Cannabis and Canabidinoids on the Inflammatory Bowel Diseases: Going Beyond Misuse.

ijms-logo“Inflammatory bowel diseases (IBD) are characterized by a chronic and recurrent gastrointestinal condition, including mainly ulcerative colitis (UC) and Crohn’s disease (CD). Cannabis sativa (CS) is widely used for medicinal, recreational, and religious purposes. The most studied compound of CS is tetrahydrocannabinol (THC) and cannabidiol (CBD). Besides many relevant therapeutic roles such as anti-inflammatory and antioxidant properties, there is still much controversy about the consumption of this plant since the misuse can lead to serious health problems. Because of these reasons, the aim of this review is to investigate the effects of CS on the treatment of UC and CD. The literature search was performed in PubMed/Medline, PMC, EMBASE, and Cochrane databases. The use of CS leads to the improvement of UC and CD scores and quality of life. The medical use of CS is on the rise. Although the literature shows relevant antioxidant and anti-inflammatory effects that could improve UC and CD scores, it is still not possible to establish a treatment criterion since the studies have no standardization regarding the variety and part of the plant that is used, route of administration and doses. Therefore, we suggest caution in the use of CS in the therapeutic approach of IBD until clinical trials with standardization and a relevant number of patients are performed.”

https://www.ncbi.nlm.nih.gov/pubmed/32331305

https://www.mdpi.com/1422-0067/21/8/2940

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An overview of cannabis based treatment in Crohn’s disease.

 Publication Cover“Cannabis use among inflammatory bowel disease (IBD) patients is common. There are many studies of various laboratory models demonstrating the anti-inflammatory effect of cannabis, but their translation to human disease is still lacking.

Areas covered: The cannabis plant contains many cannabinoids, that activate the endocannabinoid system. The two most abundant phytocannabinoids are the psychoactive Tetrahydrocannabinol (THC), and the (mostly) anti-inflammatory cannabidiol (CBD). Approximately 15% of IBD patients use cannabis to ameliorate disease symptoms. Unfortunately, so far there are only three small placebo controlled study regarding the use of cannabis in active Crohns disease, combining altogether 93 subjects. Two of the studies showed significant clinical improvement but no improvement in markers of inflammation.

Expert opinion: Cannabis seems to have a therapeutic potential in IBD. This potential must not be neglected; however, cannabis research is still at a very early stage. The complexity of the plant and the diversity of different cannabis chemovars create an inherent difficulty in cannabis research. We need more studies investigating the effect of the various cannabis compounds. These effects can then be investigated in randomized placebo controlled clinical trials to fully explore the potential of cannabis treatment in IBD.”

https://www.ncbi.nlm.nih.gov/pubmed/32149543

https://www.tandfonline.com/doi/abs/10.1080/17474124.2020.1740590?journalCode=ierh20

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Is Cannabis of Potential Value as a Therapeutic for Inflammatory Bowel Disease?

“Cannabis is commonly used by patients with inflammatory bowel disease (IBD) to ameliorate their symptoms.

Patients claim that cannabis reduces pain, increases appetite, and reduces the need for other medications.

In conclusion, considering the mechanism of action of phytocannabinoids and the accumulating evidence of their anti-inflammatory effects in experimental and in vitro studies, it is reasonable to assume that cannabis can be of benefit in the treatment of IBD.”

https://www.ncbi.nlm.nih.gov/pubmed/31388856

https://link.springer.com/article/10.1007%2Fs10620-019-05763-8

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In-hospital outcomes of inflammatory bowel disease in cannabis users: a nationwide propensity-matched analysis in the United States.

“Literature suggests the role of cannabis (marijuana) as an anti-inflammatory agent. However, the impact of recreational marijuana usage on in-hospital outcomes of inflammatory bowel disease (IBD) remains indistinct.

We assessed the outcomes of Crohn’s disease (CD) as well as ulcerative colitis (UC) with vs. without recreational marijuana usage using a nationally illustrative propensity-matched sample.

RESULTS:

Propensity-matched cohorts included 6,002 CD (2,999 cannabis users & 3,003 non-users) and 1,481 UC (742 cannabisusers & 739 non-users) hospitalizations. In CD patients, prevalence of colorectal cancer (0.3% vs. 1.2%, P<0.001), need for parenteral nutrition (3.0% vs. 4.7%, P=0.001) and anemia (25.6% vs. 30.1%, P<0.001) were lower in cannabis users. However, active fistulizing disease or intraabdominal abscess formation (8.6% vs. 5.9%, P<0.001), unspecific lower gastrointestinal (GI) hemorrhage (4.0% vs. 2.7%, P=0.004) and hypovolemia (1.2% vs. 0.5%, P=0.004) were higher with recreational cannabis use. The mean hospital stay was shorter (4.2 vs. 5.0 days) with less hospital charges ($28,956 vs. $35,180, P<0.001) in cannabis users. In patients with UC, cannabis users faced the higher frequency of fluid and electrolyte disorders (45.1% vs. 29.6%, P<0.001), and hypovolemia (2.7% vs.<11) with relatively lower frequency of postoperative infections (<11 vs. 3.4%, P=0.010). No other complications were significant enough for comparison between the cannabis users and non-users in this group. Like CD, UC-cannabis patients had shorter mean hospital stay (LOS) (4.3 vs. 5.7 days, P<0.001) and faced less financial burden ($30,393 vs. $41,308, P<0.001).

CONCLUSIONS:

We found a lower frequency of colorectal cancer, parenteral nutrition, anemia but a higher occurrences of active fistulizing disease or intraabdominal abscess formation, lower GI hemorrhage and hypovolemia in the CD cohort with cannabis usage. In patients with UC, frequency of complications could not be compared between the two cohorts, except a higher frequency of fluid and electrolyte disorders and hypovolemia, and a lower frequency of postoperative infections with cannabis use. A shorter length of stay (LOS)  and lesser hospital charges were observed in both groups with recreational marijuana usage.”

https://www.ncbi.nlm.nih.gov/pubmed/31355219

http://atm.amegroups.com/article/view/25637/24217

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Association Between Cannabis Use and Complications Related to Crohn’s Disease: A Retrospective Cohort Study.

“Crohn’s disease is an idiopathic inflammatory process that is occasionally associated with complications, which cause significant morbidity and mortality. The anti-inflammatory effect of cannabis in intestinal inflammation has been shown in several experimental models; it is unknown whether this correlates with fewer complications in Crohn’s disease patients.

AIMS:

To compare the prevalence of Crohn’s disease-related complications among cannabis users and non-users in patients admitted with a primary diagnosis of Crohn’s disease or a primary diagnosis of Crohn’s related complication and a secondary diagnosis of Crohn’s disease between 2012 and 2014.

METHODS:

We used data from the Healthcare Cost and Utilization Project-National Inpatient Sample. Cannabis users (615) were compared directly after propensity score match to non-users, in aspects of various complications and clinical end-points.

RESULTS:

Among matched cohorts, Cannabis users were less likely to have the following: active fistulizing disease and intra-abdominal abscess (11.5% vs. 15.9%; aOR 0.68 [0.49 to 0.94], p = 0.025), blood product transfusion (5.0% vs. 8.0%; aOR 0.48 [0.30 to 0.79], p = 0.037), colectomy (3.7% vs. 7.5%; aOR 0.48 [0.29-0.80], p = 0.004), and parenteral nutrition requirement (3.4% vs. 6.7%, aOR 0.39 [0.23 to 0.68], p = 0.009).

CONCLUSION:

Cannabis use may mitigate several of the well-described complications of Crohn’s disease among hospital inpatients. These effects could possibly be through the effect of cannabis in the endocannabinoid system.”

https://www.ncbi.nlm.nih.gov/pubmed/30825109

https://link.springer.com/article/10.1007%2Fs10620-019-05556-z

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Cannabis, cannabinoids and the endocannabinoid system – is there therapeutic potential for inflammatory bowel disease?

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“Cannabis sativa and its extracts have been used for centuries both medicinally and recreationally. There is accumulating evidence that exogenous cannabis and related cannabinoids improve symptoms associated with inflammatory bowel disease such as pain, loss of appetite, and diarrhoea. In vivo, exocannabinoids have been demonstrated to improve colitis, mainly in chemical models. Exocannabinoids signal through the endocannabinoid system, an increasingly understood network of endogenous lipid ligands and their receptors, together with a number of synthetic and degradative enzymes and the resulting products. Modulating the endocannabinoid system using pharmacological receptor agonists, genetic knockout models, or inhibition of degradative enzymes have largely shown improvements in colitis in vivo. Despite these promising experimental results, this has not translated into meaningful benefits for human IBD in the few clinical trials which have been conducted to date. The largest study to date being limited by poor medication tolerance due to the Δ9-tetrahydrocannabinol component. This review article synthesises the current literature surrounding the modulation of the endocannabinoid system and administration of exocannabinoids in experimental and human IBD. Findings of clinical surveys and studies of cannabis use in IBD are summarised. Discrepancies in the literature are highlighted together with identifying novel areas of interest.”

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The Role of Cannabis in the Management of Inflammatory Bowel Disease: A Review of Clinical, Scientific, and Regulatory Information: Commissioned by the Crohn’s and Colitis Foundation.

Oxford University Press

“There is significant interest among patients and providers in using cannabis (marijuana) and its derivatives to treat a number of chronic illnesses, including inflammatory bowel disease. Despite the Schedule I classification of cannabis by the federal government, state governments have sought ways to make cannabis available for specific medical conditions, and some states have legalized cannabis outright. This white paper summarizes the preclinical data, clinical data, safety data, and the regulatory landscape as they apply to medical cannabis use in inflammatory bowel disease. Animal models of cannabinoid chemistry and physiology give evidence of anti-inflammatory, antidiarrheal, and nociceptive-limiting properties. Human studies have found benefit in controlling symptoms and improving quality of life, but no studies have established true disease modification given the absent improvement in biomarker profiles or endoscopic healing. Finally, this review describes the legal, regulatory, and practical hurdles to studying the risks and benefits of medical cannabis in the United States.”

https://www.ncbi.nlm.nih.gov/pubmed/30358848

https://academic.oup.com/ibdjournal/advance-article-abstract/doi/10.1093/ibd/izy319/5144402?redirectedFrom=fulltext

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Anti-Inflammatory Activity in Colon Models Is Derived from Δ9-Tetrahydrocannabinolic Acid That Interacts with Additional Compounds in Cannabis Extracts.

“Inflammatory bowel diseases (IBDs) include Crohn’s disease, and ulcerative colitis. Cannabis sativa preparations have beneficial effects for IBD patients. However, C. sativa extracts contain hundreds of compounds. Although there is much knowledge of the activity of different cannabinoids and their receptor agonists or antagonists, the cytotoxic and anti-inflammatory activity of whole C. sativa extracts has never been characterized in detail with in vitro and ex vivo colon models.

Material and Methods: The anti-inflammatory activity of C. sativa extracts was studied on three lines of epithelial cells and on colon tissue. C. sativa flowers were extracted with ethanol, enzyme-linked immunosorbent assay was used to determine the level of interleukin-8 in colon cells and tissue biopsies, chemical analysis was performed using high-performance liquid chromatography, mass spectrometry and nuclear magnetic resonance and gene expression was determined by quantitative real-time PCR.

Results: The anti-inflammatory activity of Cannabis extracts derives from D9-tetrahydrocannabinolic acid (THCA) present in fraction 7 (F7) of the extract. However, all fractions of C. sativa at a certain combination of concentrations have a significant increased cytotoxic activity. GPR55 receptor antagonist significantly reduces the anti-inflammatory activity of F7, whereas cannabinoid type 2 receptor antagonist significantly increases HCT116 cell proliferation. Also, cannabidiol (CBD) shows dose dependent cytotoxic activity, whereas anti-inflammatory activity was found only for the low concentration of CBD, and in a bell-shaped rather than dose-dependent manner. Activity of the extract and active fraction was verified on colon tissues taken from IBD patients, and was shown to suppress cyclooxygenase-2 (COX2) and metalloproteinase-9 (MMP9) gene expression in both cell culture and colon tissue.

Conclusions: It is suggested that the anti-inflammatory activity of Cannabis extracts on colon epithelial cells derives from a fraction of the extract that contains THCA, and is mediated, at least partially, via GPR55 receptor. The cytotoxic activity of the C. sativa extract was increased by combining all fractions at a certain combination of concentrations and was partially affected by CB2 receptor antagonist that increased cell proliferation. It is suggested that in a nonpsychoactive treatment for IBD, THCA should be used rather than CBD.”

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Cannabinoid Receptor-2 Ameliorates Inflammation in Murine Model of Crohn’s Disease.

Image result for jcc journal of crohn's and colitis

“Cannabinoid receptor stimulation may have positive symptomatic effects on inflammatory bowel disease [IBD] patients through analgesic and anti-inflammatory effects.

The cannabinoid 2 receptor [CB2R] is expressed primarily on immune cells, including CD4+ T cells, and is induced by active inflammation in both humans and mice. We therefore investigated the effect of targeting CB2R in a preclinical IBD model.

 In summary, the endocannabinoid system is induced in murine ileitis but is downregulated in chronic murine and human intestinal inflammation, and CB2R activation attenuates murine ileitis, establishing an anti-inflammatory role of the endocannabinoid system.”

https://www.ncbi.nlm.nih.gov/pubmed/28981653

https://academic.oup.com/ecco-jcc/article-abstract/doi/10.1093/ecco-jcc/jjx096/3977952/Cannabinoid-Receptor-2-Ameliorates-Inflammation-in?redirectedFrom=fulltext

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Medicinal Uses of Marijuana and Cannabinoids

Publication Cover

“In the past two decades, there has been increasing interest in the therapeutic potential of cannabis and single cannabinoids, mainly cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC). THC and cannabis products rich in THC exert their effects mainly through the activation of cannabinoid receptors (CB1 and CB2). Since 1975, 140 controlled clinical trials using different cannabinoids or whole-plant preparations for the treatment of a large number of disorders and symptoms have been conducted. Results have led to the approval of cannabis-based medicines [dronabinol, nabilone, and the cannabis extract nabiximols (Sativex®, THC:CBD = 1:1)] as well as cannabis flowers in several countries. Controlled clinical studies provide substantial evidence for the use of cannabinoid receptor agonists in cancer chemotherapy induced nausea and vomiting, appetite loss and cachexia in cancer and HIV patients, neuropathic and chronic pain, and in spasticity in multiple sclerosis. In addition, there is also some evidence suggesting a therapeutic potential of cannabis-based medicines in other indications including Tourette syndrome, spinal cord injury, Crohn’s disease, irritable bowel syndrome, and glaucoma. In several other indications, small uncontrolled and single-case studies reporting beneficial effects are available, for example in posttraumatic stress disorder, attention deficit hyperactivity disorder, and migraine. The most common side effects of THC and cannabis-based medicines rich in THC are sedation and dizziness (in more than 10% of patients), psychological effects, and dry mouth. Tolerance to these side effects nearly always develops within a short time. Withdrawal symptoms are hardly ever a problem in the therapeutic setting. In recent years there is an increasing interest in the medical use of CBD, which exerts no intoxicating side effects and is usually well-tolerated. Preliminary data suggest promising effects in the treatment of anxiety disorders, schizophrenia, dystonia, and some forms of epilepsy. This review gives an overview on clinical studies which have been published over the past 40 years.”

http://www.tandfonline.com/doi/abs/10.1080/07352689.2016.1265360?needAccess=true&journalCode=bpts20

“Review Identifies 140 Controlled Clinical Trials Related to Cannabis”  http://blog.norml.org/2017/06/04/review-identifies-140-controlled-clinical-trials-related-to-cannabis/

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