Crohn’s disease and medicinal cannabis

Crohn’s disease (MC) is a chronic inflammatory bowel disease (IBD) that can affect the entire digestive tract. The disease brings severe, cramping abdominal pain and diarrhoea. Sufferers often lose their appetite, which leads to reduced performance and quality of life. The suffering caused by Crohn’s disease is usually enormous. Many patients with IBD already use cannabis-based medicines. Studies show that the cannabinoids tetrahydrocannabinol (THC) and cannabidiol (CBD) can alleviate symptoms of Crohn’s disease. Diarrhoea and pain decrease, and sleep and appetite improve. In laboratory studies, CBD was able to support the intestinal barrier through anti-inflammatory effects.

IBD like Crohn’s disease increasingly common

Chronic inflammatory bowel diseases, which include Crohn’s disease (MC) and ulcerative colitis (CU), are becoming more common worldwide. They occur particularly often in industrialised countries, which is why IBD is counted as a disease of civilisation. A review published in 2017 showed that most people affected live in Europe and North America. In 2017, 322 out of 100,000 people in Germany and 319 out of 100,000 in the United States were affected by MC. New cases have also been increasing in emerging countries (e.g. in Asia or Africa) since the turn of the millennium. This development makes it clear that much more research on IBD is needed [1].

What is Crohn’s disease?

Crohn’s disease (MC), like ulcerative colitis (CU), usually begins in young adulthood, but can occur in any age group. The exact causes of IBD are currently still unclear. While experts used to assume that it was a purely autoimmune disease, current knowledge suggests that many factors play a role. These include genetic risk factors such as a mutation of the gene NOD2 [2]. This genetic change leads to a reduced production of antimicrobial defensins, which normally fight harmful germs in the digestive tract. As a result, more bacteria migrate into the intestinal mucosa and cause inflammation [3]. The colon and duodenum in particular are richly colonised with bacteria that are peaceful in themselves (microbiome) and are frequently affected in MC [2].

Twin studies showed that this mutation increases the risk of developing MC [4]. Together with other defence disorders, it leads to the dysregulation of the intestinal flora. Other environmental factors such as smoking and frequent antibiotic treatments in adolescence also increase the risk. The immune system and nutrition are also involved [2].

Symptoms and course of disease in Crohn’s disease

Crohn’s disease mostly affects the small and large intestine, but can occur throughout the digestive tract from the mouth to the rectum. The inflammations can spread through all layers of the mucous membrane. Typically, chronic diarrhoea occurs, which, unlike ulcerative colitis, is usually bloodless and without mucus. MC often also leads to mucosal changes such as strictures, fistulas and abscesses [2].

20 to 40 percent of MC patients also suffer from symptoms outside the digestive tract, so-called extraintestinal manifestations. One in five people diagnosed with IBD also suffers from anaemia, for example due to a lack of iron, vitamin B12 and folic acid. Joints, skin and eyes can also be inflamed. These accompanying complaints are sometimes so burdensome that the treatment of the digestive problems takes a back seat. In these cases, interdisciplinary cooperation between specialists from gastroenterology, rheumatology, dermatology and ophthalmology makes sense [5].

Like other IBD, Crohn’s disease progresses in relapses. Phases of the disease with high inflammatory activity alternate with periods of rest – so-called remission phases. Then only mild symptoms occur or the patients are even completely symptom-free.

However, since MC is currently not curable, relapses with a flare-up of inflammation can occur at any time. In the first year after achieving remission, the relapse frequency is 30 to 60 and in the second year 40 to 70 percent. Long-term therapy can prolong these symptom-free phases and promote healing of the mucosa [5].

Active and also passive nicotine use can lead to a complicated course of the disease [3]. Therefore, it is recommended to refrain from smoking in order to halve the risk of relapses [5].

Possible symptoms of Crohn’s disease [2-4]:

  • Chronic diarrhoea
  • Cramping abdominal pain
  • Weight loss
  • Fever
  • Fatique, loss of performance
  • Mucosal changes in the rectal area (abscesses, fistulas, anal fissures)
  • Anaemia
  • Inflammation of joints, skin and eyes

The symptoms of IBD are often non-specific and similar to other intestinal diseases such as infectious diarrhoeal diseases or medication-related side effects (e.g. antibiotics, non-steroidal anti-inflammatory drugs). Therefore, it often takes many years before a diagnosis is made. The distinction between Crohn’s disease and ulcerative colitis is sometimes difficult or impossible [5]. Mixed forms also occur.

Drug treatment of Crohn’s disease

Drug and surgical therapies cannot cure Crohn’s disease, but they can improve the quality of life. The aim of the therapy is to maintain the resting phases (remission) and to avoid complications that would make hospital stays or operations necessary.

Treatment depends on the severity of the inflammation and the affected sections of the digestive tract, with different active substances and dosage forms being used: Suppositories, clysms and foams exert their effect locally in the intestine, while oral administration has a systemic effect on the whole body. The acute treatment of the relapse is intended to quickly reduce the inflammation and bring about remission.

  • Acute mild flares are treated with mesalazine and budesonide, for example. Budesonide is a corticosteroid that mainly acts locally in the intestine.
  • For more severe attacks or inflammation of the upper gastrointestinal tract (e.g. stomach, oesophagus and duodenum), systemic steroids such as prednisolone are often necessary. If the small intestine, the most important site for the absorption of nutrients, is severely affected, there is a risk of deficiency symptoms. If inflamed sections of the small intestine are surgically removed, the risk of nutrient deficiency also increases due to the shorter intestinal passage. Experts speak of short bowel syndrome.

If the acute therapy has contained the symptoms, long-term treatment is initiated. Steroids should not be used for this purpose, as long-term treatment is associated with severe side effects.

Possible long-term side effects of corticosteroids are:

  • Osteoporosis
  • Weight gain
  • Steroid diabetes
  • Skin thinning

The goal is therefore to achieve a steroid-free remission. If the course of the disease is mild and the prognosis is favourable, it is often sufficient to abstain from nicotine without drug treatment. In more severe courses, immunosuppressive drugs (e.g. azathioprine, methotrexate) and TNF-alpha antibodies (e.g. infliximab) are used for long-term treatment. These agents suppress the immune system and have an anti-inflammatory effect [6]. However, this increases the susceptibility to fungal and viral infections.

These infections do not normally break out in healthy people, but can have serious consequences in immunocompromised persons [7]. For immunocompromised patients, a complete vaccination against the most important pathogens is therefore advisable. In addition, depending on the active substance, there are other side effects, some of which are serious [6].

Medical cannabis for Crohn’s disease

Cannabinoid receptors are widely distributed in the digestive tract. CB1 receptors, which are activated by the psychotropic tetrahydrocannabinol (THC), occur on nerve plexuses that control intestinal movements, secretory activity as well as intestinal blood flow. THC thus counteracts diarrhoea by slowing down intestinal movements and reducing glandular secretion. THC relieves abdominal pain by acting on CB1 receptors in the brain, spinal cord and peripheral pain-conducting nerve fibres.

Cannabinoids also have an anti-inflammatory effect. Cannabidiol (CBD) activates CB2 receptors, which are mainly found on immune cells and in the gastrointestinal tract, and thus reduces inflammatory activity. Proinflammatory cytokines are produced less and the production of anti-inflammatory cytokines is promoted. The extent to which the CB1 receptor is involved in inflammation in IBD is currently not fully understood [8].

Case report: dose reduction of pain medication and improved appetite

In a case report published in 2020, dronabinol – synthetically produced THC – was able to reduce the need for painkillers. The 35-year-old patient continued to suffer from pain, especially after eating, despite taking tilidine – an opioid-based painkiller – and amitriptyline. Because of the severe pain, which the patient rated 4 to 8 on a numerical analogue scale from 0 (no pain) to 10 (most severe pain imaginable), he ate very little. Psychological stress also led to severe diarrhoea and nausea.

As the stronger opioid fentanyl did not bring any improvement either and was associated with side effects such as constipation, a cannabinoid therapy was initiated. Already one week after the start of therapy, the patient reported a reduction in pain when eating and better sleep. The opioid could not be completely discontinued because of stronger nocturnal complaints, but the dose could be significantly reduced. Due to the appetite-increasing effect of THC, the patient was able to enjoy his food again. Cannabinoids can therefore alleviate pain in Crohn’s disease and thus save opioids. The often malnourished patients also benefit from the appetite-increasing effect of THC [9].

German patients with IBD use cannabis

A German research team analysed cannabis use among patients with IBD in a cross-sectional survey in 2021. Questionnaires with a total of 71 questions were sent to a representative sample of 1,000 people, 417 questionnaires were completed. 54.7 percent of the respondents had Crohn’s disease. Another 43.4 percent were affected by ulcerative colitis. More than one in six of the patients (17.5 %) reported past cannabis use for pleasure purposes. 18 people (4.3%) reported using cannabis for symptom relief.

According to the survey results, cannabis brought about the following improvements, among others: less stomach ache, improved sleep, relief from restlessness as well as anxiety. More than half of the respondents (52.9 %) used cannabis products from the black market, which, unlike medical cannabis, is not subject to any quality controls. The results show that cannabis is used by people with IBD and that further research is needed [10].

 

THC-dominant cannabis flowers relieve pain and improve appetite

In a double-blind study published in 2013, Israeli scientists investigated the effect of inhaled cannabis flowers on 21 patients with Crohn’s disease. Steroids, immunomodulators and TNF-alpha blockers were not sufficiently effective in the patients. Clinical symptoms, measured by the CDAI (Crohn’s Activity Index), were above 200. Eleven participants received THC-rich cannabis flowers for inhalation. Patients in the placebo group used cannabis flowers from which the cannabinoids had been removed. Disease activity and laboratory parameters were closely monitored during the 8-week study phase.

With the use of THC, 5 out of 11 patients (45%) achieved a complete remission, corresponding to a CDAI of less than 150. In contrast, only 10 percent of those taking the placebo went into remission. However, the difference was not statistically significant. However, almost all participants in the cannabinoid group (10 out of 11 people) reported clinical improvements: THC improved sleep and appetite. Differences in inflammation levels (C-reactive protein) between placebo and cannabis groups could not be found [11,13].

CBD-rich cannabis oil improves clinical symptoms and quality of life
Another Israeli double-blind study from 2021 showed that cannabis oil rich in CBD can also improve the symptoms and quality of life in Crohn’s disease. The study medication contained CBD as well as a small dose of THC. 56 patients with an average age of 34.5 years participated in the study. According to the random principle, 30 persons were assigned to the cannabinoid group and 26 to the placebo group.

After 8 weeks of treatment, there were significant improvements in disease activity and quality of life in the group taking cannabis oil. Clinical symptoms were assessed with the CDAI (Crohn’s Activity Index): With cannabis, activity decreased significantly from 282 to 166, compared to an improvement from only 264 to 237 in the placebo group. Quality of life was assessed with QOL (quality of life): Before treatment, it was 74 in both groups, but improved to 91 with cannabis oil, compared to 75 with placebo, with virtually no effect. However, the results of the endoscopic examinations did not improve significantly. Similarly, the inflammation values CRP (C-reactive protein) and calprotectin remained unchanged [12].

In vitro Studie: CBD has an anti-inflammatory effect

In 2021, an Italian research team studied the effects of the cannabinoids CBD, CBDA, THC and CBDA in a “test tube”. As a model, the scientists used Caco-2 cells, which belong to a line of human colon cancer cells and mimic the properties of the intestinal barrier well. To evaluate the effects of cannabinoids under normal and pathological conditions, the intestinal cells were treated with different substances: The cytokines IFN-gamma and TNF-alpha trigger inflammation and hydrogen peroxide causes oxidative stress. Subsequently, cannabinoids of different concentrations were applied to the cell layer and the condition of the intestinal barrier was assessed by measurements and experiments. Oxidative stress contributes to the development of IBD. Reactive oxygen species (ROS) formed in this process attack the intestinal mucosa. Intact Caco-2 cells showed that certain concentrations of THC, CBD and CBDA reduced the formation of these oxygen radicals. The experiments were then repeated under oxidative conditions, i.e. after treatment with hydrogen peroxide: Under oxidative stress, THC, THCA and especially CBD significantly reduced radical formation. CBD was able to curb the radicals in every concentration examined.

  • To assess the barrier function, the Caco-2 cells were examined microscopically. So-called tight junctions keep the intestinal wall tight. Genetic causes, pro-inflammatory cytokines (INF-gamma and TNF-alpha) and oxidative stress disrupt the function of the tight junctions, causing the intestinal wall to become leaky: Experimentally, this can be seen in an increase in transepithelial electrical resistance (TEER) and increased paracellular permeability. Bacteria, toxins and antigens thus migrate more easily into the intestinal wall and trigger inflammations that disrupt the tight junctions. CBD has an anti-inflammatory effect and therefore prevents damage to the intestinal wall. The tight junctions remain intact and the barrier function is maintained.

The results of the in vitro study show that CBD can modulate inflammation in IBD through several pathways: Less oxygen radicals are produced and the normal permeability of the intestinal wall is maintained even under inflammatory and oxidative stress conditions. Non-psychotropic CBD can therefore support the treatment of IBD [14].

The psychotropic cannabinoid THC also counteracts oxidative stress [14], can improve the quality of life of patients with IBD and save painkillers in Crohn’s disease. Chronic abdominal pain decreases, sleep and appetite improve [9, 11, 13].

Conclusion

Many patients with Crohn’s disease already use cannabis products. However, randomised double-blind studies to date have failed to show any significant effect on disease activity and inflammatory parameters. Cannabinoids therefore do not seem to induce remission. However, THC and CBD can alleviate stressful symptoms such as nausea and abdominal pain. The appetite-enhancing effect of the psychotropic THC ensures that those affected can eat with pleasure again. Larger clinical trials are needed to investigate the effect of cannabinoids in Crohn’s disease in more depth. The increasing availability of medicinal cannabis worldwide facilitates future research. In particular, anti-inflammatory CBD can potentially influence disease activity and may be an important agent for treating IBD in the future. Therefore, it may be useful to start treatment of Crohn’s disease with CBD.

Sources:

[1] Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies Ng, Siew C et al. The Lancet, October 16 – 2017, Volume 390, Issue 10114, 2769 – 2778

[2] Wehkamp J, Götz M, Herrlinger K, Steurer W, Stange EF: Inflammatory bowel disease: Crohn’s disease and ulcerative colitis. Dtsch Arztebl Int 2016; 113: 72–82. DOI:   10.3238/arztebl.2016.0072

[3] Vetter, C. (2004): Morbus Crohn – Bakterieninvasion durch Defensin-Mangel. In: Dtsch Arztebl 2004; 101(22): A-1608

[4] Kaczmarek-Ryś M, Hryhorowicz ST, Lis E, et al. Crohn’s Disease Susceptibility and Onset Are   Strongly Related to Three NOD2 Gene Haplotypes. J Clin Med. 2021;10(17):3777. Published       2021 Aug 24. doi:10.3390/jcm10173777

[5] Aktualisierte S3-Leitlinie „Diagnostik und Therapie des Morbus Crohn“ der Deutschen Gesell-schaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS) August 2021 – AWMF-Registernummer: 021 004; https://www.awmf.org/uploads/tx_szleitlinien/021-                         004l_S3_Morbus_Crohn_Diagnostik_Therapie_2021-08.pdf

[6] Aktualisierte S3-Leitlinie „Diagnostik und Therapie des Morbus Crohn“ der Deutschen Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS) August 2021 – AWMF-Registernummer: 021-004

[7]  Salzberger, B., Witzke, O. Opportunistische Infektionen. Internist 60, 667–668 (2019). https://doi.org/10.1007/s00108-019-0624-5

[8] 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

[9] Bialas, P. (2020): Medizinisches Cannabis bei Morbus Crohn. Schmerzmittelreduktion. In: MMW – Fortschritte in der Medizin Sonderheft 8/2020 (2020)

[10]  Neufeld T, Pfuhlmann K, Stock-Schröer B, Kairey L, Bauer N, Häuser W, Langhorst J.  Cannabis use of patients with inflammatory bowel disease in Germany: a cross- sectional survey. Z Gastroenterol. 2021 Oct;59(10):1068-1077. English. doi: 10.1055/a-1400-2768. Epub 2021 Jun 22. PMID: 34157755.

[11] 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.

[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]Buckley MC, Kumar A, Swaminath A. Inflammatory Bowel Disease and Cannabis: A Practical    Approach for Clinicians. Adv Ther. 2021;38(7):4152-4161. doi:10.1007/s12325-021-01805-8

[14] Cocetta V, Governa P, Borgonetti V, et al. Cannabidiol Isolated From Cannabis sativa L. Protects Intestinal Barrier From In Vitro Inflammation and Oxidative Stress. Front Pharmacol. 2021;12:641210. Published 2021 Apr 28. doi:10.3389/fphar.2021.641210

About Minyi Lü

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

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