Thursday, June 28, 2018

Cannabis and Digestive Issues




Cannabis and Digestive Issues




Serious Digestive issues, or Gastrointestinal problems, may come in many forms such as Irritable Bowl Syndrome (IBS), Ulcerative Colitis, and Crohn’s Disease. Problems associated with these diseases can include: difficulty taking in food, nausea or vomiting problems, constipation, diarrhea, irritable bowel, inadequate nutrient absorption, as well as cancer developing anywhere along the GI tract from the mouth through the esophagus, the stomach, the small intestine, the large intestine, to the anus.

Patients experiencing the pain and discomfort of having GI problems have turned to cannabis as an alternative medication for relief. It has been known for centuries, that cannabis can help alleviate pain, inflammation, cramping, nausea, promotes eating, calms spasms, improves motility, and may possibly block cancer cells.

Our GI tract has many cannabinoid receptor sites, making cannabinoids CBD, THC and even CBG a perfect medicine for the gut health. 





There is clear evidence-based research that supports the anti-emetic effects of cannabis for persons suffering from nausea and vomiting. The 1999 IOM report, Marijuana and Medicine: Assessing the Science Base, agreed that the evidence supported the anti-emetic effects of cannabis, but expressed concern related to smoking the plant material. While inhalation allows for fairly immediate relief, clinicians should be recommending vaporization rather than smoking to eliminate this concern.




The gut and the brain are intimately connected.

One way that they are connected is through the Endocannabinoid System (ECS).

A 2016 review published in Gastroenterology found that the CB1 receptors control the body’s visceral sensation. “Visceral sensation” is the response and perception of the internal organs, including the gut.

The gut and the brain communicate with each other through what is called the “gut-brain axis”. This is a series of nerve connections and chemical signals that help the two major organ systems coordinate and send messages to each other.

When one part of the body is under stress, whether from signals from the central nervous system or signals from the gut, the other responds with vigor.  The ability to feel this response partly depends on the ECS. The ECS links stress to visceral pain and GI function.








Research on cannabis and GI disorders

Research demonstrates that cannabis and cannabinoids are effective in treating the symptoms of these GI disorders in part because it interacts with the endogenous cannabinoid receptors in the digestive tract, which can result in calming spasms, assuaging pain, and improving motility. Cannabis has also been shown to have anti-inflammatory properties and recent research has demonstrated that cannabinoids are immune system modulators, either enhancing or suppressing immune response.

Cannabis has a long documented history of use in treating GI distress, going back more than a century in western medicine, and far longer in the east. While clinical studies on the use of cannabis for the treatment of gastrointestinal disorders have been largely limited to investigations on nausea suppression and appetite stimulation - two conditions for which cannabis has been consistently shown to be highly effective the evidence in support of cannabis therapy for other gastrointestinal diseases and disorders is also strong. There is now extensive anecdotal evidence from patients with IBS, Crohn's disease and other painful GI disorders that cannabis eases cramping and helps modulate diarrhea, constipation and acid reflux.

Cannabis and new cannabinoid drugs are attractive for GI treatment because they can address a number of symptoms at once with minimal side-effects. Cannabinoids alter how the gut feels, affect the signals the brain sends back and forth to the gut, and modulate the actions of the GI tract itself. For instance, cannabidiol (CBD), the second most abundant cannabinoid on the plant, has been shown to reduce hypermotility, inflammation, and tissue damage in experimental models of GI diseases.

Beginning in the 1970s, a series of human clinical trials established cannabis' ability to stimulate food intake and weight gain in healthy volunteers. In a randomized trial, THC significantly improved appetite and nausea in comparison with placebo. There were also trends towards improved mood and weight gain. Unwanted effects were generally mild or moderate in intensity.

Cannabis helps combat the painful and often debilitating cramping that accompanies many GI disorders because cannabinoids relax contractions of the smooth muscle of the intestines.








The following published research articles are found through the ProjectCBD.org website.

For more information on Gut Health and cannabis go to: https://www.projectcbd.org/condition/17/Digestive-Issues





IBS, Colitis and Crohn’s




The Role of the Endocannabinoid System in the Brain-Gut Axis.


The actions of cannabis are mediated by receptors that are part of an endogenous cannabinoid system. The endocannabinoid system (ECS) consists of the naturally occurring ligands N-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol (2-AG), their biosynthetic and degradative enzymes, and the cannabinoid (CB) receptors CB1 and CB2. The ECS is a widely distributed transmitter system that controls gut functions peripherally and centrally. It is an important physiologic regulator of gastrointestinal motility. Polymorphisms in the gene encoding CB1 (CNR1) have been associated with some forms of irritable bowel syndrome. The ECS is involved in the control of nausea and vomiting and visceral sensation. The homeostatic role of the ECS also extends to the control of intestinal inflammation. We review the mechanisms by which the ECS links stress and visceral pain. CB1 in sensory ganglia controls visceral sensation, and transcription of CNR1 is modified through epigenetic processes under conditions of chronic stress. These processes might link stress with abdominal pain. The ECS is also involved centrally in the manifestation of stress, and endocannabinoid signaling reduces the activity of hypothalamic-pituitary-adrenal pathways via actions in specific brain regions, notably the prefrontal cortex, amygdala, and hypothalamus. Agents that modulate the ECS are in early stages of development for treatment of gastrointestinal diseases. Increasing our understanding of the ECS will greatly advance our knowledge of interactions between the brain and gut and could lead to new treatments for gastrointestinal disorders.



Hergenrather presents study of Crohn’s patients as a template for clinical research on Cannabis physician 

 By O’Shaughnessy’s News Service “Cannabis in Primary Care” was the title of Dr. Jeffrey Hergenrather’s presentation at the CME course accredited by UCSF, MMJ13001A and B.  The subtitle was “Issues for the Practicing Physician: IBD, patient screening and monitoring.” IBD —Inflammatory Bowel Disease, which include Crohn’s and Ulcerative Colitis— might seem relatively esoteric to include in an introductory talk about cannabis medicine. An efficient introduction to the body’s cannabinoid signaling system had been provided by Mark Ware, MD, of CB2CB1 Visceral pain Inflammation Intestinal motility in the inflamed gut Lower esophageal sphincter relaxation Gastric acid secretion Gastric damage Gastric emptying Intestinal motility Intestinal secretion Visceral pain Inflammation Growth of tumor cells. Cannabinoid receptors have been identified in the lower esophagus, stomach, small intestine, colon and rectum. They can be activated by cannabis-based medicine to alleviate many symptoms of Crohn’s disease. Hergenrather’s results strongly suggest that herbal cannabis is beneficial in the treatment of Inflammatory Bowel Disease. Stools per days were reduced by a third, pain reduced by half, vomiting was down, appetite up. Overall, Hergenrather said, “patients’ quality of life is improved significantly.” Introducing CBD Hergenrather described cannabidiol-rich cannabis as “the real star of the show.” He explained that cannabis used recreationally might have a THC-toCBD ratio of 50- or 100to-1, but now strains were being used by patients that contain various cannabinoid ratios, including some that are predominantly CBD “so that you don’t get stoned.” “CBD antagonizes THC and reduces tachycardia [rapid heartbeat],” Hergenrather said, allaying two fears in one sentence. Acid and neutral cannabinoids “In the green plant, THC is in the acid form, which is not psychoactive,” Hergenrather explained. “When it’s burned, vaporized, dried over a long period of time, or baked, you decarboxylate it. In the neutral form THC is psychoactive. But if you use the molecule in the green form you’re going to be able to go way up on dose without going up on psychoactivity. “Eventually terpenes will impart effect, but in general patients can go way up on dose when using green medicine. A patient can take a bud that would take a week to smoke and put it in a smoothie and do that two or three a times a day and not have any ‘high’ effect.

Activating the CB1 receptor, he explained, down-regulates intestinal motility and intestinal secretions while decreasing inflammation, pain and the risk of tumors. Activating the CB2 receptor decreases visceral pain and inflammation, and also down-regulates intestinal motility. “This has a huge effect on patients with Crohn’s disease,” said Hergenrather. He traced the idea for his study to the initial meeting, called by Tod Mikuriya, MD in April 2000 of the group now known as the Society of Cannabis Clinicians.  As the assembled handful of MDs compared notes, Hergenrather recalled, “We noticed right off that people were saying cannabis was working for Crohn’s Disease.” With input from his patients Hergenrather developed a questionnaire which he shared with other SCC doctors so that their patients could be included in the study. In addition to demographic information and use patterns, patients are asked to report the level of certain signs and symptoms experienced when they are and when they are not using cannabis: pain, appetite, nausea, vomiting, fatigue, stools per day, depression, activity level, and weight in pounds. Hergenrather is now tracking 38 patients —28 with Crohn’s and 10 with ulcerative colitis. Twenty-two are employed full or part-time. Seventeen (43%) have had surgical interventions. “This will be an interesting number to follow over time.” Hergenrather said, noting that 75% of Crohn’s patients have surgery during their lifetimes, according to the Centers for Disease Control. Hergenrather’s results strongly suggest that herbal cannabis is beneficial in the treatment of Irritable Bowel Disorders. Half of the patients in the SCC study had stopped the daily use of conventional pharmaceuticals to treat their IBD, except during flare-ups. The main limition on cannabis use were “social issues,” including risk of discovery by an employer. Others limited use because it made them too sleepy or too spacey. Cost was another limitation.






Cannabidiol in inflammatory bowel diseases: a brief overview.


This minireview highlights the importance of cannabidiol (CBD) as a promising drug for the therapy of inflammatory bowel diseases (IBD). Actual pharmacological treatments for IBD should be enlarged toward the search for low-toxicity and low-cost drugs that may be given alone or in combination with the conventional anti-IBD drugs to increase their efficacy in the therapy of relapsing forms of colitis. In the past, Cannabis preparations have been considered new promising pharmacological tools in view of their anti-inflammatory role in IBD as well as other gut disturbances. However, their use in the clinical therapy has been strongly limited by their psychotropic effects. CBD is a very promising compound since it shares the typical cannabinoid beneficial effects on gut lacking any psychotropic effects. For years, its activity has been enigmatic for gastroenterologists and pharmacologists, but now it is evident that this compound may interact at extra-cannabinoid system receptor sites, such as peroxisome proliferator-activated receptor-gamma. This strategic interaction makes CBD as a potential candidate for the development of a new class of anti-IBD drugs.




Cannabis finds its way into treatment of Crohn's disease.


In ancient medicine, cannabis has been widely used to cure disturbances and inflammation of the bowel. A recent clinical study now shows that the medicinal plant Cannabis sativa has lived up to expectations and proved to be highly efficient in cases of inflammatory bowel diseases. In a prospective placebo-controlled study, it has been shown what has been largely anticipated from anecdotal reports, i.e. that cannabis produces significant clinical benefits in patients with Crohn's disease. The mechanisms involved are not yet clear but most likely include peripheral actions on cannabinoid receptors 1 and 2, and may also include central actions.




Cannabidiol reduces intestinal inflammation through the control of neuroimmune axis.


Enteric glial cells (EGC) actively mediate acute and chronic inflammation in the gut; EGC proliferate and release neurotrophins, growth factors, and pro-inflammatory cytokines which, in turn, may amplify the immune response, representing a very important link between the nervous and immune systems in the intestine. Cannabidiol (CBD) is an interesting compound because of its ability to control reactive gliosis in the CNS, without any unwanted psychotropic effects. Therefore the rationale of our study was to investigate the effect of CBD on intestinal biopsies from patients with ulcerative colitis (UC) and from intestinal segments of mice with LPS-induced intestinal inflammation. CBD markedly counteracted reactive enteric gliosis in LPS-mice trough the massive reduction of astroglial signalling neurotrophin S100B. Histological, biochemical and immunohistochemical data demonstrated that S100B decrease was associated with a considerable decrease in mast cell and macrophages in the intestine of LPS-treated mice after CBD treatment. Moreover the treatment of LPS-mice with CBD reduced TNF-α expression and the presence of cleaved caspase-3. Similar results were obtained in ex vivo cultured human derived colonic biopsies. In biopsies of UC patients, both during active inflammation and in remission stimulated with LPS+INF-γ, an increased glial cell activation and intestinal damage were evidenced. CBD reduced the expression of S100B and iNOS proteins in the human biopsies confirming its well documented effect in septic mice. The activity of CBD is, at least partly, mediated via the selective PPAR-gamma receptor pathway. CBD targets enteric reactive gliosis, counteracts the inflammatory environment induced by LPS in mice and in human colonic cultures derived from UC patients. These actions lead to a reduction of intestinal damage mediated by PPARgamma receptor pathway. Our results therefore indicate that CBD indeed unravels a new therapeutic strategy to treat inflammatory bowel diseases.






Cannabidiol, a safe and non-psychotropic ingredient of the marijuana plant Cannabis sativa, is protective in a murine model of colitis.


Inflammatory bowel disease affects millions of individuals; nevertheless, pharmacological treatment is disappointingly unsatisfactory. Cannabidiol, a safe and non-psychotropic ingredient of marijuana, exerts pharmacological effects (e.g., antioxidant) and mechanisms (e.g., inhibition of endocannabinoids enzymatic degradation) potentially beneficial for the inflamed gut. Thus, we investigated the effect of cannabidiol in a murine model of colitis. Colitis was induced in mice by intracolonic administration of dinitrobenzene sulfonic acid. Inflammation was assessed both macroscopically and histologically. In the inflamed colon, cyclooxygenase-2 and inducible nitric oxide synthase (iNOS) were evaluated by Western blot, interleukin-1beta and interleukin-10 by ELISA, and endocannabinoids by isotope dilution liquid chromatography-mass spectrometry. Human colon adenocarcinoma (Caco-2) cells were used to evaluate the effect of cannabidiol on oxidative stress. Cannabidiol reduced colon injury, inducible iNOS (but not cyclooxygenase-2) expression, and interleukin-1beta, interleukin-10, and endocannabinoid changes associated with 2,4,6-dinitrobenzene sulfonic acid administration. In Caco-2 cells, cannabidiol reduced reactive oxygen species production and lipid peroxidation. In conclusion, cannabidiol, a likely safe compound, prevents experimental colitis in mice.




The effects of Delta-tetrahydrocannabinol and cannabidiol alone and in combination on damage, inflammation and in vitro motility disturbances in rat colitis.


Cannabis is taken as self-medication by patients with inflammatory bowel disease for symptomatic relief. Cannabinoid receptor agonists decrease inflammation in animal models of colitis, but their effects on the disturbed motility is not known. (-)-Cannabidiol (CBD) has been shown to interact with Delta(9)-tetrahydrocannabinol (THC) in behavioural studies, but it remains to be established if these cannabinoids interact in vivo in inflammatory disorders. Therefore the effects of CBD and THC alone and in combination were investigated in a model of colitis.

EXPERIMENTAL APPROACH:

The 2,4,6-trinitrobenzene sulphonic acid (TNBS) model of acute colitis in rats was used to assess damage, inflammation (myeloperoxidase activity) and in vitro colonic motility. Sulphasalazine was used as an active control drug.

KEY RESULTS:

Sulphasalazine, THC and CBD proved beneficial in this model of colitis with the dose-response relationship for the phytocannabinoids showing a bell-shaped pattern on the majority of parameters (optimal THC and CBD dose, 10 mg.kg(-1)). THC was the most effective drug. The effects of these phytocannabinoids were additive, and CBD increased some effects of an ineffective THC dose to the level of an effective one. THC alone and in combination with CBD protected cholinergic nerves whereas sulphasalazine did not.

CONCLUSIONS AND IMPLICATIONS:

In this model of colitis, THC and CBD not only reduced inflammation but also lowered the occurrence of functional disturbances. Moreover the combination of CBD and THC could be beneficial therapeutically, via additive or potentiating effects.




Topical and systemic cannabidiol improves trinitrobenzene sulfonic acid colitis in mice.


Compounds of Cannabis sativa are known to exert anti-inflammatory properties, some of them without inducing psychotropic side effects. Cannabidiol (CBD) is such a side effect-free phytocannabinoid that improves chemically induced colitis in rodents when given intraperitoneally. Here, we tested the possibility whether rectal and oral application of CBD would also ameliorate colonic inflammation, as these routes of application may represent a more appropriate way for delivering drugs in human colitis.

METHODS:

Colitis was induced in CD1 mice by trinitrobenzene sulfonic acid. Individual groups were either treated with CBD intraperitoneally (10 mg/kg), orally (20 mg/kg) or intrarectally (20 mg/kg). Colitis was evaluated by macroscopic scoring, histopathology and the myeloperoxidase (MPO) assay.

RESULTS:

Intraperitoneal treatment of mice with CBD led to improvement of colonic inflammation. Intrarectal treatment with CBD also led to a significant improvement of disease parameters and to a decrease in MPO activity while oral treatment, using the same dose as per rectum, had no ameliorating effect on colitis.

CONCLUSION:

The data of this study indicate that in addition to intraperitoneal application, intrarectal delivery of cannabinoids may represent a useful therapeutic administration route for the treatment of colonic inflammation.






Cannabinoids and the gut: new developments and emerging concepts.


Cannabis has been used to treat gastrointestinal (GI) conditions that range from enteric infections and inflammatory conditions to disorders of motility, emesis and abdominal pain. The mechanistic basis of these treatments emerged after the discovery of Delta(9)-tetrahydrocannabinol as the major constituent of Cannabis. Further progress was made when the receptors for Delta(9)-tetrahydrocannabinol were identified as part of an endocannabinoid system, that consists of specific cannabinoid receptors, endogenous ligands and their biosynthetic and degradative enzymes. Anatomical, physiological and pharmacological studies have shown that the endocannabinoid system is widely distributed throughout the gut, with regional variation and organ-specific actions. It is involved in the regulation of food intake, nausea and emesis, gastric secretion and gastroprotection, GI motility, ion transport, visceral sensation, intestinal inflammation and cell proliferation in the gut. Cellular targets have been defined that include the enteric nervous system, epithelial and immune cells. Molecular targets of the endocannabinoid system include, in addition to the cannabinoid receptors, transient receptor potential vanilloid 1 receptors, peroxisome proliferator-activated receptor alpha receptors and the orphan G-protein coupled receptors, GPR55 and GPR119. Pharmacological agents that act on these targets have been shown in preclinical models to have therapeutic potential. Here, we discuss cannabinoid receptors and their localization in the gut, the proteins involved in endocannabinoid synthesis and degradation and the presence of endocannabinoids in the gut in health and disease. We focus on the pharmacological actions of cannabinoids in relation to GI disorders, highlighting recent data on genetic mutations in the endocannabinoid system in GI disease.




Endocannabinoids and the gastrointestinal tract.


In the past centuries, different preparations of marijuana have been used for the treatment of gastrointestinal (GI) disorders, such as GI pain, gastroenteritis and diarrhea. Delta9-tetrahydrocannabinol (THC; the active component of marijuana), as well as endogenous and synthetic cannabinoids, exert their biological functions on the gastrointestinal tract by activating two types of cannabinoid receptors, cannabinoid type 1 receptor (CB1 receptor) and cannabinoid type 2 receptor (CB2 receptor). While CB1 receptors are located in the enteric nervous system and in sensory terminals of vagal and spinal neurons and regulate neurotransmitter release, CB2 receptors are mostly distributed in the immune system, with a role presently still difficult to establish. Under pathophysiological conditions, the endocannabinoid system conveys protection to the GI tract, eg from inflammation and abnormally high gastric and enteric secretion. For such protective activities, the endocannabinoid system may represent a new promising therapeutic target against different GI disorders, including frankly inflammatory bowel diseases (eg, Crohn's disease), functional bowel diseases (eg, irritable bowel syndrome), and secretion- and motility-related disorders.




Cannabinoids and gastrointestinal motility: animal and human studies.


The plant Cannabis has been known for centuries to be beneficial in a variety of gastrointestinal diseases, including emesis, diarrhea, inflammatory bowel disease and intestinal pain. delta9-tetrahydrocannabinol, the main psychotropic component of Cannabis, acts via at least two types of cannabinoid receptors, named CB1 and CB2 receptors. CB1 receptors are located primarily on central and peripheral neurons (including the enteric nervous system) where they modulate neurotransmitter release, whereas CB2 receptors are concerned with immune function, inflammation and pain. The discovery of endogenous ligands [i.e. anandamide and 2-arachidonoyl glycerol (2-AG)] for these receptors indicates the presence of a functional endogenous cannabinoid system in the gastrointestinal tract. Anatomical and functional evidence suggests the presence of CB1 receptors in the myenteric plexus, which are associated with cholinergic neurons in a variety of species, including in humans. Activation of prejunctional CB1 receptors reduces excitatory enteric transmission (mainly cholinergic transmission) in different regions of the gastrointestinal tract. Consistently, in vivo studies have shown that cannabinoids reduce gastrointestinal transit in rodents through activation of CB1, but not CB2, receptors. However, in pathophysiological states, both CB1 and CB2 receptors could reduce the increase of intestinal motility induced by inflammatory stimuli. Cannabinoids also reduce gastrointestinal motility in randomized clinical trials. Overall, modulation of the gut endogenous cannabinoid system may provide a useful therapeutic target for disorders of gastrointestinal motility.




Manipulation of the Endocannabinoid System in Colitis: A Comprehensive Review.


Inflammatory bowel disease (IBD) is a lifelong disease of the gastrointestinal tract whose annual incidence and prevalence is on the rise. Current immunosuppressive therapies available for treatment of IBD offer limited benefits and lose effectiveness, exposing a significant need for the development of novel therapies. In the clinical setting, cannabis has been shown to provide patients with IBD symptomatic relief, although the underlying mechanisms of their anti-inflammatory effects remain unclear.

METHODS:

This review reflects our current understanding of how targeting the endocannabinoid system, including cannabinoid receptors 1 and 2, endogenous cannabinoids anandamide and 2-arachidonoylglycerol, atypical cannabinoids, and degrading enzymes including fatty acid amide hydrolase and monoacylglycerol lipase, impacts murine colitis. In addition, the impact of cannabinoids on the human immune system is summarized.

RESULTS:

Cannabinoid receptors 1 and 2, endogenous cannabinoids, and atypical cannabinoids are upregulated in inflammation, and their presence and stimulation attenuate murine colitis, whereas cannabinoid receptor antagonism and cannabinoid receptor deficient models reverse these anti-inflammatory effects. In addition, inhibition of endocannabinoid degradation through monoacylglycerol lipase and fatty acid amide hydrolase blockade can also attenuate colitis development and is closely linked to cannabinoid receptor expression.

CONCLUSIONS:

Although manipulation of the endocannabinoid system in murine colitis has proven to be largely beneficial in attenuating inflammation, there is a paucity of human study data. Further research is essential to clearly elucidate the specific mechanisms driving this anti-inflammatory effect for the development of therapeutics to target inflammatory disease such as IBD.






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


This study examines the concept of clinical endocannabinoid deficiency (CECD), and the prospect that it could underlie the pathophysiology of migraine, fibromyalgia, irritable bowel syndrome, and other functional conditions alleviated by clinical cannabis.

METHODS:

Available literature was reviewed, and literature searches pursued via the National Library of Medicine database and other resources.

RESULTS:

Migraine has numerous relationships to endocannabinoid function. Anandamide (AEA) potentiates 5-HT1A and inhibits 5-HT2A receptors supporting therapeutic efficacy in acute and preventive migraine treatment. Cannabinoids also demonstrate dopamine-blocking and anti-inflammatory effects. AEA is tonically active in the periaqueductal gray matter, a migraine generator. THC modulates glutamatergic neurotransmission via NMDA receptors. Fibromyalgia is now conceived as a central sensitization state with secondary hyperalgesia. Cannabinoids have similarly demonstrated the ability to block spinal, peripheral and gastrointestinal mechanisms that promote pain in headache, fibromyalgia, IBS and related disorders. The past and potential clinical utility of cannabis-based medicines in their treatment is discussed, as are further suggestions for experimental investigation of CECD via CSF examination and neuro-imaging.

CONCLUSION:

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.




Cannabinoid actions at TRPV channels: effects on TRPV3 and TRPV4 and their potential relevance to gastrointestinal inflammation.


Plant cannabinoids, like Δ(9)-tetrahydrocannabinol (THC) and cannabidiol (CBD), activate/desensitize thermosensitive transient receptor potential (TRP) channels of vanilloid type-1 or -2 (TRPV1 or TRPV2). We investigated whether cannabinoids also activate/desensitize two other 'thermo-TRP's', the TRP channels of vanilloid type-3 or -4 (TRPV3 or TRPV4), and if the TRPV-inactive cannabichromene (CBC) modifies the expression of TRPV1-4 channels in the gastrointestinal tract.

METHODS:

TRP activity was assessed by evaluating elevation of [Ca(2+)](i) in rat recombinant TRPV3- and TRPV4-expressing HEK-293 cells. TRP channel mRNA expression was measured by quantitative RT-PCR in the jejunum and ileum of mice treated with vehicle or the pro-inflammatory agent croton oil.

RESULTS:

(i) CBD and tetrahydrocannabivarin (THCV) stimulated TRPV3-mediated [Ca(2+)](i) with high efficacy (50-70% of the effect of ionomycin) and potency (EC(50∼) 3.7 μm), whereas cannabigerovarin (CBGV) and cannabigerolic acid (CBGA) were significantly more efficacious at desensitizing this channel to the action of carvacrol than at activating it; (ii) cannabidivarin and THCV stimulated TRPV4-mediated [Ca(2+)](i) with moderate-high efficacy (30-60% of the effect of ionomycin) and potency (EC(50) 0.9-6.4 μm), whereas CBGA, CBGV, cannabinol and cannabigerol were significantly more efficacious at desensitizing this channel to the action of 4-α-phorbol 12,13-didecanoate (4α-PDD) than at activating it; (iii) CBC reduced TRPV1β, TRPV3 and TRPV4 mRNA in the jejunum, and TRPV3 and TRPV4 mRNA in the ileum of croton oil-treated mice.

CONCLUSIONS:

Cannabinoids can affect both the activity and the expression of TRPV1-4 channels, with various potential therapeutic applications, including in the gastrointestinal tract.




Therapeutic potential of cannabinoid-based drugs.


Cannabinoid-based drugs modeled on cannabinoids originally isolated from marijuana are now known to significantly impact the functioning of the endocannabinoid system of mammals. This system operates not only in the brain but also in organs and tissues in the periphery including the immune system. Natural and synthetic cannabinoids are tricyclic terpenes, whereas the endogenous physiological ligands are eicosanoids. Several receptors for these compounds have been extensively described, CB1 and CB2, and are G protein-coupled receptors; however, cannabinoid-based drugs are also demonstrated to function independently of these receptors. Cannabinoids regulate many physiological functions and their impact on immunity is generally antiinflammatory as powerful modulators of the cytokine cascade. This anti-inflammatory potency has led to the testing of these drugs in chronic inflammatory laboratory paradigms and even in some human diseases. Psychoactive and nonpsychoactive cannabinoid-based drugs such as Delta9-tetrahydrocannabinol, cannabidiol, HU-211, and ajulemic acid have been tested and found moderately effective in clinical trials of multiple sclerosis, traumatic brain injury, arthritis, and neuropathic pain. Furthermore, although clinical trials are not yet reported, preclinical data with cannabinoid-based drugs suggest efficacy in other inflammatory diseases such as inflammatory bowel disease, Alzheimer's disease, atherosclerosis, and osteoporosis.




Beneficial effect of the non-psychotropic plant cannabinoid cannabigerol on experimental inflammatory bowel disease


Inflammatory bowel disease (IBD) is an incurable disease which affects millions of people in industrialized countries. Anecdotal and scientific evidence suggests that Cannabis use may have a positive impact in IBD patients. Here, we investigated the effect of cannabigerol (CBG), a non-psychotropic Cannabis-derived cannabinoid, in a murine model of colitis. Colitis was induced in mice by intracolonic administration of dinitrobenzene sulphonic acid (DNBS). Inflammation was assessed by evaluating inflammatory markers/parameters (colon weight/colon length ratio and myeloperoxidase activity), by histological analysis and immunohistochemistry; interleukin-1β, interleukin-10 and interferon-γ levels by ELISA, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) by western blot and RT-PCR; CuZn-superoxide dismutase (SOD) activity by a colorimetric assay. Murine macrophages and intestinal epithelial cells were used to evaluate the effect of CBG on nitric oxide production and oxidative stress, respectively. CBG reduced colon weight/colon length ratio, myeloperoxidase activity, and iNOS expression, increased SOD activity and normalized interleukin-1β, interleukin-10 and interferon-γ changes associated to DNBS administration. In macrophages, CBG reduced nitric oxide production and iNOS protein (but not mRNA) expression. Rimonabant (a CB1 receptor antagonist) did not change the effect of CBG on nitric oxide production, while SR144528 (a CB2 receptor antagonist) further increased the inhibitory effect of CBG on nitric oxide production. In conclusion, CBG attenuated murine colitis, reduced nitric oxide production in macrophages (effect being modulated by the CB2 receptor) and reduced ROS formation in intestinal epithelial cells. CBG could be considered for clinical experimentation in IBD patients.




Videos on Cannabis and Digestive Disorders

Howcast discovers the basics of Marijuana Relief on GI Disorders:




Laura Lagano, MS, RDN, CDN is an Integrative Clinical Nutritionist as well as Founder of the Holistic Cannabis Network: http://holisticcannabisnetwork.com/

High Intensity Health shares her knowledge and experience with Cannabis and Gut Health: Medical Marijuana Science:




Cannabis can be a safe effective way to help alleviate the discomfort that comes with having digestive issues. However, cannabis is not for everyone. Make sure to talk to a trusted medical professional and ask for help with taking cannabis as an alternative medicine.

When it comes to dosing with cannabis, make sure to find a product that contains a ratio of THC and CBD. Take small doses daily. More is not better! Just a few drops of cannabis oil under the tongue daily, and at the onset of pain, should do just fine.

If you are taking other prescribed medicine, you need to talk to a trusted medical professional to see if cannabis may interfere with your other medications.

Some people may experience a psychedelic reaction to adding THC into their system. If taking a few drops of equal-ratio-oil is too much THC for certain patients, its best to take the few drops at night before bed. This way the oil may help you relax and sleep well, then wake up feeling better. Finding cannabis oil with ratios that express more CBD and less THC is another great way to uptake both essential cannabinoids while decreasing your THC intake.Unfortunately, this is not for everyone! 


So, if experimenting please remember to 
START LOW and GO SLOW!!!



For more information about Cannabis and Digestive Disorders look into:









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