Ulcerative colitis and medicinal cannabis

colitis ulcerosa

Many studies point to the medical potential of the cannabis plant. Among other things, its ingredients are said to have a pain-relieving and anti-inflammatory effect, which could be beneficial in the chronic disease ulcerative colitis.

Like Crohn’s disease, ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD). While ulcerative colitis only inflames the rectum and in some cases the colon, Crohn’s disease affects the entire digestive tract.

Another distinguishing feature of the two diseases is that the center of inflammation in ulcerative colitis is usually limited to the intestinal mucosa (top layer of the intestinal wall). In contrast, in Crohn’s disease the source can spread to all layers of the intestinal wall.

Frequency and course of the disease

In Germany, there are 3 to 3.9 new cases per year per 100,000 residents. As a rule, the disease occurs between the ages of 20 and 40. Women and men are affected with equal frequency. In over 80 percent of patients, the chronic inflammatory bowel disease is relapsing. This means that both, acute attacks with severe symptoms and symptom-free phases occur. However, ulcerative colitis can also take a chronic, continuous course without symptom-free phases. This is the case in about 10 percent of those affected.

Causes and risk factors

The causes and risk factors of most chronic inflammatory bowel diseases are unknown. This is also true for ulcerative colitis. Genetic factors are thought to play an important role, as colitis runs in families. Siblings of affected individuals have about 10 to 50 times the risk of also developing the disease, compared to other people.

However, genetic predisposition does not automatically lead to the onset of the disease. Other factors, such as infections, an unhealthy diet, psychological problems or a disturbed immune system, are likely to be involved in the development of the disease.

Symptoms of ulcerative colitis

The disease usually begins insidiously and is not noticed by sufferers at first. As the inflammation in the intestine continues to spread, the following symptoms may occur:

  • bloody-mucous diarrhea
  • crampy lower abdominal pain, often before bowel movements
  • crampy abdominal pain, often in the left lower abdomen
  • painful urge to defecate
  • mild fever
  • urge to defecate at night
  • flatulence
  • anemia caused by bloody diarrhea
  • weight loss, fatigue, loss of performance.

In addition, some patients suffer from other symptoms, such as:

  • inflammation of the joints, spine, sacrum, or eyes
  • osteoporosis
  • skin changes (small ulcers, red-purple nodules)
  • inflammation of the bile ducts

In addition, ulcerative colitis can lead to complications such as toxic megacolon, in which the intestine acutely dilates as inflammation spreads throughout the entire intestinal wall. As a result, the intestine can no longer transport the stool, as it is as if paralyzed (paralytic ileus). In this case, there is a risk of intestinal rupture. The intestinal contents enter the abdominal cavity and a dangerous peritonitis develops.

If patients suffer from symptoms such as a hard, distended and painful abdomen and a high fever, this may indicate such a complication and an emergency department should be consulted immediately. This is because a ruptured intestine can be life-threatening.

Ulcerative colitis: treatment and therapy

The cause of the inflammatory bowel disease ulcerative colitis is not yet known. Therefore, the goal of treatment is to alleviate the symptoms as well as to prolong the symptom-free phases.

Various drugs are used for this purpose: 5-aminosalicylic acid (5-ASA) is an anti-inflammatory agent that is prescribed in the form of the precursor mesalazine as tablets, suppositories, foams or enemas. Corticosteroids (cortisone) also have an anti-inflammatory effect and are used either as suppositories, enemas or tablets. Both medications containing the active ingredient mesalazine and cortisone can cause severe side effects. Cortisone in particular can cause long-term side effects.

In severe cases or when cortisone is not effective, some patients receive immunosuppressants (e.g. methotrexate, azathioprine or ciclosporin). This can have a positive effect on the course of the disease. However, TNF antibodies (e.g., infliximab, glimumab or adalimumab), which inhibit the inflammatory messenger TNF, can also be considered. When taking immunosuppressants and TNF antibodies, severe side effects such as susceptibility to infections can also occur, and poisoning is also possible.

Which drugs are used in treatment always depends on various factors, such as the extent of the symptoms and how far the inflammation has spread in the intestine, among other factors.

In addition to drug therapy, it is important for those affected to ensure a varied and balanced diet and to avoid hard-to-digest food components and hot spices during an acute episode.

Patients often also suffer from deficiency symptoms, such as a lack of folic acid, zinc, iron, and vitamin B12. If a deficiency cannot be compensated for by diet, doctors can also prescribe high-dose preparations.

Medical cannabis against chronic inflammation

Various studies have already provided clear evidence that inflammatory processes are also controlled by the endocannabinoid system. In the digestive tract, the cannabinoid receptors CB1 and CB2 have been detected. Therefore, it is possible to activate them by the administration of cannabinoids.

Researchers found that cannabinoid receptors 2 (CB2) may play a special role in the intestinal tract [1]. Although the presence and function of CB2 receptors in the gastrointestinal tract has not yet been well researched, the results so far are promising. For example, CB2 receptors may be involved in regulating abnormal motility (ability of the intestine to move), modulating intestinal inflammation, and limiting visceral tenderness and pain. According to the researchers, cannabinoid receptors 2 provide a braking system and pathophysiological mechanism for the resolution of inflammation and many of its symptoms. Therefore, activation of CB2 receptors is a very promising therapeutic target for inflammation in the gut, where immune activation and motility dysfunction are present.

Italian researchers, on the other hand, have focused on CB1 receptors, stating in a study that there is evidence in the digestive tract for the presence of high concentrations of endocannabinoids (anandamide and 2-arachidonoylglycerol) and enzymes involved in the synthesis and metabolism of endocannabinoids (endogenous cannabinoids) [2]. Also, immunohistochemical studies had demonstrated the presence of CB1 receptors on the neural plexuses along the digestive tract.

With the help of pharmacological studies, it had also been shown that activation of CB1 receptors could cause relaxation of the lower esophageal sphincter, inhibition of gastric motility and acid secretion, and intestinal motility and secretion. This inhibition was said to be due to a decreased release of the neurotransmitter acetylcholine from the enteric nerves. This enteric nervous system consists of a complex network of nerve cells that runs throughout the gastrointestinal tract.

Conversely, endocannabinoids appear to stimulate the primary sensory neurons of the gut via the vanilloid receptor VR1. Accordingly, the endocannabinoid system is involved in the physiological control of intestinal motility and in some pathophysiological conditions, including paralytic ileus, intestinal inflammation, and cholera toxin-induced diarrhea.

Furthermore, the research team states that the endocannabinoid system may represent a new therapeutic target for the treatment of several gastrointestinal disorders, including nausea and vomiting, peptic ulcers, diarrhea, paralytic ileus, inflammatory bowel disease, and gastroesophageal reflux disease.

Medicinal cannabis in the treatment of chronic bowel diseases

In 2017, researchers from Austria stated in their study that it is known from surveys and small clinical trials in patients with ulcerative colitis and Crohn’s disease that cannabis is commonly used to relieve diarrhea, abdominal pain, and loss of appetite [3]. Individual cannabinoids from cannabis, such as tetrahydrocannabinol (THC) and cannabidiol (CBD) are responsible for this positive effect.

The researchers reviewed recent data on the effects of cannabis in experimental models of inflammatory bowel diseases and in clinical trials with people with IBD (inflammatory bowel disease). They concluded that cannabinoids may be helpful for certain symptoms of ulcerative colitis and Crohn’s disease, but further clinical trials to demonstrate the efficacy, tolerability, and safety of cannabinoid-based medications in IBD patients would be lacking.

It is also worth highlighting a British study in which researchers treated rats with ulcerative colitis with THC and CBD [4]. The researchers used sulfasalazine as a control agent. All three substances showed a beneficial effect. A particularly beneficial effect was seen under treatment with THC. Finally, the research team concluded that THC and CBD not only had an anti-inflammatory effect in the rat model, but also reduced the occurrence of functional disorders in the intestine.

German cross-sectional survey: people with IBD often use cannabis

The results of a German cross-sectional survey of patients with inflammatory bowel disease (IBD) published in 2021 showed that many of them use cannabis to relieve symptoms. The researchers selected a representative sample of 1,000 patients, 417 of whom completed the questionnaires they received. The two most common conditions were Crohn’s disease (54.7 percent) and ulcerative colitis (43.4 percent). Recreational cannabis use was reported by more than one in six (17.5%) of the patients. Eighteen people (4.3%) reported cannabis use for symptom relief.

According to the survey, cannabis improved the following symptoms common in IBD: Abdominal pain, sleep, restlessness, and anxiety. However, more than half (52.9%) used unregulated cannabis products from the black market, which, unlike medical cannabis, are not subject to any quality controls. The survey results show that many patients with IBD are already using cannabinoids. Therefore, further research is needed [5].

Cannabinoids affect endocannabinoid system (ECS) in ulcerative colitis

An Israeli study published in 2021 investigated the impact of cannabinoid therapy on the endocannabinoid system (ECS) and clinical symptoms in patients with IBD. The 2-month study examined the effects of THC-dominant cannabis flowers and placebo in Chron’s disease and ulcerative colitis. Twenty-two subjects (13 with CD, 9 with UC) received cannabis and another 27 participants (17 with CD, 10 with UC) received placebo for smoking. During the course of the study, blood samples and intestinal tissue samples were taken to examine the function of the ECS [6].

Endocannabinoids and endocannabinoid-like substances examined in the blood [6]:

  • anandamide (AEA = arachidonylethanolamide)
  • palmitoylethanolamine (PEA)
  • oleoylethanolamine (OEA)
  • 2-arachidonylglycerol (2-AG)
  • arachidonic acid (AA)

Enzymes studied on colon tissue [6, 7, 8]:

  • N-acylphosphatidylethanolamine-selective phospholipase D (NAPE-PLD): this enzyme is required for the formation of endocannabinoids. NAPE-PLD is used for the biosynthesis of N-acylethanolamines (NAE) such as anandamide [7].
  • fatty acid amide hydrolase (FAAH): this enzyme serves to degrade endocannabinoids. FAAH deactivates various fatty acid amides such as anandamide and oleic acid amide (oleamide) [8].

The studies showed a different function of the ECS in patients depending on the diagnosis (CD or UC): in all 30 affected patients with Crohn’s disease, endocannabinoids remained unchanged, regardless of whether cannabis or placebo was used.

Patients with ulcerative colitis showed different observations: Participants in the placebo group had lower levels of the endocannabinoids PEA, AEA, and AA than individuals in the cannabis group. Immunohistochemical staining of intestinal tissue samples revealed that FAAH formed more frequently during the course of the study.

The research team studied the cannabis extracts in a “test tube” on Caco-2 cells, a line of human colon cancer cells that serve as a colon wall model. The artificial intestinal wall was treated with various cannabis extracts and the enzymes NAPE-PLD and FAAH were examined using Western blot, a protein detection method.

THC-containing and THC-free cannabis extracts reduced NAPE-PLD and decreased FAAH, which may explain the higher endocannabinoid levels in the cannabis group. Higher levels of the endocannabinoids PEA, anandamide (AEA), and OEA were found to be produced when NAPE-PLD enzyme activity was high. In contrast, the endocannabinoid 2-AG is produced by a different enzyme. Higher concentrations of 2-AG were associated with improved quality of life.

The study shows that cannabis therapy can positively influence the endocannabinoid system in ulcerative colitis, thereby alleviating symptoms [6].

Placebo-controlled study: symptom improvement (clinical remission) with THC-dominant cannabis flowers

Israeli researchers investigated the effect of THC-rich cannabis flowers in patients with mild to moderate ulcerative colitis in a randomized controlled trial published in 2021. Thirty-two subjects with an average age of 30 years participated. They received THC-rich cannabis flowers or a placebo to smoke: The cannabis drug used was the indica-dominant cannabis variety “Erez,” which contains small amounts of CBG and CBD, as well as terpenes (including myrcene, beta-caryophyllene, gamma-selinene, alpha-pinene), next to THC. The placebo was the same cannabis strain with the cannabinoids almost completely removed [9]. Erez is among the best-selling cannabis strains in Israel and can help with sleep disorders, pain, nausea, inflammation, and digestive problems [10].

Patient interviews, medical examinations (blood and stool tests, colonoscopy) were used to investigate symptomatology and inflammatory events. Disease activity was graded with the Lichtiger scoring index and endoscopic findings with the Mayo score: Patients* had mild to moderate ulcerative colitis at baseline (Lichtiger index of at least 4 and Mayo score of at least 1). Other IBD medications (e.g., 5-aminosalicylic acid, immunomodulators, steroids) could be continued at stable doses.

After 8 weeks of cannabis therapy, disease activity decreased from an average of 10.9 to 5 (improvement of 6.4 points). With placebo, there was only an improvement from 11 to 8 (improvement of 3 points). In two subjects, disease activity worsened under placebo, although an episode did not occur.

According to interviews, cannabis therapy had positive effects on:

  • health status
  • appetite
  • abdominal pain
  • libido
  • concentration

Such improvements were absent under placebo. Overall, the cannabis group was more satisfied with the medication: in addition to clinical successes such as reduced bowel movements and decreasing abdominal pain, quality of life was better. At the same time, cannabis therapy was well tolerated: the most common side effects were dizziness (6 subjects) and confusion (5 subjects), which did not necessitate study discontinuation.

Results of laboratory tests, on the other hand, were not so clear: endoscopic findings (decreased Mayo score) improved in both groups. Colonoscopies under THC showed better examination results, but the outcome was not significantly different from placebo. In both study groups, inflammatory parameters (C-reactive protein, fecal calprotectin) in blood and stool remained unchanged.

After the end of the study, 17 patients (8 persons in the cannabis group and 9 persons in the placebo group) received cannabis flowers for another year. In 11 patients, a colonoscopy was performed again: Endoscopic activity improved in 10 subjects. The Mayo score was only between 0 and 1. Before the start of the study, it was 3 in two patients, and eight people had a Mayo score of 2.

The researchers concluded that THC-dominant cannabis flowers can relieve symptoms (e.g., abdominal pain, loss of appetite) in ulcerative colitis. However, this is not directly related to anti-inflammatory effects, but could be explained by cannabinoid receptors in the digestive tract. The psychotropic THC reduces intestinal motility, increases fluid absorption, and has analgesic effects. Some weaknesses of the study are the small number of subjects and the smoking of the cannabis flowers, which should be rejected in principle in medical use, due to toxic combustion products [9].

Conclusion

The current study situation on the use of medical cannabinoids in the therapy of chronic intestinal diseases such as ulcerative colitis is promising, even though the involvement of the endocannabinoid system in inflammatory processes and the exact effect of the cannabinoids THC and CBD have not yet been definitively clarified. It is hoped that further clinical studies with a larger number of participants will be conducted in the future to fully clarify the mode of action of cannabis and its constituents.

Currently, it remains to be seen whether cannabis can fight intestinal inflammation in addition to relieving symptoms. Studies on the different medical forms of application such as vaporization and oral ingestion are also welcome. Furthermore, studies on application forms such as suppositories or rectal cannabinoid foams would be desirable.

Sources:

[1] Wright KL, Duncan M, Sharkey KA. Cannabinoid CB2 receptors in the gastrointestinal tract: a regulatory system in states of inflammation. Br J Pharmacol. 2008;153(2):263-270. doi:10.1038/sj.bjp.0707486

[2] Izzo AA, Coutts AA. Cannabinoids and the digestive tract. Handb Exp Pharmacol. 2005;(168):573-598. doi:10.1007/3-540-26573-2_19

[3] Hasenoehrl C, Storr M, Schicho R. Cannabinoids for treating inflammatory bowel diseases: where are we and where do we go?. Expert Rev Gastroenterol Hepatol. 2017;11(4):329-337. doi:10.1080/17474124.2017.1292851

[4] Jamontt JM, Molleman A, Pertwee RG, Parsons ME. The effects of Delta-tetrahydrocannabinol and cannabidiol alone and in combination on damage, inflammation and in vitro motility disturbances in rat colitis. Br J Pharmacol. 2010;160(3):712-723. doi:10.1111/j.1476-5381.2010.00791.x

[5] 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.

[6] Tartakover Matalon S, Azar S, Meiri D, et al. Endocannabinoid Levels in Ulcerative Colitis Patients Correlate With Clinical Parameters and Are Affected by Cannabis Consumption. Front Endocrinol (Lausanne). 2021;12:685289. Published 2021 Aug 31. doi:10.3389/fendo.2021.685289

[7] NAPEPLD N-acyl phosphatidylethanolamine phospholipase D [ Homo sapiens (human) ], Gene ID: 222236, updated on 25-Jan-2022, https://www.ncbi.nlm.nih.gov/gene/222236

[8] FAAH fatty acid amide hydrolase [ Homo sapiens (human) ], Gene ID: 2166, updated on 25-Jan-2022, https://www.ncbi.nlm.nih.gov/gene/2166

[9] Naftali T, Bar-Lev Schleider L, Scklerovsky Benjaminov F, Konikoff FM, Matalon ST, Ringel Y. Cannabis is associated with clinical but not endoscopic remission in ulcerative colitis: A randomized controlled trial. PLoS One. 2021;16(2):e0246871. Published 2021 Feb 11. doi:10.1371/journal.pone.0246871

[10] https://www.leafly.com/strains/erez

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.