Endocannabinoid concentrations in hair are associated with PTSD symptom severity

Abstract

a b s t r a c tThe endocannabinoid system has been implicated in the regulation of the stress response, fear memory formation, and inflammatory processes. Posttraumatic stress disorder (PTSD) can result from exposure to extreme stress and is characterized by strong, associative memories for the traumatic events experienced. Furthermore, an elevated physical disease risk has been observed in PTSD, likely to be mediated by inflammatory processes. Therefore, altered endocannabinoid regulation can be expected in individuals with PTSD. However, attempts to assess PTSD-associated differences in the endocannabinoid system from human blood samples have provided inconsistent results, possibly due to fluctuating levels of endocannabinoids. In hair, these neuromodulators are accumulated over time and thus give access to a more stable and reliable assessment.We therefore investigated PTSD-associated differences in hair concentrations of endocannabinoids (Nacyl-ethanolamides palmitoylethanolamide [PEA], oleoylethanolamide [OEA] and stearoylethanolamide [SEA]) in 38 rebel war survivors from Northern Uganda suffering from PTSD and N = 38 healthy rebel war survivors without current and lifetime PTSD. PTSD diagnosis and symptom severity were assessed in structured clinical interviews employing the Posttraumatic Diagnostic Scale (PDS). A significant group difference was observed for OEA, with PTSD patients showing reduced hair concentrations. Regression analyses further revealed strong negative relationships between all investigated N-acyl-ethanolamides and symptom severity of PTSD. The observed reductions in endocannabinoids might account for the increased inflammatory state as well as for the failure to extinguish fear memories observed in PTSD. Our findings add to the accumulating evidence suggesting the endocannabinoid system as a target for pharmacological enhancement of exposure-based psychotherapy for PTSD.

Is There a Future for PPARs in the Treatment of Neuropsychiatric Disorders?

“…These findings strongly support the involvement of PPARs in the neuropathology of mood and neurodevelopmental disorders [100]. A PPAR-α-allopregnanolone (i.e., endocannabinoid-like/ neurosteroids) cross-talk may have an impact for establishing relevant novel targets for the treatment of PTSD and major depression [9].…”

“…In the socially isolated mouse, PEA improved contextual fear responses and facilitated contextual fear extinction and fear extinction retention, as well as ameliorated depressive-like and anxiety-like behavior by increasing corticolimbic levels of allopregnanolone [10]. Consistently, in a cohort of Ugandan war survivors affected by PTSD, the hair levels of PEA, oleoylethanolamide (OEA), and stearoylethanolamide (SEA) were found to be decreased when compared with levels of war survivors without current or lifetime PTSD [100], thus suggesting a decreased PPAR-α signal pathway in PTSD. While it is important that these findings will be confirmed also in blood and post-mortem brain of PTSD patients [101], this observation provides support to the involvement of the PPAR-allopregnanolone axis dysfunction in PTSD.…”

Context Processing and the Neurobiology of Post-Traumatic Stress Disorder

“…These include alterations in serotonin systems (Southwick et al, 1999), DHEA (Yehuda et al, 2006), neuropeptide Y (Rasmusson et al, 2000), neurosteroids (Morris et al, 2012), endocannabinoids (Wilker et al, 2016) and endogenous opioids (van der Kolk et al, 1989). Genetic work is rapidly expanding, and has identified PTSD-linked polymorphisms in genes encoding elements within the HPA axis (FKBP5 (Binder et al, 2008) and CRHR1 (Amstadter et al, 2011; White et al, 2013; Etkin et al, 2015)), and the sympatho-adrenal system (ADRB2 (Liberzon et al, 2014) and COMT (Boscarino et al, 2011)).…”

Neurobiological Trajectories Involving Social Isolation in PTSD: A Systematic Review

“…N-palmitoylethanolamine (PEA), an endogenous lipid modulator, is considered part of the extended e-CB next to AEA and 2-AG is considered an analgesic, neuroprotective and antioxidant agent, exerting its pharmacological function by stimulating the peroxisome proliferator-activated receptor -α (PPAR-α), a ligand-activated nuclear receptor [18]. Research has shown that PEA levels in blood show strong negative association with PTSD symptom severity in humans [19] and become increased by antidepressants in corticolimbic regions of rats [20]. Furthermore, PEA binding at PPAR-α interacts with the gamma-aminobutyric acidergic (GABAergic) neurosteroid system in the biosynthesis of allopregnanolone (Allo) [18].…”