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

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Emerging role of cannabinoids and synthetic cannabinoid receptor 1/cannabinoid receptor 2 receptor agonists in cancer treatment and chemotherapy-associated cancer management

Journal of Cancer Research and Therapeutics“Cannabis was extensively utilized for its medicinal properties till the 19th century. A steep decline in its medicinal usage was observed later due to its emergence as an illegal recreational drug.

Advances in technology and scientific findings led to the discovery of delta-9-tetrahydrocannabinol (THC), the primary psychoactive compound of cannabis, that further led to the discovery of endogenous cannabinoids system consisting of G-protein-coupled receptors – cannabinoid receptor 1 and cannabinoid receptor 2 along with their ligands, mainly anandamide and 2-arachidonoylglycerol.  Endocannabinoid (EC) is shown to be a modulator not only for physiological functions but also for the immune system, endocrine network, and central nervous system.

Medicinal research and meta-data analysis over the last few decades have shown a significant potential for both THC and cannabidiol (CBD) to exert palliative effects. People suffering from many forms of advanced stages of cancers undergo chemotherapy-induced nausea and vomiting followed by severe and chronic neuropathic pain and weight loss.

THC and CBD exhibit effective analgesic, anxiolytic, and appetite-stimulating effect on patients suffering from cancer. Drugs currently available in the market to treat such chemotherapy-induced cancer-related ailments are Sativex (GW Pharmaceutical), Dronabinol (Unimed Pharmaceuticals), and Nabilone (Valeant Pharmaceuticals).

Apart from exerting palliative effects, THC also shows promising role in the treatment of cancer growth, neurodegenerative diseases (multiple sclerosis and Alzheimer’s disease), and alcohol addiction and hence should be exploited for potential benefits.

The current review discusses the nature and role of CB receptors, specific applications of cannabinoids, and major studies that have assessed the role of cannabinoids in cancer management.

Specific targeting of cannabinoid receptors can be used to manage severe side effects during chemotherapy, palliative care, and overall cancer management. Furthermore, research evidences on cannabinoids have suggested tumor inhibiting and suppressing properties which warrant reconsidering legality of the substance.

Studies on CB1 and CB2 receptors, in case of cancers, have demonstrated the psychoactive constituents of cannabinoids to be potent against tumor growth.

Interestingly, studies have also shown that activation of CB1 and CB2 cannabinoid receptors by their respective synthetic agonists tends to limit human cancer cell growth, suggesting the role of the endocannabinoid system as a novel target for treatment of cancers.

Further explorations are required to exploit cannabinoids for an effective cancer management.”

http://www.cancerjournal.net/preprintarticle.asp?id=263538

“Could Cannabis Kill Cancer Cells? A New Study Looks Promising”  https://www.portlandmercury.com/blogtown/2019/08/15/26977361/could-cannabis-kill-cancer-cells-a-new-study-looks-promising

“Study Reviews How Marijuana Compounds Inhibit Tumor Growth And Kill Cancer Cells” https://www.marijuanamoment.net/study-reviews-how-marijuana-compounds-inhibit-tumor-growth-and-kill-cancer-cells/

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New approaches to cancer therapy: combining Fatty Acid Amide Hydrolase (FAAH) inhibition with Peroxisome Proliferator-Activated Receptors (PPARs) activation.

 Go to Volume 0, Issue ja“Over the course of the last decade, Peroxisome Proliferator-Activated Receptors (PPARs) have been identified as part of the cannabinoid signaling system: both phytocannabinoids and endocannabinoids are capable of binding and activating these nuclear receptors. Fatty Acid Amide Hydrolase (FAAH) hydrolyzes the endocannabinoid Anandamide and other N-Acylethanolamines. These substances have been shown to have numerous anti-cancer effects, and indeed the inhibition of FAAH has multiple beneficial effects that are mediated by PPARα subtype and by PPARγ subtype, especially antiproliferation and activation of apoptosis. The substrates of FAAH are also PPAR agonists, which explains the PPAR-mediated effects of FAAH inhibitors. Much like cannabinoid ligands and FAAH inhibitors, PPARγ agonists show antiproliferative effects on cancer cells, suggesting that additive or synergistic effects may be achieved through the positive modulation of both signaling systems. In this perspective, we discuss the development of novel FAAH inhibitors able to directly act as PPAR agonists and their promising utilization as leads for the discovery of highly effective anti-cancer compounds.”

https://www.ncbi.nlm.nih.gov/pubmed/31407888

https://pubs.acs.org/doi/10.1021/acs.jmedchem.9b00885

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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/

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Targeting Cannabinoid Signaling in the Immune System: “High”-ly Exciting Questions, Possibilities, and Challenges

Image result for frontiers in immunology“It is well known that certain active ingredients of the plants of Cannabis genus, i.e., the “phytocannabinoids” [pCBs; e.g., (−)-trans9-tetrahydrocannabinol (THC), (−)-cannabidiol, etc.] can influence a wide array of biological processes, and the human body is able to produce endogenous analogs of these substances [“endocannabinoids” (eCB), e.g., arachidonoylethanolamine (anandamide, AEA), 2-arachidonoylglycerol (2-AG), etc.]. These ligands, together with multiple receptors (e.g., CB1 and CB2 cannabinoid receptors, etc.), and a complex enzyme and transporter apparatus involved in the synthesis and degradation of the ligands constitute the endocannabinoid system (ECS), a recently emerging regulator of several physiological processes. The ECS is widely expressed in the human body, including several members of the innate and adaptive immune system, where eCBs, as well as several pCBs were shown to deeply influence immune functions thereby regulating inflammation, autoimmunity, antitumor, as well as antipathogen immune responses, etc. Based on this knowledge, many in vitro and in vivo studies aimed at exploiting the putative therapeutic potential of cannabinoid signaling in inflammation-accompanied diseases (e.g., multiple sclerosis) or in organ transplantation, and to dissect the complex immunological effects of medical and “recreational” marijuana consumption. Thus, the objective of the current article is (i) to summarize the most recent findings of the field; (ii) to highlight the putative therapeutic potential of targeting cannabinoid signaling; (iii) to identify open questions and key challenges; and (iv) to suggest promising future directions for cannabinoid-based drug development.

Active Components of Cannabis sativa (Hemp)—Phytocannabinoids (pCBs) and Beyond

It is known since ancient times that consumption of different parts of the plant Cannabis sativa can lead to psychotropic effects. Moreover, mostly, but not exclusively because of its potent analgesic actions, it was considered to be beneficial in the management of several diseases. Nowadays it is a common knowledge that these effects were mediated by the complex mixture of biologically active substances produced by the plant. So far, at least 545 active compounds have been identified in it, among which, the best-studied ones are the so-called pCBs. It is also noteworthy that besides these compounds, ca. 140 different terpenes [including the potent and selective CB2 agonist sesquiterpene β-caryophyllene (BCP)], multiple flavonoids, alkanes, sugars, non-cannabinoid phenols, phenylpropanoids, steroids, fatty acids, and various nitrogenous compounds can be found in the plant, individual biological actions of which are mostly still nebulous. Among the so far identified > 100 pCBs, the psychotropic (−)-trans9-tetrahydrocannabinol (THC) and the non-psychotropic (−)-cannabidiol (CBD) are the best-studied ones, exerting a wide-variety of biological actions [including but not exclusively: anticonvulsive, analgesic, antiemetic, and anti inflammatory effects]. Of great importance, pCBs have been shown to modulate the activity of a plethora of cellular targets, extending their impact far beyond the “classical” (see above) cannabinoid signaling. Indeed, besides being agonists [or in some cases even antagonists of CB1 and CB2 cannabinoid receptors, some pCBs were shown to differentially modulate the activity of certain TRP channels, PPARs, serotonin, α adrenergic, adenosine or opioid receptors, and to inhibit COX and lipoxygenase enzymes, FAAH, EMT, etc.. Moreover, from a clinical point-of-view, it should also be noted that pCBs can indirectly modify pharmacokinetics of multiple drugs (e.g., cyclosporine A) by interacting with several cytochrome P 450 (CYP) enzymes. Taken together, pCBs can be considered as multitarget polypharmacons, each of them having unique “molecular fingerprints” created by the characteristic activation/inhibition pattern of its locally available cellular targets.

Concluding Remarks—Lessons to Learn from Cannabis

Research efforts of the past few decades have unambiguously evidenced that ECS is one of the central orchestrators of both innate and adaptive immune systems, and that pure pCBs as well as complex cannabis-derivatives can also deeply influence immune responses. Although, many open questions await to be answered, pharmacological modulation of the (endo)cannabinoid signaling, and restoration of the homeostatic eCB tone of the tissues augur to be very promising future directions in the management of several pathological inflammation-accompanied diseases. Moreover, in depth analysis of the (quite complex) mechanism-of-action of the most promising pCBs is likely to shed light to previously unknown immune regulatory mechanisms and can therefore pave new “high”-ways toward developing completely novel classes of therapeutic agents to manage a wide-variety of diseases.”

https://www.frontiersin.org/articles/10.3389/fimmu.2017.01487/full

www.frontiersin.org

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The Potential of Cannabidiol as a Treatment for Psychosis and Addiction: Who Benefits Most? A Systematic Review.

jcm-logo

“The endogenous cannabinoid (eCB) system plays an important role in the pathophysiology of both psychotic disorders and substance use disorders (SUDs). The non-psychoactive cannabinoid compound, cannabidiol (CBD) is a highly promising tool in the treatment of both disorders. Here we review human clinical studies that investigated the efficacy of CBD treatment for schizophrenia, substance use disorders, and their comorbidity. In particular, we examined possible profiles of patients who may benefit the most from CBD treatment. CBD, either as monotherapy or added to regular antipsychotic medication, improved symptoms in patients with schizophrenia, with particularly promising effects in the early stages of illness. A potential biomarker is the level of anandamide in blood. CBD and THC mixtures showed positive effects in reducing short-term withdrawal and craving in cannabis use disorders. Studies on schizophrenia and comorbid substance use are lacking. Future studies should focus on the effects of CBD on psychotic disorders in different stages of illness, together with the effects on comorbid substance use. These studies should use standardized measures to assess cannabis use. In addition, future efforts should be taken to study the relationship between the eCB system, GABA/glutamate, and the immune system to reveal the underlying neurobiology of the effects of CBD.”

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Cannabinoids reduce hyperalgesia and inflammation via interaction with peripheral CB1 receptors.

Image result for pain journal

“Central antinociceptive effects of cannabinoids have been well documented.

Our results indicate that cannabinoids produce antihyperalgesia via interaction with a peripheral CB1 receptor.

This hypothesis is supported by the finding that anandamide inhibited capsaicin-evoked release of calcitonin gene-related peptide from isolated hindpaw skin.

Collectively, these results indicate that cannabinoids reduce inflammation via interaction with a peripheral CB1 receptor.”

“The Endocannabinoid System and Pain. Cannabis has been used for more than twelve thousand years and for many different purposes (i.e. fiber, medicinal, recreational). However, the endocannabinoid signaling system has only recently been the focus of medical research and considered a potential therapeutic target. Cannabinoid receptors and their endogenous ligands are present at supraspinal, spinal and peripheral levels. Cannabinoids suppress behavioral responses to noxious stimulation and suppress nociceptive processing through activation of cannabinoid CB1 and CB2 receptor subtypes. These studies suggest that manipulation of peripheral endocannabinoids may be promising strategy for the management of pain.”
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2834283/

“The Analgesic Potential of Cannabinoids. Historically and anecdotally cannabinoids have been used as analgesic agents. Moreover, cannabinoids act synergistically with opioids and act as opioid sparing agents, allowing lower doses and fewer side effects from chronic opioid therapy. Thus, rational use of cannabis based medications deserves serious consideration to alleviate the suffering of patients due to severe pain.”  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3728280/
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Alcohol-induced conditioned place preference is modulated by CB2 cannabinoid receptors and modifies levels of endocannabinoids in the mesocorticolimbic system.

Pharmacology Biochemistry and Behavior

“The endocannabinoid (eCB) system is a particularly important neuronal mechanism implicated in alcohol use disorders. Animal models are key to broadening our knowledge of the neurobiological mechanisms underlying alcohol dependence.

This study has two main aims: i) to assess how eCB levels in different brain areas are modified by alcohol-induced conditioning place preference (CPP), and ii) to study how cannabinoid type 2 receptor (CB2R) is involved in alcohol-rewarding properties, using pharmacological manipulation in C57BL/6 mice.

Our results suggest that the eCB system is dysregulated throughout the mesocorticolimbic system by repeated alcohol exposure during the CPP paradigm, and that levels of anandamide (AEA) and several other N-acylethanolamines are markedly decreased in the medial prefrontal cortex and ventral midbrain of alcohol-CPP mice.

We also observed that the administering an antagonist/inverse agonist of the CB2R (AM630) during the acquisition phase of CPP reduced the rewarding effects of alcohol. However, activating CB2R signalling using the agonist JWH133 seems to reduce both alcohol- and food-rewarding behaviours. Therefore, our findings indicate that the rewarding effects of alcohol are related to its disruptive effect on AEA and other N-acylethanolamine signalling pathways.

Thus, pharmacological manipulation of CB2R is an interesting candidate treatment for alcohol use disorders.”

https://www.ncbi.nlm.nih.gov/pubmed/31220547

https://www.sciencedirect.com/science/article/pii/S0091305719300656?via%3Dihub

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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

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Cannabinoid CB2R receptors are upregulated with corneal injury and regulate the course of corneal wound healing.

Experimental Eye Research

“CB2R receptors have demonstrated beneficial effects in wound healing in several models. We therefore investigated a potential role of CB2R receptors in corneal wound healing. We examined the functional contribution of CB2R receptors to the course of wound closure in an in vivo murine model. We additionally examined corneal expression of CB2R receptors in mouse and the consequences of their activation on cellular signaling, migration and proliferation in cultured bovine corneal epithelial cells (CECs). Using a novel mouse model, we provide evidence that corneal injury increases CB2R receptor expression in cornea. The CB2R agonist JWH133 induces chemorepulsion in cultured bovine CECs but does not alter CEC proliferation. The signaling profile of CB2R activation is activating MAPK and increasing cAMP accumulation, the latter perhaps due to Gs-coupling. Lipidomic analysis in bovine cornea shows a rise in acylethanolamines including the endocannabinoid anandamide 1 h after injury. In vivo, CB2R deletion and pharmacological block result in a delayed course of wound closure. In summary, we find evidence that CB2R receptor promoter activity is increased by corneal injury and that these receptors are required for the normal course of wound closure, possibly via chemorepulsion.”

https://www.ncbi.nlm.nih.gov/pubmed/30905716

https://www.sciencedirect.com/science/article/pii/S0014483518307206?via%3Dihub

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