Endocannabinoid System as Therapeutic Target of PTSD : A Systematic Review
Luca Steardo, Jr., Elvira Anna Carbone, Giulia Menculini, Patrizia Moretti, Luca Steardo and
Life, 2021, 11, 214.
Doi : 10.3390/life11030214
Post-Traumatic Stress Disorder (PTSD) is a complex disorder involving dysregulation of stress-related hormones and neurotransmitter systems. Research focused on the endocannabinoid system (eCBS) for anxiety and stress regulation, cognitive and emotional responses modulation and aversive memories extinction, leading to the hypothesis that it could represent a possible alternative treatment target for PTSD. In this systematic review, we summarize evidence about the efficacy and safety of medicinal cannabidiol (CBD), D9-tetrahydrocannabinol (D9-THC), and nabilone in PTSD treatment. The PRISMA statement guidelines were followed. A systematic literature search was conducted in MEDLINE/ PubMed, Scopus and Web of Science by two independent researchers, who also performed data extraction and quality assessment. Among the initial 495 papers, 234 were screened for eligibility and 10 were included. Studies suggested that different medicinal cannabinoids at distinct doses and formulations could represent promising treatment strategies for the improvement of overall PTSD symptomatology as well as specific symptom domains (e.g., sleep disorders, arousal disturbances, suicidal thoughts), also influencing quality of life, pain and social impact. Although there is a robust rationale for treatment with drugs that target the eCBS and the results are promising, further studies are needed to investigate the safety and efficacy profile of their prolonged use.
Keywords : endocannabinoids; CBD; cannabidiol; THC; D9-tetrahydrocannabinol; nabilone; PTSD;
PTSD treatment; systematic review
Post-Traumatic Stress Disorder (PTSD) is a psychiatric disorder that may occur in people after experiencing or witnessing a traumatic event. This nosographic entity was previously included in the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) as an anxiety disorder, whereas in the latest edition (DSM-5) PTSD was classified under a category named “Trauma and stress-related disorders” [1,2]. With a prevalence varying up to 5% in high-income countries, PTSD is often associated with significant comorbidity rates, relevant risk of chronicization, and substantial economic
In the context of a maladaptive response to a traumatic stressor [4,5], individuals can develop symptoms such as persistent intrusive thoughts associated with the traumatic event, incessant avoidance of stimuli related to the traumatic event, negative changes in cognition and mood linked to the event, and significant and long-lasting alterations in arousal and reactivity attributable to the traumatic event. These symptoms can last for more than one month or persist for several months, causing significant distress due to poor life quality, reduced social skills, and functioning problems .
Although PTSD is caused by a psychologically traumatic environmental event and consequently it is considered a psychological phenomenon, many studies have indicated biological abnormalities, not observed in controls, which have been regarded either as risk factors for the development of the disease or as potential targets for therapeutic interventions. There have been detected changes across different stress hormones and neurotransmitter systems in the pathophysiology of PTSD. Serotoninergic, noradrenergic, glutamatergic, GABAergic, neuro-peptidergic systems and dysfunctions of the hypothalamus-adrenal axis have been reported to contribute to the disease onset and progression, even if no alteration of a single system taken individually can explain by itself the complex pathobiology underlying the disorder. In this context, and mainly based on findings from preclinical studies, a growing interest in terms of neurochemical interactions has been attracted by the endocannabinoid system (eCBS), since it makes up an extensive interconnected network of neuromodulators that controls synaptic neurotransmitter release. As it has been involved in several physiological and pathophysiological processes including synaptic plasticity, pain, memory processes, stress, and emotion regulation, its potential implication in the pathophysiology of PTSD has been regarded of considerable interest . Indeed, the eCBS plays an important role in regulating anxiety and stress and is involved in the modulation of cognitive and emotional responses , as well as in the extinction of aversive memories . This system is essential for the development of synaptic plasticity in response to endogenous and environmental salient events [9,10], determining specific learning and emotional responses related to traumatic experiences . Endocannabinoids regulate affective and emotional states and participate in memory consolidation, retrieval, and extinction [12,13]. It has been demonstrated that the learning processes regarding aversive memories are dysregulated after a traumatic event, as occurs in subjects affected by PTSD . Evidence suggests that the hypothalamic–pituitary–adrenal (HPA) system, which is essential for stress adaption, also plays a role in the pathophysiology of the disorder. Indeed, the HPA axis is chronically activated in patients with PTSD . There is a bidirectional and functional interplay between eCBS and HPA systems: the eCBS can modulate
the HPA axis function restraining the effects of severe stress on its activation [16–18], whilst the release of glucocorticoids in response to a stressor contributes to eCBS signaling deficiencies, thus facilitating PTSD symptoms .
Given the heterogeneity of the disorder and its economic and social burden, PTSD represents a challenge for safe and effective treatment . Despite more psychological treatment approaches for PTSD [21,22], the Food and Drug Administration (FDA) approved only two pharmacological treatments for PTSD, the Selective Serotonin Reuptake Inhibitors (SSRIs) paroxetine and sertraline  that do not display certain effectiveness in producing a clinical remission and may be responsible for several side effects [24,25], which can sometimes reduce treatment compliance .
Recent research has focused on the eCBS as a possible alternative target to treat PTSD [27,28]. Evidence highlighted a reduction of endocannabinoid levels  and cannabinoid receptor type 1 (CB1) receptors up-regulation in the brain of PTSD patients . Thus, the use of components derived from Cannabis sativa as cannabidiol (CBD) and D9-tetrahydrocannabinol (D9-THC) has drawn increasing interest as a possible alternative approach to treat PTSD. To reinforce this assumption several studies support cannabis use as self-medication to cope with PTSD symptoms [4,31].
While CBD is known to bind the G-protein-coupled receptor GPR55, the transient receptor potential of vanilloid type-1 channel (TRPV1), the 5-HT1a receptor, and the 3 and 1 adrenergic receptors, we will focus on the CB1 and CB2 receptors, since they are relevant to the Central Nervous System (CNS) . Preclinical and clinical studies suggested that CBD, acting also as a negative allosteric modulator of endogenous ligands of CB1 and CB2, may present a beneficial effect in PTSD treatment, enhancing the consolidation of explicit fear extinction and attenuating aversive memories of the traumatic event [33–36]. Moreover, D9-THC, a CB1 and CB2 partial agonist, showed a safe and well-tolerated profile in chronic PTSD with a significant improvement in global symptom severity, sleep quality, frequency of nightmares, and hyperarousal symptoms . More recently, nabilone, a synthetic cannabinoid that activates CB1, was reported to reduce the frequency and intensity of nightmares in PTSD patients [38–41].
Despite promising preliminary evidence, no reviews to our best knowledge have systematically summarized the effectiveness of cannabinoids or cannabino-mimetic in the treatment of PTSD. Previous literature reviewed the evidence about the eCBS as a potential target for PTSD treatment and prevention, but without following a systematic approach and focusing also on pathophysiological correlates of the disorder [28,42,43]. In consideration of what is stated above, the present systematic review is aimed at summarizing the existent evidence on medicinal cannabinoids (e.g., THC, CBD, nabilone) in the treatment of PTSD in humans, critically analyzing and discussing both the efficacy and safety of these treatment approaches.