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Cited by 200Cannabis and Cannabinoid ResearchPosttraumatic Stress Disorder ResearchStress Responses and Cortisol

Plasma concentrations of endocannabinoids and related primary fatty acid amides in patients with post-traumatic stress disorder

Open access
Hauer, Daniela, Schelling, Gustav, Gola, Hannah, Campolongo, Patrizia, Morath, Julia, Roozendaal, Benno, Hamuni, Gilava, Karabatsiakis, Alexander +3 more·2013·PLoS ONE
DOI 10.1371/journal.pone.0062741PMC PMC3647054
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Abstract

BACKGROUND: Endocannabinoids (ECs) and related N-acyl-ethanolamides (NAEs) play important roles in stress response regulation, anxiety and traumatic memories. In view of the evidence that circulating EC levels are elevated under acute mild stressful conditions in humans, we hypothesized that individuals with traumatic stress exposure and post-traumatic stress disorder (PTSD), an anxiety disorder characterized by the inappropriate persistence and uncontrolled retrieval of traumatic memories, show measurable alterations in plasma EC and NAE concentrations. METHODS: We determined plasma concentrations of the ECs anandamide (ANA) and 2-arachidonoylglycerol (2-AG) and the NAEs palmitoylethanolamide (PEA), oleoylethanolamide (OEA), stearoylethanolamine (SEA), and N-oleoyldopamine (OLDA) by HPLC-MS-MS in patients with PTSD (n = 10), trauma-exposed individuals without evidence of PTSD (n = 9) and in healthy control subjects (n = 29). PTSD was diagnosed according to DSM-IV criteria by administering the Clinician Administered PTSD Scale (CAPS), which also assesses traumatic events. RESULTS: Individuals with PTSD showed significantly higher plasma concentrations of ANA (0.48 ± 0.11 vs. 0.36 ± 0.14 ng/ml, p = 0.01), 2-AG (8.93 ± 3.20 vs. 6.26±2.10 ng/ml, p<0.01), OEA (5.90 ± 2.10 vs. 3.88 ± 1.85 ng/ml, p<0.01), SEA (2.70 ± 3.37 vs. 0.83 ± 0.47, ng/ml, p<0.05) and significantly lower plasma levels of OLDA (0.12 ± 0.05 vs. 0.45 ± 0.59 ng/ml, p<0.05) than healthy controls. Moreover, PTSD patients had higher 2-AG plasma levels (8.93 ± 3.20 vs. 6.01 ± 1.32 ng/ml, p = 0.03) and also higher plasma concentrations of PEA (4.06 ± 1.87 vs. 2.63±1.34 ng/ml, p<0.05) than trauma-exposed individuals without evidence of PTSD. CAPS scores in trauma-exposed individuals with and without PTSD (n = 19) correlated positively with PEA (r = 0.55, p = 0.02) and negatively with OLDA plasma levels (r = -0.68, p<0.01). CAPS subscores for intrusions (r = -0.65, p<0.01), avoidance (r = -0.60, p<0.01) and hyperarousal (r = -0.66, p<0.01) were all negatively related to OLDA plasma concentrations. CONCLUSIONS: PTSD appears to be associated with changes in plasma EC/NAE concentrations. This may have pathophysiological and diagnostic consequences but will need to be reproduced in larger cohorts.

AI snapshot

Written from the paper’s full text.

TL;DR

Plasma endocannabinoid and related N-acyl-ethanolamide concentrations differ between patients with PTSD, trauma-exposed individuals without PTSD, and healthy controls. The authors conclude PTSD may be associated with altered plasma EC/NAE levels, but findings require replication in larger cohorts.

Key findings

  • PTSD patients had significantly higher plasma ANA (0.48±0.11 vs. 0.36±0.14 ng/ml, p=0.01), 2-AG (8.93±3.20 vs. 6.26±2.10 ng/ml, p<0.01), OEA (5.90±2.10 vs. 3.88±1.85 ng/ml, p<0.01), and SEA (2.70±3.37 vs. 0.83±0.47 ng/ml, p<0.05), and significantly lower OLDA (0.12±0.05 vs. 0.45±0.59 ng/ml, p<0.05) than healthy controls.
  • PTSD patients also had higher 2-AG (8.93±3.20 vs. 6.01±1.32 ng/ml, p=0.03) and PEA (4.06±1.87 vs. 2.63±1.34 ng/ml, p<0.05) than trauma-exposed individuals without PTSD.
  • In trauma-exposed individuals with and without PTSD (n=19), CAPS scores correlated positively with PEA (r=0.55, p=0.02) and negatively with OLDA (r=−0.68, p<0.01); CAPS subscores for intrusions (r=−0.65), avoidance (r=−0.60), and hyperarousal (r=−0.66) were negatively related to OLDA.
  • Plasma cortisol did not differ significantly between groups (14.0±7.0 µg/dl in trauma-exposed without PTSD, 10.2±7.02 µg/dl in PTSD, 11.2±6.53 µg/dl in controls; p=0.45).

Methods

  • Case-control study comparing patients with PTSD (n=10), trauma-exposed individuals without PTSD (n=9), and healthy controls (n=29); PTSD was diagnosed by DSM-IV criteria using the Clinician Administered PTSD Scale (CAPS).
  • Plasma concentrations of ANA, 2-AG, PEA, OEA, SEA, and OLDA were measured by HPLC-MS-MS; cortisol was measured by automated electrochemiluminescence immunoassay.
  • Group comparisons used ANOVA or Kruskal-Wallis ANOVA on Ranks with post-hoc tests; relationships between continuous variables used Pearson’s r or Spearman’s ρ.

Limitations

  • The paper states that findings need to be reproduced in larger and more homogeneous cohorts, and that interpretation is hampered by limited knowledge of the biological effects and regulation of many measured ECs/NAEs.
  • The paper notes that peripheral plasma concentrations were measured although most stress/memory effects of lipid signaling are central, and that ethnic differences within the subject pool required exploratory subanalyses.
  • Evident from the text: group sizes were small (PTSD n=10, trauma-exposed without PTSD n=9), multiple secondary and subgroup analyses were performed, and the cross-sectional design cannot establish whether EC/NAE changes are causal, protective, or consequential in PTSD.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1371/journal.pone.0062741

Cites

47 of 47 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 48 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Individuals with PTSD had significantly higher plasma concentrations of oleoylethanolamide (OEA) than healthy controls (5.90±2.10 vs. 3.88±1.85 ng/ml, p<0.01).

    “OEA (5.90±2.10 vs. 3.88±1.85 ng/ml, p<0.01)”
    • Also stated in: § Endocannabinoid Plasma Concentrations · plain
      “OEA (5.90±2.10 vs. 3.88±1.85 ng/ml, p<0.01)”
    Quote in the paperSubstantial claim
  • Findingown data

    CAPS subscores for hyperarousal were negatively related to OLDA plasma concentrations (r=−0.66, p<0.01).

    “CAPS subscores for intrusions (r = −0.65, p<0.01), avoidance (r = −0.60, p<0.01) and hyperarousal (r = −0.66, p<0.01) were all negatively related to OLDA plasma concentrations.”
    Quote in the paperNot a substantial claim
  • Findingown data

    No signals of native DEA, DLE or NADA could be found in trauma-exposed subjects or controls.

    “Isotope-labeled DEA, DLE and NADA could be readily detected in the samples but no signals of native DEA, DLE or NADA could be found in trauma-exposed subjects or controls.”
    Quote in the paperNot a substantial claim
  • Findingown data

    CAPS scores in trauma-exposed individuals with and without PTSD (n=19) correlated positively with PEA plasma levels (r=0.55, p=0.02).

    “CAPS scores in trauma-exposed individuals with and without PTSD (n = 19) correlated positively with PEA (r = 0.55, p = 0.02) and negatively with OLDA plasma levels (r = −0.68, p<0.01).”
    Quote in the paperSubstantial claim
  • Findingown data

    PTSD patients had higher plasma 2-AG concentrations than trauma-exposed individuals without evidence of PTSD (8.93±3.20 vs. 6.01±1.32 ng/ml, p=0.03).

    “Moreover, PTSD patients had higher 2-AG (8.93±3.20 vs. 6.01±1.32 ng/ml, p = 0.03) and PEA plasma levels (4.06±1.87 vs. 2.63±1.34 ng/ml, p<0.05) than trauma-exposed individuals without evidence of PTSD (Figure 1).”
    Quote in the paperSubstantial claim
  • Classified as probably not a substantial claim. 40
  • May combine two claims. 23

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

    Findingown data

    Eight of the trauma-exposed individuals met DSM-IV criteria for a current major depressive episode.

    “Eight of the trauma-exposed individuals met the DSM-IV criteria for a current major depressive episode (two subjects from the trauma exposure only group and six individuals with PTSD, p = 0.15, Fisher’s exact test) and two subjects from the PTSD group fulfilled DSM-IV criteria for alcohol dependency.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    In traumatized individuals, the number of cigarettes smoked/day correlated with CAPS sum scores (r=0.505, p=0.006).

    “In traumatized individuals, the number of cigarettes smoked/day correlated with CAPS sum scores (r = 0.505, p = 0.006).”
    Quote in the paperNot a substantial claim

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

    Findingown data

    PTSD symptoms in patients with PTSD were present between 6 and 204 months.

    “PTSD symptoms in patients with PTSD were present between 6 and 204 months and all patients except one had experienced the traumatic events during early or late adulthood.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    CAPS scores correlated positively with the number of traumatic event types experienced (r=0.70, p<0.01).

    “As expected, CAPS, HAMD and SOMS scores correlated positively with the number of traumatic event types experienced (CAPS: r = 0.70, p<0.01; HAMD: r = 0.71, p<0.01; SOMS: r = 0.55, p<0.01).”
    Quote in the paperNot a substantial claim

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

    Findingown data

    All patients with PTSD except one had experienced the traumatic events during early or late adulthood.

    “PTSD symptoms in patients with PTSD were present between 6 and 204 months and all patients except one had experienced the traumatic events during early or late adulthood.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Two subjects from the PTSD group fulfilled DSM-IV criteria for alcohol dependency.

    “Eight of the trauma-exposed individuals met the DSM-IV criteria for a current major depressive episode (two subjects from the trauma exposure only group and six individuals with PTSD, p = 0.15, Fisher’s exact test) and two subjects from the PTSD group fulfilled DSM-IV criteria for alcohol dependency.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    SOMS scores correlated positively with the number of traumatic event types experienced (r=0.55, p<0.01).

    “As expected, CAPS, HAMD and SOMS scores correlated positively with the number of traumatic event types experienced (CAPS: r = 0.70, p<0.01; HAMD: r = 0.71, p<0.01; SOMS: r = 0.55, p<0.01).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Study participants including healthy controls who smoked tended to have higher EC/NAE concentrations than non-smokers, but the differences were not statistically significant.

    “Study participants including healthy controls who smoked (n = 11) tended to have higher EC/NAE concentrations than non-smokers (n = 37) but these differences were not statistically significant (Table 4).”
    Quote in the paperNot a substantial claim

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

    Findingown data

    HAMD scores correlated positively with the number of traumatic event types experienced (r=0.71, p<0.01).

    “As expected, CAPS, HAMD and SOMS scores correlated positively with the number of traumatic event types experienced (CAPS: r = 0.70, p<0.01; HAMD: r = 0.71, p<0.01; SOMS: r = 0.55, p<0.01).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    No statistically significant correlation was found between plasma concentration of EC/NAE compounds and the number of cigarettes smoked/day, neither in the whole study group nor when only trauma-exposed individuals with and without PTSD were included.

    “We found no statistically significant correlation between plasma concentration of EC/NAE compounds and the number of cigarettes smoked/day, neither in the whole study group (r≤0.155, p≥0.29, n = 48) nor when only trauma-exposed individuals with and without PTSD were included in the analyses (r≤0.312, p≥0.080, n = 19).”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Four of the trauma-exposed individuals reported chronic somatic disorders.

    “Four of the trauma-exposed individuals reported chronic somatic disorders (two had recent treatment for stomach ulcerations, one had a rheumatic disorder, and one was diagnosed as hepatitis B-positive).”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Twelve subjects were cigarette smokers.

    “Twelve subjects were cigarette smokers.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Seven of the 19 trauma-exposed individuals reported current intake of anxiolytic, antidepressant, neuroleptic or contraceptive medication.

    “Seven of the 19 trauma-exposed individuals reported current intake of anxiolytic, antidepressant, neuroleptic or contraceptive medication.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    When non-Caucasian individuals were excluded from analysis, OLDA levels remained lower in PTSD patients but significance was lost after correction for multiple comparisons.

    “OLDA levels remained also significantly lower but significance was lost after correction for multiple comparisons.”
    • Also stated in: § Endocannabinoid Plasma Concentrations · plain
      “Panel F: OLDA concentrations across the 3 study subgroups (Kruskal-Wallis ANOVA on Ranks indicated a significant difference among the groups (+p = 0.02) but significance was lost after correction for multiple comparisons (diff. of ranks 11.7, Q = 2.23, p>0.05).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    When non-Caucasian individuals were excluded from analysis, 2-AG and PEA levels were still elevated in PTSD patients but differences to healthy controls were no longer significant.

    “2-AG and PEA levels were still elevated in PTSD patients but the differences to healthy controls were no longer significant (Figure 2).”
    • Also stated in: § Endocannabinoid Plasma Concentrations · plain
      “The differences between groups shown in Panel B (2-AG) and Panel E (PEA) were not statistically significant in the subanalysis.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Individuals with PTSD show significant differences in plasma concentrations of ECs and NAEs when compared to healthy controls and to subjects after trauma exposure who did not develop PTSD.

    “Our findings indicate that individuals with PTSD show significant differences in plasma concentrations of ECs and NAEs when compared to healthy controls and to subjects after trauma exposure who did not develop PTSD.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Secondary analyses showed no differences in EC/NAE plasma concentrations in traumatized individuals on antidepressants and between depressed and non-depressed individuals.

    “Moreover, our secondary analyses showed no differences in EC/NAE plasma concentrations in traumatized individuals on antidepressants and between depressed and non-depressed individuals.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    When only refugees with presumed differences in stress exposure were compared, only 2-AG levels remained significantly higher and OLDA concentrations significantly lower.

    “When only refugees with presumed differences in stress exposure were compared, only 2-AG levels remained significantly higher and OLDA concentrations significantly lower.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    There was no significant relationship between the number of traumatic event types reported by study subjects and EC/NAE plasma concentrations; these correlated only with PTSD symptom severity.

    “However, we found no significant relationship between the number of traumatic event types reported by our study subjects and EC/NAE plasma concentrations, which correlated only with PTSD symptom severity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Chronically stressed individuals with PTSD showed sustained alterations in EC and NAE plasma concentrations which changed in proportion to PTSD symptom intensity and were seen long after termination of the actual life-threatening situation.

    “Our chronically stressed individuals with PTSD showed sustained alterations in EC and NAE plasma concentrations which changed in proportion to PTSD symptom intensity and were seen long after termination of the actual life-threatening situation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingnone given

    Study participants with PTSD had a higher incidence of depression and reported a higher use of antidepressants.

    “Study participants with PTSD had a higher incidence of depression and also reported a higher use of antidepressants.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    Controls had more years of education than trauma-exposed individuals.

    “Trauma-exposed individuals and controls did not differ significantly with respect to age or gender distribution, but controls had more years of education.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    Trauma-exposed individuals and controls did not differ significantly with respect to age or gender distribution.

    “Trauma-exposed individuals and controls did not differ significantly with respect to age or gender distribution, but controls had more years of education.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    Individuals with PTSD reported a higher use of antidepressants than non-trauma-exposed controls.

    “Individuals with PTSD reported a higher use of antidepressants than non-trauma-exposed controls.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Patients with PTSD exhibit high rates of cannabis abuse, which may represent a form of self-medication.

    “This line of reasoning is corroborated by the observation that patients with PTSD exhibit high rates of cannabis abuse which may represent a form of self-medication [16]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [16] JR Cornelius, 2010, PTSD contributes to teen and young adult cannabis use disorders, Addictive Behaviors source

      Not checked in the free run.

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

    Study design and conductcitation

    The Mini International Neuropsychiatric Interview (MINI) was applied to screen for potential comorbid mental disorders.

    “The Mini International Neuropsychiatric Interview (MINI) [25] was applied to screen for potential comorbid mental disorders.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [25] DV Sheehan, 1998, The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10, J Clin Psychiatry

      Not checked in the free run.

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

    Study design and conductown data

    With the exception of antidepressants, medication use was equally distributed between traumatized individuals and those with PTSD.

    “With the exception of antidepressives, medication use was equally distributed between traumatized individuals and those with PTSD (Table 1).”
    Quote in the paperNot a substantial claim

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

    Study design and conductcitation

    The severity of depressive symptoms was assessed with the Hamilton Depression Rating Scale (HAMD).

    “In addition, the severity of depressive symptoms was assessed with the Hamilton Depression Rating Scale (HAMD) [26].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [26] M Hamilton, 1960, A rating scale for depression, J Neurol Neurosurg Psychiatry source

      Not checked in the free run.

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

    Study design and conductnone given

    The HPLC-MS-MS method is linear within the calibration ranges used.

    “Our method is linear within these calibration ranges.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    The lower limit of detection of the method was 0.025 ng/ml for ANA and 0.33 ng/ml for 2-AG.

    “The lower limit of detection of the method (defined as a signal/noise ratio >4∶1) was 0.025 ng/ml for ANA and 0.33 ng/ml for 2-AG.”
    Quote in the paperNot a substantial claim

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

    Study design and conductcitation

    Somatic symptoms were assessed using a shortened version of Screening for Somatoform Symptoms-7 (SOMS-7).

    “Somatic symptoms were assessed using a shortened version of Screening for Somatoform Symptoms-7 (SOMS-7) [23].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [23] W Rief, 2003, A new approach to the assessment of the treatment effects of somatoform disorders, Psychosomatics source

      Not checked in the free run.

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

    Study design and conductcitation

    The time interval between blood sampling and centrifugation was kept below 10 min because EC generation in blood samples continues ex vivo.

    “The time interval between blood sampling and centrifugation was kept below 10 min because previous experiments have shown that EC generation in blood samples is continued ex vivo [33], [34].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [33] M Vogeser, 2006, Release of anandamide from blood cells, Clin Chem Lab Med source

      Not checked in the free run.

    • cites [34] A Schmidt, 2006, Determination of the endocannabinoid anandamide in human plasma by high-performance liquid chromatography, Biomed Chromatogr source

      Not checked in the free run.

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

    Premisecitation

    EC plasma levels in frozen samples remain stable for at least 6 months.

    “EC plasma levels in frozen samples have been shown to remain stable for at least 6 months [35].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [35] V Di Marzo, 2009, Role of insulin as a negative regulator of plasma endocannabinoid levels in obese and nonobese subjects, Eur J Endocrinol source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    The study estimated a sample size of 8 per group to detect significant differences between groups with alpha 0.05 and power 0.80 using ANOVA.

    “Based on an alpha value of 0.05 and a power of 0.80 and the comparison of 3 groups (healthy controls, subjects with traumatic experiences but no PTSD, and patients with PTSD) using ANOVA, we estimated a sample size of 8 per group to detect significant differences between groups.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    The investigators who performed the measurements were blinded for the group assignment of the probes.

    “The investigators who performed the measurements were blinded for the group assignment of the probes.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    PTSD was diagnosed according to DSM-IV criteria by administering the Clinician Administered PTSD Scale (CAPS), which also assesses traumatic events.

    “PTSD was diagnosed according to DSM-IV criteria by administering the Clinician Administered PTSD Scale (CAPS), which also assesses traumatic events.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductown data

    None of the study participants took steroids, had acute illness or organic disorders such as diabetes, atherosclerotic disease or obesity, had a history of cannabis or other drug abuse or were abusing drugs at the time of evaluation, or had evidence of psychosis.

    “None of the study participants took steroids (neither orally nor by inhalation), had acute illness or organic disorders such as diabetes, atherosclerotic disease or obesity (these conditions are known to influence the EC system [20], [22]), had a history of cannabis or other drug abuse or were abusing drugs at the time of evaluation or had evidence of psychosis.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [20] K Sugamura, 2009, Activated endocannabinoid system in coronary artery disease and antiinflammatory effects of cannabinoid 1 receptor blockade on macrophages, Circulation source

      Not checked in the free run.

    • cites [22] M Cote, 2007, Circulating endocannabinoid levels, abdominal adiposity and related cardiometabolic risk factors in obese men, Int J Obes (Lond) source

      Not checked in the free run.

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

    Premisecitation

    EC plasma concentrations are modified by the presence of affective disorders and severe mental illness.

    “EC plasma concentrations are also modified by the presence of affective disorders and severe mental illness [7], [8].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [7] MN Hill, 2009, Circulating endocannabinoids and N-acyl ethanolamines are differentially regulated in major depression and following exposure to social stress, Psychoneuroendocrinology source

      Not checked in the free run.

    • cites [8] E Schwarz, 2011, Alterations of primary fatty acid amides in serum of patients with severe mental illness, Frontiers in Bioscience

      Not checked in the free run.

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

    Premisecitation

    EC and NAE blood concentrations are lower in patients with depression.

    “there are a number of recent studies which demonstrated that EC and NAE blood concentrations increase in response to acute stress [7], [10] and that they are higher in individuals who show stress tolerance [10] and lower in patients with depression [18].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [18] MN Hill, 2008, Serum endocannabinoid content is altered in females with depressive disorders: a preliminary report, Pharmacopsychiatry source

      Not checked in the free run.

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

    Premisecitation

    EC and NAE blood concentrations are higher in individuals who show stress tolerance.

    “there are a number of recent studies which demonstrated that EC and NAE blood concentrations increase in response to acute stress [7], [10] and that they are higher in individuals who show stress tolerance [10] and lower in patients with depression [18].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10] A Chouker, 2010, Motion sickness, stress and the endocannabinoid system, PLoS One source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    EC and NAE blood concentrations increase in response to acute stress.

    “there are a number of recent studies which demonstrated that EC and NAE blood concentrations increase in response to acute stress [7], [10] and that they are higher in individuals who show stress tolerance [10] and lower in patients with depression [18].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [7] MN Hill, 2009, Circulating endocannabinoids and N-acyl ethanolamines are differentially regulated in major depression and following exposure to social stress, Psychoneuroendocrinology source

      Not checked in the free run.

    • cites [10] A Chouker, 2010, Motion sickness, stress and the endocannabinoid system, PLoS One source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    The association between PTSD and plasma EC/NAE changes may have pathophysiological and diagnostic consequences.

    “This may have pathophysiological and diagnostic consequences but will need to be reproduced in larger cohorts.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The presence of heart disease could have influenced plasma EC concentrations and did not allow demonstration of a direct relationship between PTSD symptoms and plasma EC levels.

    “The presence of heart disease, however, could have influenced plasma EC concentrations [20], and this did not allow the demonstration of a direct relationship between PTSD symptoms and plasma EC levels.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [20] K Sugamura, 2009, Activated endocannabinoid system in coronary artery disease and antiinflammatory effects of cannabinoid 1 receptor blockade on macrophages, Circulation source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Stimulation of EC signaling in patients with PTSD by administration of the synthetic cannabinoid nabilone resulted in an improvement of memory-related PTSD symptoms.

    “a recent study demonstrated that a stimulation of EC signaling in patients with PTSD by administration of the synthetic cannabinoid nabilone resulted in an improvement of memory-related PTSD symptoms [17].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [17] GA Fraser, 2009, The use of a synthetic cannabinoid in the management of treatment-resistant nightmares in posttraumatic stress disorder (PTSD), CNS neuroscience & therapeutics source

      Not checked in the free run.

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

    Premisecitation

    Physical stress induced by strenuous exercise during mountaineering or cycling resulted in elevated EC concentrations which returned to baseline after termination of the stressful activity.

    “Physical stress in trained and physically fit individuals induced by strenuous exercise during mountaineering or cycling also resulted in elevated EC concentrations which returned to baseline after termination of the stressful activity [37], [38].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [37] M Feuerecker, 2012, Effects of exercise stress on the endocannabinoid system in humans under field conditions, Eur J Appl Physiol source

      Not checked in the free run.

    • cites [38] E Heyman, 2011, Intense exercise increases circulating endocannabinoid and BDNF levels in humans-Possible implications for reward and depression, Psychoneuroendocrinology source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    2-AG and OLDA may represent more robust indicators of the presence of PTSD.

    “This suggests that these two compounds may represent more robust indicators of the presence of PTSD but these assumptions definitively need to be corroborated in larger studies.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Exposure of healthy volunteers to kinetic stress during a parabolic flight experiment gave rise to a significant increase in plasma EC concentrations in stress-tolerant participants, whereas highly stressed individuals showed an absent EC response and a massive activation of the HPA axis.

    “Exposure of healthy volunteers to kinetic stress during a parabolic flight experiment gave rise to a significant increase in plasma EC concentrations in stress-tolerant participants, whereas highly stressed individuals showed an absent EC response and a massive activation of the hypothalamic-pituitary-adrenal (HPA) axis [10].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10] A Chouker, 2010, Motion sickness, stress and the endocannabinoid system, PLoS One source

      Not checked in the free run.

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

    Premisecitation

    Stress induced by the Trier Social Stress Test resulted in a significant increase in ANA, PEA and OEA plasma concentrations.

    “Stress induced by the Trier Social Stress Test resulted in a significant increase in ANA, PEA and OEA plasma concentrations [30].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [30] A Dlugos, 2012, Acute stress increases circulating anandamide and other N-acylethanolamines in healthy humans, Neuropsychopharmacology source

      Not checked in the free run.

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

    Premisecitation

    Activated macrophages and other nuclear blood cells are believed to be the major source of circulating ECs in blood.

    “Activated macrophages and other nuclear blood cells are believed to be the major source of circulating ECs in blood [33], [42].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [33] M Vogeser, 2006, Release of anandamide from blood cells, Clin Chem Lab Med source

      Not checked in the free run.

    • cites [42] D Centonze, 2008, The endocannabinoid system in peripheral lymphocytes as a mirror of neuroinflammatory diseases, Curr Pharm Des source

      Not checked in the free run.

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

    Premisecitation

    Inhibition of EC signaling by CB1 receptor blockade in circulating macrophages is associated with a significant reduction in pro-inflammatory mediators.

    “whereas an inhibition of EC signaling by CB1 receptor blockade in circulating macrophages is associated with a significant reduction in pro-inflammatory mediators [20].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [20] K Sugamura, 2009, Activated endocannabinoid system in coronary artery disease and antiinflammatory effects of cannabinoid 1 receptor blockade on macrophages, Circulation source

      Not checked in the free run.

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

    Premisecitation

    There is evidence of elevated plasma levels of ANA and 2-AG in patients with atherosclerosis and coronary artery disease.

    “Although an enhanced EC signaling may have protective and adaptive effects during or after a major stress exposure, there is evidence of elevated plasma levels of ANA and 2-AG in patients with atherosclerosis and coronary artery disease [20], [41]”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [20] K Sugamura, 2009, Activated endocannabinoid system in coronary artery disease and antiinflammatory effects of cannabinoid 1 receptor blockade on macrophages, Circulation source

      Not checked in the free run.

    • cites [41] F Weis, 2010, Effect of anaesthesia and cardiopulmonary bypass on blood endocannabinoid concentrations during cardiac surgery, British Journal of Anaesthesia source

      Not checked in the free run.

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

    Premisecitation

    Patients with PTSD often abuse cannabinoids.

    “Interestingly, patients with PTSD often abuse cannabinoids [16]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [16] JR Cornelius, 2010, PTSD contributes to teen and young adult cannabis use disorders, Addictive Behaviors source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    The lipid response to acute stress is significantly higher in Caucasians than in African-Americans.

    “A recent study has shown that the lipid response to acute stress is significantly higher in Caucasians than in African-Americans [30].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [30] A Dlugos, 2012, Acute stress increases circulating anandamide and other N-acylethanolamines in healthy humans, Neuropsychopharmacology source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Despite elevated EC and NAE plasma concentrations as part of a stress reaction in PTSD patients, enhanced endocannabinoid signaling might be insufficient to completely restore homeostasis and a further reduction in symptoms by exogenous cannabinoids is possible.

    “Thus, despite elevated EC and NAE plasma concentrations as part of a stress reaction in PTSD patients, the enhanced endocannabinoid signaling might be insufficient to completely restore homeostasis and a further reduction in symptoms by exogenous cannabinoids is possible.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Changes in peripheral EC/NAE concentrations may reflect alterations in central EC signaling along with EC/NAE associated behavioral effects.

    “These findings suggest that changes in peripheral EC/NAE concentrations may indeed reflect alterations in central EC signaling along with EC/NAE associated behavioral effects.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    All subjects appeared to be comfortable during blood drawing and were habituated to the procedure from previous medical visits.

    “These effects are difficult to control for, but all our subjects appeared to be comfortable during blood drawing and were habituated to the procedure from previous medical visits.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    The finding that PTSD is associated with changes in plasma EC/NAE concentrations may have both pathophysiological and diagnostic consequences for PTSD.

    “This finding may have both pathophysiological as well as diagnostic consequences for PTSD but needs to be reproduced in larger and more homogenous study groups.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Animal studies have shown that stress reduces brain EC concentrations.

    “One should keep in mind, however, that animal studies have also shown that stress reduces brain EC concentrations [44].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [44] MN Hill, 2009, Suppression of amygdalar endocannabinoid signaling by stress contributes to activation of the hypothalamic-pituitary-adrenal axis, Neuropsychopharmacology source

      Not checked in the free run.

58 of 58

  • The authors state this as an assumption.

    Changes in endocannabinoid signaling might play a role in either the development or persistence of PTSD.

    “Given the fact that post-traumatic stress disorder (PTSD) is an anxiety disorder characterized by an inappropriate persistence and uncontrolled retrieval of traumatic memories, it can be assumed that changes in EC signaling might play a role in either the development or persistence of PTSD.”

  • The paper relies on this without support.

    The German control subjects may have a different health status or differences in overall stress exposure compared to other controls.

    “as well as individuals of German origin who may have a different health status or differences in the overall stress exposure”

  • The paper relies on this without support.

    The remaining controls (refugees) were exposed to higher stress levels during immigration, which could result in increased plasma lipid signaling.

    “They were almost certainly exposed to higher stress levels during immigration which could result in increased plasma lipid signaling, although this possibility is difficult to proof with the questionnaires and instruments used in our study.”

  • The authors state this as an assumption.

    An activated peripheral EC system might play a causal role in the reported increased risk for coronary artery disease and the associated enhanced mortality in patients with PTSD.

    “Therefore, an activated peripheral EC system might play a causal role in the reported increased risk for coronary artery disease and the associated enhanced mortality in patients with PTSD [43]. This assumption is corroborated”

  • The authors state this as an assumption.

    Increased EC signaling during acute stress is a protective response to maintain homeostasis and enhance the recovery process.

    “The latter two findings may allow speculating that an increased EC signaling during acute stress is a protective response to maintain homeostasis and enhance the recovery process. In line with this assumption”

  • The authors state this as an assumption.

    If depression and the use of antidepressants have an effect on the finding of increased EC/NAE plasma levels in PTSD patients, these confounders may have actually resulted in lower rather than increased plasma concentrations.

    “Thus, if depression and the use of antidepressants have an effect on our finding of increased EC/NAE plasma levels in PTSD patients one could assume that these confounders may have actually resulted in lower rather than increased plasma concentrations.”
6 of 6

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?

  • In patients with PTSD or depression, 2-AG plasma levels are lower than in healthy controls.

    “In patients with PTSD or depression 2-AG plasma levels have been found to be lower than in healthy controls (Hauer et al., 2013), and in mice lacking the 2-AG synthesising enzyme diacylglycerol lipase anxiety-related behaviour is enhanced (Jenniches et al., 2016;Shonesy et al., 2014).”

    From Novel pharmacological targets in drug development for the treatment of anxiety and anxiety-related disorders (2019) · cites this paper as Hauer et al., 2013

  • Reduced circulating 2-AG is found in patients with PTSD.

    “Reduced circulating 2-AG has also been found in patients with PTSD (Hill et al., 2013a) (though for the opposite effect, see Hauer et al., 2013).”

    From The endocannabinoid system as a target for novel anxiolytic drugs (2017) · cites this paper as Hauer et al., 2013

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Discussion denies a reported traumatic-events correlation

    Major

    The Discussion states that traumatic event-type counts had no significant relationship with EC/NAE concentrations. Figure 5 reports a significant relationship between CAPS traumatic event types and OLDA concentration (p = 0.03).

  • Smoker totals differ between tables

    Major

    Table 1 lists 6, 6 and 4 smokers in the three groups, totaling 16. Table 4 instead classifies only 11 of the same 48 study participants as smokers.

  • Trauma-exposed female count conflicts with Table 1

    Major

    The text reports nine females among the 19 trauma-exposed participants, but Table 1 lists three females without PTSD and two with PTSD, for a total of five.

  • Depression count differs between text and Table 2

    Minor

    The text says eight trauma-exposed individuals had a current major depressive episode, while Table 2 classifies nine as having depression.

  • CAPS subscores do not add to the reported total without PTSD

    Minor

    For trauma-exposed participants without PTSD, the three listed mean CAPS subscores add to 27.4, not the reported mean CAPS score of 24.6. The corresponding PTSD-group subscores do add to that group's reported total.

    Reported 24.6 · recomputed 27.4

  • CAPS and war-event summaries appear reversed

    Minor

    The text assigns 8.8±6.9 to CAPS event types and 8.1±2.2 to war- and torture-related events. The subgroup values in Table 1 instead combine to approximately 8.1 for CAPS events and 8.8 for war or torture events.

  • Reported age does not match the subgroup ages

    Minor

    The reported mean age of the 19 trauma-exposed participants is 33.2 years. Table 1 gives means of 33.6 years for nine participants and 33.8 years for ten, which combine to approximately 33.7 years.

  • Listed countries account for six, not seven, excluded participants

    Minor

    The country counts in the parenthesis add to six, although the passage says seven non-Caucasian individuals were excluded.

    Reported 7 · recomputed 6

8 of 8

Cites

Flagged first, then by citations

1 of the 48 references couldn’t be matched to a known paper.

Research works printed but not linked: 2

  1. D Hauer, 2008, Traumatic Memories in Surgical Patients Are a Significant Predictor of Endocannabinoid Activity, Anesthesiology, 109, A1015
  2. Schauer M, Neuner F, Elbert T (2011): Vivo Checklist for War, Detention, and Torture Events; in : Narrative Exposure Therapy (NET). A Short-Term Intervention for Traumatic Stress Disorders. Cambridge/Göttingen, Hogrefe &amp; Huber Publishers, 77–79.

Cited by

Sorted by citations

Related

Authors
Hauer, D., Schelling, G., Gola, H., Campolongo, P., Morath, J., Roozendaal, B., Hamuni, G., Karabatsiakis, A., Atsak, P., Vogeser, M., & Kolassa, I.-T.
Affiliations
  • Ludwig-Maximilians-Universität München (DE)
  • University of Konstanz (DE)
  • Sapienza University of Rome (IT)
  • Radboud University Nijmegen (NL)
  • Universität Ulm (DE)
Corresponding author
Schelling, Gustav
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2013-05-07
Volume
8
Issue
5
Pages
e62741
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0062741
PMC
PMC3647054
OpenAlex
W2008780699
Semantic Scholar
8a8ef8246cc5a9190426ce1cd930743c7f73881e
Cited by
200
References
48
Citations by year
2026: 6 · 2025: 17 · 2024: 12 · 2023: 19 · 2022: 17 · 2021: 16 · 2020: 15 · 2019: 18 · 2018: 17 · 2017: 15 · 2016: 11 · 2015: 18 · 2014: 6 · 2013: 12
FWCI
11.50
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • KOPS (University of Konstanz) (submittedVersion)
  • Radboud Repository (Radboud University) (submittedVersion, other-oa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Open access LMU (Ludwid Maxmilian's Universitat Munchen) (submittedVersion)
  • IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
  • Radboud Repository (Radboud University) (submittedVersion)
  • Universitätsbibliothek der LMU
Topics
  • Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
  • Social Sciences › Psychology › Clinical Psychology › Posttraumatic Stress Disorder Research
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
Keywords
post-traumatic stress disorder, endocannabinoids, anandamide, 2-arachidonoylglycerol, palmitoylethanolamide, oleoylethanolamide, plasma concentration, trauma exposure, anxiety, traumatic memory, stress response
MeSH terms
Adult, Amides, Female, Humans, Hydrocortisone, Male, Stress Disorders, Post-Traumatic, Stress, Psychological, Torture, Warfare, Cohort Studies, Case-Control Studies, Endocannabinoids

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 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

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.

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