Plasma Concentrations of Endocannabinoids and Related Primary Fatty Acid Amides in Patients with Post-Traumatic Stress Disorder

Abstract

BackgroundEndocannabinoids (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.MethodsWe 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.ResultsIndividuals 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.ConclusionsPTSD 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.

Endocannabinoid Signaling within the Basolateral Amygdala Integrates Multiple Stress Hormone Effects on Memory Consolidation

“…Although emotional enhancement of memory has obvious adaptive value in evolutionary terms, the present findings might also carry important implications for maladapative stress responses. Changes in glucocorticoid (Yehuda, 2009), endocannabinoid (Hauer et al, 2013;Hill et al, 2013;Neumeister et al, 2013), and catecholaminergic (Krystal and Neumeister, 2009) signaling have repeatedly been demonstrated in individuals after malignant stress exposure and the development of posttraumatic stress disorder (PTSD). Critically, a recent study reported that the combined assessment of alterations in cortisol and anandamide levels has a much higher predictive value in classifying PTSD cases than analysis of these factors individually (Neumeister et al, 2013).…”

Endocannabinoid concentrations in hair are associated with PTSD symptom severity

“…Further studies also point towards reduced concentrations of some endocannabinoids and related N-acyl-ethanolamides in PTSD Neumeister et al, 2013). However, opposite or null effects have also been reported (Hauer et al, 2013;Schaefer et al, 2014). These inconsistencies might be due to strong variations of plasma endocannabinoid concentrations during the day (Vaughn et al, 2010).…”

Fear Memory

“…This interaction takes place at two levels: postsynaptically, by increasing the efficacy of the ␤-adrenoceptor-cAMP/PKA system, and presynaptically in the locus coeruleus cell groups that project to the BLA (546). Other interactions of glucocorticoids that might play a role in the modulation of memory, particularly fear memory, are the one with cannabinoids (233), and the one with cholinergic neurons by which glucocorticoids may reprogram the mesopontine cholinergic system (87), which deserves further research because it might represent important physiological functions. ACTH and glucocorticoids are secreted in a circadian fashion (209,269,270).…”