drug dependence (Benjet et al., 2013; Enoch, 2011; Mersky et al., 2013) and HPA axis function are also salient (Carpenter et al., 2011; Heim et al., 2002; MacMillan et al., 2009).”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationreasoning
The HPA axis may be an important mechanistic link between childhood maltreatment and substance use disorders.
“Thus, the HPA axis may be an important mechanistic link between childhood maltreatment and substance use disorders.”
Quote in the paperSubstantial claim - Premisecitation
The severity of childhood maltreatment is positively associated with greater perceived threat and harm-avoidance coping strategies in cocaine-dependent individuals.
“For example, one study found that the severity of childhood maltreatment was positively associated with greater perceived threat and harm-avoidance coping strategies in cocaine-dependent individuals (Hyman et al., 2007).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Hyman et al., 2007 source
Not checked in the free run.
- Premisecitation
The neuropeptide oxytocin appears to mitigate the effects of stress in individuals with substance use disorders.
“The neuropeptide oxytocin appears to mitigate the effects of stress in individuals with SUDs.”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisereasoning
Perturbations in the HPA axis as a result of ACE play an important role in the development and maintenance of substance use disorders.
“Perturbations in the HPA axis as a result of ACE play an important role in the development and maintenance of SUDs.”
Quote in the paperSubstantial claim - Premisecitation
Exposure to childhood maltreatment is associated with psychological distress in response to aversive psychosocial stimuli among cocaine-dependent individuals.
“Studies of cocaine-dependent individuals have found a significant association between exposure to childhood maltreatment and psychological distress in response to aversive psychosocial stimuli.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Hyman et al., 2007 source
Not checked in the free run.
- Premisecitation
Changes in HPA hormones to a laboratory stress task are associated with higher amounts of cocaine use during relapse episodes in treatment seeking cocaine-dependent individuals.
“Of note, one study of treatment seeking cocaine-dependent individuals found that changes in HPA hormones to a laboratory stress task were associated with higher amounts of cocaine use during relapse episodes (Sinha et al., 2006).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Sinha et al., 2006 source
Not checked in the free run.
- Premisecitation
Alterations in the oxytocin system have been found in adults with a history of childhood maltreatment.
“Interestingly, alterations in the oxytocin system have been found in adults with a history of childhood maltreatment.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Heim et al., 2009 source
Not checked in the free run.
- cites Meinlschmidt and Heim, 2007
Not checked in the free run.
- Study design and conductown data
There were no differences for any baseline demographic or clinical characteristics.
“There were no differences for any baseline demographic or clinical characteristics.”
Quote in the paperNot a substantial claim - Interpretationreasoning
Our findings support the emerging hypothesis that intranasal oxytocin may have more beneficial effects among individuals with existing, or multiple, vulnerabilities.
“Our findings also support the emerging hypothesis that intranasal oxytocin may have more beneficial effects among individuals with existing, or multiple, vulnerabilities.”
Quote in the paperSubstantial claim - Premisecitation
Drug abstinence from six to 18 days can affect DHEA levels in cocaine-dependent subjects.
“drug abstinence from six to 18 days can affect DHEA levels in cocaine-dependent subjects (Buydens-Branchey et al., 2002).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Buydens-Branchey et al., 2002 source
Not checked in the free run.
- Premisecitation
There is significant individual variability in the DHEA response to social stress.
“data from a previous study demonstrates that there is significant individual variability in the DHEA response to social stress (Lennartsson et al., 2012).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Lennartsson et al., 2012 source
Not checked in the free run.
- Premisecitation
Cortisol reactivity in response to stress tasks predicts relapse in cocaine-dependent subjects.
“Cortisol reactivity in response to stress tasks has been shown to predict relapse in cocaine-dependent subjects (Back et al., 2010; Sinha et al., 2006).”
Quote in the paperSubstantial claim0 of 2 sources checked - Interpretationreasoning
Variability in duration of abstinence may have precluded finding a significant effect of the TSST on DHEA reactivity.
“Therefore it is possible that variability in duration of abstinence precluded us from finding a significant effect of the TSST on DHEA reactivity.”
Quote in the paperSubstantial claim- Rests on an assumption: Days abstinent can influence DHEA levels.
- Interpretationreasoning
The present findings suggest that intranasal oxytocin may be beneficial in reducing risk for relapse among cocaine-dependent individuals with a history of childhood maltreatment.
“Thus, the present findings suggest that intranasal oxytocin may be beneficial in reducing risk for relapse among cocaine-dependent individuals with a history of childhood maltreatment.”
Quote in the paperSubstantial claim - Interpretationown data
Findings are congruent with the emerging hypothesis that intranasal oxytocin may differentially attenuate social stress reactivity among individuals with specific vulnerabilities.
“Findings are congruent with the emerging hypothesis that intranasal oxytocin may differentially attenuate social stress reactivity among individuals with specific vulnerabilities.”
Quote in the paperSubstantial claim - Interpretationown data
The generalizability of our findings may be limited.
“Thus, the generalizability of our findings may be limited.”
Quote in the paperNot a substantial claim - Study design and conductown data
The internal consistency of the ACE scale fell slightly below the traditional cutoff in this sample.
“The internal consistency of the ACE scale fell slightly below the traditional cutoff in this sample”
Quote in the paperNot a substantial claim - Interpretationown data
Our findings demonstrate the modifying effects of ACE on the association between intranasal oxytocin and neuroendocrine stress reactivity in a sample of cocaine-dependent individuals.
“Our findings contribute to the existing literature by demonstrating the modifying effects of ACE on the association between intranasal oxytocin and neuroendocrine stress reactivity in a sample of cocaine-dependent individuals.”
Quote in the paperSubstantial claim
- May combine two claims. 13
- Classified as probably not a substantial claim. 37
May combine two claims.
Findingown dataThe modifying effect of ACE scores on the relationship between intranasal oxytocin and the DHEA response was similar in direction to what was seen in cortisol but failed to reach statistical significance (β = 0.19±0.11, t115=1.8, p=0.072).
“While ACE modified the relationship between intranasal oxytocin and DHEA response in a similar direction to what was seen in cortisol, it did not reach statistical significance.”
- Also stated in: § 3.3 Effect of ACE on Neuroendocrine Response to the TSST · plain
“Although the modifying effect of ACE scores on the relationship between intranasal oxytocin and the DHEA response was similar in direction to what was seen in cortisol, it failed to reach statistical significance (β = 0.19±0.11, t115=1.8, p=0.072).”
Quote in the paperNot a substantial claim- Also stated in: § 3.3 Effect of ACE on Neuroendocrine Response to the TSST · plain
May combine two claims.
Findingown dataAmong the 31 participants retained in the sample, none in the placebo group reported ACE scores greater than three, and none reported ACE scores greater than five.
“Among the 31 participants retained in our sample, none in the placebo group reported ACE scores greater than three, and none reported ACE scores greater than five.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationIntranasal oxytocin produces significantly less craving and anxiety to a social stress task than placebo in marijuana-dependent subjects.
“Others have found that intranasal oxytocin produces significantly less craving and anxiety to a social stress task than placebo in marijuana-dependent subjects (Carson et al., 2013; McRae-Clark et al., 2013; Pedersen et al., 2013).”
Quote in the paperNot a substantial claim0 of 3 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationIntranasal oxytocin enhances prosocial and affiliative behaviors in rodents and non-human primates.
“Intranasal oxytocin is also known to enhance prosocial and affiliative behaviors in rodents (Ferguson et al., 2001; Witt et al., 1992) and non-human primates (Chang and Platt, 2013).”
Quote in the paperNot a substantial claim0 of 3 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationCompared with placebo, intranasal oxytocin produces significantly lower symptoms of alcohol withdrawal and anxiety in alcohol-dependent subjects.
“For example, compared with placebo, intranasal oxytocin produced significantly lower symptoms of alcohol withdrawal and anxiety in alcohol-dependent subjects (Pedersen et al., 2013).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Pedersen et al., 2013 source
Not checked in the free run.
May combine two claims.
PremisecitationPostnatal stressors increase the reinforcing properties of drugs of abuse, an effect related to HPA hormones.
“Preclinical studies have found that postnatal stressors increase the reinforcing properties of drugs of abuse, an effect that appears to be related to HPA hormones (Daskalakis and Yehuda, 2015).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Daskalakis and Yehuda, 2015
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationChildhood maltreatment is associated with earlier initiation of illicit drug use.
“Previous studies indicate that childhood maltreatment is associated with earlier initiation of illicit drug use (Nomura et al., 2012)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Nomura et al., 2012 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationChild abuse and maltreatment is more prevalent among cocaine-dependent individuals compared to the general population.
“and that child abuse and maltreatment is more prevalent among cocaine-dependent individuals compared to the general population (Medrano et al., 2002).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Medrano et al., 2002 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationACE increases the risk for the development of substance use disorders.
“Epidemiological studies have found that ACE increases the risk for the development of substance use disorders (SUD)(Anda et al., 2002; Dube et al., 2003).”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationGlucocorticoid receptors are ubiquitous in corticolimbic brain regions that regulate emotion.
“Glucocorticoid receptors are ubiquitous in corticolimbic brain regions that regulate emotion (Aronsson et al., 1988).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Aronsson et al., 1988 source
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationStress is a significant acute and long-term risk factor for drug craving and relapse.
“These data are particularly alarming as stress is a significant acute and long-term risk factor for drug craving and relapse (Back et al., 2010; McKay et al., 1995).”
Quote in the paperSubstantial claim0 of 2 sources checkedClassified as probably not a substantial claim.
PremisecitationIndividual and contextual differences may impact the effects of intranasal oxytocin on social stress reactivity.
“However, recent literature suggests that individual and contextual differences may impact the effects of intranasal oxytocin on social stress reactivity (Bartels, 2012; Bertsch et al., 2012; Campbell and Hausmann, 2013; DeWall et al., 2014).”
Quote in the paperSubstantial claim0 of 3 sources checkedClassified as probably not a substantial claim.
PremisecitationMen with a history of maternal neglect exhibit lower oxytocin regulation of HPA axis hormones than men without a history of maternal neglect.
“Men with a history of maternal neglect exhibit lower oxytocin regulation of HPA axis hormones than men without a history of maternal neglect (Meinlschmidt and Heim, 2007).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Meinlschmidt and Heim, 2007
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenResidual normality was tested using a combination of graphical (Q-Q plots) and statistical tests (Shapiro-Wilk test).
“Residual normality was tested using a combination of graphical (Q-Q plots) and statistical tests (Shapiro-Wilk test).”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductown dataA total of 42 individuals were assessed for eligibility; 35 met requirements and were enrolled and randomized into the study.
“A total of 42 individuals were assessed for eligibility; 35 met requirements and were enrolled and randomized into the study.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationIn non-human primates, oxytocin increased social contact in subordinate males but not in dominant males.
“For example, in a study of non-human primates, oxytocin increased social contact in subordinate males but not in dominant males (Winslow and Insel, 1991).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Winslow and Insel, 1991 source
Not checked in the free run.
Classified as probably not a substantial claim.
Study design and conductreasoningParticipants were assessed at the same time of day (beginning at 11:00 am) to control for diurnal variations in HPA function.
“Participants were assessed at the same time of day (beginning at 11:00 am) to control for diurnal variations in HPA function.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
Study design and conductown dataStudy participants were randomly assigned to intranasal oxytocin (40 IU) or placebo treatment.
“Study participants were randomly assigned to intranasal oxytocin (40 IU) or placebo treatment.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductown dataTotal ACE scores were obtained by summing all items, with a Cronbach's alpha of .65.
“Total scores were obtained by summing all items (Cronbach’s α=.65).”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenWhen model residuals violated assumptions of normality or homoscedasticity, appropriate transformations were used.
“When model residuals were found to violate assumptions of normality or homoscedasticity, appropriate transformations were used.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataThe analysis sample consisted of 31 participants with valid ACE and neuroendocrine data.
“Our analysis sample consisted of 31 participants with valid ACE and neuroendocrine data.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Study design and conductown dataThe study employed a double-blind, placebo-controlled design.
“This study employed a double-blind, placebo-controlled design to examine the extent to which ACE influenced the effects of intranasal oxytocin (40 IU) on neuroendocrine reactivity to a laboratory social stress paradigm in a sample of 31 cocaine-dependent individuals.”
- Also stated in: § 2.3 Procedures · plain
“All medication was dispensed in a double-blind manner.”
Quote in the paperSubstantial claim- Also stated in: § 2.3 Procedures · plain
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationHigher ACE scores are associated with increased risk for physical and mental health problems and functional impairment in adulthood.
“While no specific cutoff scores exist for the ACE, higher are associated with increased risk for physical and mental health problems and functional impairment in adulthood (Anda et al., 2002; Chapman et al., 2004; Dube et al., 2002).”
Quote in the paperNot a substantial claim0 of 3 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductown dataBoth cortisol and DHEA mixed model errors violated model assumptions of residual normality and were transformed using the natural logarithm.
“Both cortisol and DHEA mixed model errors were in violation of model assumptions (residual normality) and were transformed using the natural logarithm.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductnone givenSignificance for all planned pairwise comparisons was set at a two-sided p value of 0.05 and no correction for multiple testing was applied to reported p values.
“Significance for all planned pairwise comparisons was set at a two-sided p value of 0.05 and no correction for multiple testing was applied to reported p values.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Study design and conductreasoningAbstinence from cocaine and other drugs for a minimum of three days prior to study procedures was assessed using self-reports, urine drug screens, and breathalyzer tests.
“Abstinence was assessed using self-reports, urine drug screens (Roche Diagnostics, Indianapolis, Indiana), and breathalyzer tests (AlcoSensor III, Intoximeters, Inc., St. Louis, Missouri).”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductcitationInclusion and exclusion criteria were determined by The Mini-International Neuropsychiatric Interview (MINI) and the substance use module of the Structured Clinical Interview for DSM-IV (SCID-IV).
“Inclusion and exclusion criteria were determined by The Mini-International Neuropsychiatric Interview (MINI; Sheehan et al., 1998b) and the substance use module of the Structured Clinical Interview for DSM-IV (SCID-IV; First et al., 1994).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Sheehan et al., 1998b
Not checked in the free run.
- cites First et al., 1994
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductown dataOf the randomized participants, 32 had valid ACE scores; two participants had missing ACE scores and one participant was excluded due to questionable validity of neuroendocrine values.
“Of the randomized participants, 32 had valid ACE scores; two participants had missing ACE scores and one participant was excluded due to questionable validity of neuroendocrine values.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
PremisecitationWomen with a history of child abuse exhibit lower levels of oxytocin as compared to women without abuse histories.
“For example, women with a history of child abuse exhibit lower levels of oxytocin as compared to women without abuse histories (Heim et al., 2009).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Heim et al., 2009 source
Not checked in the free run.
Probably not a substantial claim: may not pass S1 (asserted).
PremisecitationOne new hypothesis regarding intranasal oxytocin's effects on human behavior suggests that intranasal oxytocin attenuates stress responses more effectively for those with vulnerabilities such as poor coping and emotion regulation skills compared to those equipped with more adaptive stress responses.
“As a result, one new hypothesis regarding intranasal oxytocin’s effects on human behavior suggests that intranasal oxytocin attenuates stress responses more effectively for those with vulnerabilities such as poor coping and emotion regulation skills compared to those equipped with more adaptive stress responses (Bartz et al., 2010; Cardoso et al., 2012; Quirin et al., 2011).”
Quote in the paperNot a substantial claim0 of 3 sources checkedMay combine two claims.
InterpretationcitationIntranasal oxytocin is less likely to influence already adaptive stress responses, whereas individuals with more challenging interpersonal histories who are more prone to maladaptive social stress reactivity are more likely to reap intranasal oxytocin's benefits.
“Perhaps our findings, in combination with those from previous studies (Bartz et al., 2010; Cardoso et al., 2012), indicate that intranasal oxytocin is less likely to influence already adaptive stress responses, whereas individuals with more challenging interpersonal histories who are more prone to maladaptive social stress reactivity are more likely to reap intranasal oxytocin’s benefits.”
Quote in the paperSubstantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe TSST increases DHEA levels in marijuana-dependent subjects.
“the TSST increases DHEA levels in marijuana-dependent subjects”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites McRae-Clark et al., 2013 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe ability to regulate emotions plays a moderating role in HPA responses to social stress.
“Others have found that the ability to regulate emotions plays a similar moderating role in HPA responses to social stress (Allwood et al., 2011; Daubenmier et al., 2014)”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationIntranasal oxytocin appears to attenuate DHEA levels in marijuana-dependent subjects.
“intranasal oxytocin appears to attenuate DHEA levels in these individuals (McRae-Clark et al., 2013).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites McRae-Clark et al., 2013 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationA previous study found that intranasal oxytocin attenuated the normal diurnal reduction in basal levels of cortisol in healthy controls with a history of childhood adversity.
“A previous study found that intranasal oxytocin attenuated the normal diurnal reduction in basal levels of cortisol in healthy controls with a history of childhood adversity (Meinlschmidt and Heim, 2007).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Meinlschmidt and Heim, 2007
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationA previous study found no effect of intranasal oxytocin on cortisol levels in response to the TSST in marijuana-dependent subjects.
“A previous study found no effect of intranasal oxytocin on cortisol levels in response to the TSST in a group of marijuana-dependent subjects (McRae-Clark et al., 2013).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites McRae-Clark et al., 2013 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationSubstance dependence and ACE commonly co-occur.
“Substance dependence and ACE commonly co-occur (Mersky et al., 2013).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Mersky et al., 2013 source
Not checked in the free run.
Classified as probably not a substantial claim.
Study design and conductreasoningOur procedures required participants to be acutely abstinent from drug use to mitigate the potential for drug interaction and the potential confound of intoxication on study findings.
“our procedures required participants to be acutely abstinent from drug use to mitigate the potential for drug interaction and the potential confound of intoxication on study findings.”
Quote in the paperSubstantial claimMay combine two claims.
Study design and conductnone givenThe present study did not include groups of healthy controls or a "no-stress" condition.
“The present study did not include groups of healthy controls or a “no-stress” condition”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenThe study utilized a rigorous double-blind, placebo-controlled design.
“While this study utilized a rigorous double-blind, placebo-controlled design”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
InterpretationcitationChronic powder cocaine use may influence rhinoanatomy and intranasal oxytocin absorption, which may influence the results presented here.
“Chronic powder cocaine use may also influence rhinoanatomy and intranasal oxytocin absorption, which may influence the results presented here (Guastella et al., 2013).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Guastella et al., 2013 source
Not checked in the free run.
Classified as probably not a substantial claim. May combine two claims.
Study design and conductnone givenThe experiment was exploratory and conducted in a small sample of cocaine-dependent individuals.
“the experiment was exploratory and conducted in a small sample of cocaine-dependent individuals.”
Quote in the paperSubstantial claim
The paper relies on this without support.
Translational research focusing on oxytocin is limited by a scarcity of studies aimed at identifying populations for whom intranasal oxytocin may be beneficial.
“Translational research focusing on oxytocin is currently limited by the scarcity of studies aimed at identifying populations for whom intranasal oxytocin may be beneficial.”
The paper relies on this without support.
Studies examining the effects of intranasal oxytocin on social stress reactivity in the context of commonly co-occurring vulnerabilities, such as substance dependence and ACE, are scant.
“One critical gap in this literature is that studies examining the effects of intranasal oxytocin on social stress reactivity in the context of commonly co-occurring vulnerabilities, such as substance dependence and ACE, are scant.”
The paper relies on this without support.
Both cortisol and DHEA are released from the adrenal glands in response to ACTH.
“Both cortisol and DHEA are released from the adrenal glands in response to adrenocorticotropic hormone (ACTH)”
The paper relies on this without support.
Days abstinent can influence DHEA levels.
“we acknowledge that days abstinent can influence DHEA levels, which may have influenced the findings presented here.”
The paper relies on this without support.
No previous studies have examined the effects of intranasal oxytocin on social stress reactivity in the presence of multiple vulnerabilities such as substance dependence and ACE.
“no previous studies have examined the effects of intranasal oxytocin’s effects on social stress reactivity in the presence of multiple vulnerabilities such as substance dependence and ACE.”
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?
The dose and timing of medication administration is based on past research in our group and others.
“The dose and timing of medication administration is based on past research in our group and others (Cardoso et al., 2013; Flanagan et al., 2015; MacDonald et al., 2011).”
From Augmenting Prolonged Exposure therapy for PTSD with intranasal oxytocin: a randomized, placebo-controlled pilot trial (2018) · cites this paper as Flanagan et al., 2015
Oxytocin effects can vary as a function of social context history of childhood maltreatment.
“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 Flanagan et al., 2015
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- Authors
- Flanagan, J. C., Baker, N. L., McRae-Clark, A. L., Brady, K. T., & Moran-Santa Maria, M. M.
- Affiliations
- Medical University of South Carolina (US)
- Corresponding author
- Flanagan, Julianne C.
- Venue
- Psychiatry Research
- Publisher
- Elsevier BV
- Published
- 2015-09
- Volume
- 229
- Issue
- 1-2
- Pages
- 94-100
- ISSN
- 0165-1781 (ISSN-L)
- PMC
- PMC4546857
- OpenAlex
- W1744359224
- Cited by
- 56
- References
- 63
- Citations by year
- 2026: 1 · 2025: 1 · 2023: 3 · 2022: 5 · 2021: 7 · 2020: 7 · 2019: 9 · 2018: 8 · 2017: 9 · 2016: 6
- FWCI
- 12.58
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Psychiatry Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Child Health and Human Development and the Office of Research on Women's Health (K12HD055885)
- National Institute on Drug Abuse (P50DA016511)
- National Center for Advancing Translational Sciences (UL1TR000062)
- Topics
- Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Keywords
- adverse childhood experiences, intranasal oxytocin, cocaine dependence, cortisol response, dehydroepiandrosterone, hypothalamic-pituitary-adrenal axis, neuroendocrine reactivity, individual differences
- MeSH terms
- Administration, Intranasal, Adult, Double-Blind Method, Female, Humans, Hydrocortisone, Hypothalamo-Hypophyseal System, Male, Oxytocin, Pituitary-Adrenal System, Social Behavior, Stress, Psychological, Cocaine-Related Disorders, Adult Survivors of Child Abuse, Young Adult
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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 2026-10-09.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.
Statistics and arithmetic are recomputed, not judged.
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