The Endocannabinoid System – Ch 9: PTSD & The ECS

Introduction

PTSD (Post-traumatic Stress Disorder) is a serious mental health condition that develops as a consequence of a traumatic experience. Symptoms include re-experiencing distressing aspects of the trauma, hyper-arousal, avoidance of trauma reminders, sleep disturbances, and negative cognitions and mood. PTSD is a condition associated with immense suffering and disrupted socio-occupational functioning. Is not simply a psychiatric disorder, but one that involves pervasive physiological impairments as well.

Its symptomology is believed to be largely caused by a combination of dysregulated biological stress responses and maladaptive memory processes. At the time of trauma, sympathetic and central stress hormones (i.e. noradrenaline and cortisol) are released at excessive levels as part of the stress response. Excessive release of these hormones causes emotional salience to the events, which in turn leads to over-consolidation of the trauma and the associated environment in which the trauma occurred. Studies in humans have shown that interactions between noradrenaline and cortisol can predict the number of intrusive memories following exposure to emotional or traumatic images; however, not all people exposed to traumatic events will develop these symptoms. Therefore, researchers are often interested in understanding the predisposing factors (i.e. biomarkers, environment, etc.) that determine the patient’s development of emotional or intrusive memories following trauma. The discovery of these biomarkers will guide the evolution of precision medicine in the treatment of PTSD.

Currently, the gold-standard psychological treatment for PTSD is exposure therapy. Herein, patients are encouraged to gradually confront reminders of their trauma, enabling them to learn how to regulate their fear of the no-longer threatening situation. Unfortunately, roughly 40% of patients experience merely a partial response to the treatment. Physicians combine pharmacological therapies with exposure therapy to enhance the treatment response, though has yet to emerge a promising pharmaceutical therapy.

Recently, the ECS (endocannabinoid system) has also been recognized as a modulator of stress responses, emotional memories, and fear extinction. AEA (Anandamide) concentration was found to reduce stress responses through the modulation of the HPA axis. This results in an increase in glucocorticoids which mobilizes 2- AG, thus, mediating glucocorticoid-driven negative feedback and termination of the stress response. Accordingly, PTSD has been associated with decreased endocannabinoid concentrations in war veterans following the World Trade Centre attacks, implying that endocannabinoids are involved in trauma responses in humans. Thus, cannabis-based medicines hold a promising pharmacological therapy against PTSD. Unfortunately, despite substantial research committed to the effect of cannabinoid modulation on PTSD symptomologies, there is not a consented cannabinoid treatment for PTSD.

Literature

A review published by the University of Tasmania and the University of Melbourne in Australia presents the strengths and challenges of potential cannabinoid treatments accessible to psychological researchers. They discussed how mild to moderate doses of THC improves fear extinction and analog emotional memory tasks in animals via the mPFC (medial prefrontal cortex) CB1-dependent mechanism. In fMRIs of healthy participants, THC improved fear extinction recall by enhancing the ventral-mPFC and hippocampal responses during extinction recall. Likewise, CBD showed significant reductions in symptomology in ten out of eleven PTSD patients prescribed 25-100mg of CBD per day over an eight-week trial. Researchers also discussed the improvements in nightmares, sleep quality, hyperarousal, and overall symptomologies of PTSD patients following the administration of marketed synthetic analogs of THC such as nabilone. Finally, they reviewed the therapeutic potential of the most popular selective inhibitors of FAAH (SSR411298, JNJ-42165279, PF-04457845, PF-04457845, and SSR-411298) against the symptoms of PTSD. Generally speaking, past reviews have found that FAAH inhibition favorably enhances fear extinction and other processes relevant to PTSD.

Furthermore, a review by the Veterans Affairs San Diego Healthcare System and the University of California at San Diego outlined evidence for the potential of cannabinoids in relieving many chronic physiological abnormalities seen in PTSD. More specifically, abnormalities thought to be caused by AL (allostatic load excess). The primary metabolic assessments in measures of AL include HDL, low-density lipoprotein (LDL), triglycerides, insulin resistance (IR), body mass index (BMI), and waist-to-hip ratio (WHR). Increased AL is associated with increases in all of these except HDL, where a decrease is considered abnormal. Cannabinoids were generally found to move these measures in the opposite direction, therefore reducing AL and ameliorating PTSD symptoms.

Finally, a review published by the University of Illinois in the United States examined the role of allopregnanolone biosynthesis and the ECS for stress-induced disorders with a focus on PTSD. The biosynthesis of allopregnanolone, a modulator of GABA’s action, was found to be deficient in a number of psychopathologies including PTSD. The regulation of allopregnanolone biosynthesis through the ECS has recently opened the possibility to encounter valuable PTSD biomarkers at the interface of neuronal systems. The crosstalk between the ECS and the neurosteroid’s biosynthesis promises to provide unique bio-signatures for stress-induced disorders.

Limitations

There were a few limitations within the studies discussed. Most of the results are based on clinical studies, nonetheless, some of them still can’t be generalized to the entire human population. Moreover, details about the ideal treatment for patients such as dosages are still not well-defined.

Conclusions

In recent years, cannabinoid-based agents have become an integral part of drug discovery for PTSD treatment. Studies have begun to show that the ECS interacts with multiple signaling systems across different brain regions to influence PTSD aetiology and maintenance. Nonetheless, despite early clinical evidence showing improvements in PTSD symptomology with regular THC, chronic THC administration is yet problematic due to its off-target effects, endocannabinoid system downregulation, difficulties regulating dosing, and mental health complications. Therefore, a lot of attention has been focused on the inhibition of catabolic enzymes and CBD. Generally, the results of studies involving endocannabinoid inhibitors and CBD and extinction learning/recall tasks in healthy humans have been promising. However, there is a current need for randomized controlled trials where PTSD patients’ symptomology is measured during and after cannabinoid therapy. Future clinical studies should focus on discerning which PTSD symptoms are being improved or worsened depending on the cannabinoid treatment. Future research will also benefit from focusing on the role of the ECS in other systems relevant to PTSD, such as the dopaminergic and serotonergic systems.

Lohr, J. B., Chang, H., Sexton, M., & Palmer, B. W. (2019). Allostatic load and the cannabinoid system: implications for the treatment of physiological abnormalities in post-traumatic stress disorder (PTSD). CNS Spectrums, 1–7. doi:10.1017/s1092852919001093

L. Ney, A. Matthews, R. Bruno, et al., (2019). Cannabinoid interventions for PTSD: Where to next?, Progress in Neuropsychopharmacology & Biological Psychiatry, https://doi.org/10.1016/j.pnpbp.2019.03.017

Pinna G (2018) Biomarkers for PTSD at the Interface of the Endocannabinoid and Neurosteroid Axis. Front. Neurosci. 12:482. doi: 10.3389/fnins.2018.00482