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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Clinical endocannabinoid deficiency (CECD) revisited: Can this concept explain the therapeutic benefits of cannabis in migraine, fibromyalgia, irritable bowel syndrome and other treatment-resistant conditions?

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“Ethan B. Russo’s paper of December 1, 2003 explored the concept of a clinical endocannabinoid deficiency (CECD) underlying the pathophysiology of migraine, fibromyalgia, irritable bowel syndrome and other functional conditions alleviated by clinical cannabis.

Available literature was reviewed, including searches via the National Library of medicine database and other sources.

A review of the literature indicates that significant progress has been made since Dr. Ethan B. Russo’s landmark paper, just ten years ago (February 2, 2004). Investigation at that time suggested that cannabinoids can block spinal, peripheral and gastrointestional mechanisms that promote pain in headache, fibromyalgia, irritable bowel syndrome and muscle spasm.

CONCLUSION:

Subsequent research has confirmed that underlying endocannabinoid deficiencies indeed play a role in migraine, fibromyalgia, irritable bowel syndrome and a growing list of other medical conditions. Clinical experience is bearing this out. Further research and especially, clinical trials will further demonstrate the usefulness of medical cannabis. As legal barriers fall and scientific bias fades this will become more apparent.”  http://www.ncbi.nlm.nih.gov/pubmed/24977967

“Clinical endocannabinoid deficiency (CECD): can this concept explain therapeutic benefits of cannabis in migraine, fibromyalgia, irritable bowel syndrome and other treatment-resistant conditions? Migraine, fibromyalgia, IBS and related conditions display common clinical, biochemical and pathophysiological patterns that suggest an underlying clinical endocannabinoid deficiency that may be suitably treated with cannabinoid medicines.”  http://www.ncbi.nlm.nih.gov/pubmed/15159679

 

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Marijuana Rated Most Effective for Treating Fibromyalgia

marijuana graph

“Medical marijuana is far more effective at treating symptoms of fibromyalgia than any of the three prescription drugs approved by the Food and Drug Administration to treat the disorder.

That is one of the surprise findings in an online survey of over 1,300 fibromyalgia patients conducted by the National Pain Foundation and National Pain Report.”

Cymbalta graph

Lyrica graph

Savella graph.”

“The FDA has approved only three drugs – Cymbalta, Lyrica and Savella — for the treatment of fibromyalgia.”

http://americannewsreport.com/nationalpainreport/marijuana-rated-most-effective-for-treating-fibromyalgia-8823638.html

http://www.thctotalhealthcare.com/category/fibromyalgia/

 

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Fibromyalgia.

“Fibromyalgia is a chronic pain condition present in 2-4% of the population. Fibromyalgia consists of widespread pain with similarities to neuropathic pain in clinical findings, pathophysiology, and neuropharmacology. Pain is the predominant symptom and allodynia and hyperalgesia are common signs. Extreme fatigue, impaired cognition and nonrestorative sleep difficulties coexist in addition to other somatic symptoms.

Research including neuroimaging investigations shows abnormalities in neurotransmitters and an abnormal response to pain. Altered pain processing peripherally and centrally contribute to central sensitization and a dampened effect of the diffuse noxious inhibitory control (DNIC).

Successful management incorporates education of the patient in self-management skills, cognitive behavioral therapy (CBT), exercise, and drug therapy.

Tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors (SNRIs) (duloxetine and milnacipran), α2-δ ligands (gabapentin and pregabalin) are effective in reducing pain by≥30%. Some success has been shown with dopamine agonists (pramipexole), tramadol, other opioids and cannabinoids(nabilone).

Further evidence-based trials using complementary treatments are needed. Fibromyalgia is complex and requires a multidisciplinary approach to treatment. Patient self-management is key.”

http://www.ncbi.nlm.nih.gov/pubmed/24365316

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Therapeutic potential of cannabinoid medicines.

Drug Testing and Analysis

“Cannabis was extensively used as a medicine throughout the developed world in the nineteenth century but went into decline early in the twentieth century ahead of its emergence as the most widely used illicit recreational drug later that century. Recent advances in cannabinoid pharmacology alongside the discovery of the endocannabinoid system (ECS) have re-ignited interest in cannabis-based medicines.

The ECS has emerged as an important physiological system and plausible target for new medicines. Its receptors and endogenous ligands play a vital modulatory role in diverse functions including immune response, food intake, cognition, emotion, perception, behavioural reinforcement, motor co-ordination, body temperature, wake/sleep cycle, bone formation and resorption, and various aspects of hormonal control. In disease it may act as part of the physiological response or as a component of the underlying pathology.

In the forefront of clinical research are the cannabinoids delta-9-tetrahydrocannabinol and cannabidiol, and their contrasting pharmacology will be briefly outlined. The therapeutic potential and possible risks of drugs that inhibit the ECS will also be considered. This paper will then go on to review clinical research exploring the potential of cannabinoid medicines in the following indications: symptomatic relief in multiple sclerosis, chronic neuropathic pain, intractable nausea and vomiting, loss of appetite and weight in the context of cancer or AIDS, psychosis, epilepsy, addiction, and metabolic disorders.”

http://www.ncbi.nlm.nih.gov/pubmed/24006213

http://onlinelibrary.wiley.com/doi/10.1002/dta.1529/abstract

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