Acute stress increases circulating anandamide and other N-acylethanolamines in healthy humans

May combine two claims.

Stress significantly increased Anxiety in Caucasians and African Americans but not in Asians.

“Stress significantly increased Anxiety in Caucasians (oneway ANCOVA; p ¼ 0.002, F(1, 42) ¼ 11.52) and African Americans (one-way ANCOVA; p ¼ 0.00009, F(1, 15) ¼ 13.00) but not in Asians.”

May combine two claims.

In exploratory subanalyses, stress increased PEA in follicular women, luteal women, and men.

“These subanalyses indicated that stress increased PEA in follicular women (one-way ANOVA; p ¼ 0.05, F(1, 21) ¼ 4.32) and luteal women (one-way ANOVA; p ¼ 0.047, F(1, 24) ¼ 4.37) and in men (one-way ANOVA: p ¼ 0.028, F(1, 21) ¼ 5.54)”

May combine two claims.

The TSST significantly increased serum cortisol, systolic blood pressure, heart rate, and self-reports of Anxiety in this study.

“As described previously (Childs et al, 2010), the TSST significantly increased serum cortisol concentrations (oneway ANOVA; p ¼ 0.003, F(1, 69) ¼ 9.326), systolic blood pressure (one-way ANOVA; p ¼ 0.00005, F(1, 70) ¼ 18.36), heart rate (one-way ANOVA; p ¼ 0.00003, F(1, 45) ¼ 21.35), and self-reports of Anxiety (one-way ANOVA; F(1, 70) ¼ 49.93; p ¼ 10 À9 ).”

• cites Childs et al, 2010Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

Acute stress increased heart rate in luteal women and in men.

“stress increased heart rate and systolic blood pressure in luteal women and in men (heart rate: luteal: one-way ANOVA; p ¼ 0.002, F(1, 17) ¼ 13.15; men: one-way ANOVA; p ¼ 0.006, F(1, 12) ¼ 10.70; systolic blood pressure: luteal: one-way ANOVA; p ¼ 0.045, F(1, 25) ¼ 4.46; men: one-way ANOVA; p ¼ 0.001, F(1, 22) ¼ 14.30; Supplementary Figure S4).”

May combine two claims.

2-OG, but not 2-AG, concentrations were positively correlated with feelings of Anxiety after stress, but this was not significant after adjustment for multiple testing.

“The 2-OG, but not 2-AG, concentrations were positively correlated with feelings of Anxiety after stress (r ¼ 0.28, p ¼ 0.027; Supplementary Figure S5), which was not significant after adjustment for multiple testing.”

May combine two claims.

Baseline concentrations of AEA were negatively correlated with feelings of Anxiety, and this remained significant after adjustment for multiple testing.

“The baseline concentrations of AEA were negatively correlated with feelings of Anxiety (r ¼ À0.294, p ¼ 0.014), which remained significant after adjustment for multiple testing (Figure 5).”

• Also stated in: § DISCUSSION · plain

  “Circulating concentrations of AEA were negatively associated with Anxiety at baseline.”

May combine two claims. The quote only partly states this claim.

The increase in circulating PEA following the stress session was positively correlated with serum cortisol concentrations after the stress task, and this correlation remained significant after adjustment for multiple testing.

“The increase in circulating PEA following the stress session was positively correlated with serum cortisol concentrations after the stress task (r ¼ 0.37, p ¼ 0.002; Figure 6).”

• Also stated in: § DISCUSSION · plain

  “There was a significant, positive correlation between stress-induced increase in PEA concentration and the amount of circulating cortisol at 30 s following the end of stress.”

May combine two claims.

In our study, circulating concentrations of 2-AG and 2-OG tended to increase immediately after both the control and stress task, although they did not reach significance in either case.

“In our study, circulating concentrations of 2-AG and 2-OG tended to increase immediately after both the control and stress task, although they did not reach significance in either case.”

May combine two claims.

Stress increased the NAEs but not the secondary outcome measures in Caucasians only.

“We found interesting differences among the three racial groups represented in our sample; specifically, stress increased the NAEs but not the secondary outcome measures in Caucasians only.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Correlational analyses were corrected for multiple testing using Bonferroni-Holm corrections with p=0.0125.

“Correlational analyses were corrected for multiple testing using Bonferroni-Holm corrections according to the number of outcome measures examined using a p-value of 0.0125 for statistical significance.”

Classified as probably not a substantial claim. May combine two claims.

The study used a randomized, two-session crossover design with a stress session (TSST) and a no stress session (control).

“The study used a randomized, two-session crossover design with a stress session (TSST) and a no stress session (control).”

Probably not a substantial claim: may not pass S3 (load-bearing).

Women were randomly assigned to participate during either the follicular or luteal phase of the menstrual cycle.

“Women were randomly assigned to participate during either the follicular or luteal phase of the menstrual cycle.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Possible confounding variables (age, BMI, cannabis use frequency, and session order) were assessed by ANCOVA and considered in further analyses.

“Possible confounding variables on the main effects of stress (age, BMI, cannabis use frequency, and session order) were assessed by performing separate analyses of covariance (ANCOVAs) and considered in further statistical analyses.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Subanalyses were corrected for multiple testing with Bonferroni-Holm corrections using a threshold p=0.0166.

“Subanalyses were corrected for multiple testing with Bonferroni-Holm corrections using the a threshold p ¼ 0.0166 for statistical significance.”

Classified as probably not a substantial claim. May combine two claims.

Primary measures were not corrected for multiple comparisons because serum lipid concentrations are highly correlated and do not represent independent multiple tests.

“We did not correct our primary measures for multiple comparisons because serum concentrations of the lipids are highly correlated among each other, and hence do not represent independent multiple tests.”

May combine two claims. The quote only partly states this claim.

The finding of a negative correlation between baseline anxiety and baseline AEA supports a protective role for eCBs in anxiety.

“This finding supports a protective role for eCBs in anxiety.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Acute stress activates the HPA axis, leading to release of glucocorticoids such as cortisol, and the SAM, leading to secretion of catecholamines.

“Acute stress activates the hypothalamic-pituitaryadrenal (HPA) axis, leading to release of glucocorticoids such as cortisol (Lopez et al, 1999;Chrousos et al, 2009), and the sympathetic-adrenomedullary system (SAM), leading to secretion of catecholamines (Lopez et al, 1999;Chrousos et al, 2009).”

• cites Lopez et al, 1999 sourceNot checked yet

  Not checked in the free run.

• cites Chrousos et al, 2009 sourceNot checked yet

  Not checked in the free run.

Classified as probably not a substantial claim.

Both eCBs and their congeners are present in serum and plasma.

“Both of the eCBs and their congeners are also present in the serum and plasma (Wood et al, 2008).”

• cites Wood et al, 2008 sourceNot checked yet

  Not checked in the free run.

Classified as probably not a substantial claim. May combine two claims.

Recent preclinical evidence indicates that stress mobilizes the eCB system in both the brain and the periphery, and that the eCB system can modulate behavioral and endocrine responses to both acute and chronic stress.

“Recent preclinical evidence indicates that stress also mobilizes the endocannabinoid (eCB) system in both the brain and the periphery, and that the eCB system can modulate behavioral and endocrine responses to both acute and chronic stress (Hill et al, 2010;Patel and Hillard, 2008).”

• cites Hill et al, 2010 sourceNot checked yet

  Not checked in the free run.

• cites Patel and Hillard, 2008 sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The subgroups of men, follicular women, and luteal women did not differ at baseline or on any of the investigated demographic measures.

“The subgroups of men, follicular women, and luteal women did not differ at baseline or on any of the investigated demographic measures.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Peripheral glucocorticoid concentrations after stress are correlated with reduced AEA concentrations in stress-responsive regions of the brain.

“Preclinical studies indicate that peripheral glucocorticoid concentrations after stress are correlated with reduced AEA concentrations in stress-responsive regions of the brain (Patel et al, 2004(Patel et al, , 2005a;;Rademacher et al, 2008;Hill et al, 2009b).”

• cites Patel et al, 2004 sourceNot checked yet

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• cites Patel et al, 2005aNot checked yet

  Not checked in the free run.

• cites Rademacher et al, 2008 sourceNot checked yet

  Not checked in the free run.

Classified as probably not a substantial claim.

Prior work indicates that sex and menstrual cycle phase influence stress responses.

“These analyses were based upon earlier findings that these factors contribute to individual differences in responses to stress.”

• Also stated in: § INTRODUCTION · plain

  “Kirschbaum et al (1999) reported that, during the TSST, men exhibited significantly higher ACTH responses than women in either cycle phase, and men showed significantly higher salivary free cortisol concentrations than women in the follicular phase.”

• cites Kirschbaum et al (1999) sourceNot checked yet

  Not checked in the free run.

Classified as probably not a substantial claim.

Prior work indicates race differences in HPA axis activation during the TSST.

“Chong et al (2008) showed that HPA axis activation (ie, cortisol concentrations) during the TSST was greater in Caucasians than in people of African descent.”

• cites Chong et al (2008) sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

Stress causes a reduction in brain NAEs.

“these preclinical studies indicate that stress causes a reduction in brain NAEs.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Baseline concentrations of AEA affected reflex responses to orthostatic stress.

“in the second, baseline concentrations of AEA affected reflex responses to orthostatic stress (Schroeder et al, 2009).”

• cites Schroeder et al, 2009 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

The finding that circulating AEA is negatively associated with baseline Anxiety is in agreement with a clinical study and with findings in nonhuman models.

“This is in agreement with a clinical study (Hill et al, 2008) as well as with findings in nonhuman models, in which inhibition of AEA metabolism has anxiolytic and antidepressant effects (Bambico et al, 2007;Naidu et al, 2007).”

• cites Hill et al, 2008 sourceNot checked yet

  Not checked in the free run.

• cites Bambico et al, 2007 sourceNot checked yet

  Not checked in the free run.

• cites Naidu et al, 2007 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

In addition to being stress reactive, circulating eCBs also contribute to the magnitude of the stress response.

“Thus, these studies indicate that, in addition to being stress reactive, circulating eCBs also contribute to the magnitude of the stress response.”

Probably not a substantial claim: may not pass S3 (load-bearing).

AEA, PEA, and OEA have overlapping but not identical biosynthetic and catabolic mechanisms.

“AEA, PEA, and OEA have overlapping but not identical biosynthetic and catabolic mechanisms (Ueda et al, 2010;Tsuboi et al, 2007).”

• cites Ueda et al, 2010 sourceNot checked yet

  Not checked in the free run.

• cites Tsuboi et al, 2007 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

The study of Hill et al (2009a) did not include a no stress control condition, but instead reported an increase compared with prestress baseline.

“However, the study of Hill et al (2009a) did not include a no stress control condition, but instead reported an increase compared with prestress baseline.”

• cites Hill et al, 2009aNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

In Hill et al (2009a), circulating 2-AG was higher immediately following social stress exposure than before exposure in 15 women.

“This is in contrast to the findings of Hill et al (2009a), who found that circulating 2-AG was higher immediately following social stress exposure than before exposure in 15 women.”

• cites Hill et al, 2009aNot checked yet

  Not checked in the free run.

May combine two claims.

Decreased FAAH activity might be responsible for mediating the observed parallel increase of all three NAEs but not of O-acylglycerols in response to stress.

“Thus, decreased FAAH activity might be responsible for mediating the observed parallel increase of all three NAEs but not of O-acylglycerols in response to stress.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

All three NAEs are substrates of FAAH, with AEA being the best substrate of the three.

“All three NAEs are substrates of fatty acid amide hydrolase (FAAH), with AEA being the best substrate of the three (Ueda et al, 1995).”

• cites Ueda et al, 1995 sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

NAAA is found in lysosomes, has an acidic pH, and preferentially acts on PEA as a substrate.

“A second NAE hydrolysis enzyme, N-acylethanolamine-hydrolyzing acid amidase (NAAA), has been identified that is found in lysosomes and has an acidic pH and preferentially acts on PEA as a substrate (Tsuboi et al, 2007).”

• cites Tsuboi et al, 2007 sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

The current study does not provide insights into the enzymatic processes responsible for the changes in circulating NAEs in response to stress.

“The current study does not provide insights into the enzymatic processes responsible for the changes in circulating NAEs in response to stress.”

May combine two claims.

FAAH-knockout mice and mice treated with a FAAH inhibitor accumulate AEA but not 2-AG in response to stress.

“FAAH-knockout mice as well as mice treated with a FAAH inhibitor accumulate AEA but not 2-AG in response to stress (Gaetani et al, 2009).”

• cites Gaetani et al, 2009 sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

The study did not obtain information about current stress levels, temperament or trait anxiety, or about participants' exposure to early life stress, trauma, or early-life adversity.

“First, we did not obtain information about current stress levels, temperament or trait anxiety, or about the participants' exposure to early life stress, trauma, or early-life adversity.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Early-life mistreatment can affect responses to stress later in life.

“It is known that early-life mistreatment can affect responses to stress later in life, and thus early-life stress may have been an important source of individual variability in the present study (Dannlowski et al, 2012).”

• cites Dannlowski et al, 2012 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

In Hill et al (2009a), all three NAEs increased slightly, but did not reach statistical significance following exposure of women to stress.

“they observed that all three NAEs increased slightly, but did not reach statistical significance following exposure of women to stress.”

• cites Hill et al, 2009aNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

The finding of a possible racial difference in response to stress is consistent with several other reports of race differences.

“The finding of a possible racial difference in response to stress is consistent with several other reports of race differences (Ahwal et al, 1997;Chong et al, 2008;Sherwood et al, 1995).”

• cites Ahwal et al, 1997Not checked yet

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• cites Chong et al, 2008 sourceNot checked yet

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• cites Sherwood et al, 1995 sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

The 2-AG spectra were contaminated by a peak that migrated between 2-AG and 1,3-AG.

“Second, our 2-AG spectra were contaminated by a peak that migrated between 2-AG and 1,3-AG.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The contaminating peak was not included in the integrations, but its presence could have contributed to variability in 2-AG measurements.

“We did not include this peak in the integrations; however, its presence could have contributed to the variability in 2-AG measurements.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Our findings are consistent with other findings suggesting that eCBs and related lipids may be useful as diagnostic agents of stress-related psychiatric disorders.

“Our findings are consistent with other findings suggesting that eCBs and related lipids may be useful as diagnostic agents of stress-related psychiatric disorders (Hill et al, 2009c).”

• cites Hill et al, 2009cNot checked yet

  Not checked in the free run.