CoChat
Sign Up
Cited by 361Cannabis and Cannabinoid ResearchPosttraumatic Stress Disorder ResearchStress Responses and Cortisol

Elevated brain cannabinoid CB1 receptor availability in post-traumatic stress disorder: A positron emission tomography study

Open access
Neumeister, A, Normandin, M D, Pietrzak, R H, Piomelli, D, Zheng, M Q, Gujarro-Anton, A, Potenza, M N, Bailey, C R +7 more·2013·Molecular Psychiatry
DOI 10.1038/mp.2013.61PMC PMC3752332
Open this paper in CoChat — free account

Abstract

Endocannabinoids and their attending cannabinoid type 1 (CB1) receptor have been implicated in animal models of post-traumatic stress disorder (PTSD). However, their specific role has not been studied in people with PTSD. Herein, we present an in vivo imaging study using positron emission tomography (PET) and the CB1-selective radioligand [11C]OMAR in individuals with PTSD, and healthy controls with lifetime histories of trauma (trauma-exposed controls (TC)) and those without such histories (healthy controls (HC)). Untreated individuals with PTSD (N=25) with non-combat trauma histories, and TC (N=12) and HC (N=23) participated in a magnetic resonance imaging scan and a resting PET scan with the CB1 receptor antagonist radiotracer [11C]OMAR, which measures the volume of distribution (VT) linearly related to CB1 receptor availability. Peripheral levels of anandamide, 2-arachidonoylglycerol, oleoylethanolamide, palmitoylethanolamide and cortisol were also assessed. In the PTSD group, relative to the HC and TC groups, we found elevated brain-wide [11C]OMAR VT values (F(2,53)=7.96, P=0.001; 19.5% and 14.5% higher, respectively), which were most pronounced in women (F(1,53)=5.52, P=0.023). Anandamide concentrations were reduced in the PTSD relative to the TC (53.1% lower) and HC (58.2% lower) groups. Cortisol levels were lower in the PTSD and TC groups relative to the HC group. Three biomarkers examined collectively—OMAR VT, anandamide and cortisol—correctly classified nearly 85% of PTSD cases. These results suggest that abnormal CB1 receptor-mediated anandamide signaling is implicated in the etiology of PTSD, and provide a promising neurobiological model to develop novel, evidence-based pharmacotherapies for this disorder.

AI snapshot

Written from the paper’s full text.

TL;DR

In this cross-sectional PET study, individuals with PTSD showed elevated brain CB1 receptor availability ([11C]OMAR VT) and lower peripheral anandamide and cortisol than controls. A combination of OMAR VT, anandamide, and cortisol classified nearly 85% of PTSD cases.

Key findings

  • PTSD was associated with higher mean composite [11C]OMAR VT than both healthy controls (HC) and trauma controls (TC) (F(2,53)=7.96, p=.001; 19.5% and 14.5% higher, respectively), with a significant sex effect (F(1,53)=5.52, p=.023) and a trend toward group-by-sex interaction (p=.073).
  • Anandamide levels were lower in PTSD than in TC (53.1% lower) and HC (58.2% lower); OEA was higher in HC than TC and PTSD, while 2-AG and PEA did not differ by group.
  • Cortisol was lower in PTSD and TC than HC (HC vs TC p<.001, d=1.59; HC vs PTSD p<.001, d=1.22), with no difference between TC and PTSD (p=.35, d=.34).
  • Binary logistic regression showed that [11C]OMAR VT, anandamide, and cortisol together correctly classified nearly 85% of PTSD cases, with overall classification accuracy approaching 90%; interaction terms were not significant (all p>.21).

Methods

  • Cross-sectional PET/MR study of untreated individuals with PTSD and non-combat trauma histories (N=25), trauma-exposed controls without lifetime PTSD or other Axis I diagnosis (N=12), and healthy controls without trauma histories (N=23); 60 of 72 recruited participants completed the protocol.
  • Participants underwent resting PET with the CB1-selective antagonist radiotracer [11C]OMAR and MRI; regional total volume of distribution (VT) was estimated using kinetic analysis with metabolite-corrected arterial input functions, and peripheral anandamide, 2-AG, OEA, PEA, and cortisol were measured.
  • Group comparisons used ANOVA/χ2 and ANCOVA with group and sex as independent variables and age as a covariate; pairwise least-squares difference tests used p<.01, and binary logistic regression tested biomarker classification of PTSD vs. HC/TC.

Limitations

  • Stated in the paper: a conclusive interpretation of the CB1 receptor profile in males and females requires a broad and dynamic perspective rather than a single observation in a cross-sectional study with a single time point; the authors also note the importance of considering gender and menstrual cycle phase in CB1 imaging studies.
  • Evident from the text: the trauma control group was small (N=12), and the groups differed in race, current cigarette smoking, lifetime mood or anxiety disorder, and lifetime alcohol or drug abuse, which could affect interpretation.
  • Evident from the text: the cross-sectional design cannot establish whether altered CB1 receptor availability, anandamide, or cortisol precede or follow PTSD.

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

Integrity signals

Registry

Crossref · 10.1038/mp.2013.61

Cites

65 of 65 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

0 of 57 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Effect sizes for the differences between the PTSD group and HC and TC groups were consistently large in magnitude.

    “As shown in Figure 1, effect sizes for the differences between the PTSD group and HC and TC groups were consistently large in magnitude.”
    Quote in the paperNot a substantial claim
  • Findingown data

    Composite [11C]OMAR VT values did not correlate with cortisol levels (r= −.06, p=.67).

    “but not cortisol levels (r= −.06, p=.67)”
    Quote in the paperNot a substantial claim
  • Findingown data

    Composite [11C]OMAR VT values correlated negatively with anandamide levels (r= −.27, p=.038).

    “Composite [11C]OMAR VT values also correlated negatively with anandamide levels (r= −.27, p=.038)”
    Quote in the paperNot a substantial claim
  • Findingown data

    Anandamide concentrations were reduced in the PTSD group relative to the TC (53.1% lower) and HC (58.2% lower) groups.

    “Anandamide concentrations were reduced in the PTSD relative to the TC (53.1% lower) and HC (58.2% lower) groups.”
    • Also stated in: § RESULTS · plain
      “Pairwise comparisons revealed that the PTSD group had lower anandamide levels than both the HC (p=.001; Cohen's d=1.10) and TC (p=.001; Cohen's d=1.36) groups”
    Quote in the paperSubstantial claim
  • Findingown data

    [11C]OMAR VT values across brain regions were highly correlated (r values=.73 to .96).

    “Because [11C]OMAR VT values across brain regions were highly correlated (r values=.73 to .96), mean composite [11C]OMAR VT values were computed by averaging [11C]OMAR VT values across all brain regions for each individual.”
    Quote in the paperSubstantial claim
  • May combine two claims. 24
  • Classified as probably not a substantial claim. 35

  • May combine two claims.

    Findingown data

    Analyses of [11C]OMAR VT values in brain regions outside of the amygdala-hippocampal-cortico-striatal neural circuit implicated in PTSD revealed this same pattern of results, with the PTSD group having significantly greater [11C]OMAR VT values than both the HC and TC groups (all F's for group effect>4.91, all p's<.01; all p's for pairwise comparisons<.01).

    “Analyses of [11C]OMAR VT values in brain regions outside of the amygdala-hippocampal-cortico-striatal neural circuit implicated in PTSD revealed this same pattern of results, with the PTSD group having significantly greater [11C]OMAR VT values than both the HC and TC groups (all F's for group effect>4.91, all p's<.01; all p's for pairwise comparisons<.01).”
    Quote in the paperSubstantial claim

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

    Findingown data

    There was a trend towards a significant group-by-sex interaction (F(2,53)=2.75, p=.073).

    “there was a trend towards a significant group-by-sex interaction (F(2,53)=2.75, p=.073).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Mean [11C]OMAR VT values were significantly higher among women in the HC (p=.009; d=1.26) and PTSD (p=.011; d=1.16) groups, but not in the TC group (p=.65; d=.32).

    “Pairwise comparisons revealed that mean [11C]OMAR VT values were significantly higher among women in the HC (p=.009; d=1.26) and PTSD (p=.011; d=1.16) groups, but not in the TC group (p=.65; d=.32).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The PTSD group scored higher on the MADRS and HAM-A relative to both control groups, and on the CAPS relative to the TC group.

    “The PTSD group scored higher on the MADRS and HAM-A relative to both control groups, and on the CAPS relative to the TC group.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Composite [11C]OMAR VT values correlated negatively with age (r= −.34, p=.007).

    “Bivariate correlations revealed that composite [11C]OMAR VT values correlated negatively with age (r= −.34, p=.007)”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Composite [11C]OMAR VT values correlated positively with female sex (r= .39, p=.002).

    “and positively with female sex (r= .39, p=.002).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Other demographic variables, BMI, lifetime and current alcohol use, current cigarette smoking status and nicotine dependence, and trauma-related variables and lifetime history of mood or anxiety disorders, and alcohol or drug abuse were not associated with [11C]OMAR VT values (all r values<|.22|, all p values>.10).

    “Other demographic variables, BMI, lifetime and current alcohol use, current cigarette smoking status and nicotine dependence, and trauma-related variables and lifetime history of mood or anxiety disorders, and alcohol or drug abuse were not associated with [11C]OMAR VT values (all r values<|.22|, all p values>.10).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    An ANCOVA examining anandamide levels in the HC, TC, and PTSD groups revealed significant main effects of group (F(2,53)=9.75, p<.001) and sex (F(1,53)=4.23, p=.045), but age (F(1,53)=1.00, p=.32) and the interaction of group-by-sex (F(2,53)=1.47, p=.24) were not significant.

    “An ANCOVA examining anandamide levels in the HC, TC, and PTSD groups revealed significant main effects of group (F(2,53)=9.75, p<.001) and sex (F(1,53)=4.23, p=.045), but age (F(1,53)=1.00, p=.32) and the interaction of group-by-sex (F(2,53)=1.47, p=.24) were not significant.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    An ANCOVA examining mean composite [11C]OMAR VT values in the HC, TC, and PTSD groups revealed significant main effects of group (F(2,53)=7.96, p=.001), sex (F(1,53)=5.52, p=.023), and age (F(1,53=11.95, p=.001).

    “An ANCOVA examining mean composite [11C]OMAR VT values in the HC, TC, and PTSD groups revealed significant main effects of group (F(2,53)=7.96, p=.001), sex (F(1,53)=5.52, p=.023), and age (F(1,53=11.95, p=.001)”
    Quote in the paperSubstantial claim

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

    Findingown data

    The correlation between anandamide and cortisol levels was not significant (r= .02, p=.88).

    “and the correlation between anandamide and cortisol levels was also not significant (r= .02, p=.88).”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Differences between the TC and HC groups were generally small in magnitude.

    “Differences between the TC and HC groups were generally small in magnitude.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Classification accuracy increased as additional biomarkers were added to the model, with the highest classification accuracy observed when [11C]OMAR VT values, anandamide, and cortisol were entered simultaneously.

    “Results revealed that the classification accuracy increased as additional biomarkers were added to the model, with the highest classification accuracy observed when [11C]OMAR VT values, anandamide, and cortisol were entered simultaneously.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Age, sex, and the interaction of group × sex were not significant for OEA levels.

    “age (F(1,45)=2.91, p=.095), sex (F(1,45)=.55, p=.46), and the interaction of group × sex (F(2,45)=.02, p=.98) were not significant.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The elevation in [11C]OMAR VT in PTSD was present in an amygdala-hippocampal-cortico-striatal neural circuit implicated in PTSD and in brain regions outside this circuit.

    “Notably, this elevation was found in an amygdala-hippocampal-cortico-striatal neural circuit implicated in PTSD, as well as in brain regions outside this circuit.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: [11C]OMAR VT quantitatively reflects CB1 receptor availability.

  • May combine two claims.

    Findingown data

    In the current study, OEA levels were higher in healthy controls (HC) than in trauma controls (TC) and PTSD participants, while groups did not differ in 2-AG and PEA levels.

    “OEA levels were higher in HC relative to TC and PTSD participants in the current study, but groups did not differ with respect to 2-AG and PEA levels.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    An ANCOVA examining cortisol levels in the HC, TC, and PTSD groups revealed a significant main effect of group (F(2,52)=12.69, p<.001), but sex (F(1,52)=.05, p=.82), age (F(1,52)=1.84, p=.18), and the interaction of group-by-sex were not significant (F(2,52)=.33, p=.72).

    “An ANCOVA examining cortisol levels in the HC, TC, and PTSD groups revealed a significant main effect of group (F(2,52)=12.69, p<.001), but sex (F(1,52)=.05, p=.82), age (F(1,52)=1.84, p=.18), and the interaction of group-by-sex were not significant (F(2,52)=.33, p=.72).”
    Quote in the paperNot a substantial claim

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

    Findingown data

    2-AG and PEA levels did not differ by group.

    “2-AG and PEA levels did not differ by group.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    None of the interaction terms were significant (all p values>.21).

    “None of the interaction terms were significant (all p values>.21).”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    The primary component of the stress response appears to be a noradrenergic signal that is necessary for encoding emotionally salient information.

    “The primary component of this response appears to be a noradrenergic signal that is necessary for encoding emotionally salient information3.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [3] Roozendaal B, Okuda S, de Quervain DJ, McGaugh JL . Glucocorticoids interact with emotion-induced noradrenergic activation in influencing different memory functions. Neuroscience 2006; 138: 901–910. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    The hyperconsolidation of traumatic memories in PTSD is driven by a glucocorticoid-hormone-facilitated potentiation of norepinephrine inputs to the basolateral amygdala (BLA).

    “The hyperconsolidation of traumatic memories in PTSD is driven by a glucocorticoid-hormone-facilitated potentiation of norepinephrine inputs to the basolateral amygdala (BLA)4, 5.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [4] Roozendaal B, Barsegyan A, Lee S . Adrenal stress hormones, amygdala activation, and memory for emotionally arousing experiences. Progr Brain Res 2008; 167: 79–97. source

      Not checked in the free run.

    • cites [5] Atsak P, Roozendaal B, Campolongo P . Role of the endocannabinoid system in regulating glucocorticoid effects on memory for emotional experiences. Neuroscience 2012; 204: 104–116. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    The process by which emotionally-aversive memories become consolidated is recognized to be an interaction between glucocorticoid hormones and norepinephrine, both of which are released in response to stress.

    “The process by which emotionally-aversive memories become consolidated is recognized to be an interaction between glucocorticoid hormones and norepinephrine, both of which are released in response to stress2.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [2] Roozendaal B, McGaugh JL . Memory modulation. Behav Neurosci 2011; 125: 797–824. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    CB1 receptors are found in high concentrations within an amygdala-hippocampal-cortico-striatal circuit responsible for processing and storing fear-related memories and coordinating fear-related behaviors.

    “and are found in high concentrations within an amygdala-hippocampal-cortico-striatal circuit responsible for processing and storing fear-related memories and coordinating fear-related behaviors14–16.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [14] Rogan MT, Staubli UV, LeDoux JE . Fear conditioning induces associative long-term potentiation in the amygdala. Nature 1997; 390: 604–607. source

      Not checked in the free run.

    • cites [15] LeDoux JE . Emotion circuits in the brain. Annu Rev Neurosci 2000; 23: 155–184. source

      Not checked in the free run.

    • cites [16] Rodrigues SM, Schafe GE, LeDoux JE . Molecular mechanisms underlying emotional learning and memory in the lateral amygdala. Neuron 2004; 44: 75–91. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    There is an emerging body of evidence demonstrating an important role for CB1 receptor-mediated endocannabinoid signaling in the extinction of aversive memories.

    “Moreover, there is an emerging body of evidence demonstrating an important role for CB1 receptor-mediated endocannabinoid signaling in the extinction of aversive memories8.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [8] Marsicano G, Wotjak CT, Azad SC, Bisogno T, Rammes G, Cascio MG et al. The endogenous cannabinoid system controls extinction of aversive memories. Nature 2002; 418: 530–534. source

      Not checked in the free run.

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

    Premisecitation

    CB1 receptors are the most abundant G-protein-coupled receptors in the central nervous system.

    “CB1 receptors are the most abundant G-protein-coupled receptors in the central nervous system12, 13”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [12] Glass M, Dragunow M, Faull RL . Cannabinoid receptors in the human brain: a detailed anatomical and quantitative autoradiographic study in the fetal, neonatal and adult human brain. Neuroscience 1997; 77: 299–318. source

      Not checked in the free run.

    • cites [13] Herkenham M, Lynn AB, Little MD, Johnson MR, Melvin LS, de Costa BR et al. Cannabinoid receptor localization in brain. Proc Natl Acad Sci USA 1990; 87: 1932–1936. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    These CB1 receptor adaptations give rise to an anxious/depressive phenotype.

    “which in turn give rise to an anxious/depressive phenotype20, 21.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [20] Haller J, Bakos N, Szirmay M, Ledent C, Freund TF . The effects of genetic and pharmacological blockade of the CB1 cannabinoid receptor on anxiety. Eur J Neurosci 2002; 16: 1395–1398. source

      Not checked in the free run.

    • cites [21] Haller J, Varga B, Ledent C, Freund TF . CB1 cannabinoid receptors mediate anxiolytic effects: convergent genetic and pharmacological evidence with CB1-specific agents. Behav Pharmacol 2004; 15: 299–304. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Augmenting levels of anandamide in the amygdala modulates short-term fear extinction.

    “Augmenting levels of anandamide in the amygdala modulates short-term fear extinction9”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [9] Pamplona FA, Bitencourt RM, Takahashi RN . Short- and long-term effects of cannabinoids on the extinction of contextual fear memory in rats. Neurobiol Learn Mem 2008; 90: 290–293. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Augmenting levels of anandamide in the amygdala results in long-term reduction in fear.

    “thereby resulting in long-term reduction in fear10”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [10] Gunduz-Cinar O, Macpherson KP, Cinar R, Gamble-George J, Sugden K, Williams B et al. Convergent translational evidence of a role for anandamide in amygdala-mediated fear extinction, threat processing and stress-reactivity. Mol Psychiatry, advance online publication, 12 June 2012; doi:10.1038/mp.2012.72 (e-pub ahead of print). source

      Not checked in the free run.

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

    Interpretationreasoning

    The endocannabinoid system is a candidate system for developing novel pharmacotherapies for PTSD.

    “highlighting the endocannabinoid system as a candidate system for developing novel pharmacotherapies for PTSD11.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [11] Neumeister A . The endocannabinoid system provides an avenue for evidence-based treatment development for PTSD. Depress Anxiety 2013; 30: 93–96. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Animal studies have shown that chronic stress is associated with decreased brain levels of the endocannabinoid anandamide and CB1 receptor adaptations.

    “Animal studies17 have shown that chronic stress is associated with decreased brain levels of the endocannabinoid anandamide and CB1 receptor adaptations17–19”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [17] Hill MN, Patel S, Carrier EJ, Rademacher DJ, Ormerod BK, Hillard CJ et al. Downregulation of endocannabinoid signaling in the hippocampus following chronic unpredictable stress. Neuropsychopharmacology 2005; 30: 508–515. source

      Not checked in the free run.

    • cites [18] Reich CG, Taylor ME, McCarthy MM . Differential effects of chronic unpredictable stress on hippocampal CB1 receptors in male and female rats. Behav Brain Res 2009; 203: 264–269. source

      Not checked in the free run.

    • cites [19] Hill MN, Carrier EJ, McLaughlin RJ, Morrish AC, Meier SE, Hillard CJ et al. Regional alterations in the endocannabinoid system in an animal model of depression: effects of concurrent antidepressant treatment. J Neurochem 2008; 106: 2322–2336. source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductown data

    [11C]OMAR injection parameters, age, sex, education, nature of trauma histories, and body mass index did not differ among the groups.

    “[11C]OMAR injection parameters, age, sex, education, nature of trauma histories, and body mass index did not differ among the groups”
    Quote in the paperSubstantial claim

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

    Study design and conductown data

    Seventy-two participants were recruited into the study and 60 completed the protocol.

    “Seventy-two participants were recruited into the study and 60 completed the protocol.”
    Quote in the paperNot a substantial claim

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

    Study design and conductcitation

    Trauma history was assessed using the Traumatic Life Events Questionnaire (TLEQ).

    “trauma history was assessed using the Traumatic Life Events Questionnaire (TLEQ)28.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [28] Kubany ES, Haynes SN, Leisen MB, Owens JA, Kaplan AS, Watson SB et al. Development and preliminary validation of a brief broad-spectrum measure of trauma exposure: the Traumatic Life Events Questionnaire. Psychol Assess 2000; 12: 210–224. source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductown data

    The PTSD group was significantly more likely than the HC and TC groups to currently smoke cigarettes, and to have a lifetime history of mood or anxiety disorder, and alcohol or drug abuse.

    “The PTSD group was significantly more likely than the HC and TC groups to currently smoke cigarettes, and to have a lifetime history of mood or anxiety disorder, and alcohol or drug abuse”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    The absence of substance use (including cannabis) was determined by self-report and confirmed by urine toxicology and breathalyzer test at screening, and on the days of MR and PET imaging.

    “The absence of substance use (including cannabis) was determined by self-report and confirmed by urine toxicology and breathalyzer test at screening, and on the days of MR and PET imaging.”
    Quote in the paperSubstantial claim

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

    Study design and conductcitation

    Head motion was measured using the Polaris Vicra optical tracking system and incorporated into PET image reconstruction with all corrections.

    “Head motion was measured using the Polaris Vicra optical tracking system (Northern Digital Inc., Waterloo, Ontario, Canada) and incorporated into PET image reconstruction with all corrections.37.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [37] Design of a motion-compensation OSEM List-mode Algorithm for Resolution-Recovery Reconstruction of the HRRT. Proceedings of the Conf Record IEEE Nuclear Science Symposium and Medical Imaging. Portland, OR, 2003.

      Not checked in the free run.

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

    Study design and conductown data

    The groups did not differ with respect to lifetime and current alcohol use and nicotine dependence.

    “but the groups did not differ with respect to lifetime and current alcohol use and nicotine dependence.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    There was a greater proportion of white individuals in the HC than TC and PTSD groups.

    “there was a greater proportion of white individuals in the HC than TC and PTSD groups.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    Psychiatric diagnoses were made using DSM-IV-TR criteria and the Structured Clinical Interview for DSM-IV (SCID), administered by an experienced psychiatric clinician.

    “Psychiatric diagnoses were made using Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition – Text Revision (DSM-IV-TR) criteria and the Structured Clinical Interview for DSM-IV (SCID), which was administered by an experienced psychiatric clinician25, 26.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [25] First MB, Spitzer RL, Gibbons M, Williams JBW . Structured Clinical Interview for DSM-IV Axis I Disorders. New York State Psychiatric Institute, Biometrics Research: New York, NY, USA, 1995.

      Not checked in the free run.

    • cites [26] DSM-IV APATFo. Diagnostic and Statisical Manual of Mental Disorders: DSM-IV-TR, 4th, Text Revision Edn. American Psychiatric Association: Washington, DC, USA, 2000.

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    PTSD symptom severity was assessed using the Clinician-Administered PTSD Scale for DSM-IV (CAPS).

    “PTSD symptom severity was assessed using the Clinician-Administered PTSD Scale for DSM-IV (CAPS)27”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [27] Blake DD, Weathers FW, Nagy LM, Kaloupek DG, Gusman FD, Charney DS et al. The development of a Clinician-Administered PTSD Scale. J Trauma Stress 1995; 8: 75–90. source

      Not checked in the free run.

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

    Premisecitation

    Stress-related up-regulation of CB1 receptors is observed predominantly in female animals.

    “with stress-related up-regulation of CB1 receptors observed predominantly in female animals18.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [18] Reich CG, Taylor ME, McCarthy MM . Differential effects of chronic unpredictable stress on hippocampal CB1 receptors in male and female rats. Behav Brain Res 2009; 203: 264–269. source

      Not checked in the free run.

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

    Premisecitation

    In animals, CB1 receptor levels are higher in males than females.

    “Animal data showing higher CB1 receptor levels in male relative to female animals18, 56, 57”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [18] Reich CG, Taylor ME, McCarthy MM . Differential effects of chronic unpredictable stress on hippocampal CB1 receptors in male and female rats. Behav Brain Res 2009; 203: 264–269. source

      Not checked in the free run.

    • cites [56] Riebe CJ, Hill MN, Lee TT, Hillard CJ, Gorzalka BB . Estrogenic regulation of limbic cannabinoid receptor binding. Psychoneuroendocrinology 2010; 35: 1265–1269. source

      Not checked in the free run.

    • cites [57] Rubino T, Vigano D, Realini N, Guidali C, Braida D, Capurro V et al. Chronic delta 9-tetrahydrocannabinol during adolescence provokes sex-dependent changes in the emotional profile in adult rats: behavioral and biochemical correlates. Neuropsychopharmacology 2008; 33: 2760–2771. source

      Not checked in the free run.

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

    Premisecitation

    The [18F]MK-9470 study found greater plasma parent fraction and higher normalized brain uptake (SUV) in men.

    “That report found greater plasma parent fraction and higher normalized brain uptake (SUV) in men, which is consistent with our findings.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [59] Van Laere K, Goffin K, Casteels C, Dupont P, Mortelmans L, de Hoon J et al. Gender-dependent increases with healthy aging of the human cerebral cannabinoid-type 1 receptor binding using [(18)F]MK-9470 PET. NeuroImage 2008; 39: 1533–1541. source

      Not checked in the free run.

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

    Premisecitation

    Individuals with PTSD have elevated rates of cannabis abuse/dependence.

    “Notably, elevated rates of cannabis abuse/dependence among individuals with PTSD have been reported48, 49.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [48] Vetter S, Rossegger A, Rossler W, Bisson JI, Endrass J . Exposure to the Tsunami disaster, PTSD symptoms and increased substance use—an Internet based survey of male and female residents of Switzerland. BMC Public Health 2008; 8: 92. source

      Not checked in the free run.

    • cites [49] Cornelius JR, Kirisci L, Reynolds M, Clark DB, Hayes J, Tarter R . PTSD contributes to teen and young adult cannabis use disorders. Addict Behav 2010; 35: 91–94. source

      Not checked in the free run.

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

    Interpretationcitation

    The current study's results are largely in agreement with a previous [18F]MK-9470 PET study on age and gender.

    “Our results are largely in agreement with a previous study that used the CB1 PET tracer [18F]MK-9470 to investigate the effects of age and gender59.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [59] Van Laere K, Goffin K, Casteels C, Dupont P, Mortelmans L, de Hoon J et al. Gender-dependent increases with healthy aging of the human cerebral cannabinoid-type 1 receptor binding using [(18)F]MK-9470 PET. NeuroImage 2008; 39: 1533–1541. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Women are at greater risk for developing PTSD following exposure to various types of trauma than men even when sexual trauma is excluded.

    “why women are at greater risk for developing PTSD following exposure to various types of trauma than men even when sexual trauma—which is more common in women—is excluded61.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [61] Stein MB, Walker JR, Forde DR . Gender differences in susceptibility to posttraumatic stress disorder. Behav Res Ther 2000; 38: 619–628. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable). May combine two claims.

    Interpretationown data

    The data reported in this paper provide a foundation to develop and validate informative biomarkers of PTSD vulnerability and to guide rational development of next-generation evidence-based treatments for PTSD.

    “As such, they provide a foundation upon which to develop and validate informative biomarkers of PTSD vulnerability, as well as to guide the rational development of the next generation of evidence-based treatments for PTSD.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Drug development in PTSD has been opportunistic, building almost entirely on empirical observations with drugs approved for other indications.
    • Rests on an assumption: [11C]OMAR VT quantitatively reflects CB1 receptor availability.

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

    Premisecitation

    Enhanced anandamide signaling can curb the effects of chronic stress, possibly by maintaining normal amygdala function via extinction-driven reductions in fear resulting in improved stress-reactivity in humans.

    “as emerging data have revealed that enhanced anandamide signaling can curb the effects of chronic stress, possibly by maintaining normal amygdala function64 via extinction-driven reductions in fear resulting in improved stress-reactivity in humans10.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [64] Hill MN, Kumar SA, Filipski SB, Iverson M, Stuhr KL, Keith JM et al. Disruption of fatty acid amide hydrolase activity prevents the effects of chronic stress on anxiety and amygdalar microstructure. Mol Psychiatry, advance online publication, 10 July 2012; doi:10.1038/mp.2012.90 (e-pub ahead of print). source

      Not checked in the free run.

    • cites [10] Gunduz-Cinar O, Macpherson KP, Cinar R, Gamble-George J, Sugden K, Williams B et al. Convergent translational evidence of a role for anandamide in amygdala-mediated fear extinction, threat processing and stress-reactivity. Mol Psychiatry, advance online publication, 12 June 2012; doi:10.1038/mp.2012.72 (e-pub ahead of print). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Women may be at increased risk for PTSD when exposed to trauma because they show higher CB1 receptor availability than men under basal, non-stress conditions.

    “If, as our results suggest, women show higher CB1 receptor availability than men already under basal, non-stress conditions, then they may be at increased risk for PTSD when exposed to trauma.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: [11C]OMAR VT quantitatively reflects CB1 receptor availability.

  • May combine two claims.

    Premisecitation

    Down-regulation of CB1 receptors may result in a depression-like phenotype in certain individuals and increase risk of addiction.

    “which may in turn result in a depression-like phenotype in certain individuals54 and increase risk of addiction55.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [54] Beyer CE, Dwyer JM, Piesla MJ, Platt BJ, Shen R, Rahman Z et al. Depression-like phenotype following chronic CB1 receptor antagonism. Neurobiol Dis 2010; 39: 148–155. source

      Not checked in the free run.

    • cites [55] Klugmann M, Klippenstein V, Leweke FM, Spanagel R, Schneider M . Cannabinoid exposure in pubertal rats increases spontaneous ethanol consumption and NMDA receptor associated protein levels. Int J Neuropsychopharmacol 2011; 14: 505–517. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The current measurements are compatible with the [18F]MK-9470 data, and discrepant interpretations are accounted for by different endpoints (arterial input function kinetic VT vs SUV).

    “Thus, our measurements are compatible with those of the previously reported [18F]MK-9470 data and the discrepant interpretations appear to be accounted for by different endpoints centered on our use of arterial input functions in kinetic analyses rather than the simplified outcome of normalized brain concentration.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    The available data do not support recommending self-medication with cannabis (tetrahydrocannabinol) for the treatment of PTSD.

    “However, such data do not allow the conclusion that self-medication with cannabis with its primary psychoactive constituent tetrahydrocannabinol should be recommended for the treatment of PTSD”
    Quote in the paperSubstantial claim
51 of 51

  • The paper relies on this without support.

    The specific role of endocannabinoids and CB1 receptors in people with PTSD has not been studied.

    “However, their specific role has not been studied in people with PTSD.”

  • The paper relies on this without support.

    It is not clear whether animal findings about chronic stress and CB1 receptors apply to PTSD in humans.

    “However, it is not clear whether these animal findings apply to PTSD in humans.”

  • The paper relies on this without support.

    [11C]OMAR volume of distribution (VT) is directly proportional to CB1 receptor availability.

    “which is directly proportional to CB1 receptor availability.”

  • The paper relies on this without support.

    Peripheral anandamide levels reflect central CB1 receptor-mediated endocannabinoid signaling.

    “These results suggest that abnormal CB1 receptor-mediated anandamide signaling is implicated in the etiology of PTSD”

  • The paper relies on this without support.

    Drug development in PTSD has been opportunistic, building almost entirely on empirical observations with drugs approved for other indications.

    “To date, drug development in PTSD has been opportunistic, building almost entirely on empirical observations with drugs approved for other indications.”

  • The paper relies on this without support.

    [11C]OMAR VT quantitatively reflects CB1 receptor availability.

    “which quantitatively reflects CB1 receptor availability”
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?

  • AEA levels are reduced in PTSD patients.

    “AEA levels have been shown to be reduced in PTSD patients (Hill et al., 2013;Neumeister et al., 2013) and depressed patients with high anxiety scores (Hill, Miller, Carrier, Gorzalka, & Hillard, 2009;Hill, Miller, Ho, Gorzalka, & Hillard, 2008).”

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

  • AEA levels are reduced in patients with major depression and PTSD.

    “a number of studies have detected reduced levels of AEA in patients suffering from stress-related psychiatric illnesses, including major depression (Hill et al., 2009) and PTSD (Neumeister et al., 2013).”

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

  • Recent clinical reports have demonstrated decreased peripheral levels of AEA and increases in brain CB1R-binding in patients with anxiety disorders, such as PTSD.

    “Moreover, recent clinical reports have demonstrated decreased peripheral levels of AEA and increases in brain CB1R-binding in patients with anxiety disorders, such as post-traumatic stress disorder [107].”

    From Amygdala FAAH and anandamide: mediating protection and recovery from stress (2013) · cites this paper as [107]

Statistics recomputed

Every reported test result, recomputed from its test statistic and degrees of freedom. A result shows as not adding up only once an independent check has confirmed it.

  • ConsistentF(2, 53) = 7.96reported p = .001 · recomputed p < .001

    “F(2,53)=7.96, p = .001”

  • ConsistentF(1, 53) = 5.52reported p = .023 · recomputed p = .023

    “F(1,53)=5.52, p = .023”

  • ConsistentF(2, 53) = 2.75reported p = .073 · recomputed p = .073

    “F(2,53)=2.75, p = .073”

  • ConsistentF(2, 53) = 9.75reported p < .001 · recomputed p < .001

    “F(2,53)=9.75, p < .001”

  • ConsistentF(1, 53) = 4.23reported p = .045 · recomputed p = .045

    “F(1,53)=4.23, p = .045”

  • ConsistentF(1, 53) = 1reported p = .32 · recomputed p = .322

    “F(1,53)=1.00, p = .32”

  • ConsistentF(2, 53) = 1.47reported p = .24 · recomputed p = .239

    “F(2,53)=1.47, p = .24”

  • ConsistentF(1, 45) = 2.91reported p = .095 · recomputed p = .095

    “F(1,45)=2.91, p = .095”

  • ConsistentF(1, 45) = 0.55reported p = .46 · recomputed p = .462

    “F(1,45)=.55, p = .46”

  • ConsistentF(2, 45) = 0.02reported p = .98 · recomputed p = .980

    “F(2,45)=.02, p = .98”

  • ConsistentF(2, 52) = 12.69reported p < .001 · recomputed p < .001

    “F(2,52)=12.69, p < .001”

  • ConsistentF(1, 52) = 0.05reported p = .82 · recomputed p = .824

    “F(1,52)=.05, p = .82”

  • ConsistentF(1, 52) = 1.84reported p = .18 · recomputed p = .181

    “F(1,52)=1.84, p = .18”

  • ConsistentF(2, 52) = 0.33reported p = .72 · recomputed p = .720

    “F(2,52)=.33, p = .72”

14 of 14

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.

  • Reported CB1 means reverse the stated sex difference

    Minor

    The means are presented in women-then-men order, but 1.233 is lower than 1.369, contrary to the statement that women had higher values.

  • Abstract attributes the sex main-effect test to a stronger PTSD elevation in women

    Minor

    The abstract cites F(1,53)=5.52, p=.023 for the claim that the PTSD-related elevation was most pronounced in women. The results identify that statistic as the main effect of sex; the group-by-sex interaction is instead reported as F(2,53)=2.75, p=.073.

  • Reported anandamide means reverse the stated sex difference

    Minor

    The means are presented in women-then-men order, but 2.44 is higher than 1.76, contrary to the statement that women had lower levels.

3 of 3

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Normandin MD, Zheng M-Q, Ropchan J, Najafzadeh S, Hull R, Qian W et al. Test–retest reproducibility and gender differences in binding of CB1 PET tracer [11C]OMAR in humans. 57th Annual Meeting of SNM. Salt Lake City, UT, 2010.

Cited by

Sorted by citations

Related

Authors
Neumeister, A., Normandin, M. D., Pietrzak, R. H., Piomelli, D., Zheng, M. Q., Gujarro-Anton, A., Potenza, M. N., Bailey, C. R., Lin, S. F., Najafzadeh, S., Ropchan, J., Henry, S., Corsi-Travali, S., Carson, R. E., & Huang, Y.
Affiliations
  • NYU Langone Health (US)
  • Harvard University (US)
  • United States Department of Veterans Affairs (US)
  • University of California, Irvine (US)
  • Yale University (US)
  • Johns Hopkins Medicine (US)
Corresponding author
Neumeister, A
ORCID
Venue
Molecular Psychiatry
Publisher
Springer Science and Business Media LLC
Published
2013-05-14
Volume
18
Issue
9
Pages
1034-1040
ISSN
  • 1359-4184 (ISSN-L)
  • 1476-5578
DOI
10.1038/mp.2013.61
PMC
PMC3752332
OpenAlex
W2110064169
Semantic Scholar
bbfea0a0e7a46564b1d4a301c4259d6e7f2f6acb
Cited by
361
References
65
Citations by year
2026: 15 · 2025: 18 · 2024: 25 · 2023: 26 · 2022: 24 · 2021: 39 · 2020: 32 · 2019: 28 · 2018: 32 · 2017: 27 · 2016: 32 · 2015: 26 · 2014: 20 · 2013: 16
FWCI
23.05
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Psychiatry (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
Funders
  • National Institute on Alcohol Abuse and Alcoholism (RL1AA017540)
  • National Institute of Mental Health (R21MH085627, R01MH096876, R21MH096105, R21MH094763)
  • National Center for Research Resources (UL1RR024139)
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, CB1 receptor, endocannabinoids, anandamide, receptor availability, trauma exposure, cortisol, biomarkers, sex differences, 2-arachidonoylglycerol, oleoylethanolamide, palmitoylethanolamide
MeSH terms
Adult, Amides, Analysis of Variance, Arachidonic Acids, Brain, Ethanolamines, Female, Glycerides, Humans, Hydrocortisone, Imidazoles, Male, Palmitic Acids, Piperidines, Pyrazoles, Radionuclide Imaging, Stress Disorders, Post-Traumatic, Logistic Models, Receptor, Cannabinoid, CB1, Polyunsaturated Alkamides, Young Adult, 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.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review