Endocannabinoid Signaling in the Central Amygdala and Bed Nucleus of the Stria Terminalis: Implications for the Pathophysiology and Treatment of Alcohol Use Disorder.

Alcoholism: Clinical and Experimental Research banner“High rates of relapse are a chronic and debilitating obstacle to effective treatment of alcohol use disorder (AUD); however, no effective treatments are available to treat symptoms induced by protracted abstinence.

In the first part of this two-part review series, we examine the literature supporting the effects of alcohol exposure within the extended amygdala (EA) neural circuitry.

In part two, we focus in on a potential way to combat negative affect associated with AUD, by exploring the therapeutic potential of the endogenous cannabinoid (eCB) system.

The eCB system is a potent modulator of neural activity in the brain, and its ability to mitigate stress and negative affect has long been an area of interest for developing novel therapeutics.

This review details the recent advances in our understanding of eCB signaling in two key regions of the EA, the central nucleus of the amygdala (CeA) and the bed nucleus of the stria terminalis (BNST), and their role in regulating negative affect.

Despite an established role for EA eCB signaling in reducing negative affect, few studies have examined the potential for eCB-based therapies to treat AUD-associated negative affect.

In this review, we present an overview of studies focusing on eCB signaling in EA and cannabinoid modulation on EA synaptic activity. We further discuss studies suggesting dysregulation of eCB signaling in models of AUD and propose that pharmacological augmentation of eCB could be a novel approach to treat aspects of AUD.

Lastly, future directions are proposed to advance our understanding of the relationship between AUD-associated negative affect and the EA eCB system that could yield new pharmacotherapies targeting negative affective symptoms associated with AUD.”

https://www.ncbi.nlm.nih.gov/pubmed/31373708

https://onlinelibrary.wiley.com/doi/abs/10.1111/acer.14159

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Therapeutic potential of cannabinoids as neuroprotective agents for damaged cells conducing to movement disorders.

International Review of Neurobiology“The basal ganglia (BG), an organized network of nuclei that integrates cortical information, play a crucial role in controlling motor function. In fact, movement disorders such as Parkinson’s disease (PD) and Huntington’s disease (HD) are caused by the degeneration of specific structures within the BG.

There is substantial evidence supporting the idea that cannabinoids may constitute novel promising compounds for the treatment of movement disorders as neuroprotective and anti-inflammatory agents.

This potential therapeutic role of cannabinoids is based, among other qualities, on their capacity to reduce oxidative injury and excitotoxicity, control calcium influx and limit the toxicity of reactive microglia.

The mechanisms involved in these effects are related to CB1 and CB2 receptor activation, although some of the effects are CB receptor independent.

Thus, taking into account the aforementioned properties, compounds that act on the endocannabinoid system could be useful as a basis for developing disease-modifying therapies for PD and HD.”

https://www.ncbi.nlm.nih.gov/pubmed/31349929

https://www.sciencedirect.com/science/article/pii/S0074774219300327?via%3Dihub

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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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HCV-Related Mortality Among HIV/HCV Co-infected Patients: The Importance of Behaviors in the HCV Cure Era (ANRS CO13 HEPAVIH Cohort).

 “Mortality among individuals co-infected with HIV and hepatitis C virus (HCV) is relatively high. We evaluated the association between psychoactive substance use and both HCV and non-HCV mortality in HIV/HCV co-infected patients in France, using Fine and Gray’s competing-risk model adjusted for socio-demographic, clinical predictors and confounding factors, while accounting for competing causes of death. Over a 5-year median follow-up period, 77 deaths occurred among 1028 patients.

Regular/daily cannabis use, elevated coffee intake, and not currently smoking were independently associated with reduced HCV-mortality (adjusted sub-hazard ratio [95% CI] 0.28 [0.10-0.83], 0.38 [0.15-0.95], and 0.28 [0.10-0.79], respectively). Obesity and severe thinness were associated with increased HCV-mortality (2.44 [1.00-5.93] and 7.25 [2.22-23.6] versus normal weight, respectively). Regular binge drinking was associated with increased non-HCV-mortality (2.19 [1.10-4.37]). Further research is needed to understand the causal mechanisms involved.

People living with HIV/HCV co-infection should be referred for tobacco, alcohol and weight control interventions and potential benefits of cannabis-based therapies investigated.”

https://www.ncbi.nlm.nih.gov/pubmed/31286317

https://link.springer.com/article/10.1007%2Fs10461-019-02585-7

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Cannabis and multiple sclerosis.

BMJ Journals

“Patients with multiple sclerosis have long turned to complementary therapies to manage symptoms that licensed products can only partially control. Around half of patients with multiple sclerosis admit to previous or current cannabis use for medicinal purposes and would endorse legalisation. Despite many governments worldwide relaxing regulations around medicinal cannabis, there remain many unanswered questions as to how clinicians should prescribe or recommend products, and access to pharmaceutical-grade products remains highly restricted. Here we address what adult neurologists need to know about cannabis and its use in multiple sclerosis.”

https://www.ncbi.nlm.nih.gov/pubmed/31201234

https://pn.bmj.com/content/early/2019/06/14/practneurol-2018-002137

“There are many anectodal reports of multiple sclerosis (MS) sufferers using the drug and reporting beneficial effects on spasticity, pain, tremor and mood.”  https://pn.bmj.com/content/2/3/154?int_source=trendmd&int_campaign=usage-042019&int_medium=cpc

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The Endocannabinoid System and its Modulation by Cannabidiol (CBD).

Image result for Altern Ther Health Med. “The endocannabinoid system (ECS) is an extensive endogenous signaling system with multiple elements, the number of which may be increasing as scientists continue to elucidate its role in human health and disease. The ECS is seemingly ubiquitous in animal species and is modulated by diet, sleep, exercise, stress, and a multitude of other factors, including exposure to phytocannabinoids, like Cannabidiol (CBD). Modulating the activity of this system may offer tremendous therapeutic promise for a diverse scope of diseases, ranging from mental health disorders, neurological and movement disorders, pain, autoimmune disease, spinal cord injury, cancer, cardiometabolic disease, stroke, TBI, osteoporosis, and others.”

https://www.ncbi.nlm.nih.gov/pubmed/31202198

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Dramatic response to Laetrile and cannabidiol (CBD) oil in a patient with metastatic low grade serous ovarian carcinoma.

Gynecologic Oncology Reports

“Complimentary alternative medicine use is common in women with gynecologic cancers. Cannabinoid receptors are potential therapeutic targets in ovarian cancer. Communication with patients is critical regarding use of alternative therapies.”  https://www.ncbi.nlm.nih.gov/pubmed/31193514

In this case report, we present the case of a female patient who demonstrated disease response after declining standard therapy and taking a combination of Laetrile and CBD oil. Previous clinical trials in humans have demonstrated no therapeutic effect in cancer patients taking Laetrile. However, basic science studies have identified cannabinoid receptors in ovarian cancer as potential therapeutic targets for cannabinoid use in treating malignancy.

In this case report, we highlight a dramatic response to combination Laetrile and CBD oil in a patient with widely metastatic Low grade serous ovarian cancer (LGSOC).

Laetrile is a semi-synthetic version of amygdaline, a chemical compound found in plants and fruit seeds. Both Laetrile and amygdaline contain cyanide within a common structural component. Theoretically, Laetrile has anti-cancer effects when cyanide is released via enzymatic degradation. However, a Cochrane review published in 2015 found no randomized or quasi randomized control trials supporting the use of Laetrile in cancer patients. Further, they argued that due to the risk of cyanide poisoning, Laetrile use should be discouraged in patients seeking the compound for alternative cancer therapy. Concerns for toxicity in combination with inability to demonstrate clinical efficacy led to an effective ban on the substance by the FDA in the 1980s. Nevertheless, the substance remains available for purchase in variable formulations commercially.

Cannabidiol (CBD) is a compound naturally derived from the cannabis plant.

The anti-cancer effects of CBD have been evaluated predominantly in the laboratory setting. Interestingly, ovarian cancer cell lines express GPR55, a target that is inhibited indirectly by CBD and that plays a role in prostate and ovarian cancer cell proliferation. Mouse model studies have also demonstrated cannabinoids inhibit tumor cell growth and induce apoptosis in gliomas, lymphomas, prostate, breast, lung, skin, and pancreatic cancer cells.”

https://www.sciencedirect.com/science/article/pii/S2352578919300517?via%3Dihub

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Cannabinoids: Current and Future Options to Treat Chronic and Chemotherapy-Induced Neuropathic Pain.

“Increases in cancer diagnosis have tremendous negative impacts on patients and their families, and major societal and economic costs. The beneficial effect of chemotherapeutic agents on tumor suppression comes with major unwanted side effects such as weight and hair loss, nausea and vomiting, and neuropathic pain. Chemotherapy-induced peripheral neuropathy (CIPN), which can include both painful and non-painful symptoms, can persist 6 months or longer after the patient’s last chemotherapeutic treatment. These peripheral sensory and motor deficits are poorly treated by our current analgesics with limited effectiveness. Therefore, the development of novel treatment strategies is an important preclinical research focus and an urgent need for patients. Approaches to prevent CIPN have yielded disappointing results since these compounds may interfere with the anti-tumor properties of chemotherapeutic agents. Nevertheless, the first (serotonin noradrenaline reuptake inhibitors [SNRIs], anticonvulsants, tricyclic antidepressants) and second (5% lidocaine patches, 8% capsaicin patches and weak opioids such as tramadol) lines of treatment for CIPN have shown some efficacy. The clinical challenge of CIPN management in cancer patients and the need to target novel therapies with long-term efficacy in alleviating CIPN are an ongoing focus of research. The endogenous cannabinoid system has shown great promise and efficacy in alleviating CIPN in preclinical and clinical studies. In this review, we will discuss the mechanisms through which the platinum, taxane, and vinca alkaloid classes of chemotherapeutics may produce CIPN and the potential therapeutic effect of drugs targeting the endocannabinoid system in preclinical and clinical studies, in addition to cannabinoid compounds diffuse mechanisms of action in alleviation of CIPN.”

https://www.ncbi.nlm.nih.gov/pubmed/31127530

https://link.springer.com/article/10.1007%2Fs40265-019-01132-x

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Synthetic, non-intoxicating 8,9-dihydrocannabidiol for the mitigation of seizures.

 Scientific Reports“There can be a fine line between therapeutic intervention and substance abuse, and this point is clearly exemplified in herbal cannabis and its products. Therapies involving cannabis have been the treatment of last resort for some cases of refractory epilepsy, and this has been among the strongest medical justifications for legalization of marijuana. In order to circumvent the narcotic effects of Δ9-tetrahydrocannabinol (THC), many studies have concentrated on its less intoxicating isomer cannabidiol (CBD). However, CBD, like all natural cannabinoids, is a controlled substance in most countries, and its conversion into THC can be easily performed using common chemicals. We describe here the anticonvulsant properties of 8,9-dihydrocannibidiol (H2CBD), a fully synthetic analogue of CBD that is prepared from inexpensive, non-cannabis derived precursors. H2CBD was found to have effectiveness comparable to CBD both for decreasing the number and reducing the severity of pentylenetetrazole-induced seizures in rats. Finally, H2CBD cannot be converted by any reasonable synthetic route into THC, and thus has the potential to act as a safe, noncontroversial drug for seizure mitigation.”

https://www.ncbi.nlm.nih.gov/pubmed/31123271

https://www.nature.com/articles/s41598-019-44056-y

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Supplementation of Cannabis sativa L. leaf powder accelerates functional recovery and ameliorates haemoglobin level following an induced injury to sciatic nerve in mouse model.

Image result for Pak J Pharm Sci.

“Peripheral nerve injury is a common condition with a multitude of signs and symptoms. The major consequence of injury is limited physical activity. Presently, we are lacking effective therapies for PNI and it is need of the hour is to explore potential remedies for the recovery of functional loss.

Here, we have investigated the role of crude Cannabis sativa L. leaf powder in promoting functions recovery, in mouse model subjected to a traumatic sciatic nerve injury.

A dose of 200mg/kg of the body weight per day was administered orally from the day of nerve crush till the end of the experiment. The motor functions were evaluated by measuring sciatic functional index, muscle grip strength and muscle mass; whereas the sensory functions were assessed by hotplate test. The haematology and serum analyses were carried out to estimate the effect of treatment on the systemic index and oxidative stress.

The gain of motor functions was significantly improved and was early noticed in the treated mice. Restoration of muscle mass and elevated haemoglobin level were statistically significant in the treatment group.

This study indicates that Cannabis sativa L. supplementation accelerates the motor functions recovery after nerve compression injury.”

https://www.ncbi.nlm.nih.gov/pubmed/31103973

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