Chronic inflammatory bowel disease – Can they benefit from cannabinoids?

Cannabinoide und chronisch-entzündliche Darmerkrankungen (CED) | Kalapa Clinic

Chronic inflammatory bowel disease (IBD) is a collective term for Crohn’s disease (MC), ulcerative colitis (CU) and a few lesser-known forms. Those affected have to struggle with persistent diarrhoea, weight loss, severe abdominal pain and loss of performance. The suffering is often enormous. Studies show that tetrahydrocannabinol (THC) and cannabidiol (CBD) can alleviate the symptoms of IBD and improve the quality of life of patients.

What is IBD?

In addition to the most common chronic inflammatory bowel diseases, Crohn’s disease and ulcerative colitis, there are also rarer forms such as microscopic colitis [3]. The causes and risk factors of most IBD are currently unknown. Scientists believe that many factors are involved. These include genetic and environmental factors such as diet, the gut microbiome (gut bacteria) and the immune system [10]. Depending on which parts of the gastrointestinal tract are affected, different symptoms may occur.

The number of patients with inflammatory bowel disease is increasing worldwide. Between 1990 and 2017, the number of people affected rose from 3.7 million to over 6.8 million [1]. In Germany it is estimated that 420,000 to 470,000 patients suffer from IBD [2]. As the disease is a risk factor for colorectal cancer, effective treatment is important.

Inflammatory bowel diseases (IBD) include [3]:

  • Crohn’s disease
  • Ulcerative colitis
  • Pouchitis: inflammation of the pouch (a pouch formed from the small intestine that serves as an outlet for the bowel after surgical removal of the colon and rectum)
    • microscopic colitis
    • collagenous colitis
    • lymphocytic colitis
  • eosinophilic gastroenteritis
  • Colitis cystica profunda or enterocolitis cystica profunda

Common features of Crohn’s disease and ulcerative colitis

Crohn’s disease and ulcerative colitis usually start in young adulthood, but can occur at any age.

Possible symptoms include: chronische Durchfälle

  • Chronic diarrhoea
  • Cramping abdominal pain
  • Weight loss
  • Fever
  • Anaemia due to bloody diarrhoea
  • Fatigue and loss of performance

The inflammatory changes can also appear outside the gastrointestinal tract. Inflammation of the joints, skin and eyes can occur. Both genetic risk factors and environmental influences can favour MC and CU. Characteristically, the symptoms occur in relapses. This means that phases of the disease alternate with phases with few symptoms, so-called remission phases [4][5]. Remission is understood to be a temporary or permanent reduction in symptoms. However, there is no cure, i.e. relapses can occur with a flare-up of the symptoms.

Temporary or permanent alleviation of symptoms in chronics diseases without a cure

Difference between Crohn’s disease and ulcerative colitis [4]

Crohn’s diseaseUlcerative colitis
Inflammation of all mucosal layersInflammation of the outer mucosal layers (mucosa and submocosa)
Infestation of the entire gastrointestinal tract possibleInfestation predominantly of the colon
Discontinuous spread over all intestinal segmentsContinuous spread starting from the rectum
Mostly bloodless diarrhoeaMostly bloody-mucous diarrhoea
Frequent changes in the mucosa such as strictures, fistulas, abscessesRarely changes in the mucosa
Often severe weight lossRarely weight loss

Diagnosis of inflammatory bowel disease (IBD)

Since IBD manifests itself through non-specific symptoms such as abdominal pain and diarrhoea, doctors have to rule out other diseases such as infections or irritable bowel syndrome in order to make a diagnosis. This involves blood and stool tests as well as imaging procedures. Patients with IBD have elevated levels of inflammation in their blood and stool. The (bloody) diarrhoea often causes anaemia with symptoms such as severe fatigue. An increase in the protein calprotectin in the stool is characteristic. Calprotectin is found in immune cells which migrate more into the intestinal mucosa in IBD. In addition an infection with Clostridium difficile must be ruled out, a normally harmless intestinal inhabitant which can multiply strongly after therapy with antibiotics and cause infectious colitis.

Using imaging techniques such as ultrasound or magnetic resonance imaging (MRI), the doctor can examine the intestine in detail. During a colonoscopy the mucous membrane is examined from the inside with an endoscope. The examiner pushes a flexible tube equipped with a camera to the affected parts of the intestine. Tissue samples of the mucous membrane with inflammatory changes can also be taken with a small forceps [6].

Medicine therapy for IBD

The medicine treatment of IBD depends on the affected bowel segments and the course of the disease. Doctors treat MC and CU according to a step-by-step scheme, starting with mild therapies and moving on to highly effective medications and surgery. Regular examinations are indispensable, as the course of the disease varies from person to person and cannot be predicted.

Acute attacks of Crohn’s disease are treated with corticosteroids, such as the active ingredient budesonide, to quickly reduce the inflammation. Depending on the severity of the attack and the localisation of the inflammation, steroids are used in various forms: suppositories, clysms and foams act locally in the intestine. Steroids taken orally affect the whole body. If patients do not respond to steroids, they are examined to see if local mucosal changes such as abscesses are present. Therapy is intensified with immunosuppressive drugs such as infliximab (anti-TNF-alpha antibody), azathioprine or methotrexate. These drugs inhibit the activity of the immune system and thus the inflammation. This achieves a remission, i.e. a weakening of the acute symptoms.

Alternatively, surgical treatment can also be useful. The goal is to achieve remission with steroids and immunosuppressants. Since a new relapse can occur at any time, long-term therapy is initiated afterwards so that the attacked mucous membrane can heal and the quality of life improves. Because of the severe side effects such as osteoporosis, weight gain, steroid diabetes and skin changes, steroids are not considered for remission maintenance. Immunosuppressants are therefore used for long-term use, although it must be noted that patients are more susceptible to infectious diseases due to the suppression of the immune system and the drugs can have further side effects, some of them serious, depending on the active substance [7].

In ulcerative colitis, an acute episode manifests itself with typical symptoms such as bloody diarrhoea, pain and disturbances during bowel movements. If only the rectum is inflamed, it is first treated locally with mesalazine (5-aminosalicylic acid). If this is not effective, it can be combined with locally acting steroids and the oral intake of mesalazine. In severe relapses cortisone is also used orally. After remission has been achieved the corticosteroid should be discontinued and long-term therapy with mesalazine continued. The drug is applied orally or rectally depending on the pattern of the disease. In therapy-resistant courses or malignant mucosal changes, surgical removal of the diseased colon can be useful [8].

Cannabinoids in inflammatory bowel disease

The endocannabinoid system (ECS) of the digestive tract forms CB1 and CB2 receptors. The CB1 receptor, which is mainly activated by the psychotropic cannabinoid THC, occurs in the intestine on two large nerve plexuses that perform different tasks:Auerbach-Plexus (Plexus myentericus):

  • Auerbach’s plexus (myenteric plexus): Control of intestinal movements (motility)
  • Meissner’s plexus (submucosal plexus): Control of glandular secretion and intestinal blood flow by narrowing or widening the blood vessels.

The anti-inflammatory effect of cannabinoids is mediated among other things via CB2 receptors that are located on white blood cells (e.g. macrophages, plasma cells) and in the lamina propia, a connective tissue layer directly under the intestinal epithelial cells. These immune cells have the task of recognising potential pathogens and foreign substances from food and making them harmless [9].

Mechanism of action of cannabinoids in IBD

THC reduces the motility of the intestine by binding to CB1 receptors in the Auerbach’s plexus. The secretion of digestive fluid by the intestinal glands is also reduced. Thus the cannabinoid counteracts diarrhoea. In addition THC has pain-relieving (analgesic) effects via two pathways: Via CB1 receptors in the brain and spinal cord and by inhibiting C-fibres that transmit painful stimuli from peripheral organs – such as the digestive organs – to the spinal cord. Peripheral hyperalgesia (increased sensitivity to pain) improves as a result.

Cannabinoids have an anti-inflammatory effect by binding to CB2 receptors of the immune cells. The production of proinflammatory cytokines is reduced. In contrast, anti-inflammatory messenger substances (anti-inflammatory cytokines) are increasingly produced. The inflammations in Crohn’s disease and ulcerative colitis can thus be combated. In animal models, scientists were also able to show that CBD has an analgesic effect by attaching to CB2 receptors of peripheral nerve endings.

The role of ECS in the digestive system is not fully understood. For example, the role of the CB1 receptor in the inflammatory process remains to be determined [9].

Medical cannabis in Crohn’s disease

In a placebo-controlled study from 2013, 21 MC patients participated in whom steroids, immunomodulators, and TNF-alpha blockers were not sufficiently effective. Medication for the 11 individuals in the cannabis group consisted of THC-containing cannabis flowers for inhalation. Patients in the placebo group inhaled cannabis flowers from which the THC had been removed. During the 8-week treatment period, patients were closely monitored for effects on disease activity and laboratory results. At the end of the study, complete remission was seen in 5 of 11 THC patients. In 10 of the 11 patients, symptoms were reduced. Compared to the placebo group, the cannabinoid group was more satisfied with therapy and reported greater pain relief and improved appetite [9] [10].

A study published in 2021 provides evidence for the efficacy of CBD-rich cannabis oil in the treatment of Crohn’s disease. The randomized, placebo-controlled study involved 56 patients* of whom 30 took cannabis and 26 took a placebo. The cannabis oil contained a high dose of CBD and a low dose of THC. After two months of treatment, the group taking the CBD-rich cannabis oil experienced significant improvements in quality of life and clinical symptoms. However, inflammatory values such as calprotectin and endoscopic findings did not improve significantly [12].

Medical cannabis for ulcerative colitis

In 2018, a randomized, placebo-controlled, double-blind study investigated the effect of an oral, CBD-rich cannabis extract in CU. A total of 46 participants* completed the study. Seven of 17 people (41%) in the cannabinoid group showed clinical improvement in their bowel inflammation, compared with 30 percent in the placebo group. Those taking CBD experienced more mild to moderate side effects, such as dizziness and headache. Those taking CBD also reported improved quality of life. However, the researchers concluded that these effects were not statistically significant due to the small number of subjects [11].

 

Abdominal pain, loss of appetite and diarrhea are most commonly treated

In 2013, 292 IBD patients with MC, CU, or indeterminate colitis participated in a survey conducted in Massachusetts, USA. More than half of the respondents (51.4%) reported current or past cannabis use. 48 Patients* used cannabis for medicinal purposes and mostly reported good relief of their symptoms. The symptoms most commonly treated with cannabinoids were abdominal pain (89.5%), loss of appetite (72.9%), and diarrhea (41.6%). Slightly more than half of those without cannabis experience would use medical cannabis for their symptoms if it were legally available [15].

THC reduces steroid requirements in patients with IBD

In a 2013 randomized controlled trial, researchers investigated the effects of inhaled THC-rich cannabis flower in patients with MC or CU who did not respond to steroids, immunomodulators, or anti-TNF-alpha antibodies. 10 participants* with CU and 22 sufferers with MC completed the study. After eight weeks of therapy, five of the patients in the THC group but only one person in the placebo group achieved remission. Five of the sufferers were able to discontinue steroids as a result of cannabinoid treatment. Improvements in endoscopic findings were also noted in three patients who underwent colonoscopy before and after therapy with THC. No serious side effects occurred.

The research team concluded that THC is a safe and promising treatment option for IBD and may reduce the need for corticosteroids. Larger studies are needed to further explore its efficacy, proper dosing, and mechanism of action [13].

Conclusion

According to surveys, cannabis use is common among patients with IBD. Many people who have no previous cannabis experience would also use medicinal cannabis. Cannabinoids do not seem to be able to induce remission of IBD. However, many patients* with IBD can use cannabis-based medications to alleviate their extremely distressing symptoms and improve their quality of life. Future studies should therefore investigate more deeply the role of ECS in digestion. To provide further evidence in therapy, clinical trials with large groups of people are needed to investigate efficacy in more detail. In addition, which dosage, which drug formulation, and which route of administration of medicinal cannabis is most beneficial in CED should still be clarified.

Sources:

[1]        GBD 2017 Inflammatory Bowel Disease Collaborators. The global, regional, and national burden of inflammatory bowel disease in 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet Gastroenterol Hepatol. 2020 Jan;5(1):17-30. doi: 10.1016/S2468-1253(19)30333-4. Epub 2019 Oct 21. PMID: 31648971; PMCID: PMC7026709.

[2]        Andreas Stallmach, Winfried Häuser, Helmut L’hoest, Ursula Marschall „Die chronisch entzündlichen Darmerkrankungen Morbus Crohn und Colitis ulcerosa: Herausforderungen an die Versorgung“ AUSZUG aus: BARMER GEK Gesundheitswesen aktuell 2012 (Seite 286-309)

[3]        Hoffmann u.a., Chronisch entzündliche Darmerkrankungen (9783131381125) © 2008 Georg Thieme Verlag KG, Seite 87

[4]        Chronisch entzündliche Darmerkrankungen Morbus Crohn und Colitis ulcerosa Jan Wehkamp, Martin Götz, Klaus Herrlinger, Wolfgang Steurer, Eduard F. Stange Dtsch Arztebl Int 2016; 113: 72–82. DOI: 10.3238/arztebl.2016.0072

[5]        Review article The Diagnosis and Treatment of Crohn’s Disease and Ulcerative Colitis Dtsch Arztebl Int 2009; 106(8): 123-33. DOI: 10.3238/arztebl.2009.0123

[6]        Christian Maaser, Andreas Sturm, Stephan R Vavricka, Torsten Kucharzik, Gionata Fiorino, Vito Annese, Emma Calabrese, Daniel C Baumgart, Dominik Bettenworth, Paula Borralho Nunes, Johan Burisch, Fabiana Castiglione, Rami Eliakim, Pierre Ellul, Yago González-Lama, Hannah Gordon, Steve Halligan, Konstantinos Katsanos, Uri Kopylov, Paulo G Kotze, Eduards Krustiņš, Andrea Laghi, Jimmy K Limdi, Florian Rieder, Jordi Rimola, Stuart A Taylor, Damian Tolan, Patrick van Rheenen, Bram Verstockt, Jaap Stoker, ECCO-ESGAR Guideline for Diagnostic Assessment in IBD Part 1: Initial diagnosis, monitoring of known IBD, detection of complications, Journal of Crohn’s and Colitis, Volume 13, Issue 2, February 2019, Pages 144–164K, https://doi.org/10.1093/ecco-jcc/jjy113

[7]        Aktualisierte S3-Leitlinie „Diagnostik und Therapie des M. Crohn“ 2014* AWMF-Registriernummer: 021-004

[8]        Aktualisierte S3-Leitlinie Colitis ulcerosa – Living Guideline August 2020 – AWMF-Registriernummer: 021-009

[9]        Perisetti, A., Rimu, A. H., Khan, S. A., Bansal, P., & Goyal, H. (2020). Role of cannabis in inflammatory bowel diseases. Annals of gastroenterology, 33(2), 134–144. https://doi.org/10.20524/aog.2020.0452

[10]      Naftali T, Bar-Lev Schleider L, Dotan I, Lansky EP, Sklerovsky Benjaminov F, Konikoff FM. Cannabis induces a clinical response in patients with Crohn’s disease: a prospective placebo-controlled study. Clin Gastroenterol Hepatol. 2013 Oct;11(10):1276-1280.e1. doi: 10.1016/j.cgh.2013.04.034. Epub 2013 May 4. PMID: 23648372.

[11]      Kafil  TS, Nguyen  TM, MacDonald  JK, Chande  N. Cannabis for the treatment of ulcerative colitis. Cochrane Database of Systematic Reviews 2018, Issue 11. Art. No.: CD012954. DOI: 10.1002/14651858.CD012954.pub2. Accessed 07 May 2021.

[12]      Timna Naftali, Lihi Bar-Lev Schleider, Shlomo Almog, David Meiri, Fred M Konikoff, Oral CBD-rich cannabis induces clinical but not endoscopic response in patients with Crohn’s disease, a randomized controlled trial, Journal of Crohn’s and Colitis, 2021;, jjab069, https://doi.org/10.1093/ecco-jcc/jjab069

[13]      T. Naftali, L. Barlev, G. Gabay, Y. Chowers, I. Dotan, A. Stein, M. Bronstein, F.M. Konikoff, P358 Tetrahydrocannabinol (THC) induces clinical and biochemical improvement with a steroid sparing effect in active inflammatory bowel disease, Journal of Crohn’s and Colitis, Volume 7, Issue Supplement_1, February 2013, Page S153, https://doi.org/10.1016/S1873-9946(13)60379-7

[14]      B Doeve, F van Schaik, M van de Meeberg, H Fidder, P448 Cannabis and cannabinoids for the treatment of inflammatory bowel disease: a systematic review and meta-analysis, Journal of Crohn’s and Colitis, Volume 13, Issue Supplement_1, March 2019, Pages S335–S336, https://doi.org/10.1093/ecco-jcc/jjy222.572

[15]      Jessica Ravikoff Allegretti, MD, Andrew Courtwright, MD, PhD, Matthew Lucci, BS, Joshua       R. Korzenik, MD, Jonathan Levine, MD, Marijuana Use Patterns Among Patients with              Inflammatory Bowel Disease, Inflammatory Bowel Diseases, Volume 19, Issue 13, 1                 December 2013, Pages 2809–2814, https://doi.org/10.1097/01.MIB.0000435851.94391.37

About Minyi

Minyi Lü leidet an chronischen Schmerzen aufgrund ihrer Fingerarthrose. Ihre Beschwerden behandelt sie seit 2017 sehr erfolgreich mit medizinischem Cannabis. Als PTA und Pharmaziestudentin bringt sie nun ihr Know-how ein, um über die neuesten wissenschaftlichen Erkenntnisse rund um Medizinalcannabis zu berichten.