Endocannabinoid System Alterations in Posttraumatic Stress Disorder: A Review of Developmental and Accumulative Effects of Trauma.

 Image result for sage journals chronic stress“The role of the endocannabinoid system in stress-related psychiatric symptoms has been investigated in many animal and human studies.

Although most of these studies consistently report long-lasting effects of prolonged stress and trauma on the endocannabinoid system, the nature and direction of these changes are controversial.

We reviewed the available preclinical and clinical studies investigating the endocannabinoid system alterations long after chronic stress and trauma.

We propose that the effects of prolonged stress or trauma on the endocannabinoid system are different based on the developmental age of subjects at the time of experiencing the trauma and its repetitiveness and accumulative effects.

The current literature consistently demonstrates decreased levels of endocannabinoid ligands and receptors if the trauma occurs in childhood, whereas decreased levels of endocannabinoid ligands and increased levels of cannabinoid receptors are reported when trauma has happened in adulthood.

It is important to note that these changes are region-specific in the brain and also there are important sex differences, which are beyond the scope of this review.”

https://www.ncbi.nlm.nih.gov/pubmed/31660473

“More studies are needed to compare the effects of childhood and adulthood trauma, with or without PTSD presentations, on the eCB system. These studies would have important clinical implications, not only for individuals with trauma and PTSD who commonly have comorbid recreational cannabis use, and medical marijuana users with PTSD being one of its main indicators but also for studies investigating the potential therapeutic use of cannabinoids and eCB enhancers in PTSD treatment.”

https://journals.sagepub.com/doi/10.1177/2470547019864096

A time-dependent contribution of hippocampal CB1, CB2, and PPARγ receptors to cannabidiol-induced disruption of fear memory consolidation.

Publication cover image“Preclinical studies have shown that cannabidiol (CBD) mitigates fear memories by facilitating their extinction or interfering with their generalization and reconsolidation. The brain regions and mechanisms underlying these effects, and their temporal window, are still poorly understood. The present paper aimed at investigating related questions in the dorsal hippocampus (DH) during contextual fear consolidation.

KEY RESULTS:

CBD impaired memory consolidation when given immediately or 1 h after fear conditioning, but not after 3 h. The DH Arc expression was reduced by systemic CBD treatment in both cases. Immediately after fear conditioning, the CBD effect was abolished by CB1 or CB2 receptor blockade, partly reduced by 5-HT1A or A2A antagonism, and remained unchanged after antagonism of PPARγ receptors. 1 h after fear conditioning, the CBD effect was only prevented by PPARγ receptor antagonism. Besides, the FAAH inhibition impaired memory consolidation when URB597 was infused immediately, but not 1 hour after fear conditioning.

CONCLUSIONS AND IMPLICATIONS:

CBD disrupts memory consolidation up to 1 h after fear conditioning, allowing an extended window of opportunity to mitigate aversive memories after their acquisition. The results suggest time-dependent participation of DH anandamide, CB1, CB2, and PPARγ receptors in this process.”

https://www.ncbi.nlm.nih.gov/pubmed/31648363

https://bpspubs.onlinelibrary.wiley.com/doi/abs/10.1111/bph.14895

Cannabinoid receptor type 1 modulates the effects of polyunsaturated fatty acids on memory of stressed rats.

 Publication Cover“Memory and GABAergic activity in the hippocampus of stressed rats improve after n-3 polyunsaturated fatty acid (PUFA) supplementation.

On the other hand, cannabinoid receptor type 1 (CB1) strongly regulates inhibitory neurotransmission in the hippocampus. Speculation about a possible relation between stress, endocannabinoids, and PUFAs.

Here, we examined whether the effects of PUFAs on memory of chronically stressed rats depends on pharmacological manipulation of CB1 receptors.

Memory improved in the stressed rats that were treated with AM251 and/or n-3 PUFAs. Supplementation with n-6 PUFAs did not affect memory of stressed rats, but co-treatment with AM251 improved it, while co-treatment with WIN55,212-2 did not affect memory.

Our results demonstrate that activity of the CB1 receptors may modulate the effects of PUFAs on memory of stressed rats. This study suggests that endocannabinoids and PUFAs can both become a singular system by being self-regulated in limbic areas, so they control the effects of stress on the brain.”

https://www.ncbi.nlm.nih.gov/pubmed/31637966

https://www.tandfonline.com/doi/abs/10.1080/1028415X.2019.1659561?journalCode=ynns20

Neuropeptide Y and cannabinoids interaction in the amygdala after exposure to shock and reminders model of PTSD.

Neuropharmacology“Modulation of cannabinoid and neuropeptide Y (NPY) receptors may offer therapeutic benefits for post-traumatic stress disorder (PTSD).

In this study, we aimed to investigate the functional interaction between these systems in the basolateral amygdala (BLA) in a rat model of PTSD.

The findings suggest that the functional interaction between the eCB and NPY1 systems is complex and provide a rationale for exploring novel therapeutic strategies that target the cannabinoid and NPY systems for stress-related diseases.”

https://www.ncbi.nlm.nih.gov/pubmed/31622603

https://www.sciencedirect.com/science/article/pii/S0028390819303661?via%3Dihub

The Effectiveness of Cannabinoids in the Treatment of Posttraumatic Stress Disorder (PTSD): A Systematic Review.

Publication CoverPosttraumatic stress disorder (PTSD) is a potentially debilitating mental health problem.

There has been a recent surge of interest regarding the use of cannabinoids in the treatment of PTSD.

We therefore sought to systematically review and assess the quality of the clinical evidence of the effectiveness of cannabinoids for the treatment of PTSD.

We found that cannabinoids may decrease PTSD symptomology, in particular sleep disturbances and nightmares.

Evidence that cannabinoids may help reduce global PTSD symptoms, sleep disturbances, and nightmares indicates that future well-controlled, randomized, double-blind clinical trials are highly warranted.”

https://www.ncbi.nlm.nih.gov/pubmed/31479625

https://www.tandfonline.com/doi/full/10.1080/15504263.2019.1652380

Use of Medicinal Cannabis and Synthetic Cannabinoids in Post-Traumatic Stress Disorder (PTSD): A Systematic Review.

medicina-logo“Post-traumatic stress disorder (PTSD) is a common psychiatric disorder resulting from a traumatic event, is manifested through hyperarousal, anxiety, depressive symptoms, and sleep disturbances.

Despite several therapeutic approaches being available, both pharmacological and psychological, recently a growing interest has developed in using cannabis and synthetic cannabinoids stems from their consideration as more efficient and better tolerated alternatives for the treatment of this condition.

The present paper aims to evaluate the clinical and therapeutic potentials of medical cannabis and synthetic cannabinoids in treating PTSD patients.

Present data show that cannabis and synthetic cannabinoids, both acting on the endocannabinoids system, may have a potential therapeutic use for improving PTSD symptoms, e.g., reducing anxiety, modulating memory-related processes, and improving sleep.”

https://www.ncbi.nlm.nih.gov/pubmed/31450833

https://www.mdpi.com/1010-660X/55/9/525

Cannabidiol and the Remainder of the Plant Extract Modulate the Effects of Δ9-Tetrahydrocannabinol on Fear Memory Reconsolidation.

Image result for frontiers in behavioral neuroscience “Δ9-Tetrahydrocannabinol (THC, a CB1 receptor agonist) and Cannabidiol (CBD, a non-competitive antagonist of endogenous CB1 and CB2 ligands) are two primary components of Cannabis species, and may modulate fear learning in mammals.

The CB1 receptor is widely distributed throughout the cortex and some limbic regions typically associated with fear learning. Humans with posttraumatic disorder (PTSD) have widespread upregulation of CB1 receptor density and reduced availability of endogenous cannabinoid anandamide, suggesting a role for the endocannabinoid system in PTSD.

Pharmacological blockade of memory reconsolidation following recall of a conditioned response modulates the expression of learned fear and may represent a viable target for the development of new treatments for PTSD.

In this study, we focused on assessing the impact of the key compounds of the marijuana plant both singly and, more importantly, in concert on attenuation of learned fear. Specifically, we assessed the impact of THC, CBD, and/or the remaining plant materials (post-extraction; background material), on reconsolidation of learned fear.

Results: CBD alone, but not THC alone, significantly attenuated fear memory reconsolidation when administered immediately after recall. The effect persisted for at least 7 days. A combination of CBD and THC also attenuated the fear response. Plant BM also significantly attenuated reconsolidation of learned fear both on its own and in combination with THC and CBD. Finally, THC attenuated reconsolidation of learned fear only when co-administered with CBD or plant BM.

Conclusion: CBD may provide a novel treatment strategy for targeting fear-memories. Furthermore, plant BM also significantly attenuated the fear response. However, whereas THC alone had no significant effects, its effects were modulated by the addition of other compounds. Future research should investigate some of the other components present in the plant BM (such as terpenes) for their effects alone, or in combination with isolated pure cannabinoids, on fear learning.”

https://www.ncbi.nlm.nih.gov/pubmed/31417379

https://www.frontiersin.org/articles/10.3389/fnbeh.2019.00174/full

Endogenous cannabinoid levels and suicidality in combat veterans.

Psychiatry Research“Combat veterans are at elevated suicide risk. The goal of this study was to test the hypothesis that combat veterans who have made a suicide attempt post-deployment can be distinguished from combat veterans who have never made a suicide attempt based on differences in psychological and biological variables. For the latter, we focused on endogenous cannabinoids, neuroendocrine markers that are associated with stress. Demographic and clinical parameters of suicide attempters and non-attempters were assessed. Blood samples were assayed for anandamide (AEA), 2-arachidonoylglycerol (2-AG), and cortisol. Suicide attempters had higher Scale for Suicidal Ideation (SSI) scores in comparison to non-attempters. Controlling for gender, 2-AG levels were higher among suicide attempters in comparison to non-attempters. Cortisol levels positively correlated with 2-AG levels and negatively correlated with SSI scores among non-attempters but not among attempters. AEA levels negatively correlated with SSI scores among attempters but not among non-attempters. Our results indicate that there are psychological and biological differences between combat veterans with or without a history of suicidal attempt. Our findings also suggest that clinically observed differences between the groups may have a neurobiological basis.”

https://www.ncbi.nlm.nih.gov/pubmed/31375282

https://www.sciencedirect.com/science/article/abs/pii/S0165178119315173?via%3Dihub

“Role of the Endocannabinoid System in the Neurobiology of Suicide”  https://www.ncbi.nlm.nih.gov/books/NBK107200/

Allostatic load and the cannabinoid system: implications for the treatment of physiological abnormalities in post-traumatic stress disorder (PTSD).

Image result for cns spectrums“It is becoming clear that post-traumatic stress disorder (PTSD) is not simply a psychiatric disorder, but one that involves pervasive physiological impairments as well. These physiological disturbances deserve attention in any attempt at integrative treatment of PTSD that requires a focus beyond the PTSD symptoms themselves. The physiological disturbances in PTSD range over many systems, but a common thread thought to underlie them is that the chronic effects of PTSD involve problems with allostatic control mechanisms that result in an excess in what has been termed “allostatic load” (AL).

A pharmacological approach to reducing AL would be valuable, but, because of the large range of physiological issues involved – including metabolic, inflammatory, and cardiovascular systems – it is unclear whether there exists a simple comprehensive way to address the AL landscape. In this paper, we propose that the cannabinoid system may offer just such an approach, and we outline evidence for the potential utility of cannabinoids in reducing many of the chronic physiological abnormalities seen in PTSD which are thought to be related to excess AL.” https://www.ncbi.nlm.nih.gov/pubmed/31303187
https://www.cambridge.org/core/journals/cns-spectrums/article/allostatic-load-and-the-cannabinoid-system-implications-for-the-treatment-of-physiological-abnormalities-in-posttraumatic-stress-disorder-ptsd/F85D2588638C20BE9DD86DEC2F768242

Cannabinoid Regulation of Fear and Anxiety: an Update.

 

“Anxiety- and trauma-related disorders are prevalent and debilitating mental illnesses associated with a significant socioeconomic burden. Current treatment approaches often have inadequate therapeutic responses, leading to symptom relapse. Here we review recent preclinical and clinical findings on the potential of cannabinoids as novel therapeutics for regulating fear and anxiety.

RECENT FINDINGS:

Evidence from preclinical studies has shown that the non-psychotropic phytocannabinoid cannabidiol and the endocannabinoid anandamide have acute anxiolytic effects and also regulate learned fear by dampening its expression, enhancing its extinction and disrupting its reconsolidation. The findings from the relevant clinical literature are still very preliminary but are nonetheless encouraging. Based on this preclinical evidence, larger-scale placebo-controlled clinical studies are warranted to investigate the effects of cannabidiol in particular as an adjunct to psychological therapy or medication to determine its potential utility for treating anxiety-related disorders in the future.”

https://www.ncbi.nlm.nih.gov/pubmed/31030284

https://link.springer.com/article/10.1007%2Fs11920-019-1026-z