The Consumption of Cannabis by Fibromyalgia Patients in Israel.

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“OBJECTIVE:

To report on the habits of cannabis consumption among fibromyalgia patients in Israel.

RESULTS:

Of 2,705 people, 383 (14%) responded to the questionnaire, with a mean age of 42.2±14.2 years. Of the responders, 84% reported consuming cannabis, and 44% were licensed for MC. The mean amount per month of cannabis consumed was 31.4±16.3g, and 80% of cannabis consumers (CC) smoked pure cannabis or cannabis mixed with tobacco. Pain relief was reported by 94% of CC, while 93% reported improved sleep quality, 87% reported improvement in depression, and 62% reported improvement in anxiety. Of MC-licensed CC, 55% bought cannabis beyond the medical allowance on the black market. Adverse effects were reported by 12% of CC. Only 8% reported dependence on cannabis. Most CC (64%) worked either full- or part-time jobs, and 74% reported driving “as usual” under cannabis use.

CONCLUSIONS:

Cannabis consumption among fibromyalgia patients in our country is very common and is mostly not licensed. Nearly all CC reported favorable effects on pain and sleep, and few reported adverse effects or feeling of dependence on cannabis.”

“The results of our study should encourage both the Rheumatology Association in our country and the MCA to reconsider their stand on cannabis and include fibromyalgia among the indications for MC under certain restrictions.”
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The relationship of endocannabinoidome lipid mediators with pain and psychological stress in women with fibromyalgia – a case control study.

“Characterized by chronic widespread pain, generalized hyperalgesia, and psychological stress fibromyalgia (FM) is difficult to diagnose and lacks effective treatments.

The endocannabinoids – arachidonoylethanolamide (AEA), 2-arachidonoylglycerol (2-AG), and the related oleoylethanolamide (OEA), palmitoylethanolamide (PEA), and stearoylethanolamide (SEA) – are endogenous lipid mediators with analgesic and anti-inflammatory characteristics, in company with psychological modulating properties (e.g., stress and anxiety), and are included in a new emerging “ome”, the endocannabinoidome.

This case -control study compared the concentration differences of AEA, OEA, PEA, SEA, and 2-AG in 104 women with FM and 116 healthy controls (CON). All participants OEArated their pain, anxiety, depression, and current health status. The relationships between the lipid concentrations and the clinical assessments were investigated using powerful multivariate data analysis and traditional bivariate statistics. The concentrations of OEA, PEA, SEA, and 2-AG were significantly higher in FM than in CON; significance remained for OEA and SEA after controlling for BMI and age. 2-AG correlated positively with FM duration and BMI, and to some extent negatively with pain, anxiety, depression, and health status. In FM, AEA correlated positively with depression ratings.

The elevated circulating levels of endocannabinoidome lipids suggest that these lipids play a role in the complex pathophysiology of FM and might be signs of ongoing low-grade inflammation in FM. Although the investigated lipids are significantly altered in FM their biological roles are uncertain with respect to the clinical manifestations of FM. Thus, plasma lipids alone are not good biomarkers for FM.

PERSPECTIVE:

This study reports about elevated plasma levels of endocannabinoidome lipid mediators in FM. The lipids suitability to work as biomarkers for FM in the clinic were low, however their altered levels indicate that a metabolic asymmetry is ongoing in FM, which could serve as basis during explorative FM pain management.”

https://www.ncbi.nlm.nih.gov/pubmed/29885369

https://www.jpain.org/article/S1526-5900(18)30197-4/fulltext

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Endogenous systems involved in exercise-induced analgesia.

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“Exercise-induced analgesia is a phenomenon discussed worldwide. This effect began to be investigated in the early 1970s in healthy individuals and rodents during and after an acute or chronic session of running or swimming. Thereafter, studies found this effect was also induced by resistance exercises. Over the years, many studies have demonstrated the importance of exercise-induced analgesia in relieving pain caused by different conditions, such as fibromyalgia, low back pain, neuropathy, and osteoarthritis. This review aims to provide the reader with an in-depth description of the main endogenous systems, substances, neurotransmitters, receptors and enzymes that are thought to be involved in the analgesic effect induced by exercise. Many hypotheses have been proposed to elucidate the mechanisms responsible for exercise-induced analgesia. One of the most accepted hypotheses has been the activation of several endogenous systems described as analgesics. Studies have demonstrated that during and after exercise different endogenous systems are activated, which release substances or neurotransmitters, such as opioids, nitric oxide, serotonin, catecholamines and endocannabinoids, that may modulate the pain perception.”  https://www.ncbi.nlm.nih.gov/pubmed/29769416

http://www.jpp.krakow.pl/journal/archive/02_18/pdf/jpp.2018.1.01.pdf

“Exercise activates the endocannabinoid system.”  https://www.ncbi.nlm.nih.gov/pubmed/14625449

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Medical Cannabis for the Treatment of Fibromyalgia.

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“Fibromyalgia is a chronic pain syndrome, characterized by chronic musculoskeletal pain, fatigue, and mood disturbances. There are nearly no data on the effect of medical cannabis (MC) treatment on patients with fibromyalgia.

Data were obtained from the registries of 2 hospitals in Israel (Laniado Hospital and Nazareth Hospital) on patients with a diagnosis of fibromyalgia who were treated with MC. After obtaining patient consent, demographic, clinical, and laboratory parameters were documented. All the patients also completed the Revised Fibromyalgia Impact Questionnaire regarding the period before and after MC treatment.

Thirty patients were identified, and 26 patients were included in the study. There were 19 female patients (73%), and the mean age of the study group was 37.8 ± 7.6 years. The mean dosage of MC was 26 ± 8.3 g per month, and the mean duration of MC use was 10.4 ± 11.3 months. After commencing MC treatment, all the patients reported a significant improvement in every parameter on the questionnaire, and 13 patients (50%) stopped taking any other medications for fibromyalgia. Eight patients (30%) experienced very mild adverse effects.

 

CONCLUSIONS:

Medical cannabis treatment had a significant favorable effect on patients with fibromyalgia, with few adverse effects.”

https://insights.ovid.com/crossref?an=00124743-900000000-99352

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Clinical Endocannabinoid Deficiency Reconsidered: Current Research Supports the Theory in Migraine, Fibromyalgia, Irritable Bowel, and Other Treatment-Resistant Syndromes

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“Medicine continues to struggle in its approaches to numerous common subjective pain syndromes that lack objective signs and remain treatment resistant. Foremost among these are migraine, fibromyalgia, and irritable bowel syndrome, disorders that may overlap in their affected populations and whose sufferers have all endured the stigma of a psychosomatic label, as well as the failure of endless pharmacotherapeutic interventions with substandard benefit. The commonality in symptomatology in these conditions displaying hyperalgesia and central sensitization with possible common underlying pathophysiology suggests that a clinical endocannabinoid deficiency might characterize their origin. Its base hypothesis is that all humans have an underlying endocannabinoid tone that is a reflection of levels of the endocannabinoids, anandamide (arachidonylethanolamide), and 2-arachidonoylglycerol, their production, metabolism, and the relative abundance and state of cannabinoid receptors. Its theory is that in certain conditions, whether congenital or acquired, endocannabinoid tone becomes deficient and productive of pathophysiological syndromes. When first proposed in 2001 and subsequently, this theory was based on genetic overlap and comorbidity, patterns of symptomatology that could be mediated by the endocannabinoid system (ECS), and the fact that exogenous cannabinoid treatment frequently provided symptomatic benefit. However, objective proof and formal clinical trial data were lacking. Currently, however, statistically significant differences in cerebrospinal fluid anandamide levels have been documented in migraineurs, and advanced imaging studies have demonstrated ECS hypofunction in post-traumatic stress disorder. Additional studies have provided a firmer foundation for the theory, while clinical data have also produced evidence for decreased pain, improved sleep, and other benefits to cannabinoid treatment and adjunctive lifestyle approaches affecting the ECS.

Various strategies to treat CED conditions are possible. A direct approach with CB1 agonists must recognize the fact that the ECS operates as a homeostatic regulator that sometimes requires a gentle pharmacological nudge, rather than a forceful shove, by synthetic full agonists. Thus, small doses of a weak partial agonist (e.g., THC) should be considered, which would not induce tolerance and may jump-start the ECS. Even THC alone is poorly tolerated or appreciated by patients,98 and standardized whole cannabis extracts that contain additional synergistic and buffering components, such as CBD and cannabis terpenoids, are certainly preferable.93 Alternatively, FAAH inhibitors will also raise AEA levels, but only CBD among them has achieved current legal commercial market availability. Pharmaceutical approaches affecting endocannabinoid transport or its genetic regulation would also hold promise. Beyond drug interventions, a growing body of knowledge supports the realistic goal that lifestyle approaches should be integral to the treatment of CED; specifically, low-impact aerobic regimens have demonstrated beneficial effects on endocannabinoid function,99 and as discussed above, dietary manipulations with probiotics and prebiotics may ameliorate not only IBS symptoms but also the entire spectrum of CED conditions. Ultimately, multimodality approaches are most likely to be fruitful in treatment of these common yet difficult clinical challenges.

http://online.liebertpub.com/doi/pdf/10.1089/can.2016.0009

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Medical Cannabis – another piece in the mosaic of autoimmunity?

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“Legalization of cannabis’ medicinal use is rapidly increasing worldwide, raising the need to evaluate medical implications of cannabis. Currently evidence supports cannabis and its active ingredients as an immune-modulating agents, affecting T-cells, B-cells, Monocytes and Microglia-cells, causing an overall reduction in pro-inflammatory cytokine expression and an increase in anti-inflammatory cytokines. Due to the supporting evidence of cannabinoids as an immune-modulating agent, research focusing on cannabinoids and autoimmunity has emerged. Several clinical trials in multiple sclerosis, inflammatory bowel disease and fibromyalgia suggest cannabis’ effectiveness as an immune-modulator. However, contradicting results and lack of large scale clinical trials obscure these results. Though lacking clinical research, in-vitro and in-vivo experiments in rheumatoid arthritis, diabetes type 1 and systemic sclerosis, demonstrate a correlation between disease activity and cannabinoids.”

https://www.ncbi.nlm.nih.gov/pubmed/27859024

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High-Intensity Swimming Exercise Decreases Glutamate-Induced Nociception by Activation of G-Protein-Coupled Receptors Inhibiting Phosphorylated Protein Kinase A.

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“Several studies in humans have reported that improved pain control is associated with exercise in a variety of painful conditions, including osteoarthritis, fibromyalgia, and neuropathic pain.

Despite the growing amount of experimental data on physical exercise and nociception, the precise mechanisms through which high-intensity exercise reduces pain remain elusive.

Since the glutamatergic system plays a major role in pain transmission, we firstly analyzed if physical exercise could be able to decrease glutamate-induced nociception through G-protein-coupled receptor (G-PCR) activation.

The second purpose of this study was to examine the effect of exercising upon phosphorylation of protein kinase A (PKA) isoforms induced by intraplantar (i.pl.) glutamate injection in mice.

Our results demonstrate that high-intensity swimming exercise decreases nociception induced by glutamate and that i.pl. or intrathecal injections of cannabinoid, opioid, and adenosine receptor antagonists, AM281, naloxone, and 1,3-dipropyl-8-cyclopentylxanthine (DPCPX), respectively, prevent this effect.

Furthermore, the peripheral A1 and opioid receptors, but not CB1, are also involved in exercise’s effect. We also verified that glutamate injection increases levels of phosphorylated PKA (p-PKA). High-intensity swimming exercise significantly prevented p-PKA increase.

The current data show the direct involvement of the glutamatergic system on the hyponociceptive effect of high-intensity swimming exercise as well as demonstrate that physical exercise can activate multiple intracellular pathways through G-PCR activation, which share the same endogenous mechanism, i.e., inhibition of p-PKA.”

http://www.ncbi.nlm.nih.gov/pubmed/27624384

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Fibromyalgia Research Might Benefit from Finding Cannabinoid Receptors in Muscles

Fibromyalgia News Today

“Receptors for the body’s own cannabinoid substances are present in muscle fascia — soft connective tissue surrounding all muscles and involved in several pain states, according to recent research from the University of Padua in Italy.

In addition to casting light on disease processes in fibromyalgia, the findings might lead to better approaches for managing pain and inflammation in the disease, for which current treatments often fail to adequately treat symptoms.

Endocannabinoids are bodily substances chemically resembling the cannabinoid molecules in cannabis. The factors send signals through two receptors that scientists have primarily explored in the brain and in immune cells, and studies show that stimulating the receptors can relieve pain and suppress inflammation.

 Patients with pain conditions such as fibromyalgia often turn to cannabis when prescription drugs are not enough to manage their symptoms. A 2005 study from the United Kingdom listed fibromyalgia among those conditions where patients frequently turn to marijuana for symptom relief, and a 2014 study of 217 U.S. patients showed that pain was the most commonly reported ailment in patients who use medical cannabis.

Research has also demonstrated that patients with fibromyalgia report that marijuana use lowers pain and improves health-related quality of life, making researchers suspect that endocannabinoid receptors, which also mediate the effects of marijuana, might exist in tissues other than the brain and immune cells.

To explore this, the study, “Expression of the endocannabinoid receptors in human fascial tissue,“ published in the European Journal of Histochemistryturned to muscle fascia, a tissue that has also been linked to other muscle pain conditions.

Extracting the tissue from thigh muscles of 11 volunteers who had orthopedic surgery, researchers isolated the main cell type of the fascia, called fibroblasts. They found both types of receptors, called CB1 and CB2, in the cells. Examining whole tissue levels of the two receptors, researchers noted somewhat higher levels, indicating that the receptors may also be present in other cell types.

A better understanding of how endocannabinoid receptors are involved in fibromyalgia might lead to treatments specifically targeting the receptors in the muscles, avoiding the effects of manipulating cannabinoid receptors in the brain which mediate the psychotropic actions of cannabis.”

https://fibromyalgianewstoday.com/2016/07/08/fibromyalgia-drug-research-might-benefit-from-finding-cannabinoid-receptors-in-muscles/

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Expression of the endocannabinoid receptors in human fascial tissue.

“Cannabinoid receptors have been localized in the central and peripheral nervous system as well as on cells of the immune system, but recent studies on animal tissue gave evidence for the presence of cannabinoid receptors in different types of tissues.

Their presence was supposed also in myofascial tissue, suggesting that the endocannabinoid system may help resolve myofascial trigger points and relieve symptoms of fibromyalgia.

However, until now the expression of CB1 (cannabinoid receptor 1) and CB2 (cannabinoid receptor 2) in fasciae has not yet been established.

Small samples of fascia were collected from volunteers patients during orthopedic surgery. For each sample were done a cell isolation, immunohistochemical investigation (CB1 and CB2 antibodies) and real time RT-PCR to detect the expression of CB1 and CB2.

Both cannabinoid receptors are expressed in human fascia and in human fascial fibroblasts culture cells, although to a lesser extent than the control gene. We can assume that the expression of mRNA and protein of CB1 and CB2 receptors in fascial tissue are concentrated into the fibroblasts.

This is the first demonstration that the fibroblasts of the muscular fasciae express CB1 and CB2. The presence of these receptors could help to provide a description of cannabinoid receptors distribution and to better explain the role of fasciae as pain generator and the efficacy of some fascial treatments.

Indeed the endocannabinoid receptors of fascial fibroblasts can contribute to modulate the fascial fibrosis and inflammation.”

http://www.ncbi.nlm.nih.gov/pubmed/27349320

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ENDOCANNABINOID SYSTEM: A multi-facet therapeutic target.

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“Cannabis sativa is also popularly known as marijuana. It is being cultivated and used by man for recreational and medicinal purposes from many centuries.

Study of cannabinoids was at bay for very long time and its therapeutic value could not be adequately harnessed due to its legal status as proscribed drug in most of the countries.

The research of drugs acting on endocannabinoid system has seen many ups and down in recent past. Presently, it is known that endocannabinoids has role in pathology of many disorders and they also serve “protective role” in many medical conditions.

Several diseases like emesis, pain, inflammation, multiple sclerosis, anorexia, epilepsy, glaucoma, schizophrenia, cardiovascular disorders, cancer, obesity, metabolic syndrome related diseases, Parkinson’s disease, Huntington’s disease, Alzheimer’s disease and Tourette’s syndrome could possibly be treated by drugs modulating endocannabinoid system.

Presently, cannabinoid receptor agonists like nabilone and dronabinol are used for reducing the chemotherapy induced vomiting. Sativex (cannabidiol and THC combination) is approved in the UK, Spain and New Zealand to treat spasticity due to multiple sclerosis. In US it is under investigation for cancer pain, another drug Epidiolex (cannabidiol) is also under investigation in US for childhood seizures. Rimonabant, CB1 receptor antagonist appeared as a promising anti-obesity drug during clinical trials but it also exhibited remarkable psychiatric side effect profile. Due to which the US Food and Drug Administration did not approve Rimonabant in US. It sale was also suspended across the EU in 2008.

Recent discontinuation of clinical trial related to FAAH inhibitor due to occurrence of serious adverse events in the participating subjects could be discouraging for the research fraternity. Despite of some mishaps in clinical trials related to drugs acting on endocannabinoid system, still lot of research is being carried out to explore and establish the therapeutic targets for both cannabinoid receptor agonists and antagonists.

One challenge is to develop drugs that target only cannabinoid receptors in a particular tissue and another is to invent drugs that acts selectively on cannabinoid receptors located outside the blood brain barrier. Besides this, development of the suitable dosage forms with maximum efficacy and minimum adverse effects is also warranted.

Another angle to be introspected for therapeutic abilities of this group of drugs is non-CB1 and non-CB2 receptor targets for cannabinoids.

In order to successfully exploit the therapeutic potential of endocannabinoid system, it is imperative to further characterize the endocannabinoid system in terms of identification of the exact cellular location of cannabinoid receptors and their role as “protective” and “disease inducing substance”, time-dependent changes in the expression of cannabinoid receptors.”

http://www.ncbi.nlm.nih.gov/pubmed/27086601

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