Integrating Endocannabinoid Signaling and Cannabinoids into the Biology and Treatment of Posttraumatic Stress Disorder

Hill, Matthew N.; Campolongo, Patrizia; Yehuda, Rachel; Patel, Sachin

doi:10.1038/npp.2017.162

Cited by 193 publications

(150 citation statements)

References 362 publications

(470 reference statements)

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“…Cannabis, a psychoactive substance, is demonstrated to have anti‐inflammatory properties and might be beneficial in the treatment of PTSD . The endocannabinoid system is shown to be involved in multiple aspects of the pathophysiology of PTSD, including inflammatory processes, and in line with this, several uncontrolled or small studies have reported the potential usefulness of cannabis (including whole plant marijuana and related cannabinoids) in the treatment of this disorder, particularly for the domains of sleep and nightmares . At present, however, a balanced view would be that obvious risks of cannabis, such as psychosis and substance misuse, outweigh unestablished benefits for PTSD …”

Section: Potential Anti‐inflammatory Treatment Strategiesmentioning

confidence: 99%

Inflammation and post‐traumatic stress disorder

Hori

Kim

2019

Psychiatry Clin Neurosci

278

176

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While post‐traumatic stress disorder (PTSD) is currently diagnosed based solely on classic psychological and behavioral symptoms, a growing body of evidence has highlighted a link between this disorder and alterations in the immune and inflammatory systems. Epidemiological studies have demonstrated that PTSD is associated with significantly increased rates of physical comorbidities in which immune dysregulation is involved, such as metabolic syndrome, atherosclerotic cardiovascular disease, and autoimmune diseases. In line with this, a number of blood biomarker studies have reported that compared to healthy controls, individuals with PTSD exhibit significantly elevated levels of proinflammatory markers, such as interleukin‐1β, interleukin‐6, tumor necrosis factor‐α, and C‐reactive protein. Moreover, various lines of animal and human research have suggested that inflammation is not only associated with PTSD but also can play an important role in its pathogenesis and pathophysiology. In this review, we first summarize evidence suggestive of increased inflammation in PTSD. We then examine findings that suggest possible mechanisms of inflammation in this disorder in terms of two different but interrelated perspectives: putative causes of increased proinflammatory activities and potential consequences that inflammation generates. Given that there is currently a dearth of treatment options for PTSD, possibilities of new therapeutic approaches using pharmacological and non‐pharmacological treatments/interventions that have anti‐inflammatory effects are also discussed. Despite the increasing attention given to the inflammatory pathology of PTSD, there remains much to be elucidated, including more detailed mechanisms of inflammation, potential usefulness of inflammatory biomarkers as diagnostic and prognostic markers, and efficacy of novel treatment strategies targeting inflammation.

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Section: Potential Anti‐inflammatory Treatment Strategiesmentioning

confidence: 99%

Inflammation and post‐traumatic stress disorder

Hori

Kim

2019

Psychiatry Clin Neurosci

278

176

View full text Add to dashboard Cite

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“…As mentioned, catecholamines are compounds produced by the adrenal gland to serve as either neurotransmitters (i.e., dopamine, epinephrine, norepinephrine) for the facilitation of neuronal communication, or as hormones, which regulate physiological functions such as heart rate and blood pressure (Langer, ; Smith & Winkler, ). With regard to pain modulation, fight‐or‐flight responses signal for the release of endocannabinoid‐mediated analgesics, which function to reduce the experience of pain without the immobilizing side effects of opioid analgesics (Dasilva et al, ; Nuseir et al, ; for a review, see Hill, Yehuda, & Patel, ; Hillard, ; Lanius et al, ). These physiological alterations culminate in an active defensive response in animals and humans alike and are coordinated principally by the periaqueductal gray of the midbrain (De Oca et al, ; for a review, see Carrive, ) (Figure ).…”

Section: Fight‐or‐flightmentioning

confidence: 99%

The effects of trauma on brain and body: A unifying role for the midbrain periaqueductal gray

Terpou

Harricharan

McKinnon

et al. 2019

J of Neuroscience Research

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Post-traumatic stress disorder (PTSD), a diagnosis that may follow the experience of trauma, has multiple symptomatic phenotypes. Generally, individuals with PTSD display symptoms of hyperarousal and of hyperemotionality in the presence of fearful stimuli. A subset of individuals with PTSD; however, elicit dissociative symptomatology (i.e., depersonalization, derealization) in the wake of a perceived threat. This pattern of response characterizes the dissociative subtype of the disorder, which is often associated with emotional numbing and hypoarousal. Both symptomatic phenotypes exhibit attentional threat biases, where threat stimuli are processed preferentially leading to a hypervigilant state that is thought to promote defensive behaviors during threat processing. Accordingly, PTSD and its dissociative subtype are thought to differ in their proclivity to elicit active (i.e., fight, flight) versus passive (i.e., tonic immobility, emotional shutdown) defensive responses, which are characterized by the increased and the decreased expression of the sympathetic nervous system, respectively. Moreover, active and passive defenses are accompanied by primarily endocannabinoid-and opioid-mediated analgesics, respectively. Through critical review of the literature, we apply the defense cascade model to better understand the pathological presentation of defensive responses in PTSD with a focus on the functioning of lower-level midbrain and extended brainstem systems. K E Y W O R D Sbrainstem, dissociation, periaqueductal gray, PTSD, trauma | INTRODUC TI ONIn this review, we integrate literature from trauma experiences, the defense cascade, and the threat-response neurocircuitry within a framework of post-traumatic stress disorder (PTSD). We begin by introducing the concepts of the hypothalamic-pituitary-adrenal (HPA) axis, general PTSD, and defensive responses. Following these primers, we discuss the influences of trauma onset and prolonged exposure to trauma and their effects on the development of PTSD and the dissociative subtype of PTSD. Next, we introduce the defense cascade model and its underlying neurocircuitry as described in the animal literature and relate it to PTSD. In addition, we discuss the current state of the neuroimaging literature, which Edited by Sandra Chanraud.All peer review communications can be found with the online version of the article. | 1111TERPOU ET al. suggests that functional alterations are detectable in the midbrain of individuals with PTSD and its dissociative subtype as compared to healthy controls. We conclude by presenting directions for future research and the clinical implications for treatment of persons with PTSD that arise from this review of the extant literature.

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“…Moreover, elucidating conserved molecular mechanisms linking stress to affective psychopathology could reveal novel therapeutic approaches to mitigate the adverse effects of stress on mental health. Although identification of a number of stress-regulatory neuromodulatory signaling systems has revealed potentially novel therapeutic targets for affective disorders, endogenous cannabinoid (eCB) signaling represents a leading drug-development candidate (2017; Hill et al, 2018;Hill and Patel, 2013;Lowe et al, 2018;Patel et al, 2017). eCB signaling systems have been heavily implicated in stress-response physiology and pharmacological augmentation of eCB signaling has been suggested to represent a novel approach for the treatment of stress and trauma-related psychiatric disorders Patel et al, 2017).…”

Section: Introductionmentioning

confidence: 99%