Circulating Endocannabinoids and Genetic Polymorphisms As Predictors of Posttraumatic Stress Disorder Symptom Severity: Heterogeneity in a Community-based Cohort

Overview

Journal Transl Psychiatry

Specialties Psychiatry
Public Health

Date 2022 Feb 2

PMID 35105857

Authors

Terri A deRoon-Cassini

Carisa L Bergner

Samantha A Chesney

Nicholas R Schumann

Tara Sander Lee

Karen J Brasel

Cecilia J Hillard

Affiliations

Soon will be listed here.

Abstract

The endocannabinoid signaling system (ECSS) regulates fear and anxiety. While ECSS hypoactivity can contribute to symptoms of established post-traumatic stress disorder (PTSD), the role of the ECSS in PTSD development following trauma is unknown. A prospective, longitudinal cohort study of 170 individuals (47% non-Hispanic Caucasian and 70% male) treated at a level 1 trauma center for traumatic injury was carried out. PTSD symptom assessments and blood were obtained during hospitalization and at follow-up (6-8 months post injury). Serum concentrations of the endocannabinoids N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG) were determined at both time points and selected genetic polymorphisms in endocannabinoid genes, including rs324420 in fatty acid amide hydrolase, were assessed. For the entire sample, serum concentrations of AEA at hospitalization were significantly higher in those diagnosed with PTSD at follow-up (p = 0.030). Serum concentrations of 2-AG were significantly, positively correlated with PTSD symptom severity at follow-up only in minorities (p = 0.014). Minority participants (mostly Black/African American) also demonstrated significant, negative correlations between serum AEA concentrations and PTSD symptom severity both measured at hospitalization (p = 0.015). The A/A genotype at rs324420 was associated with significantly higher PTSD symptom severity (p = 0.025) and occurred exclusively in the Black participants. Collectively, these results are contrary to our hypothesis and find positive associations between circulating endocannabinoids and risk for PTSD. Minority status is an important modulator of the association between endocannabinoids and risk for PTSD, suggesting that the ECSS contributes to risk most significantly in these individuals and the contextual factors related to these findings should be further explored.

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References

Crombie K, Leitzelar B, Brellenthin A, Hillard C, Koltyn K . Loss of exercise- and stress-induced increases in circulating 2-arachidonoylglycerol concentrations in adults with chronic PTSD. Biol Psychol. 2019; 145:1-7. DOI: 10.1016/j.biopsycho.2019.04.002. View

Morena M, Nastase A, Santori A, Cravatt B, Shansky R, Hill M . Sex-dependent effects of endocannabinoid modulation of conditioned fear extinction in rats. Br J Pharmacol. 2020; 178(4):983-996. PMC: 8311789. DOI: 10.1111/bph.15341. View

Spagnolo P, Ramchandani V, Schwandt M, Kwako L, George D, Mayo L . FAAH Gene Variation Moderates Stress Response and Symptom Severity in Patients with Posttraumatic Stress Disorder and Comorbid Alcohol Dependence. Alcohol Clin Exp Res. 2016; 40(11):2426-2434. PMC: 5748341. DOI: 10.1111/acer.13210. View

Best L, Williams B, Le Foll B, Mansouri E, Bazinet R, Lin L . Lower brain fatty acid amide hydrolase in treatment-seeking patients with alcohol use disorder: a positron emission tomography study with [C-11]CURB. Neuropsychopharmacology. 2020; 45(8):1289-1296. PMC: 7298050. DOI: 10.1038/s41386-020-0606-2. View

Kessler R, Aguilar-Gaxiola S, Alonso J, Bromet E, Gureje O, Karam E . The associations of earlier trauma exposures and history of mental disorders with PTSD after subsequent traumas. Mol Psychiatry. 2017; 23(9):1892-1899. PMC: 5858954. DOI: 10.1038/mp.2017.194. View

Hillard C . Circulating Endocannabinoids: From Whence Do They Come and Where are They Going?. Neuropsychopharmacology. 2017; 43(1):155-172. PMC: 5719092. DOI: 10.1038/npp.2017.130. View

deRoon-Cassini T, Mancini A, Rusch M, Bonanno G . Psychopathology and resilience following traumatic injury: a latent growth mixture model analysis. Rehabil Psychol. 2010; 55(1):1-11. DOI: 10.1037/a0018601. View

Morena M, Roozendaal B, Trezza V, Ratano P, Peloso A, Hauer D . Endogenous cannabinoid release within prefrontal-limbic pathways affects memory consolidation of emotional training. Proc Natl Acad Sci U S A. 2014; 111(51):18333-8. PMC: 4280626. DOI: 10.1073/pnas.1420285111. View

Morena M, Aukema R, Leitl K, Rashid A, Vecchiarelli H, Josselyn S . Upregulation of Anandamide Hydrolysis in the Basolateral Complex of Amygdala Reduces Fear Memory Expression and Indices of Stress and Anxiety. J Neurosci. 2018; 39(7):1275-1292. PMC: 6381235. DOI: 10.1523/JNEUROSCI.2251-18.2018. View

10.

Gray J, Vecchiarelli H, Morena M, Lee T, Hermanson D, Kim A . Corticotropin-releasing hormone drives anandamide hydrolysis in the amygdala to promote anxiety. J Neurosci. 2015; 35(9):3879-92. PMC: 4348185. DOI: 10.1523/JNEUROSCI.2737-14.2015. View

11.

Shin L, Liberzon I . The neurocircuitry of fear, stress, and anxiety disorders. Neuropsychopharmacology. 2009; 35(1):169-91. PMC: 3055419. DOI: 10.1038/npp.2009.83. View

12.

Marsicano G, Wotjak C, Azad S, Bisogno T, Rammes G, Cascio M . The endogenous cannabinoid system controls extinction of aversive memories. Nature. 2002; 418(6897):530-4. DOI: 10.1038/nature00839. View

13.

Herrera-Escobar J, Seshadri A, Rivero R, Toppo A, Al Rafai S, Scott J . Lower education and income predict worse long-term outcomes after injury. J Trauma Acute Care Surg. 2019; 87(1):104-110. DOI: 10.1097/TA.0000000000002329. View

14.

Ozer E, Best S, Lipsey T, Weiss D . Predictors of posttraumatic stress disorder and symptoms in adults: a meta-analysis. Psychol Bull. 2003; 129(1):52-73. DOI: 10.1037/0033-2909.129.1.52. View

15.

Hanlon E, Tasali E, Leproult R, Stuhr K, Doncheck E, de Wit H . Circadian rhythm of circulating levels of the endocannabinoid 2-arachidonoylglycerol. J Clin Endocrinol Metab. 2014; 100(1):220-6. PMC: 5399498. DOI: 10.1210/jc.2014-3455. View

16.

Galatzer-Levy I, Ma S, Statnikov A, Yehuda R, Shalev A . Utilization of machine learning for prediction of post-traumatic stress: a re-examination of cortisol in the prediction and pathways to non-remitting PTSD. Transl Psychiatry. 2017; 7(3):e0. PMC: 5416681. DOI: 10.1038/tp.2017.38. View

17.

Gunduz-Cinar O, MacPherson K, Cinar R, Gamble-George J, Sugden K, Williams B . Convergent translational evidence of a role for anandamide in amygdala-mediated fear extinction, threat processing and stress-reactivity. Mol Psychiatry. 2012; 18(7):813-23. PMC: 3549323. DOI: 10.1038/mp.2012.72. View

18.

Mouthaan J, Sijbrandij M, Luitse J, Goslings J, Gersons B, Olff M . The role of acute cortisol and DHEAS in predicting acute and chronic PTSD symptoms. Psychoneuroendocrinology. 2014; 45:179-86. DOI: 10.1016/j.psyneuen.2014.04.001. View

19.

Di S, Malcher-Lopes R, Halmos K, Tasker J . Nongenomic glucocorticoid inhibition via endocannabinoid release in the hypothalamus: a fast feedback mechanism. J Neurosci. 2003; 23(12):4850-7. PMC: 6741208. View

20.

Hauer D, Schelling G, Gola H, Campolongo P, Morath J, Roozendaal B . Plasma concentrations of endocannabinoids and related primary fatty acid amides in patients with post-traumatic stress disorder. PLoS One. 2013; 8(5):e62741. PMC: 3647054. DOI: 10.1371/journal.pone.0062741. View